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Patients with mRCC survive longer at high-volume centers

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Fri, 01/04/2019 - 14:23

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Once again, a study has shown that when it comes to managing patients with serious advanced malignancies – in this case, metastatic renal cell carcinoma – experience matters.

A review of data on 41,836 patients with metastatic renal cell carcinoma (mRCC) treated at 1,222 facilities (TFs) showed that across all cohorts, including patients with known liver and lung metastases who received systemic therapies, treatment-center volume was significantly associated with longer survival, reported Daniel M. Geynisman, MD of Fox Chase Cancer Center in Philadelphia, and his colleagues.

“These findings may help define the optimal treatment environment for the management of patients with mRCC. The improved survival outcomes at higher-volume TFs should also be a call to improve mRCC management at lower-volume facilities. Given the negative externalities of care regionalization, focus should shift toward policies that help equalize mRCC management at lower-volume TFs by expanding treatment options, clinical trial access, and specialized resource availability,” the researchers wrote. Their report is in European Urology.

The investigators noted that several studies have demonstrated that patients with localized RCC treated at high-volume centers had better postoperative outcomes and few complications following surgery for renal cancer, but whether treatment volume makes a difference for patients with metastatic disease was less clear.

To get a better understanding of the association between case volume and outcomes for patients with advanced RCC, the investigators searched the National Cancer Database for information on all U.S. patients with mRCC from 2004 through 2013 for whom survival data were available.

To confirm the association with volume, they created five cohorts with increasingly restrictive inclusion criteria, as follows:

Cohort A: All patients with survival data (41,836 patients).
Cohort B: Patients with mRCC who received active treatment of any kind (27,557).
Cohort C: Patients treated with systemic therapy with or without primary surgery (19,138).
Cohort D: Patients treated with systemic therapy at the reporting facility (12,000).
Cohort E: Patients with known sites of metastases (4,933).

The investigators also conducted sensitivity analyses on subcohorts of patients who did not receive nephrectomies in cohorts C, D, and E.

They found in a multivariable analysis that increased volume, measured as cases per year, was associated with reduced overall mortality across all cohorts.

For example, in cohort A, the hazard ratio (HR) for overall mortality for TFs caring for a mean of 5 patients per year was 0.92, compared with 0.84 for centers with 10 cases per year, and 0.74 for TFs caring for a mean of 20 patients per year (P less than .001). Similarly, the respective HRs for patients in cohort E were 0.88, 0.79, and 0.72 (P less than .001).

The overall probability of mortality was also significantly lower in higher-volume centers for those patients in cohorts C, D, and E who did not undergo nephrectomy.

The investigators acknowledged that the study was limited by the retrospective nature of the database information, and by the absence of data on treatment regimens used at specific facilities, which may explain mechanisms of the effects they observed.

The investigators did not specify a study funding source. Dr. Geynisman reported having no conflicts of interest.

SOURCE: Joshi SS et al. Eur Urol. 2018 Sep;74[3]:387-93.

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Obesity: Are shared medical appointments part of the answer?

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Thu, 03/28/2019 - 14:34

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Obesity: Are shared medical appointments part of the answer?

Author(s)

Kelly Shibuya, BS

Kevin M. Pantalone, DO, ECNU, FACE

Bartolome Burguera, MD, PhD

Obesity is a major health problem in the United States. The facts are well known:

Its prevalence has almost tripled since the early 1960s¹
More than 35% of US adults are obese (body mass index [BMI] ≥ 30 kg/m²)²
It increases the risk of comorbid conditions including type 2 diabetes mellitus, heart disease, hypertension, obstructive sleep apnea, certain cancers, asthma, and osteoarthritis^3,4
It decreases life expectancy⁵
Medical costs are up to 6 times higher per patient.⁶

Moreover, obesity is often not appropriately managed, owing to a variety of factors. In this article, we describe use of shared medical appointments as a strategy to improve the efficiency and effectiveness of treating patients with obesity.

Big benefits from small changes in weight

As little as 3% to 5% weight loss is associated with significant clinical benefits, such as improved glycemic control, reduced blood pressure, and reduced cholesterol levels.^7,8 However, many patients are unable to reach this modest goal using current approaches to obesity management.

This failure is partially related to the complexity and chronic nature of obesity, which requires continued medical management from a multidisciplinary team. We believe this is an area of care that can be appropriately addressed through shared medical appointments.

CURRENT APPROACHES

Interventions for obesity have increased along with the prevalence of the disease. Hundreds of diets, exercise plans, natural products, and behavioral interventions are marketed, all claiming to be successful. More-intense treatment options include antiobesity medications, intra-abdominal weight loss devices, and bariatric surgery. Despite the availability of treatments, rates of obesity have not declined.

Counseling is important, but underused

Lifestyle modifications that encompass nutrition, physical activity, and behavioral interventions are the mainstay of obesity treatment.

Intensive interventions work better than less-intensive ones. In large clinical trials in overweight patients with diabetes, those who received intensive lifestyle interventions lost 3 to 5 kg more (3% to 8% of body weight) than those who received brief diet and nutrition counseling, as is often performed in a physician’s office.^9–12 The US Preventive Services Task Force recommends that patients whose BMI is 30 kg/m² or higher be offered intensive lifestyle intervention consisting of at least 12 sessions in 1 year.¹³

But fewer than half of primary care practitioners consistently provide specific guidance on diet, exercise, or weight control to patients with obesity, including those with a weight-related comorbidity.¹⁴ The rate has decreased since the 1990s despite the increase in obesity.¹⁵

One reason for the underuse is that many primary care practitioners do not have the training or time to deliver the recommended high-intensity obesity treatment.¹⁴ Plus, evidence does not clearly show a weight loss benefit from low-intensity interventions. Even when patients lose weight, most regain it, and only 20% are able to maintain their weight loss 1 year after treatment ends.¹⁶

Drugs and surgery also underused

Antiobesity medications and bariatric surgery are effective when added to lifestyle interventions, but they are also underused.

Bariatric surgery provides the greatest and most durable weight loss—15% to 30% of body weight—along with improvement in comorbidities such as type 2 diabetes, and its benefits are sustained for at least 10 years.¹⁷ However, fewer than 1% of eligible patients undergo bariatric surgery because of its limited availability, invasive nature, potential complications, limited insurance coverage, and high cost.¹⁷

The story is similar for antiobesity drugs. They are useful adjuncts to lifestyle interventions, providing an additional 3% to 7% weight loss,¹⁸ but fewer than 2% of eligible patients receive them.¹⁹ This may be attributed to their modest effectiveness, weight regain after discontinuation, potential adverse effects, and expense due to lack of insurance coverage.

ARE SHARED MEDICAL APPOINTMEMNTS AN ANSWER?

Although treatments have shown some effectiveness at producing weight loss, none has had a widespread impact on obesity. Lifestyle interventions, drugs, and bariatric surgery continue to be underused. Current treatment models are not providing patients with the intensive interventions needed.

Providers often find themselves offering repetitive advice to patients with obesity regarding nutrition and exercise, while simultaneously trying to manage obesity-related comorbidities, all in a 20-minute appointment. Too often, a patient returns home with prescriptions for hypertension or diabetes but no clear plan for weight management.

What can a shared medical appointment do?

A shared medical appointment is a group medical visit in which several patients with a similar clinical diagnosis, such as obesity, see a multidisciplinary team of healthcare providers. Typically, 5 to 10 patients have consultations with providers during a 60- to 90-minute appointment.²⁰

Part of the session is dedicated to education on the patients’ common medical condition with the goal of improving their self-management, but most of the time is spent addressing individual patient concerns.

Each patient takes a turn consulting with a provider, as in a traditional medical appointment, but in a group setting. This allows others in the group to observe and learn from their peers’ experiences. During this consultation, the patient’s concerns are addressed, medications are managed, necessary tests are ordered, and a treatment plan is made.

Patients can continue to receive follow-up care through shared medical appointments at predetermined times, instead of traditional individual medical appointments.

BENEFITS OF SHARED APPOINTMENTS

Shared medical appointments could improve patient access, clinical outcomes, and patient and provider satisfaction and decrease costs.^20,21 Since being introduced in the 1990s, their use has dramatically increased. For example, in the first 2 years of conducting shared medical appointments at Cleveland Clinic (2002–2004), there were just 385 shared medical appointments,²¹ but in 2017 there were approximately 12,300. They are used in a variety of medical and surgical specialties, and have been studied most for treating diabetes.^22–24

Increased face time and access

Individual patient follow-up visits typically last 15 to 20 minutes, limiting the provider to seeing a maximum of 6 patients in 90 minutes. In that same time in the setting of a shared appointment, a multidisciplinary team can see up to 10 patients, and the patients receive up to 90 minutes of time with multiple providers.

Additionally, shared medical appointments can improve patient access to timely appointments. In a busy bariatric surgery practice, implementing shared medical appointments reduced patients’ wait time for an appointment by more than half.²⁵ This is particularly important for patients with obesity, who usually require 12 to 26 appointments per year.

Improved patient outcomes

Use of shared medical appointments has improved clinical outcomes compared with traditional care. Patients with type 2 diabetes who attend shared medical appointments are more likely to reach target hemoglobin A_1c and blood pressure levels.²²⁻²⁴ These benefits may be attributed to increased access to care, improved self-management skills, more frequent visits, peer support of the group, and the synergistic knowledge of multiple providers on the shared medical appointment team.

Although some trials reported patient retention rates of 75% to 90% in shared medical appointments, many trials did not report their rates. It is likely that some patients declined randomization to avoid shared medical appointments, which could have led to potential attrition and selection biases.²³

Increased patient and provider satisfaction

Both patients and providers report high satisfaction with shared medical appointments.^22,26 Although patients may initially hesitate to participate, their opinions significantly improve after attending 1 session.²⁶ From 85% to 90% of patients who attend a shared medical appointment schedule their next follow-up appointment as a shared appointment as well.^21,25

In comparative studies, patients who attended shared medical appointments had satisfaction rates equal to or higher than rates in patients who participated in usual care,²²noting better access to care and more sensitivity to their needs.²⁷ Providers report greater satisfaction from working more directly with a team of providers, clearing up a backlogged schedule, and adding variety to their practice.^21,24

Decreased costs

Data on the cost-effectiveness of shared medical appointments are mixed; however, some studies have shown that they are associated with a decrease in hospital admissions and emergency department visits.²² It seems reasonable to assume that, in an appropriate patient population, shared medical appointments can be cost-effective owing to increased provider productivity, but more research is needed to verify this.

CHALLENGES TO STARTING SHARED APPOINTMENTS FOR OBESITY

Despite their potential to provide comprehensive care to patients, shared medical appointments have limitations. These need to be addressed before implementing a shared medical appointment program.

Adequate resources and staff training

To be successful, a shared medical appointment program needs to have intensive physical and staffing resources. You need a space large enough to accommodate the group and access to the necessary equipment (eg, projector, whiteboard) for educational sessions. Larger or armless chairs may better accommodate patients with obesity. Facilitators need training in how to lead the group sessions, including time management and handling conflicts between patients. Schedulers and clinical intake staff need training in answering patient questions regarding these appointments.

Maintaining patient attendance

The benefits of provider efficiency rest on having an adequate number of patients attend the shared appointments.²¹ Patient cancellations and no-shows decrease both the efficiency and cost-effectiveness of this model, and they detract from the peer support and group learning that occurs in the group dynamic. To help minimize patient dropout, a discussion of patient expectations should take place prior to enrollment in shared medical appointments. This should include information on the concept of shared appointments, frequency and duration of appointments, and realistic weight loss goals.

Logistical challenges

A shared medical appointment requires a longer patient time slot and is usually less flexible than an individual appointment. Not all patients can take the time for a prescheduled 60- to 90-minute appointment. However, reduced waiting-room time and increased face time with a provider offset some of these challenges.

Recruiting patients

A shared medical appointment is a novel experience for some, and concerns about it may make it a challenge to recruit patients. Patients might worry that the presence of the group will compromise the patient-doctor relationship. Other concerns include potential irrelevance of other patients’ medical issues and reluctance to participate because of body image and the stigma of obesity.

One solution is to select patients from your existing practice so that the individual patient-provider relationship is established before introducing the concept of shared appointments. You will need to explain how shared appointments work, discuss their pros and cons, stress your expectations about attendance and confidentiality, and address any concerns of the patient. It is also important to emphasize that nearly all patients find shared medical appointments useful.

