Cardiovascular disease became the leading cause of death in the United States in the early 20th century, and it accounts for nearly half of all deaths in industrialized nations.1 The mortality it inflicts was thought to be shared equally between both sexes and among all age groups and races.2 The cardiology community implemented innovative epidemiologic research, through which risk factors for cardiovascular disease were established.1 The development of coronary care units reduced in-hospital mortality from acute myocardial infarction from 30% to 15%.2–5 Further advances in pharmacology, revascularization, and imaging have aided in the detection and treatment of cardiovascular disease.6 Though cardiovascular disease remains the number-one cause of death worldwide, rates are on the decline.7
For several decades, health disparities have been recognized as a source of pathology in cardiovascular medicine, resulting in inequity of care administration among select populations. In this review, we examine whether the same forward thinking that has resulted in a decline in cardiovascular disease has had an impact on the pervasive disparities in cardiovascular medicine.
DISPARITIES DEFINED
Compared with whites, members of minority groups have a higher burden of chronic diseases, receive lower quality care, and have less access to medical care. Recognizing the potential public health ramifications, in 1999 the US Congress tasked the Institute of Medicine to study and assess the extent of healthcare disparities. This led to the landmark publication, Unequal Treatment: Confronting Racial and Ethnic Disparities in Health Care.8
The Institute of Medicine defines disparities in healthcare as racial or ethnic differences in the quality of healthcare that are not due to access-related factors, clinical needs, preferences, and appropriateness of intervention.8 Disparities can also exist according to socioeconomic status and sex.9
In an early study documenting the concept of disparities in cardiovascular disease, Stone and Vanzant10 concluded that heart disease was more common in African Americans than in whites, and that hypertension was the principal cause of cardiovascular disease mortality in African Americans.
Data from US Centers for Disease Control and Prevention, reference 11
Figure 1. Avoidable deaths from heart disease, stroke, and hypertensive disease, 2001 and 2010.
Although avoidable deaths from heart disease, stroke, and hypertensive disease declined between 2001 and 2010, African Americans still have a higher mortality rate than other racial and ethnic groups (Figure 1).11
DISPARITIES AND CARDIOVASCULAR HEALTH
The concept of cardiovascular health was established by the American Heart Association (AHA) in efforts to achieve an additional 20% reduction in cardiovascular disease-related mortality by 2020.7 Cardiovascular health is defined as the absence of clinically manifest cardiovascular disease and is measured by 7 components:
Not smoking or abstaining from smoking for at least 1 year
A normal body weight, defined as a body mass index less than 25 kg/m2
Optimal physical activity, defined as 75 minutes of vigorous physical activity or 150 minutes of moderate-intensity physical activity per week
Regular consumption of a healthy diet
Total cholesterol below 200 mg/dL
Blood pressure less than 120/80 mm Hg
Fasting blood sugar below 100 mg/dL.
Nearly 70% of the US population can claim 2, 3, or 4 of these components, but differences exist according to race,12 and 60% of adult white Americans are limited to achieving no more than 3 of these healthy metrics, compared with 70% of adult African Americans and Hispanic Americans.
Smoking
Smoking is a major risk factor for cardiovascular disease.12–14
Data from National Health Interview Surgery, Jamal et al, reference 16
Figure 2. Percentage of adults who are active smokers, 2005 and 2014.
During adolescence, white males are more likely to smoke than African American and Hispanic males,12 but this trend reverses in adulthood, when African American men have a higher prevalence of smoking than white men (21.4% vs 19%).7 Rates of lifetime use are highest among American Indian or Alaskan natives and whites (75.9%), followed by African Americans (58.4%), native Hawaiians (56.8%), and Hispanics (56.7%).15 Trends for current smoking are similar (Figure 2).16 Moreover, households with lower socioeconomic status have a higher prevalence of smoking.7
Physical activity
People with a sedentary lifestyle are more likely to die of cardiovascular disease. As many as 250,000 deaths annually in the United States are attributed to lack of regular physical activity.17
Recognizing the potential public health ramifications, the AHA and the 2018 Federal Guidelines on Physical Activity recommend that children engage in 60 minutes of daily physical activity and that adults participate in 150 minutes of moderate-intensity or 75 minutes of vigorous physical activity weekly.18,19
Data from Behavioral Risk Factor Surveillance System, Omura et al, reference 20
Figure 3. Prevalence of inactivitya in the United States, 2013.aPercentage of US adults eligible for intensive behavioral counseling for cardiovascular disease prevention and not meeting aerobic exercise guideline
In the United States, 15.2% of adolescents reported being physically inactive, according to data published in 2016.7 Similar to most cardiovascular risk factors, minority populations and those of lower socioeconomic status had the worst profiles. The prevalence of physical inactivity was highest in African Americans and Hispanics (Figure 3).20
Studies have shown an association between screen-based sedentary behavior (computers, television, and video games) and cardiovascular disease.21–23 In the United States, 41% of adolescents used computers for activities other than homework for more than 3 hours per day on a school day.7 The pattern of use was highest in African American boys and African American girls, followed by Hispanic girls and Hispanic boys.18 Trends were similar with regard to watching television for more than 3 hours per day.
Sedentary behavior persists into adulthood, with rates of inactivity of 38.3% in African Americans, 40.1% in Hispanics, and 26.3% in white adults.7
Nutrition and obesity
Nutrition plays a major role in cardiovascular disease, specifically in the pathogenesis of atherosclerotic disease and hypertension.24 Most Americans do not meet dietary recommendations, with minority communities performing worse in specific metrics.7
Dietary patterns are reflected in the rate of obesity in this nation. Studies have shown a direct correlation between obesity and cardiovascular disease such as coronary artery disease, heart failure, and atrial fibrillation.25–28 According to data from the National Health and Nutrition Examination Survey (NHANES), 31% of children between the ages of 2 and 19 years are classified as obese or overweight. The highest rates of obesity are seen in Hispanic and African American boys and girls. The obesity epidemic is disproportionately rampant in children living in households with low income, low education, and high unemployment rates.7,29–31
Despite the risks associated with obesity, only 64.8% of obese adults report being informed by a doctor or health professional that they were overweight. The proportion of obese adults informed that they were overweight was significantly lower for African Americans and Hispanics compared with whites. Similar differences are seen based on socioeconomic status, as middle-income patients were less likely to be informed than those in the higher income strata (62.4% vs 70.6%).7,31
Blood pressure
Hypertension is a well-established risk factor for cardiovascular disease and stroke, and a blood pressure of 120/80 mm Hg or lower is identified as a component of ideal cardiovascular health.
In the United States the prevalence of hypertension in adults older than 20 is 32%.7 The prevalence of hypertension in African Americans is among the highest in the world.32,33 African Americans develop high blood pressure at earlier ages, and their average resting blood pressures are higher than in whites.34,35 For a 45-year-old without hypertension, the 40-year risk of developing hypertension is 92.7% for African Americans and 86% for whites.35 Hypertension is a major risk factor for stroke, and African Americans have a 1.8 times greater rate of fatal stroke than whites.7
In 2013 there were 71,942 deaths attributable to high blood pressure, and the 2011 death rate associated with hypertension was 18.9 per 100,000. By race, the death rate was 17.6 per 100,000 for white males and an alarming 47.1 per 100,000 for African American males; rates were 15.2 per 100,000 for white females and 35.1 per 100,000 for African American females.7
It is unclear what accounts for the racial difference in prevalence in hypertension. Studies have shown that African Americans are more likely than whites to have been told on more than 2 occasions that they have hypertension. And 85.7% of African Americans are aware that they have high blood pressure, compared with 82.7% of whites.14
African Americans and Hispanics have poorer hypertension control compared with whites.36,37 These observed differences cannot be attributed to access alone, as African Americans were more likely to be on higher-intensity blood pressure therapy, whereas Hispanics were more likely to be undertreated.36,38 In a meta-analysis of 13 trials, Peck et al39 showed that African Americans showed a lesser reduction in systolic and diastolic blood pressure when treated with angiotensin-converting enzyme (ACE) inhibitors.
The 2017 American College of Cardiology (ACC) and AHA guidelines for the prevention, detection, evaluation, and management of high blood pressure in adults40 identifies 4 drug classes as reducing cardiovascular disease morbidity and mortality: thiazide diuretics, ACE inhibitors, angiotensin II receptor blockers (ARBs), and calcium channel blockers. Of these 4 classes, thiazide diuretics and calcium channel blockers have been shown to lower blood pressure more effectively in African Americans than renin-angiotensin-aldosterone inhibition with ACE inhibitors or ARBs.
Glycemic control
Type 2 diabetes mellitus secondary to insulin resistance disproportionately affects minority groups, as the prevalence of diabetes mellitus in African Americans is almost twice as high as that in whites, and 35% higher in Hispanics compared with whites.7,41 Based on NHANES data between 1984 and 2004, the prevalence of diabetes mellitus is expected to increase by 99% in whites, 107% in African Americans, and 127% in Hispanics by 2050. Alarmingly, African Americans over age 75 are expected to experience a 606% increase by 2050.42
With regard to mortality, 21.7 deaths per 100,000 population were attributable to diabetes mellitus according to reports by the AHA in 2016. The death rate in white males was 24.3 per 100,000 compared with 44.9 per 100,000 for African Americans males. The associated mortality rate for white women was 16.2 per 100,000, and 35.8 per 100,000 for African American females.7
DISPARITIES AND CORONARY ARTERY DISEASE CARE
The management of coronary artery disease has evolved from prolonged bed rest to surgical, pharmacologic, and percutaneous revascularization.2,5 Coronary revascularization procedures are now relatively common: 950,000 percutaneous coronary interventions and 397,000 coronary artery bypass procedures were performed in 2010.7
Nevertheless, despite similar clinical presentations, African Americans with acute myocardial infarction were less likely to be referred for coronary artery bypass grafting than whites.43–46 They were also less likely to be given thrombolytics47 and less likely to undergo coronary angiography with percutaneous coronary intervention.48 Similar differences have been reported when comparing Hispanics with whites.49
Some suggest that healthcare access is a key mediator of health disparities.50 In 2009, Hispanics and African Americans accounted for more than 50% of those without health insurance.51 Improved access to healthcare might mitigate the disparity in revascularizations.
Massachusetts was one of the first states to mandate that all residents obtain health insurance. As a result, the uninsured rates declined in African Americans and Hispanics in Massachusetts, but a disparity in revascularization persisted. African Americans and Hispanics were 27% and 16% less likely to undergo revascularization procedures (coronary artery bypass grafting or percutaneous coronary intervention) than whites,51 suggesting that disparities in revascularization are not solely secondary to healthcare access.
These findings are consistent with a 2004 Veterans Administration study,52 in which healthcare access was equal among races. The study showed that African Americans received fewer cardiac procedures after an acute myocardial infarction compared with whites.
Have we made progress? The largest disparity between African Americans and whites in coronary artery disease mortality existed in 1990. The disparity persisted to 2012, and although decreased, it is projected to persist to 2030.53
DISPARITIES IN HEART FAILURE
An estimated 5.7 million Americans have heart failure, and 915,000 new cases are diagnosed annually.7 Unlike coronary artery disease, heart failure is expected to increase in prevalence by 46%, to 8 million Americans with heart failure by 2030.7,54
Our knowledge of disparities in the area of heart failure is derived primarily from epidemiologic studies. The Multi-Ethnic Study of Atherosclerosis55 showed that African Americans (4.6 per 1,000), followed by Hispanics (3.5 per 1,000) had a higher risk of developing heart failure compared with whites (2.4 per 1,000).The higher risk is in part due to disparities in socioeconomic status and prevalence of hypertension, as African Americans accounted for 75% of cases of nonischemic-related heart failure.55 African Americans also have a higher 5-year mortality rate than whites.55
Even though the 5-year mortality rate in heart failure is still 50%, the past 30 years have seen innovations in pharmacologic and device therapy and thus improved outcomes in heart failure patients. Still, significant gaps in the use of guideline-recommended therapies, quality of care, and clinical outcomes persist in contemporary practice for racial minorities with heart failure.
Disparities in inpatient care for heart failure
Patients admitted for heart failure and cared for by a cardiologist are more likely to be discharged on guideline-directed medical therapy, have fewer heart failure readmissions, and lower mortality.56,57 Breathett et al,58 in a study of 104,835 patients hospitalized in an intensive care unit for heart failure, found that primary intensive care by a cardiologist was associated with higher survival in both races. However, in the same study, white patients had a higher odds of receiving care from a cardiologist than African American patients.
Disparities and cardiac resynchronization therapy devices
In one-third of patients with heart failure, conduction delays result in dyssynchronous left ventricular contraction.59 Dyssynchrony leads to reduced cardiac performance, left ventricular remodeling, and increased mortality.56
Cardiac resynchronization therapy (CRT) was approved for clinical use in 2001, and studies have shown that it improves quality of life, exercise tolerance, cardiac performance, and morbidity and mortality rates.59–66 The 2013 ACC/AHA guidelines for the management of heart failure give a class IA recommendation (the highest) for its use in patients with a left ventricular ejection fraction of 35% or less, sinus rhythm, left bundle branch block and a QRS duration of 150 ms or greater, and New York Heart Association class II, III, or ambulatory IV symptoms while on guideline-directed medical therapy.67
Despite these recommendations, racial differences are observed. A study using the Nationwide Inpatient Sample database59 showed that between 2002 and 2010, a total of 374,202 CRT devices were implanted, averaging 41,578 annually. After adjusting for heart failure admissions, the study showed that CRT use was favored in men and in whites.
Another study, using the National Cardiovascular Data Registry,68 looked at patients who received implantable cardiac defibrillators (ICDs) and were eligible to receive CRT. It found that African Americans and Hispanics were less likely than whites to receive CRT, even though they were more likely to meet established criteria.
Disparities and left ventricular assist devices
The Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart failure (REMATCH) trial and Heart Mate II trial demonstrated that left ventricular assist devices (LVADs) were durable options for long-term support for patients with end-stage heart failure.69,70 Studies that examined the role of race and clinical outcomes after LVAD implantation have reported mixed findings.71,72 Few studies have looked at the role racial differences play in accessing LVAD therapy.
Joyce et al73 reviewed data from the Nationwide Inpatient Sample from 2002 to 2003 on patients admitted to the hospital with a primary diagnosis of heart failure or cardiogenic shock. A total of 297,866 patients were included in the study, of whom only 291 underwent LVAD implantation. A multivariate analysis found that factors such as age over 65, female sex, admission to a nonacademic center, geographic region, and African American race adversely influenced access to LVAD therapy.
Breathett et al74 evaluated racial differences in LVAD implantations from 2012 to 2015, a period that corresponds to increased health insurance expansion, and found LVAD implantations increased among African American patients with advanced heart failure, but no other racial or ethnic group.
Disparities and heart transplant
For patients with end-stage heart failure, orthotopic heart transplant is the most definitive and durable option for long-term survival. According to data from the United Network for Organ Sharing, 62,508 heart transplants were performed from January 1, 1988 to December 31, 2015. Compared with transplants of other solid organs, heart transplant occurs in significantly infrequent rates.
Barriers to transplant include lack of health insurance, considered a surrogate for low socioeconomic status. Hispanics and African Americans are less likely to have private health insurance than non-Hispanic whites, and this difference is magnified among the working poor.
Despite these perceived barriers, Kilic et al75 found that African Americans comprised 16.4% of heart transplant recipients, although they make up only approximately 13% of the US population. They also had significantly shorter wait-list times than whites. On the negative side, African Americans had a higher unadjusted mortality rate than whites (15% vs 12% P = .002). African Americans also tended to receive their transplants at centers with lower transplant volumes and higher transplant mortality rates.
Several other studies also showed that African Americans compared to whites have significantly worse outcomes after transplant.76–79 What accounts for this difference? Kilic et al75 showed that African Americans had the lowest proportion of blood type matching and lowest human leukocyte antigen matching, were younger (because African Americans develop more advanced heart failure at younger ages), had higher serum creatinine levels, and were more often bridged to transplant with an LVAD.
DISPARITIES IN CARDIOVASCULAR RESEARCH
Although the United States has the most sophisticated and robust medical system in the world, select groups have significant differences in delivery and healthcare outcomes. There are many explanations for these differences, but a contributing factor may be the paucity of research dedicated to understand racial and ethnic differences.80
Differences observed in epidemiologic studies may be secondary to pathophysiology, genetic differences, environment, and lifestyle choices. Historically, clinical trials were conducted in homogeneous populations with respect to age (middle-aged), sex (male), and race (white), and the results were generalized to heterogeneous populations.80
Disparities in research have implications in clinical practice. Overall, the primary cause of heart failure is ischemia; however, in African Americans, the primary cause is hypertensive heart disease.81 Studies in hypertension have shown that African Americans have less of a response to neurohormonal blockade with ACE inhibitors and beta-blockers than non-African Americans.82 Nevertheless, neurohormonal blockade has become the cornerstone of heart failure treatment.
Retrospective analysis of the Vasodilator-Heart Failure trials83 showed that treatment with isosorbide dinitrate plus hydralazine, compared with placebo, conferred a survival benefit for African Americans but not whites.80 No survival advantage was noted when isosorbide dinitrate/hydralazine was compared to enalapril in African Americans, although enalapril was superior to isosorbide dinitrate in whites.45 These observations were recognized 10 to 15 years after trial completion, and were only possible because the trials included sufficient numbers of African American patients to complete analysis.
In 1993, the US Congress passed the National Institutes of Health (NIH) Revitalization Act, which established guidelines requiring NIH grant applicants to include minorities in human subject research, as they were historically underrepresented in clinical research trials.84,85
In 2001, the Beta-Blocker Evaluation of Survival Trial86 reported its results investigating whether bucindolol, a nonselective beta-blocker, would reduce mortality in patients with advanced heart failure (New York Heart Association class III or IV). This was one of the first trials to prospectively investigate racial and ethnic differences in response to treatment. Though it showed no overall benefit in the use of bucindolol in the treatment of advanced heart failure, subgroup analysis showed that whites did enjoy a benefit in terms of lower mortality, whereas African Americans did not.
Results of the Vasodilator-Heart Failure trials led to further population-directed research, most notably the African American Heart Failure Trial,87 a double-blind, placebo-controlled, randomized trial in patients who identified as African American. Patients who were randomized to receive a fixed dose of hydralazine and isosorbide dinitrate had a 43% lower mortality rate, a 33% lower hospitalization rate for heart failure, and better quality of life than patients in the placebo group, leading to early termination of the trial. The outcomes suggested that the combination of isosorbide dinitrate and hydralazine treats heart failure in a manner independent of pure neurohormonal blockade.
CHALLENGES IN STUDY PARTICIPATION
Recruitment of minority participants in biomedical research is a challenging task for clinical investigators.88,89 Some of the factors thought to pose potential barriers for racial and ethnic minority participation in health research include poor access to primary medical care, failure of researchers to recruit minority populations actively, and language and cultural barriers.90
Further, it is widely claimed that African Americans are less willing than nonminority individuals to participate in clinical research trials due to general distrust of the medical community as a result of the Tuskegee Syphilis Experiment.91 That infamous study, conducted by the US Public Health Service between 1932 and 1972, sought to record the natural progression of untreated syphilis in poor African American men in Alabama. The participants were not informed of the true purpose of the study, and they were under the impression that they were simply receiving free healthcare from the US government. Further, they were denied appropriate treatment even after it became readily available, in order for researchers to observe the progression of the disease.
While the 1993 mandate did in fact increase pressure on researchers to develop strategies to overcome participation barriers, the issue of underrepresentation of racial minorities in clinical research, including cardiovascular research, has not been resolved and continues to be a problem today.
The overall goal of clinical research is to determine the best strategies to prevent and treat disease. But if the study population is not representative of the affected population at large, the results cannot be generalized to underrepresented subgroups. The implications of underrepresentation in research are far-reaching, and can further contribute to disparate care of minority patients such as African Americans, who have a higher prevalence of cardiovascular risk factors and greater burden of heart failure.
PROPOSING SOLUTIONS
Between 1986 and 2018, according to a PUBMED search, 10,462 articles highlighted the presence of a health-related disparity. Solutions to address and ultimately eradicate disparities will need to eliminate healthcare bias, increase patient access, and increase diversity and inclusion in the physician work force.
Eliminating bias
Implicit bias refers to attitudes, thoughts, and feelings that exist outside of the conscious awareness.92 These biases can be triggered by race, gender, or socioeconomic status. They have manifested in society as stereotypes that men are more competent than women, women are more verbal than men, and African Americans are more athletic than whites.93
The concept of implicit bias is important, in that the populations that experience the greatest health disparities also suffer from negative cultural stereotypes.94 Healthcare professionals are not inoculated against implicit bias.95 Studies have shown that most healthcare providers have implicit biases that reflect positive attitudes toward whites and negative attitudes toward people of color.92,94,96–98
The Implicit Association Test, introduced in 1998, is widely used to measure implicit bias. It measures response time of subjects to match particular social groups to particular attributes.99 Green et al,99 using this test, showed that although physicians reported no explicit preference for white vs African American patients or differences in perceived cooperativeness, the test revealed implicit preference favoring white Americans and implicit stereotypes of African Americans as less cooperative for medical procedures and in general. This also manifested in clinical decision-making, as white Americans were more likely, and African Americans less likely, to be treated with thrombolysis.99
Sabin et al100 showed that implicit bias was present among pediatricians, although less than in society as a whole and in other healthcare professionals.
But how does one change feelings that exist outside of the conscious awareness? Green et al99 showed that making physicians aware of their susceptibility to bias changed their behavior. A subset of physicians who were made aware that bias was a focus of the study were more likely to refer African Americans for thrombolysis even if they had a high degree of implicit pro-white bias.94,100 Perhaps mandating that all healthcare providers take a self-administered and confidentially reported Implicit Association Test will lead to awareness of implicit bias and minimize healthcare behaviors that contribute to the current state of disparities.
Improving access
Common indicators of access to healthcare include health insurance status, having a usual source of healthcare, and having a regular physician.101 Health insurance does offer protection from the costs associated with illness and health maintenance.101 It is also a major contributing factor in racial and ethnic disparities.
Chen et al102 examined the effects of the Affordable Care Act and found that it was associated with reduction in the probability of being uninsured, delaying necessary care, and forgoing necessary care, and increased probability of having a physician. However, earlier studies showed that access to health insurance by itself does not equate to equitable care.103,104
Diversifying the work force
African Americans comprise 4% of physicians and Hispanic Americans 5%, despite accounting for 13% and 16% of the US population.105 This underrepresentation has led to African American and Hispanic American patients being more likely than white patients to be treated by a physician from a dissimilar racial or ethnic background.106 Studies have shown that minority patients in a race- or ethnic-concordant relationship are more likely to use needed health services, less likely to postpone seeking care, and report greater satisfaction.106,107 Minority physicians often locate and practice in neighborhoods with high minority populations, and they disproportionately care for disadvantaged patients of lower socioeconomic status and poorer health.106,108
WE ARE STILL IN THE TUNNEL, BUT THERE IS LIGHT AT THE END
The cardiovascular community has faced tremendous challenges in the past and responded with innovative research that has led to imaging that aids in the diagnosis of subclinical cardiovascular disease and invasive and pharmacologic strategies that have improved cardiovascular outcomes. One may say that there is light at the end of the tunnel; however, the existence of disparate care reminds us that we are still in the tunnel.
Disparities in cardiovascular disease management present a unique challenge for the community. There is no drug, device, or invasive procedure to eliminate this pathology. However, by acknowledging the problem and implementing changes at the system, provider, and patient level, the cardiovascular community can achieve yet another momentous achievement: the end of cardiovascular health disparities. Cardiovascular disease makes no distinction in race, sex, age, or socioeconomic status, and neither should the medical community.
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Quentin R. Youmans, MD Division of Cardiology, Feinberg School of Medicine, Northwestern University, Chicago, IL
Lindsey Hastings-Spaine, MD Rutgers New Jersey Medical School, Department of Emergency Medicine, Newark, NJ
Oluseyi Princewill, MD, MPH MedStar Health Cardiology Associates, Olney, MD
Titilayo Shobayo, BS Morehouse School of Medicine, Atlanta, GA
Ike S. Okwuosa, MD Assistant Professor of Medicine, Division of Cardiology, Feinberg School of Medicine, Northwestern University, Chicago, IL
Address: Ike S. Okwuosa, MD, Feinberg School of Medicine, Division of Cardiology, Northwestern University, 676 N St. Clair Street, Chicago, IL 60611; isokwuosa@gmail.com
Quentin R. Youmans, MD Division of Cardiology, Feinberg School of Medicine, Northwestern University, Chicago, IL
Lindsey Hastings-Spaine, MD Rutgers New Jersey Medical School, Department of Emergency Medicine, Newark, NJ
Oluseyi Princewill, MD, MPH MedStar Health Cardiology Associates, Olney, MD
Titilayo Shobayo, BS Morehouse School of Medicine, Atlanta, GA
Ike S. Okwuosa, MD Assistant Professor of Medicine, Division of Cardiology, Feinberg School of Medicine, Northwestern University, Chicago, IL
Address: Ike S. Okwuosa, MD, Feinberg School of Medicine, Division of Cardiology, Northwestern University, 676 N St. Clair Street, Chicago, IL 60611; isokwuosa@gmail.com
Author and Disclosure Information
Quentin R. Youmans, MD Division of Cardiology, Feinberg School of Medicine, Northwestern University, Chicago, IL
Lindsey Hastings-Spaine, MD Rutgers New Jersey Medical School, Department of Emergency Medicine, Newark, NJ
Oluseyi Princewill, MD, MPH MedStar Health Cardiology Associates, Olney, MD
Titilayo Shobayo, BS Morehouse School of Medicine, Atlanta, GA
Ike S. Okwuosa, MD Assistant Professor of Medicine, Division of Cardiology, Feinberg School of Medicine, Northwestern University, Chicago, IL
Address: Ike S. Okwuosa, MD, Feinberg School of Medicine, Division of Cardiology, Northwestern University, 676 N St. Clair Street, Chicago, IL 60611; isokwuosa@gmail.com
Cardiovascular disease became the leading cause of death in the United States in the early 20th century, and it accounts for nearly half of all deaths in industrialized nations.1 The mortality it inflicts was thought to be shared equally between both sexes and among all age groups and races.2 The cardiology community implemented innovative epidemiologic research, through which risk factors for cardiovascular disease were established.1 The development of coronary care units reduced in-hospital mortality from acute myocardial infarction from 30% to 15%.2–5 Further advances in pharmacology, revascularization, and imaging have aided in the detection and treatment of cardiovascular disease.6 Though cardiovascular disease remains the number-one cause of death worldwide, rates are on the decline.7
For several decades, health disparities have been recognized as a source of pathology in cardiovascular medicine, resulting in inequity of care administration among select populations. In this review, we examine whether the same forward thinking that has resulted in a decline in cardiovascular disease has had an impact on the pervasive disparities in cardiovascular medicine.
DISPARITIES DEFINED
Compared with whites, members of minority groups have a higher burden of chronic diseases, receive lower quality care, and have less access to medical care. Recognizing the potential public health ramifications, in 1999 the US Congress tasked the Institute of Medicine to study and assess the extent of healthcare disparities. This led to the landmark publication, Unequal Treatment: Confronting Racial and Ethnic Disparities in Health Care.8
The Institute of Medicine defines disparities in healthcare as racial or ethnic differences in the quality of healthcare that are not due to access-related factors, clinical needs, preferences, and appropriateness of intervention.8 Disparities can also exist according to socioeconomic status and sex.9
In an early study documenting the concept of disparities in cardiovascular disease, Stone and Vanzant10 concluded that heart disease was more common in African Americans than in whites, and that hypertension was the principal cause of cardiovascular disease mortality in African Americans.
Data from US Centers for Disease Control and Prevention, reference 11
Figure 1. Avoidable deaths from heart disease, stroke, and hypertensive disease, 2001 and 2010.
Although avoidable deaths from heart disease, stroke, and hypertensive disease declined between 2001 and 2010, African Americans still have a higher mortality rate than other racial and ethnic groups (Figure 1).11
DISPARITIES AND CARDIOVASCULAR HEALTH
The concept of cardiovascular health was established by the American Heart Association (AHA) in efforts to achieve an additional 20% reduction in cardiovascular disease-related mortality by 2020.7 Cardiovascular health is defined as the absence of clinically manifest cardiovascular disease and is measured by 7 components:
Not smoking or abstaining from smoking for at least 1 year
A normal body weight, defined as a body mass index less than 25 kg/m2
Optimal physical activity, defined as 75 minutes of vigorous physical activity or 150 minutes of moderate-intensity physical activity per week
Regular consumption of a healthy diet
Total cholesterol below 200 mg/dL
Blood pressure less than 120/80 mm Hg
Fasting blood sugar below 100 mg/dL.
Nearly 70% of the US population can claim 2, 3, or 4 of these components, but differences exist according to race,12 and 60% of adult white Americans are limited to achieving no more than 3 of these healthy metrics, compared with 70% of adult African Americans and Hispanic Americans.
Smoking
Smoking is a major risk factor for cardiovascular disease.12–14
Data from National Health Interview Surgery, Jamal et al, reference 16
Figure 2. Percentage of adults who are active smokers, 2005 and 2014.
During adolescence, white males are more likely to smoke than African American and Hispanic males,12 but this trend reverses in adulthood, when African American men have a higher prevalence of smoking than white men (21.4% vs 19%).7 Rates of lifetime use are highest among American Indian or Alaskan natives and whites (75.9%), followed by African Americans (58.4%), native Hawaiians (56.8%), and Hispanics (56.7%).15 Trends for current smoking are similar (Figure 2).16 Moreover, households with lower socioeconomic status have a higher prevalence of smoking.7
Physical activity
People with a sedentary lifestyle are more likely to die of cardiovascular disease. As many as 250,000 deaths annually in the United States are attributed to lack of regular physical activity.17
Recognizing the potential public health ramifications, the AHA and the 2018 Federal Guidelines on Physical Activity recommend that children engage in 60 minutes of daily physical activity and that adults participate in 150 minutes of moderate-intensity or 75 minutes of vigorous physical activity weekly.18,19
Data from Behavioral Risk Factor Surveillance System, Omura et al, reference 20
Figure 3. Prevalence of inactivitya in the United States, 2013.aPercentage of US adults eligible for intensive behavioral counseling for cardiovascular disease prevention and not meeting aerobic exercise guideline
In the United States, 15.2% of adolescents reported being physically inactive, according to data published in 2016.7 Similar to most cardiovascular risk factors, minority populations and those of lower socioeconomic status had the worst profiles. The prevalence of physical inactivity was highest in African Americans and Hispanics (Figure 3).20
Studies have shown an association between screen-based sedentary behavior (computers, television, and video games) and cardiovascular disease.21–23 In the United States, 41% of adolescents used computers for activities other than homework for more than 3 hours per day on a school day.7 The pattern of use was highest in African American boys and African American girls, followed by Hispanic girls and Hispanic boys.18 Trends were similar with regard to watching television for more than 3 hours per day.
Sedentary behavior persists into adulthood, with rates of inactivity of 38.3% in African Americans, 40.1% in Hispanics, and 26.3% in white adults.7
Nutrition and obesity
Nutrition plays a major role in cardiovascular disease, specifically in the pathogenesis of atherosclerotic disease and hypertension.24 Most Americans do not meet dietary recommendations, with minority communities performing worse in specific metrics.7
Dietary patterns are reflected in the rate of obesity in this nation. Studies have shown a direct correlation between obesity and cardiovascular disease such as coronary artery disease, heart failure, and atrial fibrillation.25–28 According to data from the National Health and Nutrition Examination Survey (NHANES), 31% of children between the ages of 2 and 19 years are classified as obese or overweight. The highest rates of obesity are seen in Hispanic and African American boys and girls. The obesity epidemic is disproportionately rampant in children living in households with low income, low education, and high unemployment rates.7,29–31
Despite the risks associated with obesity, only 64.8% of obese adults report being informed by a doctor or health professional that they were overweight. The proportion of obese adults informed that they were overweight was significantly lower for African Americans and Hispanics compared with whites. Similar differences are seen based on socioeconomic status, as middle-income patients were less likely to be informed than those in the higher income strata (62.4% vs 70.6%).7,31
Blood pressure
Hypertension is a well-established risk factor for cardiovascular disease and stroke, and a blood pressure of 120/80 mm Hg or lower is identified as a component of ideal cardiovascular health.
In the United States the prevalence of hypertension in adults older than 20 is 32%.7 The prevalence of hypertension in African Americans is among the highest in the world.32,33 African Americans develop high blood pressure at earlier ages, and their average resting blood pressures are higher than in whites.34,35 For a 45-year-old without hypertension, the 40-year risk of developing hypertension is 92.7% for African Americans and 86% for whites.35 Hypertension is a major risk factor for stroke, and African Americans have a 1.8 times greater rate of fatal stroke than whites.7
In 2013 there were 71,942 deaths attributable to high blood pressure, and the 2011 death rate associated with hypertension was 18.9 per 100,000. By race, the death rate was 17.6 per 100,000 for white males and an alarming 47.1 per 100,000 for African American males; rates were 15.2 per 100,000 for white females and 35.1 per 100,000 for African American females.7
It is unclear what accounts for the racial difference in prevalence in hypertension. Studies have shown that African Americans are more likely than whites to have been told on more than 2 occasions that they have hypertension. And 85.7% of African Americans are aware that they have high blood pressure, compared with 82.7% of whites.14
African Americans and Hispanics have poorer hypertension control compared with whites.36,37 These observed differences cannot be attributed to access alone, as African Americans were more likely to be on higher-intensity blood pressure therapy, whereas Hispanics were more likely to be undertreated.36,38 In a meta-analysis of 13 trials, Peck et al39 showed that African Americans showed a lesser reduction in systolic and diastolic blood pressure when treated with angiotensin-converting enzyme (ACE) inhibitors.
The 2017 American College of Cardiology (ACC) and AHA guidelines for the prevention, detection, evaluation, and management of high blood pressure in adults40 identifies 4 drug classes as reducing cardiovascular disease morbidity and mortality: thiazide diuretics, ACE inhibitors, angiotensin II receptor blockers (ARBs), and calcium channel blockers. Of these 4 classes, thiazide diuretics and calcium channel blockers have been shown to lower blood pressure more effectively in African Americans than renin-angiotensin-aldosterone inhibition with ACE inhibitors or ARBs.
Glycemic control
Type 2 diabetes mellitus secondary to insulin resistance disproportionately affects minority groups, as the prevalence of diabetes mellitus in African Americans is almost twice as high as that in whites, and 35% higher in Hispanics compared with whites.7,41 Based on NHANES data between 1984 and 2004, the prevalence of diabetes mellitus is expected to increase by 99% in whites, 107% in African Americans, and 127% in Hispanics by 2050. Alarmingly, African Americans over age 75 are expected to experience a 606% increase by 2050.42
With regard to mortality, 21.7 deaths per 100,000 population were attributable to diabetes mellitus according to reports by the AHA in 2016. The death rate in white males was 24.3 per 100,000 compared with 44.9 per 100,000 for African Americans males. The associated mortality rate for white women was 16.2 per 100,000, and 35.8 per 100,000 for African American females.7
DISPARITIES AND CORONARY ARTERY DISEASE CARE
The management of coronary artery disease has evolved from prolonged bed rest to surgical, pharmacologic, and percutaneous revascularization.2,5 Coronary revascularization procedures are now relatively common: 950,000 percutaneous coronary interventions and 397,000 coronary artery bypass procedures were performed in 2010.7
Nevertheless, despite similar clinical presentations, African Americans with acute myocardial infarction were less likely to be referred for coronary artery bypass grafting than whites.43–46 They were also less likely to be given thrombolytics47 and less likely to undergo coronary angiography with percutaneous coronary intervention.48 Similar differences have been reported when comparing Hispanics with whites.49
Some suggest that healthcare access is a key mediator of health disparities.50 In 2009, Hispanics and African Americans accounted for more than 50% of those without health insurance.51 Improved access to healthcare might mitigate the disparity in revascularizations.
Massachusetts was one of the first states to mandate that all residents obtain health insurance. As a result, the uninsured rates declined in African Americans and Hispanics in Massachusetts, but a disparity in revascularization persisted. African Americans and Hispanics were 27% and 16% less likely to undergo revascularization procedures (coronary artery bypass grafting or percutaneous coronary intervention) than whites,51 suggesting that disparities in revascularization are not solely secondary to healthcare access.
These findings are consistent with a 2004 Veterans Administration study,52 in which healthcare access was equal among races. The study showed that African Americans received fewer cardiac procedures after an acute myocardial infarction compared with whites.
Have we made progress? The largest disparity between African Americans and whites in coronary artery disease mortality existed in 1990. The disparity persisted to 2012, and although decreased, it is projected to persist to 2030.53
DISPARITIES IN HEART FAILURE
An estimated 5.7 million Americans have heart failure, and 915,000 new cases are diagnosed annually.7 Unlike coronary artery disease, heart failure is expected to increase in prevalence by 46%, to 8 million Americans with heart failure by 2030.7,54
Our knowledge of disparities in the area of heart failure is derived primarily from epidemiologic studies. The Multi-Ethnic Study of Atherosclerosis55 showed that African Americans (4.6 per 1,000), followed by Hispanics (3.5 per 1,000) had a higher risk of developing heart failure compared with whites (2.4 per 1,000).The higher risk is in part due to disparities in socioeconomic status and prevalence of hypertension, as African Americans accounted for 75% of cases of nonischemic-related heart failure.55 African Americans also have a higher 5-year mortality rate than whites.55
Even though the 5-year mortality rate in heart failure is still 50%, the past 30 years have seen innovations in pharmacologic and device therapy and thus improved outcomes in heart failure patients. Still, significant gaps in the use of guideline-recommended therapies, quality of care, and clinical outcomes persist in contemporary practice for racial minorities with heart failure.
Disparities in inpatient care for heart failure
Patients admitted for heart failure and cared for by a cardiologist are more likely to be discharged on guideline-directed medical therapy, have fewer heart failure readmissions, and lower mortality.56,57 Breathett et al,58 in a study of 104,835 patients hospitalized in an intensive care unit for heart failure, found that primary intensive care by a cardiologist was associated with higher survival in both races. However, in the same study, white patients had a higher odds of receiving care from a cardiologist than African American patients.
Disparities and cardiac resynchronization therapy devices
In one-third of patients with heart failure, conduction delays result in dyssynchronous left ventricular contraction.59 Dyssynchrony leads to reduced cardiac performance, left ventricular remodeling, and increased mortality.56
Cardiac resynchronization therapy (CRT) was approved for clinical use in 2001, and studies have shown that it improves quality of life, exercise tolerance, cardiac performance, and morbidity and mortality rates.59–66 The 2013 ACC/AHA guidelines for the management of heart failure give a class IA recommendation (the highest) for its use in patients with a left ventricular ejection fraction of 35% or less, sinus rhythm, left bundle branch block and a QRS duration of 150 ms or greater, and New York Heart Association class II, III, or ambulatory IV symptoms while on guideline-directed medical therapy.67
Despite these recommendations, racial differences are observed. A study using the Nationwide Inpatient Sample database59 showed that between 2002 and 2010, a total of 374,202 CRT devices were implanted, averaging 41,578 annually. After adjusting for heart failure admissions, the study showed that CRT use was favored in men and in whites.
Another study, using the National Cardiovascular Data Registry,68 looked at patients who received implantable cardiac defibrillators (ICDs) and were eligible to receive CRT. It found that African Americans and Hispanics were less likely than whites to receive CRT, even though they were more likely to meet established criteria.
Disparities and left ventricular assist devices
The Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart failure (REMATCH) trial and Heart Mate II trial demonstrated that left ventricular assist devices (LVADs) were durable options for long-term support for patients with end-stage heart failure.69,70 Studies that examined the role of race and clinical outcomes after LVAD implantation have reported mixed findings.71,72 Few studies have looked at the role racial differences play in accessing LVAD therapy.
Joyce et al73 reviewed data from the Nationwide Inpatient Sample from 2002 to 2003 on patients admitted to the hospital with a primary diagnosis of heart failure or cardiogenic shock. A total of 297,866 patients were included in the study, of whom only 291 underwent LVAD implantation. A multivariate analysis found that factors such as age over 65, female sex, admission to a nonacademic center, geographic region, and African American race adversely influenced access to LVAD therapy.
Breathett et al74 evaluated racial differences in LVAD implantations from 2012 to 2015, a period that corresponds to increased health insurance expansion, and found LVAD implantations increased among African American patients with advanced heart failure, but no other racial or ethnic group.
Disparities and heart transplant
For patients with end-stage heart failure, orthotopic heart transplant is the most definitive and durable option for long-term survival. According to data from the United Network for Organ Sharing, 62,508 heart transplants were performed from January 1, 1988 to December 31, 2015. Compared with transplants of other solid organs, heart transplant occurs in significantly infrequent rates.
Barriers to transplant include lack of health insurance, considered a surrogate for low socioeconomic status. Hispanics and African Americans are less likely to have private health insurance than non-Hispanic whites, and this difference is magnified among the working poor.
Despite these perceived barriers, Kilic et al75 found that African Americans comprised 16.4% of heart transplant recipients, although they make up only approximately 13% of the US population. They also had significantly shorter wait-list times than whites. On the negative side, African Americans had a higher unadjusted mortality rate than whites (15% vs 12% P = .002). African Americans also tended to receive their transplants at centers with lower transplant volumes and higher transplant mortality rates.
Several other studies also showed that African Americans compared to whites have significantly worse outcomes after transplant.76–79 What accounts for this difference? Kilic et al75 showed that African Americans had the lowest proportion of blood type matching and lowest human leukocyte antigen matching, were younger (because African Americans develop more advanced heart failure at younger ages), had higher serum creatinine levels, and were more often bridged to transplant with an LVAD.
DISPARITIES IN CARDIOVASCULAR RESEARCH
Although the United States has the most sophisticated and robust medical system in the world, select groups have significant differences in delivery and healthcare outcomes. There are many explanations for these differences, but a contributing factor may be the paucity of research dedicated to understand racial and ethnic differences.80
Differences observed in epidemiologic studies may be secondary to pathophysiology, genetic differences, environment, and lifestyle choices. Historically, clinical trials were conducted in homogeneous populations with respect to age (middle-aged), sex (male), and race (white), and the results were generalized to heterogeneous populations.80
Disparities in research have implications in clinical practice. Overall, the primary cause of heart failure is ischemia; however, in African Americans, the primary cause is hypertensive heart disease.81 Studies in hypertension have shown that African Americans have less of a response to neurohormonal blockade with ACE inhibitors and beta-blockers than non-African Americans.82 Nevertheless, neurohormonal blockade has become the cornerstone of heart failure treatment.
Retrospective analysis of the Vasodilator-Heart Failure trials83 showed that treatment with isosorbide dinitrate plus hydralazine, compared with placebo, conferred a survival benefit for African Americans but not whites.80 No survival advantage was noted when isosorbide dinitrate/hydralazine was compared to enalapril in African Americans, although enalapril was superior to isosorbide dinitrate in whites.45 These observations were recognized 10 to 15 years after trial completion, and were only possible because the trials included sufficient numbers of African American patients to complete analysis.
In 1993, the US Congress passed the National Institutes of Health (NIH) Revitalization Act, which established guidelines requiring NIH grant applicants to include minorities in human subject research, as they were historically underrepresented in clinical research trials.84,85
In 2001, the Beta-Blocker Evaluation of Survival Trial86 reported its results investigating whether bucindolol, a nonselective beta-blocker, would reduce mortality in patients with advanced heart failure (New York Heart Association class III or IV). This was one of the first trials to prospectively investigate racial and ethnic differences in response to treatment. Though it showed no overall benefit in the use of bucindolol in the treatment of advanced heart failure, subgroup analysis showed that whites did enjoy a benefit in terms of lower mortality, whereas African Americans did not.
Results of the Vasodilator-Heart Failure trials led to further population-directed research, most notably the African American Heart Failure Trial,87 a double-blind, placebo-controlled, randomized trial in patients who identified as African American. Patients who were randomized to receive a fixed dose of hydralazine and isosorbide dinitrate had a 43% lower mortality rate, a 33% lower hospitalization rate for heart failure, and better quality of life than patients in the placebo group, leading to early termination of the trial. The outcomes suggested that the combination of isosorbide dinitrate and hydralazine treats heart failure in a manner independent of pure neurohormonal blockade.
CHALLENGES IN STUDY PARTICIPATION
Recruitment of minority participants in biomedical research is a challenging task for clinical investigators.88,89 Some of the factors thought to pose potential barriers for racial and ethnic minority participation in health research include poor access to primary medical care, failure of researchers to recruit minority populations actively, and language and cultural barriers.90
Further, it is widely claimed that African Americans are less willing than nonminority individuals to participate in clinical research trials due to general distrust of the medical community as a result of the Tuskegee Syphilis Experiment.91 That infamous study, conducted by the US Public Health Service between 1932 and 1972, sought to record the natural progression of untreated syphilis in poor African American men in Alabama. The participants were not informed of the true purpose of the study, and they were under the impression that they were simply receiving free healthcare from the US government. Further, they were denied appropriate treatment even after it became readily available, in order for researchers to observe the progression of the disease.
While the 1993 mandate did in fact increase pressure on researchers to develop strategies to overcome participation barriers, the issue of underrepresentation of racial minorities in clinical research, including cardiovascular research, has not been resolved and continues to be a problem today.
The overall goal of clinical research is to determine the best strategies to prevent and treat disease. But if the study population is not representative of the affected population at large, the results cannot be generalized to underrepresented subgroups. The implications of underrepresentation in research are far-reaching, and can further contribute to disparate care of minority patients such as African Americans, who have a higher prevalence of cardiovascular risk factors and greater burden of heart failure.
PROPOSING SOLUTIONS
Between 1986 and 2018, according to a PUBMED search, 10,462 articles highlighted the presence of a health-related disparity. Solutions to address and ultimately eradicate disparities will need to eliminate healthcare bias, increase patient access, and increase diversity and inclusion in the physician work force.
Eliminating bias
Implicit bias refers to attitudes, thoughts, and feelings that exist outside of the conscious awareness.92 These biases can be triggered by race, gender, or socioeconomic status. They have manifested in society as stereotypes that men are more competent than women, women are more verbal than men, and African Americans are more athletic than whites.93
The concept of implicit bias is important, in that the populations that experience the greatest health disparities also suffer from negative cultural stereotypes.94 Healthcare professionals are not inoculated against implicit bias.95 Studies have shown that most healthcare providers have implicit biases that reflect positive attitudes toward whites and negative attitudes toward people of color.92,94,96–98
The Implicit Association Test, introduced in 1998, is widely used to measure implicit bias. It measures response time of subjects to match particular social groups to particular attributes.99 Green et al,99 using this test, showed that although physicians reported no explicit preference for white vs African American patients or differences in perceived cooperativeness, the test revealed implicit preference favoring white Americans and implicit stereotypes of African Americans as less cooperative for medical procedures and in general. This also manifested in clinical decision-making, as white Americans were more likely, and African Americans less likely, to be treated with thrombolysis.99
Sabin et al100 showed that implicit bias was present among pediatricians, although less than in society as a whole and in other healthcare professionals.
But how does one change feelings that exist outside of the conscious awareness? Green et al99 showed that making physicians aware of their susceptibility to bias changed their behavior. A subset of physicians who were made aware that bias was a focus of the study were more likely to refer African Americans for thrombolysis even if they had a high degree of implicit pro-white bias.94,100 Perhaps mandating that all healthcare providers take a self-administered and confidentially reported Implicit Association Test will lead to awareness of implicit bias and minimize healthcare behaviors that contribute to the current state of disparities.