Once a group is established, it may be a challenge to keep a constant group membership to promote positive group dynamics. In practice, patients may drop out or be added, and facilitators need to be able to integrate new members into the group. It is important to emphasize to the group that obesity is chronic and that patients at all stages and levels of treatment can contribute to group learning.

Despite the advantages of shared medical appointments, some patients may not find them useful, even after attending several sessions. These patients should be offered individual follow-up visits. Also, shared appointments may not be suitable for patients who cannot speak English very well, are hearing-impaired, have significant cognitive impairment, or have acute medical issues.

Maintaining patient confidentiality

Maintaining confidentiality of personal and health information in a shared medical appointment is an important concern for patients but can be appropriately managed. In a survey of patients attending pulmonary hypertension shared medical appointments, 24% had concerns about confidentiality before participating, but after a few sessions, this rate was cut in half.²⁸

Patients have reported initially withholding some information, but over time, they usually become more comfortable with the group and disclose more helpful information.²⁹ Strategies to ensure confidentiality include having patients sign a confidentiality agreement at each appointment, providing specific instruction on what characterizes confidentiality breaches, and allowing patients the opportunity to schedule individual appointments as needed.

Ensuring insurance coverage

A shared medical appointment should be billed as an individual medical appointment for level of care, rather than time spent with the provider. This ensures that insurance coverage and copayments are the same as for individual medical appointments.

Lack of insurance coverage is a major barrier to obesity treatment in general. The US Centers for Medicare and Medicaid Services reimburses intensive behavioral obesity treatment delivered by a primary care practitioner, but limits it to 1 year of treatment and requires patients to meet weight loss goals. Some individual and employer-based healthcare plans do not cover dietitian visits, weight management programs, or antiobesity prescriptions.

EVIDENCE OF EFFECTIVENESS IN OBESITY

Few studies have investigated the use of shared medical appointments in obesity treatment. In the pediatric population, these programs significantly decreased BMI and some other anthropometric measurements,^30–32 but they did not consistently involve a prescribing provider. This means they did not manage medications or comorbidities as would be expected in a shared medical appointment.

In adults, reported effects have been encouraging, although the studies are not particularly robust. In a 2-year observational study of a single physician conducting biweekly weight management shared medical appointments, participants lost 1% of their baseline weight, while those continuing with usual care gained 0.8%, a statistically significant difference.³³ However, participation rates were low, with patients attending an average of only 3 shared medical appointments during the study.

In a meta-analysis of 13 randomized controlled trials of shared medical appointments for patients with type 2 diabetes, only 3 studies reported weight outcomes.²³ These results indicated a trend toward weight loss among patients attending shared appointments, but they were not statistically significant.

Positive results also were reported by the Veterans Administration’s MOVE! (Managing Overweight/obesity for Veterans Everywhere) program.³⁴ Participants in shared medical appointments reported that they felt empowered to make positive lifestyle changes, gained knowledge about obesity, were held accountable by their peers, and appreciated the individualized care they received from the multidisciplinary healthcare teams.

A systematic review involving 336 participants in group-based obesity interventions found group treatment produced more robust weight loss than individual treatment.³⁵ However, shared medical appointments are different from weight loss groups in that they combine an educational session and a medical appointment in a peer-group setting, which requires a provider with prescribing privileges to be present. Thus, shared medical appointments can manage medications as well as weight-related comorbidities such as diabetes, hypertension, polycystic ovarian syndrome, and hyperlipidemia.

One more point is that continued attendance at shared medical appointments, even after successful weight loss, may help to maintain the weight loss, which has otherwise been found to be extremely challenging using traditional medical approaches.

WHO SHOULD BE ON THE TEAM?

Because obesity is multifactorial, it requires a comprehensive treatment approach that can be difficult to deliver given the limited time of an individual appointment. In a shared appointment, providers across multiple specialties can meet with patients at the same time to coordinate approaches to obesity treatment.

A multidisciplinary team for shared medical appointments for obesity needs a physician or a nurse practitioner—or ideally, both— who specializes in obesity to facilitate the session. Other key providers include a registered dietitian, an exercise physiologist, a behavioral health specialist, a sleep specialist, and a social worker to participate as needed in the educational component of the appointment or act as outside consultants.

WHAT ARE REALISTIC TARGETS?

Interventions to address in shared medical appointments for obesity

A shared medical appointment program for obesity should target 5 areas of weight management (Table 1):

Nutrition
Physical activity
Appetite control
Sleep
Stress and mood disorders.

Nutrition

A calorie deficit of 500 to 750 calories per day is recommended for weight loss.^7,8 Although there is no consensus on the best nutritional content of a diet, adherence to a diet is a significant predictor of weight loss.³⁶ One reason diets fail to bring about weight loss is that patients tend to underestimate their caloric intake by almost 50%.³⁷ Thus, they may benefit from a structured and supervised diet plan.

A dietitian can help patients develop an individualized diet plan that will promote adherence, which includes specific information on food choices, portion sizes, and timing of meals.

Physical activity

At least 150 minutes of physical activity per week is recommended for weight loss, and 200 to 300 minutes per week is recommended for long-term weight maintenance.^7,8

An exercise physiologist can help patients design a personalized exercise plan to help achieve these goals. This plan should take into account the patient’s cardiac status, activity level, degree of mobility, and lifestyle.

Most patients are not able to achieve the recommended physical activity goals initially, and activity levels need to be gradually increased over a period of weeks to months. Patients who were previously inactive or have evidence of cardiovascular, renal, or metabolic disease may require a cardiopulmonary assessment, including an electrocardiogram and cardiac stress test, before starting an exercise program.

Appetite control

It is very difficult for patients to lose weight without appetite control. Weight loss that results from diet and exercise is often accompanied by a change in weight-regulating hormones (eg, leptin, ghrelin, peptide YY, and cholecystokinin) that promote weight regain.³⁸ Thus, multiple compensatory mechanisms promote weight regain through increases in appetite and decreases in energy expenditure, resisting weight loss efforts.

Antiobesity drugs can help mitigate these adaptive weight-promoting responses through several mechanisms. They are indicated for use with lifestyle interventions for patients with a BMI of at least 30 mg/kg² or a BMI of at least 27 kg/m² with an obesity-related comorbidity.

These drugs promote an additional 3% to 7% weight loss when added to lifestyle interventions.¹⁸ But their effects are limited without appropriate lifestyle interventions.

Sleep

Adequate sleep is an often-overlooked component of obesity treatment. Inadequate sleep is associated with weight gain and an appetite-inducing hormone profile.³⁹ Just 2 days of sleep deprivation in healthy normal-weight adult men was associated with a 70% increase in the ghrelin-to-leptin ratio, which showed a linear relationship with self-reported increased hunger.³⁹ Sleep disorders, especially obstructive sleep apnea, are common in patients with obesity but are often underdiagnosed and undertreated.⁴⁰

Healthy sleep habits and sleep quality should be addressed in shared medical appointments for obesity, as patients may be unaware of the impact that sleep may be having on their obesity treatment. The STOP-BANG questionnaire (snoring, tiredness, observed apnea, high blood pressure, BMI, age, neck circumference, and male sex) is a simple and reliable tool to screen for obstructive sleep apnea.⁴¹ Patients with symptoms of a sleep disorder should be referred to a sleep specialist for diagnosis and management.

Stress management and mood disorders

Stress and psychiatric disorders are underappreciated contributors to obesity. All patients receiving obesity treatment need to be screened for mood disorders and suicidal ideation.⁸

Chronic stress promotes weight gain through activation of the hypothalamic-pituitary-adrenocortical axis, whereby increased cortisol levels enhance appetite and accumulation of visceral fat.⁴² In addition, obesity is associated with a 25% increased risk of mood disorders, although the mechanism and direction of this association are unclear.⁴³ Weight gain as a side effect of antidepressant or other psychiatric medications is another important consideration.

Management of stress and psychiatric disorders through goal-setting, self-monitoring, and patient education is vital to help patients fully participate in lifestyle changes and maximize weight loss. Patients participating in shared medical appointments usually benefit from consultations with psychiatrists or psychologists to manage psychiatric comorbidities and assist with adherence to behavior modification.  

IN FAVOR OF SHARED MEDICAL APPOINTMENTS FOR OBESITY

Shared medical appointments can be an effective method of addressing the challenges of treating patients with obesity, using a multidisciplinary approach that combines nutrition, physical activity, appetite suppression, sleep improvement, and stress management. In addition, shared appointments allow practitioners to treat the primary problem of excess weight, rather than just its comorbidities, recognizing that obesity is a chronic disease that requires long-term, individualized treatment. Satisfaction rates are high for both patients and providers. Overall, education is essential to implementing and maintaining a successful shared medical appointment program.

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Chung F, Yegneswaran B, Liao P, et al. STOP questionnaire: a tool to screen patients for obstructive sleep apnea. Anesthesiology 2008; 108(5):812–821. doi:10.1097/ALN.0b013e31816d83e4
Charmandari E, Tsigos C, Chrousos G. Endocrinology of the stress response. Annu Rev Physiol 2005; 67:259–284. doi:10.1146/annurev.physiol.67.040403.120816
Simon GE, Von Korff M, Saunders K, et al. Association between obesity and psychiatric disorders in the US adult population. Arch Gen Psychiatry 2006; 63(7):824-830. doi:10.1001/archpsyc.63.7.824

Article PDF

shibuya_obesitysharedappointments.pdf

Author and Disclosure Information

Kelly Shibuya, BS
Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Kevin M. Pantalone, DO, ECNU, FACE
Staff Endocrinologist, Director of Clinical Research, Department of Endocrinology, Endocrinology and Metabolism Institute, Cleveland Clinic; Clinical Assistant Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Bartolome Burguera, MD, PhD
Endocrinology and Metabolism Institute, Cleveland Clinic; National Diabetes and Obesity Research Institute, Tradition, MS; Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Address: Bartolome Burguera, MD, PhD, Endocrinology and Metabolism Institute, M62, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; burgueb@ccf.org

Dr. Pantalone has disclosed teaching and speaking for AstraZeneca; consulting, research support, and teaching and speaking for Merck; consulting, research support, and teaching and speaking for Novo Nordisk; and consulting for Sanofi-Aventis.

Issue

Cleveland Clinic Journal of Medicine - 85(9)

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Cleveland Clinic Journal of Medicine

Topics

Obesity

Practice Management

Business of Medicine

Page Number

699-706

Legacy Keywords

obesity, overweight, weight loss, shared medical appointments, Kelly Shibuya, Kevin Pantalone, Bartolome Burguera

Read more about Obesity: Are shared medical appointments part of the answer?

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Author(s)

Kelly Shibuya, BS

Kevin M. Pantalone, DO, ECNU, FACE

Bartolome Burguera, MD, PhD

Author(s)

Kelly Shibuya, BS

Kevin M. Pantalone, DO, ECNU, FACE

Bartolome Burguera, MD, PhD

Author and Disclosure Information

Kelly Shibuya, BS
Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Address: Bartolome Burguera, MD, PhD, Endocrinology and Metabolism Institute, M62, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; burgueb@ccf.org

Author and Disclosure Information

Kelly Shibuya, BS
Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Address: Bartolome Burguera, MD, PhD, Endocrinology and Metabolism Institute, M62, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; burgueb@ccf.org

Article PDF

shibuya_obesitysharedappointments.pdf

Article PDF

shibuya_obesitysharedappointments.pdf

Obesity is a major health problem in the United States. The facts are well known:

Its prevalence has almost tripled since the early 1960s¹
More than 35% of US adults are obese (body mass index [BMI] ≥ 30 kg/m²)²
It increases the risk of comorbid conditions including type 2 diabetes mellitus, heart disease, hypertension, obstructive sleep apnea, certain cancers, asthma, and osteoarthritis^3,4
It decreases life expectancy⁵
Medical costs are up to 6 times higher per patient.⁶

Big benefits from small changes in weight

CURRENT APPROACHES

Counseling is important, but underused

Lifestyle modifications that encompass nutrition, physical activity, and behavioral interventions are the mainstay of obesity treatment.

Drugs and surgery also underused

Antiobesity medications and bariatric surgery are effective when added to lifestyle interventions, but they are also underused.

ARE SHARED MEDICAL APPOINTMEMNTS AN ANSWER?

What can a shared medical appointment do?

Patients can continue to receive follow-up care through shared medical appointments at predetermined times, instead of traditional individual medical appointments.