Improving access
Common indicators of access to healthcare include health insurance status, having a usual source of healthcare, and having a regular physician.101 Health insurance does offer protection from the costs associated with illness and health maintenance.101 It is also a major contributing factor in racial and ethnic disparities.
Chen et al102 examined the effects of the Affordable Care Act and found that it was associated with reduction in the probability of being uninsured, delaying necessary care, and forgoing necessary care, and increased probability of having a physician. However, earlier studies showed that access to health insurance by itself does not equate to equitable care.103,104
Diversifying the work force
African Americans comprise 4% of physicians and Hispanic Americans 5%, despite accounting for 13% and 16% of the US population.105 This underrepresentation has led to African American and Hispanic American patients being more likely than white patients to be treated by a physician from a dissimilar racial or ethnic background.106 Studies have shown that minority patients in a race- or ethnic-concordant relationship are more likely to use needed health services, less likely to postpone seeking care, and report greater satisfaction.106,107 Minority physicians often locate and practice in neighborhoods with high minority populations, and they disproportionately care for disadvantaged patients of lower socioeconomic status and poorer health.106,108
WE ARE STILL IN THE TUNNEL, BUT THERE IS LIGHT AT THE END
The cardiovascular community has faced tremendous challenges in the past and responded with innovative research that has led to imaging that aids in the diagnosis of subclinical cardiovascular disease and invasive and pharmacologic strategies that have improved cardiovascular outcomes. One may say that there is light at the end of the tunnel; however, the existence of disparate care reminds us that we are still in the tunnel.
Disparities in cardiovascular disease management present a unique challenge for the community. There is no drug, device, or invasive procedure to eliminate this pathology. However, by acknowledging the problem and implementing changes at the system, provider, and patient level, the cardiovascular community can achieve yet another momentous achievement: the end of cardiovascular health disparities. Cardiovascular disease makes no distinction in race, sex, age, or socioeconomic status, and neither should the medical community.
Cardiovascular disease became the leading cause of death in the United States in the early 20th century, and it accounts for nearly half of all deaths in industrialized nations.1 The mortality it inflicts was thought to be shared equally between both sexes and among all age groups and races.2 The cardiology community implemented innovative epidemiologic research, through which risk factors for cardiovascular disease were established.1 The development of coronary care units reduced in-hospital mortality from acute myocardial infarction from 30% to 15%.2–5 Further advances in pharmacology, revascularization, and imaging have aided in the detection and treatment of cardiovascular disease.6 Though cardiovascular disease remains the number-one cause of death worldwide, rates are on the decline.7
For several decades, health disparities have been recognized as a source of pathology in cardiovascular medicine, resulting in inequity of care administration among select populations. In this review, we examine whether the same forward thinking that has resulted in a decline in cardiovascular disease has had an impact on the pervasive disparities in cardiovascular medicine.
DISPARITIES DEFINED
Compared with whites, members of minority groups have a higher burden of chronic diseases, receive lower quality care, and have less access to medical care. Recognizing the potential public health ramifications, in 1999 the US Congress tasked the Institute of Medicine to study and assess the extent of healthcare disparities. This led to the landmark publication, Unequal Treatment: Confronting Racial and Ethnic Disparities in Health Care.8
The Institute of Medicine defines disparities in healthcare as racial or ethnic differences in the quality of healthcare that are not due to access-related factors, clinical needs, preferences, and appropriateness of intervention.8 Disparities can also exist according to socioeconomic status and sex.9
In an early study documenting the concept of disparities in cardiovascular disease, Stone and Vanzant10 concluded that heart disease was more common in African Americans than in whites, and that hypertension was the principal cause of cardiovascular disease mortality in African Americans.
Data from US Centers for Disease Control and Prevention, reference 11
Figure 1. Avoidable deaths from heart disease, stroke, and hypertensive disease, 2001 and 2010.
Although avoidable deaths from heart disease, stroke, and hypertensive disease declined between 2001 and 2010, African Americans still have a higher mortality rate than other racial and ethnic groups (Figure 1).11
DISPARITIES AND CARDIOVASCULAR HEALTH
The concept of cardiovascular health was established by the American Heart Association (AHA) in efforts to achieve an additional 20% reduction in cardiovascular disease-related mortality by 2020.7 Cardiovascular health is defined as the absence of clinically manifest cardiovascular disease and is measured by 7 components:
Not smoking or abstaining from smoking for at least 1 year
A normal body weight, defined as a body mass index less than 25 kg/m2
Optimal physical activity, defined as 75 minutes of vigorous physical activity or 150 minutes of moderate-intensity physical activity per week
Regular consumption of a healthy diet
Total cholesterol below 200 mg/dL
Blood pressure less than 120/80 mm Hg
Fasting blood sugar below 100 mg/dL.
Nearly 70% of the US population can claim 2, 3, or 4 of these components, but differences exist according to race,12 and 60% of adult white Americans are limited to achieving no more than 3 of these healthy metrics, compared with 70% of adult African Americans and Hispanic Americans.
Smoking
Smoking is a major risk factor for cardiovascular disease.12–14
Data from National Health Interview Surgery, Jamal et al, reference 16
Figure 2. Percentage of adults who are active smokers, 2005 and 2014.
During adolescence, white males are more likely to smoke than African American and Hispanic males,12 but this trend reverses in adulthood, when African American men have a higher prevalence of smoking than white men (21.4% vs 19%).7 Rates of lifetime use are highest among American Indian or Alaskan natives and whites (75.9%), followed by African Americans (58.4%), native Hawaiians (56.8%), and Hispanics (56.7%).15 Trends for current smoking are similar (Figure 2).16 Moreover, households with lower socioeconomic status have a higher prevalence of smoking.7
Physical activity
People with a sedentary lifestyle are more likely to die of cardiovascular disease. As many as 250,000 deaths annually in the United States are attributed to lack of regular physical activity.17
Recognizing the potential public health ramifications, the AHA and the 2018 Federal Guidelines on Physical Activity recommend that children engage in 60 minutes of daily physical activity and that adults participate in 150 minutes of moderate-intensity or 75 minutes of vigorous physical activity weekly.18,19
Data from Behavioral Risk Factor Surveillance System, Omura et al, reference 20
Figure 3. Prevalence of inactivitya in the United States, 2013.aPercentage of US adults eligible for intensive behavioral counseling for cardiovascular disease prevention and not meeting aerobic exercise guideline
In the United States, 15.2% of adolescents reported being physically inactive, according to data published in 2016.7 Similar to most cardiovascular risk factors, minority populations and those of lower socioeconomic status had the worst profiles. The prevalence of physical inactivity was highest in African Americans and Hispanics (Figure 3).20
Studies have shown an association between screen-based sedentary behavior (computers, television, and video games) and cardiovascular disease.21–23 In the United States, 41% of adolescents used computers for activities other than homework for more than 3 hours per day on a school day.7 The pattern of use was highest in African American boys and African American girls, followed by Hispanic girls and Hispanic boys.18 Trends were similar with regard to watching television for more than 3 hours per day.
Sedentary behavior persists into adulthood, with rates of inactivity of 38.3% in African Americans, 40.1% in Hispanics, and 26.3% in white adults.7
Nutrition and obesity
Nutrition plays a major role in cardiovascular disease, specifically in the pathogenesis of atherosclerotic disease and hypertension.24 Most Americans do not meet dietary recommendations, with minority communities performing worse in specific metrics.7
Dietary patterns are reflected in the rate of obesity in this nation. Studies have shown a direct correlation between obesity and cardiovascular disease such as coronary artery disease, heart failure, and atrial fibrillation.25–28 According to data from the National Health and Nutrition Examination Survey (NHANES), 31% of children between the ages of 2 and 19 years are classified as obese or overweight. The highest rates of obesity are seen in Hispanic and African American boys and girls. The obesity epidemic is disproportionately rampant in children living in households with low income, low education, and high unemployment rates.7,29–31
Despite the risks associated with obesity, only 64.8% of obese adults report being informed by a doctor or health professional that they were overweight. The proportion of obese adults informed that they were overweight was significantly lower for African Americans and Hispanics compared with whites. Similar differences are seen based on socioeconomic status, as middle-income patients were less likely to be informed than those in the higher income strata (62.4% vs 70.6%).7,31
Blood pressure
Hypertension is a well-established risk factor for cardiovascular disease and stroke, and a blood pressure of 120/80 mm Hg or lower is identified as a component of ideal cardiovascular health.
In the United States the prevalence of hypertension in adults older than 20 is 32%.7 The prevalence of hypertension in African Americans is among the highest in the world.32,33 African Americans develop high blood pressure at earlier ages, and their average resting blood pressures are higher than in whites.34,35 For a 45-year-old without hypertension, the 40-year risk of developing hypertension is 92.7% for African Americans and 86% for whites.35 Hypertension is a major risk factor for stroke, and African Americans have a 1.8 times greater rate of fatal stroke than whites.7
In 2013 there were 71,942 deaths attributable to high blood pressure, and the 2011 death rate associated with hypertension was 18.9 per 100,000. By race, the death rate was 17.6 per 100,000 for white males and an alarming 47.1 per 100,000 for African American males; rates were 15.2 per 100,000 for white females and 35.1 per 100,000 for African American females.7
It is unclear what accounts for the racial difference in prevalence in hypertension. Studies have shown that African Americans are more likely than whites to have been told on more than 2 occasions that they have hypertension. And 85.7% of African Americans are aware that they have high blood pressure, compared with 82.7% of whites.14
African Americans and Hispanics have poorer hypertension control compared with whites.36,37 These observed differences cannot be attributed to access alone, as African Americans were more likely to be on higher-intensity blood pressure therapy, whereas Hispanics were more likely to be undertreated.36,38 In a meta-analysis of 13 trials, Peck et al39 showed that African Americans showed a lesser reduction in systolic and diastolic blood pressure when treated with angiotensin-converting enzyme (ACE) inhibitors.
The 2017 American College of Cardiology (ACC) and AHA guidelines for the prevention, detection, evaluation, and management of high blood pressure in adults40 identifies 4 drug classes as reducing cardiovascular disease morbidity and mortality: thiazide diuretics, ACE inhibitors, angiotensin II receptor blockers (ARBs), and calcium channel blockers. Of these 4 classes, thiazide diuretics and calcium channel blockers have been shown to lower blood pressure more effectively in African Americans than renin-angiotensin-aldosterone inhibition with ACE inhibitors or ARBs.
Glycemic control
Type 2 diabetes mellitus secondary to insulin resistance disproportionately affects minority groups, as the prevalence of diabetes mellitus in African Americans is almost twice as high as that in whites, and 35% higher in Hispanics compared with whites.7,41 Based on NHANES data between 1984 and 2004, the prevalence of diabetes mellitus is expected to increase by 99% in whites, 107% in African Americans, and 127% in Hispanics by 2050. Alarmingly, African Americans over age 75 are expected to experience a 606% increase by 2050.42
With regard to mortality, 21.7 deaths per 100,000 population were attributable to diabetes mellitus according to reports by the AHA in 2016. The death rate in white males was 24.3 per 100,000 compared with 44.9 per 100,000 for African Americans males. The associated mortality rate for white women was 16.2 per 100,000, and 35.8 per 100,000 for African American females.7
DISPARITIES AND CORONARY ARTERY DISEASE CARE
The management of coronary artery disease has evolved from prolonged bed rest to surgical, pharmacologic, and percutaneous revascularization.2,5 Coronary revascularization procedures are now relatively common: 950,000 percutaneous coronary interventions and 397,000 coronary artery bypass procedures were performed in 2010.7
Nevertheless, despite similar clinical presentations, African Americans with acute myocardial infarction were less likely to be referred for coronary artery bypass grafting than whites.43–46 They were also less likely to be given thrombolytics47 and less likely to undergo coronary angiography with percutaneous coronary intervention.48 Similar differences have been reported when comparing Hispanics with whites.49
Some suggest that healthcare access is a key mediator of health disparities.50 In 2009, Hispanics and African Americans accounted for more than 50% of those without health insurance.51 Improved access to healthcare might mitigate the disparity in revascularizations.
Massachusetts was one of the first states to mandate that all residents obtain health insurance. As a result, the uninsured rates declined in African Americans and Hispanics in Massachusetts, but a disparity in revascularization persisted. African Americans and Hispanics were 27% and 16% less likely to undergo revascularization procedures (coronary artery bypass grafting or percutaneous coronary intervention) than whites,51 suggesting that disparities in revascularization are not solely secondary to healthcare access.
These findings are consistent with a 2004 Veterans Administration study,52 in which healthcare access was equal among races. The study showed that African Americans received fewer cardiac procedures after an acute myocardial infarction compared with whites.
Have we made progress? The largest disparity between African Americans and whites in coronary artery disease mortality existed in 1990. The disparity persisted to 2012, and although decreased, it is projected to persist to 2030.53
DISPARITIES IN HEART FAILURE
An estimated 5.7 million Americans have heart failure, and 915,000 new cases are diagnosed annually.7 Unlike coronary artery disease, heart failure is expected to increase in prevalence by 46%, to 8 million Americans with heart failure by 2030.7,54
Our knowledge of disparities in the area of heart failure is derived primarily from epidemiologic studies. The Multi-Ethnic Study of Atherosclerosis55 showed that African Americans (4.6 per 1,000), followed by Hispanics (3.5 per 1,000) had a higher risk of developing heart failure compared with whites (2.4 per 1,000).The higher risk is in part due to disparities in socioeconomic status and prevalence of hypertension, as African Americans accounted for 75% of cases of nonischemic-related heart failure.55 African Americans also have a higher 5-year mortality rate than whites.55
Even though the 5-year mortality rate in heart failure is still 50%, the past 30 years have seen innovations in pharmacologic and device therapy and thus improved outcomes in heart failure patients. Still, significant gaps in the use of guideline-recommended therapies, quality of care, and clinical outcomes persist in contemporary practice for racial minorities with heart failure.
Disparities in inpatient care for heart failure
Patients admitted for heart failure and cared for by a cardiologist are more likely to be discharged on guideline-directed medical therapy, have fewer heart failure readmissions, and lower mortality.56,57 Breathett et al,58 in a study of 104,835 patients hospitalized in an intensive care unit for heart failure, found that primary intensive care by a cardiologist was associated with higher survival in both races. However, in the same study, white patients had a higher odds of receiving care from a cardiologist than African American patients.
Disparities and cardiac resynchronization therapy devices
In one-third of patients with heart failure, conduction delays result in dyssynchronous left ventricular contraction.59 Dyssynchrony leads to reduced cardiac performance, left ventricular remodeling, and increased mortality.56
Cardiac resynchronization therapy (CRT) was approved for clinical use in 2001, and studies have shown that it improves quality of life, exercise tolerance, cardiac performance, and morbidity and mortality rates.59–66 The 2013 ACC/AHA guidelines for the management of heart failure give a class IA recommendation (the highest) for its use in patients with a left ventricular ejection fraction of 35% or less, sinus rhythm, left bundle branch block and a QRS duration of 150 ms or greater, and New York Heart Association class II, III, or ambulatory IV symptoms while on guideline-directed medical therapy.67
Despite these recommendations, racial differences are observed. A study using the Nationwide Inpatient Sample database59 showed that between 2002 and 2010, a total of 374,202 CRT devices were implanted, averaging 41,578 annually. After adjusting for heart failure admissions, the study showed that CRT use was favored in men and in whites.
Another study, using the National Cardiovascular Data Registry,68 looked at patients who received implantable cardiac defibrillators (ICDs) and were eligible to receive CRT. It found that African Americans and Hispanics were less likely than whites to receive CRT, even though they were more likely to meet established criteria.
Disparities and left ventricular assist devices
The Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart failure (REMATCH) trial and Heart Mate II trial demonstrated that left ventricular assist devices (LVADs) were durable options for long-term support for patients with end-stage heart failure.69,70 Studies that examined the role of race and clinical outcomes after LVAD implantation have reported mixed findings.71,72 Few studies have looked at the role racial differences play in accessing LVAD therapy.
Joyce et al73 reviewed data from the Nationwide Inpatient Sample from 2002 to 2003 on patients admitted to the hospital with a primary diagnosis of heart failure or cardiogenic shock. A total of 297,866 patients were included in the study, of whom only 291 underwent LVAD implantation. A multivariate analysis found that factors such as age over 65, female sex, admission to a nonacademic center, geographic region, and African American race adversely influenced access to LVAD therapy.
Breathett et al74 evaluated racial differences in LVAD implantations from 2012 to 2015, a period that corresponds to increased health insurance expansion, and found LVAD implantations increased among African American patients with advanced heart failure, but no other racial or ethnic group.
Disparities and heart transplant
For patients with end-stage heart failure, orthotopic heart transplant is the most definitive and durable option for long-term survival. According to data from the United Network for Organ Sharing, 62,508 heart transplants were performed from January 1, 1988 to December 31, 2015. Compared with transplants of other solid organs, heart transplant occurs in significantly infrequent rates.
Barriers to transplant include lack of health insurance, considered a surrogate for low socioeconomic status. Hispanics and African Americans are less likely to have private health insurance than non-Hispanic whites, and this difference is magnified among the working poor.
Despite these perceived barriers, Kilic et al75 found that African Americans comprised 16.4% of heart transplant recipients, although they make up only approximately 13% of the US population. They also had significantly shorter wait-list times than whites. On the negative side, African Americans had a higher unadjusted mortality rate than whites (15% vs 12% P = .002). African Americans also tended to receive their transplants at centers with lower transplant volumes and higher transplant mortality rates.
Several other studies also showed that African Americans compared to whites have significantly worse outcomes after transplant.76–79 What accounts for this difference? Kilic et al75 showed that African Americans had the lowest proportion of blood type matching and lowest human leukocyte antigen matching, were younger (because African Americans develop more advanced heart failure at younger ages), had higher serum creatinine levels, and were more often bridged to transplant with an LVAD.
DISPARITIES IN CARDIOVASCULAR RESEARCH
Although the United States has the most sophisticated and robust medical system in the world, select groups have significant differences in delivery and healthcare outcomes. There are many explanations for these differences, but a contributing factor may be the paucity of research dedicated to understand racial and ethnic differences.80
Differences observed in epidemiologic studies may be secondary to pathophysiology, genetic differences, environment, and lifestyle choices. Historically, clinical trials were conducted in homogeneous populations with respect to age (middle-aged), sex (male), and race (white), and the results were generalized to heterogeneous populations.80
Disparities in research have implications in clinical practice. Overall, the primary cause of heart failure is ischemia; however, in African Americans, the primary cause is hypertensive heart disease.81 Studies in hypertension have shown that African Americans have less of a response to neurohormonal blockade with ACE inhibitors and beta-blockers than non-African Americans.82 Nevertheless, neurohormonal blockade has become the cornerstone of heart failure treatment.
Retrospective analysis of the Vasodilator-Heart Failure trials83 showed that treatment with isosorbide dinitrate plus hydralazine, compared with placebo, conferred a survival benefit for African Americans but not whites.80 No survival advantage was noted when isosorbide dinitrate/hydralazine was compared to enalapril in African Americans, although enalapril was superior to isosorbide dinitrate in whites.45 These observations were recognized 10 to 15 years after trial completion, and were only possible because the trials included sufficient numbers of African American patients to complete analysis.
In 1993, the US Congress passed the National Institutes of Health (NIH) Revitalization Act, which established guidelines requiring NIH grant applicants to include minorities in human subject research, as they were historically underrepresented in clinical research trials.84,85
In 2001, the Beta-Blocker Evaluation of Survival Trial86 reported its results investigating whether bucindolol, a nonselective beta-blocker, would reduce mortality in patients with advanced heart failure (New York Heart Association class III or IV). This was one of the first trials to prospectively investigate racial and ethnic differences in response to treatment. Though it showed no overall benefit in the use of bucindolol in the treatment of advanced heart failure, subgroup analysis showed that whites did enjoy a benefit in terms of lower mortality, whereas African Americans did not.
Results of the Vasodilator-Heart Failure trials led to further population-directed research, most notably the African American Heart Failure Trial,87 a double-blind, placebo-controlled, randomized trial in patients who identified as African American. Patients who were randomized to receive a fixed dose of hydralazine and isosorbide dinitrate had a 43% lower mortality rate, a 33% lower hospitalization rate for heart failure, and better quality of life than patients in the placebo group, leading to early termination of the trial. The outcomes suggested that the combination of isosorbide dinitrate and hydralazine treats heart failure in a manner independent of pure neurohormonal blockade.
CHALLENGES IN STUDY PARTICIPATION
Recruitment of minority participants in biomedical research is a challenging task for clinical investigators.88,89 Some of the factors thought to pose potential barriers for racial and ethnic minority participation in health research include poor access to primary medical care, failure of researchers to recruit minority populations actively, and language and cultural barriers.90
Further, it is widely claimed that African Americans are less willing than nonminority individuals to participate in clinical research trials due to general distrust of the medical community as a result of the Tuskegee Syphilis Experiment.91 That infamous study, conducted by the US Public Health Service between 1932 and 1972, sought to record the natural progression of untreated syphilis in poor African American men in Alabama. The participants were not informed of the true purpose of the study, and they were under the impression that they were simply receiving free healthcare from the US government. Further, they were denied appropriate treatment even after it became readily available, in order for researchers to observe the progression of the disease.
While the 1993 mandate did in fact increase pressure on researchers to develop strategies to overcome participation barriers, the issue of underrepresentation of racial minorities in clinical research, including cardiovascular research, has not been resolved and continues to be a problem today.
The overall goal of clinical research is to determine the best strategies to prevent and treat disease. But if the study population is not representative of the affected population at large, the results cannot be generalized to underrepresented subgroups. The implications of underrepresentation in research are far-reaching, and can further contribute to disparate care of minority patients such as African Americans, who have a higher prevalence of cardiovascular risk factors and greater burden of heart failure.
PROPOSING SOLUTIONS
Between 1986 and 2018, according to a PUBMED search, 10,462 articles highlighted the presence of a health-related disparity. Solutions to address and ultimately eradicate disparities will need to eliminate healthcare bias, increase patient access, and increase diversity and inclusion in the physician work force.
Eliminating bias
Implicit bias refers to attitudes, thoughts, and feelings that exist outside of the conscious awareness.92 These biases can be triggered by race, gender, or socioeconomic status. They have manifested in society as stereotypes that men are more competent than women, women are more verbal than men, and African Americans are more athletic than whites.93
The concept of implicit bias is important, in that the populations that experience the greatest health disparities also suffer from negative cultural stereotypes.94 Healthcare professionals are not inoculated against implicit bias.95 Studies have shown that most healthcare providers have implicit biases that reflect positive attitudes toward whites and negative attitudes toward people of color.92,94,96–98
The Implicit Association Test, introduced in 1998, is widely used to measure implicit bias. It measures response time of subjects to match particular social groups to particular attributes.99 Green et al,99 using this test, showed that although physicians reported no explicit preference for white vs African American patients or differences in perceived cooperativeness, the test revealed implicit preference favoring white Americans and implicit stereotypes of African Americans as less cooperative for medical procedures and in general. This also manifested in clinical decision-making, as white Americans were more likely, and African Americans less likely, to be treated with thrombolysis.99
Sabin et al100 showed that implicit bias was present among pediatricians, although less than in society as a whole and in other healthcare professionals.
But how does one change feelings that exist outside of the conscious awareness? Green et al99 showed that making physicians aware of their susceptibility to bias changed their behavior. A subset of physicians who were made aware that bias was a focus of the study were more likely to refer African Americans for thrombolysis even if they had a high degree of implicit pro-white bias.94,100 Perhaps mandating that all healthcare providers take a self-administered and confidentially reported Implicit Association Test will lead to awareness of implicit bias and minimize healthcare behaviors that contribute to the current state of disparities.
Improving access
Common indicators of access to healthcare include health insurance status, having a usual source of healthcare, and having a regular physician.101 Health insurance does offer protection from the costs associated with illness and health maintenance.101 It is also a major contributing factor in racial and ethnic disparities.
Chen et al102 examined the effects of the Affordable Care Act and found that it was associated with reduction in the probability of being uninsured, delaying necessary care, and forgoing necessary care, and increased probability of having a physician. However, earlier studies showed that access to health insurance by itself does not equate to equitable care.103,104
Diversifying the work force
African Americans comprise 4% of physicians and Hispanic Americans 5%, despite accounting for 13% and 16% of the US population.105 This underrepresentation has led to African American and Hispanic American patients being more likely than white patients to be treated by a physician from a dissimilar racial or ethnic background.106 Studies have shown that minority patients in a race- or ethnic-concordant relationship are more likely to use needed health services, less likely to postpone seeking care, and report greater satisfaction.106,107 Minority physicians often locate and practice in neighborhoods with high minority populations, and they disproportionately care for disadvantaged patients of lower socioeconomic status and poorer health.106,108
WE ARE STILL IN THE TUNNEL, BUT THERE IS LIGHT AT THE END
The cardiovascular community has faced tremendous challenges in the past and responded with innovative research that has led to imaging that aids in the diagnosis of subclinical cardiovascular disease and invasive and pharmacologic strategies that have improved cardiovascular outcomes. One may say that there is light at the end of the tunnel; however, the existence of disparate care reminds us that we are still in the tunnel.
Disparities in cardiovascular disease management present a unique challenge for the community. There is no drug, device, or invasive procedure to eliminate this pathology. However, by acknowledging the problem and implementing changes at the system, provider, and patient level, the cardiovascular community can achieve yet another momentous achievement: the end of cardiovascular health disparities. Cardiovascular disease makes no distinction in race, sex, age, or socioeconomic status, and neither should the medical community.
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LaVeist TA, Nuru-Jeter A. Is doctor-patient race concordance associated with greater satisfaction with care? J Health Soc Behav 2002; 43(3):296–306. pmid:12467254
Marrast LM, Zallman L, Woolhandler S, Bor DH, McCormick D. Minority physicians’ role in the care of underserved patients: diversifying the physician workforce may be key in addressing health disparities. JAMA Intern Med 2014; 174(2):289–291. doi:10.1001/jamainternmed.2013.12756
Although avoidable deaths from heart disease, stroke, and hypertensive disease have declined overall, African Americans still have a higher mortality rate than other racial and ethnic groups.
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Disparities in care exist and may persist even with equal access to care.
Since 1993, studies funded by the National Institutes of Health must include minorities that were historically underrepresented in clinical research trials.
Solutions to disparities will need to eliminate healthcare bias, increase patient access, and increase diversity and inclusion in the physician work force.
Cardiovascular disease makes no distinction in race, sex, age, or socioeconomic status, and neither should the medical community.
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Aspects of modern life that may promote hemorrhoids include increased consumption of processed foods, a sedentary lifestyle, and using cell phones while defecating, which translates to much more time spent on the toilet.
Hemorrhoids accounted for more than 3.5 million US outpatient visits in 2010, and they were the third leading cause of hospital admissions related to gastrointestinal disease.1
Here, we review the process for diagnosing and grading hemorrhoids, as well as for selecting the appropriate medical or surgical treatment based on the most recent clinical evidence.
DIAGNOSING AND CLASSIFYING HEMORRHOIDS
Hemorrhoids are the distal prolapse of the arteriovenous bundle, muscle fibers, and surrounding connective tissue as an envelope below the dentate line in the anal canal. They usually present with painless rectal bleeding.2
The diagnosis of hemorrhoids relies on the history and physical examination rather than on laboratory testing or imaging studies. Typically, the presenting symptom is painless rectal bleeding associated with bowel movements, usually appearing as bright red blood on the toilet paper or coating the stool. Severe itching and anal discomfort are also common, especially with chronic hemorrhoids.
Detailed patient history
A detailed patient history is important. It should include the extent, severity, and duration of symptoms, frequency of bowel movements, associated symptoms (eg, constipation, fecal incontinence), daily dietary habits, and details of bowel movements (eg, time spent during each bowel movement and concomitant cell phone use).3
Regarding bowel habits, some patients experience lifelong constipation or diarrhea. Therefore, what a patient considers a normal bowel habit may not be normal and should be investigated.4 Also, it is important to exclude external thrombosed hemorrhoids, anal fissure, anal abscess, and Crohn disease.5
Physical examination
A digital rectal examination is the second step. During the examination, look for skin tags, sphincter tone, perianal hygiene, and synchronous anal lesions.3 Of note, the Valsalva maneuver can be performed during the digital rectal examination.
Red flags for colorectal cancer on the digital rectal examination include a mass with or without presence of hemorrhoidal sacs and a bleeding source above the level of internal hemorrhoids.
Figure 1. Patient with Crohn disease. Note the fistula orifices and the skin tag.
Patients with recurrent abscesses, fistulas, or skin tags (especially cauliflower-type skin tags) should be investigated for Crohn disease (Figure 1).
Endoscopy
Since rectal bleeding can be a sign of several diseases, including colorectal cancer, it is important to review any previous endoscopic results. Patients at high risk of colon cancer should undergo rigid proctoscopy, flexible sigmoidoscopy, or colonoscopy.3,4 In our practice, we recommend endoscopic evaluation for patients over age 40 with rectal bleeding, especially if they have a family history of colorectal cancer.
External or internal (grades I–IV)
Hemorrhoids can be categorized as either external or internal.
External hemorrhoids are distinguished by their outer covering with perianal skin and anoderm and their location inferior to the dentate line. They are painful if the hemorrhoidal sac is occluded by a thrombotic clot.
Internal hemorrhoids are above the dentate line and covered with rectal columnar and transitional mucosa. They are further graded on a 4-point scale3:
Grade I—Visible hemorrhoids that do not prolapse
Grade II—Hemorrhoids that prolapse during the Valsalva maneuver but spontaneously reduce
Grade III—Hemorrhoids that prolapse during the Valsalva maneuver and need manual reduction
Grade IV—Nonreducible hemorrhoids.
A RANGE OF TREATMENTS
In choosing the treatment for hemorrhoids, one should consider the disease grade and severity, its impact on the quality of life, the degree of pain it causes, the patient’s likelihood of adhering to treatment, and the patient’s personal preference.
Regardless of severity, treatment almost always starts with a high-fiber diet and other lifestyle modifications that include bowel movement behaviors. This requires practitioners to spend significant time on patient education regardless of the type or the severity of the disease.
Treatments can be grouped in 3 categories: conservative, office-based, and surgical. Practitioners should thoroughly discuss the options with the patient, emphasizing the pros and cons of each.
CONSERVATIVE MEASURES
Conservative measures are aimed at softening the stool, relieving pain, and correcting bad toileting habits. In most cases, the primary precipitating factor is lifestyle, and unless patients change it, they are more likely to have recurrent symptoms in the long term.
No phone in the bathroom
People take their phones into the bathroom, and this habit is blamed for increasing the time on the toilet and leading to increased pressure on the anal region and straining during defecation. Some research points to a direct correlation between the time spent on the toilet and hemorrhoidal disease, although the exact cause-and-effect relationship with cell phone use has not been determined. In general, spending excessive time on the commode, including reading, should be discouraged.
Less time in the bathroom
Johannsson et al6 reported that patients with hemorrhoids spent more time on the toilet and had to strain harder and more often than controls in the community and hospital.
Garg and Singh7 and Garg8 use the mnemonic “TONE” for appropriate defecation habits:
Three minutes during defecation
Once-daily defecation
No straining and no cell phone use during defecation
Enough fiber.
More fiber
Fiber draws water into the lumen of the colon, increasing the water content of the stool. Recommended daily fiber intake is about 28 g for women and 38 g for men.9 This high level of intake is hard to achieve without supplements for someone who consumes a classic American diet with a lot of fast food.
Fiber supplements are strongly recommended in the American Society of Colon and Rectal Surgeons (ASCRS) practice guidelines3 based on a Cochrane review.10 In this meta-analysis, with fiber supplements, the relative risk of persisting or nonimproving symptoms was 0.53 (95% confidence interval [CI] 0.38–0.73) and the relative risk of bleeding was 0.50 (95% CI 028–0.89). Psyllium husk is an inexpensive bulk-forming fiber supplement; the optimal daily dosage is not known.
We recommend at least 28 g of daily fiber intake for women and 38 g for men, for which psyllium husk can be used to complement the diet.
Laxatives for some
Laxatives such as docusate are used to change the stool consistency when there is an organic bowel problem rather than a dietary issue. They can be used as a complementary treatment to enhance the effect of the fiber treatment.
Other measures
Topical anesthesia (eg, 5% lidocaine) is commonly used to treat pain from low-grade lesions, but no reliable data have been published. As most cases of hemorrhoids tend to progress over time, one should not expect long-term improvement with topical anesthesia. Nevertheless, it can be used as an ancillary treatment in select cases when short-term improvement is the main goal, and we recommend it based on our own experience.
Hygiene. Bidet use or cleaning the perianal area with water is recommended.
Phlebotonics contain a variety of ingredients including natural plant extracts such as flavonoids and synthetic products. Even though the exact mechanism of action is not known, phlebotonics are thought to increase venous and lymphatic drainage, normalize capillary permeability, and decrease inflammation in the hemorrhoidal cushions.4,11–13
In a Cochrane review of 24 randomized controlled trials, Perera et al14 found that phlebotonics improved the outcomes of:
Bleeding (odds ratio [OR] 0.21, number needed to treat [NNT] 4.8, P = .0002)
Pruritus (OR 0.23, NNT 9.1, P = .02)
Discharge or leakage (OR 0.12, NNT 5, P = .0008)
Overall symptoms (OR 15.99, NNT 2.7, P < .00001). Overall symptoms were also improved in the subgroup of pregnant patients.
Although phlebotonics give better results than placebo in the short-term management of hemorrhoids, there is a paucity of long-term data. Thus, the ASCRS clinical practice guidelines gives the regular use of these agents only a weak recommendation.3
Flavonoids (diosmin, hesperidin, rutoside), in a meta-analysis vs placebo in 1,514 patients, showed a beneficial response in terms of bleeding (relative risk [RR] 0.33), pruritus (relative risk [RR] 0.65), and recurrences (RR 0.53).15
Although Preparation H is commonly used as an over-the-counter medication, there are no good data on it, and it is not considered a phlebotonic.
OFFICE-BASED TREATMENTS
Office-based treatments—rubber band ligation, infrared photocoagulation, and sclerotherapy—are commonly used for grade I, II, and III hemorrhoids that have not responded to conservative management. The primary goal of these treatments is to decrease blood flow into the hemorrhoidal sac.
Even though office-based treatments are highly effective and major complications are uncommon, recurrence rates can be high, requiring patients to undergo additional treatments. Moreover, septic complications can occur, so patients should be closely observed for fever and urinary problems. Pain is a common symptom after office-based treatments, and bleeding may also occur.
The ASCRS guidelines strongly recommend office-based treatments for patients with grade I and II hemorrhoids, and for some with grade III hemorrhoids.3
Rubber band ligation
Figure 2. In rubber band ligation, an internal hemorrhoid is grasped with a forceps (A) and drawn into the cylinder of the ligator (B). A band is deployed around the base of the hemorrhoid (C), cutting off its blood supply and causing it to fall off within a few days.
Ligating the apex of the hemorrhoidal cushion stops the arterial flow and causes the hemorrhoidal tissue to undergo necrosis (Figure 2). The ligation is performed above the dentate line, where the sensory nerve fibers differ from those found below the line; therefore, the operation causes less pain than one would expect. One or more hemorrhoidal cushions can be ligated at the same time, although increased pain, bleeding, and vasomotor reactions have been reported with multiple banding during a single procedure.16,17
Iyer et al18 reported that patients on warfarin therapy had up to a 9 times higher risk of postprocedural bleeding, and patients on aspirin had a risk up to 3 times higher. Therefore, whether patients on anticoagulant therapy should undergo this procedure is unclear.
A Cochrane database review19 found this technique effective for hemorrhoid grades I through III, although some patients with grade III hemorrhoids may benefit more from excisional hemorrhoidectomy, which is associated with a lower recurrence rate than rubber band ligation.
Brown et al20 performed a randomized controlled trial comparing hemorrhoidal artery ligation and rubber band ligation for symptomatic hemorrhoids in 372 patients with grade II and III hemorrhoids. Postprocedural pain scores on days 1 and 7 were significantly lower with rubber band ligation, but recurrences were more common (49% vs 30%, P = .0005, respectively).
Overall, rubber band ligation is an excellent option for grade II hemorrhoids, as it is easy to perform, is associated with low pain scores, and can be used to treat recurrences.
Infrared photocoagulation
In this procedure, an infrared probe produces heat to induce coagulation, fibrosis, and ultimately necrosis of the protruding tissue in the hemorrhoidal cushions.21 Even though its use was initially directed at grade I and II hemorrhoids, recent reports showed acceptable results for grades III and IV.22,23 A randomized controlled trial comparing infrared photocoagulation and rubber band ligation in 94 patients found that both procedures were well accepted and highly effective; however, patients had better pain scores with photocoagulation in the first 24 hours after the procedure (P < .05).24
Sclerotherapy
Figure 3. Sclerotherapy involves injecting an irritating solution into the hemorrhoid, reducing its blood supply and causing it to shrink.
Sclerotherapy involves injection of a sclerotic agent into the submucosa of the hemorrhoidal sac (Figure 3), which causes an inflammatory reaction and eventually forms fibrotic tissue that stops the blood flow to the hemorrhoid. Many sclerotic agents are available, including 5% phenol in almond or vegetable oil, quinine, ethanolamine, and hypertonic saline.21
The injection can cause prostatic abscess and sepsis, although this is rare.25 Nevertheless, high fever and postprocedural pain should be carefully evaluated.
There have been few randomized trials of sclerotherapy, but success rates so far have been higher for grade I hemorrhoids than for grades II and III.26–28 It is the preferred method for patients who have bleeding abnormalities caused by medications or other diseases (eg, cirrhosis).
SURGERY
Although nonsurgical treatments have substantially improved, surgery is the most effective and strongly recommended treatment for patients with high-grade internal hemorrhoids (grades III and IV), external and mixed hemorrhoids, and recurrent hemorrhoids.
The most popular surgical options are open or closed hemorrhoidectomy, stapled hemorrhoidopexy, and Doppler-guided hemorrhoidal artery ligation. Each has different success rates and different complication profiles, which need to be discussed with the patient.
Overall, surgery is associated with more adverse effects than office-based treatments or medical management. Postoperative pain is the most common complaint, but anal stricture (rare) or incontinence may occur due to excessive tissue excision and damage to the sphincter muscles. These can be avoided by maintaining the normal anoderm between excisions, by not excising all hemorrhoid sacs at once if the patient has extensive lesions, and by performing a careful dissection in the submucosal plane.
Patients with profuse bleeding or an underlying bleeding abnormality are best managed with surgical approaches performed in an operating room.
Excisional surgical hemorrhoidectomy
Excision of the hemorrhoidal sac, the most conventional surgical technique, is generally reserved for prolapsing disease. The recurrence rate after excisional hemorrhoidectomy is significantly lower than with any other approach.29
Excisional hemorrhoidectomy can be performed using either an open approach, in which the edges of the mucosal defect are not reapproximated, or a closed approach, in which they are. In a systematic review, Bhatti et al30 compared open vs closed techniques and found that the closed technique resulted in less postoperative pain, better wound healing, and less bleeding. Rates of recurrence, postoperative complications, and surgical site infection and lengths of stay were comparable with either procedure.
Overall, excisional hemorrhoidectomy is associated with higher pain scores than any other surgical method.29 Recently, the use of electrodiathermy energy devices, also described as electrosurgical vessel-sealing devices, have further improved overall patient satisfaction.31
Multiple painful hemorrhoidal sacs require a careful surgical approach, as extensive resection may cause widespread fibrosis and stricture. As with anal stricture, fecal incontinence can be prevented by careful dissection. However, already existing incontinence is not a contraindication for the surgery.
Doppler-guided hemorrhoidal artery ligation
Doppler-guided hemorrhoidal artery ligation involves using a Doppler probe to find and ligate individual hemorrhoidal arteries. Additionally, mucopexy (transanal rectoanal repair) is performed to relocate the prolapsing tissue. Avital et al32 reported that at 1 year after this procedure, recurrence rates were 5.3% for grade II hemorrhoids and 13% for grade III hemorrhoids. At 5 years, recurrence rates were 12% for grade II and 31% for grade III.
To date, this procedure appears to be suitable for grade I, II, and III hemorrhoids, especially for grade II, but more studies are needed to prove its efficacy and recurrence rates for more advanced lesions. Although this technique has a high morbidity rate (18%), primarily pain or tenesmus, it causes less postoperative pain than other surgical methods.33 Overall, it has the potential to become a favored treatment.
Stapled hemorrhoidopexy
Figure 4. In stapled hemorrhoidopexy, a special tool is inserted (A). Excess tissue is excised (B), and the remaining tissue is drawn up to its normal position and fastened in place, yielding the result pictured in panel C.
In this procedure, the prolapsing part of the internal hemorrhoidal cushion is moved upward by stapling the rectal mucosa just above the hemorrhoid (Figure 4). This is not an option for patients with thrombosed internal hemorrhoids or with external hemorrhoids.
Although pain scores are lower with stapled hemorrhoidopexy than with excisional hemorrhoidectomy, this procedure is not superior in terms of recurrences.34,35 Also, practitioners should be careful about specific complications of stapled hemorrhoidopexy, such as rectovaginal fistula, anal stenosis, or sphincter injuries. These specific complications should be clearly explained to patients, and necessary information should be given to patients upon discharge. The primary care physician should also be careful about fistulas and stenoses in this particular patient population.
NO ‘BEST’ TREATMENT
There is no best treatment for hemorrhoids. Every patient is different, and the physician and patient need to understand each other’s expectations, weigh the risks and benefits, and arrive at a mutual decision. A good patient-doctor relationship is essential.
Figure 5. Algorithm for hemorrhoid management.
A thorough history and physical examination will enable the practitioner to understand the patient’s problem (Figure 5).
Given the variety of available treatments, head-to-head comparisons are difficult. Moreover, the efficacy and applicability of each technique changes with the grade of the lesion or lesions and the skill of the practitioner. Lacking comprehensive studies comparing conservative, office-based, and surgical management, no decisive statements can be made based on current evidence.
Patients with compounding conditions
Pregnant patients often develop hemorrhoids as intra-abdominal pressure increases, particularly during the third trimester.36 Also, acute episodes of pain and bleeding are common in pregnant women with preexisting hemorrhoids.
Conservative treatment is the main approach in pregnant patients because most hemorrhoids regress after childbirth. This includes increased dietary fiber, stool softeners, and sitz baths, which are safe to use for external hemorrhoids. Any office-based or surgical intervention should be postponed until after childbirth, if possible. Kegel exercises and lying on the left side are also recommended to relieve symptoms. In cases of severe bleeding, anal packing appears to be useful.
Immunosuppressed patients and those on anticoagulant therapy are more prone to serious complications such as sepsis and profuse bleeding. Thus, conservative management should be used in these patients as well. Injection sclerotherapy may be beneficial, as it has been shown to decrease bleeding. Of note, patients on immunosuppressive agents should stop taking them and start taking an antibiotic, and patients on anticoagulant or antiplatelet medications should be instructed to stop them 1 week before any intervention.
Crohn disease. Some patients with Crohn disease may have hemorrhoids, though this is rare. Eglinton et al,37 in a series of 715 patients with Crohn disease, reported that 190 (26.6%) had symptomatic perianal disease. Of these, only 3 (1.6%) had hemorrhoids. Treatment is always conservative and directed at the Crohn disease rather than the hemorrhoids.
Patients with portal hypertension (eg, due to cirrhosis) are prone to have anorectal varices that may resemble hemorrhoids. Anorectal varices can be treated with vascular ligation, whereas sclerotherapy is the preferred method for hemorrhoids in this group, in whom coagulopathy is common.
TAKE-HOME MESSAGES
Hemorrhoidal disease is common in the United States, and with our diet and lifestyle, the incidence is likely to increase. (A national survey found that overall dietary quality improved modestly in children and adolescents in the United States from 1999 to 2012 but remained far below optimal.38) Practitioners need to carefully assess hemorrhoidal symptoms and complete any necessary screening tests before establishing a diagnosis. This helps to avoid missing any underlying disease.
Fiber supplements along with dietary and lifestyle changes constitute the baseline of the management regardless of the disease grade. Office-based interventions are beneficial for grade I and II hemorrhoids and for some grade III hemorrhoids. Repeated interventions can increase the success rate. In patients with high-grade, symptomatic hemorrhoids, surgical hemorrhoidectomy is the most effective modality with the lowest recurrence rates, although it causes more pain than conservative methods.
References
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Johannsson HO, Graf W, Påhlman L. Bowel habits in hemorrhoid patients and normal subjects. Am J Gastroenterol 2005; 100(2):401–406. doi:10.1111/j.1572-0241.2005.40195.x
Garg P, Singh P. Adequate dietary fiber supplement and TONE can help avoid surgery in most patients with advanced hemorrhoids. Minerva Gastroenterol Dietol 2017; 63(2):92–96. doi:10.23736/S1121-421X.17.02364-9
Garg P. Conservative treatment of hemorrhoids deserves more attention in guidelines and clinical practice [letter]. Dis Colon Rectum 2018; 61(7):e348. doi:10.1097/DCR.0000000000001127
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Alonso-Coello P, Guyatt G, Heels-Ansdell D, et al. Laxatives for the treatment of hemorrhoids. Cochrane Database Syst Rev 2005; (4):CD004649. doi:10.1002/14651858.CD004649.pub2
Struckmann JR. Clinical efficacy of micronized purified flavonoid fraction: an overview. J Vasc Res 1999; 36(suppl 1):37–41. doi:10.1159/000054072
Meyer OC. Safety and security of Daflon 500 mg in venous insufficiency and in hemorrhoidal disease. Angiology 1994; 45(6 pt 2):579–584. pmid:8203791
Perera N, Liolitsa D, Iype S, et al. Phlebotonics for haemorrhoids. Cochrane Database Syst Rev 2012;(8):CD004322. doi:10.1002/14651858.CD004322.pub3
Alonso-Coello P, Zhou Q, Martinez-Zapata MJ, et al. Meta-analysis of flavonoids for the treatment of haemorrhoids. Br J Surg 2006; 93(8):909–920. doi:10.1002/bjs.5378
Lee HH, Spencer RJ, Beart RW Jr. Multiple hemorrhoidal bandings in a single session. Dis Colon Rectum 1994; 37(1):37–41. pmid:8287745
Law WL, Chu KW. Triple rubber band ligation for hemorrhoids: prospective, randomized trial of use of local anesthetic injection. Dis Colon Rectum 1999; 42(3):363–366. pmid:10223757
Iyer VS, Shrier I, Gordon PH. Long-term outcome of rubber band ligation for symptomatic primary and recurrent internal hemorrhoids. Dis Colon Rectum 2004; 47(8):1364–1370. pmid:15484351
Shanmugam V, Thaha MA, Rabindranath KS, Campbell KL, Steele RJ, Loudon MA. Rubber band ligation versus excisional haemorrhoidectomy for haemorrhoids. Cochrane Database Syst Rev 2005; (3):CD005034. doi:10.1002/14651858.CD005034.pub2
Brown SR, Tiernan JP, Watson AJM, et al; HubBLe Study team. Haemorrhoidal artery ligation versus rubber band ligation for the management of symptomatic second-degree and third-degree haemorrhoids (HubBLe): a multicentre, open-label, randomised controlled trial. Lancet 2016; 388(10042):356–364. doi:10.1016/S0140-6736(16)30584-0
ASGE Technology Committee; Siddiqui UD, Barth BA, Banerjee S, et al. Devices for the endoscopic treatment of hemorrhoids. Gastrointest Endosc 2014; 79(1):8–14. doi:10.1016/j.gie.2013.07.021
Ahmad A, Kant R, Gupta A. Comparative analysis of Doppler guided hemorrhoidal artery ligation (DG-HAL) & infrared coagulation (IRC) in management of hemorrhoids. Indian J Surg 2013; 75(4):274–277. doi:10.1007/s12262-012-0444-5
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Marques CF, Nahas SC, Nahas CS, Sobrado CW Jr, Habr-Gama A, Kiss DR. Early results of the treatment of internal hemorrhoid disease by infrared coagulation and elastic banding: a prospective randomized cross-over trial. Tech Coloproctol 2006; 10(4):312–317. doi:10.1007/s10151-006-0299-5
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Eglinton TW, Barclay ML, Gearry RB, Frizelle FA. The spectrum of perianal Crohn’s disease in a population-based cohort. Dis Colon Rectum 2012; 55(7):773–777. doi:10.1097/DCR.0b013e31825228b0
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Turgut Bora Cengiz, MD Department of General Surgery, Digestive Disease and Surgery Institute, Cleveland Clinic
Emre Gorgun, MD, FACS, FASCRS Department of Colorectal Surgery, Digestive Disease and Surgery Institute, Cleveland Clinic; Clinical Assistant Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH
Address: Emre Gorgun, MD, FACS, FASCRS, Department of Colorectal Surgery, A30, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; gorgune@ccf.org
Turgut Bora Cengiz, MD Department of General Surgery, Digestive Disease and Surgery Institute, Cleveland Clinic
Emre Gorgun, MD, FACS, FASCRS Department of Colorectal Surgery, Digestive Disease and Surgery Institute, Cleveland Clinic; Clinical Assistant Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH
Address: Emre Gorgun, MD, FACS, FASCRS, Department of Colorectal Surgery, A30, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; gorgune@ccf.org
Author and Disclosure Information
Turgut Bora Cengiz, MD Department of General Surgery, Digestive Disease and Surgery Institute, Cleveland Clinic
Emre Gorgun, MD, FACS, FASCRS Department of Colorectal Surgery, Digestive Disease and Surgery Institute, Cleveland Clinic; Clinical Assistant Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH
Address: Emre Gorgun, MD, FACS, FASCRS, Department of Colorectal Surgery, A30, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; gorgune@ccf.org
Aspects of modern life that may promote hemorrhoids include increased consumption of processed foods, a sedentary lifestyle, and using cell phones while defecating, which translates to much more time spent on the toilet.
Hemorrhoids accounted for more than 3.5 million US outpatient visits in 2010, and they were the third leading cause of hospital admissions related to gastrointestinal disease.1
Here, we review the process for diagnosing and grading hemorrhoids, as well as for selecting the appropriate medical or surgical treatment based on the most recent clinical evidence.
DIAGNOSING AND CLASSIFYING HEMORRHOIDS
Hemorrhoids are the distal prolapse of the arteriovenous bundle, muscle fibers, and surrounding connective tissue as an envelope below the dentate line in the anal canal. They usually present with painless rectal bleeding.2
The diagnosis of hemorrhoids relies on the history and physical examination rather than on laboratory testing or imaging studies. Typically, the presenting symptom is painless rectal bleeding associated with bowel movements, usually appearing as bright red blood on the toilet paper or coating the stool. Severe itching and anal discomfort are also common, especially with chronic hemorrhoids.
Detailed patient history
A detailed patient history is important. It should include the extent, severity, and duration of symptoms, frequency of bowel movements, associated symptoms (eg, constipation, fecal incontinence), daily dietary habits, and details of bowel movements (eg, time spent during each bowel movement and concomitant cell phone use).3
Regarding bowel habits, some patients experience lifelong constipation or diarrhea. Therefore, what a patient considers a normal bowel habit may not be normal and should be investigated.4 Also, it is important to exclude external thrombosed hemorrhoids, anal fissure, anal abscess, and Crohn disease.5
Physical examination
A digital rectal examination is the second step. During the examination, look for skin tags, sphincter tone, perianal hygiene, and synchronous anal lesions.3 Of note, the Valsalva maneuver can be performed during the digital rectal examination.
Red flags for colorectal cancer on the digital rectal examination include a mass with or without presence of hemorrhoidal sacs and a bleeding source above the level of internal hemorrhoids.
Figure 1. Patient with Crohn disease. Note the fistula orifices and the skin tag.
Patients with recurrent abscesses, fistulas, or skin tags (especially cauliflower-type skin tags) should be investigated for Crohn disease (Figure 1).
Endoscopy
Since rectal bleeding can be a sign of several diseases, including colorectal cancer, it is important to review any previous endoscopic results. Patients at high risk of colon cancer should undergo rigid proctoscopy, flexible sigmoidoscopy, or colonoscopy.3,4 In our practice, we recommend endoscopic evaluation for patients over age 40 with rectal bleeding, especially if they have a family history of colorectal cancer.
External or internal (grades I–IV)
Hemorrhoids can be categorized as either external or internal.
External hemorrhoids are distinguished by their outer covering with perianal skin and anoderm and their location inferior to the dentate line. They are painful if the hemorrhoidal sac is occluded by a thrombotic clot.
Internal hemorrhoids are above the dentate line and covered with rectal columnar and transitional mucosa. They are further graded on a 4-point scale3:
Grade I—Visible hemorrhoids that do not prolapse
Grade II—Hemorrhoids that prolapse during the Valsalva maneuver but spontaneously reduce
Grade III—Hemorrhoids that prolapse during the Valsalva maneuver and need manual reduction
Grade IV—Nonreducible hemorrhoids.
A RANGE OF TREATMENTS
In choosing the treatment for hemorrhoids, one should consider the disease grade and severity, its impact on the quality of life, the degree of pain it causes, the patient’s likelihood of adhering to treatment, and the patient’s personal preference.
Regardless of severity, treatment almost always starts with a high-fiber diet and other lifestyle modifications that include bowel movement behaviors. This requires practitioners to spend significant time on patient education regardless of the type or the severity of the disease.
Treatments can be grouped in 3 categories: conservative, office-based, and surgical. Practitioners should thoroughly discuss the options with the patient, emphasizing the pros and cons of each.
CONSERVATIVE MEASURES
Conservative measures are aimed at softening the stool, relieving pain, and correcting bad toileting habits. In most cases, the primary precipitating factor is lifestyle, and unless patients change it, they are more likely to have recurrent symptoms in the long term.
No phone in the bathroom
People take their phones into the bathroom, and this habit is blamed for increasing the time on the toilet and leading to increased pressure on the anal region and straining during defecation. Some research points to a direct correlation between the time spent on the toilet and hemorrhoidal disease, although the exact cause-and-effect relationship with cell phone use has not been determined. In general, spending excessive time on the commode, including reading, should be discouraged.
Less time in the bathroom
Johannsson et al6 reported that patients with hemorrhoids spent more time on the toilet and had to strain harder and more often than controls in the community and hospital.
Garg and Singh7 and Garg8 use the mnemonic “TONE” for appropriate defecation habits:
Three minutes during defecation
Once-daily defecation
No straining and no cell phone use during defecation
Enough fiber.
More fiber
Fiber draws water into the lumen of the colon, increasing the water content of the stool. Recommended daily fiber intake is about 28 g for women and 38 g for men.9 This high level of intake is hard to achieve without supplements for someone who consumes a classic American diet with a lot of fast food.
Fiber supplements are strongly recommended in the American Society of Colon and Rectal Surgeons (ASCRS) practice guidelines3 based on a Cochrane review.10 In this meta-analysis, with fiber supplements, the relative risk of persisting or nonimproving symptoms was 0.53 (95% confidence interval [CI] 0.38–0.73) and the relative risk of bleeding was 0.50 (95% CI 028–0.89). Psyllium husk is an inexpensive bulk-forming fiber supplement; the optimal daily dosage is not known.
We recommend at least 28 g of daily fiber intake for women and 38 g for men, for which psyllium husk can be used to complement the diet.
Laxatives for some
Laxatives such as docusate are used to change the stool consistency when there is an organic bowel problem rather than a dietary issue. They can be used as a complementary treatment to enhance the effect of the fiber treatment.
Other measures
Topical anesthesia (eg, 5% lidocaine) is commonly used to treat pain from low-grade lesions, but no reliable data have been published. As most cases of hemorrhoids tend to progress over time, one should not expect long-term improvement with topical anesthesia. Nevertheless, it can be used as an ancillary treatment in select cases when short-term improvement is the main goal, and we recommend it based on our own experience.
Hygiene. Bidet use or cleaning the perianal area with water is recommended.
Phlebotonics contain a variety of ingredients including natural plant extracts such as flavonoids and synthetic products. Even though the exact mechanism of action is not known, phlebotonics are thought to increase venous and lymphatic drainage, normalize capillary permeability, and decrease inflammation in the hemorrhoidal cushions.4,11–13
In a Cochrane review of 24 randomized controlled trials, Perera et al14 found that phlebotonics improved the outcomes of:
Bleeding (odds ratio [OR] 0.21, number needed to treat [NNT] 4.8, P = .0002)
Pruritus (OR 0.23, NNT 9.1, P = .02)
Discharge or leakage (OR 0.12, NNT 5, P = .0008)
Overall symptoms (OR 15.99, NNT 2.7, P < .00001). Overall symptoms were also improved in the subgroup of pregnant patients.
Although phlebotonics give better results than placebo in the short-term management of hemorrhoids, there is a paucity of long-term data. Thus, the ASCRS clinical practice guidelines gives the regular use of these agents only a weak recommendation.3
Flavonoids (diosmin, hesperidin, rutoside), in a meta-analysis vs placebo in 1,514 patients, showed a beneficial response in terms of bleeding (relative risk [RR] 0.33), pruritus (relative risk [RR] 0.65), and recurrences (RR 0.53).15
Although Preparation H is commonly used as an over-the-counter medication, there are no good data on it, and it is not considered a phlebotonic.
OFFICE-BASED TREATMENTS
Office-based treatments—rubber band ligation, infrared photocoagulation, and sclerotherapy—are commonly used for grade I, II, and III hemorrhoids that have not responded to conservative management. The primary goal of these treatments is to decrease blood flow into the hemorrhoidal sac.
Even though office-based treatments are highly effective and major complications are uncommon, recurrence rates can be high, requiring patients to undergo additional treatments. Moreover, septic complications can occur, so patients should be closely observed for fever and urinary problems. Pain is a common symptom after office-based treatments, and bleeding may also occur.
The ASCRS guidelines strongly recommend office-based treatments for patients with grade I and II hemorrhoids, and for some with grade III hemorrhoids.3
Rubber band ligation
Figure 2. In rubber band ligation, an internal hemorrhoid is grasped with a forceps (A) and drawn into the cylinder of the ligator (B). A band is deployed around the base of the hemorrhoid (C), cutting off its blood supply and causing it to fall off within a few days.
Ligating the apex of the hemorrhoidal cushion stops the arterial flow and causes the hemorrhoidal tissue to undergo necrosis (Figure 2). The ligation is performed above the dentate line, where the sensory nerve fibers differ from those found below the line; therefore, the operation causes less pain than one would expect. One or more hemorrhoidal cushions can be ligated at the same time, although increased pain, bleeding, and vasomotor reactions have been reported with multiple banding during a single procedure.16,17
Iyer et al18 reported that patients on warfarin therapy had up to a 9 times higher risk of postprocedural bleeding, and patients on aspirin had a risk up to 3 times higher. Therefore, whether patients on anticoagulant therapy should undergo this procedure is unclear.
A Cochrane database review19 found this technique effective for hemorrhoid grades I through III, although some patients with grade III hemorrhoids may benefit more from excisional hemorrhoidectomy, which is associated with a lower recurrence rate than rubber band ligation.
Brown et al20 performed a randomized controlled trial comparing hemorrhoidal artery ligation and rubber band ligation for symptomatic hemorrhoids in 372 patients with grade II and III hemorrhoids. Postprocedural pain scores on days 1 and 7 were significantly lower with rubber band ligation, but recurrences were more common (49% vs 30%, P = .0005, respectively).
Overall, rubber band ligation is an excellent option for grade II hemorrhoids, as it is easy to perform, is associated with low pain scores, and can be used to treat recurrences.
Infrared photocoagulation
In this procedure, an infrared probe produces heat to induce coagulation, fibrosis, and ultimately necrosis of the protruding tissue in the hemorrhoidal cushions.21 Even though its use was initially directed at grade I and II hemorrhoids, recent reports showed acceptable results for grades III and IV.22,23 A randomized controlled trial comparing infrared photocoagulation and rubber band ligation in 94 patients found that both procedures were well accepted and highly effective; however, patients had better pain scores with photocoagulation in the first 24 hours after the procedure (P < .05).24
Sclerotherapy
Figure 3. Sclerotherapy involves injecting an irritating solution into the hemorrhoid, reducing its blood supply and causing it to shrink.
Sclerotherapy involves injection of a sclerotic agent into the submucosa of the hemorrhoidal sac (Figure 3), which causes an inflammatory reaction and eventually forms fibrotic tissue that stops the blood flow to the hemorrhoid. Many sclerotic agents are available, including 5% phenol in almond or vegetable oil, quinine, ethanolamine, and hypertonic saline.21
The injection can cause prostatic abscess and sepsis, although this is rare.25 Nevertheless, high fever and postprocedural pain should be carefully evaluated.
There have been few randomized trials of sclerotherapy, but success rates so far have been higher for grade I hemorrhoids than for grades II and III.26–28 It is the preferred method for patients who have bleeding abnormalities caused by medications or other diseases (eg, cirrhosis).
SURGERY
Although nonsurgical treatments have substantially improved, surgery is the most effective and strongly recommended treatment for patients with high-grade internal hemorrhoids (grades III and IV), external and mixed hemorrhoids, and recurrent hemorrhoids.
The most popular surgical options are open or closed hemorrhoidectomy, stapled hemorrhoidopexy, and Doppler-guided hemorrhoidal artery ligation. Each has different success rates and different complication profiles, which need to be discussed with the patient.
Overall, surgery is associated with more adverse effects than office-based treatments or medical management. Postoperative pain is the most common complaint, but anal stricture (rare) or incontinence may occur due to excessive tissue excision and damage to the sphincter muscles. These can be avoided by maintaining the normal anoderm between excisions, by not excising all hemorrhoid sacs at once if the patient has extensive lesions, and by performing a careful dissection in the submucosal plane.
Patients with profuse bleeding or an underlying bleeding abnormality are best managed with surgical approaches performed in an operating room.
Excisional surgical hemorrhoidectomy
Excision of the hemorrhoidal sac, the most conventional surgical technique, is generally reserved for prolapsing disease. The recurrence rate after excisional hemorrhoidectomy is significantly lower than with any other approach.29
Excisional hemorrhoidectomy can be performed using either an open approach, in which the edges of the mucosal defect are not reapproximated, or a closed approach, in which they are. In a systematic review, Bhatti et al30 compared open vs closed techniques and found that the closed technique resulted in less postoperative pain, better wound healing, and less bleeding. Rates of recurrence, postoperative complications, and surgical site infection and lengths of stay were comparable with either procedure.
Overall, excisional hemorrhoidectomy is associated with higher pain scores than any other surgical method.29 Recently, the use of electrodiathermy energy devices, also described as electrosurgical vessel-sealing devices, have further improved overall patient satisfaction.31
Multiple painful hemorrhoidal sacs require a careful surgical approach, as extensive resection may cause widespread fibrosis and stricture. As with anal stricture, fecal incontinence can be prevented by careful dissection. However, already existing incontinence is not a contraindication for the surgery.
Doppler-guided hemorrhoidal artery ligation
Doppler-guided hemorrhoidal artery ligation involves using a Doppler probe to find and ligate individual hemorrhoidal arteries. Additionally, mucopexy (transanal rectoanal repair) is performed to relocate the prolapsing tissue. Avital et al32 reported that at 1 year after this procedure, recurrence rates were 5.3% for grade II hemorrhoids and 13% for grade III hemorrhoids. At 5 years, recurrence rates were 12% for grade II and 31% for grade III.
To date, this procedure appears to be suitable for grade I, II, and III hemorrhoids, especially for grade II, but more studies are needed to prove its efficacy and recurrence rates for more advanced lesions. Although this technique has a high morbidity rate (18%), primarily pain or tenesmus, it causes less postoperative pain than other surgical methods.33 Overall, it has the potential to become a favored treatment.
Stapled hemorrhoidopexy
Figure 4. In stapled hemorrhoidopexy, a special tool is inserted (A). Excess tissue is excised (B), and the remaining tissue is drawn up to its normal position and fastened in place, yielding the result pictured in panel C.
In this procedure, the prolapsing part of the internal hemorrhoidal cushion is moved upward by stapling the rectal mucosa just above the hemorrhoid (Figure 4). This is not an option for patients with thrombosed internal hemorrhoids or with external hemorrhoids.
Although pain scores are lower with stapled hemorrhoidopexy than with excisional hemorrhoidectomy, this procedure is not superior in terms of recurrences.34,35 Also, practitioners should be careful about specific complications of stapled hemorrhoidopexy, such as rectovaginal fistula, anal stenosis, or sphincter injuries. These specific complications should be clearly explained to patients, and necessary information should be given to patients upon discharge. The primary care physician should also be careful about fistulas and stenoses in this particular patient population.
NO ‘BEST’ TREATMENT
There is no best treatment for hemorrhoids. Every patient is different, and the physician and patient need to understand each other’s expectations, weigh the risks and benefits, and arrive at a mutual decision. A good patient-doctor relationship is essential.
Figure 5. Algorithm for hemorrhoid management.
A thorough history and physical examination will enable the practitioner to understand the patient’s problem (Figure 5).
Given the variety of available treatments, head-to-head comparisons are difficult. Moreover, the efficacy and applicability of each technique changes with the grade of the lesion or lesions and the skill of the practitioner. Lacking comprehensive studies comparing conservative, office-based, and surgical management, no decisive statements can be made based on current evidence.
Patients with compounding conditions
Pregnant patients often develop hemorrhoids as intra-abdominal pressure increases, particularly during the third trimester.36 Also, acute episodes of pain and bleeding are common in pregnant women with preexisting hemorrhoids.
Conservative treatment is the main approach in pregnant patients because most hemorrhoids regress after childbirth. This includes increased dietary fiber, stool softeners, and sitz baths, which are safe to use for external hemorrhoids. Any office-based or surgical intervention should be postponed until after childbirth, if possible. Kegel exercises and lying on the left side are also recommended to relieve symptoms. In cases of severe bleeding, anal packing appears to be useful.
Immunosuppressed patients and those on anticoagulant therapy are more prone to serious complications such as sepsis and profuse bleeding. Thus, conservative management should be used in these patients as well. Injection sclerotherapy may be beneficial, as it has been shown to decrease bleeding. Of note, patients on immunosuppressive agents should stop taking them and start taking an antibiotic, and patients on anticoagulant or antiplatelet medications should be instructed to stop them 1 week before any intervention.
Crohn disease. Some patients with Crohn disease may have hemorrhoids, though this is rare. Eglinton et al,37 in a series of 715 patients with Crohn disease, reported that 190 (26.6%) had symptomatic perianal disease. Of these, only 3 (1.6%) had hemorrhoids. Treatment is always conservative and directed at the Crohn disease rather than the hemorrhoids.
Patients with portal hypertension (eg, due to cirrhosis) are prone to have anorectal varices that may resemble hemorrhoids. Anorectal varices can be treated with vascular ligation, whereas sclerotherapy is the preferred method for hemorrhoids in this group, in whom coagulopathy is common.
TAKE-HOME MESSAGES
Hemorrhoidal disease is common in the United States, and with our diet and lifestyle, the incidence is likely to increase. (A national survey found that overall dietary quality improved modestly in children and adolescents in the United States from 1999 to 2012 but remained far below optimal.38) Practitioners need to carefully assess hemorrhoidal symptoms and complete any necessary screening tests before establishing a diagnosis. This helps to avoid missing any underlying disease.
Fiber supplements along with dietary and lifestyle changes constitute the baseline of the management regardless of the disease grade. Office-based interventions are beneficial for grade I and II hemorrhoids and for some grade III hemorrhoids. Repeated interventions can increase the success rate. In patients with high-grade, symptomatic hemorrhoids, surgical hemorrhoidectomy is the most effective modality with the lowest recurrence rates, although it causes more pain than conservative methods.
Aspects of modern life that may promote hemorrhoids include increased consumption of processed foods, a sedentary lifestyle, and using cell phones while defecating, which translates to much more time spent on the toilet.
Hemorrhoids accounted for more than 3.5 million US outpatient visits in 2010, and they were the third leading cause of hospital admissions related to gastrointestinal disease.1
Here, we review the process for diagnosing and grading hemorrhoids, as well as for selecting the appropriate medical or surgical treatment based on the most recent clinical evidence.
DIAGNOSING AND CLASSIFYING HEMORRHOIDS
Hemorrhoids are the distal prolapse of the arteriovenous bundle, muscle fibers, and surrounding connective tissue as an envelope below the dentate line in the anal canal. They usually present with painless rectal bleeding.2
The diagnosis of hemorrhoids relies on the history and physical examination rather than on laboratory testing or imaging studies. Typically, the presenting symptom is painless rectal bleeding associated with bowel movements, usually appearing as bright red blood on the toilet paper or coating the stool. Severe itching and anal discomfort are also common, especially with chronic hemorrhoids.
Detailed patient history
A detailed patient history is important. It should include the extent, severity, and duration of symptoms, frequency of bowel movements, associated symptoms (eg, constipation, fecal incontinence), daily dietary habits, and details of bowel movements (eg, time spent during each bowel movement and concomitant cell phone use).3
Regarding bowel habits, some patients experience lifelong constipation or diarrhea. Therefore, what a patient considers a normal bowel habit may not be normal and should be investigated.4 Also, it is important to exclude external thrombosed hemorrhoids, anal fissure, anal abscess, and Crohn disease.5
Physical examination
A digital rectal examination is the second step. During the examination, look for skin tags, sphincter tone, perianal hygiene, and synchronous anal lesions.3 Of note, the Valsalva maneuver can be performed during the digital rectal examination.
Red flags for colorectal cancer on the digital rectal examination include a mass with or without presence of hemorrhoidal sacs and a bleeding source above the level of internal hemorrhoids.
Figure 1. Patient with Crohn disease. Note the fistula orifices and the skin tag.
Patients with recurrent abscesses, fistulas, or skin tags (especially cauliflower-type skin tags) should be investigated for Crohn disease (Figure 1).
Endoscopy
Since rectal bleeding can be a sign of several diseases, including colorectal cancer, it is important to review any previous endoscopic results. Patients at high risk of colon cancer should undergo rigid proctoscopy, flexible sigmoidoscopy, or colonoscopy.3,4 In our practice, we recommend endoscopic evaluation for patients over age 40 with rectal bleeding, especially if they have a family history of colorectal cancer.
External or internal (grades I–IV)
Hemorrhoids can be categorized as either external or internal.
External hemorrhoids are distinguished by their outer covering with perianal skin and anoderm and their location inferior to the dentate line. They are painful if the hemorrhoidal sac is occluded by a thrombotic clot.
Internal hemorrhoids are above the dentate line and covered with rectal columnar and transitional mucosa. They are further graded on a 4-point scale3:
Grade I—Visible hemorrhoids that do not prolapse
Grade II—Hemorrhoids that prolapse during the Valsalva maneuver but spontaneously reduce
Grade III—Hemorrhoids that prolapse during the Valsalva maneuver and need manual reduction
Grade IV—Nonreducible hemorrhoids.
A RANGE OF TREATMENTS
In choosing the treatment for hemorrhoids, one should consider the disease grade and severity, its impact on the quality of life, the degree of pain it causes, the patient’s likelihood of adhering to treatment, and the patient’s personal preference.
Regardless of severity, treatment almost always starts with a high-fiber diet and other lifestyle modifications that include bowel movement behaviors. This requires practitioners to spend significant time on patient education regardless of the type or the severity of the disease.
Treatments can be grouped in 3 categories: conservative, office-based, and surgical. Practitioners should thoroughly discuss the options with the patient, emphasizing the pros and cons of each.
CONSERVATIVE MEASURES
Conservative measures are aimed at softening the stool, relieving pain, and correcting bad toileting habits. In most cases, the primary precipitating factor is lifestyle, and unless patients change it, they are more likely to have recurrent symptoms in the long term.
No phone in the bathroom
People take their phones into the bathroom, and this habit is blamed for increasing the time on the toilet and leading to increased pressure on the anal region and straining during defecation. Some research points to a direct correlation between the time spent on the toilet and hemorrhoidal disease, although the exact cause-and-effect relationship with cell phone use has not been determined. In general, spending excessive time on the commode, including reading, should be discouraged.
Less time in the bathroom
Johannsson et al6 reported that patients with hemorrhoids spent more time on the toilet and had to strain harder and more often than controls in the community and hospital.
Garg and Singh7 and Garg8 use the mnemonic “TONE” for appropriate defecation habits:
Three minutes during defecation
Once-daily defecation
No straining and no cell phone use during defecation
Enough fiber.
More fiber
Fiber draws water into the lumen of the colon, increasing the water content of the stool. Recommended daily fiber intake is about 28 g for women and 38 g for men.9 This high level of intake is hard to achieve without supplements for someone who consumes a classic American diet with a lot of fast food.
Fiber supplements are strongly recommended in the American Society of Colon and Rectal Surgeons (ASCRS) practice guidelines3 based on a Cochrane review.10 In this meta-analysis, with fiber supplements, the relative risk of persisting or nonimproving symptoms was 0.53 (95% confidence interval [CI] 0.38–0.73) and the relative risk of bleeding was 0.50 (95% CI 028–0.89). Psyllium husk is an inexpensive bulk-forming fiber supplement; the optimal daily dosage is not known.
We recommend at least 28 g of daily fiber intake for women and 38 g for men, for which psyllium husk can be used to complement the diet.
Laxatives for some
Laxatives such as docusate are used to change the stool consistency when there is an organic bowel problem rather than a dietary issue. They can be used as a complementary treatment to enhance the effect of the fiber treatment.
Other measures
Topical anesthesia (eg, 5% lidocaine) is commonly used to treat pain from low-grade lesions, but no reliable data have been published. As most cases of hemorrhoids tend to progress over time, one should not expect long-term improvement with topical anesthesia. Nevertheless, it can be used as an ancillary treatment in select cases when short-term improvement is the main goal, and we recommend it based on our own experience.
Hygiene. Bidet use or cleaning the perianal area with water is recommended.
Phlebotonics contain a variety of ingredients including natural plant extracts such as flavonoids and synthetic products. Even though the exact mechanism of action is not known, phlebotonics are thought to increase venous and lymphatic drainage, normalize capillary permeability, and decrease inflammation in the hemorrhoidal cushions.4,11–13
In a Cochrane review of 24 randomized controlled trials, Perera et al14 found that phlebotonics improved the outcomes of:
Bleeding (odds ratio [OR] 0.21, number needed to treat [NNT] 4.8, P = .0002)
Pruritus (OR 0.23, NNT 9.1, P = .02)
Discharge or leakage (OR 0.12, NNT 5, P = .0008)
Overall symptoms (OR 15.99, NNT 2.7, P < .00001). Overall symptoms were also improved in the subgroup of pregnant patients.
Although phlebotonics give better results than placebo in the short-term management of hemorrhoids, there is a paucity of long-term data. Thus, the ASCRS clinical practice guidelines gives the regular use of these agents only a weak recommendation.3
Flavonoids (diosmin, hesperidin, rutoside), in a meta-analysis vs placebo in 1,514 patients, showed a beneficial response in terms of bleeding (relative risk [RR] 0.33), pruritus (relative risk [RR] 0.65), and recurrences (RR 0.53).15
Although Preparation H is commonly used as an over-the-counter medication, there are no good data on it, and it is not considered a phlebotonic.
OFFICE-BASED TREATMENTS
Office-based treatments—rubber band ligation, infrared photocoagulation, and sclerotherapy—are commonly used for grade I, II, and III hemorrhoids that have not responded to conservative management. The primary goal of these treatments is to decrease blood flow into the hemorrhoidal sac.
Even though office-based treatments are highly effective and major complications are uncommon, recurrence rates can be high, requiring patients to undergo additional treatments. Moreover, septic complications can occur, so patients should be closely observed for fever and urinary problems. Pain is a common symptom after office-based treatments, and bleeding may also occur.
The ASCRS guidelines strongly recommend office-based treatments for patients with grade I and II hemorrhoids, and for some with grade III hemorrhoids.3
Rubber band ligation
Figure 2. In rubber band ligation, an internal hemorrhoid is grasped with a forceps (A) and drawn into the cylinder of the ligator (B). A band is deployed around the base of the hemorrhoid (C), cutting off its blood supply and causing it to fall off within a few days.
Ligating the apex of the hemorrhoidal cushion stops the arterial flow and causes the hemorrhoidal tissue to undergo necrosis (Figure 2). The ligation is performed above the dentate line, where the sensory nerve fibers differ from those found below the line; therefore, the operation causes less pain than one would expect. One or more hemorrhoidal cushions can be ligated at the same time, although increased pain, bleeding, and vasomotor reactions have been reported with multiple banding during a single procedure.16,17
Iyer et al18 reported that patients on warfarin therapy had up to a 9 times higher risk of postprocedural bleeding, and patients on aspirin had a risk up to 3 times higher. Therefore, whether patients on anticoagulant therapy should undergo this procedure is unclear.
A Cochrane database review19 found this technique effective for hemorrhoid grades I through III, although some patients with grade III hemorrhoids may benefit more from excisional hemorrhoidectomy, which is associated with a lower recurrence rate than rubber band ligation.
Brown et al20 performed a randomized controlled trial comparing hemorrhoidal artery ligation and rubber band ligation for symptomatic hemorrhoids in 372 patients with grade II and III hemorrhoids. Postprocedural pain scores on days 1 and 7 were significantly lower with rubber band ligation, but recurrences were more common (49% vs 30%, P = .0005, respectively).
Overall, rubber band ligation is an excellent option for grade II hemorrhoids, as it is easy to perform, is associated with low pain scores, and can be used to treat recurrences.
Infrared photocoagulation
In this procedure, an infrared probe produces heat to induce coagulation, fibrosis, and ultimately necrosis of the protruding tissue in the hemorrhoidal cushions.21 Even though its use was initially directed at grade I and II hemorrhoids, recent reports showed acceptable results for grades III and IV.22,23 A randomized controlled trial comparing infrared photocoagulation and rubber band ligation in 94 patients found that both procedures were well accepted and highly effective; however, patients had better pain scores with photocoagulation in the first 24 hours after the procedure (P < .05).24
Sclerotherapy
Figure 3. Sclerotherapy involves injecting an irritating solution into the hemorrhoid, reducing its blood supply and causing it to shrink.
Sclerotherapy involves injection of a sclerotic agent into the submucosa of the hemorrhoidal sac (Figure 3), which causes an inflammatory reaction and eventually forms fibrotic tissue that stops the blood flow to the hemorrhoid. Many sclerotic agents are available, including 5% phenol in almond or vegetable oil, quinine, ethanolamine, and hypertonic saline.21
The injection can cause prostatic abscess and sepsis, although this is rare.25 Nevertheless, high fever and postprocedural pain should be carefully evaluated.
There have been few randomized trials of sclerotherapy, but success rates so far have been higher for grade I hemorrhoids than for grades II and III.26–28 It is the preferred method for patients who have bleeding abnormalities caused by medications or other diseases (eg, cirrhosis).
SURGERY
Although nonsurgical treatments have substantially improved, surgery is the most effective and strongly recommended treatment for patients with high-grade internal hemorrhoids (grades III and IV), external and mixed hemorrhoids, and recurrent hemorrhoids.
The most popular surgical options are open or closed hemorrhoidectomy, stapled hemorrhoidopexy, and Doppler-guided hemorrhoidal artery ligation. Each has different success rates and different complication profiles, which need to be discussed with the patient.
Overall, surgery is associated with more adverse effects than office-based treatments or medical management. Postoperative pain is the most common complaint, but anal stricture (rare) or incontinence may occur due to excessive tissue excision and damage to the sphincter muscles. These can be avoided by maintaining the normal anoderm between excisions, by not excising all hemorrhoid sacs at once if the patient has extensive lesions, and by performing a careful dissection in the submucosal plane.
Patients with profuse bleeding or an underlying bleeding abnormality are best managed with surgical approaches performed in an operating room.
Excisional surgical hemorrhoidectomy
Excision of the hemorrhoidal sac, the most conventional surgical technique, is generally reserved for prolapsing disease. The recurrence rate after excisional hemorrhoidectomy is significantly lower than with any other approach.29
Excisional hemorrhoidectomy can be performed using either an open approach, in which the edges of the mucosal defect are not reapproximated, or a closed approach, in which they are. In a systematic review, Bhatti et al30 compared open vs closed techniques and found that the closed technique resulted in less postoperative pain, better wound healing, and less bleeding. Rates of recurrence, postoperative complications, and surgical site infection and lengths of stay were comparable with either procedure.
Overall, excisional hemorrhoidectomy is associated with higher pain scores than any other surgical method.29 Recently, the use of electrodiathermy energy devices, also described as electrosurgical vessel-sealing devices, have further improved overall patient satisfaction.31
Multiple painful hemorrhoidal sacs require a careful surgical approach, as extensive resection may cause widespread fibrosis and stricture. As with anal stricture, fecal incontinence can be prevented by careful dissection. However, already existing incontinence is not a contraindication for the surgery.
Doppler-guided hemorrhoidal artery ligation
Doppler-guided hemorrhoidal artery ligation involves using a Doppler probe to find and ligate individual hemorrhoidal arteries. Additionally, mucopexy (transanal rectoanal repair) is performed to relocate the prolapsing tissue. Avital et al32 reported that at 1 year after this procedure, recurrence rates were 5.3% for grade II hemorrhoids and 13% for grade III hemorrhoids. At 5 years, recurrence rates were 12% for grade II and 31% for grade III.
To date, this procedure appears to be suitable for grade I, II, and III hemorrhoids, especially for grade II, but more studies are needed to prove its efficacy and recurrence rates for more advanced lesions. Although this technique has a high morbidity rate (18%), primarily pain or tenesmus, it causes less postoperative pain than other surgical methods.33 Overall, it has the potential to become a favored treatment.
Stapled hemorrhoidopexy
Figure 4. In stapled hemorrhoidopexy, a special tool is inserted (A). Excess tissue is excised (B), and the remaining tissue is drawn up to its normal position and fastened in place, yielding the result pictured in panel C.
In this procedure, the prolapsing part of the internal hemorrhoidal cushion is moved upward by stapling the rectal mucosa just above the hemorrhoid (Figure 4). This is not an option for patients with thrombosed internal hemorrhoids or with external hemorrhoids.
Although pain scores are lower with stapled hemorrhoidopexy than with excisional hemorrhoidectomy, this procedure is not superior in terms of recurrences.34,35 Also, practitioners should be careful about specific complications of stapled hemorrhoidopexy, such as rectovaginal fistula, anal stenosis, or sphincter injuries. These specific complications should be clearly explained to patients, and necessary information should be given to patients upon discharge. The primary care physician should also be careful about fistulas and stenoses in this particular patient population.
NO ‘BEST’ TREATMENT
There is no best treatment for hemorrhoids. Every patient is different, and the physician and patient need to understand each other’s expectations, weigh the risks and benefits, and arrive at a mutual decision. A good patient-doctor relationship is essential.
Figure 5. Algorithm for hemorrhoid management.
A thorough history and physical examination will enable the practitioner to understand the patient’s problem (Figure 5).
Given the variety of available treatments, head-to-head comparisons are difficult. Moreover, the efficacy and applicability of each technique changes with the grade of the lesion or lesions and the skill of the practitioner. Lacking comprehensive studies comparing conservative, office-based, and surgical management, no decisive statements can be made based on current evidence.
Patients with compounding conditions
Pregnant patients often develop hemorrhoids as intra-abdominal pressure increases, particularly during the third trimester.36 Also, acute episodes of pain and bleeding are common in pregnant women with preexisting hemorrhoids.
Conservative treatment is the main approach in pregnant patients because most hemorrhoids regress after childbirth. This includes increased dietary fiber, stool softeners, and sitz baths, which are safe to use for external hemorrhoids. Any office-based or surgical intervention should be postponed until after childbirth, if possible. Kegel exercises and lying on the left side are also recommended to relieve symptoms. In cases of severe bleeding, anal packing appears to be useful.
Immunosuppressed patients and those on anticoagulant therapy are more prone to serious complications such as sepsis and profuse bleeding. Thus, conservative management should be used in these patients as well. Injection sclerotherapy may be beneficial, as it has been shown to decrease bleeding. Of note, patients on immunosuppressive agents should stop taking them and start taking an antibiotic, and patients on anticoagulant or antiplatelet medications should be instructed to stop them 1 week before any intervention.
Crohn disease. Some patients with Crohn disease may have hemorrhoids, though this is rare. Eglinton et al,37 in a series of 715 patients with Crohn disease, reported that 190 (26.6%) had symptomatic perianal disease. Of these, only 3 (1.6%) had hemorrhoids. Treatment is always conservative and directed at the Crohn disease rather than the hemorrhoids.
Patients with portal hypertension (eg, due to cirrhosis) are prone to have anorectal varices that may resemble hemorrhoids. Anorectal varices can be treated with vascular ligation, whereas sclerotherapy is the preferred method for hemorrhoids in this group, in whom coagulopathy is common.
TAKE-HOME MESSAGES
Hemorrhoidal disease is common in the United States, and with our diet and lifestyle, the incidence is likely to increase. (A national survey found that overall dietary quality improved modestly in children and adolescents in the United States from 1999 to 2012 but remained far below optimal.38) Practitioners need to carefully assess hemorrhoidal symptoms and complete any necessary screening tests before establishing a diagnosis. This helps to avoid missing any underlying disease.
Fiber supplements along with dietary and lifestyle changes constitute the baseline of the management regardless of the disease grade. Office-based interventions are beneficial for grade I and II hemorrhoids and for some grade III hemorrhoids. Repeated interventions can increase the success rate. In patients with high-grade, symptomatic hemorrhoids, surgical hemorrhoidectomy is the most effective modality with the lowest recurrence rates, although it causes more pain than conservative methods.
References
Peery AF, Crockett SD, Barritt AS, et al. Burden of gastrointestinal, liver, and pancreatic diseases in the United States. Gastroenterology 2015; 149(7):1731–1741.e3. doi:10.1053/j.gastro.2015.08.045
Thomson WH. The nature and cause of haemorrhoids. Proc R Soc Med 1975; 68(9):574–575. pmid:1197343
Davis BR, Lee-Kong SA, Migaly J, Feingold DL, Steele SR. The American Society of Colon and Rectal Surgeons clinical practice guidelines for the management of hemorrhoids. Dis Colon Rectum 2018; 61(3):284–292. doi:10.1097/DCR.0000000000001030
Lohsiriwat V. Treatment of hemorrhoids: a coloproctologist’s view. World J Gastroenterol 2015; 21(31):9245–9252. doi:10.3748/wjg.v21.i31.9245
Wolf AMD, Fontham ETH, Church TR, et al. Colorectal cancer screening for average-risk adults: 2018 guideline update from the American Cancer Society. CA Cancer J Clin 2018; 68(4):250–281. doi:10.3322/caac.21457
Johannsson HO, Graf W, Påhlman L. Bowel habits in hemorrhoid patients and normal subjects. Am J Gastroenterol 2005; 100(2):401–406. doi:10.1111/j.1572-0241.2005.40195.x
Garg P, Singh P. Adequate dietary fiber supplement and TONE can help avoid surgery in most patients with advanced hemorrhoids. Minerva Gastroenterol Dietol 2017; 63(2):92–96. doi:10.23736/S1121-421X.17.02364-9
Garg P. Conservative treatment of hemorrhoids deserves more attention in guidelines and clinical practice [letter]. Dis Colon Rectum 2018; 61(7):e348. doi:10.1097/DCR.0000000000001127
Rakinic J, Poola VP. Hemorrhoids and fistulas: new solutions to old problems. Curr Probl Surg 2014; 51(3):98–137. doi:10.1067/j.cpsurg.2013.11.002
Alonso-Coello P, Guyatt G, Heels-Ansdell D, et al. Laxatives for the treatment of hemorrhoids. Cochrane Database Syst Rev 2005; (4):CD004649. doi:10.1002/14651858.CD004649.pub2
Struckmann JR. Clinical efficacy of micronized purified flavonoid fraction: an overview. J Vasc Res 1999; 36(suppl 1):37–41. doi:10.1159/000054072
Meyer OC. Safety and security of Daflon 500 mg in venous insufficiency and in hemorrhoidal disease. Angiology 1994; 45(6 pt 2):579–584. pmid:8203791
Perera N, Liolitsa D, Iype S, et al. Phlebotonics for haemorrhoids. Cochrane Database Syst Rev 2012;(8):CD004322. doi:10.1002/14651858.CD004322.pub3
Alonso-Coello P, Zhou Q, Martinez-Zapata MJ, et al. Meta-analysis of flavonoids for the treatment of haemorrhoids. Br J Surg 2006; 93(8):909–920. doi:10.1002/bjs.5378
Lee HH, Spencer RJ, Beart RW Jr. Multiple hemorrhoidal bandings in a single session. Dis Colon Rectum 1994; 37(1):37–41. pmid:8287745
Law WL, Chu KW. Triple rubber band ligation for hemorrhoids: prospective, randomized trial of use of local anesthetic injection. Dis Colon Rectum 1999; 42(3):363–366. pmid:10223757
Iyer VS, Shrier I, Gordon PH. Long-term outcome of rubber band ligation for symptomatic primary and recurrent internal hemorrhoids. Dis Colon Rectum 2004; 47(8):1364–1370. pmid:15484351
Shanmugam V, Thaha MA, Rabindranath KS, Campbell KL, Steele RJ, Loudon MA. Rubber band ligation versus excisional haemorrhoidectomy for haemorrhoids. Cochrane Database Syst Rev 2005; (3):CD005034. doi:10.1002/14651858.CD005034.pub2
Brown SR, Tiernan JP, Watson AJM, et al; HubBLe Study team. Haemorrhoidal artery ligation versus rubber band ligation for the management of symptomatic second-degree and third-degree haemorrhoids (HubBLe): a multicentre, open-label, randomised controlled trial. Lancet 2016; 388(10042):356–364. doi:10.1016/S0140-6736(16)30584-0
ASGE Technology Committee; Siddiqui UD, Barth BA, Banerjee S, et al. Devices for the endoscopic treatment of hemorrhoids. Gastrointest Endosc 2014; 79(1):8–14. doi:10.1016/j.gie.2013.07.021
Ahmad A, Kant R, Gupta A. Comparative analysis of Doppler guided hemorrhoidal artery ligation (DG-HAL) & infrared coagulation (IRC) in management of hemorrhoids. Indian J Surg 2013; 75(4):274–277. doi:10.1007/s12262-012-0444-5
Poen AC, Felt-Bersma RJ, Cuesta MA, Devillé W, Meuwissen SG. A randomized controlled trial of rubber band ligation versus infra-red coagulation in the treatment of internal haemorrhoids. Eur J Gastroenterol Hepatol 2000; 12(5):535–539. pmid:10833097
Marques CF, Nahas SC, Nahas CS, Sobrado CW Jr, Habr-Gama A, Kiss DR. Early results of the treatment of internal hemorrhoid disease by infrared coagulation and elastic banding: a prospective randomized cross-over trial. Tech Coloproctol 2006; 10(4):312–317. doi:10.1007/s10151-006-0299-5
Madoff RD, Fleshman JW; Clinical Practice Committee, American Gastroenterological Association. American Gastroenterological Association technical review on the diagnosis and treatment of hemorrhoids. Gastroenterology 2004; 126(5):1463–1473. pmid:15131807
Yano T, Yano K. Comparison of injection sclerotherapy between 5% phenol in almond oil and aluminum potassium sulfate and tannic acid for grade 3 hemorrhoids. Ann Coloproctol 2015; 31(3):103–105. doi:10.3393/ac.2015.31.3.103
Kanellos I, Goulimaris I, Vakalis I, Dadoukis I. Long-term evaluation of sclerotherapy for haemorrhoids. A prospective study. Int J Surg Investig 2000; 2(4):295–298. pmid:12678531
Moser KH, Mosch C, Walgenbach M, et al. Efficacy and safety of sclerotherapy with polidocanol foam in comparison with fluid sclerosant in the treatment of first-grade haemorrhoidal disease: a randomised, controlled, single-blind, multicentre trial. Int J Colorectal Dis 2013; 28(10):1439–1447. doi:10.1007/s00384-013-1729-2
MacRae HM, McLeod RS. Comparison of hemorrhoidal treatments: a meta-analysis. Can J Surg 1997; 40(1):14–7. pmid:9030078
Bhatti MI, Sajid MS, Baig MK. Milligan-Morgan (open) versus Ferguson haemorrhoidectomy (closed): a systematic review and meta-analysis of published randomized, controlled trials. World J Surg 2016; 40(6):1509–1519. doi:10.1007/s00268-016-3419-z
Nienhuijs S, de Hingh I. Conventional versus LigaSure hemorrhoidectomy for patients with symptomatic hemorrhoids. Cochrane Database Syst Rev 2009; (1):CD006761. doi:10.1002/14651858.CD006761.pub2
Avital S, Inbar R, Karin E, Greenberg R. Five-year follow-up of Doppler-guided hemorrhoidal artery ligation. Tech Coloproctol 2012; 16(1):61–65. doi:10.1007/s10151-011-0801-6
Ratto C, Parello A, Veronese E, et al. Doppler-guided transanal haemorrhoidal dearterialization for haemorrhoids: results from a multicentre trial. Colorectal Dis 2015; 17(1):010–019. doi:10.1111/codi.12779
Senagore AJ, Singer M, Abcarian H, et al; Procedure for Prolapse and Hemmorrhoids (PPH) Multicenter Study Group. A prospective, randomized, controlled multicenter trial comparing stapled hemorrhoidopexy and Ferguson hemorrhoidectomy: perioperative and one-year results. Dis Colon Rectum 2004; 47(11):1824–1836. pmid:15622574
Jayaraman S, Colquhoun PH, Malthaner RA. Stapled versus conventional surgery for hemorrhoids. Cochrane Database Syst Rev 2006; (4):CD005393.