BENEFITS OF SHARED APPOINTMENTS

Increased face time and access

Improved patient outcomes

Increased patient and provider satisfaction

Decreased costs

CHALLENGES TO STARTING SHARED APPOINTMENTS FOR OBESITY

Despite their potential to provide comprehensive care to patients, shared medical appointments have limitations. These need to be addressed before implementing a shared medical appointment program.

Adequate resources and staff training

Maintaining patient attendance

Logistical challenges

Recruiting patients

Maintaining patient confidentiality

Ensuring insurance coverage

EVIDENCE OF EFFECTIVENESS IN OBESITY

WHO SHOULD BE ON THE TEAM?

WHAT ARE REALISTIC TARGETS?

A shared medical appointment program for obesity should target 5 areas of weight management (Table 1):

Nutrition
Physical activity
Appetite control
Sleep
Stress and mood disorders.

Nutrition

A dietitian can help patients develop an individualized diet plan that will promote adherence, which includes specific information on food choices, portion sizes, and timing of meals.

Physical activity

At least 150 minutes of physical activity per week is recommended for weight loss, and 200 to 300 minutes per week is recommended for long-term weight maintenance.^7,8

Appetite control

These drugs promote an additional 3% to 7% weight loss when added to lifestyle interventions.¹⁸ But their effects are limited without appropriate lifestyle interventions.

Sleep

Stress management and mood disorders

Stress and psychiatric disorders are underappreciated contributors to obesity. All patients receiving obesity treatment need to be screened for mood disorders and suicidal ideation.⁸

IN FAVOR OF SHARED MEDICAL APPOINTMENTS FOR OBESITY

Obesity is a major health problem in the United States. The facts are well known:

Its prevalence has almost tripled since the early 1960s¹
More than 35% of US adults are obese (body mass index [BMI] ≥ 30 kg/m²)²
It increases the risk of comorbid conditions including type 2 diabetes mellitus, heart disease, hypertension, obstructive sleep apnea, certain cancers, asthma, and osteoarthritis^3,4
It decreases life expectancy⁵
Medical costs are up to 6 times higher per patient.⁶

Big benefits from small changes in weight

CURRENT APPROACHES

Counseling is important, but underused

Lifestyle modifications that encompass nutrition, physical activity, and behavioral interventions are the mainstay of obesity treatment.

Drugs and surgery also underused

Antiobesity medications and bariatric surgery are effective when added to lifestyle interventions, but they are also underused.

ARE SHARED MEDICAL APPOINTMEMNTS AN ANSWER?

What can a shared medical appointment do?

Patients can continue to receive follow-up care through shared medical appointments at predetermined times, instead of traditional individual medical appointments.

BENEFITS OF SHARED APPOINTMENTS

Increased face time and access

Improved patient outcomes

Increased patient and provider satisfaction

Decreased costs

CHALLENGES TO STARTING SHARED APPOINTMENTS FOR OBESITY

Despite their potential to provide comprehensive care to patients, shared medical appointments have limitations. These need to be addressed before implementing a shared medical appointment program.

Adequate resources and staff training

Maintaining patient attendance

Logistical challenges

Recruiting patients

Maintaining patient confidentiality

Ensuring insurance coverage

EVIDENCE OF EFFECTIVENESS IN OBESITY

WHO SHOULD BE ON THE TEAM?

WHAT ARE REALISTIC TARGETS?

A shared medical appointment program for obesity should target 5 areas of weight management (Table 1):

Nutrition
Physical activity
Appetite control
Sleep
Stress and mood disorders.

Nutrition

A dietitian can help patients develop an individualized diet plan that will promote adherence, which includes specific information on food choices, portion sizes, and timing of meals.

Physical activity

At least 150 minutes of physical activity per week is recommended for weight loss, and 200 to 300 minutes per week is recommended for long-term weight maintenance.^7,8

Appetite control

These drugs promote an additional 3% to 7% weight loss when added to lifestyle interventions.¹⁸ But their effects are limited without appropriate lifestyle interventions.

Sleep

Stress management and mood disorders

Stress and psychiatric disorders are underappreciated contributors to obesity. All patients receiving obesity treatment need to be screened for mood disorders and suicidal ideation.⁸

IN FAVOR OF SHARED MEDICAL APPOINTMENTS FOR OBESITY

References

Ogden CL, Carroll MD. National Center for Health Statistics. Prevalence of overweight, obesity, and extreme obesity among adults: United States, trends 1960-62 through 2007–2008. www.cdc.gov/nchs/data/hestat/obesity_adult_07_08/obesity_adult_07_08.pdf. Accessed August 8, 2018.
Flegal KM, Kruszon-Moran D, Carroll MD, Fryar CD, Ogden CL. Trends in obesity among adults in the United States, 2005 to 2014. JAMA 2016; 315(21):2284–2291. doi:10.1001/jama.2016.6458
Pantalone KM, Hobbs TM, Chagin KM, et al. Prevalence and recognition of obesity and its associated comorbidities: cross-sectional analysis of electronic health record data from a large US integrated health system. BMJ Open 2017; 7(11):e017583. doi:10.1136/bmjopen-2017-017583
Guh DP, Zhang W, Bansback N, Amarsi Z, Birmingham CL, Anis AH. The incidence of co-morbidities related to obesity and overweight: a systematic review and meta-analysis. BMC Public Health 2009;9:88. doi:10.1186/1471-2458-9-88
Fontaine KR, Redden DT, Wang C, Westfall AO, Allison DB. Years of life lost due to obesity. JAMA 2003; 289(2):187–193. pmid:12517229
Tsai AG, Williamson DF, Glick HA. Direct medical cost of overweight and obesity in the United States: a quantitative systematic review. Int Assoc Study Obes Rev 2011; 12(1):50–61. doi:10.1111/j.1467-789X.2009.00708.x
Jensen MD. Notice of duplicate publication of Jensen MD, Ryan DH, Apovian CM, et al; American College of Cardiology/American Heart Association Task Force on Practice Guidelines; Obesity Society. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. Circulation 2014; 129(25 suppl 2):S102–S138. doi:10.1161/01.cir.0000437739.71477.ee. J Am Coll Cardiol 2014; 63(25 Pt B):2985–3023. doi:10.1016/j.jacc.2013.11.004
Garvey WT, Mechanick JI, Brett EM, et al; Reviewers of the AACE/ACE Obesity Clinical Practice Guidelines. American Association of Clinical Endocrinologists and American College of Endocrinology comprehensive clinical practice guidelines for medical care of patients with obesity: executive summary. Endocr Pract 2016; 22(7):842–884. doi:10.4158/EP161356.ESGL
Knowler WC, Barrett-Connor E, Fowler SE, et al; Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 346(6):393–403. doi:10.1056/NEJMoa012512
Eriksson J, Lindstrom J, Valle T, et al. Prevention of type II diabetes in subjects with impaired glucose tolerance: The Diabetes Prevention Study (DPS) in Finland. Study design and 1-year interim report on the feasibility of the lifestyle intervention programme. Diabetologia 1999; 42(7):793–801. pmid:10440120
Look AHEAD Research Group; Pi-Sunyer X, Blackburn G, Brancati FL, et al. Reduction in weight and cardiovascular disease risk factors in individuals with type 2 diabetes: one-year results of the look AHEAD trial. Diabetes Care 2007; 30(6):1374–1383. doi:10.2337/dc07-0048
Burguera B, Jesús Tur J, Escudero AJ, et al. An intensive lifestyle intervention is an effective treatment of morbid obesity: the TRAMOMTANA study—a two-year randomized controlled clinical trial. Int J Endocrinol 2015; 2015:194696. doi:10.1155/2015/194696
Moyer VA; US Preventive Services Task Force. Screening for and management of obesity in adults: US Preventative Task Force Recommendation Statement. Ann Intern Med 2012; 157(5):373–378. doi:10.7326/0003-4819-157-5-201209040-00475
Smith AW, Borowski LA, Liu B, et al. US primary care physicians’ diet-, physical activity-, and weight-related care of adult patients. Am J Prev Med 2011; 41(1):33–42. doi:10.1016/j.amepre.2011.03.017
Kraschnewski JL, Sciamanna CN, Stuckey HL, et al. A silent response to the obesity epidemic: decline in US physician weight counseling. Med Care 2013; 51(2):186–192. doi:10.1097/MLR.0b013e3182726c33
Wing RR, Hill JO. Successful weight loss maintenance. Annu Rev Nutr 2001; 21:323–341. doi:10.1146/annurev.nutr.21.1.323
Nguyen NT, Varela JE. Bariatric surgery for obesity and metabolic disorders: state of the art. Nat Rev Gastroenterol Hepatol 2017; 14(3):160–169. doi:10.1038/nrgastro.2016.170
Yanovski SZ, Yanovski JA. Long-term drug treatment for obesity: a systematic and clinical review. JAMA 2014; 311(1):74–86. doi:10.1001/jama.2013.281361
Xia Y, Kelton CM, Guo JJ, Bian B, Heaton PC. Treatment of obesity: pharmacotherapy trends in the United States from 1999 to 2010. Obesity (Silver Spring) 2015; 23(8):1721–1728. doi:10.1002/oby.21136
Ramdas K, Darzi A. Adopting innovations in care delivery—the care of shared medical appointments. N Engl J Med 2017; 376(12):1105–1107. doi:10.1056/NEJMp1612803
Bronson DL, Maxwell RA. Shared medical appointments: increasing patient access without increasing physician hours. Cleve Clin J Med 2004; 71(5):369–377. pmid:15195773
Edelman D, McDuffie JR, Oddone E, et al. Shared Medical Appointments for Chronic Medical Conditions: A Systematic Review. Washington, DC: Department of Veterans Affairs; 2012.
Housden L, Wong ST, Dawes M. Effectiveness of group medical visits for improving diabetes care: a systematic review and meta-analysis. CMAJ 2013; 185(13):E635–E644. doi:10.1503/cmaj.130053
Housden LM, Wong ST. Using group medical visits with those who have diabetes: examining the evidence. Curr Diab Rep 2016; 16(12):134. doi:10.1007/s11892-016-0817-4
Kaidar-Person O, Swartz EW, Lefkowitz M, et al. Shared medical appointments: new concept for high-volume follow-up for bariatric patients. Surg Obes Relat Dis 2006; 2(5):509–512. doi:10.1016/j.soard.2006.05.010
Seager MJ, Egan RJ, Meredith HE, Bates SE, Norton SA, Morgan JD. Shared medical appointments for bariatric surgery follow-up: a patient satisfaction questionnaire. Obes Surg 2012; 22(4):641–645. doi:10.1007/s11695-012-0603-6
Heyworth L, Rozenblum R, Burgess JF Jr, et al. Influence of shared medical appointments on patient satisfaction: a retrospective 3-year study. Ann Fam Med 2014; 12(4):324–330. doi:10.1370/afm.1660
Rahaghi FF, Chastain VL, Benavides R, et al. Shared medical appointments in pulmonary hypertension. Pulm Circ 2014; 4(1):53–60. doi:10.1086/674883
Wong ST, Lavoie JG, Browne AJ, Macleod ML, Chongo M. Patient confidentiality within the context of group medical visits: Is there cause for concern? Health Expect 2015; 18(5):727–739. doi:10.1111/hex.12156
Geller JS, Dube ET, Cruz GA, Stevens J, Keating Bench K. Pediatric Obesity Empowerment Model Group Medical Visits (POEM-GMV) as treatment for pediatric obesity in an underserved community. Child Obes 2015; 11(5):638–646. doi:10.1089/chi.2014.0163
Weigel C, Kokocinski K, Lederer P, Dötsch J, Rascher W, Knerr I. Childhood obesity: concept, feasibility, and interim results of a local group-based, long-term treatment program. J Nutr Educ Behav 2008; 40(6):369–373. doi:10.1016/j.jneb.2007.07.009
Hinchman J, Beno L, Mims A. Kaiser Permanente Georgia’s experience with operation zero: a group medical appointment to address pediatric overweight. Perm J 2006; 10(3):66–71. pmid:21519478
Palaniappan LP, Muzaffar AL, Wang EJ, Wong EC, Orchard TJ, Mbbch M. Shared medical appointments: promoting weight loss in a clinical setting. J Am Board Fam Med 2011; 24(3):326–328. doi:10.3122/jabfm.2011.03.100220
Cohen S, Hartley S, Mavi J, Vest B, Wilson M. Veteran experiences related to participation in shared medical appointments. Mil Med 2012; 177(11):1287–1292. pmid:23198503
Paul-Ebhohimhen V, Avenell A. A systematic review of the effectiveness of group versus individual treatments for adult obesity. Obes Facts 2009; 2(1):17–24. doi:10.1159/000186144
Sacks FM, Bray GA, Carey VJ, et al. Comparison of weight-loss diets with different compositions of fat, protein, and carbohydrates. N Engl J Med 2009; 360(9):859–873. doi:10.1056/NEJMoa0804748
Lichtman SW, Pisarska K, Berman ER, et al. Discrepancy between self-reported and actual caloric intake and exercise in obese subjects. N Engl J Med 1992; 327(27):1893–1898. doi:10.1056/NEJM199212313272701
Sumithran P, Prendergast LA, Delbridge E, et al. Long-term persistence of hormonal adaptations to weight loss. N Engl J Med 2011; 365(17):1597–1604. doi:10.1056/NEJMoa1105816
Spiegel K, Tasali E, Penev P, Van Cauter E. Brief communication: sleep curtailment in healthy young men is associated with decreased leptin levels, elevated ghrelin levels, and increased hunger and appetite. Ann Intern Med 2004; 141(11):846–850. pmid:15583226
Kapur V, Strohl KP, Redline S, Iber C, O’Connor G, Nieto J. Underdiagnosis of sleep apnea syndrome in US communities. Sleep Breath 2002; 6(2):49–54. doi:10.1007/s11325-002-0049-5
Chung F, Yegneswaran B, Liao P, et al. STOP questionnaire: a tool to screen patients for obstructive sleep apnea. Anesthesiology 2008; 108(5):812–821. doi:10.1097/ALN.0b013e31816d83e4
Charmandari E, Tsigos C, Chrousos G. Endocrinology of the stress response. Annu Rev Physiol 2005; 67:259–284. doi:10.1146/annurev.physiol.67.040403.120816
Simon GE, Von Korff M, Saunders K, et al. Association between obesity and psychiatric disorders in the US adult population. Arch Gen Psychiatry 2006; 63(7):824-830. doi:10.1001/archpsyc.63.7.824