Poskus T, Buzinskiene D, Drasutiene G, et al. Haemorrhoids and anal fissures during pregnancy and after childbirth: a prospective cohort study. BJOG 2014; 121(13):1666–1671. doi:10.1111/1471-0528.12838
Eglinton TW, Barclay ML, Gearry RB, Frizelle FA. The spectrum of perianal Crohn’s disease in a population-based cohort. Dis Colon Rectum 2012; 55(7):773–777. doi:10.1097/DCR.0b013e31825228b0
Gu X, Tucker KL. Dietary quality of the US child and adolescent population: trends from 1999 to 2012 and associations with the use of federal nutrition assistance programs. Am J Clin Nutr 2017; 105(1):194–202. doi:10.3945/ajcn.116.135095
References
Peery AF, Crockett SD, Barritt AS, et al. Burden of gastrointestinal, liver, and pancreatic diseases in the United States. Gastroenterology 2015; 149(7):1731–1741.e3. doi:10.1053/j.gastro.2015.08.045
Thomson WH. The nature and cause of haemorrhoids. Proc R Soc Med 1975; 68(9):574–575. pmid:1197343
Davis BR, Lee-Kong SA, Migaly J, Feingold DL, Steele SR. The American Society of Colon and Rectal Surgeons clinical practice guidelines for the management of hemorrhoids. Dis Colon Rectum 2018; 61(3):284–292. doi:10.1097/DCR.0000000000001030
Lohsiriwat V. Treatment of hemorrhoids: a coloproctologist’s view. World J Gastroenterol 2015; 21(31):9245–9252. doi:10.3748/wjg.v21.i31.9245
Wolf AMD, Fontham ETH, Church TR, et al. Colorectal cancer screening for average-risk adults: 2018 guideline update from the American Cancer Society. CA Cancer J Clin 2018; 68(4):250–281. doi:10.3322/caac.21457
Johannsson HO, Graf W, Påhlman L. Bowel habits in hemorrhoid patients and normal subjects. Am J Gastroenterol 2005; 100(2):401–406. doi:10.1111/j.1572-0241.2005.40195.x
Garg P, Singh P. Adequate dietary fiber supplement and TONE can help avoid surgery in most patients with advanced hemorrhoids. Minerva Gastroenterol Dietol 2017; 63(2):92–96. doi:10.23736/S1121-421X.17.02364-9
Garg P. Conservative treatment of hemorrhoids deserves more attention in guidelines and clinical practice [letter]. Dis Colon Rectum 2018; 61(7):e348. doi:10.1097/DCR.0000000000001127
Rakinic J, Poola VP. Hemorrhoids and fistulas: new solutions to old problems. Curr Probl Surg 2014; 51(3):98–137. doi:10.1067/j.cpsurg.2013.11.002
Alonso-Coello P, Guyatt G, Heels-Ansdell D, et al. Laxatives for the treatment of hemorrhoids. Cochrane Database Syst Rev 2005; (4):CD004649. doi:10.1002/14651858.CD004649.pub2
Struckmann JR. Clinical efficacy of micronized purified flavonoid fraction: an overview. J Vasc Res 1999; 36(suppl 1):37–41. doi:10.1159/000054072
Meyer OC. Safety and security of Daflon 500 mg in venous insufficiency and in hemorrhoidal disease. Angiology 1994; 45(6 pt 2):579–584. pmid:8203791
Perera N, Liolitsa D, Iype S, et al. Phlebotonics for haemorrhoids. Cochrane Database Syst Rev 2012;(8):CD004322. doi:10.1002/14651858.CD004322.pub3
Alonso-Coello P, Zhou Q, Martinez-Zapata MJ, et al. Meta-analysis of flavonoids for the treatment of haemorrhoids. Br J Surg 2006; 93(8):909–920. doi:10.1002/bjs.5378
Lee HH, Spencer RJ, Beart RW Jr. Multiple hemorrhoidal bandings in a single session. Dis Colon Rectum 1994; 37(1):37–41. pmid:8287745
Law WL, Chu KW. Triple rubber band ligation for hemorrhoids: prospective, randomized trial of use of local anesthetic injection. Dis Colon Rectum 1999; 42(3):363–366. pmid:10223757
Iyer VS, Shrier I, Gordon PH. Long-term outcome of rubber band ligation for symptomatic primary and recurrent internal hemorrhoids. Dis Colon Rectum 2004; 47(8):1364–1370. pmid:15484351
Shanmugam V, Thaha MA, Rabindranath KS, Campbell KL, Steele RJ, Loudon MA. Rubber band ligation versus excisional haemorrhoidectomy for haemorrhoids. Cochrane Database Syst Rev 2005; (3):CD005034. doi:10.1002/14651858.CD005034.pub2
Brown SR, Tiernan JP, Watson AJM, et al; HubBLe Study team. Haemorrhoidal artery ligation versus rubber band ligation for the management of symptomatic second-degree and third-degree haemorrhoids (HubBLe): a multicentre, open-label, randomised controlled trial. Lancet 2016; 388(10042):356–364. doi:10.1016/S0140-6736(16)30584-0
ASGE Technology Committee; Siddiqui UD, Barth BA, Banerjee S, et al. Devices for the endoscopic treatment of hemorrhoids. Gastrointest Endosc 2014; 79(1):8–14. doi:10.1016/j.gie.2013.07.021
Ahmad A, Kant R, Gupta A. Comparative analysis of Doppler guided hemorrhoidal artery ligation (DG-HAL) & infrared coagulation (IRC) in management of hemorrhoids. Indian J Surg 2013; 75(4):274–277. doi:10.1007/s12262-012-0444-5
Poen AC, Felt-Bersma RJ, Cuesta MA, Devillé W, Meuwissen SG. A randomized controlled trial of rubber band ligation versus infra-red coagulation in the treatment of internal haemorrhoids. Eur J Gastroenterol Hepatol 2000; 12(5):535–539. pmid:10833097
Marques CF, Nahas SC, Nahas CS, Sobrado CW Jr, Habr-Gama A, Kiss DR. Early results of the treatment of internal hemorrhoid disease by infrared coagulation and elastic banding: a prospective randomized cross-over trial. Tech Coloproctol 2006; 10(4):312–317. doi:10.1007/s10151-006-0299-5
Madoff RD, Fleshman JW; Clinical Practice Committee, American Gastroenterological Association. American Gastroenterological Association technical review on the diagnosis and treatment of hemorrhoids. Gastroenterology 2004; 126(5):1463–1473. pmid:15131807
Yano T, Yano K. Comparison of injection sclerotherapy between 5% phenol in almond oil and aluminum potassium sulfate and tannic acid for grade 3 hemorrhoids. Ann Coloproctol 2015; 31(3):103–105. doi:10.3393/ac.2015.31.3.103
Kanellos I, Goulimaris I, Vakalis I, Dadoukis I. Long-term evaluation of sclerotherapy for haemorrhoids. A prospective study. Int J Surg Investig 2000; 2(4):295–298. pmid:12678531
Moser KH, Mosch C, Walgenbach M, et al. Efficacy and safety of sclerotherapy with polidocanol foam in comparison with fluid sclerosant in the treatment of first-grade haemorrhoidal disease: a randomised, controlled, single-blind, multicentre trial. Int J Colorectal Dis 2013; 28(10):1439–1447. doi:10.1007/s00384-013-1729-2
MacRae HM, McLeod RS. Comparison of hemorrhoidal treatments: a meta-analysis. Can J Surg 1997; 40(1):14–7. pmid:9030078
Bhatti MI, Sajid MS, Baig MK. Milligan-Morgan (open) versus Ferguson haemorrhoidectomy (closed): a systematic review and meta-analysis of published randomized, controlled trials. World J Surg 2016; 40(6):1509–1519. doi:10.1007/s00268-016-3419-z
Nienhuijs S, de Hingh I. Conventional versus LigaSure hemorrhoidectomy for patients with symptomatic hemorrhoids. Cochrane Database Syst Rev 2009; (1):CD006761. doi:10.1002/14651858.CD006761.pub2
Avital S, Inbar R, Karin E, Greenberg R. Five-year follow-up of Doppler-guided hemorrhoidal artery ligation. Tech Coloproctol 2012; 16(1):61–65. doi:10.1007/s10151-011-0801-6
Ratto C, Parello A, Veronese E, et al. Doppler-guided transanal haemorrhoidal dearterialization for haemorrhoids: results from a multicentre trial. Colorectal Dis 2015; 17(1):010–019. doi:10.1111/codi.12779
Senagore AJ, Singer M, Abcarian H, et al; Procedure for Prolapse and Hemmorrhoids (PPH) Multicenter Study Group. A prospective, randomized, controlled multicenter trial comparing stapled hemorrhoidopexy and Ferguson hemorrhoidectomy: perioperative and one-year results. Dis Colon Rectum 2004; 47(11):1824–1836. pmid:15622574
Jayaraman S, Colquhoun PH, Malthaner RA. Stapled versus conventional surgery for hemorrhoids. Cochrane Database Syst Rev 2006; (4):CD005393.
Poskus T, Buzinskiene D, Drasutiene G, et al. Haemorrhoids and anal fissures during pregnancy and after childbirth: a prospective cohort study. BJOG 2014; 121(13):1666–1671. doi:10.1111/1471-0528.12838
Eglinton TW, Barclay ML, Gearry RB, Frizelle FA. The spectrum of perianal Crohn’s disease in a population-based cohort. Dis Colon Rectum 2012; 55(7):773–777. doi:10.1097/DCR.0b013e31825228b0
Gu X, Tucker KL. Dietary quality of the US child and adolescent population: trends from 1999 to 2012 and associations with the use of federal nutrition assistance programs. Am J Clin Nutr 2017; 105(1):194–202. doi:10.3945/ajcn.116.135095
Hemorrhoids account for more than 3.5 million office visits annually.
Most patients present with painless rectal bleeding, but this can also be a sign of colorectal cancer, which needs to be ruled out.
Fiber supplements along with dietary and lifestyle changes are recommended for all patients with hemorrhoids regardless of symptom severity.
Hemorrhoids are graded on a scale of I (least severe) through IV (most severe). Office-based treatments are effective for grades I, II, and some grade III hemorrhoids. Surgical excision is the standard for high-grade hemorrhoids.
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The pharmacologic management of patients who have a chronic disease such as heart failure or diabetes is not straightforward. As the understanding of the pathophysiology of these disorders has become more comprehensive, new therapies have been developed that target specific disease pathways. And as the drugs are developed and tested in preclinical models and then in large-scale clinical trials, we learn more about the pathophysiology and the complex relationship between the disease, the patient, and associated comorbidities. The management of heart failure is no longer only about managing the patient’s volume status and attempting to improve myocardial contractility. And as Makin and Lansang discuss in this issue of the Journal, management of the patient with diabetes is no longer just about lowering their glucose.
There has been increasing emphasis from drug regulatory agencies on collecting robust data on multiple outcomes from clinical trials in addition to the efficacy outcomes and usual safety data. For about a decade, the US Food and Drug Administration has required the collection of cardiovascular outcome data during the testing of new antidiabetic therapies. There are several potential consequences of this mandate, in addition to our now having a better understanding of cardiovascular risk. Studies are likely to be larger, longer, and more expensive. Patient cohorts are selected with this in mind, meaning that studies may be harder to compare, and labeled indications may be more specific. And we now have several drugs carrying a specific indication to reduce cardiovascular death in patients with diabetes!
But as we dig deeper into the reduction in cardiovascular deaths seen in clinical trials with some of the sodium-glucose cotransporter 2 (SGLT2) inhibitors, several questions arise. Why is their effect on mortality and cardiovascular events (and preservation of renal function) not a consistent drug class effect? All of these inhibitors decrease glucose reabsorption and thus cause glucosuria, resulting in lower blood glucose levels with modest caloric wasting and weight loss, as well as natriuresis with mild volume depletion. But the individual drugs behaved slightly differently in clinical trials. Perhaps this was due to slightly different trial populations, or chance (despite large trial numbers), or maybe molecular differences in the drugs despite their shared effect on glucosuria, resulting in distinct “off-target” effects. Perhaps the drugs differentially affect other transporters, on cells other than renal tubular cells, altering their function. An additional known effect of the drug class is uricosuria and mild relative hypouricemia. The differential effects of these drugs on urate transport into and out of different cells that may influence components of the metabolic syndrome and cardiovascular and renal outcomes has yet to be fully explored.
But one thing that seems to be true is that the effect of empagliflozin and canagliflozin on cardiac mortality is not due to simply lowering the blood glucose. Trials like the UK Prospective Diabetes Study1 demonstrated that better glucose control reduced microvascular complications, but they did not initially show a reduction in myocardial infarction. It took long-term follow-up studies to indicate that more intensive initial glucose control could reduce cardiovascular events. But a beneficial effect of empagliflozin (compared with placebo) on cardiovascular mortality (but interestingly not on stroke or nonfatal myocardial infarction) was seen within 3 months.2 This observation suggests unique properties of this drug and some others in the class, in addition to their glucose-lowering effect. Puzzling to me, looking at several of the SGLT2 inhibitor drug studies, is why they seemed to behave differently in terms of different cardiovascular outcomes (eg, heart failure, stroke, nonfatal myocardial infarction, need for limb amputation). While some of these seemingly paradoxical outcomes have also been seen in studies of other drugs, these differences are hard for me to understand on a biological basis: they do not seem consistent with simply differential drug effects on either acute thrombosis or chronic hypoperfusion. We have much more to learn.
For the moment, I suppose we should let our practice be guided by the results of specific clinical trials, hoping that at some point head-to-head comparator drug trials will be undertaken to provide us with even better guidance in drug selection.
We can also hope that our patients with diabetes will somehow be able to afford our increasingly complex and evidence-supported pharmacotherapy, as now not only can we lower the levels of blood glucose and biomarkers of comorbidity, we can also reduce adverse cardiovascular outcomes.
References
Holman RR, Paul SK, Bethel MA, Matthews DR, Neil AW. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008; 359(15):1577–1589. doi:10.1056/NEJMoa0806470
Zinman B, Wanner C, Lachin JM, et al; EMPA-REG OuTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015; 373(22):2117–2128. doi:10.1056/NEJMoa1504720
The pharmacologic management of patients who have a chronic disease such as heart failure or diabetes is not straightforward. As the understanding of the pathophysiology of these disorders has become more comprehensive, new therapies have been developed that target specific disease pathways. And as the drugs are developed and tested in preclinical models and then in large-scale clinical trials, we learn more about the pathophysiology and the complex relationship between the disease, the patient, and associated comorbidities. The management of heart failure is no longer only about managing the patient’s volume status and attempting to improve myocardial contractility. And as Makin and Lansang discuss in this issue of the Journal, management of the patient with diabetes is no longer just about lowering their glucose.
There has been increasing emphasis from drug regulatory agencies on collecting robust data on multiple outcomes from clinical trials in addition to the efficacy outcomes and usual safety data. For about a decade, the US Food and Drug Administration has required the collection of cardiovascular outcome data during the testing of new antidiabetic therapies. There are several potential consequences of this mandate, in addition to our now having a better understanding of cardiovascular risk. Studies are likely to be larger, longer, and more expensive. Patient cohorts are selected with this in mind, meaning that studies may be harder to compare, and labeled indications may be more specific. And we now have several drugs carrying a specific indication to reduce cardiovascular death in patients with diabetes!
But as we dig deeper into the reduction in cardiovascular deaths seen in clinical trials with some of the sodium-glucose cotransporter 2 (SGLT2) inhibitors, several questions arise. Why is their effect on mortality and cardiovascular events (and preservation of renal function) not a consistent drug class effect? All of these inhibitors decrease glucose reabsorption and thus cause glucosuria, resulting in lower blood glucose levels with modest caloric wasting and weight loss, as well as natriuresis with mild volume depletion. But the individual drugs behaved slightly differently in clinical trials. Perhaps this was due to slightly different trial populations, or chance (despite large trial numbers), or maybe molecular differences in the drugs despite their shared effect on glucosuria, resulting in distinct “off-target” effects. Perhaps the drugs differentially affect other transporters, on cells other than renal tubular cells, altering their function. An additional known effect of the drug class is uricosuria and mild relative hypouricemia. The differential effects of these drugs on urate transport into and out of different cells that may influence components of the metabolic syndrome and cardiovascular and renal outcomes has yet to be fully explored.
But one thing that seems to be true is that the effect of empagliflozin and canagliflozin on cardiac mortality is not due to simply lowering the blood glucose. Trials like the UK Prospective Diabetes Study1 demonstrated that better glucose control reduced microvascular complications, but they did not initially show a reduction in myocardial infarction. It took long-term follow-up studies to indicate that more intensive initial glucose control could reduce cardiovascular events. But a beneficial effect of empagliflozin (compared with placebo) on cardiovascular mortality (but interestingly not on stroke or nonfatal myocardial infarction) was seen within 3 months.2 This observation suggests unique properties of this drug and some others in the class, in addition to their glucose-lowering effect. Puzzling to me, looking at several of the SGLT2 inhibitor drug studies, is why they seemed to behave differently in terms of different cardiovascular outcomes (eg, heart failure, stroke, nonfatal myocardial infarction, need for limb amputation). While some of these seemingly paradoxical outcomes have also been seen in studies of other drugs, these differences are hard for me to understand on a biological basis: they do not seem consistent with simply differential drug effects on either acute thrombosis or chronic hypoperfusion. We have much more to learn.
For the moment, I suppose we should let our practice be guided by the results of specific clinical trials, hoping that at some point head-to-head comparator drug trials will be undertaken to provide us with even better guidance in drug selection.
We can also hope that our patients with diabetes will somehow be able to afford our increasingly complex and evidence-supported pharmacotherapy, as now not only can we lower the levels of blood glucose and biomarkers of comorbidity, we can also reduce adverse cardiovascular outcomes.
The pharmacologic management of patients who have a chronic disease such as heart failure or diabetes is not straightforward. As the understanding of the pathophysiology of these disorders has become more comprehensive, new therapies have been developed that target specific disease pathways. And as the drugs are developed and tested in preclinical models and then in large-scale clinical trials, we learn more about the pathophysiology and the complex relationship between the disease, the patient, and associated comorbidities. The management of heart failure is no longer only about managing the patient’s volume status and attempting to improve myocardial contractility. And as Makin and Lansang discuss in this issue of the Journal, management of the patient with diabetes is no longer just about lowering their glucose.
There has been increasing emphasis from drug regulatory agencies on collecting robust data on multiple outcomes from clinical trials in addition to the efficacy outcomes and usual safety data. For about a decade, the US Food and Drug Administration has required the collection of cardiovascular outcome data during the testing of new antidiabetic therapies. There are several potential consequences of this mandate, in addition to our now having a better understanding of cardiovascular risk. Studies are likely to be larger, longer, and more expensive. Patient cohorts are selected with this in mind, meaning that studies may be harder to compare, and labeled indications may be more specific. And we now have several drugs carrying a specific indication to reduce cardiovascular death in patients with diabetes!
But as we dig deeper into the reduction in cardiovascular deaths seen in clinical trials with some of the sodium-glucose cotransporter 2 (SGLT2) inhibitors, several questions arise. Why is their effect on mortality and cardiovascular events (and preservation of renal function) not a consistent drug class effect? All of these inhibitors decrease glucose reabsorption and thus cause glucosuria, resulting in lower blood glucose levels with modest caloric wasting and weight loss, as well as natriuresis with mild volume depletion. But the individual drugs behaved slightly differently in clinical trials. Perhaps this was due to slightly different trial populations, or chance (despite large trial numbers), or maybe molecular differences in the drugs despite their shared effect on glucosuria, resulting in distinct “off-target” effects. Perhaps the drugs differentially affect other transporters, on cells other than renal tubular cells, altering their function. An additional known effect of the drug class is uricosuria and mild relative hypouricemia. The differential effects of these drugs on urate transport into and out of different cells that may influence components of the metabolic syndrome and cardiovascular and renal outcomes has yet to be fully explored.
But one thing that seems to be true is that the effect of empagliflozin and canagliflozin on cardiac mortality is not due to simply lowering the blood glucose. Trials like the UK Prospective Diabetes Study1 demonstrated that better glucose control reduced microvascular complications, but they did not initially show a reduction in myocardial infarction. It took long-term follow-up studies to indicate that more intensive initial glucose control could reduce cardiovascular events. But a beneficial effect of empagliflozin (compared with placebo) on cardiovascular mortality (but interestingly not on stroke or nonfatal myocardial infarction) was seen within 3 months.2 This observation suggests unique properties of this drug and some others in the class, in addition to their glucose-lowering effect. Puzzling to me, looking at several of the SGLT2 inhibitor drug studies, is why they seemed to behave differently in terms of different cardiovascular outcomes (eg, heart failure, stroke, nonfatal myocardial infarction, need for limb amputation). While some of these seemingly paradoxical outcomes have also been seen in studies of other drugs, these differences are hard for me to understand on a biological basis: they do not seem consistent with simply differential drug effects on either acute thrombosis or chronic hypoperfusion. We have much more to learn.
For the moment, I suppose we should let our practice be guided by the results of specific clinical trials, hoping that at some point head-to-head comparator drug trials will be undertaken to provide us with even better guidance in drug selection.
We can also hope that our patients with diabetes will somehow be able to afford our increasingly complex and evidence-supported pharmacotherapy, as now not only can we lower the levels of blood glucose and biomarkers of comorbidity, we can also reduce adverse cardiovascular outcomes.
References
Holman RR, Paul SK, Bethel MA, Matthews DR, Neil AW. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008; 359(15):1577–1589. doi:10.1056/NEJMoa0806470
Zinman B, Wanner C, Lachin JM, et al; EMPA-REG OuTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015; 373(22):2117–2128. doi:10.1056/NEJMoa1504720
References
Holman RR, Paul SK, Bethel MA, Matthews DR, Neil AW. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008; 359(15):1577–1589. doi:10.1056/NEJMoa0806470
Zinman B, Wanner C, Lachin JM, et al; EMPA-REG OuTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015; 373(22):2117–2128. doi:10.1056/NEJMoa1504720
Figure 1. The patient had multiple pink to yellowish papules 2 to 5 mm in diameter over the extensor surface of the right upper arm (A) and left thigh (B).
A 21-year-old woman with obesity, type 2 diabetes mellitus, and dyslipidemia presented with eruptive lesions on her extremities that first appeared 2 weeks earlier. Yellowish erythematous papules were noted on the extensor surfaces of both arms and thighs (Figure 1).
Figure 2. Biopsy study showed foamy histiocytes (arrows) mixed with streaks of connective tissue (arrowhead) in the dermis, features typical of eruptive xanthoma (hematoxylin and eosin, × 200).
Skin biopsy study showed foamy histiocytes mixed with streaks of connective tissue in the dermis (Figure 2). Her fasting serum triglyceride level was 10,250 mg/dL (reference range < 150) and her hemoglobin A1c level was 12.4% (reference range 4%–5.6%). On further questioning, the patient said that she had stopped taking her prescribed antidiabetic medications and fenofibrate a year previously.
A workup for secondary causes of hypertriglyceridemia was negative for hypothyroidism and nephrotic syndrome. She was currently taking no medications. She had no family history of dyslipidemia, and she denied alcohol consumption.
Based on the patient’s presentation, history, and the results of laboratory testing and skin biopsy, the diagnosis was eruptive xanthoma.
A RESULT OF ELEVATED TRIGLYCERIDES
Eruptive xanthoma is associated with elevation of chylomicrons and triglycerides.1 Hyperlipidemia that causes eruptive xanthoma may be familial (ie, due to a primary genetic defect) or secondary to another disease, or both.
Types of primary hypertriglyceridemia include elevated chylomicrons (Frederickson classification type I), elevated very-low-density lipoprotein (VLDL) (Frederickson type IV), and elevation of both chylomicrons and VLDL (Frederickson type V).2,3 Hypertriglyceridemia may also be secondary to obesity, diabetes mellitus, hypothyroidism, nephrotic syndrome, liver cirrhosis, excess ethanol ingestion, and medicines such as retinoids and estrogens.2,3
Lesions of eruptive xanthoma are yellowish papules 2 to 5 mm in diameter surrounded by an erythematous border. They are formed by clusters of foamy cells caused by phagocytosis of macrophages as a consequence of increased accumulations of intracellular lipids. The most common sites are the buttocks, extensor surfaces of the arms, and the back.4
Eruptive xanthoma occurs with markedly elevated triglyceride levels (ie, > 1,000 mg/dL),5 with an estimated prevalence of 18 cases per 100,000 people (< 0.02%).6 Diagnosis is usually established through the clinical history, physical examination, and prompt laboratory confirmation of hypertriglyceridemia. Skin biopsy is rarely if ever needed.
RECOGNIZE AND TREAT PROMPTLY TO AVOID FURTHER COMPLICATIONS
Severe hypertriglyceridemia poses an increased risk of acute pancreatitis. Early recognition and medical treatment in our patient prevented serious complications.
Treatment of eruptive xanthoma includes identifying the underlying cause of hypertriglyceridemia and commencing lifestyle modifications that include weight reduction, aerobic exercise, a strict low-fat diet with avoidance of simple carbohydrates and alcohol,7 and drug therapy.
The patient’s treatment plan
Although HMG-CoA reductase inhibitors (statins) have a modest triglyceride-lowering effect and are useful to modify cardiovascular risk, fibric acid derivatives (eg, gemfibrozil, fenofibrate) are the first-line therapy.8 Omega-3 fatty acids, statins, or niacin may be added if necessary.8
Our patient’s uncontrolled glycemia caused marked hypertriglyceridemia, perhaps from a decrease in lipoprotein lipase activity in adipose tissue and muscle. Lifestyle modifications, glucose-lowering agents (metformin, glimepiride), and fenofibrate were prescribed. She was also advised to seek medical attention if she developed upper-abdominal pain, which could be a symptom of pancreatitis.
References
Flynn PD, Burns T, Breathnach S, Cox N, Griffiths C. Xanthomas and abnormalities of lipid metabolism and storage. In: Rook’s Textbook of Dermatology. 8th ed. Oxford: Blackwell Science; 2010.
Breckenridge WC, Alaupovic P, Cox DW, Little JA. Apolipoprotein and lipoprotein concentrations in familial apolipoprotein C-II deficiency. Atherosclerosis 1982; 44(2):223–235. pmid:7138621
Santamarina-Fojo S. The familial chylomicronemia syndrome. Endocrinol Metab Clin North Am 1998; 27(3):551–567. pmid:9785052
Melmed S, Polonsky KS, Larsen PR, Kronenberg H. Williams Textbook of Endocrinology. 13th ed. Philadelphia: Elsevier; 2016.
Zak A, Zeman M, Slaby A, Vecka M. Xanthomas: clinical and pathophysiological relations. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2014; 158(2):181–188. doi:10.5507/bp.2014.016
Leaf DA. Chylomicronemia and the chylomicronemia syndrome: a practical approach to management. Am J Med 2008; 121(1):10–12. doi:10.1016/j.amjmed.2007.10.004
Hegele RA, Ginsberg HN, Chapman MJ, et al; European Atherosclerosis Society Consensus Panel. The polygenic nature of hypertriglyceridaemia: implications for definition, diagnosis, and management. Lancet Diabetes Endocrinol 2014; 2(8):655–666. doi:10.1016/S2213-8587(13)70191-8
Berglund L, Brunzell JD, Goldberg AC, et al; Endocrine Society. Evaluation and treatment of hypertriglyceridemia: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2012; 97(9):2969–2989. doi:10.1210/jc.2011-3213
Yu-Chun Hsueh, MD Division of Endocrinology and Metabolism, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
Chuan-Liang Chou, MD Division of Endocrinology and Metabolism, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
Ting-I. Lee, MD, PhD Division of Endocrinology and Metabolism, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University; Department of General Medicine, School of Medicine, College of Medicine, Taipei Medical University; Division of Endocrinology and Metabolism, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
Address: Ting-I. Lee, MD, PhD, Wan Fang Hospital, Taipei Medical University, 111 Shin Lung Road Section 3, Taipei, Taiwan; agleems29@gmail.com
Yu-Chun Hsueh, MD Division of Endocrinology and Metabolism, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
Chuan-Liang Chou, MD Division of Endocrinology and Metabolism, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
Ting-I. Lee, MD, PhD Division of Endocrinology and Metabolism, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University; Department of General Medicine, School of Medicine, College of Medicine, Taipei Medical University; Division of Endocrinology and Metabolism, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
Address: Ting-I. Lee, MD, PhD, Wan Fang Hospital, Taipei Medical University, 111 Shin Lung Road Section 3, Taipei, Taiwan; agleems29@gmail.com
Author and Disclosure Information
Yu-Chun Hsueh, MD Division of Endocrinology and Metabolism, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
Chuan-Liang Chou, MD Division of Endocrinology and Metabolism, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
Ting-I. Lee, MD, PhD Division of Endocrinology and Metabolism, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University; Department of General Medicine, School of Medicine, College of Medicine, Taipei Medical University; Division of Endocrinology and Metabolism, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
Address: Ting-I. Lee, MD, PhD, Wan Fang Hospital, Taipei Medical University, 111 Shin Lung Road Section 3, Taipei, Taiwan; agleems29@gmail.com
Figure 1. The patient had multiple pink to yellowish papules 2 to 5 mm in diameter over the extensor surface of the right upper arm (A) and left thigh (B).
A 21-year-old woman with obesity, type 2 diabetes mellitus, and dyslipidemia presented with eruptive lesions on her extremities that first appeared 2 weeks earlier. Yellowish erythematous papules were noted on the extensor surfaces of both arms and thighs (Figure 1).
Figure 2. Biopsy study showed foamy histiocytes (arrows) mixed with streaks of connective tissue (arrowhead) in the dermis, features typical of eruptive xanthoma (hematoxylin and eosin, × 200).
Skin biopsy study showed foamy histiocytes mixed with streaks of connective tissue in the dermis (Figure 2). Her fasting serum triglyceride level was 10,250 mg/dL (reference range < 150) and her hemoglobin A1c level was 12.4% (reference range 4%–5.6%). On further questioning, the patient said that she had stopped taking her prescribed antidiabetic medications and fenofibrate a year previously.
A workup for secondary causes of hypertriglyceridemia was negative for hypothyroidism and nephrotic syndrome. She was currently taking no medications. She had no family history of dyslipidemia, and she denied alcohol consumption.
Based on the patient’s presentation, history, and the results of laboratory testing and skin biopsy, the diagnosis was eruptive xanthoma.
A RESULT OF ELEVATED TRIGLYCERIDES
Eruptive xanthoma is associated with elevation of chylomicrons and triglycerides.1 Hyperlipidemia that causes eruptive xanthoma may be familial (ie, due to a primary genetic defect) or secondary to another disease, or both.
Types of primary hypertriglyceridemia include elevated chylomicrons (Frederickson classification type I), elevated very-low-density lipoprotein (VLDL) (Frederickson type IV), and elevation of both chylomicrons and VLDL (Frederickson type V).2,3 Hypertriglyceridemia may also be secondary to obesity, diabetes mellitus, hypothyroidism, nephrotic syndrome, liver cirrhosis, excess ethanol ingestion, and medicines such as retinoids and estrogens.2,3
Lesions of eruptive xanthoma are yellowish papules 2 to 5 mm in diameter surrounded by an erythematous border. They are formed by clusters of foamy cells caused by phagocytosis of macrophages as a consequence of increased accumulations of intracellular lipids. The most common sites are the buttocks, extensor surfaces of the arms, and the back.4
Eruptive xanthoma occurs with markedly elevated triglyceride levels (ie, > 1,000 mg/dL),5 with an estimated prevalence of 18 cases per 100,000 people (< 0.02%).6 Diagnosis is usually established through the clinical history, physical examination, and prompt laboratory confirmation of hypertriglyceridemia. Skin biopsy is rarely if ever needed.
RECOGNIZE AND TREAT PROMPTLY TO AVOID FURTHER COMPLICATIONS
Severe hypertriglyceridemia poses an increased risk of acute pancreatitis. Early recognition and medical treatment in our patient prevented serious complications.
Treatment of eruptive xanthoma includes identifying the underlying cause of hypertriglyceridemia and commencing lifestyle modifications that include weight reduction, aerobic exercise, a strict low-fat diet with avoidance of simple carbohydrates and alcohol,7 and drug therapy.
The patient’s treatment plan
Although HMG-CoA reductase inhibitors (statins) have a modest triglyceride-lowering effect and are useful to modify cardiovascular risk, fibric acid derivatives (eg, gemfibrozil, fenofibrate) are the first-line therapy.8 Omega-3 fatty acids, statins, or niacin may be added if necessary.8
Our patient’s uncontrolled glycemia caused marked hypertriglyceridemia, perhaps from a decrease in lipoprotein lipase activity in adipose tissue and muscle. Lifestyle modifications, glucose-lowering agents (metformin, glimepiride), and fenofibrate were prescribed. She was also advised to seek medical attention if she developed upper-abdominal pain, which could be a symptom of pancreatitis.
Figure 1. The patient had multiple pink to yellowish papules 2 to 5 mm in diameter over the extensor surface of the right upper arm (A) and left thigh (B).
A 21-year-old woman with obesity, type 2 diabetes mellitus, and dyslipidemia presented with eruptive lesions on her extremities that first appeared 2 weeks earlier. Yellowish erythematous papules were noted on the extensor surfaces of both arms and thighs (Figure 1).
Figure 2. Biopsy study showed foamy histiocytes (arrows) mixed with streaks of connective tissue (arrowhead) in the dermis, features typical of eruptive xanthoma (hematoxylin and eosin, × 200).
Skin biopsy study showed foamy histiocytes mixed with streaks of connective tissue in the dermis (Figure 2). Her fasting serum triglyceride level was 10,250 mg/dL (reference range < 150) and her hemoglobin A1c level was 12.4% (reference range 4%–5.6%). On further questioning, the patient said that she had stopped taking her prescribed antidiabetic medications and fenofibrate a year previously.
A workup for secondary causes of hypertriglyceridemia was negative for hypothyroidism and nephrotic syndrome. She was currently taking no medications. She had no family history of dyslipidemia, and she denied alcohol consumption.
Based on the patient’s presentation, history, and the results of laboratory testing and skin biopsy, the diagnosis was eruptive xanthoma.
A RESULT OF ELEVATED TRIGLYCERIDES
Eruptive xanthoma is associated with elevation of chylomicrons and triglycerides.1 Hyperlipidemia that causes eruptive xanthoma may be familial (ie, due to a primary genetic defect) or secondary to another disease, or both.
Types of primary hypertriglyceridemia include elevated chylomicrons (Frederickson classification type I), elevated very-low-density lipoprotein (VLDL) (Frederickson type IV), and elevation of both chylomicrons and VLDL (Frederickson type V).2,3 Hypertriglyceridemia may also be secondary to obesity, diabetes mellitus, hypothyroidism, nephrotic syndrome, liver cirrhosis, excess ethanol ingestion, and medicines such as retinoids and estrogens.2,3
Lesions of eruptive xanthoma are yellowish papules 2 to 5 mm in diameter surrounded by an erythematous border. They are formed by clusters of foamy cells caused by phagocytosis of macrophages as a consequence of increased accumulations of intracellular lipids. The most common sites are the buttocks, extensor surfaces of the arms, and the back.4
Eruptive xanthoma occurs with markedly elevated triglyceride levels (ie, > 1,000 mg/dL),5 with an estimated prevalence of 18 cases per 100,000 people (< 0.02%).6 Diagnosis is usually established through the clinical history, physical examination, and prompt laboratory confirmation of hypertriglyceridemia. Skin biopsy is rarely if ever needed.
RECOGNIZE AND TREAT PROMPTLY TO AVOID FURTHER COMPLICATIONS
Severe hypertriglyceridemia poses an increased risk of acute pancreatitis. Early recognition and medical treatment in our patient prevented serious complications.
Treatment of eruptive xanthoma includes identifying the underlying cause of hypertriglyceridemia and commencing lifestyle modifications that include weight reduction, aerobic exercise, a strict low-fat diet with avoidance of simple carbohydrates and alcohol,7 and drug therapy.
The patient’s treatment plan
Although HMG-CoA reductase inhibitors (statins) have a modest triglyceride-lowering effect and are useful to modify cardiovascular risk, fibric acid derivatives (eg, gemfibrozil, fenofibrate) are the first-line therapy.8 Omega-3 fatty acids, statins, or niacin may be added if necessary.8
Our patient’s uncontrolled glycemia caused marked hypertriglyceridemia, perhaps from a decrease in lipoprotein lipase activity in adipose tissue and muscle. Lifestyle modifications, glucose-lowering agents (metformin, glimepiride), and fenofibrate were prescribed. She was also advised to seek medical attention if she developed upper-abdominal pain, which could be a symptom of pancreatitis.
References
Flynn PD, Burns T, Breathnach S, Cox N, Griffiths C. Xanthomas and abnormalities of lipid metabolism and storage. In: Rook’s Textbook of Dermatology. 8th ed. Oxford: Blackwell Science; 2010.
Breckenridge WC, Alaupovic P, Cox DW, Little JA. Apolipoprotein and lipoprotein concentrations in familial apolipoprotein C-II deficiency. Atherosclerosis 1982; 44(2):223–235. pmid:7138621
Santamarina-Fojo S. The familial chylomicronemia syndrome. Endocrinol Metab Clin North Am 1998; 27(3):551–567. pmid:9785052
Melmed S, Polonsky KS, Larsen PR, Kronenberg H. Williams Textbook of Endocrinology. 13th ed. Philadelphia: Elsevier; 2016.
Zak A, Zeman M, Slaby A, Vecka M. Xanthomas: clinical and pathophysiological relations. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2014; 158(2):181–188. doi:10.5507/bp.2014.016
Leaf DA. Chylomicronemia and the chylomicronemia syndrome: a practical approach to management. Am J Med 2008; 121(1):10–12. doi:10.1016/j.amjmed.2007.10.004
Hegele RA, Ginsberg HN, Chapman MJ, et al; European Atherosclerosis Society Consensus Panel. The polygenic nature of hypertriglyceridaemia: implications for definition, diagnosis, and management. Lancet Diabetes Endocrinol 2014; 2(8):655–666. doi:10.1016/S2213-8587(13)70191-8
Berglund L, Brunzell JD, Goldberg AC, et al; Endocrine Society. Evaluation and treatment of hypertriglyceridemia: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2012; 97(9):2969–2989. doi:10.1210/jc.2011-3213
References
Flynn PD, Burns T, Breathnach S, Cox N, Griffiths C. Xanthomas and abnormalities of lipid metabolism and storage. In: Rook’s Textbook of Dermatology. 8th ed. Oxford: Blackwell Science; 2010.
Breckenridge WC, Alaupovic P, Cox DW, Little JA. Apolipoprotein and lipoprotein concentrations in familial apolipoprotein C-II deficiency. Atherosclerosis 1982; 44(2):223–235. pmid:7138621
Santamarina-Fojo S. The familial chylomicronemia syndrome. Endocrinol Metab Clin North Am 1998; 27(3):551–567. pmid:9785052
Melmed S, Polonsky KS, Larsen PR, Kronenberg H. Williams Textbook of Endocrinology. 13th ed. Philadelphia: Elsevier; 2016.
Zak A, Zeman M, Slaby A, Vecka M. Xanthomas: clinical and pathophysiological relations. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2014; 158(2):181–188. doi:10.5507/bp.2014.016
Leaf DA. Chylomicronemia and the chylomicronemia syndrome: a practical approach to management. Am J Med 2008; 121(1):10–12. doi:10.1016/j.amjmed.2007.10.004
Hegele RA, Ginsberg HN, Chapman MJ, et al; European Atherosclerosis Society Consensus Panel. The polygenic nature of hypertriglyceridaemia: implications for definition, diagnosis, and management. Lancet Diabetes Endocrinol 2014; 2(8):655–666. doi:10.1016/S2213-8587(13)70191-8
Berglund L, Brunzell JD, Goldberg AC, et al; Endocrine Society. Evaluation and treatment of hypertriglyceridemia: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2012; 97(9):2969–2989. doi:10.1210/jc.2011-3213
An 83-year-old woman with hypertension, hypothyroidism, and a history of depression presented to the emergency department with acute shortness of breath and hypoxia. She was found to have submassive pulmonary embolism, and a heparin infusion was started immediately.
Figure 1. (A) After 48 hours of heparin infusion, the patient developed violaceous swelling at the floor of the oral cavity. (B) At 2 months after anticoagulation was stopped, the sublingual hematoma had completely resolved.
After 48 hours, she developed uncontrolled drooling and hoarseness. Physical examination at that time revealed inspiratory stridor and violaceous swelling at the floor of the oral cavity (Figure 1), and laboratory testing revealed a supratherapeutic activated partial thromboplastin time (aPTT) of 240 seconds (therapeutic range 76–112 for a patient on heparin for pulmonary embolism).
Urgent nasopharyngeal laryngoscopy revealed a hematoma at the base of her tongue that extended into the vallecula, piriform sinuses, and aryepiglottic fold, causing acute airway obstruction. These features combined with the supratherapeutic aPTT led to the diagnosis of pseudo-Ludwig angina.
DANGER OF RAPID AIRWAY COMPROMISE
Pseudo-Ludwig angina is a rare condition in which over-anticoagulation causes sublingual swelling leading to airway obstruction, whereas true Ludwig angina is an infectious regional suppuration of the neck.
Most reported cases of pseudo-Ludwig angina have resulted from overanticogulation with warfarin or warfarin-like substances (rodenticides), or from coagulopathy due to liver disease.1–3 Early recognition is essential to avoid airway compromise.
In our patient, all anticoagulation was discontinued, and she was intubated until the hematoma began to resolve, the aPTT returned to normal, and respiratory compromise improved. At follow-up 2 months later, the sublingual hematoma had completely resolved (Figure 1). And at a 6-month follow-up visit, the pulmonary embolism had resolved, and pulmonary pressures by 2-dimensional echocardiography were normal.
References
Lovallo E, Patterson S, Erickson M, Chin C, Blanc P, Durrani TS. When is “pseudo-Ludwig’s angina” associated with coagulopathy also a “pseudo” hemorrhage? J Investig Med High Impact Case Rep 2013; 1(2):2324709613492503. doi:10.1177/2324709613492503
Smith RG, Parker TJ, Anderson TA. Noninfectious acute upper airway obstruction (pseudo-Ludwig phenomenon): report of a case. J Oral Maxillofac Surg 1987; 45(8):701–704. pmid:3475442
Zacharia GS, Kandiyil S, Thomas V. Pseudo-Ludwig's phenomenon: a rare clinical manifestation in liver cirrhosis. ACG Case Rep J 2014; 2(1):53–54. doi:10.14309/crj.2014.83
An 83-year-old woman with hypertension, hypothyroidism, and a history of depression presented to the emergency department with acute shortness of breath and hypoxia. She was found to have submassive pulmonary embolism, and a heparin infusion was started immediately.
Figure 1. (A) After 48 hours of heparin infusion, the patient developed violaceous swelling at the floor of the oral cavity. (B) At 2 months after anticoagulation was stopped, the sublingual hematoma had completely resolved.
After 48 hours, she developed uncontrolled drooling and hoarseness. Physical examination at that time revealed inspiratory stridor and violaceous swelling at the floor of the oral cavity (Figure 1), and laboratory testing revealed a supratherapeutic activated partial thromboplastin time (aPTT) of 240 seconds (therapeutic range 76–112 for a patient on heparin for pulmonary embolism).
Urgent nasopharyngeal laryngoscopy revealed a hematoma at the base of her tongue that extended into the vallecula, piriform sinuses, and aryepiglottic fold, causing acute airway obstruction. These features combined with the supratherapeutic aPTT led to the diagnosis of pseudo-Ludwig angina.
DANGER OF RAPID AIRWAY COMPROMISE
Pseudo-Ludwig angina is a rare condition in which over-anticoagulation causes sublingual swelling leading to airway obstruction, whereas true Ludwig angina is an infectious regional suppuration of the neck.
Most reported cases of pseudo-Ludwig angina have resulted from overanticogulation with warfarin or warfarin-like substances (rodenticides), or from coagulopathy due to liver disease.1–3 Early recognition is essential to avoid airway compromise.
In our patient, all anticoagulation was discontinued, and she was intubated until the hematoma began to resolve, the aPTT returned to normal, and respiratory compromise improved. At follow-up 2 months later, the sublingual hematoma had completely resolved (Figure 1). And at a 6-month follow-up visit, the pulmonary embolism had resolved, and pulmonary pressures by 2-dimensional echocardiography were normal.
An 83-year-old woman with hypertension, hypothyroidism, and a history of depression presented to the emergency department with acute shortness of breath and hypoxia. She was found to have submassive pulmonary embolism, and a heparin infusion was started immediately.
Figure 1. (A) After 48 hours of heparin infusion, the patient developed violaceous swelling at the floor of the oral cavity. (B) At 2 months after anticoagulation was stopped, the sublingual hematoma had completely resolved.
After 48 hours, she developed uncontrolled drooling and hoarseness. Physical examination at that time revealed inspiratory stridor and violaceous swelling at the floor of the oral cavity (Figure 1), and laboratory testing revealed a supratherapeutic activated partial thromboplastin time (aPTT) of 240 seconds (therapeutic range 76–112 for a patient on heparin for pulmonary embolism).
Urgent nasopharyngeal laryngoscopy revealed a hematoma at the base of her tongue that extended into the vallecula, piriform sinuses, and aryepiglottic fold, causing acute airway obstruction. These features combined with the supratherapeutic aPTT led to the diagnosis of pseudo-Ludwig angina.
DANGER OF RAPID AIRWAY COMPROMISE
Pseudo-Ludwig angina is a rare condition in which over-anticoagulation causes sublingual swelling leading to airway obstruction, whereas true Ludwig angina is an infectious regional suppuration of the neck.
Most reported cases of pseudo-Ludwig angina have resulted from overanticogulation with warfarin or warfarin-like substances (rodenticides), or from coagulopathy due to liver disease.1–3 Early recognition is essential to avoid airway compromise.
In our patient, all anticoagulation was discontinued, and she was intubated until the hematoma began to resolve, the aPTT returned to normal, and respiratory compromise improved. At follow-up 2 months later, the sublingual hematoma had completely resolved (Figure 1). And at a 6-month follow-up visit, the pulmonary embolism had resolved, and pulmonary pressures by 2-dimensional echocardiography were normal.
References
Lovallo E, Patterson S, Erickson M, Chin C, Blanc P, Durrani TS. When is “pseudo-Ludwig’s angina” associated with coagulopathy also a “pseudo” hemorrhage? J Investig Med High Impact Case Rep 2013; 1(2):2324709613492503. doi:10.1177/2324709613492503
Smith RG, Parker TJ, Anderson TA. Noninfectious acute upper airway obstruction (pseudo-Ludwig phenomenon): report of a case. J Oral Maxillofac Surg 1987; 45(8):701–704. pmid:3475442
Zacharia GS, Kandiyil S, Thomas V. Pseudo-Ludwig's phenomenon: a rare clinical manifestation in liver cirrhosis. ACG Case Rep J 2014; 2(1):53–54. doi:10.14309/crj.2014.83
References
Lovallo E, Patterson S, Erickson M, Chin C, Blanc P, Durrani TS. When is “pseudo-Ludwig’s angina” associated with coagulopathy also a “pseudo” hemorrhage? J Investig Med High Impact Case Rep 2013; 1(2):2324709613492503. doi:10.1177/2324709613492503
Smith RG, Parker TJ, Anderson TA. Noninfectious acute upper airway obstruction (pseudo-Ludwig phenomenon): report of a case. J Oral Maxillofac Surg 1987; 45(8):701–704. pmid:3475442
Zacharia GS, Kandiyil S, Thomas V. Pseudo-Ludwig's phenomenon: a rare clinical manifestation in liver cirrhosis. ACG Case Rep J 2014; 2(1):53–54. doi:10.14309/crj.2014.83
A 50-year-old man with Crohn disease and psoriatic arthritis treated with infliximab and methotrexate presented to a tertiary care hospital with fever, cough, and chest discomfort. The symptoms had first appeared 2 weeks earlier, and he had gone to an urgent care center, where he was prescribed a 5-day course of azithromycin and a corticosteroid, but this had not relieved his symptoms.
Figure 1. (A) An enlarged lymph node (2.4 cm × 2.0 cm) at the bifurcation of the bronchus intermedius. (B) An enlarged inferior mediastinal lymph node (2.0 cm × 5.4 cm).
He reported no recent travel, exposure to animals, or sick contacts. His temperature was 38.3°C (100.9°F). Results of the physical examination and initial laboratory testing were unremarkable. Chest computed tomography revealed prominent right hilar and mediastinal lymphadenopathy (Figure 1).
Bronchoscopy revealed edematous mucosa throughout, with minimal secretion. Specimens for bacterial, acid-fast bacillus, and fungal cultures were obtained from bronchoalveolar lavage. Endobronchial lymph node biopsy with ultrasonographic guidance revealed nonnecrotizing granuloma.
Bronchoalveolar lavage cultures showed no growth, but the patient’s serum histoplasma antigen was positive at 5.99 ng/dL (reference range: none detected), leading to the diagnosis of mediastinal granuloma due to histoplasmosis with possible dissemination. His immunosuppressant drugs were stopped, and oral itraconazole was started.
At a follow-up visit 2 months later, his serum antigen level had decreased to 0.68 ng/dL, and he had no symptoms whatsoever. At a visit 1 month after that, infliximab and methotrexate were restarted because of an exacerbation of Crohn disease. His oral itraconazole treatment was to be continued for at least 12 months, given the high suspicion for disseminated histoplasmosis while on immunosuppressant therapy.
DIFFERENTIAL DIAGNOSIS OF GRANULOMATOUS LUNG DISEASE AND LYMPHADENOPATHY
The differential diagnosis of granulomatous lung disease and lymphadenopathy is broad and includes noninfectious and infectious conditions.1
Noninfectious causes include lymphoma, sarcoidosis, inflammatory bowel disease, hypersensitivity pneumonia, side effects of drugs (eg, methotrexate, etanercept), rheumatoid nodules, vasculitis (eg, Churg-Strauss syndrome, granulomatosis with polyangiitis, primary amyloidosis, pneumoconiosis (eg, beryllium, cobalt), and Castleman disease.
There is concern that tumor necrosis factor antagonists may increase the risk of lymphoma, but a 2017 study found no evidence of this.2
Infectious conditions associated with granulomatous lung disease include tuberculosis, nontuberculous mycobacterial infection, fungal infection (eg, Cryptococcus, Coccidioides, Histoplasma, Blastomyces), brucellosis, tularemia (respiratory type B), parasitic infection (eg, Toxocara, Leishmania, Echinococcus, Schistosoma), and Whipple disease.
HISTOPLASMOSIS
Histoplasmosis, caused by infection with Histoplasma capsulatum, is the most prevalent endemic mycotic disease in the United States.3 The fungus is commonly found in the Ohio and Mississippi River valleys in the United States, and also in Central and South America and Asia.
Risk factors for histoplasmosis include living in or traveling to an endemic area, exposure to aerosolized soil that contains spores, and exposure to bats or birds and their droppings.4
Fewer than 5% of exposed individuals develop symptoms, which include fever, chills, headache, myalgia, anorexia, cough, and chest pain.5 Patients may experience symptoms shortly after exposure or may remain free of symptoms for years, with intermittent relapses of symptoms.6 Hilar or mediastinal lymphadenopathy is common in acute pulmonary histoplasmosis.7
The risk of disseminated histoplasmosis is greater in patients with reduced cell-mediated immunity, such as in human immunodeficiency virus infection, acquired immunodeficiency syndrome, solid-organ or bone marrow transplant, hematologic malignancies, immunosuppression (corticosteroids, disease-modifying antirheumatic drugs, and tumor necrosis factor antagonists), and congenital T-cell deficiencies.8
In a retrospective study, infliximab was the tumor necrosis factor antagonist most commonly associated with histoplasmosis.9 In a study of patients with rheumatoid arthritis, the disease-modifying drug most commonly associated was methotrexate.10
GOLD STANDARD FOR DIAGNOSIS
Isolation of H capsulatum from clinical specimens remains the gold standard for confirmation of histoplasmosis. The sensitivity of culture to detect H capsulatum depends on the clinical manifestations: it is 74% in patients with disseminated histoplasmosis, but only 42% in patients with acute pulmonary histoplasmosis.11 The serum histoplasma antigen test has a sensitivity of 91.8% in disseminated histoplasmosis, 87.5% in chronic pulmonary histoplasmosis, and 83% in acute pulmonary histoplasmosis.12
Urine testing for histoplasma antigen has generally proven to be slightly more sensitive than serum testing in all manifestations of histoplasmosis.13 Combining urine and serum testing increases the likelihood of antigen detection.
TREATMENT
Asymptomatic patients with mediastinal histoplasmosis do not require treatment. (Note: in some cases, lymphadenopathy is found incidentally, and biopsy is done to rule out malignancy.)
Standard treatment of symptomatic mediastinal histoplasmosis is oral itraconazole 200 mg, 3 times daily for 3 days, followed by 200 mg orally once or twice daily for 6 to 12 weeks.14
Although stopping immunosuppressant drugs is considered the standard of care in treating histoplasmosis in immunocompromised patients, there are no guidelines on when to resume them. However, a retrospective study of 98 cases of histoplasmosis in patients on tumor necrosis factor antagonists found that resuming immunosuppressants might be safe with close monitoring during the course of antifungal therapy.9 The role of long-term suppressive therapy with antifungal agents in patients on chronic immunosuppressive therapy is still unknown and needs further study.
TAKE-HOME MESSAGES
Histoplasmosis is the most prevalent endemic mycotic disease in the United States, and mediastinal lymphadenopathy is commonly seen in acute pulmonary histoplasmosis.
Histoplasmosis should be included in the differential diagnosis of granulomatous lung disease in patients from an endemic area or with a history of travel to an endemic area.
Immunosuppressive agents such as tumor necrosis factor antagonists and disease-modifying antirheumatic drugs can predispose to invasive fungal infection, including histoplasmosis.
While isolation of H capsulatum from culture remains the gold standard for the diagnosis of histoplasmosis, the histoplasma antigen tests (serum and urine) is more sensitive than culture.
References
Ohshimo S, Guzman J, Costabel U, Bonella F. Differential diagnosis of granulomatous lung disease: clues and pitfalls: number 4 in the Series “Pathology for the clinician.” Edited by Peter Dorfmüller and Alberto Cavazza. Eur Respir Rev 2017; 26(145). doi:10.1183/16000617.0012-2017
Mercer LK, Galloway JB, Lunt M, et al. Risk of lymphoma in patients exposed to antitumour necrosis factor therapy: results from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis. Ann Rheum Dis 2017; 76(3):497–503. doi:10.1136/annrheumdis-2016-209389
Chu JH, Feudtner C, Heydon K, Walsh TJ, Zaoutis TE. Hospitalizations for endemic mycoses: a population-based national study. Clin Infect Dis 2006; 42(6):822–825. doi:10.1086/500405
Benedict K, Mody RK. Epidemiology of histoplasmosis outbreaks, United States, 1938–2013. Emerg Infect Dis 2016; 22(3):370–378. doi:10.3201/eid2203.151117
Wheat LJ. Diagnosis and management of histoplasmosis. Eur J Clin Microbiol Infect Dis 1989; 8(5):480–490. pmid:2502413
Goodwin RA Jr, Shapiro JL, Thurman GH, Thurman SS, Des Prez RM. Disseminated histoplasmosis: clinical and pathologic correlations. Medicine (Baltimore) 1980; 59(1):1–33. pmid:7356773
Wheat LJ, Conces D, Allen SD, Blue-Hnidy D, Loyd J. Pulmonary histoplasmosis syndromes: recognition, diagnosis, and management. Semin Respir Crit Care Med 2004; 25(2):129–144. doi:10.1055/s-2004-824898
Assi MA, Sandid MS, Baddour LM, Roberts GD, Walker RC. Systemic histoplasmosis: a 15-year retrospective institutional review of 111 patients. Medicine (Baltimore) 2007; 86(3):162–169. doi:10.1097/md.0b013e3180679130
Vergidis P, Avery RK, Wheat LJ, et al. Histoplasmosis complicating tumor necrosis factor-a blocker therapy: a retrospective analysis of 98 cases. Clin Infect Dis 2015; 61(3):409–417. doi:10.1093/cid/civ299
Olson TC, Bongartz T, Crowson CS, Roberts GD, Orenstein R, Matteson EL. Histoplasmosis infection in patients with rheumatoid arthritis, 1998–2009. BMC Infect Dis 2011; 11:145. doi:10.1186/1471-2334-11-145
Hage CA, Ribes JA, Wengenack NL, et al. A multicenter evaluation of tests for diagnosis of histoplasmosis. Clin Infect Dis 2011; 53(5):448–454. doi:10.1093/cid/cir435
Azar MM, Hage CA. Laboratory diagnostics for histoplasmosis. J Clin Microbiol 2017; 55(6):1612–1620. doi:10.1128/JCM.02430-16
Swartzentruber S, Rhodes L, Kurkjian K, et al. Diagnosis of acute pulmonary histoplasmosis by antigen detection. Clin Infect Dis 2009; 49(12):1878–1882. doi:10.1086/648421
Wheat LJ, Freifeld AG, Kleiman MB, et al; Infectious Diseases Society of America. Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America. Clin Infect Dis 2007; 45(7):807–825. doi:10.1086/521259
Takaaki Kobayashi, MD Fellow, Infectious Disease, University of Iowa Hospitals and Clinics, Iowa City, IA
Christine Cho, MD Associate, Infectious Disease, University of Iowa Hospitals and Clinics, Iowa City, IA
Address: Takaaki Kobayashi, MD, Infectious Disease, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA 52242; taka.kobayashi1126@gmail.com
Takaaki Kobayashi, MD Fellow, Infectious Disease, University of Iowa Hospitals and Clinics, Iowa City, IA
Christine Cho, MD Associate, Infectious Disease, University of Iowa Hospitals and Clinics, Iowa City, IA
Address: Takaaki Kobayashi, MD, Infectious Disease, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA 52242; taka.kobayashi1126@gmail.com
Author and Disclosure Information
Takaaki Kobayashi, MD Fellow, Infectious Disease, University of Iowa Hospitals and Clinics, Iowa City, IA
Christine Cho, MD Associate, Infectious Disease, University of Iowa Hospitals and Clinics, Iowa City, IA
Address: Takaaki Kobayashi, MD, Infectious Disease, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA 52242; taka.kobayashi1126@gmail.com
A 50-year-old man with Crohn disease and psoriatic arthritis treated with infliximab and methotrexate presented to a tertiary care hospital with fever, cough, and chest discomfort. The symptoms had first appeared 2 weeks earlier, and he had gone to an urgent care center, where he was prescribed a 5-day course of azithromycin and a corticosteroid, but this had not relieved his symptoms.
Figure 1. (A) An enlarged lymph node (2.4 cm × 2.0 cm) at the bifurcation of the bronchus intermedius. (B) An enlarged inferior mediastinal lymph node (2.0 cm × 5.4 cm).
He reported no recent travel, exposure to animals, or sick contacts. His temperature was 38.3°C (100.9°F). Results of the physical examination and initial laboratory testing were unremarkable. Chest computed tomography revealed prominent right hilar and mediastinal lymphadenopathy (Figure 1).
Bronchoscopy revealed edematous mucosa throughout, with minimal secretion. Specimens for bacterial, acid-fast bacillus, and fungal cultures were obtained from bronchoalveolar lavage. Endobronchial lymph node biopsy with ultrasonographic guidance revealed nonnecrotizing granuloma.
Bronchoalveolar lavage cultures showed no growth, but the patient’s serum histoplasma antigen was positive at 5.99 ng/dL (reference range: none detected), leading to the diagnosis of mediastinal granuloma due to histoplasmosis with possible dissemination. His immunosuppressant drugs were stopped, and oral itraconazole was started.
At a follow-up visit 2 months later, his serum antigen level had decreased to 0.68 ng/dL, and he had no symptoms whatsoever. At a visit 1 month after that, infliximab and methotrexate were restarted because of an exacerbation of Crohn disease. His oral itraconazole treatment was to be continued for at least 12 months, given the high suspicion for disseminated histoplasmosis while on immunosuppressant therapy.
DIFFERENTIAL DIAGNOSIS OF GRANULOMATOUS LUNG DISEASE AND LYMPHADENOPATHY
The differential diagnosis of granulomatous lung disease and lymphadenopathy is broad and includes noninfectious and infectious conditions.1
Noninfectious causes include lymphoma, sarcoidosis, inflammatory bowel disease, hypersensitivity pneumonia, side effects of drugs (eg, methotrexate, etanercept), rheumatoid nodules, vasculitis (eg, Churg-Strauss syndrome, granulomatosis with polyangiitis, primary amyloidosis, pneumoconiosis (eg, beryllium, cobalt), and Castleman disease.
There is concern that tumor necrosis factor antagonists may increase the risk of lymphoma, but a 2017 study found no evidence of this.2
Infectious conditions associated with granulomatous lung disease include tuberculosis, nontuberculous mycobacterial infection, fungal infection (eg, Cryptococcus, Coccidioides, Histoplasma, Blastomyces), brucellosis, tularemia (respiratory type B), parasitic infection (eg, Toxocara, Leishmania, Echinococcus, Schistosoma), and Whipple disease.
HISTOPLASMOSIS
Histoplasmosis, caused by infection with Histoplasma capsulatum, is the most prevalent endemic mycotic disease in the United States.3 The fungus is commonly found in the Ohio and Mississippi River valleys in the United States, and also in Central and South America and Asia.
Risk factors for histoplasmosis include living in or traveling to an endemic area, exposure to aerosolized soil that contains spores, and exposure to bats or birds and their droppings.4
Fewer than 5% of exposed individuals develop symptoms, which include fever, chills, headache, myalgia, anorexia, cough, and chest pain.5 Patients may experience symptoms shortly after exposure or may remain free of symptoms for years, with intermittent relapses of symptoms.6 Hilar or mediastinal lymphadenopathy is common in acute pulmonary histoplasmosis.7
The risk of disseminated histoplasmosis is greater in patients with reduced cell-mediated immunity, such as in human immunodeficiency virus infection, acquired immunodeficiency syndrome, solid-organ or bone marrow transplant, hematologic malignancies, immunosuppression (corticosteroids, disease-modifying antirheumatic drugs, and tumor necrosis factor antagonists), and congenital T-cell deficiencies.8
In a retrospective study, infliximab was the tumor necrosis factor antagonist most commonly associated with histoplasmosis.9 In a study of patients with rheumatoid arthritis, the disease-modifying drug most commonly associated was methotrexate.10
GOLD STANDARD FOR DIAGNOSIS
Isolation of H capsulatum from clinical specimens remains the gold standard for confirmation of histoplasmosis. The sensitivity of culture to detect H capsulatum depends on the clinical manifestations: it is 74% in patients with disseminated histoplasmosis, but only 42% in patients with acute pulmonary histoplasmosis.11 The serum histoplasma antigen test has a sensitivity of 91.8% in disseminated histoplasmosis, 87.5% in chronic pulmonary histoplasmosis, and 83% in acute pulmonary histoplasmosis.12
Urine testing for histoplasma antigen has generally proven to be slightly more sensitive than serum testing in all manifestations of histoplasmosis.13 Combining urine and serum testing increases the likelihood of antigen detection.
TREATMENT
Asymptomatic patients with mediastinal histoplasmosis do not require treatment. (Note: in some cases, lymphadenopathy is found incidentally, and biopsy is done to rule out malignancy.)
Standard treatment of symptomatic mediastinal histoplasmosis is oral itraconazole 200 mg, 3 times daily for 3 days, followed by 200 mg orally once or twice daily for 6 to 12 weeks.14
Although stopping immunosuppressant drugs is considered the standard of care in treating histoplasmosis in immunocompromised patients, there are no guidelines on when to resume them. However, a retrospective study of 98 cases of histoplasmosis in patients on tumor necrosis factor antagonists found that resuming immunosuppressants might be safe with close monitoring during the course of antifungal therapy.9 The role of long-term suppressive therapy with antifungal agents in patients on chronic immunosuppressive therapy is still unknown and needs further study.
TAKE-HOME MESSAGES
Histoplasmosis is the most prevalent endemic mycotic disease in the United States, and mediastinal lymphadenopathy is commonly seen in acute pulmonary histoplasmosis.
Histoplasmosis should be included in the differential diagnosis of granulomatous lung disease in patients from an endemic area or with a history of travel to an endemic area.
Immunosuppressive agents such as tumor necrosis factor antagonists and disease-modifying antirheumatic drugs can predispose to invasive fungal infection, including histoplasmosis.
While isolation of H capsulatum from culture remains the gold standard for the diagnosis of histoplasmosis, the histoplasma antigen tests (serum and urine) is more sensitive than culture.
A 50-year-old man with Crohn disease and psoriatic arthritis treated with infliximab and methotrexate presented to a tertiary care hospital with fever, cough, and chest discomfort. The symptoms had first appeared 2 weeks earlier, and he had gone to an urgent care center, where he was prescribed a 5-day course of azithromycin and a corticosteroid, but this had not relieved his symptoms.
Figure 1. (A) An enlarged lymph node (2.4 cm × 2.0 cm) at the bifurcation of the bronchus intermedius. (B) An enlarged inferior mediastinal lymph node (2.0 cm × 5.4 cm).
He reported no recent travel, exposure to animals, or sick contacts. His temperature was 38.3°C (100.9°F). Results of the physical examination and initial laboratory testing were unremarkable. Chest computed tomography revealed prominent right hilar and mediastinal lymphadenopathy (Figure 1).
Bronchoscopy revealed edematous mucosa throughout, with minimal secretion. Specimens for bacterial, acid-fast bacillus, and fungal cultures were obtained from bronchoalveolar lavage. Endobronchial lymph node biopsy with ultrasonographic guidance revealed nonnecrotizing granuloma.
Bronchoalveolar lavage cultures showed no growth, but the patient’s serum histoplasma antigen was positive at 5.99 ng/dL (reference range: none detected), leading to the diagnosis of mediastinal granuloma due to histoplasmosis with possible dissemination. His immunosuppressant drugs were stopped, and oral itraconazole was started.
At a follow-up visit 2 months later, his serum antigen level had decreased to 0.68 ng/dL, and he had no symptoms whatsoever. At a visit 1 month after that, infliximab and methotrexate were restarted because of an exacerbation of Crohn disease. His oral itraconazole treatment was to be continued for at least 12 months, given the high suspicion for disseminated histoplasmosis while on immunosuppressant therapy.
DIFFERENTIAL DIAGNOSIS OF GRANULOMATOUS LUNG DISEASE AND LYMPHADENOPATHY
The differential diagnosis of granulomatous lung disease and lymphadenopathy is broad and includes noninfectious and infectious conditions.1
Noninfectious causes include lymphoma, sarcoidosis, inflammatory bowel disease, hypersensitivity pneumonia, side effects of drugs (eg, methotrexate, etanercept), rheumatoid nodules, vasculitis (eg, Churg-Strauss syndrome, granulomatosis with polyangiitis, primary amyloidosis, pneumoconiosis (eg, beryllium, cobalt), and Castleman disease.
There is concern that tumor necrosis factor antagonists may increase the risk of lymphoma, but a 2017 study found no evidence of this.2
Infectious conditions associated with granulomatous lung disease include tuberculosis, nontuberculous mycobacterial infection, fungal infection (eg, Cryptococcus, Coccidioides, Histoplasma, Blastomyces), brucellosis, tularemia (respiratory type B), parasitic infection (eg, Toxocara, Leishmania, Echinococcus, Schistosoma), and Whipple disease.
HISTOPLASMOSIS
Histoplasmosis, caused by infection with Histoplasma capsulatum, is the most prevalent endemic mycotic disease in the United States.3 The fungus is commonly found in the Ohio and Mississippi River valleys in the United States, and also in Central and South America and Asia.
Risk factors for histoplasmosis include living in or traveling to an endemic area, exposure to aerosolized soil that contains spores, and exposure to bats or birds and their droppings.4
Fewer than 5% of exposed individuals develop symptoms, which include fever, chills, headache, myalgia, anorexia, cough, and chest pain.5 Patients may experience symptoms shortly after exposure or may remain free of symptoms for years, with intermittent relapses of symptoms.6 Hilar or mediastinal lymphadenopathy is common in acute pulmonary histoplasmosis.7
The risk of disseminated histoplasmosis is greater in patients with reduced cell-mediated immunity, such as in human immunodeficiency virus infection, acquired immunodeficiency syndrome, solid-organ or bone marrow transplant, hematologic malignancies, immunosuppression (corticosteroids, disease-modifying antirheumatic drugs, and tumor necrosis factor antagonists), and congenital T-cell deficiencies.8
In a retrospective study, infliximab was the tumor necrosis factor antagonist most commonly associated with histoplasmosis.9 In a study of patients with rheumatoid arthritis, the disease-modifying drug most commonly associated was methotrexate.10
GOLD STANDARD FOR DIAGNOSIS
Isolation of H capsulatum from clinical specimens remains the gold standard for confirmation of histoplasmosis. The sensitivity of culture to detect H capsulatum depends on the clinical manifestations: it is 74% in patients with disseminated histoplasmosis, but only 42% in patients with acute pulmonary histoplasmosis.11 The serum histoplasma antigen test has a sensitivity of 91.8% in disseminated histoplasmosis, 87.5% in chronic pulmonary histoplasmosis, and 83% in acute pulmonary histoplasmosis.12
Urine testing for histoplasma antigen has generally proven to be slightly more sensitive than serum testing in all manifestations of histoplasmosis.13 Combining urine and serum testing increases the likelihood of antigen detection.
TREATMENT
Asymptomatic patients with mediastinal histoplasmosis do not require treatment. (Note: in some cases, lymphadenopathy is found incidentally, and biopsy is done to rule out malignancy.)
Standard treatment of symptomatic mediastinal histoplasmosis is oral itraconazole 200 mg, 3 times daily for 3 days, followed by 200 mg orally once or twice daily for 6 to 12 weeks.14
Although stopping immunosuppressant drugs is considered the standard of care in treating histoplasmosis in immunocompromised patients, there are no guidelines on when to resume them. However, a retrospective study of 98 cases of histoplasmosis in patients on tumor necrosis factor antagonists found that resuming immunosuppressants might be safe with close monitoring during the course of antifungal therapy.9 The role of long-term suppressive therapy with antifungal agents in patients on chronic immunosuppressive therapy is still unknown and needs further study.
TAKE-HOME MESSAGES
Histoplasmosis is the most prevalent endemic mycotic disease in the United States, and mediastinal lymphadenopathy is commonly seen in acute pulmonary histoplasmosis.
Histoplasmosis should be included in the differential diagnosis of granulomatous lung disease in patients from an endemic area or with a history of travel to an endemic area.
Immunosuppressive agents such as tumor necrosis factor antagonists and disease-modifying antirheumatic drugs can predispose to invasive fungal infection, including histoplasmosis.
While isolation of H capsulatum from culture remains the gold standard for the diagnosis of histoplasmosis, the histoplasma antigen tests (serum and urine) is more sensitive than culture.
References
Ohshimo S, Guzman J, Costabel U, Bonella F. Differential diagnosis of granulomatous lung disease: clues and pitfalls: number 4 in the Series “Pathology for the clinician.” Edited by Peter Dorfmüller and Alberto Cavazza. Eur Respir Rev 2017; 26(145). doi:10.1183/16000617.0012-2017
Mercer LK, Galloway JB, Lunt M, et al. Risk of lymphoma in patients exposed to antitumour necrosis factor therapy: results from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis. Ann Rheum Dis 2017; 76(3):497–503. doi:10.1136/annrheumdis-2016-209389
Chu JH, Feudtner C, Heydon K, Walsh TJ, Zaoutis TE. Hospitalizations for endemic mycoses: a population-based national study. Clin Infect Dis 2006; 42(6):822–825. doi:10.1086/500405
Benedict K, Mody RK. Epidemiology of histoplasmosis outbreaks, United States, 1938–2013. Emerg Infect Dis 2016; 22(3):370–378. doi:10.3201/eid2203.151117
Wheat LJ. Diagnosis and management of histoplasmosis. Eur J Clin Microbiol Infect Dis 1989; 8(5):480–490. pmid:2502413
Goodwin RA Jr, Shapiro JL, Thurman GH, Thurman SS, Des Prez RM. Disseminated histoplasmosis: clinical and pathologic correlations. Medicine (Baltimore) 1980; 59(1):1–33. pmid:7356773
Wheat LJ, Conces D, Allen SD, Blue-Hnidy D, Loyd J. Pulmonary histoplasmosis syndromes: recognition, diagnosis, and management. Semin Respir Crit Care Med 2004; 25(2):129–144. doi:10.1055/s-2004-824898
Assi MA, Sandid MS, Baddour LM, Roberts GD, Walker RC. Systemic histoplasmosis: a 15-year retrospective institutional review of 111 patients. Medicine (Baltimore) 2007; 86(3):162–169. doi:10.1097/md.0b013e3180679130
Vergidis P, Avery RK, Wheat LJ, et al. Histoplasmosis complicating tumor necrosis factor-a blocker therapy: a retrospective analysis of 98 cases. Clin Infect Dis 2015; 61(3):409–417. doi:10.1093/cid/civ299
Olson TC, Bongartz T, Crowson CS, Roberts GD, Orenstein R, Matteson EL. Histoplasmosis infection in patients with rheumatoid arthritis, 1998–2009. BMC Infect Dis 2011; 11:145. doi:10.1186/1471-2334-11-145
Hage CA, Ribes JA, Wengenack NL, et al. A multicenter evaluation of tests for diagnosis of histoplasmosis. Clin Infect Dis 2011; 53(5):448–454. doi:10.1093/cid/cir435
Azar MM, Hage CA. Laboratory diagnostics for histoplasmosis. J Clin Microbiol 2017; 55(6):1612–1620. doi:10.1128/JCM.02430-16
Swartzentruber S, Rhodes L, Kurkjian K, et al. Diagnosis of acute pulmonary histoplasmosis by antigen detection. Clin Infect Dis 2009; 49(12):1878–1882. doi:10.1086/648421
Wheat LJ, Freifeld AG, Kleiman MB, et al; Infectious Diseases Society of America. Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America. Clin Infect Dis 2007; 45(7):807–825. doi:10.1086/521259
References
Ohshimo S, Guzman J, Costabel U, Bonella F. Differential diagnosis of granulomatous lung disease: clues and pitfalls: number 4 in the Series “Pathology for the clinician.” Edited by Peter Dorfmüller and Alberto Cavazza. Eur Respir Rev 2017; 26(145). doi:10.1183/16000617.0012-2017
Mercer LK, Galloway JB, Lunt M, et al. Risk of lymphoma in patients exposed to antitumour necrosis factor therapy: results from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis. Ann Rheum Dis 2017; 76(3):497–503. doi:10.1136/annrheumdis-2016-209389
Chu JH, Feudtner C, Heydon K, Walsh TJ, Zaoutis TE. Hospitalizations for endemic mycoses: a population-based national study. Clin Infect Dis 2006; 42(6):822–825. doi:10.1086/500405
Benedict K, Mody RK. Epidemiology of histoplasmosis outbreaks, United States, 1938–2013. Emerg Infect Dis 2016; 22(3):370–378. doi:10.3201/eid2203.151117
Wheat LJ. Diagnosis and management of histoplasmosis. Eur J Clin Microbiol Infect Dis 1989; 8(5):480–490. pmid:2502413
Goodwin RA Jr, Shapiro JL, Thurman GH, Thurman SS, Des Prez RM. Disseminated histoplasmosis: clinical and pathologic correlations. Medicine (Baltimore) 1980; 59(1):1–33. pmid:7356773
Wheat LJ, Conces D, Allen SD, Blue-Hnidy D, Loyd J. Pulmonary histoplasmosis syndromes: recognition, diagnosis, and management. Semin Respir Crit Care Med 2004; 25(2):129–144. doi:10.1055/s-2004-824898
Assi MA, Sandid MS, Baddour LM, Roberts GD, Walker RC. Systemic histoplasmosis: a 15-year retrospective institutional review of 111 patients. Medicine (Baltimore) 2007; 86(3):162–169. doi:10.1097/md.0b013e3180679130
Vergidis P, Avery RK, Wheat LJ, et al. Histoplasmosis complicating tumor necrosis factor-a blocker therapy: a retrospective analysis of 98 cases. Clin Infect Dis 2015; 61(3):409–417. doi:10.1093/cid/civ299
Olson TC, Bongartz T, Crowson CS, Roberts GD, Orenstein R, Matteson EL. Histoplasmosis infection in patients with rheumatoid arthritis, 1998–2009. BMC Infect Dis 2011; 11:145. doi:10.1186/1471-2334-11-145
Hage CA, Ribes JA, Wengenack NL, et al. A multicenter evaluation of tests for diagnosis of histoplasmosis. Clin Infect Dis 2011; 53(5):448–454. doi:10.1093/cid/cir435
Azar MM, Hage CA. Laboratory diagnostics for histoplasmosis. J Clin Microbiol 2017; 55(6):1612–1620. doi:10.1128/JCM.02430-16
Swartzentruber S, Rhodes L, Kurkjian K, et al. Diagnosis of acute pulmonary histoplasmosis by antigen detection. Clin Infect Dis 2009; 49(12):1878–1882. doi:10.1086/648421
Wheat LJ, Freifeld AG, Kleiman MB, et al; Infectious Diseases Society of America. Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America. Clin Infect Dis 2007; 45(7):807–825. doi:10.1086/521259
No, they are not required or needed, but daily radiography and arterial blood gas testing are common practice: eg, 60% of intensive care unit (ICU) patients get daily radiographs,1 even though results provide low diagnostic yield and are unlikely to alter patient management compared with testing only when indicated.
The Choosing Wisely campaign,2 a collaborative effort of a number of professional societies, advises against ordering these diagnostic tests daily because routine testing increases risks to patients and burdens the healthcare system. Instead, testing is recommended only in response to a specific clinical question, or when the test results will affect the patient’s treatment.
CHEST RADIOGRAPHS: DAILY VS CLINICALLY INDICATED
Chest radiographs enable practitioners to monitor the position of endotracheal tubes and central venous catheters, evaluate fluid status, follow up on abnormal findings, detect complications of procedures (such as a pneumothorax), and identify otherwise undetected conditions.
And daily chest radiographs often detect abnormalities. A 1991 study by Hall et al3 of 538 chest radiographs in 74 patients on mechanical ventilation reported that 30% of daily routine chest radiographs disclosed a new but minor finding (eg, a small change in endotracheal tube position or a small infiltrate). The new findings were major in 13 (17.6%) of the 74 patients (95% confidence interval [CI] 9%–26%). These included findings that required an immediate diagnostic or therapeutic intervention (eg, endotracheal tube below the tracheal carina, malposition of a catheter, pneumothorax, large pleural effusion).
But most studies say daily radiographs are not needed. In a large prospective study published in 2006, Graat et al4 evaluated the clinical value of 2,457 routine chest radiographs in 754 patients in a combined surgical and medical ICU. Daily chest radiographs revealed new or unexpected findings in 5.8% of cases, but only 2.2% warranted a change in therapy. No differences were found between the medical and surgical patients. The authors concluded that daily routine radiographs in ICU patients seldom reveal unexpected, clinically relevant abnormalities, and those findings rarely require urgent intervention.
A 2010 meta-analysis of 8 studies (7,078 patients) by Oba and Zaza5 compared on-demand and daily routine strategies of performing chest radiographs. They estimated that eliminating daily routine chest radiographs would not affect death rates in the hospital (odds ratio [OR] 1.02, 95% CI 0.89–1.17, P = .78) or the ICU (OR 0.92, 95% CI 0.76–1.11, P = .4). They also found no significant differences in length of stay or duration of mechanical ventilation. This meta-analysis suggests that routine radiographs can be eliminated without adversely affecting outcomes in ICU patients.
A larger meta-analysis (9 trials, 39,358 radiographs, 9,611 patients) published in 2012 by Ganapathy et al6 also found no harm associated with restrictive radiography protocols. These investigators compared a daily chest radiography protocol against a protocol based on clinical indications. The primary outcome was the mortality rate in the ICU; secondary outcomes were the mortality rate in the hospital, the length of stay in the ICU, and duration of mechanical ventilation. They found no differences between routine and restrictive strategies in terms of ICU mortality (risk ratio [RR] 1.04, 95% CI 0.84–1.28, P = .72), hospital mortality (RR 0.98, 95% CI 0.68–1.41, P = .91), or other secondary outcomes.
Clinically indicated testing is better
The conclusion from these studies is that routine chest radiographs in patients undergoing mechanical ventilation does not improve patient outcomes, and thus, a clinically indicated protocol is preferred.
Furthermore, routine daily radiographs have adverse effects such as more cumulative radiation exposure to the patient7 and greater risk of accidental removal of devices (eg, catheters, tubes).8 Another concern is a higher risk of hospital-associated infections from bacterial spread from caregivers’ hands.9
Finally, daily radiographs increase the use of healthcare resources and expenditures. In a 2011 study, Gershengorn et al1 estimated that adopting a clinically indicated radiography strategy could save more than $144 million annually in the United States.
The ACR agrees. Appropriateness criteria published by the American College of Radiology (ACR) in 201510 recommend against routine daily chest radiographs in the ICU, in keeping with the findings of the critical care community. The ACR recommends an initial radiograph at admission to the ICU. However, follow-up radiographs should be obtained only for specific clinical indications, including a change in the patient’s clinical condition or to check for proper placement of endotracheal or nasogastric or orogastric tubes, pulmonary arterial catheters, central venous catheters, chest tubes, and other life-support devices.
Ultrasonography as an alternative
Ultrasonography is widely available and provides an alternative to chest radiography for detecting significant abnormalities in patients on mechanical ventilation without exposing them to radiation and using relatively fewer resources.
A 2012 meta-analysis (8 studies, 1,048 patients) found that bedside ultrasonography reliably detects pneumothorax.11 It can also provide a rapid diagnosis of the cause of acute respiratory failure such as pneumonia or pulmonary edema.12 Ultrasonography, with the appropriate expertise, can also confirm the position of an endotracheal tube13 or central venous catheter.14
ARTERIAL BLOOD GAS TESTING: DAILY VS CLINICALLY INDICATED
Arterial blood gas testing has value for managing patients undergoing mechanical ventilation, and it is one of the most commonly performed diagnostic tests in the ICU. It provides reliable information about the patient’s oxygenation and acid-base status. It is commonly requested when changing ventilator settings.
Downsides. Arterial blood gas measurements account for 10% to 20% of the cost incurred during ICU stay.15 In addition, they require an arterial puncture—an invasive procedure associated with potentially serious complications such as occlusion of the artery, digital embolization leading to digital ischemia, local infection, pseudoaneurysm, hematoma, bleeding, and skin necrosis.
Is daily testing needed?
Guidelines say no. The 2013 American Association for Respiratory Care16 guidelines suggest that arterial blood gas testing should be based on the clinical assessment of the patient. They recommend blood gas analysis to evaluate the patient’s ventilatory status (reflected by the partial pressure of arterial carbon dioxide [PaCO2], acid-base status (reflected by pH), arterial oxygenation (partial pressure of arterial oxygen [PaO2] and oxyhemoglobin saturation), oxygen-carrying capacity, and whether the patient likely has an intrapulmonary shunt. They state that testing is useful to quantify the response to therapeutic or diagnostic interventions such as cardiopulmonary exercise testing, to monitor severity and progression of documented disease, and to assess the adequacy of circulatory response.
Studies agree
The ACR recommendation to test “as clinically indicated” is supported by studies showing that patient outcomes are not inferior for arterial blood gas testing when clinically indicated instead of daily, and that this practice is associated with fewer complications, less resource use, and reduced overall patient care costs.
A 2015 study compared the efficacy and safety of obtaining arterial blood gases based on clinical assessment vs daily in 300 critically ill patients.17 Overall, fewer samples were obtained per patient in the clinical assessment group than in the daily group (all patients 3.7 vs 5.5; ventilated patients 2.03 vs 6.12; P < .001 for both). In ventilated patients, there was a 60% decrease in arterial blood gas orders without affecting patient outcomes and safety, including a lower risk of complications and overall cost of care.
In another study, Martinez-Balzano et al18 evaluated the effect of guidelines they developed to optimize the use of arterial blood gas testing in their ICUs. These guidelines encouraged testing of arterial blood gases after an acute respiratory event or for a rational clinical concern, and discouraged testing for routine surveillance, after planned changes of positive end-expiratory pressure or inspired oxygen fraction on mechanical ventilation, for spontaneous breathing trials, or when a disorder was not suspected.
Compared with data collected before implementation, these guidelines reduced the number of arterial blood gas tests by 821.5 per month (41.5%), or approximately 1 test per patient per mechanical-ventilation day for each month (43.1%; P < .001). Appropriately indicated testing rose to 83.4% from a baseline of 67.5% (P = .002). Additionally, this approach was associated with saving 49 liters of blood, reducing ICU costs by $39,432, and freeing up 1,643 staff work hours for other tasks. There were no significant differences in days on mechanical ventilation, severity of illness, or mortality between the 2 periods.18
Extubation effects. Routine arterial blood gas testing has not been shown to affect extubation decisions in patients on mechanical ventilation. In a study of 83 patients who completed a spontaneous breathing trial (total of 100 trials), Salam et al19 found arterial blood gas values obtained during the trial did not change the extubation decision in 93% of the cases.
In a study of 54 extubations in 52 patients,20 65% of the extubations were performed without obtaining an arterial blood gas test after the patient completed a trial of spontaneous breathing. The extubation success rate was 94% for the entire group, and it was the same regardless of whether testing was done (94.7% vs 94.3%, respectively).
Alternatives to arterial blood gases
There are less-invasive means to obtain the information that comes from an arterial blood gas test.
Pulse oximetry is a rapid noninvasive tool that provides continuous assessment of peripheral arterial oxygen saturation as a surrogate marker for tissue arterial oxygenation. However, it cannot measure PaO2 or PaCO2.21
Transcutaneous carbon dioxide (PTCO2) monitoring is another continuous noninvasive alternative. The newer PTCO2 devices are useful in patients with acute respiratory failure and in critically ill patients on vasopressors or vasodilators. Studies have shown good correlation between PTCO2 and PaCO2.22,23
End-tidal carbon dioxide (PetCO2) is another alternative to estimate PaCO2. It can also be used to confirm endotracheal tube placement, during transportation, during procedures in which the patient is under conscious sedation, and to monitor the effectiveness of cardiopulmonary resuscitation and return of circulation after cardiac arrest. PetCO2 measurements are not as accurate as arterial blood gas testing owing to a difference of approximately 2 to 5 mm Hg between PaCO2 and PetCO2 in normal lungs due to alveolar dead space. This difference may be much higher depending on the clinical condition and the degree of alveolar dead space.21,24,25
Venous blood gases, which can be obtained from a peripheral or central venous catheter, are adequate to assess pH and partial pressure of carbon dioxide (PCO2) in hemodynamically stable patients. Walkey et al26 found that the accuracy of venous blood gas measurement to predict arterial blood gases was 90%. They recommended adjusting the venous pH up by 0.05 and the PCO2 down by 5 mm Hg to account for the positive bias of venous blood gases. A limitation of this method is that the values are not reliable in patients who are in shock.
These alternatives can be used as a substitute for daily arterial blood gases. However, in certain clinical scenarios, arterial blood gas measurement remains a necessary and useful clinical tool.
TAKE-HOME MESSAGE
Most scientific evidence suggests that chest radiographs and arterial blood gas measurement in patients undergoing mechanical ventilation—and critically ill, in general—are best done when clinically indicated rather than routinely on a daily basis. This will reduce cost and harm to patients that may result from these unnecessary tests and not adversely affect outcomes.
References
Gershengorn HB, Wunsch H, Scales DC, Rubenfeld GD. Trends in use of daily chest radiographs among US adults receiving mechanical ventilation. JAMA Netw Open 2018; 1(4):e181119. doi:10.1001/jamanetworkopen.2018.1119
Hall JB, White SR, Karrison T. Efficacy of daily routine chest radiographs in intubated, mechanically ventilated patients. Crit Care Med 1991; 19(5):689–693. pmid:2026031
Graat ME, Choi G, Wolthuis EK, et al. The clinical value of daily routine chest radiographs in a mixed medical-surgical intensive care unit is low. Crit Care 2006; 10(1):R11. doi:10.1186/cc3955
Oba Y, Zaza T. Abandoning daily routine chest radiography in the intensive care unit: meta-analysis. Radiology 2010; 255(2):386–395. doi:10.1148/radiol.10090946
Ganapathy A, Adhikari NK, Spiegelman J, Scales DC. Routine chest x-rays in intensive care units: a systematic review and meta-analysis. Crit Care 2012; 16(2):R68. doi:10.1186/cc11321
Krishnan S, Moghekar A, Duggal A, et al. Radiation exposure in the medical ICU: predictors and characteristics. Chest 2018; 153(5):1160–1168. doi:10.1016/j.chest.2018.01.019
Hejblum G, Chalumeau-Lemoine L, Ioos V, et al. Comparison of routine and on-demand prescription of chest radiographs in mechanically ventilated adults: a multicentre, cluster-randomised, two-period crossover study. Lancet 2009; 374(9702):1687–1693. doi:10.1016/S0140-6736(09)61459-8
Levin PD, Shatz O, Sviri S, et al. Contamination of portable radiograph equipment with resistant bacteria in the ICU. Chest 2009; 136(2):426–432. doi:10.1378/chest.09-0049
Suh RD, Genshaft SJ, Kirsch J, et al. ACR Appropriateness Criteria® Intensive Care Unit Patients. J Thorac Imaging 2015; 30(6):W63–W65. doi:10.1097/RTI.0000000000000174
Alrajhi K, Woo MY, Vaillancourt C. Test characteristics of ultrasonography for the detection of pneumothorax: a systematic review and meta-analysis. Chest 2012; 141(3):703–708. doi:10.1378/chest.11-0131
Lichetenstein DA, Meziere GA. Relevance of lung ultrasound in the diagnosis of acute respiratory failure: the BLUE protocol. Chest 2008; 134(1):117–125. doi:10.1378/chest.07-2800
Das SK, Choupoo NS, Haldar R, Lahkar A. Transtracheal ultrasound for verification of endotracheal tube placement: a systematic review and meta-analysis. Can J Anaesth 2015; 62(4):413–423. doi:10.1007/s12630-014-0301-z
Ablordeppey EA, Drewry AM, Beyer AB, et al. Diagnostic accuracy of central venous catheter confirmation by bedside ultrasound versus chest radiography in critically ill patients: a systematic review and meta-analysis. Crit Care Med 2017; 45(4):715–724. doi:10.1097/CCM.0000000000002188
DellaVolpe JD, Chakraborti C, Cerreta K, et al. Effects of implementing a protocol for arterial blood gas use on ordering practices and diagnostic yield. Healthc (Amst) 2014; 2(2):130–135. doi:10.1016/j.hjdsi.2013.09.006
Davis MD, Walsh BK, Sittig SE, Restrepo RD. AARC clinical practice guideline: blood gas analysis and hemoximetry. Respir Care 2013; 58(10):1694–1703. doi:10.4187/respcare.02786
Blum FE, Lund ET, Hall HA, Tachauer AD, Chedrawy EG, Zilberstein J. Reevaluation of the utilization of arterial blood gas analysis in the intensive care unit: effects on patient safety and patient outcome. J Crit Care 2015; 30(2):438.e1–e5. doi:10.1016/j.jcrc.2014.10.025
Martínez-Balzano CD, Oliveira P, O’Rourke M, Hills L, Sosa AF; Critical Care Operations Committee of the UMass Memorial Healthcare Center. An educational intervention optimizes the use of arterial blood gas determinations across ICUs from different specialties: a quality-improvement study. Chest 2017; 151(3):579–585. doi:10.1016/j.chest.2016.10.035
Salam A, Smina M, Gada P, et al. The effect of arterial blood gas values on extubation decisions. Respir Care 2003; 48(11):1033–1037. pmid:14585115
Pawson SR, DePriest JL. Are blood gases necessary in mechanically ventilated patients who have successfully completed a spontaneous breathing trial? Respir Care 2004; 49(11):1316–1319. pmid:15507165
Soubani AO. Noninvasive monitoring of oxygen and carbon dioxide. Am J Emerg Med 2001; 19(2):141–146. doi:10.1053/ajem.2001.21353
Nicolini A, Ferrari MB. Evaluation of a transcutaneous carbon dioxide monitor in patients with acute respiratory failure. Ann Thorac Med 2011; 6(4):217–220. doi:10.4103/1817-1737.84776
Bendjelid K, Schütz N, Stotz M, Gerard I, Suter PM, Romand JA. Transcutaneous PCO2 monitoring in critically ill adults: clinical evaluation of a new sensor. Crit Care Med 2005; 33(10):2203–2206. pmid:16215371
Huttmann SE, Windisch W, Storre JH. Techniques for the measurement and monitoring of carbon dioxide in the blood. Ann Am Thorac Soc 2014; 11(4):645–652. doi:10.1513/AnnalsATS.201311-387FR
McSwain SD, Hamel DS, Smith PB, et al. End-tidal and arterial carbon dioxide measurements correlate across all levels of physiologic dead space. Respir Care 2010; 55(3):288–293. pmid:20196877
Walkey AJ, Farber HW, O'Donnell C, Cabral H, Eagan JS, Philippides GJ. The accuracy of the central venous blood gas for acid-base monitoring. J Intensive Care Med 2010; 25(2):104–110. doi:10.1177/0885066609356164
Shyam Ganti, MD Division of Pulmonary, Critical Care, and Sleep Medicine, Wayne State University School of Medicine, Detroit, MI
Ravinder D. Bhanot, MD Division of Pulmonary and Critical Care, Ascension St. Mary’s, Saginaw, MI
Jasleen Kaur, MD Department of Internal Medicine, Wayne State University School of Medicine, Detroit, MI
Cassondra Cramer-Bour, MD Department of Medicine, Boston University School of Medicine, Boston, MA
Ayman O. Soubani, MD Professor of Medicine, Wayne State University School of Medicine; Medical Director, Medical ICU, Harper University Hospital; Service Chief, Pulmonary and Critical Care, and Medical Director, Critical Care Service, Karmanos Cancer Center; Division of Pulmonary, Critical Care and Sleep Medicine, Wayne State University School of Medicine, Detroit, MI
Address: Ayman O. Soubani, MD, Division of Pulmonary, Critical Care and Sleep Medicine. Wayne State University School of Medicine, 3990 John R-3 Hudson, Detroit, MI 48201; asoubani@med.wayne.edu
Shyam Ganti, MD Division of Pulmonary, Critical Care, and Sleep Medicine, Wayne State University School of Medicine, Detroit, MI
Ravinder D. Bhanot, MD Division of Pulmonary and Critical Care, Ascension St. Mary’s, Saginaw, MI
Jasleen Kaur, MD Department of Internal Medicine, Wayne State University School of Medicine, Detroit, MI
Cassondra Cramer-Bour, MD Department of Medicine, Boston University School of Medicine, Boston, MA
Ayman O. Soubani, MD Professor of Medicine, Wayne State University School of Medicine; Medical Director, Medical ICU, Harper University Hospital; Service Chief, Pulmonary and Critical Care, and Medical Director, Critical Care Service, Karmanos Cancer Center; Division of Pulmonary, Critical Care and Sleep Medicine, Wayne State University School of Medicine, Detroit, MI
Address: Ayman O. Soubani, MD, Division of Pulmonary, Critical Care and Sleep Medicine. Wayne State University School of Medicine, 3990 John R-3 Hudson, Detroit, MI 48201; asoubani@med.wayne.edu
Author and Disclosure Information
Shyam Ganti, MD Division of Pulmonary, Critical Care, and Sleep Medicine, Wayne State University School of Medicine, Detroit, MI
Ravinder D. Bhanot, MD Division of Pulmonary and Critical Care, Ascension St. Mary’s, Saginaw, MI
Jasleen Kaur, MD Department of Internal Medicine, Wayne State University School of Medicine, Detroit, MI
Cassondra Cramer-Bour, MD Department of Medicine, Boston University School of Medicine, Boston, MA
Ayman O. Soubani, MD Professor of Medicine, Wayne State University School of Medicine; Medical Director, Medical ICU, Harper University Hospital; Service Chief, Pulmonary and Critical Care, and Medical Director, Critical Care Service, Karmanos Cancer Center; Division of Pulmonary, Critical Care and Sleep Medicine, Wayne State University School of Medicine, Detroit, MI
Address: Ayman O. Soubani, MD, Division of Pulmonary, Critical Care and Sleep Medicine. Wayne State University School of Medicine, 3990 John R-3 Hudson, Detroit, MI 48201; asoubani@med.wayne.edu
No, they are not required or needed, but daily radiography and arterial blood gas testing are common practice: eg, 60% of intensive care unit (ICU) patients get daily radiographs,1 even though results provide low diagnostic yield and are unlikely to alter patient management compared with testing only when indicated.