References

Ogden CL, Carroll MD. National Center for Health Statistics. Prevalence of overweight, obesity, and extreme obesity among adults: United States, trends 1960-62 through 2007–2008. www.cdc.gov/nchs/data/hestat/obesity_adult_07_08/obesity_adult_07_08.pdf. Accessed August 8, 2018.
Flegal KM, Kruszon-Moran D, Carroll MD, Fryar CD, Ogden CL. Trends in obesity among adults in the United States, 2005 to 2014. JAMA 2016; 315(21):2284–2291. doi:10.1001/jama.2016.6458
Pantalone KM, Hobbs TM, Chagin KM, et al. Prevalence and recognition of obesity and its associated comorbidities: cross-sectional analysis of electronic health record data from a large US integrated health system. BMJ Open 2017; 7(11):e017583. doi:10.1136/bmjopen-2017-017583
Guh DP, Zhang W, Bansback N, Amarsi Z, Birmingham CL, Anis AH. The incidence of co-morbidities related to obesity and overweight: a systematic review and meta-analysis. BMC Public Health 2009;9:88. doi:10.1186/1471-2458-9-88
Fontaine KR, Redden DT, Wang C, Westfall AO, Allison DB. Years of life lost due to obesity. JAMA 2003; 289(2):187–193. pmid:12517229
Tsai AG, Williamson DF, Glick HA. Direct medical cost of overweight and obesity in the United States: a quantitative systematic review. Int Assoc Study Obes Rev 2011; 12(1):50–61. doi:10.1111/j.1467-789X.2009.00708.x
Jensen MD. Notice of duplicate publication of Jensen MD, Ryan DH, Apovian CM, et al; American College of Cardiology/American Heart Association Task Force on Practice Guidelines; Obesity Society. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. Circulation 2014; 129(25 suppl 2):S102–S138. doi:10.1161/01.cir.0000437739.71477.ee. J Am Coll Cardiol 2014; 63(25 Pt B):2985–3023. doi:10.1016/j.jacc.2013.11.004
Garvey WT, Mechanick JI, Brett EM, et al; Reviewers of the AACE/ACE Obesity Clinical Practice Guidelines. American Association of Clinical Endocrinologists and American College of Endocrinology comprehensive clinical practice guidelines for medical care of patients with obesity: executive summary. Endocr Pract 2016; 22(7):842–884. doi:10.4158/EP161356.ESGL
Knowler WC, Barrett-Connor E, Fowler SE, et al; Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 346(6):393–403. doi:10.1056/NEJMoa012512
Eriksson J, Lindstrom J, Valle T, et al. Prevention of type II diabetes in subjects with impaired glucose tolerance: The Diabetes Prevention Study (DPS) in Finland. Study design and 1-year interim report on the feasibility of the lifestyle intervention programme. Diabetologia 1999; 42(7):793–801. pmid:10440120
Look AHEAD Research Group; Pi-Sunyer X, Blackburn G, Brancati FL, et al. Reduction in weight and cardiovascular disease risk factors in individuals with type 2 diabetes: one-year results of the look AHEAD trial. Diabetes Care 2007; 30(6):1374–1383. doi:10.2337/dc07-0048
Burguera B, Jesús Tur J, Escudero AJ, et al. An intensive lifestyle intervention is an effective treatment of morbid obesity: the TRAMOMTANA study—a two-year randomized controlled clinical trial. Int J Endocrinol 2015; 2015:194696. doi:10.1155/2015/194696
Moyer VA; US Preventive Services Task Force. Screening for and management of obesity in adults: US Preventative Task Force Recommendation Statement. Ann Intern Med 2012; 157(5):373–378. doi:10.7326/0003-4819-157-5-201209040-00475
Smith AW, Borowski LA, Liu B, et al. US primary care physicians’ diet-, physical activity-, and weight-related care of adult patients. Am J Prev Med 2011; 41(1):33–42. doi:10.1016/j.amepre.2011.03.017
Kraschnewski JL, Sciamanna CN, Stuckey HL, et al. A silent response to the obesity epidemic: decline in US physician weight counseling. Med Care 2013; 51(2):186–192. doi:10.1097/MLR.0b013e3182726c33
Wing RR, Hill JO. Successful weight loss maintenance. Annu Rev Nutr 2001; 21:323–341. doi:10.1146/annurev.nutr.21.1.323
Nguyen NT, Varela JE. Bariatric surgery for obesity and metabolic disorders: state of the art. Nat Rev Gastroenterol Hepatol 2017; 14(3):160–169. doi:10.1038/nrgastro.2016.170
Yanovski SZ, Yanovski JA. Long-term drug treatment for obesity: a systematic and clinical review. JAMA 2014; 311(1):74–86. doi:10.1001/jama.2013.281361
Xia Y, Kelton CM, Guo JJ, Bian B, Heaton PC. Treatment of obesity: pharmacotherapy trends in the United States from 1999 to 2010. Obesity (Silver Spring) 2015; 23(8):1721–1728. doi:10.1002/oby.21136
Ramdas K, Darzi A. Adopting innovations in care delivery—the care of shared medical appointments. N Engl J Med 2017; 376(12):1105–1107. doi:10.1056/NEJMp1612803
Bronson DL, Maxwell RA. Shared medical appointments: increasing patient access without increasing physician hours. Cleve Clin J Med 2004; 71(5):369–377. pmid:15195773
Edelman D, McDuffie JR, Oddone E, et al. Shared Medical Appointments for Chronic Medical Conditions: A Systematic Review. Washington, DC: Department of Veterans Affairs; 2012.
Housden L, Wong ST, Dawes M. Effectiveness of group medical visits for improving diabetes care: a systematic review and meta-analysis. CMAJ 2013; 185(13):E635–E644. doi:10.1503/cmaj.130053
Housden LM, Wong ST. Using group medical visits with those who have diabetes: examining the evidence. Curr Diab Rep 2016; 16(12):134. doi:10.1007/s11892-016-0817-4
Kaidar-Person O, Swartz EW, Lefkowitz M, et al. Shared medical appointments: new concept for high-volume follow-up for bariatric patients. Surg Obes Relat Dis 2006; 2(5):509–512. doi:10.1016/j.soard.2006.05.010
Seager MJ, Egan RJ, Meredith HE, Bates SE, Norton SA, Morgan JD. Shared medical appointments for bariatric surgery follow-up: a patient satisfaction questionnaire. Obes Surg 2012; 22(4):641–645. doi:10.1007/s11695-012-0603-6
Heyworth L, Rozenblum R, Burgess JF Jr, et al. Influence of shared medical appointments on patient satisfaction: a retrospective 3-year study. Ann Fam Med 2014; 12(4):324–330. doi:10.1370/afm.1660
Rahaghi FF, Chastain VL, Benavides R, et al. Shared medical appointments in pulmonary hypertension. Pulm Circ 2014; 4(1):53–60. doi:10.1086/674883
Wong ST, Lavoie JG, Browne AJ, Macleod ML, Chongo M. Patient confidentiality within the context of group medical visits: Is there cause for concern? Health Expect 2015; 18(5):727–739. doi:10.1111/hex.12156
Geller JS, Dube ET, Cruz GA, Stevens J, Keating Bench K. Pediatric Obesity Empowerment Model Group Medical Visits (POEM-GMV) as treatment for pediatric obesity in an underserved community. Child Obes 2015; 11(5):638–646. doi:10.1089/chi.2014.0163
Weigel C, Kokocinski K, Lederer P, Dötsch J, Rascher W, Knerr I. Childhood obesity: concept, feasibility, and interim results of a local group-based, long-term treatment program. J Nutr Educ Behav 2008; 40(6):369–373. doi:10.1016/j.jneb.2007.07.009
Hinchman J, Beno L, Mims A. Kaiser Permanente Georgia’s experience with operation zero: a group medical appointment to address pediatric overweight. Perm J 2006; 10(3):66–71. pmid:21519478
Palaniappan LP, Muzaffar AL, Wang EJ, Wong EC, Orchard TJ, Mbbch M. Shared medical appointments: promoting weight loss in a clinical setting. J Am Board Fam Med 2011; 24(3):326–328. doi:10.3122/jabfm.2011.03.100220
Cohen S, Hartley S, Mavi J, Vest B, Wilson M. Veteran experiences related to participation in shared medical appointments. Mil Med 2012; 177(11):1287–1292. pmid:23198503
Paul-Ebhohimhen V, Avenell A. A systematic review of the effectiveness of group versus individual treatments for adult obesity. Obes Facts 2009; 2(1):17–24. doi:10.1159/000186144
Sacks FM, Bray GA, Carey VJ, et al. Comparison of weight-loss diets with different compositions of fat, protein, and carbohydrates. N Engl J Med 2009; 360(9):859–873. doi:10.1056/NEJMoa0804748
Lichtman SW, Pisarska K, Berman ER, et al. Discrepancy between self-reported and actual caloric intake and exercise in obese subjects. N Engl J Med 1992; 327(27):1893–1898. doi:10.1056/NEJM199212313272701
Sumithran P, Prendergast LA, Delbridge E, et al. Long-term persistence of hormonal adaptations to weight loss. N Engl J Med 2011; 365(17):1597–1604. doi:10.1056/NEJMoa1105816
Spiegel K, Tasali E, Penev P, Van Cauter E. Brief communication: sleep curtailment in healthy young men is associated with decreased leptin levels, elevated ghrelin levels, and increased hunger and appetite. Ann Intern Med 2004; 141(11):846–850. pmid:15583226
Kapur V, Strohl KP, Redline S, Iber C, O’Connor G, Nieto J. Underdiagnosis of sleep apnea syndrome in US communities. Sleep Breath 2002; 6(2):49–54. doi:10.1007/s11325-002-0049-5
Chung F, Yegneswaran B, Liao P, et al. STOP questionnaire: a tool to screen patients for obstructive sleep apnea. Anesthesiology 2008; 108(5):812–821. doi:10.1097/ALN.0b013e31816d83e4
Charmandari E, Tsigos C, Chrousos G. Endocrinology of the stress response. Annu Rev Physiol 2005; 67:259–284. doi:10.1146/annurev.physiol.67.040403.120816
Simon GE, Von Korff M, Saunders K, et al. Association between obesity and psychiatric disorders in the US adult population. Arch Gen Psychiatry 2006; 63(7):824-830. doi:10.1001/archpsyc.63.7.824

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Obesity: Are shared medical appointments part of the answer?