The Choosing Wisely campaign,2 a collaborative effort of a number of professional societies, advises against ordering these diagnostic tests daily because routine testing increases risks to patients and burdens the healthcare system. Instead, testing is recommended only in response to a specific clinical question, or when the test results will affect the patient’s treatment.
CHEST RADIOGRAPHS: DAILY VS CLINICALLY INDICATED
Chest radiographs enable practitioners to monitor the position of endotracheal tubes and central venous catheters, evaluate fluid status, follow up on abnormal findings, detect complications of procedures (such as a pneumothorax), and identify otherwise undetected conditions.
And daily chest radiographs often detect abnormalities. A 1991 study by Hall et al3 of 538 chest radiographs in 74 patients on mechanical ventilation reported that 30% of daily routine chest radiographs disclosed a new but minor finding (eg, a small change in endotracheal tube position or a small infiltrate). The new findings were major in 13 (17.6%) of the 74 patients (95% confidence interval [CI] 9%–26%). These included findings that required an immediate diagnostic or therapeutic intervention (eg, endotracheal tube below the tracheal carina, malposition of a catheter, pneumothorax, large pleural effusion).
But most studies say daily radiographs are not needed. In a large prospective study published in 2006, Graat et al4 evaluated the clinical value of 2,457 routine chest radiographs in 754 patients in a combined surgical and medical ICU. Daily chest radiographs revealed new or unexpected findings in 5.8% of cases, but only 2.2% warranted a change in therapy. No differences were found between the medical and surgical patients. The authors concluded that daily routine radiographs in ICU patients seldom reveal unexpected, clinically relevant abnormalities, and those findings rarely require urgent intervention.
A 2010 meta-analysis of 8 studies (7,078 patients) by Oba and Zaza5 compared on-demand and daily routine strategies of performing chest radiographs. They estimated that eliminating daily routine chest radiographs would not affect death rates in the hospital (odds ratio [OR] 1.02, 95% CI 0.89–1.17, P = .78) or the ICU (OR 0.92, 95% CI 0.76–1.11, P = .4). They also found no significant differences in length of stay or duration of mechanical ventilation. This meta-analysis suggests that routine radiographs can be eliminated without adversely affecting outcomes in ICU patients.
A larger meta-analysis (9 trials, 39,358 radiographs, 9,611 patients) published in 2012 by Ganapathy et al6 also found no harm associated with restrictive radiography protocols. These investigators compared a daily chest radiography protocol against a protocol based on clinical indications. The primary outcome was the mortality rate in the ICU; secondary outcomes were the mortality rate in the hospital, the length of stay in the ICU, and duration of mechanical ventilation. They found no differences between routine and restrictive strategies in terms of ICU mortality (risk ratio [RR] 1.04, 95% CI 0.84–1.28, P = .72), hospital mortality (RR 0.98, 95% CI 0.68–1.41, P = .91), or other secondary outcomes.
Clinically indicated testing is better
The conclusion from these studies is that routine chest radiographs in patients undergoing mechanical ventilation does not improve patient outcomes, and thus, a clinically indicated protocol is preferred.
Furthermore, routine daily radiographs have adverse effects such as more cumulative radiation exposure to the patient7 and greater risk of accidental removal of devices (eg, catheters, tubes).8 Another concern is a higher risk of hospital-associated infections from bacterial spread from caregivers’ hands.9
Finally, daily radiographs increase the use of healthcare resources and expenditures. In a 2011 study, Gershengorn et al1 estimated that adopting a clinically indicated radiography strategy could save more than $144 million annually in the United States.
The ACR agrees. Appropriateness criteria published by the American College of Radiology (ACR) in 201510 recommend against routine daily chest radiographs in the ICU, in keeping with the findings of the critical care community. The ACR recommends an initial radiograph at admission to the ICU. However, follow-up radiographs should be obtained only for specific clinical indications, including a change in the patient’s clinical condition or to check for proper placement of endotracheal or nasogastric or orogastric tubes, pulmonary arterial catheters, central venous catheters, chest tubes, and other life-support devices.
Ultrasonography as an alternative
Ultrasonography is widely available and provides an alternative to chest radiography for detecting significant abnormalities in patients on mechanical ventilation without exposing them to radiation and using relatively fewer resources.
A 2012 meta-analysis (8 studies, 1,048 patients) found that bedside ultrasonography reliably detects pneumothorax.11 It can also provide a rapid diagnosis of the cause of acute respiratory failure such as pneumonia or pulmonary edema.12 Ultrasonography, with the appropriate expertise, can also confirm the position of an endotracheal tube13 or central venous catheter.14
ARTERIAL BLOOD GAS TESTING: DAILY VS CLINICALLY INDICATED
Arterial blood gas testing has value for managing patients undergoing mechanical ventilation, and it is one of the most commonly performed diagnostic tests in the ICU. It provides reliable information about the patient’s oxygenation and acid-base status. It is commonly requested when changing ventilator settings.
Downsides. Arterial blood gas measurements account for 10% to 20% of the cost incurred during ICU stay.15 In addition, they require an arterial puncture—an invasive procedure associated with potentially serious complications such as occlusion of the artery, digital embolization leading to digital ischemia, local infection, pseudoaneurysm, hematoma, bleeding, and skin necrosis.
Is daily testing needed?
Guidelines say no. The 2013 American Association for Respiratory Care16 guidelines suggest that arterial blood gas testing should be based on the clinical assessment of the patient. They recommend blood gas analysis to evaluate the patient’s ventilatory status (reflected by the partial pressure of arterial carbon dioxide [PaCO2], acid-base status (reflected by pH), arterial oxygenation (partial pressure of arterial oxygen [PaO2] and oxyhemoglobin saturation), oxygen-carrying capacity, and whether the patient likely has an intrapulmonary shunt. They state that testing is useful to quantify the response to therapeutic or diagnostic interventions such as cardiopulmonary exercise testing, to monitor severity and progression of documented disease, and to assess the adequacy of circulatory response.
Studies agree
The ACR recommendation to test “as clinically indicated” is supported by studies showing that patient outcomes are not inferior for arterial blood gas testing when clinically indicated instead of daily, and that this practice is associated with fewer complications, less resource use, and reduced overall patient care costs.
A 2015 study compared the efficacy and safety of obtaining arterial blood gases based on clinical assessment vs daily in 300 critically ill patients.17 Overall, fewer samples were obtained per patient in the clinical assessment group than in the daily group (all patients 3.7 vs 5.5; ventilated patients 2.03 vs 6.12; P < .001 for both). In ventilated patients, there was a 60% decrease in arterial blood gas orders without affecting patient outcomes and safety, including a lower risk of complications and overall cost of care.
In another study, Martinez-Balzano et al18 evaluated the effect of guidelines they developed to optimize the use of arterial blood gas testing in their ICUs. These guidelines encouraged testing of arterial blood gases after an acute respiratory event or for a rational clinical concern, and discouraged testing for routine surveillance, after planned changes of positive end-expiratory pressure or inspired oxygen fraction on mechanical ventilation, for spontaneous breathing trials, or when a disorder was not suspected.
Compared with data collected before implementation, these guidelines reduced the number of arterial blood gas tests by 821.5 per month (41.5%), or approximately 1 test per patient per mechanical-ventilation day for each month (43.1%; P < .001). Appropriately indicated testing rose to 83.4% from a baseline of 67.5% (P = .002). Additionally, this approach was associated with saving 49 liters of blood, reducing ICU costs by $39,432, and freeing up 1,643 staff work hours for other tasks. There were no significant differences in days on mechanical ventilation, severity of illness, or mortality between the 2 periods.18
Extubation effects. Routine arterial blood gas testing has not been shown to affect extubation decisions in patients on mechanical ventilation. In a study of 83 patients who completed a spontaneous breathing trial (total of 100 trials), Salam et al19 found arterial blood gas values obtained during the trial did not change the extubation decision in 93% of the cases.
In a study of 54 extubations in 52 patients,20 65% of the extubations were performed without obtaining an arterial blood gas test after the patient completed a trial of spontaneous breathing. The extubation success rate was 94% for the entire group, and it was the same regardless of whether testing was done (94.7% vs 94.3%, respectively).
Alternatives to arterial blood gases
There are less-invasive means to obtain the information that comes from an arterial blood gas test.
Pulse oximetry is a rapid noninvasive tool that provides continuous assessment of peripheral arterial oxygen saturation as a surrogate marker for tissue arterial oxygenation. However, it cannot measure PaO2 or PaCO2.21
Transcutaneous carbon dioxide (PTCO2) monitoring is another continuous noninvasive alternative. The newer PTCO2 devices are useful in patients with acute respiratory failure and in critically ill patients on vasopressors or vasodilators. Studies have shown good correlation between PTCO2 and PaCO2.22,23
End-tidal carbon dioxide (PetCO2) is another alternative to estimate PaCO2. It can also be used to confirm endotracheal tube placement, during transportation, during procedures in which the patient is under conscious sedation, and to monitor the effectiveness of cardiopulmonary resuscitation and return of circulation after cardiac arrest. PetCO2 measurements are not as accurate as arterial blood gas testing owing to a difference of approximately 2 to 5 mm Hg between PaCO2 and PetCO2 in normal lungs due to alveolar dead space. This difference may be much higher depending on the clinical condition and the degree of alveolar dead space.21,24,25
Venous blood gases, which can be obtained from a peripheral or central venous catheter, are adequate to assess pH and partial pressure of carbon dioxide (PCO2) in hemodynamically stable patients. Walkey et al26 found that the accuracy of venous blood gas measurement to predict arterial blood gases was 90%. They recommended adjusting the venous pH up by 0.05 and the PCO2 down by 5 mm Hg to account for the positive bias of venous blood gases. A limitation of this method is that the values are not reliable in patients who are in shock.
These alternatives can be used as a substitute for daily arterial blood gases. However, in certain clinical scenarios, arterial blood gas measurement remains a necessary and useful clinical tool.
TAKE-HOME MESSAGE
Most scientific evidence suggests that chest radiographs and arterial blood gas measurement in patients undergoing mechanical ventilation—and critically ill, in general—are best done when clinically indicated rather than routinely on a daily basis. This will reduce cost and harm to patients that may result from these unnecessary tests and not adversely affect outcomes.
No, they are not required or needed, but daily radiography and arterial blood gas testing are common practice: eg, 60% of intensive care unit (ICU) patients get daily radiographs,1 even though results provide low diagnostic yield and are unlikely to alter patient management compared with testing only when indicated.
The Choosing Wisely campaign,2 a collaborative effort of a number of professional societies, advises against ordering these diagnostic tests daily because routine testing increases risks to patients and burdens the healthcare system. Instead, testing is recommended only in response to a specific clinical question, or when the test results will affect the patient’s treatment.
CHEST RADIOGRAPHS: DAILY VS CLINICALLY INDICATED
Chest radiographs enable practitioners to monitor the position of endotracheal tubes and central venous catheters, evaluate fluid status, follow up on abnormal findings, detect complications of procedures (such as a pneumothorax), and identify otherwise undetected conditions.
And daily chest radiographs often detect abnormalities. A 1991 study by Hall et al3 of 538 chest radiographs in 74 patients on mechanical ventilation reported that 30% of daily routine chest radiographs disclosed a new but minor finding (eg, a small change in endotracheal tube position or a small infiltrate). The new findings were major in 13 (17.6%) of the 74 patients (95% confidence interval [CI] 9%–26%). These included findings that required an immediate diagnostic or therapeutic intervention (eg, endotracheal tube below the tracheal carina, malposition of a catheter, pneumothorax, large pleural effusion).
But most studies say daily radiographs are not needed. In a large prospective study published in 2006, Graat et al4 evaluated the clinical value of 2,457 routine chest radiographs in 754 patients in a combined surgical and medical ICU. Daily chest radiographs revealed new or unexpected findings in 5.8% of cases, but only 2.2% warranted a change in therapy. No differences were found between the medical and surgical patients. The authors concluded that daily routine radiographs in ICU patients seldom reveal unexpected, clinically relevant abnormalities, and those findings rarely require urgent intervention.
A 2010 meta-analysis of 8 studies (7,078 patients) by Oba and Zaza5 compared on-demand and daily routine strategies of performing chest radiographs. They estimated that eliminating daily routine chest radiographs would not affect death rates in the hospital (odds ratio [OR] 1.02, 95% CI 0.89–1.17, P = .78) or the ICU (OR 0.92, 95% CI 0.76–1.11, P = .4). They also found no significant differences in length of stay or duration of mechanical ventilation. This meta-analysis suggests that routine radiographs can be eliminated without adversely affecting outcomes in ICU patients.
A larger meta-analysis (9 trials, 39,358 radiographs, 9,611 patients) published in 2012 by Ganapathy et al6 also found no harm associated with restrictive radiography protocols. These investigators compared a daily chest radiography protocol against a protocol based on clinical indications. The primary outcome was the mortality rate in the ICU; secondary outcomes were the mortality rate in the hospital, the length of stay in the ICU, and duration of mechanical ventilation. They found no differences between routine and restrictive strategies in terms of ICU mortality (risk ratio [RR] 1.04, 95% CI 0.84–1.28, P = .72), hospital mortality (RR 0.98, 95% CI 0.68–1.41, P = .91), or other secondary outcomes.
Clinically indicated testing is better
The conclusion from these studies is that routine chest radiographs in patients undergoing mechanical ventilation does not improve patient outcomes, and thus, a clinically indicated protocol is preferred.
Furthermore, routine daily radiographs have adverse effects such as more cumulative radiation exposure to the patient7 and greater risk of accidental removal of devices (eg, catheters, tubes).8 Another concern is a higher risk of hospital-associated infections from bacterial spread from caregivers’ hands.9
Finally, daily radiographs increase the use of healthcare resources and expenditures. In a 2011 study, Gershengorn et al1 estimated that adopting a clinically indicated radiography strategy could save more than $144 million annually in the United States.
The ACR agrees. Appropriateness criteria published by the American College of Radiology (ACR) in 201510 recommend against routine daily chest radiographs in the ICU, in keeping with the findings of the critical care community. The ACR recommends an initial radiograph at admission to the ICU. However, follow-up radiographs should be obtained only for specific clinical indications, including a change in the patient’s clinical condition or to check for proper placement of endotracheal or nasogastric or orogastric tubes, pulmonary arterial catheters, central venous catheters, chest tubes, and other life-support devices.
Ultrasonography as an alternative
Ultrasonography is widely available and provides an alternative to chest radiography for detecting significant abnormalities in patients on mechanical ventilation without exposing them to radiation and using relatively fewer resources.
A 2012 meta-analysis (8 studies, 1,048 patients) found that bedside ultrasonography reliably detects pneumothorax.11 It can also provide a rapid diagnosis of the cause of acute respiratory failure such as pneumonia or pulmonary edema.12 Ultrasonography, with the appropriate expertise, can also confirm the position of an endotracheal tube13 or central venous catheter.14
ARTERIAL BLOOD GAS TESTING: DAILY VS CLINICALLY INDICATED
Arterial blood gas testing has value for managing patients undergoing mechanical ventilation, and it is one of the most commonly performed diagnostic tests in the ICU. It provides reliable information about the patient’s oxygenation and acid-base status. It is commonly requested when changing ventilator settings.
Downsides. Arterial blood gas measurements account for 10% to 20% of the cost incurred during ICU stay.15 In addition, they require an arterial puncture—an invasive procedure associated with potentially serious complications such as occlusion of the artery, digital embolization leading to digital ischemia, local infection, pseudoaneurysm, hematoma, bleeding, and skin necrosis.
Is daily testing needed?
Guidelines say no. The 2013 American Association for Respiratory Care16 guidelines suggest that arterial blood gas testing should be based on the clinical assessment of the patient. They recommend blood gas analysis to evaluate the patient’s ventilatory status (reflected by the partial pressure of arterial carbon dioxide [PaCO2], acid-base status (reflected by pH), arterial oxygenation (partial pressure of arterial oxygen [PaO2] and oxyhemoglobin saturation), oxygen-carrying capacity, and whether the patient likely has an intrapulmonary shunt. They state that testing is useful to quantify the response to therapeutic or diagnostic interventions such as cardiopulmonary exercise testing, to monitor severity and progression of documented disease, and to assess the adequacy of circulatory response.
Studies agree
The ACR recommendation to test “as clinically indicated” is supported by studies showing that patient outcomes are not inferior for arterial blood gas testing when clinically indicated instead of daily, and that this practice is associated with fewer complications, less resource use, and reduced overall patient care costs.
A 2015 study compared the efficacy and safety of obtaining arterial blood gases based on clinical assessment vs daily in 300 critically ill patients.17 Overall, fewer samples were obtained per patient in the clinical assessment group than in the daily group (all patients 3.7 vs 5.5; ventilated patients 2.03 vs 6.12; P < .001 for both). In ventilated patients, there was a 60% decrease in arterial blood gas orders without affecting patient outcomes and safety, including a lower risk of complications and overall cost of care.
In another study, Martinez-Balzano et al18 evaluated the effect of guidelines they developed to optimize the use of arterial blood gas testing in their ICUs. These guidelines encouraged testing of arterial blood gases after an acute respiratory event or for a rational clinical concern, and discouraged testing for routine surveillance, after planned changes of positive end-expiratory pressure or inspired oxygen fraction on mechanical ventilation, for spontaneous breathing trials, or when a disorder was not suspected.
Compared with data collected before implementation, these guidelines reduced the number of arterial blood gas tests by 821.5 per month (41.5%), or approximately 1 test per patient per mechanical-ventilation day for each month (43.1%; P < .001). Appropriately indicated testing rose to 83.4% from a baseline of 67.5% (P = .002). Additionally, this approach was associated with saving 49 liters of blood, reducing ICU costs by $39,432, and freeing up 1,643 staff work hours for other tasks. There were no significant differences in days on mechanical ventilation, severity of illness, or mortality between the 2 periods.18
Extubation effects. Routine arterial blood gas testing has not been shown to affect extubation decisions in patients on mechanical ventilation. In a study of 83 patients who completed a spontaneous breathing trial (total of 100 trials), Salam et al19 found arterial blood gas values obtained during the trial did not change the extubation decision in 93% of the cases.
In a study of 54 extubations in 52 patients,20 65% of the extubations were performed without obtaining an arterial blood gas test after the patient completed a trial of spontaneous breathing. The extubation success rate was 94% for the entire group, and it was the same regardless of whether testing was done (94.7% vs 94.3%, respectively).
Alternatives to arterial blood gases
There are less-invasive means to obtain the information that comes from an arterial blood gas test.
Pulse oximetry is a rapid noninvasive tool that provides continuous assessment of peripheral arterial oxygen saturation as a surrogate marker for tissue arterial oxygenation. However, it cannot measure PaO2 or PaCO2.21
Transcutaneous carbon dioxide (PTCO2) monitoring is another continuous noninvasive alternative. The newer PTCO2 devices are useful in patients with acute respiratory failure and in critically ill patients on vasopressors or vasodilators. Studies have shown good correlation between PTCO2 and PaCO2.22,23
End-tidal carbon dioxide (PetCO2) is another alternative to estimate PaCO2. It can also be used to confirm endotracheal tube placement, during transportation, during procedures in which the patient is under conscious sedation, and to monitor the effectiveness of cardiopulmonary resuscitation and return of circulation after cardiac arrest. PetCO2 measurements are not as accurate as arterial blood gas testing owing to a difference of approximately 2 to 5 mm Hg between PaCO2 and PetCO2 in normal lungs due to alveolar dead space. This difference may be much higher depending on the clinical condition and the degree of alveolar dead space.21,24,25
Venous blood gases, which can be obtained from a peripheral or central venous catheter, are adequate to assess pH and partial pressure of carbon dioxide (PCO2) in hemodynamically stable patients. Walkey et al26 found that the accuracy of venous blood gas measurement to predict arterial blood gases was 90%. They recommended adjusting the venous pH up by 0.05 and the PCO2 down by 5 mm Hg to account for the positive bias of venous blood gases. A limitation of this method is that the values are not reliable in patients who are in shock.
These alternatives can be used as a substitute for daily arterial blood gases. However, in certain clinical scenarios, arterial blood gas measurement remains a necessary and useful clinical tool.
TAKE-HOME MESSAGE
Most scientific evidence suggests that chest radiographs and arterial blood gas measurement in patients undergoing mechanical ventilation—and critically ill, in general—are best done when clinically indicated rather than routinely on a daily basis. This will reduce cost and harm to patients that may result from these unnecessary tests and not adversely affect outcomes.
References
Gershengorn HB, Wunsch H, Scales DC, Rubenfeld GD. Trends in use of daily chest radiographs among US adults receiving mechanical ventilation. JAMA Netw Open 2018; 1(4):e181119. doi:10.1001/jamanetworkopen.2018.1119
Hall JB, White SR, Karrison T. Efficacy of daily routine chest radiographs in intubated, mechanically ventilated patients. Crit Care Med 1991; 19(5):689–693. pmid:2026031
Graat ME, Choi G, Wolthuis EK, et al. The clinical value of daily routine chest radiographs in a mixed medical-surgical intensive care unit is low. Crit Care 2006; 10(1):R11. doi:10.1186/cc3955
Oba Y, Zaza T. Abandoning daily routine chest radiography in the intensive care unit: meta-analysis. Radiology 2010; 255(2):386–395. doi:10.1148/radiol.10090946
Ganapathy A, Adhikari NK, Spiegelman J, Scales DC. Routine chest x-rays in intensive care units: a systematic review and meta-analysis. Crit Care 2012; 16(2):R68. doi:10.1186/cc11321
Krishnan S, Moghekar A, Duggal A, et al. Radiation exposure in the medical ICU: predictors and characteristics. Chest 2018; 153(5):1160–1168. doi:10.1016/j.chest.2018.01.019
Hejblum G, Chalumeau-Lemoine L, Ioos V, et al. Comparison of routine and on-demand prescription of chest radiographs in mechanically ventilated adults: a multicentre, cluster-randomised, two-period crossover study. Lancet 2009; 374(9702):1687–1693. doi:10.1016/S0140-6736(09)61459-8
Levin PD, Shatz O, Sviri S, et al. Contamination of portable radiograph equipment with resistant bacteria in the ICU. Chest 2009; 136(2):426–432. doi:10.1378/chest.09-0049
Suh RD, Genshaft SJ, Kirsch J, et al. ACR Appropriateness Criteria® Intensive Care Unit Patients. J Thorac Imaging 2015; 30(6):W63–W65. doi:10.1097/RTI.0000000000000174
Alrajhi K, Woo MY, Vaillancourt C. Test characteristics of ultrasonography for the detection of pneumothorax: a systematic review and meta-analysis. Chest 2012; 141(3):703–708. doi:10.1378/chest.11-0131
Lichetenstein DA, Meziere GA. Relevance of lung ultrasound in the diagnosis of acute respiratory failure: the BLUE protocol. Chest 2008; 134(1):117–125. doi:10.1378/chest.07-2800
Das SK, Choupoo NS, Haldar R, Lahkar A. Transtracheal ultrasound for verification of endotracheal tube placement: a systematic review and meta-analysis. Can J Anaesth 2015; 62(4):413–423. doi:10.1007/s12630-014-0301-z
Ablordeppey EA, Drewry AM, Beyer AB, et al. Diagnostic accuracy of central venous catheter confirmation by bedside ultrasound versus chest radiography in critically ill patients: a systematic review and meta-analysis. Crit Care Med 2017; 45(4):715–724. doi:10.1097/CCM.0000000000002188
DellaVolpe JD, Chakraborti C, Cerreta K, et al. Effects of implementing a protocol for arterial blood gas use on ordering practices and diagnostic yield. Healthc (Amst) 2014; 2(2):130–135. doi:10.1016/j.hjdsi.2013.09.006
Davis MD, Walsh BK, Sittig SE, Restrepo RD. AARC clinical practice guideline: blood gas analysis and hemoximetry. Respir Care 2013; 58(10):1694–1703. doi:10.4187/respcare.02786
Blum FE, Lund ET, Hall HA, Tachauer AD, Chedrawy EG, Zilberstein J. Reevaluation of the utilization of arterial blood gas analysis in the intensive care unit: effects on patient safety and patient outcome. J Crit Care 2015; 30(2):438.e1–e5. doi:10.1016/j.jcrc.2014.10.025
Martínez-Balzano CD, Oliveira P, O’Rourke M, Hills L, Sosa AF; Critical Care Operations Committee of the UMass Memorial Healthcare Center. An educational intervention optimizes the use of arterial blood gas determinations across ICUs from different specialties: a quality-improvement study. Chest 2017; 151(3):579–585. doi:10.1016/j.chest.2016.10.035
Salam A, Smina M, Gada P, et al. The effect of arterial blood gas values on extubation decisions. Respir Care 2003; 48(11):1033–1037. pmid:14585115
Pawson SR, DePriest JL. Are blood gases necessary in mechanically ventilated patients who have successfully completed a spontaneous breathing trial? Respir Care 2004; 49(11):1316–1319. pmid:15507165
Soubani AO. Noninvasive monitoring of oxygen and carbon dioxide. Am J Emerg Med 2001; 19(2):141–146. doi:10.1053/ajem.2001.21353
Nicolini A, Ferrari MB. Evaluation of a transcutaneous carbon dioxide monitor in patients with acute respiratory failure. Ann Thorac Med 2011; 6(4):217–220. doi:10.4103/1817-1737.84776
Bendjelid K, Schütz N, Stotz M, Gerard I, Suter PM, Romand JA. Transcutaneous PCO2 monitoring in critically ill adults: clinical evaluation of a new sensor. Crit Care Med 2005; 33(10):2203–2206. pmid:16215371
Huttmann SE, Windisch W, Storre JH. Techniques for the measurement and monitoring of carbon dioxide in the blood. Ann Am Thorac Soc 2014; 11(4):645–652. doi:10.1513/AnnalsATS.201311-387FR
McSwain SD, Hamel DS, Smith PB, et al. End-tidal and arterial carbon dioxide measurements correlate across all levels of physiologic dead space. Respir Care 2010; 55(3):288–293. pmid:20196877
Walkey AJ, Farber HW, O'Donnell C, Cabral H, Eagan JS, Philippides GJ. The accuracy of the central venous blood gas for acid-base monitoring. J Intensive Care Med 2010; 25(2):104–110. doi:10.1177/0885066609356164
References
Gershengorn HB, Wunsch H, Scales DC, Rubenfeld GD. Trends in use of daily chest radiographs among US adults receiving mechanical ventilation. JAMA Netw Open 2018; 1(4):e181119. doi:10.1001/jamanetworkopen.2018.1119
Hall JB, White SR, Karrison T. Efficacy of daily routine chest radiographs in intubated, mechanically ventilated patients. Crit Care Med 1991; 19(5):689–693. pmid:2026031
Graat ME, Choi G, Wolthuis EK, et al. The clinical value of daily routine chest radiographs in a mixed medical-surgical intensive care unit is low. Crit Care 2006; 10(1):R11. doi:10.1186/cc3955
Oba Y, Zaza T. Abandoning daily routine chest radiography in the intensive care unit: meta-analysis. Radiology 2010; 255(2):386–395. doi:10.1148/radiol.10090946
Ganapathy A, Adhikari NK, Spiegelman J, Scales DC. Routine chest x-rays in intensive care units: a systematic review and meta-analysis. Crit Care 2012; 16(2):R68. doi:10.1186/cc11321
Krishnan S, Moghekar A, Duggal A, et al. Radiation exposure in the medical ICU: predictors and characteristics. Chest 2018; 153(5):1160–1168. doi:10.1016/j.chest.2018.01.019
Hejblum G, Chalumeau-Lemoine L, Ioos V, et al. Comparison of routine and on-demand prescription of chest radiographs in mechanically ventilated adults: a multicentre, cluster-randomised, two-period crossover study. Lancet 2009; 374(9702):1687–1693. doi:10.1016/S0140-6736(09)61459-8
Levin PD, Shatz O, Sviri S, et al. Contamination of portable radiograph equipment with resistant bacteria in the ICU. Chest 2009; 136(2):426–432. doi:10.1378/chest.09-0049
Suh RD, Genshaft SJ, Kirsch J, et al. ACR Appropriateness Criteria® Intensive Care Unit Patients. J Thorac Imaging 2015; 30(6):W63–W65. doi:10.1097/RTI.0000000000000174
Alrajhi K, Woo MY, Vaillancourt C. Test characteristics of ultrasonography for the detection of pneumothorax: a systematic review and meta-analysis. Chest 2012; 141(3):703–708. doi:10.1378/chest.11-0131
Lichetenstein DA, Meziere GA. Relevance of lung ultrasound in the diagnosis of acute respiratory failure: the BLUE protocol. Chest 2008; 134(1):117–125. doi:10.1378/chest.07-2800
Das SK, Choupoo NS, Haldar R, Lahkar A. Transtracheal ultrasound for verification of endotracheal tube placement: a systematic review and meta-analysis. Can J Anaesth 2015; 62(4):413–423. doi:10.1007/s12630-014-0301-z
Ablordeppey EA, Drewry AM, Beyer AB, et al. Diagnostic accuracy of central venous catheter confirmation by bedside ultrasound versus chest radiography in critically ill patients: a systematic review and meta-analysis. Crit Care Med 2017; 45(4):715–724. doi:10.1097/CCM.0000000000002188
DellaVolpe JD, Chakraborti C, Cerreta K, et al. Effects of implementing a protocol for arterial blood gas use on ordering practices and diagnostic yield. Healthc (Amst) 2014; 2(2):130–135. doi:10.1016/j.hjdsi.2013.09.006
Davis MD, Walsh BK, Sittig SE, Restrepo RD. AARC clinical practice guideline: blood gas analysis and hemoximetry. Respir Care 2013; 58(10):1694–1703. doi:10.4187/respcare.02786
Blum FE, Lund ET, Hall HA, Tachauer AD, Chedrawy EG, Zilberstein J. Reevaluation of the utilization of arterial blood gas analysis in the intensive care unit: effects on patient safety and patient outcome. J Crit Care 2015; 30(2):438.e1–e5. doi:10.1016/j.jcrc.2014.10.025
Martínez-Balzano CD, Oliveira P, O’Rourke M, Hills L, Sosa AF; Critical Care Operations Committee of the UMass Memorial Healthcare Center. An educational intervention optimizes the use of arterial blood gas determinations across ICUs from different specialties: a quality-improvement study. Chest 2017; 151(3):579–585. doi:10.1016/j.chest.2016.10.035
Salam A, Smina M, Gada P, et al. The effect of arterial blood gas values on extubation decisions. Respir Care 2003; 48(11):1033–1037. pmid:14585115
Pawson SR, DePriest JL. Are blood gases necessary in mechanically ventilated patients who have successfully completed a spontaneous breathing trial? Respir Care 2004; 49(11):1316–1319. pmid:15507165
Soubani AO. Noninvasive monitoring of oxygen and carbon dioxide. Am J Emerg Med 2001; 19(2):141–146. doi:10.1053/ajem.2001.21353
Nicolini A, Ferrari MB. Evaluation of a transcutaneous carbon dioxide monitor in patients with acute respiratory failure. Ann Thorac Med 2011; 6(4):217–220. doi:10.4103/1817-1737.84776
Bendjelid K, Schütz N, Stotz M, Gerard I, Suter PM, Romand JA. Transcutaneous PCO2 monitoring in critically ill adults: clinical evaluation of a new sensor. Crit Care Med 2005; 33(10):2203–2206. pmid:16215371
Huttmann SE, Windisch W, Storre JH. Techniques for the measurement and monitoring of carbon dioxide in the blood. Ann Am Thorac Soc 2014; 11(4):645–652. doi:10.1513/AnnalsATS.201311-387FR
McSwain SD, Hamel DS, Smith PB, et al. End-tidal and arterial carbon dioxide measurements correlate across all levels of physiologic dead space. Respir Care 2010; 55(3):288–293. pmid:20196877
Walkey AJ, Farber HW, O'Donnell C, Cabral H, Eagan JS, Philippides GJ. The accuracy of the central venous blood gas for acid-base monitoring. J Intensive Care Med 2010; 25(2):104–110. doi:10.1177/0885066609356164
An 18-year-old man without any significant medical history was transferred from another hospital for higher-level care after presenting with unremitting chest pain. He had been in his usual state of good health until 7 days before presentation, when he developed mild rhinorrhea and a sore throat, but not a cough. He went to an outpatient clinic, where a rapid test for group A streptococci was done; the result was negative, and he was sent home on supportive measures.
On the day of admission, he awoke with severe, pressure-like, midsternal, nonradiating pain, which he rated 10 on a scale of 10. The pain intensified in the supine position and improved with sitting. A complete review of systems was otherwise negative. He denied having had similar symptoms in the past, as well as sick contacts, recent travel, toxin exposure, illicit substance abuse, pets at home, or tick bites. His family history was negative for cardiac arrhythmias, premature coronary artery disease, thoracic aneurysms or dissection, and infiltrative disorders. His surgical and social histories were unremarkable. He said he had no drug allergies.
Figure 1. The patient’s electrocardiogram on presentation shows ST-segment elevation (arrows) over the lateral and inferior distribution (V4–V6, II, III, and aVF).
An electrocardiogram was obtained (Figure 1). His troponin I level was 7.0 ng/mL (reference range < 0.04 ng/mL).
On examination, his temperature was 38.1°C (100.6°F), heart rate 101 beats per minute, blood pressure 142/78 mm Hg, respiratory rate 16 breaths per minute, and oxygen saturation 98% on room air. He appeared anxious but was in no acute distress. Neck examination showed no elevation in jugular venous pulsation, bruits, thyromegaly, or lymphadenopathy. Cardiac examination revealed tachycardia without murmurs, rubs, or gallops. Lungs were clear to auscultation. Examination of all 4 extremities found 2+ pulses (on a scale of 0 to 4+) throughout and no cyanosis, clubbing, or edema. Abdominal, neurologic, and dermatologic examinations were unremarkable.
Further blood testing revealed the following:
Troponin I (3 hours after the first level) 15.5 ng/mL
B-type natriuretic peptide 200 mg/dL (reference range 0–100 mg/dL)
C-reactive protein 0.9 mg/dL (reference range 0.0–0.8 mg/dL)
Erythrocyte sedimentation rate 10 mm/h (reference range < 15 mm/h).
Metabolic and hematologic assessments were unremarkable. A toxicology screen for drugs of abuse was negative. Viral serologic testing was not done.
A chest radiograph showed no acute cardiopulmonary processes.
Given his presenting symptoms, persistent tachycardia, rapidly rising troponin I level, and electrocardiogram showing diffuse ST elevation, he was taken for urgent cardiac catheterization. Coronary angiography revealed no evidence of atherosclerotic disease, acute thrombosis, dissection, or aneurysm. Echocardiography 2 hours after the procedure showed a normal ejection fraction and no regional wall-motion abnormalities or valvular heart disease.
FURTHER TESTING
1. Which test should be done next to further evaluate this patient’s chest pain?
Serum viral serologic testing
Serum free light chain assay
Nuclear myocardial perfusion study
Cardiac magnetic resonance imaging (MRI)
Endomyocardial biopsy
In this patient without ischemic coronary disease or valvular heart disease, the recent upper respiratory tract prodrome, active positional chest pain, and diffuse electrocardiographic changes raise the possibility of myocarditis with pericardial involvement.
Viral serologic tests
Viral serologic tests are often obtained in the workup of myocarditis as a noninvasive means of detecting an infectious cause.
However, this approach has several problems. First, a positive serologic result is a signal of the peripheral immune response to a pathogen but does not necessarily indicate active myocardial inflammation. Additionally, circulating immunoglobulin G against cardiotropic viruses is commonly found, even in the absence of myocarditis.1 This is often the result of a high prevalence and exposure to these viruses in the general population. Further, trials have shown no correlation between serologic results and organisms identified by endomyocardial biopsy.2
Thus, serologic testing seems to be of limited utility, reserved for testing for infection with Borrelia burgdorferi (Lyme disease) in endemic areas, hepatitis C virus, human immunodeficiency virus in patients at high risk, Rickettsia conorii, and Rickettsia rickettsii.3
Serum free light chain testing for amyloidosis
Serum free light chain testing is replacing serum and urine protein electrophoresis in the workup of cardiac amyloidosis,4 as electrophoresis has poor sensitivity.4,5
Cardiac amyloidosis often affects older persons, although in rare cases it can affect young patients who carry mutations in the transthyretin gene (ATTR amyloidosis).6 This diagnosis is unlikely in our patient, as he has no other affected organ systems (amyloidosis often affects the renal and neurologic systems), normal QRS voltages on electrocardiography (which are often but not always low in amyloidosis), and no left ventricular hypertrophy or diastolic dysfunction on echocardiography (which are often seen in amyloidosis).4
Nuclear perfusion imaging for sarcoidosis
Nuclear imaging has a limited role in evaluating myocarditis,3 but positron-emission tomography with fluorine-18 fluorodeoxyglucose has a diagnostic role in sarcoidosis, an immune-mediated cause of myocarditis.7
Based on the acuity of the patient’s presentation, preceded by upper respiratory tract symptoms, sarcoidosis is less likely. Sarcoidosis is difficult to diagnose, although when it is the cause of myocarditis, some clues exist, as patients usually present with heart failure symptoms, a second- or third-degree atrioventricular block, or a dilated left ventricle on echocardiography.3 All of these were absent in our patient.
Cardiac MRI
Cardiac MRI has undergone many advances, making it an extremely useful noninvasive test. It has excellent utility as a stand-alone test in diagnosing myocarditis and has synergistic value when combined with endomyocardial biopsy.8 It is indicated in hemodynamically stable patients with a clinical suspicion of myocarditis, persistent symptoms, absence of heart failure, and when imaging findings will change management. It is particularly useful to help elucidate a cause and guide tailored therapy.9 Therefore, it is a reasonable next step in the diagnostic pathway for this patient.10
Cardiac MRI also allows for concurrent assessment of scar. In myocardial infarction, the late gadolinium enhancement is subendocardial or transmural. In myocarditis, the pattern differs, being found in the subepicardial lateral free wall (in most patients with parvovirus B19) and mid-myocardial septum (in most patients with herpesvirus 6).9,11 Cardiac MRI also confers prognostic information for patients with suspected myocarditis.12
The Lake Louise criteria9 for the diagnosis of myocarditis require 2 of the following:
Evidence of myocardial edema
Increased ratio of early gadolinium enhancement between myocardium and skeletal muscle (indicates hyperemia)
At least 1 focal lesion with nonischemic late gadolinium enhancement (indicates cardiac myocyte injury or scarring).
The Lake Louise criteria may be replaced by T1 and T2 mapping, which was found to be considerably better for diagnosing myocarditis when the 2 were compared.9,13,14
Endomyocardial biopsy
Endomyocardial biopsy should not be delayed while waiting for cardiac MRI in patients who are hemodynamically unstable or present with life-threatening features (ventricular arrhythmia, left ventricular failure, or resuscitation after sudden cardiac death).3,10
The indications for endomyocardial biopsy have been highly debated. The 2013 guidelines from the European Society of Cardiology (ESC) recommending endomyocardial biopsy in all clinically suspected cases of myocarditis have only heightened the controversy.3 The American Heart Association (AHA) guidelines reserve biopsy for patients with suspected myocarditis who have acute or subacute heart failure symptoms or who do not respond to standard medical therapy.15 Other reasonable indications may include the following: myocarditis with life-threatening ventricular arrhythmias, suspicion of giant cell myocarditis, necrotizing eosinophilic myocarditis, or cardiac sarcoidosis.16
Endomyocardial biopsy is the only way to make a definitive diagnosis of myocarditis.3 However, given the patchy distribution of myocardial involvement, a negative result does not rule out myocarditis. The diagnostic utility can be improved by increasing the number of samples taken (at least 3 but up to 10), obtaining samples from both ventricles, and using cardiac MRI data to determine which sites to biopsy.3,13,17,18
Noninvasive testing such as cardiac MRI does not distinguish cell type or etiology (viral vs nonviral).3 Further, endomyocardial biopsy must be performed before immunosuppressive therapy can be safely started.3,16 At experienced centers, the complication rate is 0% to 0.8%.3 The addition of immunohistochemical testing and viral genomic detection by polymerase chain reaction testing have increased the sensitivity of this technique.19 Finally, endomyocardial biopsy can help rule out some of the other possibilities in the differential diagnosis for myocarditis, including infiltrative and storage diseases, and possibly cardiac tumors.3
Of additional note, the diffuse ST-segment elevation seen on the patient’s electrocardiogram (Figure 1) is indicative of subepicardial inflammation. Since the distribution involves more than one epicardial coronary territory, this helps to differentiate the changes from those that occur with myocardial infarction.20
CASE CONTINUED
Figure 2. Cardiac magnetic resonance imaging shows areas of patchy subepicardial late gadolinium enhancement (arrows).
The patient underwent cardiac MRI, which showed myocardial edema and patchy areas of late gadolinium enhancement, raising suspicion for myocarditis (Figure 2).
Causes of myocarditis are numerous (Table 1),3,21,22 but viral and postinfectious etiologies remain the most common causes of acute myocarditis.23
2. What is the most likely causative infectious agent?
Parvovirus B19
Coxsackievirus B
Adenovirus species
Human herpesvirus 6
Staphylococcus aureus
Corynebacterium diphtheria
Trypanosoma cruzi
Influenza H1/N1
INFECTIOUS CAUSES OF MYOCARDITIS
Coxsackievirus B was the agent most often linked to this condition from the 1950s through the 1990s. However, in the last 2 decades, adenovirus species and human herpesvirus 6 have been increasingly encountered, and recently, parvovirus B19 has been credited as the most common culprit,11,23 at least in the Western world. In developing nations, T cruzi and C diphtheria are the most common offenders.21
S aureus is a common cause of endocarditis, but it rarely plays a role in myocarditis. When it does, the myocarditis is often the sequela of profound bacteremia. This was much more common before antibiotics were invented.24,25
Influenza H1/N1 is not among the most common causes of viral myocarditis, but it should be considered during flu season, given its ability to result in fulminant myocarditis.3,26
TREATMENT FOR MYOCARDITIS
3. Which treatment is the most appropriate at this time?
Intravenous immunoglobulin
Interferon beta
Acyclovir
Prednisone
Colchicine
Treatment for myocarditis depends on the cause but always includes supportive care to address the constellation of presenting symptoms. Standard therapies for tachy- or bradyarrhythmias, heart failure, and hemodynamic derangement should be started.
Supportive care
In patients with severe left ventricular dysfunction, an implantable cardiac electronic device, left ventricular assist device, or heart transplant may ultimately be needed. However, if possible these should be deferred for several months to determine response to treatment, since the myocardium can possibly recover.16
Diuretics, beta-blockers, angiotensin II receptor blockers, angiotensin-converting enzyme inhibitors, and aldosterone antagonists should be given as part of guideline-directed medical therapy for patients with heart failure and reduced ejection fraction.3,27 However, whether and how the patient should be weaned from these agents after disease recovery are unknown.3
Intravenous immunoglobulin
Intravenous immunoglobulin in high doses has had mixed results. Its efficacy is well documented in children,21 but limited supportive data are available in adults.3 As such, recent ESC guidelines do not provide recommendations regarding its use in adults.3
Interferon beta
Interferon beta has shown promise in improving New York Heart Association class and left ventricular ejection fraction.3 This is attributed to its effects on eliminating adenoviral species and enteroviruses. Treatment of enteroviral organisms in particular has been associated with improved 10-year prognosis.3 Interferon beta also has in vitro data showing efficacy at diminishing apoptosis from parvovirus B19.28
Nucleoside analogues
Empiric treatment with nucleoside analogues (acyclovir, ganciclovir, and valacyclovir) has been tried for patients in whom human herpesvirus is suspected as the causative organism, although with unconfirmed effects.3 Consultation with an infectious disease specialist is recommended before starting these agents, and biopsy is often needed beforehand.3
Immunosuppressive agents
Immunosuppressive agents such as prednisone, azathioprine, and cyclosporine can be used in cases of biopsy-proven disease with manifestations of severe heart failure, especially if biopsy results reveal sarcoidosis, giant cell myocarditis, or necrotizing eosinophilic myocarditis. Although the results were neutral in the Myocarditis Treatment Trial,29 the cause of myocarditis in this trial was unknown. Therapy with such agents should be initiated after active infection is ruled out, which also would require a biopsy.
Colchicine
Mechanisms of chest pain in myocarditis include associated pericarditis and coronary artery vasospasm.3,23 Our patient’s chest pain changed when he changed position, possibly indicating associated pericarditis. In myocarditis with accompanying pericarditis symptoms, colchicine (1–2 mg as an initial dose and then 0.6 mg daily for up to 3 months) can be helpful in alleviating symptoms.21,30 Thus, starting this agent in a patient who presents with myocarditis in absence of heart failure, arrhythmias, or left ventricular dysfunction is prudent.
Colchicine is used mainly to address the pain associated with pericarditis. For patients who present with pericarditis without myocarditis, nonsteroidal anti-inflammatory drugs (NSAIDs) remain the first-line treatment, with the addition of colchicine leading to faster symptom resolution.30 The benefit of colchicine for isolated myocarditis is not well established, with only limited data showing some clinical effects.31
CASE CONTINUED
The patient was given colchicine 1.2 mg on the first day and then 0.6 mg daily. Within 2 days, his chest pain had resolved. He did not receive any immunosuppressive agents.
DISCHARGE INSTRUCTIONS
4. Before discharge, this patient should be instructed to do which of the following?
Take over-the-counter NSAIDs to supplement the effects of colchicine
Avoid competitive sports and athletics for at least 6 months
Call to schedule repeat cardiac MRI
No further instruction is needed
NSAIDs are used by themselves or in combination with colchicine in the treatment of pericarditis, but their use may be associated with worse outcomes in myocarditis.3,21 Thus, their use is not recommended in most cases.3
Excessive physical activity should be avoided for at least 6 months after the clinical syndrome resolves. This recommendation is included in the most recent ESC guidelines but is based mainly on expert opinion and murine models with coxsackievirus B.3 Periodic reassessment is indicated with exercise stress testing before return to strenuous activity.3,16,32 Testing should look for exercise tolerance, and exercise electrocardiography also helps to evaluate for clinically relevant arrythmias.