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Obesity: Are shared medical appointments part of the answer?

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obesity, overweight, weight loss, shared medical appointments, Kelly Shibuya, Kevin Pantalone, Bartolome Burguera

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obesity, overweight, weight loss, shared medical appointments, Kelly Shibuya, Kevin Pantalone, Bartolome Burguera

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Shared medical appointments have been shown to improve clinical outcomes and patient satisfaction compared with traditional care. However, they have not been well studied in patients with obesity.
A shared medical appointment allows multiple patients to be medically managed by a multidisciplinary team, promoting more efficient delivery of care.
Both patients and practitioners are satisfied with shared medical appointments and find them clinically useful.

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Coronary artery calcium scoring: Its practicality and clinical utility in primary care

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Coronary artery calcium scoring: Its practicality and clinical utility in primary care

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Parth Parikh, MD

Nishant Shah, MD

Haitham Ahmed, MD, MPH

Paul Schoenhagen, MD

Maan Fares, MD

The United States has seen a decline in fatal myocardial infarctions, largely thanks to early detection of coronary artery disease. Current guidelines on assessment of cardiovascular risk still rely on the traditional 10-year risk model in clinical practice. However, the predictive value of this approach is only moderate, and many coronary events occur in people considered to be at low or intermediate risk.

See related editorial

Coronary artery calcium scoring has emerged as a means of risk stratification by direct measurement of disease. Primary care providers are either using it or are seeing it used by consulting physicians, and its relatively low cost and ease of performance have contributed to its widespread use. However, downstream costs, radiation exposure, and lack of randomized controlled trials have raised concerns.

This article reviews the usefulness and pitfalls of coronary artery calcium scoring, providing a better understanding of the test, its limitations, and the interpretation of results.

ATHEROSCLEROSIS AND CALCIUM

Figure 1. Pathogenic mechanism of atherosclerotic lesions and its relationship to the coronary artery calcium score. — Figure 1. Pathogenic mechanism of atherosclerotic lesions and its relationship to the coronary artery calcium (CAC) score. A type 1 lesion (not depicted) contains lipoproteins that initiate an inflammatory response. A type 2 lesion contains an accumulation of foam cells. The type 3 lesion contains collections of extracellular lipid droplets. Eventually, these extracellular lipid pools form a lipid core, and a type 4 lesion is created. With time, this core develops a fibrous connective-tissue thickening that can calcify and give rise to a type 5 lesion detectable by imaging. Type 6 is a complicated lesion that can include thrombus from plaque rupture.

Atherosclerosis begins in the first few decades of life with a fatty streak in which lipoproteins are deposited in the intimal and medial layers of blood vessels (Figure 1). Inflammatory cells such as macrophages and foam cells are then recruited to the areas of deposition where they cause apoptosis, creating a necrotic core with calcium deposits.^1–3

As the calcium deposits grow, they can be detected by imaging tests such as computed tomography (CT), and quantified to assess the extent of disease.⁴

CALCIFICATION AND CORONARY ARTERY DISEASE

Coronary calcification occurs almost exclusively in atherosclerosis. Several autopsy studies^5,6 and histopathologic studies⁷ have shown a direct relationship between the extent of calcification and atherosclerotic disease.

Sangiorgi et al⁷ performed a histologic analysis of 723 coronary artery segments. The amount of calcium correlated well with the area of plaque:

r = 0.89, P < .0001 in the left anterior descending artery
r = 0.7, P < .001 in the left circumflex artery
r = 0.89, P < .0001 in the right coronary artery.

Coronary artery calcium has also been associated with obstructive coronary artery disease in studies using intravascular ultrasonography and optical coherence tomography.^8,9

TECHNICAL INFORMATION ABOUT THE TEST

First-generation CT scanners used for calcium scoring in the 1980s were electron-beam systems in which a stationary x-ray tube generated an oscillating electron beam, which was reflected around the patient table.¹⁰ A single, stationary detector ring captured the images.

These systems have been replaced by multidetector scanners, in which the x-ray tube and multiple rows of detectors are combined in a gantry that rotates at high speed around the patient.

Coronary calcium is measured by noncontrast CT of the heart. Thus, there is no risk of contrast-induced nephropathy or allergic reactions. Images are acquired while the patient holds his or her breath for 3 to 5 seconds. Electrocardiographic gating is used to reduce motion artifact.^11,12 With modern scanners, the effective radiation dose associated with calcium testing is as low as 0.5 to 1.5 mSv,^13,14 ie, about the same dose as that with mammography. The entire test takes 10 to 15 minutes.

Table 1. Categories of coronary artery calcium scores

Figure 2. A screenshot from a standard calcium scoring program. The images show a small calcified plaque in the mid-left anterior descending artery (left upper panel, colored yellow), left circumflex artery (right upper panel, colored blue), and right coronary artery (right lower panel, colored red). The table in the left lower panel lists the results of the calcium score. (The Agatston score is listed as “Score”). The graph in the right lower panel shows the results of the individual patient relative to an age- and sex-matched patient population (eg, the MESA trial). This patient has a score of 62.2, indicating relatively mild calcification and falling on the 75% percentile for age, sex, and ethnicity in a control group.

Coronary calcium on CT is most commonly quantified using the Agatston score. Calcification is defined as a hyperattenuating lesion above the threshold of 130 Hounsfield units with an area of 3 or more pixels (1 mm²). The score is calculated based on the area of calcification per coronary cross-section, multiplied by a factor that depends on the maximum amount of calcium in a cross-section (a weighted value system based on Hounsfield units of dense calcification in each major coronary artery).¹⁵ The sum of calcium in the right coronary, left anterior descending, and left circumflex arteries gives the total Agatston calcium score.

The results fall into 4 categories, which correlate with the severity of coronary artery disease, ranging from no significant disease to severe disease (Table 1). Other scores, which are not commonly used, include the calcium volume score¹⁶ and the calcium mass score.¹⁷ Figure 2 shows a screenshot from a coronary artery calcium scoring program.

CALCIUM SCORING AS A DIAGNOSTIC TOOL

Early multicenter studies evaluated the utility of calcium scoring to predict coronary stenosis in patients who underwent both cardiac CT and coronary angiography. The sensitivity of calcium scoring for angiographically significant disease was high (95%), but its specificity was low (about 44%).¹⁸

Budoff et al,¹⁹ reviewing these and subsequent results, concluded that the value of calcium scoring is its high negative predictive value (about 98%); a negative score (no calcification) is strongly associated with the absence of obstructive coronary disease.

Blaha et al²⁰ concluded that a score of 0 would indicate that the patient had a low risk of cardiovascular disease. A test with these characteristics is helpful in excluding cardiovascular disease or at least in determining that it is less likely to be present in a patient deemed to be at intermediate risk.

CALCIUM SCORING AS A PROGNOSTIC TOOL

Early on, investigators recognized the value of calcium scoring in predicting the risk of future cardiovascular events and death.^21–25

Predicting cardiovascular events

Pletcher et al21 performed a meta-analysis of studies that measured calcification in asymptomatic patients with subsequent follow-up. The summary-adjusted relative risk of cardiac events such as myocardial infarction, coronary artery revascularization, and coronary heart disease-related death rose with the calcium score:

2.1 (95% confidence interval [CI] 1.6–2.9) with a score of 1 to 100
4.2 (95% CI 2.5–7.2) with scores of 101 to 400
7.2 (95% CI 3.9-13.0) with scores greater than 400.

The meta-analysis was limited in that it included only 4 studies, which were observational.

Kavousi et al,²² in a subsequent meta-analysis of 6,739 women at low risk of atherosclerotic cardiovascular disease based on the American College of Cardiology/American Heart Association (ACC/AHA) pooled cohort equation (10-year risk < 7.5%), found that 36.1% had calcium scores greater than 0. Compared with those whose score was 0, those with higher scores had a higher risk of atherosclerotic cardiovascular disease events. The incidence rates per 1,000 person-years were 1.41 vs 4.33 (relative risk 2.92, 95% CI 2.02–3.83; multivariable-adjusted hazard ratio 2.04, 95% CI 1.44–2.90). This study was limited because the population was mostly of European descent, making it less generalizable to non-European populations.

Calcium scoring has also been shown to be a strong predictor of incident cardiovascular events across different races beyond traditional risk factors such as hypertension, hyperlipidemia, and tobacco use.

Detrano et al,²³ in a study of 6,722 patients with diverse ethnic backgrounds, found that the adjusted risk of a coronary event was increased by a factor of 7.73 for calcium scores between 101 and 300 and by a factor of 9.67 for scores above 300 (P < .001). A limitation of this study was that the patients and physicians were informed of the scores, which could have led to bias.

Carr et al²⁴ found an association between calcium and coronary heart disease in a younger population (ages 32–46). In 12.5 years of follow-up, the hazard ratio for cardiovascular events increased exponentially with the calcium score:

2.6 (95% CI 1.0–5.7, P = .03) with calcium scores of 1 through 19
9.8 (95% CI 4.5–20.5, P < .001) with scores greater than 100.

Predicting mortality

Budoff et al,²⁵ in an observational study of 25,253 patients, found coronary calcium to be an independent predictor of mortality in a multivariable model controlling for age, sex, ethnicity, and cardiac risk factors (model chi-square = 2,017, P < .0001). However, most of the patients were already known to have cardiac risk factors, making the study findings less generalizable to the general population.

Nasir et al²⁶ found that mortality rates rose with the calcium score in a study with 44,052 participants. The annualized mortality rates per 1,000 person-years were:

0.87 (95% CI 0.72–1.06) with a score of 0
2.97 (95% CI 2.61–3.37) with scores of 1–100
6.90 (95% CI 6.02–7.90) with scores of 101–400
17.68 (95% CI 5.93–19.62) with scores higher than 400.

The mortality rate also rose with the number of traditional risk factors present, ie, current tobacco use, dyslipidemia, diabetes mellitus, hypertension, and family history of coronary artery disease. Interestingly, those with no risk factors but a calcium score greater than 400 had a higher mortality rate than those with no coronary calcium but more than 3 risk factors (16.89 per 1,000 person-years vs 2.72 per 1,000 person years). As in the previous study, the patient population that was analyzed was at high risk and therefore the findings are not generalizable.

Shaw et al²⁷ found that patients without symptoms but with elevated coronary calcium scores had higher all-cause mortality rates at 15 years than those with a score of 0. The difference remained significant after Cox regression was performed, adjusting for traditional risk factors.

Coronary artery calcium scoring vs other risk-stratification methods

Current guidelines on assessing risk still rely on the traditional 10-year risk model in clinical practice.²⁵ Patients are thus classified as being at low, intermediate, or high risk based on their probability of developing a cardiovascular event or cardiovascular disease-related death in the subsequent 10 years.

However, the predictive value of this approach is only moderate,²⁸ and a significant number of cardiovascular events, including sudden cardiac death, occur in people who were believed to be at low or intermediate risk according to traditional risk factor-based predictions. Because risk scores are strongly influenced by age,²⁹ they are least reliable in young adults.³⁰

Akosah et al³¹ reviewed the records of 222 young adults (women age 55 or younger, men age 65 or younger) who presented with their first myocardial infarction, and found that only 25% would have qualified for primary prevention pharmacologic treatments according to the National Cholesterol Education Program III guidelines.^32,33 Similar findings have been reported regarding previous versions of the risk scores.³³

Thus, risk predictions based exclusively on traditional risk factors are not sensitive for detecting young individuals at increased risk, and lead to late treatment of young adults with atherosclerosis, which may be a less effective strategy.³⁴

The reliance on age in risk algorithms also results in low specificity in elderly adults. Using risk scores, elderly adults are systematically stratified in higher risk categories, expanding the indication for statin therapy to almost all men age 65 or older regardless of their actual vascular health, according to current clinical practice guidelines.^35,36

Risk scores are based on self-reported history and single-day measurements, since this kind of information is readily available to the physician in the clinic. Moreover, our knowledge about genetic and epigenetic factors associated with the development of atherosclerosis is still in its infancy, with current guidelines not supporting genetic testing as part of cardiovascular risk assessment.³⁷ Thus, a reliable measure of an individual’s lifelong exposure to a number of environmental and genetic factors that may affect cardiovascular health appears unfeasible.