Cardiac MRI can help clarify the prognosis in myocarditis, but the role of repeat testing in guiding therapy is limited.3 Indications for repeat cardiac MRI include presence of 0 or 1 of the Lake Louise criteria (recall that 2 are necessary to make the diagnosis) with recurrence of symptoms and a high suspicion for myocardial inflammation.3,9 Repeat cardiac MRI was not performed for our patient.
CASE CONCLUDED
The patient was evaluated in the cardiology clinic within 1 week of discharge. At that time, he was in sinus tachycardia with a heart rate of 102 bpm, and he was instructed to avoid any exercise until further notice.
At 6-month follow-up, the sinus tachycardia had resolved. However, because persistent tachycardia had been noted at the first postdischarge visit, and in view of the extent of myocardial involvement, he underwent exercise treadmill testing to evaluate for ventricular arrhythmias. The study did show premature ventricular complexes and 1 ventricular couplet at submaximal exercise levels. As this indicated a higher risk of exercise-induced arrhythmias, he was asked to continue normal activity levels but to abstain from exercise until the next evaluation.
During his 1-year follow-up, a repeat treadmill test showed no ventricular ectopy. Holter monitoring was ordered and showed no premature ventricular complexes, supraventricular arrhythmias, or atrioventricular block within the 48-hour period.
At his 2-year evaluation, he had returned to playing basketball and soccer on weekends and reported no recurrence of his initial symptoms.
KEY POINTS
Figure 3. Our suggested approach to suspected acute myocarditis.Cardiac MRI has emerged as an excellent noninvasive imaging modality for the diagnosis of myocarditis.
Treatment of myocarditis depends on the cause and severity of the patient’s presentation, spanning the spectrum from conservative care to immunosuppressive agents and even heart failure therapy.
Excessive physical activity should be avoided for the first 6 months after disease diagnosis and treatment.
If myocarditis is associated with pericardial involvement, colchicine is the agent of choice, and NSAIDs should be avoided.
Our suggested strategy for approaching myocarditis is shown in Figure 3.
Mahfoud F, Gärtner B, Kindermann M, et al. Virus serology in patients with suspected myocarditis: utility or futility? Eur Heart J 2011; 32(7):897–903. doi:10.1093/eurheartj/ehq493
Caforio AL, Pankuweit S, Arbustini E, et al; European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J 2013; 34(33):2636–2648, 2648a–2648d. doi:10.1093/eurheartj/eht210
Donnelly JP, Hanna M. Cardiac amyloidosis: an update on diagnosis and treatment. Cleve Clin J Med 2017; 84(12 suppl 3):12–26. doi:10.3949/ccjm.84.s3.02
Siddiqi OK, Ruberg FL. Cardiac amyloidosis: an update on pathophysiology, diagnosis, and treatment. Trends Cardiovasc Med 2018; 28(1):10–21. doi:10.1016/j.tcm.2017.07.004
Gertz MA, Benson MD, Dyck PJ, et al. Diagnosis, prognosis, and therapy of transthyretin amyloidosis. J Am Coll Cardiol 2015; 66(21):2451–2466. doi:10.1016/j.jacc.2015.09.075
Blankstein R, Osborne M, Naya M, et al. Cardiac positron emission tomography enhances prognostic assessments of patients with suspected cardiac sarcoidosis. J Am Coll Cardiol 2014; 63(4):329–336. doi:10.1016/j.jacc.2013.09.022
Baccouche H, Mahrholtz H, Meinhardt G, et al. Diagnostic synergy of non-invasive cardiovascular magnetic resonance and invasive endomyocardial biopsy in troponin-positive patients without coronary artery disease. Eur Heart J 2009; 30(23):2869–2879. doi:10.1093/eurheartj/ehp328
Friedrich MG, Sechtem U, Schulz-Menger J, et al; International Consensus Group on Cardiovascular Magnetic Resonance in Myocarditis. Cardiovascular magnetic resonance in myocarditis: a JACC white paper. J Am Coll Cardiol 2009; 53(17):1475–1487. doi:10.1016/j.jacc.2009.02.007
Kindermann I, Barth C, Mahfoud F, et al. Update on myocarditis. J Am Coll Cardiol 2012; 59(9):779–792. doi:10.1016/j.jacc.2011.09.074
Mahrholdt H, Wagner A, Deluigi CC, et al. Presentation, patterns of myocardial damage, and clinical course of viral myocarditis. Circulation 2006; 114(15):1581–1590. doi:10.1161/CIRCULATIONAHA.105.606509
Gräni C, Eichhorn C, Bière L, et al. Prognostic value of cardiac magnetic resonance tissue characterization in risk stratifying patients with suspected myocarditis. J Am Coll Cardiol 2017; 70(16):1964–1976. doi:10.1016/j.jacc.2017.08.050
Lurz P, Luecke C, Eitel I, et al. Comprehensive cardiac magnetic resonance imaging in patients with suspected myocarditis: the MyoRacer-Trial. J Am Coll Cardiol 2016; 67(15):1800–1811. doi:10.1016/j.jacc.2016.02.013
Gannon MP, Schaub E, Griens CL, Saba SG. State of the art: evaluation and prognostication of myocarditis using cardiac MRI. J Magn Reson Imaging 2019; 49(7):e122–e131. doi:10.1002/jmri.26611
Cooper LT, Baughman KL, Feldman AM, et al. The role of endomyocardial biopsy in the management of cardiovascular disease: a scientific statement from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology endorsed by the Heart Failure Society of America and the Heart Failure Association of the European Society of Cardiology. Eur Heart J 2007; 28(24):3076–3093. doi:10.1093/eurheartj/ehm456
Sinagra G, Anzini M, Pereira NL, et al. Myocarditis in clinical practice. Mayo Clin Proc 2016; 91(9):1256–1266. doi:10.1016/j.mayocp.2016.05.013
Cooper LT, Baughman KL, Feldman AM, et al; American Heart Association; American College of Cardiology; European Society of Cardiology. The role of endomyocardial biopsy in the management of cardiovascular disease: a scientific statement from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology. Circulation 2007; 116(19):2216–2233. doi:10.1161/CIRCULATIONAHA.107.186093
Leone O, Veinot JP, Angelini A, et al. 2011 consensus statement on endomyocardial biopsy from the Association for European Cardiovascular Pathology and the Society for Cardiovascular Pathology. Cardiovasc Pathol 2012; 21(4):245–274. doi:10.1016/j.carpath.2011.10.001
Alraies MC, Klein AL. Should we still use electrocardiography to diagnose pericardial disease? Cleve Clin J Med 2013; 80(2):97–100. doi:10.3949/ccjm.80a.11144
Wasi F, Shuter J. Primary bacterial infection of the myocardium. Front Biosci 2003; 8:s228–s231. pmid:12700039
Al-Amoodi M, Rao K, Rao S, Brewer JH, Magalski A, Chhatriwalla AK. Fulminant myocarditis due to H1N1 influenza. Circ Heart Fail 2010; 3(3):e7–e9. doi:10.1161/CIRCHEARTFAILURE.110.938506
Yancy CW, Jessup M, Bozkurt B, et al. 2016 ACC/AHA/HFSA focused update on new pharmacological therapy for heart failure: an update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. J Am Coll Cardiol 2016; 68(13):1476–1488. doi:10.1016/j.jacc.2016.05.011
Schmidt-Lucke C, Spillmann F, Bock T, et al. Interferon beta modulates endothelial damage in patients with cardiac persistence of human parvovirus b19 infection. J Infect Dis 2010; 201(6):936–945. doi:10.1086/650700
Mason JW, O’Connell JB, Herskowitz A, et al. A clinical trial of immunosuppressive therapy for myocarditis: the Myocarditis Treatment Trial Investigators. N Engl J Med 1995; 333(5):269–275. doi:10.1056/NEJM199508033330501
Imazio M, Bobbio M, Cecchi E, et al. Colchicine in addition to conventional therapy for acute pericarditis: results of the COlchicine for acute PEricarditis (COPE) trial. Circulation 2005; 112(13):2012–2016. doi:10.1161/CIRCULATIONAHA.105.542738
Morgenstern D, Lisko J, Boniface NC, Mikolich BM, Mikolich JR. Myocarditis and colchicine: a new perspective from cardiac MRI. J Cardiovasc Magn Reson 2016; 18(suppl 1):0100.
Maron BJ, Zipes DP, Kovacs RJ. Eligibility and disqualification recommendations for competitive athletes with cardiovascular abnormalities: preamble, principles, and general considerations: a scientific statement from the American Heart Association and American College of Cardiology. J Am Coll Cardiol 2015; 66(21):2343–2349. doi:10.1016/j.jacc.2015.09.032
Amir Farid, MD Department of Cardiology, University of California Davis Medical Center, Sacramento
Neil Beri, MD Department of Cardiology, University of California Davis Medical Center, Sacramento
David Torres-Barba, MD, PhD Department of Cardiology, University of California San Diego
Charles Whitcomb, MD Department of Cardiology, University of California Davis Medical Center, Sacramento
Address: David Torres-Barba, MD, PhD, Department of Internal Medicine, University of California, Davis, 4150 V. Street, Sacramento, CA 95817; davidtorresbarba@gmail.com
Amir Farid, MD Department of Cardiology, University of California Davis Medical Center, Sacramento
Neil Beri, MD Department of Cardiology, University of California Davis Medical Center, Sacramento
David Torres-Barba, MD, PhD Department of Cardiology, University of California San Diego
Charles Whitcomb, MD Department of Cardiology, University of California Davis Medical Center, Sacramento
Address: David Torres-Barba, MD, PhD, Department of Internal Medicine, University of California, Davis, 4150 V. Street, Sacramento, CA 95817; davidtorresbarba@gmail.com
Author and Disclosure Information
Amir Farid, MD Department of Cardiology, University of California Davis Medical Center, Sacramento
Neil Beri, MD Department of Cardiology, University of California Davis Medical Center, Sacramento
David Torres-Barba, MD, PhD Department of Cardiology, University of California San Diego
Charles Whitcomb, MD Department of Cardiology, University of California Davis Medical Center, Sacramento
Address: David Torres-Barba, MD, PhD, Department of Internal Medicine, University of California, Davis, 4150 V. Street, Sacramento, CA 95817; davidtorresbarba@gmail.com
An 18-year-old man without any significant medical history was transferred from another hospital for higher-level care after presenting with unremitting chest pain. He had been in his usual state of good health until 7 days before presentation, when he developed mild rhinorrhea and a sore throat, but not a cough. He went to an outpatient clinic, where a rapid test for group A streptococci was done; the result was negative, and he was sent home on supportive measures.
On the day of admission, he awoke with severe, pressure-like, midsternal, nonradiating pain, which he rated 10 on a scale of 10. The pain intensified in the supine position and improved with sitting. A complete review of systems was otherwise negative. He denied having had similar symptoms in the past, as well as sick contacts, recent travel, toxin exposure, illicit substance abuse, pets at home, or tick bites. His family history was negative for cardiac arrhythmias, premature coronary artery disease, thoracic aneurysms or dissection, and infiltrative disorders. His surgical and social histories were unremarkable. He said he had no drug allergies.
Figure 1. The patient’s electrocardiogram on presentation shows ST-segment elevation (arrows) over the lateral and inferior distribution (V4–V6, II, III, and aVF).
An electrocardiogram was obtained (Figure 1). His troponin I level was 7.0 ng/mL (reference range < 0.04 ng/mL).
On examination, his temperature was 38.1°C (100.6°F), heart rate 101 beats per minute, blood pressure 142/78 mm Hg, respiratory rate 16 breaths per minute, and oxygen saturation 98% on room air. He appeared anxious but was in no acute distress. Neck examination showed no elevation in jugular venous pulsation, bruits, thyromegaly, or lymphadenopathy. Cardiac examination revealed tachycardia without murmurs, rubs, or gallops. Lungs were clear to auscultation. Examination of all 4 extremities found 2+ pulses (on a scale of 0 to 4+) throughout and no cyanosis, clubbing, or edema. Abdominal, neurologic, and dermatologic examinations were unremarkable.
Further blood testing revealed the following:
Troponin I (3 hours after the first level) 15.5 ng/mL
B-type natriuretic peptide 200 mg/dL (reference range 0–100 mg/dL)
C-reactive protein 0.9 mg/dL (reference range 0.0–0.8 mg/dL)
Erythrocyte sedimentation rate 10 mm/h (reference range < 15 mm/h).
Metabolic and hematologic assessments were unremarkable. A toxicology screen for drugs of abuse was negative. Viral serologic testing was not done.
A chest radiograph showed no acute cardiopulmonary processes.
Given his presenting symptoms, persistent tachycardia, rapidly rising troponin I level, and electrocardiogram showing diffuse ST elevation, he was taken for urgent cardiac catheterization. Coronary angiography revealed no evidence of atherosclerotic disease, acute thrombosis, dissection, or aneurysm. Echocardiography 2 hours after the procedure showed a normal ejection fraction and no regional wall-motion abnormalities or valvular heart disease.
FURTHER TESTING
1. Which test should be done next to further evaluate this patient’s chest pain?
Serum viral serologic testing
Serum free light chain assay
Nuclear myocardial perfusion study
Cardiac magnetic resonance imaging (MRI)
Endomyocardial biopsy
In this patient without ischemic coronary disease or valvular heart disease, the recent upper respiratory tract prodrome, active positional chest pain, and diffuse electrocardiographic changes raise the possibility of myocarditis with pericardial involvement.
Viral serologic tests
Viral serologic tests are often obtained in the workup of myocarditis as a noninvasive means of detecting an infectious cause.
However, this approach has several problems. First, a positive serologic result is a signal of the peripheral immune response to a pathogen but does not necessarily indicate active myocardial inflammation. Additionally, circulating immunoglobulin G against cardiotropic viruses is commonly found, even in the absence of myocarditis.1 This is often the result of a high prevalence and exposure to these viruses in the general population. Further, trials have shown no correlation between serologic results and organisms identified by endomyocardial biopsy.2
Thus, serologic testing seems to be of limited utility, reserved for testing for infection with Borrelia burgdorferi (Lyme disease) in endemic areas, hepatitis C virus, human immunodeficiency virus in patients at high risk, Rickettsia conorii, and Rickettsia rickettsii.3
Serum free light chain testing for amyloidosis
Serum free light chain testing is replacing serum and urine protein electrophoresis in the workup of cardiac amyloidosis,4 as electrophoresis has poor sensitivity.4,5
Cardiac amyloidosis often affects older persons, although in rare cases it can affect young patients who carry mutations in the transthyretin gene (ATTR amyloidosis).6 This diagnosis is unlikely in our patient, as he has no other affected organ systems (amyloidosis often affects the renal and neurologic systems), normal QRS voltages on electrocardiography (which are often but not always low in amyloidosis), and no left ventricular hypertrophy or diastolic dysfunction on echocardiography (which are often seen in amyloidosis).4
Nuclear perfusion imaging for sarcoidosis
Nuclear imaging has a limited role in evaluating myocarditis,3 but positron-emission tomography with fluorine-18 fluorodeoxyglucose has a diagnostic role in sarcoidosis, an immune-mediated cause of myocarditis.7
Based on the acuity of the patient’s presentation, preceded by upper respiratory tract symptoms, sarcoidosis is less likely. Sarcoidosis is difficult to diagnose, although when it is the cause of myocarditis, some clues exist, as patients usually present with heart failure symptoms, a second- or third-degree atrioventricular block, or a dilated left ventricle on echocardiography.3 All of these were absent in our patient.
Cardiac MRI
Cardiac MRI has undergone many advances, making it an extremely useful noninvasive test. It has excellent utility as a stand-alone test in diagnosing myocarditis and has synergistic value when combined with endomyocardial biopsy.8 It is indicated in hemodynamically stable patients with a clinical suspicion of myocarditis, persistent symptoms, absence of heart failure, and when imaging findings will change management. It is particularly useful to help elucidate a cause and guide tailored therapy.9 Therefore, it is a reasonable next step in the diagnostic pathway for this patient.10
Cardiac MRI also allows for concurrent assessment of scar. In myocardial infarction, the late gadolinium enhancement is subendocardial or transmural. In myocarditis, the pattern differs, being found in the subepicardial lateral free wall (in most patients with parvovirus B19) and mid-myocardial septum (in most patients with herpesvirus 6).9,11 Cardiac MRI also confers prognostic information for patients with suspected myocarditis.12
The Lake Louise criteria9 for the diagnosis of myocarditis require 2 of the following:
Evidence of myocardial edema
Increased ratio of early gadolinium enhancement between myocardium and skeletal muscle (indicates hyperemia)
At least 1 focal lesion with nonischemic late gadolinium enhancement (indicates cardiac myocyte injury or scarring).
The Lake Louise criteria may be replaced by T1 and T2 mapping, which was found to be considerably better for diagnosing myocarditis when the 2 were compared.9,13,14
Endomyocardial biopsy
Endomyocardial biopsy should not be delayed while waiting for cardiac MRI in patients who are hemodynamically unstable or present with life-threatening features (ventricular arrhythmia, left ventricular failure, or resuscitation after sudden cardiac death).3,10
The indications for endomyocardial biopsy have been highly debated. The 2013 guidelines from the European Society of Cardiology (ESC) recommending endomyocardial biopsy in all clinically suspected cases of myocarditis have only heightened the controversy.3 The American Heart Association (AHA) guidelines reserve biopsy for patients with suspected myocarditis who have acute or subacute heart failure symptoms or who do not respond to standard medical therapy.15 Other reasonable indications may include the following: myocarditis with life-threatening ventricular arrhythmias, suspicion of giant cell myocarditis, necrotizing eosinophilic myocarditis, or cardiac sarcoidosis.16
Endomyocardial biopsy is the only way to make a definitive diagnosis of myocarditis.3 However, given the patchy distribution of myocardial involvement, a negative result does not rule out myocarditis. The diagnostic utility can be improved by increasing the number of samples taken (at least 3 but up to 10), obtaining samples from both ventricles, and using cardiac MRI data to determine which sites to biopsy.3,13,17,18
Noninvasive testing such as cardiac MRI does not distinguish cell type or etiology (viral vs nonviral).3 Further, endomyocardial biopsy must be performed before immunosuppressive therapy can be safely started.3,16 At experienced centers, the complication rate is 0% to 0.8%.3 The addition of immunohistochemical testing and viral genomic detection by polymerase chain reaction testing have increased the sensitivity of this technique.19 Finally, endomyocardial biopsy can help rule out some of the other possibilities in the differential diagnosis for myocarditis, including infiltrative and storage diseases, and possibly cardiac tumors.3
Of additional note, the diffuse ST-segment elevation seen on the patient’s electrocardiogram (Figure 1) is indicative of subepicardial inflammation. Since the distribution involves more than one epicardial coronary territory, this helps to differentiate the changes from those that occur with myocardial infarction.20
CASE CONTINUED
Figure 2. Cardiac magnetic resonance imaging shows areas of patchy subepicardial late gadolinium enhancement (arrows).
The patient underwent cardiac MRI, which showed myocardial edema and patchy areas of late gadolinium enhancement, raising suspicion for myocarditis (Figure 2).
Causes of myocarditis are numerous (Table 1),3,21,22 but viral and postinfectious etiologies remain the most common causes of acute myocarditis.23
2. What is the most likely causative infectious agent?
Parvovirus B19
Coxsackievirus B
Adenovirus species
Human herpesvirus 6
Staphylococcus aureus
Corynebacterium diphtheria
Trypanosoma cruzi
Influenza H1/N1
INFECTIOUS CAUSES OF MYOCARDITIS
Coxsackievirus B was the agent most often linked to this condition from the 1950s through the 1990s. However, in the last 2 decades, adenovirus species and human herpesvirus 6 have been increasingly encountered, and recently, parvovirus B19 has been credited as the most common culprit,11,23 at least in the Western world. In developing nations, T cruzi and C diphtheria are the most common offenders.21
S aureus is a common cause of endocarditis, but it rarely plays a role in myocarditis. When it does, the myocarditis is often the sequela of profound bacteremia. This was much more common before antibiotics were invented.24,25
Influenza H1/N1 is not among the most common causes of viral myocarditis, but it should be considered during flu season, given its ability to result in fulminant myocarditis.3,26
TREATMENT FOR MYOCARDITIS
3. Which treatment is the most appropriate at this time?
Intravenous immunoglobulin
Interferon beta
Acyclovir
Prednisone
Colchicine
Treatment for myocarditis depends on the cause but always includes supportive care to address the constellation of presenting symptoms. Standard therapies for tachy- or bradyarrhythmias, heart failure, and hemodynamic derangement should be started.
Supportive care
In patients with severe left ventricular dysfunction, an implantable cardiac electronic device, left ventricular assist device, or heart transplant may ultimately be needed. However, if possible these should be deferred for several months to determine response to treatment, since the myocardium can possibly recover.16
Diuretics, beta-blockers, angiotensin II receptor blockers, angiotensin-converting enzyme inhibitors, and aldosterone antagonists should be given as part of guideline-directed medical therapy for patients with heart failure and reduced ejection fraction.3,27 However, whether and how the patient should be weaned from these agents after disease recovery are unknown.3
Intravenous immunoglobulin
Intravenous immunoglobulin in high doses has had mixed results. Its efficacy is well documented in children,21 but limited supportive data are available in adults.3 As such, recent ESC guidelines do not provide recommendations regarding its use in adults.3
Interferon beta
Interferon beta has shown promise in improving New York Heart Association class and left ventricular ejection fraction.3 This is attributed to its effects on eliminating adenoviral species and enteroviruses. Treatment of enteroviral organisms in particular has been associated with improved 10-year prognosis.3 Interferon beta also has in vitro data showing efficacy at diminishing apoptosis from parvovirus B19.28
Nucleoside analogues
Empiric treatment with nucleoside analogues (acyclovir, ganciclovir, and valacyclovir) has been tried for patients in whom human herpesvirus is suspected as the causative organism, although with unconfirmed effects.3 Consultation with an infectious disease specialist is recommended before starting these agents, and biopsy is often needed beforehand.3
Immunosuppressive agents
Immunosuppressive agents such as prednisone, azathioprine, and cyclosporine can be used in cases of biopsy-proven disease with manifestations of severe heart failure, especially if biopsy results reveal sarcoidosis, giant cell myocarditis, or necrotizing eosinophilic myocarditis. Although the results were neutral in the Myocarditis Treatment Trial,29 the cause of myocarditis in this trial was unknown. Therapy with such agents should be initiated after active infection is ruled out, which also would require a biopsy.
Colchicine
Mechanisms of chest pain in myocarditis include associated pericarditis and coronary artery vasospasm.3,23 Our patient’s chest pain changed when he changed position, possibly indicating associated pericarditis. In myocarditis with accompanying pericarditis symptoms, colchicine (1–2 mg as an initial dose and then 0.6 mg daily for up to 3 months) can be helpful in alleviating symptoms.21,30 Thus, starting this agent in a patient who presents with myocarditis in absence of heart failure, arrhythmias, or left ventricular dysfunction is prudent.
Colchicine is used mainly to address the pain associated with pericarditis. For patients who present with pericarditis without myocarditis, nonsteroidal anti-inflammatory drugs (NSAIDs) remain the first-line treatment, with the addition of colchicine leading to faster symptom resolution.30 The benefit of colchicine for isolated myocarditis is not well established, with only limited data showing some clinical effects.31
CASE CONTINUED
The patient was given colchicine 1.2 mg on the first day and then 0.6 mg daily. Within 2 days, his chest pain had resolved. He did not receive any immunosuppressive agents.
DISCHARGE INSTRUCTIONS
4. Before discharge, this patient should be instructed to do which of the following?
Take over-the-counter NSAIDs to supplement the effects of colchicine
Avoid competitive sports and athletics for at least 6 months
Call to schedule repeat cardiac MRI
No further instruction is needed
NSAIDs are used by themselves or in combination with colchicine in the treatment of pericarditis, but their use may be associated with worse outcomes in myocarditis.3,21 Thus, their use is not recommended in most cases.3
Excessive physical activity should be avoided for at least 6 months after the clinical syndrome resolves. This recommendation is included in the most recent ESC guidelines but is based mainly on expert opinion and murine models with coxsackievirus B.3 Periodic reassessment is indicated with exercise stress testing before return to strenuous activity.3,16,32 Testing should look for exercise tolerance, and exercise electrocardiography also helps to evaluate for clinically relevant arrythmias.
Cardiac MRI can help clarify the prognosis in myocarditis, but the role of repeat testing in guiding therapy is limited.3 Indications for repeat cardiac MRI include presence of 0 or 1 of the Lake Louise criteria (recall that 2 are necessary to make the diagnosis) with recurrence of symptoms and a high suspicion for myocardial inflammation.3,9 Repeat cardiac MRI was not performed for our patient.
CASE CONCLUDED
The patient was evaluated in the cardiology clinic within 1 week of discharge. At that time, he was in sinus tachycardia with a heart rate of 102 bpm, and he was instructed to avoid any exercise until further notice.
At 6-month follow-up, the sinus tachycardia had resolved. However, because persistent tachycardia had been noted at the first postdischarge visit, and in view of the extent of myocardial involvement, he underwent exercise treadmill testing to evaluate for ventricular arrhythmias. The study did show premature ventricular complexes and 1 ventricular couplet at submaximal exercise levels. As this indicated a higher risk of exercise-induced arrhythmias, he was asked to continue normal activity levels but to abstain from exercise until the next evaluation.
During his 1-year follow-up, a repeat treadmill test showed no ventricular ectopy. Holter monitoring was ordered and showed no premature ventricular complexes, supraventricular arrhythmias, or atrioventricular block within the 48-hour period.
At his 2-year evaluation, he had returned to playing basketball and soccer on weekends and reported no recurrence of his initial symptoms.
KEY POINTS
Figure 3. Our suggested approach to suspected acute myocarditis.Cardiac MRI has emerged as an excellent noninvasive imaging modality for the diagnosis of myocarditis.
Treatment of myocarditis depends on the cause and severity of the patient’s presentation, spanning the spectrum from conservative care to immunosuppressive agents and even heart failure therapy.
Excessive physical activity should be avoided for the first 6 months after disease diagnosis and treatment.
If myocarditis is associated with pericardial involvement, colchicine is the agent of choice, and NSAIDs should be avoided.
Our suggested strategy for approaching myocarditis is shown in Figure 3.
An 18-year-old man without any significant medical history was transferred from another hospital for higher-level care after presenting with unremitting chest pain. He had been in his usual state of good health until 7 days before presentation, when he developed mild rhinorrhea and a sore throat, but not a cough. He went to an outpatient clinic, where a rapid test for group A streptococci was done; the result was negative, and he was sent home on supportive measures.
On the day of admission, he awoke with severe, pressure-like, midsternal, nonradiating pain, which he rated 10 on a scale of 10. The pain intensified in the supine position and improved with sitting. A complete review of systems was otherwise negative. He denied having had similar symptoms in the past, as well as sick contacts, recent travel, toxin exposure, illicit substance abuse, pets at home, or tick bites. His family history was negative for cardiac arrhythmias, premature coronary artery disease, thoracic aneurysms or dissection, and infiltrative disorders. His surgical and social histories were unremarkable. He said he had no drug allergies.
Figure 1. The patient’s electrocardiogram on presentation shows ST-segment elevation (arrows) over the lateral and inferior distribution (V4–V6, II, III, and aVF).
An electrocardiogram was obtained (Figure 1). His troponin I level was 7.0 ng/mL (reference range < 0.04 ng/mL).
On examination, his temperature was 38.1°C (100.6°F), heart rate 101 beats per minute, blood pressure 142/78 mm Hg, respiratory rate 16 breaths per minute, and oxygen saturation 98% on room air. He appeared anxious but was in no acute distress. Neck examination showed no elevation in jugular venous pulsation, bruits, thyromegaly, or lymphadenopathy. Cardiac examination revealed tachycardia without murmurs, rubs, or gallops. Lungs were clear to auscultation. Examination of all 4 extremities found 2+ pulses (on a scale of 0 to 4+) throughout and no cyanosis, clubbing, or edema. Abdominal, neurologic, and dermatologic examinations were unremarkable.
Further blood testing revealed the following:
Troponin I (3 hours after the first level) 15.5 ng/mL
B-type natriuretic peptide 200 mg/dL (reference range 0–100 mg/dL)
C-reactive protein 0.9 mg/dL (reference range 0.0–0.8 mg/dL)
Erythrocyte sedimentation rate 10 mm/h (reference range < 15 mm/h).
Metabolic and hematologic assessments were unremarkable. A toxicology screen for drugs of abuse was negative. Viral serologic testing was not done.
A chest radiograph showed no acute cardiopulmonary processes.
Given his presenting symptoms, persistent tachycardia, rapidly rising troponin I level, and electrocardiogram showing diffuse ST elevation, he was taken for urgent cardiac catheterization. Coronary angiography revealed no evidence of atherosclerotic disease, acute thrombosis, dissection, or aneurysm. Echocardiography 2 hours after the procedure showed a normal ejection fraction and no regional wall-motion abnormalities or valvular heart disease.
FURTHER TESTING
1. Which test should be done next to further evaluate this patient’s chest pain?
Serum viral serologic testing
Serum free light chain assay
Nuclear myocardial perfusion study
Cardiac magnetic resonance imaging (MRI)
Endomyocardial biopsy
In this patient without ischemic coronary disease or valvular heart disease, the recent upper respiratory tract prodrome, active positional chest pain, and diffuse electrocardiographic changes raise the possibility of myocarditis with pericardial involvement.
Viral serologic tests
Viral serologic tests are often obtained in the workup of myocarditis as a noninvasive means of detecting an infectious cause.
However, this approach has several problems. First, a positive serologic result is a signal of the peripheral immune response to a pathogen but does not necessarily indicate active myocardial inflammation. Additionally, circulating immunoglobulin G against cardiotropic viruses is commonly found, even in the absence of myocarditis.1 This is often the result of a high prevalence and exposure to these viruses in the general population. Further, trials have shown no correlation between serologic results and organisms identified by endomyocardial biopsy.2
Thus, serologic testing seems to be of limited utility, reserved for testing for infection with Borrelia burgdorferi (Lyme disease) in endemic areas, hepatitis C virus, human immunodeficiency virus in patients at high risk, Rickettsia conorii, and Rickettsia rickettsii.3
Serum free light chain testing for amyloidosis
Serum free light chain testing is replacing serum and urine protein electrophoresis in the workup of cardiac amyloidosis,4 as electrophoresis has poor sensitivity.4,5
Cardiac amyloidosis often affects older persons, although in rare cases it can affect young patients who carry mutations in the transthyretin gene (ATTR amyloidosis).6 This diagnosis is unlikely in our patient, as he has no other affected organ systems (amyloidosis often affects the renal and neurologic systems), normal QRS voltages on electrocardiography (which are often but not always low in amyloidosis), and no left ventricular hypertrophy or diastolic dysfunction on echocardiography (which are often seen in amyloidosis).4
Nuclear perfusion imaging for sarcoidosis
Nuclear imaging has a limited role in evaluating myocarditis,3 but positron-emission tomography with fluorine-18 fluorodeoxyglucose has a diagnostic role in sarcoidosis, an immune-mediated cause of myocarditis.7
Based on the acuity of the patient’s presentation, preceded by upper respiratory tract symptoms, sarcoidosis is less likely. Sarcoidosis is difficult to diagnose, although when it is the cause of myocarditis, some clues exist, as patients usually present with heart failure symptoms, a second- or third-degree atrioventricular block, or a dilated left ventricle on echocardiography.3 All of these were absent in our patient.
Cardiac MRI
Cardiac MRI has undergone many advances, making it an extremely useful noninvasive test. It has excellent utility as a stand-alone test in diagnosing myocarditis and has synergistic value when combined with endomyocardial biopsy.8 It is indicated in hemodynamically stable patients with a clinical suspicion of myocarditis, persistent symptoms, absence of heart failure, and when imaging findings will change management. It is particularly useful to help elucidate a cause and guide tailored therapy.9 Therefore, it is a reasonable next step in the diagnostic pathway for this patient.10
Cardiac MRI also allows for concurrent assessment of scar. In myocardial infarction, the late gadolinium enhancement is subendocardial or transmural. In myocarditis, the pattern differs, being found in the subepicardial lateral free wall (in most patients with parvovirus B19) and mid-myocardial septum (in most patients with herpesvirus 6).9,11 Cardiac MRI also confers prognostic information for patients with suspected myocarditis.12
The Lake Louise criteria9 for the diagnosis of myocarditis require 2 of the following:
Evidence of myocardial edema
Increased ratio of early gadolinium enhancement between myocardium and skeletal muscle (indicates hyperemia)
At least 1 focal lesion with nonischemic late gadolinium enhancement (indicates cardiac myocyte injury or scarring).
The Lake Louise criteria may be replaced by T1 and T2 mapping, which was found to be considerably better for diagnosing myocarditis when the 2 were compared.9,13,14
Endomyocardial biopsy
Endomyocardial biopsy should not be delayed while waiting for cardiac MRI in patients who are hemodynamically unstable or present with life-threatening features (ventricular arrhythmia, left ventricular failure, or resuscitation after sudden cardiac death).3,10
The indications for endomyocardial biopsy have been highly debated. The 2013 guidelines from the European Society of Cardiology (ESC) recommending endomyocardial biopsy in all clinically suspected cases of myocarditis have only heightened the controversy.3 The American Heart Association (AHA) guidelines reserve biopsy for patients with suspected myocarditis who have acute or subacute heart failure symptoms or who do not respond to standard medical therapy.15 Other reasonable indications may include the following: myocarditis with life-threatening ventricular arrhythmias, suspicion of giant cell myocarditis, necrotizing eosinophilic myocarditis, or cardiac sarcoidosis.16
Endomyocardial biopsy is the only way to make a definitive diagnosis of myocarditis.3 However, given the patchy distribution of myocardial involvement, a negative result does not rule out myocarditis. The diagnostic utility can be improved by increasing the number of samples taken (at least 3 but up to 10), obtaining samples from both ventricles, and using cardiac MRI data to determine which sites to biopsy.3,13,17,18
Noninvasive testing such as cardiac MRI does not distinguish cell type or etiology (viral vs nonviral).3 Further, endomyocardial biopsy must be performed before immunosuppressive therapy can be safely started.3,16 At experienced centers, the complication rate is 0% to 0.8%.3 The addition of immunohistochemical testing and viral genomic detection by polymerase chain reaction testing have increased the sensitivity of this technique.19 Finally, endomyocardial biopsy can help rule out some of the other possibilities in the differential diagnosis for myocarditis, including infiltrative and storage diseases, and possibly cardiac tumors.3
Of additional note, the diffuse ST-segment elevation seen on the patient’s electrocardiogram (Figure 1) is indicative of subepicardial inflammation. Since the distribution involves more than one epicardial coronary territory, this helps to differentiate the changes from those that occur with myocardial infarction.20
CASE CONTINUED
Figure 2. Cardiac magnetic resonance imaging shows areas of patchy subepicardial late gadolinium enhancement (arrows).
The patient underwent cardiac MRI, which showed myocardial edema and patchy areas of late gadolinium enhancement, raising suspicion for myocarditis (Figure 2).
Causes of myocarditis are numerous (Table 1),3,21,22 but viral and postinfectious etiologies remain the most common causes of acute myocarditis.23
2. What is the most likely causative infectious agent?
Parvovirus B19
Coxsackievirus B
Adenovirus species
Human herpesvirus 6
Staphylococcus aureus
Corynebacterium diphtheria
Trypanosoma cruzi
Influenza H1/N1
INFECTIOUS CAUSES OF MYOCARDITIS
Coxsackievirus B was the agent most often linked to this condition from the 1950s through the 1990s. However, in the last 2 decades, adenovirus species and human herpesvirus 6 have been increasingly encountered, and recently, parvovirus B19 has been credited as the most common culprit,11,23 at least in the Western world. In developing nations, T cruzi and C diphtheria are the most common offenders.21
S aureus is a common cause of endocarditis, but it rarely plays a role in myocarditis. When it does, the myocarditis is often the sequela of profound bacteremia. This was much more common before antibiotics were invented.24,25
Influenza H1/N1 is not among the most common causes of viral myocarditis, but it should be considered during flu season, given its ability to result in fulminant myocarditis.3,26
TREATMENT FOR MYOCARDITIS
3. Which treatment is the most appropriate at this time?
Intravenous immunoglobulin
Interferon beta
Acyclovir
Prednisone
Colchicine
Treatment for myocarditis depends on the cause but always includes supportive care to address the constellation of presenting symptoms. Standard therapies for tachy- or bradyarrhythmias, heart failure, and hemodynamic derangement should be started.
Supportive care
In patients with severe left ventricular dysfunction, an implantable cardiac electronic device, left ventricular assist device, or heart transplant may ultimately be needed. However, if possible these should be deferred for several months to determine response to treatment, since the myocardium can possibly recover.16
Diuretics, beta-blockers, angiotensin II receptor blockers, angiotensin-converting enzyme inhibitors, and aldosterone antagonists should be given as part of guideline-directed medical therapy for patients with heart failure and reduced ejection fraction.3,27 However, whether and how the patient should be weaned from these agents after disease recovery are unknown.3
Intravenous immunoglobulin
Intravenous immunoglobulin in high doses has had mixed results. Its efficacy is well documented in children,21 but limited supportive data are available in adults.3 As such, recent ESC guidelines do not provide recommendations regarding its use in adults.3
Interferon beta
Interferon beta has shown promise in improving New York Heart Association class and left ventricular ejection fraction.3 This is attributed to its effects on eliminating adenoviral species and enteroviruses. Treatment of enteroviral organisms in particular has been associated with improved 10-year prognosis.3 Interferon beta also has in vitro data showing efficacy at diminishing apoptosis from parvovirus B19.28
Nucleoside analogues
Empiric treatment with nucleoside analogues (acyclovir, ganciclovir, and valacyclovir) has been tried for patients in whom human herpesvirus is suspected as the causative organism, although with unconfirmed effects.3 Consultation with an infectious disease specialist is recommended before starting these agents, and biopsy is often needed beforehand.3
Immunosuppressive agents
Immunosuppressive agents such as prednisone, azathioprine, and cyclosporine can be used in cases of biopsy-proven disease with manifestations of severe heart failure, especially if biopsy results reveal sarcoidosis, giant cell myocarditis, or necrotizing eosinophilic myocarditis. Although the results were neutral in the Myocarditis Treatment Trial,29 the cause of myocarditis in this trial was unknown. Therapy with such agents should be initiated after active infection is ruled out, which also would require a biopsy.
Colchicine
Mechanisms of chest pain in myocarditis include associated pericarditis and coronary artery vasospasm.3,23 Our patient’s chest pain changed when he changed position, possibly indicating associated pericarditis. In myocarditis with accompanying pericarditis symptoms, colchicine (1–2 mg as an initial dose and then 0.6 mg daily for up to 3 months) can be helpful in alleviating symptoms.21,30 Thus, starting this agent in a patient who presents with myocarditis in absence of heart failure, arrhythmias, or left ventricular dysfunction is prudent.
Colchicine is used mainly to address the pain associated with pericarditis. For patients who present with pericarditis without myocarditis, nonsteroidal anti-inflammatory drugs (NSAIDs) remain the first-line treatment, with the addition of colchicine leading to faster symptom resolution.30 The benefit of colchicine for isolated myocarditis is not well established, with only limited data showing some clinical effects.31
CASE CONTINUED
The patient was given colchicine 1.2 mg on the first day and then 0.6 mg daily. Within 2 days, his chest pain had resolved. He did not receive any immunosuppressive agents.
DISCHARGE INSTRUCTIONS
4. Before discharge, this patient should be instructed to do which of the following?
Take over-the-counter NSAIDs to supplement the effects of colchicine
Avoid competitive sports and athletics for at least 6 months
Call to schedule repeat cardiac MRI
No further instruction is needed
NSAIDs are used by themselves or in combination with colchicine in the treatment of pericarditis, but their use may be associated with worse outcomes in myocarditis.3,21 Thus, their use is not recommended in most cases.3
Excessive physical activity should be avoided for at least 6 months after the clinical syndrome resolves. This recommendation is included in the most recent ESC guidelines but is based mainly on expert opinion and murine models with coxsackievirus B.3 Periodic reassessment is indicated with exercise stress testing before return to strenuous activity.3,16,32 Testing should look for exercise tolerance, and exercise electrocardiography also helps to evaluate for clinically relevant arrythmias.
Cardiac MRI can help clarify the prognosis in myocarditis, but the role of repeat testing in guiding therapy is limited.3 Indications for repeat cardiac MRI include presence of 0 or 1 of the Lake Louise criteria (recall that 2 are necessary to make the diagnosis) with recurrence of symptoms and a high suspicion for myocardial inflammation.3,9 Repeat cardiac MRI was not performed for our patient.
CASE CONCLUDED
The patient was evaluated in the cardiology clinic within 1 week of discharge. At that time, he was in sinus tachycardia with a heart rate of 102 bpm, and he was instructed to avoid any exercise until further notice.
At 6-month follow-up, the sinus tachycardia had resolved. However, because persistent tachycardia had been noted at the first postdischarge visit, and in view of the extent of myocardial involvement, he underwent exercise treadmill testing to evaluate for ventricular arrhythmias. The study did show premature ventricular complexes and 1 ventricular couplet at submaximal exercise levels. As this indicated a higher risk of exercise-induced arrhythmias, he was asked to continue normal activity levels but to abstain from exercise until the next evaluation.
During his 1-year follow-up, a repeat treadmill test showed no ventricular ectopy. Holter monitoring was ordered and showed no premature ventricular complexes, supraventricular arrhythmias, or atrioventricular block within the 48-hour period.
At his 2-year evaluation, he had returned to playing basketball and soccer on weekends and reported no recurrence of his initial symptoms.
KEY POINTS
Figure 3. Our suggested approach to suspected acute myocarditis.Cardiac MRI has emerged as an excellent noninvasive imaging modality for the diagnosis of myocarditis.
Treatment of myocarditis depends on the cause and severity of the patient’s presentation, spanning the spectrum from conservative care to immunosuppressive agents and even heart failure therapy.
Excessive physical activity should be avoided for the first 6 months after disease diagnosis and treatment.
If myocarditis is associated with pericardial involvement, colchicine is the agent of choice, and NSAIDs should be avoided.
Our suggested strategy for approaching myocarditis is shown in Figure 3.
Mahfoud F, Gärtner B, Kindermann M, et al. Virus serology in patients with suspected myocarditis: utility or futility? Eur Heart J 2011; 32(7):897–903. doi:10.1093/eurheartj/ehq493
Caforio AL, Pankuweit S, Arbustini E, et al; European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J 2013; 34(33):2636–2648, 2648a–2648d. doi:10.1093/eurheartj/eht210
Donnelly JP, Hanna M. Cardiac amyloidosis: an update on diagnosis and treatment. Cleve Clin J Med 2017; 84(12 suppl 3):12–26. doi:10.3949/ccjm.84.s3.02
Siddiqi OK, Ruberg FL. Cardiac amyloidosis: an update on pathophysiology, diagnosis, and treatment. Trends Cardiovasc Med 2018; 28(1):10–21. doi:10.1016/j.tcm.2017.07.004
Gertz MA, Benson MD, Dyck PJ, et al. Diagnosis, prognosis, and therapy of transthyretin amyloidosis. J Am Coll Cardiol 2015; 66(21):2451–2466. doi:10.1016/j.jacc.2015.09.075
Blankstein R, Osborne M, Naya M, et al. Cardiac positron emission tomography enhances prognostic assessments of patients with suspected cardiac sarcoidosis. J Am Coll Cardiol 2014; 63(4):329–336. doi:10.1016/j.jacc.2013.09.022
Baccouche H, Mahrholtz H, Meinhardt G, et al. Diagnostic synergy of non-invasive cardiovascular magnetic resonance and invasive endomyocardial biopsy in troponin-positive patients without coronary artery disease. Eur Heart J 2009; 30(23):2869–2879. doi:10.1093/eurheartj/ehp328
Friedrich MG, Sechtem U, Schulz-Menger J, et al; International Consensus Group on Cardiovascular Magnetic Resonance in Myocarditis. Cardiovascular magnetic resonance in myocarditis: a JACC white paper. J Am Coll Cardiol 2009; 53(17):1475–1487. doi:10.1016/j.jacc.2009.02.007
Kindermann I, Barth C, Mahfoud F, et al. Update on myocarditis. J Am Coll Cardiol 2012; 59(9):779–792. doi:10.1016/j.jacc.2011.09.074
Mahrholdt H, Wagner A, Deluigi CC, et al. Presentation, patterns of myocardial damage, and clinical course of viral myocarditis. Circulation 2006; 114(15):1581–1590. doi:10.1161/CIRCULATIONAHA.105.606509
Gräni C, Eichhorn C, Bière L, et al. Prognostic value of cardiac magnetic resonance tissue characterization in risk stratifying patients with suspected myocarditis. J Am Coll Cardiol 2017; 70(16):1964–1976. doi:10.1016/j.jacc.2017.08.050
Lurz P, Luecke C, Eitel I, et al. Comprehensive cardiac magnetic resonance imaging in patients with suspected myocarditis: the MyoRacer-Trial. J Am Coll Cardiol 2016; 67(15):1800–1811. doi:10.1016/j.jacc.2016.02.013
Gannon MP, Schaub E, Griens CL, Saba SG. State of the art: evaluation and prognostication of myocarditis using cardiac MRI. J Magn Reson Imaging 2019; 49(7):e122–e131. doi:10.1002/jmri.26611
Cooper LT, Baughman KL, Feldman AM, et al. The role of endomyocardial biopsy in the management of cardiovascular disease: a scientific statement from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology endorsed by the Heart Failure Society of America and the Heart Failure Association of the European Society of Cardiology. Eur Heart J 2007; 28(24):3076–3093. doi:10.1093/eurheartj/ehm456
Sinagra G, Anzini M, Pereira NL, et al. Myocarditis in clinical practice. Mayo Clin Proc 2016; 91(9):1256–1266. doi:10.1016/j.mayocp.2016.05.013
Cooper LT, Baughman KL, Feldman AM, et al; American Heart Association; American College of Cardiology; European Society of Cardiology. The role of endomyocardial biopsy in the management of cardiovascular disease: a scientific statement from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology. Circulation 2007; 116(19):2216–2233. doi:10.1161/CIRCULATIONAHA.107.186093
Leone O, Veinot JP, Angelini A, et al. 2011 consensus statement on endomyocardial biopsy from the Association for European Cardiovascular Pathology and the Society for Cardiovascular Pathology. Cardiovasc Pathol 2012; 21(4):245–274. doi:10.1016/j.carpath.2011.10.001
Alraies MC, Klein AL. Should we still use electrocardiography to diagnose pericardial disease? Cleve Clin J Med 2013; 80(2):97–100. doi:10.3949/ccjm.80a.11144
Wasi F, Shuter J. Primary bacterial infection of the myocardium. Front Biosci 2003; 8:s228–s231. pmid:12700039
Al-Amoodi M, Rao K, Rao S, Brewer JH, Magalski A, Chhatriwalla AK. Fulminant myocarditis due to H1N1 influenza. Circ Heart Fail 2010; 3(3):e7–e9. doi:10.1161/CIRCHEARTFAILURE.110.938506
Yancy CW, Jessup M, Bozkurt B, et al. 2016 ACC/AHA/HFSA focused update on new pharmacological therapy for heart failure: an update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. J Am Coll Cardiol 2016; 68(13):1476–1488. doi:10.1016/j.jacc.2016.05.011
Schmidt-Lucke C, Spillmann F, Bock T, et al. Interferon beta modulates endothelial damage in patients with cardiac persistence of human parvovirus b19 infection. J Infect Dis 2010; 201(6):936–945. doi:10.1086/650700
Mason JW, O’Connell JB, Herskowitz A, et al. A clinical trial of immunosuppressive therapy for myocarditis: the Myocarditis Treatment Trial Investigators. N Engl J Med 1995; 333(5):269–275. doi:10.1056/NEJM199508033330501
Imazio M, Bobbio M, Cecchi E, et al. Colchicine in addition to conventional therapy for acute pericarditis: results of the COlchicine for acute PEricarditis (COPE) trial. Circulation 2005; 112(13):2012–2016. doi:10.1161/CIRCULATIONAHA.105.542738
Morgenstern D, Lisko J, Boniface NC, Mikolich BM, Mikolich JR. Myocarditis and colchicine: a new perspective from cardiac MRI. J Cardiovasc Magn Reson 2016; 18(suppl 1):0100.