Atherosclerosis is a process in which interactions between genetic, epigenetic, environmental, and traditional risk factors result in subclinical inflammation that could develop into clinically significant disease. Therefore, subclinical coronary atherosclerosis has been shown to be a strong predictor of future incident cardiovascular disease events and death. Thus, alternative approaches that directly measure disease, such as calcium scoring, may help further refine risk stratification of cardiovascular disease.

The MESA trial (Multi-Ethnic Study of Atherosclerosis), for instance, in 6,814 participants, found coronary calcium to provide better discrimination and risk reclassification than the ankle-brachial index, high sensitivity C-reactive protein level, and family history.³⁸ Coronary calcium also had the highest incremental improvement of the area under the receiver operating curve when added to the Framingham Risk Score (0.623 vs 0.784).

Reclassifying cardiovascular risk also has implications regarding whether to start therapies such as statins and aspirin.

For considering statin therapy

Nasir et al³⁹ showed that, in patients eligible for statin therapy by the pooled cohort equation, the absence of coronary artery calcium reclassified approximately one-half of candidates as not eligible for statin therapy. The number needed to treat to prevent an atherosclerotic cardiovascular event in the population who were recommended a statin was 64 with a calcium score of 0, and 24 with a calcium score greater than 100. In the population for whom a statin was considered, the number needed to treat was 223 with a calcium score of 0 and 46 for those with a score greater than 100. Moreover, 57% of intermediate-risk patients and 41% of high-risk patients based on the Framingham Risk Score were found to have a calcium score of 0, implying that these patients may actually be at a lower risk.

The Society of Cardiovascular Computed Tomography guidelines⁴⁰ say that statin therapy can be considered in patients who have a calcium score greater than 0.

For considering aspirin therapy

Miedema et al⁴¹ studied the role of coronary artery calcium in guiding aspirin therapy in 4,229 participants in the MESA trial who were not taking aspirin at baseline. Those with a calcium score higher than 100 had a number needed to treat of 173 in the group with a Framingham Risk Score less than 10% and 92 with a Framingham Risk Score of 10% or higher. The estimated number needed to harm for a major bleeding event was 442. For those who had a score of 0, the estimated number needed to treat was 2,036 for a Framingham Risk Score less than 10% and 808 for a Framingham Risk Score of 10% or higher, with an estimated number needed to harm of 442 for a major bleeding event.

The Society of Cardiovascular Computed Tomography guidelines⁴⁰ recommend considering aspirin therapy for patients with a coronary calcium score of more than 100.

McClelland et al⁴² developed a MESA risk score to predict 10-year risk of coronary heart disease using the traditional risk factors along with coronary calcium. The score was validated externally with 2 separate longitudinal studies. Thus, this may serve as another tool to help providers further risk-stratify patients.

COST-EFFECTIVENESS OF THE TEST

As coronary calcium measurement began to be widely used, concerns were raised about the lack of data on its cost-effectiveness.

Cost-effectiveness depends not only on patient selection but also on the cost of therapy. For example, if the cost of a generic statin is $85 per year, then calcium scoring would not be beneficial. However, if the cost of a statin is more than $200, then calcium scoring would be much more cost-effective, offering a way to avoid treating some patients who do not need to be treated.⁴³

Hong et al⁴³ showed that coronary calcium testing was cost-effective when the patient and physician share decision-making about initiating statin therapy. This is especially important if the patient has financial limitations, is concerned about side effects, or wants to avoid taking unnecessary medications.

RISKS AND DOWNSIDES OF CALCIUM SCORING

According to some reports, $8.5 billion is spent annually for low-value care.⁴⁴ Many of the 80 million CT scans performed annually in the United States are believed to be unnecessary and may lead to additional testing to investigate incidental findings.⁴⁵

Growing use of coronary calcium measurement has raised similar concerns about radiation exposure, healthcare costs, and increased downstream testing triggered by the detection of incidental noncardiac findings. For instance, Onuma et al⁴⁶ reported that, in 503 patients undergoing CT to evaluate coronary artery disease, noncardiac findings were seen in 58.1% of them, but only 22.7% of the 503 had clinically significant findings.

Some of these concerns have been addressed. Modern scanners can acquire images in only a few seconds, entailing lower radiation doses than in the past.^13,14 The cost of the test is currently less than $100 in many US metropolitan areas.⁴⁷ However, further studies are needed to adequately and cost-effectively guide follow-up imaging of incidental noncardiac findings.⁴⁸

An important limitation of calcium scoring for risk assessment is that no randomized controlled trial has evaluated the impact of preventive interventions guided by calcium scores on hard event outcomes. It can be argued that there have been plenty of observational studies that have shown the benefit of coronary calcium scoring when judiciously done in the appropriate population.⁴⁹ Similarly, no randomized controlled trial has tested the pooled cohort equation and the application of statins based on its use with the current guidelines. The feasibility and cost of a large randomized controlled trial to assess outcomes after coronary artery calcium measurement must also be considered.

Another limitation of coronary calcium scoring is that it cannot rule out the presence of noncalcified atherosclerotic plaque, which often is more unstable and prone to rupture.

In addition, calcification in the coronary vascular bed (even if severe) does not necessarily mean there is clinically relevant coronary stenosis. For instance, an asymptomatic patient could have a coronary artery calcium score higher than 100 and then get a coronary angiogram that reveals only a 30% lesion in the left anterior descending coronary artery. This is because accumulation of (calcified) plaque in the vessel wall is accommodated by expansion of vessel diameter, maintaining luminal dimensions (positive remodeling). By definition, this patient does have coronary artery disease but would be best served by medical management. This could have been determined without an invasive test in an otherwise asymptomatic patient. Thus, performing coronary angiography based on a coronary artery calcium score alone would not have changed this patient’s management and may have exposed the patient to risks of procedural complications, in addition to extra healthcare costs. Therefore, the presence or absence of symptoms should guide the clinician on whether to pursue stress testing for invasive coronary angiography based on the appropriate use criteria.^50,51

WHO SHOULD BE TESTED?

In the ACC/AHA 2013 guidelines,³⁷ coronary calcium scoring has a class IIB recommendation in scenarios where it may appear that the risk-based treatment decision is uncertain after formal risk estimation has been done. As discussed above, a score higher than 100 could be a rationale for starting aspirin therapy, and a score higher than 0 for statin therapy. The current guidelines also mention that the coronary calcium score is comparable to other predictors such as the C-reactive protein level and the ankle-brachial index.

Compared with the ACC/AHA guidelines, the 2016 Society of Cardiovascular Computed Tomography guidelines and expert consensus recently have added more specifics in terms of using this test for asymptomatic patients at intermediate risk (10-year risk of atherosclerotic cardiovascular disease 5%–20%) and in selected patients with a family history of premature coronary artery disease and 10-year risk less than 5%.^40,52 The 2010 ACC/AHA guidelines were more specific, offering a class IIA recommendation for patients who were at intermediate risk (Framingham Risk Score 10%–20%).⁵³

The ACC/AHA cited cost and radiation exposure as reasons they did not give coronary calcium measurement a stronger recommendation.³⁷ However, as data continue to come in, the guidelines may change, especially since low-dose radiation tools are being used for cancer screening (lungs and breast) and since the cost has declined over the past decade.

OUR APPROACH

Given the negative predictive value of the coronary calcium score, our approach has been to use this test in asymptomatic patients who are found to be at intermediate risk of atherosclerotic cardiovascular disease based on the ACC/AHA risk calculation and are reluctant to start pharmacologic therapy, or who want a more personalized measure of coronary artery disease. This is preceded by a lengthy patient-physician discussion about the risks and benefits of the test.⁵⁴

The patient’s risk can then be further clarified and possibly reclassified as either low or high if it doesn’t remain intermediate. A discussion can then take place on potentially starting pharmacologic therapy, intensive lifestyle modifications, or both.^54,55 If an electronic medical record is available, CT results can be shown to the patient in the office to point out coronary calcifications. Seeing the lesions may serve an as additional motivating factor as patients embark on primary preventive efforts.⁵⁶

Below, we describe cases of what we would consider appropriate and inappropriate use of coronary artery calcium scoring.

Example 1

A 55-year-old man presents for an annual physical and is found to have a 10-year risk of atherosclerotic cardiovascular disease of 7%, placing him in the intermediate-risk category. Despite an extensive conversation about lifestyle modifications and pharmacologic therapy, he is reluctant to initiate these measures. He is otherwise asymptomatic. Would calcium scoring be reasonable?

Yes, it would be reasonable to perform coronary artery calcium scoring in an otherwise asymptomatic man to help reclassify his risk for a coronary vascular event. The objective data provided by the test could motivate the patient to undertake primary prevention efforts or, if his score is 0, to show that he may not need drug therapy.

Example 2

A 55-year-old man who has a family history of coronary artery disease, is an active smoker, and has diabetes mellitus presents to the clinic with 2 months of exertional chest pain that resolves with rest. Would coronary artery calcium scoring be reasonable?

This patient is symptomatic and is at high risk of coronary artery disease. Statin therapy is already indicated in the AHA/ACC guidelines, since he has diabetes. Therefore, calcium scoring would not be helpful, as it would not change this patient’s management. Instead, he would be best served by stress testing or coronary angiography based on the stability of his symptoms and cardiac biomarkers.

Example 3

A 30-year-old woman with no medical history presents with on-and-off chest pain at both exertion and rest. Her electrocardiogram is unremarkable, and cardiac enzyme tests are negative. Would coronary calcium scoring be reasonable?

This young patient’s story is not typical for coronary artery disease. Therefore, she has a low pretest probability of obstructive coronary artery disease. Moreover, calcium scoring may not be helpful because at her young age there has not been enough time for calcification to develop (median age is the fifth decade of life). Thus, she would be exposed to radiation unnecessarily at a young age.

What to do with an elevated calcium score?

Coronary artery calcification is now being incidentally detected as patients undergo CT for other reasons such as screening for lung cancer based on the US Preventive Services Task Force guidelines. Patients may also get the test done on their own and then present to a provider with an elevated score.

It is important to consider the entire clinical scenario in such patients and not just the score. If a patient presents with an elevated calcium score but has no symptoms and falls in the intermediate-risk group, there is evidence to suggest that he or she should be started on statin or aspirin therapy or both.

As mentioned above, an abnormal test result does not mean that the patient should undergo more-invasive testing such as cardiac catheterization or even stress testing, especially if he or she has no symptoms. However, if the patient is symptomatic, then further cardiac evaluation would be recommended.

SUMMARY

Measuring coronary artery calcium has been found to be valuable in detecting coronary artery disease and in predicting cardiovascular events and death. The test is relatively easy to perform, with newer technology allowing for less radiation and cost. It serves as a more personalized measure of disease and can help facilitate patient-physician discussions about starting pharmacologic therapy, especially if a patient is reluctant.

Currently, coronary calcium scoring has a class IIB recommendation in scenarios in which the risk-based treatment decision is uncertain after formal risk estimation has been done according to the ACC/AHA guideline. The Society of Cardiovascular Computed Tomography guideline and expert consensus documents are more specific in recommending the test in asymptomatic patients in the intermediate-risk group.

Limitations of calcium scoring include the possibility of unnecessary cardiovascular testing such as cardiac catheterization or stress testing being driven by the calcium score alone, as well as the impact of incidental findings. With increased reporting of the coronary calcium score in patients undergoing CT for lung cancer screening, the score should be interpreted in view of the entire clinical scenario.

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Jackson G, Nehra A, Miner M, et al. The assessment of vascular risk in men with erectile dysfunction: the role of the cardiologist and general physician. Int J Clin Pract 2013; 67(11):1163–1172. doi:10.1111/ijcp.12200
Cook NR, Paynter NP, Eaton CB, et al. Comparison of the Framingham and Reynolds risk scores for global cardiovascular risk prediction in the multiethnic Women’s Health Initiative. Circulation 2012; 125(14):1748–1756. doi:10.1161/CIRCULATIONAHA.111.075929
Ford ES, Giles WH, Mokdad AH. The distribution of 10-year risk for coronary heart disease among U.S. adults: findings from the National Health and Nutrition Examination Survey III. J Am Coll Cardiol 2004; 43(10):1791–1796. doi:10.1016/j.jacc.2003.11.061
Akosah KO, Schaper A, Cogbill C, Schoenfeld P. Preventing myocardial infarction in the young adult in the first place: how do the National Cholesterol Education Panel III guidelines perform? J Am Coll Cardiol 2003;41(9):1475–1479. doi:10.1016/S0735-1097(03)00187-6
Lloyd-Jones DM, Leip EP, Larson MG, et al. Prediction of lifetime risk for cardiovascular disease by risk factor burden at 50 years of age. Circulation 2006;113(6):791–798. doi:10.1161/CIRCULATIONAHA.105.548206
Expert Panel on Detection and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001; 285:24862497. pmid:11368702
Akosah KO, Gower E, Groon L, Rooney BL, Schaper A. Mild hypercholesterolemia and premature heart disease: do the national criteria underestimate disease risk? J Am Coll Cardiol 2000; 35(5):1178–1184. doi:10.1016/S0735-1097(00)00556-8
Steinberg D, Grundy SM. The case for treating hypercholesterolemia at an earlier age: moving toward consensus. J Am Coll Cardiol 2012; 60(25):2640–2641. doi:10.1016/j.jacc.2012.09.016
Martin SS, Blaha MJ, Blankstein R, et al. Dyslipidemia, coronary artery calcium, and incident atherosclerotic cardiovascular disease: Implications for statin therapy from the multi-ethnic study of atherosclerosis. Circulation 2014; 129(1):77–86. doi:10.1161/CIRCULATIONAHA.113.003625
Goff DC, Lloyd-Jones DM, Bennett G, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice guidelines. Circulation 2014; 129(25 suppl 2):S49–S73. doi:10.1161/01.cir.0000437741.48606.98
Yeboah J, McClelland RL, Polonsky TS, et al. Comparison of novel risk markers for improvement in cardiovascular risk assessment in intermediate-risk individuals. JAMA 2012; 308(8):788–795. doi:10.1001/jama.2012.9624
Nasir K, Bittencourt MS, Blaha MJ, et al. Implications of coronary artery calcium testing among statin candidates according to American College of Cardiology/American Heart Association cholesterol management guidelines MESA (Multi-Ethnic Study of Atherosclerosis). J Am Coll Cardiol 2015; 66(15):1657–1668. doi:10.1016/j.jacc.2015.07.066
Hecht H, Blaha MJ, Berman DS, et al. Clinical indications for coronary artery calcium scoring in asymptomatic patients: expert consensus statement from the Society of Cardiovascular Computed Tomography. J Cardiovasc Comput Tomogr 2017; 11(2):157–168. doi:10.1016/j.jcct.2017.02.010
Miedema MD, Duprez DA, Misialek JR, et al. Use of coronary artery calcium testing to guide aspirin utilization for primary prevention: estimates from the multi-ethnic study of atherosclerosis. Circ Cardiovasc Qual Outcomes 2014; 7(3):453–460. doi:10.1161/CIRCOUTCOMES.113.000690
McClelland RL, Jorgensen NW, Budoff M, et al. 10-year coronary heart disease risk prediction using coronary artery calcium and traditional risk factors. J Am Coll Cardiol 2015; 66(15):1643–1653. doi:10.1016/j.jacc.2015.08.035
Hong JC, Blankstein R, Shaw LJ, et al. Implications of coronary artery calcium testing for treatment decisions among statin candidates according to the ACC/AHA cholesterol management guidelines: a cost-effectiveness analysis. JACC Cardiovasc Imaging 2017; 10(8):938–952. doi:10.1016/j.jcmg.2017.04.014
Schwartz AL, Landon BE, Elshaug AG, Chernew ME, McWilliams JM. Measuring low-value care in Medicare. JAMA Intern Med 2014; 174(7):1067–1076. doi:10.1001/jamainternmed.2014.1541
Lehnert BE, Bree RL. Analysis of appropriateness of outpatient CT and MRI referred from primary care clinics at an academic medical center: how critical is the need for improved decision support? J Am Coll Radiol 2010; 7(3):192–197. doi:10.1016/j.jacr.2009.11.010
Onuma Y, Tanabe K, Nakazawa G, et al. Noncardiac findings in cardiac imaging with multidetector computed tomography. J Am Coll Cardiol 2006; 48(2):402–406. doi:10.1016/j.jacc.2006.04.071
Hecht HS. Coronary artery calcium scanning: past, present, and future. JACC Cardiovasc Imaging 2015; 8(5):579–596. doi:10.1016/j.jcmg.2015.02.006
MacHaalany J, Yam Y, Ruddy TD, et al. Potential clinical and economic consequences of noncardiac incidental findings on cardiac computed tomography. J Am Coll Cardiol 2009; 54(16):1533–1541. doi:10.1016/j.jacc.2009.06.026
McEvoy JW, Martin SS, Blaha MJ, et al. The case for and against a coronary artery calcium trial: means, motive, and opportunity. JACC Cardiovasc Imaging 2016; 9(8):994–1002. doi:10.1016/j.jcmg.2016.03.012
Patel MR, Bailey SR, Bonow RO, et al. ACCF/SCAI/AATS/AHA/ASE/ASNC/HFSA/HRS/SCCM/SCCT/SCMR/STS 2012 appropriate use criteria for diagnostic catheterization. J Thorac Cardiovasc Surg 2012; 144(1):39–71. doi:10.1016/j.jtcvs.2012.04.013
Villines TC, Hulten EA, Shaw LJ, et al. Prevalence and severity of coronary artery disease and adverse events among symptomatic patients with coronary artery calcification scores of zero undergoing coronary computed tomography angiography. J Am Coll Cardiol 2011; 58(24):2533–2540. doi:10.1016/j.jacc.2011.10.851
Hecht HS, Cronin P, Blaha MJ, et al. 2016 SCCT/STR guidelines for coronary artery calcium scoring of noncontrast noncardiac chest CT scans: a report of the Society of Cardiovascular Computed Tomography and Society of Thoracic Radiology. J Thorac Imaging 2017; 32(5):W54–W66. doi:10.1097/RTI.0000000000000287
Greenland P, Alpert JS, Beller GA, et al. 2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults: executive summary: a report of the American College of Cardiology foundation/American Heart Association task force on practice guidelines. Circulation 2010; 122(25):2748–2764. doi:10.1161/CIR.0b013e3182051bab
Martin SS, Sperling LS, Blaha MJ, et al. Clinician-patient risk discussion for atherosclerotic cardiovascular disease prevention: importance to implementation of the 2013 ACC/AHA guidelines. J Am Coll Cardiol 2015; 65(13):1361–1368. doi:10.1016/j.jacc.2015.01.043
Gupta A, Lau E, Varshney R, et al. The identification of calcified coronary plaque is associated with initiation and continuation of pharmacologic and lifestyle preventive therapies: a systematic review and meta-analysis. JACC Cardiovasc Imaging 2017; 10(8):833–842. doi:10.1016/j.jcmg.2017.01.030
Rozanski A, Gransar H, Shaw LJ, et al. Impact of coronary artery calcium scanning on coronary risk factors and downstream testing: The EISNER (Early Identification of Subclinical Atherosclerosis by Noninvasive Imaging Research) prospective randomized trial. J Am Coll Cardiol 2011; 57(15):1622–1632. doi:10.1016/j.jacc.2011.01.019

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Parth Parikh, MD
Department of Internal Medicine, Cleveland Clinic; Clinical Instructor of Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Nishant Shah, MD
Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic

Haitham Ahmed, MD, MPH
Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic; Assistant Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Paul Schoenhagen, MD
Department of Diagnostic Radiology, Imaging Institute, and Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic; Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Maan Fares, MD
Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic; Assistant Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Address: Maan Fares, MD, Department of Cardiovascular Medicine, J2-4, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; faresm@ccf.org

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Cleveland Clinic Journal of Medicine - 85(9)

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Cleveland Clinic Journal of Medicine

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Imaging

Preventive Care

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707-716

Legacy Keywords

coronary artery calcium, CAC, calcium score, computed tomography, CT, coronary artery disease, atherosclerosis, risk assessment, prognosis, Parth Parikh, Nishant Shah, Haitham Ahmed, Paul Schoenhagen, Maan Fares

Read more about Coronary artery calcium scoring: Its practicality and clinical utility in primary care

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Parth Parikh, MD

Nishant Shah, MD

Haitham Ahmed, MD, MPH

Author(s)

Haitham Ahmed, MD, MPH

Paul Schoenhagen, MD

Maan Fares, MD

Author and Disclosure Information

Parth Parikh, MD
Department of Internal Medicine, Cleveland Clinic; Clinical Instructor of Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Nishant Shah, MD
Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic

Address: Maan Fares, MD, Department of Cardiovascular Medicine, J2-4, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; faresm@ccf.org

Author and Disclosure Information

Parth Parikh, MD
Department of Internal Medicine, Cleveland Clinic; Clinical Instructor of Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Nishant Shah, MD
Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic

Address: Maan Fares, MD, Department of Cardiovascular Medicine, J2-4, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; faresm@ccf.org

Article PDF

parikh_coronarycalciumscoring.pdf

Article PDF

parikh_coronarycalciumscoring.pdf

See related editorial

This article reviews the usefulness and pitfalls of coronary artery calcium scoring, providing a better understanding of the test, its limitations, and the interpretation of results.

ATHEROSCLEROSIS AND CALCIUM

As the calcium deposits grow, they can be detected by imaging tests such as computed tomography (CT), and quantified to assess the extent of disease.⁴

CALCIFICATION AND CORONARY ARTERY DISEASE

Sangiorgi et al⁷ performed a histologic analysis of 723 coronary artery segments. The amount of calcium correlated well with the area of plaque:

r = 0.89, P < .0001 in the left anterior descending artery
r = 0.7, P < .001 in the left circumflex artery
r = 0.89, P < .0001 in the right coronary artery.

Coronary artery calcium has also been associated with obstructive coronary artery disease in studies using intravascular ultrasonography and optical coherence tomography.^8,9

TECHNICAL INFORMATION ABOUT THE TEST

These systems have been replaced by multidetector scanners, in which the x-ray tube and multiple rows of detectors are combined in a gantry that rotates at high speed around the patient.

CALCIUM SCORING AS A DIAGNOSTIC TOOL

CALCIUM SCORING AS A PROGNOSTIC TOOL

Early on, investigators recognized the value of calcium scoring in predicting the risk of future cardiovascular events and death.^21–25

Predicting cardiovascular events

2.1 (95% confidence interval [CI] 1.6–2.9) with a score of 1 to 100
4.2 (95% CI 2.5–7.2) with scores of 101 to 400
7.2 (95% CI 3.9-13.0) with scores greater than 400.

The meta-analysis was limited in that it included only 4 studies, which were observational.

2.6 (95% CI 1.0–5.7, P = .03) with calcium scores of 1 through 19
9.8 (95% CI 4.5–20.5, P < .001) with scores greater than 100.

Predicting mortality

Nasir et al²⁶ found that mortality rates rose with the calcium score in a study with 44,052 participants. The annualized mortality rates per 1,000 person-years were:

0.87 (95% CI 0.72–1.06) with a score of 0
2.97 (95% CI 2.61–3.37) with scores of 1–100
6.90 (95% CI 6.02–7.90) with scores of 101–400
17.68 (95% CI 5.93–19.62) with scores higher than 400.

Coronary artery calcium scoring vs other risk-stratification methods

Reclassifying cardiovascular risk also has implications regarding whether to start therapies such as statins and aspirin.

For considering statin therapy

The Society of Cardiovascular Computed Tomography guidelines⁴⁰ say that statin therapy can be considered in patients who have a calcium score greater than 0.

For considering aspirin therapy

The Society of Cardiovascular Computed Tomography guidelines⁴⁰ recommend considering aspirin therapy for patients with a coronary calcium score of more than 100.

COST-EFFECTIVENESS OF THE TEST

As coronary calcium measurement began to be widely used, concerns were raised about the lack of data on its cost-effectiveness.

RISKS AND DOWNSIDES OF CALCIUM SCORING

Another limitation of coronary calcium scoring is that it cannot rule out the presence of noncalcified atherosclerotic plaque, which often is more unstable and prone to rupture.

WHO SHOULD BE TESTED?

OUR APPROACH

Below, we describe cases of what we would consider appropriate and inappropriate use of coronary artery calcium scoring.

Example 1

Example 2

Example 3

What to do with an elevated calcium score?

SUMMARY

See related editorial

This article reviews the usefulness and pitfalls of coronary artery calcium scoring, providing a better understanding of the test, its limitations, and the interpretation of results.