Maron BJ, Zipes DP, Kovacs RJ. Eligibility and disqualification recommendations for competitive athletes with cardiovascular abnormalities: preamble, principles, and general considerations: a scientific statement from the American Heart Association and American College of Cardiology. J Am Coll Cardiol 2015; 66(21):2343–2349. doi:10.1016/j.jacc.2015.09.032
Mahfoud F, Gärtner B, Kindermann M, et al. Virus serology in patients with suspected myocarditis: utility or futility? Eur Heart J 2011; 32(7):897–903. doi:10.1093/eurheartj/ehq493
Caforio AL, Pankuweit S, Arbustini E, et al; European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J 2013; 34(33):2636–2648, 2648a–2648d. doi:10.1093/eurheartj/eht210
Donnelly JP, Hanna M. Cardiac amyloidosis: an update on diagnosis and treatment. Cleve Clin J Med 2017; 84(12 suppl 3):12–26. doi:10.3949/ccjm.84.s3.02
Siddiqi OK, Ruberg FL. Cardiac amyloidosis: an update on pathophysiology, diagnosis, and treatment. Trends Cardiovasc Med 2018; 28(1):10–21. doi:10.1016/j.tcm.2017.07.004
Gertz MA, Benson MD, Dyck PJ, et al. Diagnosis, prognosis, and therapy of transthyretin amyloidosis. J Am Coll Cardiol 2015; 66(21):2451–2466. doi:10.1016/j.jacc.2015.09.075
Blankstein R, Osborne M, Naya M, et al. Cardiac positron emission tomography enhances prognostic assessments of patients with suspected cardiac sarcoidosis. J Am Coll Cardiol 2014; 63(4):329–336. doi:10.1016/j.jacc.2013.09.022
Baccouche H, Mahrholtz H, Meinhardt G, et al. Diagnostic synergy of non-invasive cardiovascular magnetic resonance and invasive endomyocardial biopsy in troponin-positive patients without coronary artery disease. Eur Heart J 2009; 30(23):2869–2879. doi:10.1093/eurheartj/ehp328
Friedrich MG, Sechtem U, Schulz-Menger J, et al; International Consensus Group on Cardiovascular Magnetic Resonance in Myocarditis. Cardiovascular magnetic resonance in myocarditis: a JACC white paper. J Am Coll Cardiol 2009; 53(17):1475–1487. doi:10.1016/j.jacc.2009.02.007
Kindermann I, Barth C, Mahfoud F, et al. Update on myocarditis. J Am Coll Cardiol 2012; 59(9):779–792. doi:10.1016/j.jacc.2011.09.074
Mahrholdt H, Wagner A, Deluigi CC, et al. Presentation, patterns of myocardial damage, and clinical course of viral myocarditis. Circulation 2006; 114(15):1581–1590. doi:10.1161/CIRCULATIONAHA.105.606509
Gräni C, Eichhorn C, Bière L, et al. Prognostic value of cardiac magnetic resonance tissue characterization in risk stratifying patients with suspected myocarditis. J Am Coll Cardiol 2017; 70(16):1964–1976. doi:10.1016/j.jacc.2017.08.050
Lurz P, Luecke C, Eitel I, et al. Comprehensive cardiac magnetic resonance imaging in patients with suspected myocarditis: the MyoRacer-Trial. J Am Coll Cardiol 2016; 67(15):1800–1811. doi:10.1016/j.jacc.2016.02.013
Gannon MP, Schaub E, Griens CL, Saba SG. State of the art: evaluation and prognostication of myocarditis using cardiac MRI. J Magn Reson Imaging 2019; 49(7):e122–e131. doi:10.1002/jmri.26611
Cooper LT, Baughman KL, Feldman AM, et al. The role of endomyocardial biopsy in the management of cardiovascular disease: a scientific statement from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology endorsed by the Heart Failure Society of America and the Heart Failure Association of the European Society of Cardiology. Eur Heart J 2007; 28(24):3076–3093. doi:10.1093/eurheartj/ehm456
Sinagra G, Anzini M, Pereira NL, et al. Myocarditis in clinical practice. Mayo Clin Proc 2016; 91(9):1256–1266. doi:10.1016/j.mayocp.2016.05.013
Cooper LT, Baughman KL, Feldman AM, et al; American Heart Association; American College of Cardiology; European Society of Cardiology. The role of endomyocardial biopsy in the management of cardiovascular disease: a scientific statement from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology. Circulation 2007; 116(19):2216–2233. doi:10.1161/CIRCULATIONAHA.107.186093
Leone O, Veinot JP, Angelini A, et al. 2011 consensus statement on endomyocardial biopsy from the Association for European Cardiovascular Pathology and the Society for Cardiovascular Pathology. Cardiovasc Pathol 2012; 21(4):245–274. doi:10.1016/j.carpath.2011.10.001
Alraies MC, Klein AL. Should we still use electrocardiography to diagnose pericardial disease? Cleve Clin J Med 2013; 80(2):97–100. doi:10.3949/ccjm.80a.11144
Wasi F, Shuter J. Primary bacterial infection of the myocardium. Front Biosci 2003; 8:s228–s231. pmid:12700039
Al-Amoodi M, Rao K, Rao S, Brewer JH, Magalski A, Chhatriwalla AK. Fulminant myocarditis due to H1N1 influenza. Circ Heart Fail 2010; 3(3):e7–e9. doi:10.1161/CIRCHEARTFAILURE.110.938506
Yancy CW, Jessup M, Bozkurt B, et al. 2016 ACC/AHA/HFSA focused update on new pharmacological therapy for heart failure: an update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. J Am Coll Cardiol 2016; 68(13):1476–1488. doi:10.1016/j.jacc.2016.05.011
Schmidt-Lucke C, Spillmann F, Bock T, et al. Interferon beta modulates endothelial damage in patients with cardiac persistence of human parvovirus b19 infection. J Infect Dis 2010; 201(6):936–945. doi:10.1086/650700
Mason JW, O’Connell JB, Herskowitz A, et al. A clinical trial of immunosuppressive therapy for myocarditis: the Myocarditis Treatment Trial Investigators. N Engl J Med 1995; 333(5):269–275. doi:10.1056/NEJM199508033330501
Imazio M, Bobbio M, Cecchi E, et al. Colchicine in addition to conventional therapy for acute pericarditis: results of the COlchicine for acute PEricarditis (COPE) trial. Circulation 2005; 112(13):2012–2016. doi:10.1161/CIRCULATIONAHA.105.542738
Morgenstern D, Lisko J, Boniface NC, Mikolich BM, Mikolich JR. Myocarditis and colchicine: a new perspective from cardiac MRI. J Cardiovasc Magn Reson 2016; 18(suppl 1):0100.
Maron BJ, Zipes DP, Kovacs RJ. Eligibility and disqualification recommendations for competitive athletes with cardiovascular abnormalities: preamble, principles, and general considerations: a scientific statement from the American Heart Association and American College of Cardiology. J Am Coll Cardiol 2015; 66(21):2343–2349. doi:10.1016/j.jacc.2015.09.032
Inhibition of the renin-angiotensin-aldosterone system with angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) is widely used in the treatment of heart failure, hypertension, chronic kidney disease, and coronary artery disease with left ventricular dysfunction.
In this issue, Momoniat et al1 review the benefits of ACE inhibitors and ARBs and how to manage adverse effects. I would like to add some of my own observations.
ARE ACE INHIBITORS REALLY BETTER THAN ARBs?
ACE inhibitors have been the cornerstone of treatment for patients with heart failure with reduced ejection fraction (HFrEF), in whom their use is associated with reduced rates of morbidity and death.2,3 The use of ARBs in these patients is also associated with decreased rates of morbidity and death4,5; however, in early comparisons, ACE inhibitors were deemed more effective in decreasing the incidence of myocardial infarction, cardiovascular death, and all-cause mortality in patients with hypertension, diabetes, and increased cardiovascular risk,6 and all-cause mortality in patients with HFrEF.7
This presumed superiority of ACE inhibitors over ARBs was thought to be a result of a greater vasodilatory effect caused by inhibiting the degradation of bradykinin and leading to increased levels of nitric oxide and vasoactive prostaglandins.8 Another proposed explanation was that because ARBs block angiotensin II AT1 receptors but not AT2 receptors, the increased stimulation of markedly upregulated AT2 receptors in atheromatous plaques in response to elevated serum levels of angiotensin II was deleterious.6 Therefore, ACE inhibitors have been recommended as first-line therapy by most guidelines, whereas ARBs are recommended as second-line therapy, when patients are unable to tolerate ACE inhibitors.
Nevertheless, the much debated differences in outcomes between ACE inhibitors and ARBs do not seem to be real and may have originated from a generational gap in the trials.
The ACE inhibitor trials were performed a decade earlier than the ARB trials. Indirect comparisons of their respective placebo-controlled trials assumed that the placebo groups used for comparison in the 2 sets of trials were similar.9,10 Actually, the rate of cardiovascular disease decreased nearly 50% between the decades of 1990 to 2000 and 2000 to 2010, the likely result of aggressive primary and secondary prevention strategies in clinical practice, including revascularization and lipid-lowering therapy.10
In fact, a meta-regression analysis showed that the differences between ACE inhibitors and ARBs compared with placebo were due to higher event rates in the placebo groups in the ACE inhibitor trials than in the ARB trials for the outcomes of death, cardiovascular death, and myocardial infarction.11 Sensitivity analyses restricted to trials published after 2000 to control for this generational gap showed similar efficacy with ACE inhibitors vs placebo and with ARBs vs placebo for all clinical outcomes.11 Moreover, recent studies have shown that ARBs produce a greater decrease in cardiovascular events than ACE inhibitors, especially in patients with established cardiovascular disease.12,13
An advantage of ARBs over ACE inhibitors is fewer adverse effects: in general, ARBs are better tolerated than ACE inhibitors.14 There are also ethnic differences in the risks of adverse reactions to these medications. African Americans have a higher risk of developing angioedema with ACE inhibitors compared with the rest of the US population, and Chinese Americans have a higher risk than whites of developing cough with ACE inhibitors.9,15
HOW I MANAGE THESE MEDICATIONS
In my medical practice, I try to make sure patients with HFrEF, hypertension, chronic kidney disease, and coronary artery disease with left ventricular dysfunction receive an inhibitor of the renin-angiotensin-aldosterone system.
Which agent?
I prefer ARBs because patients tolerate them better. I continue ACE inhibitors in patients who are already taking them without adverse effects, and I change to ARBs in patients who later become unable to tolerate ACE inhibitors.
Most antihypertensive agents increase the risk of incident gout, except for calcium channel blockers and losartan.16 Losartan is the only ARB with a uricosuric effect, although a mild one,17,18 due to inhibition of the urate transporter 1,19 and therefore I prefer to use it instead of other ARBs or ACE inhibitors in patients who have a concomitant diagnosis of gout.
Which combinations of agents?
The addition of beta-blockers and mineralocorticoid receptor blockers to ACE inhibitors or ARBs is associated with a further decrease in the mortality risk for patients with HFrEF,20–22 but some patients cannot tolerate these combinations or optimized doses of these medications because of worsening hypotension or increased risk of developing acute kidney injury or hyperkalemia.
In most cases, I try not to combine ACE inhibitors with ARBs. This combination may be useful in nondiabetic patients with proteinuria refractory to maximum treatment with 1 class of these agents, but it is associated with an increased risk of hyperkalemia or acute kidney injury in patients with diabetic nephropathy without improving rates of the clinical outcomes of death or cardiovascular events.23 I prefer adding a daily low dose of a mineralocorticoid receptor blocker to an ACE inhibitor or an ARB, which is more effective in controlling refractory proteinuria.24 This regimen is associated with decreased rates of mortality, cardiovascular mortality, and hospitalization for heart failure in patients with HFrEF,22 although it can lead to a higher frequency of hyperkalemia,25 and patients on it require frequent dietary education and monitoring of serum potassium.
I avoid combining direct renin inhibitors with ACE inhibitors or ARBs, since this combination has been contraindicated by the US Food and Drug Administration due to lack of reduction in target-organ damage and an associated increased risk of hypotension, hyperkalemia, and kidney failure, and a slight increase in the risk of stroke or death in patients with diabetic nephropathy.26
Valsartan-sacubitril
Neprilysin is a membrane-bound endopeptidase that degrades vasoactive peptides, including B-type natriuretic peptide and atrial natriuretic peptide.27 The combination of the ARB valsartan and the neprilysin inhibitor sacubitril is associated with a 20% further decrease in rates of cardiovascular mortality and hospitalization and a 16% decrease in total mortality for patients with HFrEF compared with an ACE inhibitor, although there can also be more hypotension and angioedema with the combination.27,28
Very importantly, an ACE inhibitor cannot be used together with valsartan-sacubitril due to increased risk of angioedema and cough. I change ACE inhibitors or ARBs to valsartan-sacubitril in patients with HFrEF who still have symptoms of heart failure. Interestingly, a network meta-analysis showed that the combination of valsartan-sacubitril plus a mineralocorticoid receptor blocker and a beta-blocker resulted in the greatest mortality reduction in patients with HFrEF.7 A word of caution, though: one can also expect an increased risk of hypotension, hyperkalemia, and kidney failure.
Monitoring
It is crucial to monitor blood pressure, serum potassium, and renal function in patients receiving ACE inhibitors, ARBs, mineralocorticoid receptor blockers, valsartan-sacubitril, or combinations of these medications, particularly in elderly patients, who are more susceptible to complications. I use a multidisciplinary approach in my clinic: a patient educator, dietitian, pharmacist, and advanced practice nurse play key roles in educating and monitoring patients for the development of possible complications from this therapy or interactions with other medications.
A recent population-based cohort study found an association of ACE inhibitor use with a 14% relative increase in lung cancer incidence after 10 years of use, compared with ARBs,29 but this may not represent a large absolute risk (calculated number needed to harm of 2,970 after 10 years of ACE inhibitor use) and should be balanced against the improvement in morbidity and mortality gained with use of an ACE inhibitor. Additional studies with long-term follow-up are needed to investigate this possible association.
TAKE-HOME POINTS
Blockade of the renin-angiotensin-aldosterone system is a cornerstone in the therapy of cardiovascular disease.
ARBs are as effective as ACE inhibitors and have a better tolerability profile.
ACE inhibitors cause more angioedema in African Americans and more cough in Chinese Americans than in the rest of the population.
ACE inhibitors and most ARBs (except for losartan) increase the risk of gout.
The combination of beta-blockers and mineralocorticoid receptor blockers with ACE inhibitors or ARBs and, lately, the use of the valsartan-sacubitril combination have been increasingly beneficial for patients with HFrEF.
References
Momoniat T, Ilyas D, Bhandari S. ACE inhibitors and ARBs: managing potassium and renal function. Cleve Clin J Med 2019; 86(9):601–607. doi:10.3949/ccjm.86a.18024
CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 1987; 316(23):1429–1435. doi:10.1056/NEJM198706043162301
SOLVD Investigators; Yusuf S, Pitt B, Davis CE, Hood WB, Cohn JN. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991; 325(5):293–302. doi:10.1056/NEJM199108013250501
Young JB, Dunlap ME, Pfeffer MA, et al; Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM) Investigators and Committees. Mortality and morbidity reduction with candesartan in patients with chronic heart failure and left ventricular systolic dysfunction: results of the CHARM low-left ventricular ejection fraction trials. Circulation 2004; 110(17):2618–2626. doi:10.1161/01.CIR.0000146819.43235.A9
Cohn JN, Tognoni G; Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 2001; 345(23):1667–1675. doi:10.1056/NEJMoa010713
Straus MH, Hall AS. Angiotensin receptor blockers do not reduce risk of myocardial infarction, cardiovascular death, or total mortality: further evidence for the ARB-MI paradox. Circulation 2017; 135(22):2088–2090. doi:10.1161/CIRCULATIONAHA.117.026112
Burnett H, Earley A, Voors AA, et al. Thirty years of evidence on the efficacy of drug treatments for chronic heart failure with reduced ejection fraction. A network meta-analysis. Circ Heart Fail 2017; 10(1). pii:e003529. doi:10.1161/CIRCHEARTFAILURE.116.003529
Messerli FH, Bangalore S, Bavishi C, Rimoldi SF. Angiotensin-converting enzyme inhibitors in hypertension: to use or not to use? J Am Coll Cardiol 2018; 71(13):1474–1482. doi:10.1016/j.jacc.2018.01.058
Messerli FH, Bangalore S. Angiotensin receptor blockers reduce cardiovascular events, including the risk of myocardial infarction. Circulation 2017; 135(22):2085–2087. doi:10.1161/CIRCULATIONAHA.116.025950
Bangalore S, Fakheri R, Toklu B, Ogedegbe G, Weintraub H, Messerli FH. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in patients without heart failure? Insights from 254,301 patients from randomized trials. Mayo Clin Proc 2016; 91(1):51–60. doi:10.1016/j.mayocp.2015.10.019
Potier L, Roussel R, Elbez Y, et al; REACH Registry Investigators. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in high vascular risk. Heart 2017; 103(17):1339–1346. doi:10.1136/heartjnl-2016-310705
Bangalore S, Kumar S, Wetterslev J, Messerli FH. Angiotensin receptor blockers and risk of myocardial infarction: meta-analyses and trial sequential analyses of 147,020 patients from randomized trials. BMJ 2011; 342:d2234. doi:10.1136/bmj.d2234
Saglimbene V, Palmer SC, Ruospo M, et al; Long-Term Impact of RAS Inhibition on Cardiorenal Outcomes (LIRICO) Investigators. The long-term impact of renin-angiotensin system (RAS) inhibition on cardiorenal outcomes (LIRICO): a randomized, controlled trial. J Am Soc Nephrol 2018; 29(12):2890–2899. doi:10.1681/ASN.2018040443
McDowell SE, Coleman JJ, Ferner RE. Systematic review and meta-analysis of ethnic differences in risks of adverse reactions to drugs used in cardiovascular medicine. BMJ 2006; 332(7551):1177–1181. doi:10.1136/bmj.38803.528113.55
Choi HK, Soriano LC, Zhang Y, Rodríguez LA. Antihypertensive drugs and risk of incident gout among patients with hypertension: population based case-control study. BMJ 2012; 344:d8190. doi:10.1136/bmj.d8190
Wolff ML, Cruz JL, Vanderman AJ, Brown JN. The effect of angiotensin II receptor blockers on hyperuricemia. Ther Adv Chronic Dis 2015; 6(6):339–346. doi:10.1177/2040622315596119
Schmidt A, Gruber U, Böhmig G, Köller E, Mayer G. The effect of ACE inhibitor and angiotensin II receptor antagonist therapy on serum uric acid levels and potassium homeostasis in hypertensive renal transplant recipients treated with CsA. Nephrol Dial Transplant 2001; 16(5):1034–1037. pmid:11328912
Hamada T, Ichida K, Hosoyamada M, et al. Uricosuric action of losartan via the inhibition of urate transporter 1 (URAT1) in hypertensive patients. Am J Hypertens 2008; 21(10):1157–1162. doi:10.1038/ajh.2008.245
Packer M, Coats AJ, Fowler MB, et al; Carvedilol Prospective Randomized Cumulative Survival Study Group. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001; 344(22):1651–1658. doi:10.1056/NEJM200105313442201
Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999; 341(10):709–717. doi:10.1056/NEJM199909023411001
Zannad F, McMurray JJ, Krum H, et al; EMPHASIS-HF Study Group. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011; 364(1):11-21. doi:10.1056/NEJMoa1009492
Fried LF, Emanuele N, Zhang JH, et al. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med 2013; 369(20):1892–1903. doi:10.1056/NEJMoa1303154
Chrysostomou A, Pedagogos E, MacGregor L, Becker GJ. Double-blind, placebo-controlled study on the effect of the aldosterone receptor antagonist spironolactone in patients who have persistent proteinuria and are on long-term angiotensin-converting enzyme inhibitor therapy, with or without an angiotensin II receptor blocker. Clin J Am Soc Nephrol 2006; 1(2):256–262. doi:10.2215/CJN.01040905
Abbas S, Ihle P, Harder S, Schubert I. Risk of hyperkalemia and combined use of spironolactone and long-term ACE inhibitor/angiotensin receptor blocker therapy in heart failure using real-life data: a population- and insurance-based cohort. Pharmacoepidemiol Drug Saf 2015; 24(4):406–413. doi:10.1002/pds.3748
US Food and Drug Administration. FDA drug safety communication: new warning and contraindication for blood pressure medicines containing aliskiren (Tekturna). www.fda.gov/Drugs/DrugSafety/ucm300889.htm. Accessed March 8, 2019.
Jhund PS, McMurray JJ. The neprilysin pathway in heart failure: a review and guide on the use of sacubitril/valsartan. Heart 2016; 102(17):1342–1347. doi:10.1136/heartjnl-2014-306775
McMurray JJ, Packer M, Desai AS, et al; PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014; 371(11):993–1004. doi:10.1056/NEJMoa1409077
Hicks BM, Filion KB, Yin H, Sakr L, Udell JA, Azoulay L. Angiotensin converting enzyme inhibitors and risk of lung cancer: population based cohort study. BMJ 2018; 363:k4209. doi:10.1136/bmj.k4209
Hernan Rincon-Choles, MD, MS Department of Nephrology and Hypertension, Glickman Urological and Kidney Institute, Cleveland Clinic; Assistant Professor of Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH; Medical Director of the East Cleveland Dialysis Center, Ohio Renal Care Group, East Cleveland, OH
Address: Hernan Rincon-Choles, MD, MS, Department of Nephrology and Hypertension, Q7, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; rinconh@ccf.org
Hernan Rincon-Choles, MD, MS Department of Nephrology and Hypertension, Glickman Urological and Kidney Institute, Cleveland Clinic; Assistant Professor of Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH; Medical Director of the East Cleveland Dialysis Center, Ohio Renal Care Group, East Cleveland, OH
Address: Hernan Rincon-Choles, MD, MS, Department of Nephrology and Hypertension, Q7, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; rinconh@ccf.org
Author and Disclosure Information
Hernan Rincon-Choles, MD, MS Department of Nephrology and Hypertension, Glickman Urological and Kidney Institute, Cleveland Clinic; Assistant Professor of Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH; Medical Director of the East Cleveland Dialysis Center, Ohio Renal Care Group, East Cleveland, OH
Address: Hernan Rincon-Choles, MD, MS, Department of Nephrology and Hypertension, Q7, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; rinconh@ccf.org
Inhibition of the renin-angiotensin-aldosterone system with angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) is widely used in the treatment of heart failure, hypertension, chronic kidney disease, and coronary artery disease with left ventricular dysfunction.
In this issue, Momoniat et al1 review the benefits of ACE inhibitors and ARBs and how to manage adverse effects. I would like to add some of my own observations.
ARE ACE INHIBITORS REALLY BETTER THAN ARBs?
ACE inhibitors have been the cornerstone of treatment for patients with heart failure with reduced ejection fraction (HFrEF), in whom their use is associated with reduced rates of morbidity and death.2,3 The use of ARBs in these patients is also associated with decreased rates of morbidity and death4,5; however, in early comparisons, ACE inhibitors were deemed more effective in decreasing the incidence of myocardial infarction, cardiovascular death, and all-cause mortality in patients with hypertension, diabetes, and increased cardiovascular risk,6 and all-cause mortality in patients with HFrEF.7
This presumed superiority of ACE inhibitors over ARBs was thought to be a result of a greater vasodilatory effect caused by inhibiting the degradation of bradykinin and leading to increased levels of nitric oxide and vasoactive prostaglandins.8 Another proposed explanation was that because ARBs block angiotensin II AT1 receptors but not AT2 receptors, the increased stimulation of markedly upregulated AT2 receptors in atheromatous plaques in response to elevated serum levels of angiotensin II was deleterious.6 Therefore, ACE inhibitors have been recommended as first-line therapy by most guidelines, whereas ARBs are recommended as second-line therapy, when patients are unable to tolerate ACE inhibitors.
Nevertheless, the much debated differences in outcomes between ACE inhibitors and ARBs do not seem to be real and may have originated from a generational gap in the trials.
The ACE inhibitor trials were performed a decade earlier than the ARB trials. Indirect comparisons of their respective placebo-controlled trials assumed that the placebo groups used for comparison in the 2 sets of trials were similar.9,10 Actually, the rate of cardiovascular disease decreased nearly 50% between the decades of 1990 to 2000 and 2000 to 2010, the likely result of aggressive primary and secondary prevention strategies in clinical practice, including revascularization and lipid-lowering therapy.10
In fact, a meta-regression analysis showed that the differences between ACE inhibitors and ARBs compared with placebo were due to higher event rates in the placebo groups in the ACE inhibitor trials than in the ARB trials for the outcomes of death, cardiovascular death, and myocardial infarction.11 Sensitivity analyses restricted to trials published after 2000 to control for this generational gap showed similar efficacy with ACE inhibitors vs placebo and with ARBs vs placebo for all clinical outcomes.11 Moreover, recent studies have shown that ARBs produce a greater decrease in cardiovascular events than ACE inhibitors, especially in patients with established cardiovascular disease.12,13
An advantage of ARBs over ACE inhibitors is fewer adverse effects: in general, ARBs are better tolerated than ACE inhibitors.14 There are also ethnic differences in the risks of adverse reactions to these medications. African Americans have a higher risk of developing angioedema with ACE inhibitors compared with the rest of the US population, and Chinese Americans have a higher risk than whites of developing cough with ACE inhibitors.9,15
HOW I MANAGE THESE MEDICATIONS
In my medical practice, I try to make sure patients with HFrEF, hypertension, chronic kidney disease, and coronary artery disease with left ventricular dysfunction receive an inhibitor of the renin-angiotensin-aldosterone system.
Which agent?
I prefer ARBs because patients tolerate them better. I continue ACE inhibitors in patients who are already taking them without adverse effects, and I change to ARBs in patients who later become unable to tolerate ACE inhibitors.
Most antihypertensive agents increase the risk of incident gout, except for calcium channel blockers and losartan.16 Losartan is the only ARB with a uricosuric effect, although a mild one,17,18 due to inhibition of the urate transporter 1,19 and therefore I prefer to use it instead of other ARBs or ACE inhibitors in patients who have a concomitant diagnosis of gout.
Which combinations of agents?
The addition of beta-blockers and mineralocorticoid receptor blockers to ACE inhibitors or ARBs is associated with a further decrease in the mortality risk for patients with HFrEF,20–22 but some patients cannot tolerate these combinations or optimized doses of these medications because of worsening hypotension or increased risk of developing acute kidney injury or hyperkalemia.
In most cases, I try not to combine ACE inhibitors with ARBs. This combination may be useful in nondiabetic patients with proteinuria refractory to maximum treatment with 1 class of these agents, but it is associated with an increased risk of hyperkalemia or acute kidney injury in patients with diabetic nephropathy without improving rates of the clinical outcomes of death or cardiovascular events.23 I prefer adding a daily low dose of a mineralocorticoid receptor blocker to an ACE inhibitor or an ARB, which is more effective in controlling refractory proteinuria.24 This regimen is associated with decreased rates of mortality, cardiovascular mortality, and hospitalization for heart failure in patients with HFrEF,22 although it can lead to a higher frequency of hyperkalemia,25 and patients on it require frequent dietary education and monitoring of serum potassium.
I avoid combining direct renin inhibitors with ACE inhibitors or ARBs, since this combination has been contraindicated by the US Food and Drug Administration due to lack of reduction in target-organ damage and an associated increased risk of hypotension, hyperkalemia, and kidney failure, and a slight increase in the risk of stroke or death in patients with diabetic nephropathy.26
Valsartan-sacubitril
Neprilysin is a membrane-bound endopeptidase that degrades vasoactive peptides, including B-type natriuretic peptide and atrial natriuretic peptide.27 The combination of the ARB valsartan and the neprilysin inhibitor sacubitril is associated with a 20% further decrease in rates of cardiovascular mortality and hospitalization and a 16% decrease in total mortality for patients with HFrEF compared with an ACE inhibitor, although there can also be more hypotension and angioedema with the combination.27,28
Very importantly, an ACE inhibitor cannot be used together with valsartan-sacubitril due to increased risk of angioedema and cough. I change ACE inhibitors or ARBs to valsartan-sacubitril in patients with HFrEF who still have symptoms of heart failure. Interestingly, a network meta-analysis showed that the combination of valsartan-sacubitril plus a mineralocorticoid receptor blocker and a beta-blocker resulted in the greatest mortality reduction in patients with HFrEF.7 A word of caution, though: one can also expect an increased risk of hypotension, hyperkalemia, and kidney failure.
Monitoring
It is crucial to monitor blood pressure, serum potassium, and renal function in patients receiving ACE inhibitors, ARBs, mineralocorticoid receptor blockers, valsartan-sacubitril, or combinations of these medications, particularly in elderly patients, who are more susceptible to complications. I use a multidisciplinary approach in my clinic: a patient educator, dietitian, pharmacist, and advanced practice nurse play key roles in educating and monitoring patients for the development of possible complications from this therapy or interactions with other medications.
A recent population-based cohort study found an association of ACE inhibitor use with a 14% relative increase in lung cancer incidence after 10 years of use, compared with ARBs,29 but this may not represent a large absolute risk (calculated number needed to harm of 2,970 after 10 years of ACE inhibitor use) and should be balanced against the improvement in morbidity and mortality gained with use of an ACE inhibitor. Additional studies with long-term follow-up are needed to investigate this possible association.
TAKE-HOME POINTS
Blockade of the renin-angiotensin-aldosterone system is a cornerstone in the therapy of cardiovascular disease.
ARBs are as effective as ACE inhibitors and have a better tolerability profile.
ACE inhibitors cause more angioedema in African Americans and more cough in Chinese Americans than in the rest of the population.
ACE inhibitors and most ARBs (except for losartan) increase the risk of gout.
The combination of beta-blockers and mineralocorticoid receptor blockers with ACE inhibitors or ARBs and, lately, the use of the valsartan-sacubitril combination have been increasingly beneficial for patients with HFrEF.
Inhibition of the renin-angiotensin-aldosterone system with angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) is widely used in the treatment of heart failure, hypertension, chronic kidney disease, and coronary artery disease with left ventricular dysfunction.
In this issue, Momoniat et al1 review the benefits of ACE inhibitors and ARBs and how to manage adverse effects. I would like to add some of my own observations.
ARE ACE INHIBITORS REALLY BETTER THAN ARBs?
ACE inhibitors have been the cornerstone of treatment for patients with heart failure with reduced ejection fraction (HFrEF), in whom their use is associated with reduced rates of morbidity and death.2,3 The use of ARBs in these patients is also associated with decreased rates of morbidity and death4,5; however, in early comparisons, ACE inhibitors were deemed more effective in decreasing the incidence of myocardial infarction, cardiovascular death, and all-cause mortality in patients with hypertension, diabetes, and increased cardiovascular risk,6 and all-cause mortality in patients with HFrEF.7
This presumed superiority of ACE inhibitors over ARBs was thought to be a result of a greater vasodilatory effect caused by inhibiting the degradation of bradykinin and leading to increased levels of nitric oxide and vasoactive prostaglandins.8 Another proposed explanation was that because ARBs block angiotensin II AT1 receptors but not AT2 receptors, the increased stimulation of markedly upregulated AT2 receptors in atheromatous plaques in response to elevated serum levels of angiotensin II was deleterious.6 Therefore, ACE inhibitors have been recommended as first-line therapy by most guidelines, whereas ARBs are recommended as second-line therapy, when patients are unable to tolerate ACE inhibitors.
Nevertheless, the much debated differences in outcomes between ACE inhibitors and ARBs do not seem to be real and may have originated from a generational gap in the trials.
The ACE inhibitor trials were performed a decade earlier than the ARB trials. Indirect comparisons of their respective placebo-controlled trials assumed that the placebo groups used for comparison in the 2 sets of trials were similar.9,10 Actually, the rate of cardiovascular disease decreased nearly 50% between the decades of 1990 to 2000 and 2000 to 2010, the likely result of aggressive primary and secondary prevention strategies in clinical practice, including revascularization and lipid-lowering therapy.10
In fact, a meta-regression analysis showed that the differences between ACE inhibitors and ARBs compared with placebo were due to higher event rates in the placebo groups in the ACE inhibitor trials than in the ARB trials for the outcomes of death, cardiovascular death, and myocardial infarction.11 Sensitivity analyses restricted to trials published after 2000 to control for this generational gap showed similar efficacy with ACE inhibitors vs placebo and with ARBs vs placebo for all clinical outcomes.11 Moreover, recent studies have shown that ARBs produce a greater decrease in cardiovascular events than ACE inhibitors, especially in patients with established cardiovascular disease.12,13
An advantage of ARBs over ACE inhibitors is fewer adverse effects: in general, ARBs are better tolerated than ACE inhibitors.14 There are also ethnic differences in the risks of adverse reactions to these medications. African Americans have a higher risk of developing angioedema with ACE inhibitors compared with the rest of the US population, and Chinese Americans have a higher risk than whites of developing cough with ACE inhibitors.9,15
HOW I MANAGE THESE MEDICATIONS
In my medical practice, I try to make sure patients with HFrEF, hypertension, chronic kidney disease, and coronary artery disease with left ventricular dysfunction receive an inhibitor of the renin-angiotensin-aldosterone system.
Which agent?
I prefer ARBs because patients tolerate them better. I continue ACE inhibitors in patients who are already taking them without adverse effects, and I change to ARBs in patients who later become unable to tolerate ACE inhibitors.
Most antihypertensive agents increase the risk of incident gout, except for calcium channel blockers and losartan.16 Losartan is the only ARB with a uricosuric effect, although a mild one,17,18 due to inhibition of the urate transporter 1,19 and therefore I prefer to use it instead of other ARBs or ACE inhibitors in patients who have a concomitant diagnosis of gout.
Which combinations of agents?
The addition of beta-blockers and mineralocorticoid receptor blockers to ACE inhibitors or ARBs is associated with a further decrease in the mortality risk for patients with HFrEF,20–22 but some patients cannot tolerate these combinations or optimized doses of these medications because of worsening hypotension or increased risk of developing acute kidney injury or hyperkalemia.
In most cases, I try not to combine ACE inhibitors with ARBs. This combination may be useful in nondiabetic patients with proteinuria refractory to maximum treatment with 1 class of these agents, but it is associated with an increased risk of hyperkalemia or acute kidney injury in patients with diabetic nephropathy without improving rates of the clinical outcomes of death or cardiovascular events.23 I prefer adding a daily low dose of a mineralocorticoid receptor blocker to an ACE inhibitor or an ARB, which is more effective in controlling refractory proteinuria.24 This regimen is associated with decreased rates of mortality, cardiovascular mortality, and hospitalization for heart failure in patients with HFrEF,22 although it can lead to a higher frequency of hyperkalemia,25 and patients on it require frequent dietary education and monitoring of serum potassium.
I avoid combining direct renin inhibitors with ACE inhibitors or ARBs, since this combination has been contraindicated by the US Food and Drug Administration due to lack of reduction in target-organ damage and an associated increased risk of hypotension, hyperkalemia, and kidney failure, and a slight increase in the risk of stroke or death in patients with diabetic nephropathy.26
Valsartan-sacubitril
Neprilysin is a membrane-bound endopeptidase that degrades vasoactive peptides, including B-type natriuretic peptide and atrial natriuretic peptide.27 The combination of the ARB valsartan and the neprilysin inhibitor sacubitril is associated with a 20% further decrease in rates of cardiovascular mortality and hospitalization and a 16% decrease in total mortality for patients with HFrEF compared with an ACE inhibitor, although there can also be more hypotension and angioedema with the combination.27,28
Very importantly, an ACE inhibitor cannot be used together with valsartan-sacubitril due to increased risk of angioedema and cough. I change ACE inhibitors or ARBs to valsartan-sacubitril in patients with HFrEF who still have symptoms of heart failure. Interestingly, a network meta-analysis showed that the combination of valsartan-sacubitril plus a mineralocorticoid receptor blocker and a beta-blocker resulted in the greatest mortality reduction in patients with HFrEF.7 A word of caution, though: one can also expect an increased risk of hypotension, hyperkalemia, and kidney failure.
Monitoring
It is crucial to monitor blood pressure, serum potassium, and renal function in patients receiving ACE inhibitors, ARBs, mineralocorticoid receptor blockers, valsartan-sacubitril, or combinations of these medications, particularly in elderly patients, who are more susceptible to complications. I use a multidisciplinary approach in my clinic: a patient educator, dietitian, pharmacist, and advanced practice nurse play key roles in educating and monitoring patients for the development of possible complications from this therapy or interactions with other medications.
A recent population-based cohort study found an association of ACE inhibitor use with a 14% relative increase in lung cancer incidence after 10 years of use, compared with ARBs,29 but this may not represent a large absolute risk (calculated number needed to harm of 2,970 after 10 years of ACE inhibitor use) and should be balanced against the improvement in morbidity and mortality gained with use of an ACE inhibitor. Additional studies with long-term follow-up are needed to investigate this possible association.
TAKE-HOME POINTS
Blockade of the renin-angiotensin-aldosterone system is a cornerstone in the therapy of cardiovascular disease.
ARBs are as effective as ACE inhibitors and have a better tolerability profile.
ACE inhibitors cause more angioedema in African Americans and more cough in Chinese Americans than in the rest of the population.
ACE inhibitors and most ARBs (except for losartan) increase the risk of gout.
The combination of beta-blockers and mineralocorticoid receptor blockers with ACE inhibitors or ARBs and, lately, the use of the valsartan-sacubitril combination have been increasingly beneficial for patients with HFrEF.
References
Momoniat T, Ilyas D, Bhandari S. ACE inhibitors and ARBs: managing potassium and renal function. Cleve Clin J Med 2019; 86(9):601–607. doi:10.3949/ccjm.86a.18024
CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 1987; 316(23):1429–1435. doi:10.1056/NEJM198706043162301
SOLVD Investigators; Yusuf S, Pitt B, Davis CE, Hood WB, Cohn JN. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991; 325(5):293–302. doi:10.1056/NEJM199108013250501
Young JB, Dunlap ME, Pfeffer MA, et al; Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM) Investigators and Committees. Mortality and morbidity reduction with candesartan in patients with chronic heart failure and left ventricular systolic dysfunction: results of the CHARM low-left ventricular ejection fraction trials. Circulation 2004; 110(17):2618–2626. doi:10.1161/01.CIR.0000146819.43235.A9
Cohn JN, Tognoni G; Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 2001; 345(23):1667–1675. doi:10.1056/NEJMoa010713
Straus MH, Hall AS. Angiotensin receptor blockers do not reduce risk of myocardial infarction, cardiovascular death, or total mortality: further evidence for the ARB-MI paradox. Circulation 2017; 135(22):2088–2090. doi:10.1161/CIRCULATIONAHA.117.026112
Burnett H, Earley A, Voors AA, et al. Thirty years of evidence on the efficacy of drug treatments for chronic heart failure with reduced ejection fraction. A network meta-analysis. Circ Heart Fail 2017; 10(1). pii:e003529. doi:10.1161/CIRCHEARTFAILURE.116.003529
Messerli FH, Bangalore S, Bavishi C, Rimoldi SF. Angiotensin-converting enzyme inhibitors in hypertension: to use or not to use? J Am Coll Cardiol 2018; 71(13):1474–1482. doi:10.1016/j.jacc.2018.01.058
Messerli FH, Bangalore S. Angiotensin receptor blockers reduce cardiovascular events, including the risk of myocardial infarction. Circulation 2017; 135(22):2085–2087. doi:10.1161/CIRCULATIONAHA.116.025950
Bangalore S, Fakheri R, Toklu B, Ogedegbe G, Weintraub H, Messerli FH. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in patients without heart failure? Insights from 254,301 patients from randomized trials. Mayo Clin Proc 2016; 91(1):51–60. doi:10.1016/j.mayocp.2015.10.019
Potier L, Roussel R, Elbez Y, et al; REACH Registry Investigators. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in high vascular risk. Heart 2017; 103(17):1339–1346. doi:10.1136/heartjnl-2016-310705
Bangalore S, Kumar S, Wetterslev J, Messerli FH. Angiotensin receptor blockers and risk of myocardial infarction: meta-analyses and trial sequential analyses of 147,020 patients from randomized trials. BMJ 2011; 342:d2234. doi:10.1136/bmj.d2234
Saglimbene V, Palmer SC, Ruospo M, et al; Long-Term Impact of RAS Inhibition on Cardiorenal Outcomes (LIRICO) Investigators. The long-term impact of renin-angiotensin system (RAS) inhibition on cardiorenal outcomes (LIRICO): a randomized, controlled trial. J Am Soc Nephrol 2018; 29(12):2890–2899. doi:10.1681/ASN.2018040443
McDowell SE, Coleman JJ, Ferner RE. Systematic review and meta-analysis of ethnic differences in risks of adverse reactions to drugs used in cardiovascular medicine. BMJ 2006; 332(7551):1177–1181. doi:10.1136/bmj.38803.528113.55
Choi HK, Soriano LC, Zhang Y, Rodríguez LA. Antihypertensive drugs and risk of incident gout among patients with hypertension: population based case-control study. BMJ 2012; 344:d8190. doi:10.1136/bmj.d8190
Wolff ML, Cruz JL, Vanderman AJ, Brown JN. The effect of angiotensin II receptor blockers on hyperuricemia. Ther Adv Chronic Dis 2015; 6(6):339–346. doi:10.1177/2040622315596119
Schmidt A, Gruber U, Böhmig G, Köller E, Mayer G. The effect of ACE inhibitor and angiotensin II receptor antagonist therapy on serum uric acid levels and potassium homeostasis in hypertensive renal transplant recipients treated with CsA. Nephrol Dial Transplant 2001; 16(5):1034–1037. pmid:11328912
Hamada T, Ichida K, Hosoyamada M, et al. Uricosuric action of losartan via the inhibition of urate transporter 1 (URAT1) in hypertensive patients. Am J Hypertens 2008; 21(10):1157–1162. doi:10.1038/ajh.2008.245
Packer M, Coats AJ, Fowler MB, et al; Carvedilol Prospective Randomized Cumulative Survival Study Group. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001; 344(22):1651–1658. doi:10.1056/NEJM200105313442201
Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999; 341(10):709–717. doi:10.1056/NEJM199909023411001
Zannad F, McMurray JJ, Krum H, et al; EMPHASIS-HF Study Group. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011; 364(1):11-21. doi:10.1056/NEJMoa1009492
Fried LF, Emanuele N, Zhang JH, et al. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med 2013; 369(20):1892–1903. doi:10.1056/NEJMoa1303154
Chrysostomou A, Pedagogos E, MacGregor L, Becker GJ. Double-blind, placebo-controlled study on the effect of the aldosterone receptor antagonist spironolactone in patients who have persistent proteinuria and are on long-term angiotensin-converting enzyme inhibitor therapy, with or without an angiotensin II receptor blocker. Clin J Am Soc Nephrol 2006; 1(2):256–262. doi:10.2215/CJN.01040905
Abbas S, Ihle P, Harder S, Schubert I. Risk of hyperkalemia and combined use of spironolactone and long-term ACE inhibitor/angiotensin receptor blocker therapy in heart failure using real-life data: a population- and insurance-based cohort. Pharmacoepidemiol Drug Saf 2015; 24(4):406–413. doi:10.1002/pds.3748
US Food and Drug Administration. FDA drug safety communication: new warning and contraindication for blood pressure medicines containing aliskiren (Tekturna). www.fda.gov/Drugs/DrugSafety/ucm300889.htm. Accessed March 8, 2019.
Jhund PS, McMurray JJ. The neprilysin pathway in heart failure: a review and guide on the use of sacubitril/valsartan. Heart 2016; 102(17):1342–1347. doi:10.1136/heartjnl-2014-306775
McMurray JJ, Packer M, Desai AS, et al; PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014; 371(11):993–1004. doi:10.1056/NEJMoa1409077
Hicks BM, Filion KB, Yin H, Sakr L, Udell JA, Azoulay L. Angiotensin converting enzyme inhibitors and risk of lung cancer: population based cohort study. BMJ 2018; 363:k4209. doi:10.1136/bmj.k4209
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Packer M, Coats AJ, Fowler MB, et al; Carvedilol Prospective Randomized Cumulative Survival Study Group. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001; 344(22):1651–1658. doi:10.1056/NEJM200105313442201
Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999; 341(10):709–717. doi:10.1056/NEJM199909023411001
Zannad F, McMurray JJ, Krum H, et al; EMPHASIS-HF Study Group. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011; 364(1):11-21. doi:10.1056/NEJMoa1009492
Fried LF, Emanuele N, Zhang JH, et al. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med 2013; 369(20):1892–1903. doi:10.1056/NEJMoa1303154
Chrysostomou A, Pedagogos E, MacGregor L, Becker GJ. Double-blind, placebo-controlled study on the effect of the aldosterone receptor antagonist spironolactone in patients who have persistent proteinuria and are on long-term angiotensin-converting enzyme inhibitor therapy, with or without an angiotensin II receptor blocker. Clin J Am Soc Nephrol 2006; 1(2):256–262. doi:10.2215/CJN.01040905
Abbas S, Ihle P, Harder S, Schubert I. Risk of hyperkalemia and combined use of spironolactone and long-term ACE inhibitor/angiotensin receptor blocker therapy in heart failure using real-life data: a population- and insurance-based cohort. Pharmacoepidemiol Drug Saf 2015; 24(4):406–413. doi:10.1002/pds.3748
US Food and Drug Administration. FDA drug safety communication: new warning and contraindication for blood pressure medicines containing aliskiren (Tekturna). www.fda.gov/Drugs/DrugSafety/ucm300889.htm. Accessed March 8, 2019.
Jhund PS, McMurray JJ. The neprilysin pathway in heart failure: a review and guide on the use of sacubitril/valsartan. Heart 2016; 102(17):1342–1347. doi:10.1136/heartjnl-2014-306775
McMurray JJ, Packer M, Desai AS, et al; PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014; 371(11):993–1004. doi:10.1056/NEJMoa1409077
Hicks BM, Filion KB, Yin H, Sakr L, Udell JA, Azoulay L. Angiotensin converting enzyme inhibitors and risk of lung cancer: population based cohort study. BMJ 2018; 363:k4209. doi:10.1136/bmj.k4209