ATHEROSCLEROSIS AND CALCIUM

As the calcium deposits grow, they can be detected by imaging tests such as computed tomography (CT), and quantified to assess the extent of disease.⁴

CALCIFICATION AND CORONARY ARTERY DISEASE

Sangiorgi et al⁷ performed a histologic analysis of 723 coronary artery segments. The amount of calcium correlated well with the area of plaque:

r = 0.89, P < .0001 in the left anterior descending artery
r = 0.7, P < .001 in the left circumflex artery
r = 0.89, P < .0001 in the right coronary artery.

Coronary artery calcium has also been associated with obstructive coronary artery disease in studies using intravascular ultrasonography and optical coherence tomography.^8,9

TECHNICAL INFORMATION ABOUT THE TEST

These systems have been replaced by multidetector scanners, in which the x-ray tube and multiple rows of detectors are combined in a gantry that rotates at high speed around the patient.

CALCIUM SCORING AS A DIAGNOSTIC TOOL

CALCIUM SCORING AS A PROGNOSTIC TOOL

Early on, investigators recognized the value of calcium scoring in predicting the risk of future cardiovascular events and death.^21–25

Predicting cardiovascular events

2.1 (95% confidence interval [CI] 1.6–2.9) with a score of 1 to 100
4.2 (95% CI 2.5–7.2) with scores of 101 to 400
7.2 (95% CI 3.9-13.0) with scores greater than 400.

The meta-analysis was limited in that it included only 4 studies, which were observational.

2.6 (95% CI 1.0–5.7, P = .03) with calcium scores of 1 through 19
9.8 (95% CI 4.5–20.5, P < .001) with scores greater than 100.

Predicting mortality

Nasir et al²⁶ found that mortality rates rose with the calcium score in a study with 44,052 participants. The annualized mortality rates per 1,000 person-years were:

0.87 (95% CI 0.72–1.06) with a score of 0
2.97 (95% CI 2.61–3.37) with scores of 1–100
6.90 (95% CI 6.02–7.90) with scores of 101–400
17.68 (95% CI 5.93–19.62) with scores higher than 400.

Coronary artery calcium scoring vs other risk-stratification methods

Reclassifying cardiovascular risk also has implications regarding whether to start therapies such as statins and aspirin.

For considering statin therapy

The Society of Cardiovascular Computed Tomography guidelines⁴⁰ say that statin therapy can be considered in patients who have a calcium score greater than 0.

For considering aspirin therapy

The Society of Cardiovascular Computed Tomography guidelines⁴⁰ recommend considering aspirin therapy for patients with a coronary calcium score of more than 100.

COST-EFFECTIVENESS OF THE TEST

As coronary calcium measurement began to be widely used, concerns were raised about the lack of data on its cost-effectiveness.

RISKS AND DOWNSIDES OF CALCIUM SCORING

Another limitation of coronary calcium scoring is that it cannot rule out the presence of noncalcified atherosclerotic plaque, which often is more unstable and prone to rupture.

WHO SHOULD BE TESTED?

OUR APPROACH

Below, we describe cases of what we would consider appropriate and inappropriate use of coronary artery calcium scoring.

Example 1

Example 2

Example 3

What to do with an elevated calcium score?

SUMMARY

References

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Ford ES, Giles WH, Mokdad AH. The distribution of 10-year risk for coronary heart disease among U.S. adults: findings from the National Health and Nutrition Examination Survey III. J Am Coll Cardiol 2004; 43(10):1791–1796. doi:10.1016/j.jacc.2003.11.061
Akosah KO, Schaper A, Cogbill C, Schoenfeld P. Preventing myocardial infarction in the young adult in the first place: how do the National Cholesterol Education Panel III guidelines perform? J Am Coll Cardiol 2003;41(9):1475–1479. doi:10.1016/S0735-1097(03)00187-6
Lloyd-Jones DM, Leip EP, Larson MG, et al. Prediction of lifetime risk for cardiovascular disease by risk factor burden at 50 years of age. Circulation 2006;113(6):791–798. doi:10.1161/CIRCULATIONAHA.105.548206
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Nasir K, Bittencourt MS, Blaha MJ, et al. Implications of coronary artery calcium testing among statin candidates according to American College of Cardiology/American Heart Association cholesterol management guidelines MESA (Multi-Ethnic Study of Atherosclerosis). J Am Coll Cardiol 2015; 66(15):1657–1668. doi:10.1016/j.jacc.2015.07.066
Hecht H, Blaha MJ, Berman DS, et al. Clinical indications for coronary artery calcium scoring in asymptomatic patients: expert consensus statement from the Society of Cardiovascular Computed Tomography. J Cardiovasc Comput Tomogr 2017; 11(2):157–168. doi:10.1016/j.jcct.2017.02.010
Miedema MD, Duprez DA, Misialek JR, et al. Use of coronary artery calcium testing to guide aspirin utilization for primary prevention: estimates from the multi-ethnic study of atherosclerosis. Circ Cardiovasc Qual Outcomes 2014; 7(3):453–460. doi:10.1161/CIRCOUTCOMES.113.000690
McClelland RL, Jorgensen NW, Budoff M, et al. 10-year coronary heart disease risk prediction using coronary artery calcium and traditional risk factors. J Am Coll Cardiol 2015; 66(15):1643–1653. doi:10.1016/j.jacc.2015.08.035
Hong JC, Blankstein R, Shaw LJ, et al. Implications of coronary artery calcium testing for treatment decisions among statin candidates according to the ACC/AHA cholesterol management guidelines: a cost-effectiveness analysis. JACC Cardiovasc Imaging 2017; 10(8):938–952. doi:10.1016/j.jcmg.2017.04.014
Schwartz AL, Landon BE, Elshaug AG, Chernew ME, McWilliams JM. Measuring low-value care in Medicare. JAMA Intern Med 2014; 174(7):1067–1076. doi:10.1001/jamainternmed.2014.1541
Lehnert BE, Bree RL. Analysis of appropriateness of outpatient CT and MRI referred from primary care clinics at an academic medical center: how critical is the need for improved decision support? J Am Coll Radiol 2010; 7(3):192–197. doi:10.1016/j.jacr.2009.11.010
Onuma Y, Tanabe K, Nakazawa G, et al. Noncardiac findings in cardiac imaging with multidetector computed tomography. J Am Coll Cardiol 2006; 48(2):402–406. doi:10.1016/j.jacc.2006.04.071
Hecht HS. Coronary artery calcium scanning: past, present, and future. JACC Cardiovasc Imaging 2015; 8(5):579–596. doi:10.1016/j.jcmg.2015.02.006
MacHaalany J, Yam Y, Ruddy TD, et al. Potential clinical and economic consequences of noncardiac incidental findings on cardiac computed tomography. J Am Coll Cardiol 2009; 54(16):1533–1541. doi:10.1016/j.jacc.2009.06.026
McEvoy JW, Martin SS, Blaha MJ, et al. The case for and against a coronary artery calcium trial: means, motive, and opportunity. JACC Cardiovasc Imaging 2016; 9(8):994–1002. doi:10.1016/j.jcmg.2016.03.012
Patel MR, Bailey SR, Bonow RO, et al. ACCF/SCAI/AATS/AHA/ASE/ASNC/HFSA/HRS/SCCM/SCCT/SCMR/STS 2012 appropriate use criteria for diagnostic catheterization. J Thorac Cardiovasc Surg 2012; 144(1):39–71. doi:10.1016/j.jtcvs.2012.04.013
Villines TC, Hulten EA, Shaw LJ, et al. Prevalence and severity of coronary artery disease and adverse events among symptomatic patients with coronary artery calcification scores of zero undergoing coronary computed tomography angiography. J Am Coll Cardiol 2011; 58(24):2533–2540. doi:10.1016/j.jacc.2011.10.851
Hecht HS, Cronin P, Blaha MJ, et al. 2016 SCCT/STR guidelines for coronary artery calcium scoring of noncontrast noncardiac chest CT scans: a report of the Society of Cardiovascular Computed Tomography and Society of Thoracic Radiology. J Thorac Imaging 2017; 32(5):W54–W66. doi:10.1097/RTI.0000000000000287
Greenland P, Alpert JS, Beller GA, et al. 2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults: executive summary: a report of the American College of Cardiology foundation/American Heart Association task force on practice guidelines. Circulation 2010; 122(25):2748–2764. doi:10.1161/CIR.0b013e3182051bab
Martin SS, Sperling LS, Blaha MJ, et al. Clinician-patient risk discussion for atherosclerotic cardiovascular disease prevention: importance to implementation of the 2013 ACC/AHA guidelines. J Am Coll Cardiol 2015; 65(13):1361–1368. doi:10.1016/j.jacc.2015.01.043
Gupta A, Lau E, Varshney R, et al. The identification of calcified coronary plaque is associated with initiation and continuation of pharmacologic and lifestyle preventive therapies: a systematic review and meta-analysis. JACC Cardiovasc Imaging 2017; 10(8):833–842. doi:10.1016/j.jcmg.2017.01.030
Rozanski A, Gransar H, Shaw LJ, et al. Impact of coronary artery calcium scanning on coronary risk factors and downstream testing: The EISNER (Early Identification of Subclinical Atherosclerosis by Noninvasive Imaging Research) prospective randomized trial. J Am Coll Cardiol 2011; 57(15):1622–1632. doi:10.1016/j.jacc.2011.01.019

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Budoff MJ, Achenbach S, Blumenthal RS, et al. Assessment of coronary artery disease by cardiac computed tomography: a scientific statement from the American Heart Association Committee on Cardiovascular Imaging and Intervention, Council on Cardiovascular Radiology and Intervention, and Committee on C. Circulation 2006; 114(16):1761–1791. doi:10.1161/CIRCULATIONAHA.106.178458
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Nakazato R, Dey D, Gutstein A, et al. Coronary artery calcium scoring using a reduced tube voltage and radiation dose protocol with dual-source computed tomography. J Cardiovasc Comput Tomogr 2009; 3(6):394–400. doi:10.1016/j.jcct.2009.10.002
Hecht HS, De Siqueira MEM, Cham M, et al. Low- vs. standard-dose coronary artery calcium scanning. Eur Heart J Cardiovasc Imaging 2015; 16(4):358–363. doi:10.1093/ehjci/jeu218
Agatston AS, Janowitz WR, Hildner FJ, Zusmer NR, Viamonte M, Detrano R. Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol 1990; 15(4):827–832. doi:10.1016/0735-1097(90)90282-T
Nezarat N, Kim M, Budoff M. Role of coronary calcium for risk stratification and prognostication. Curr Treat Options Cardiovasc Med 2017; 19(2):8. doi:10.1007/s11936-017-0509-7
Callister TQ, Cooil B, Raya SP, Lippolis NJ, Russo DJ, Raggi P. Coronary artery disease: improved reproducibility of calcium scoring with an electron-beam CT volumetric method. Radiology 1998; 208(3):807–814. doi:10.1148/radiology.208.3.9722864
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Carr JJ, Jacobs DR, Terry JG, et al. Association of coronary artery calcium in adults aged 32 to 46 years with incident coronary heart disease and death. JAMA Cardiol 2017; 2(4):391–399. doi:10.1001/jamacardio.2016.5493
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Shaw LJ, Giambrone AE, Blaha MJ, et al. Long-term prognosis after coronary artery calcification testing in asymptomatic patients: a cohort study. Ann Intern Med 2015; 163(1):14–21. doi:10.7326/M14-0612
Jackson G, Nehra A, Miner M, et al. The assessment of vascular risk in men with erectile dysfunction: the role of the cardiologist and general physician. Int J Clin Pract 2013; 67(11):1163–1172. doi:10.1111/ijcp.12200
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Ford ES, Giles WH, Mokdad AH. The distribution of 10-year risk for coronary heart disease among U.S. adults: findings from the National Health and Nutrition Examination Survey III. J Am Coll Cardiol 2004; 43(10):1791–1796. doi:10.1016/j.jacc.2003.11.061
Akosah KO, Schaper A, Cogbill C, Schoenfeld P. Preventing myocardial infarction in the young adult in the first place: how do the National Cholesterol Education Panel III guidelines perform? J Am Coll Cardiol 2003;41(9):1475–1479. doi:10.1016/S0735-1097(03)00187-6
Lloyd-Jones DM, Leip EP, Larson MG, et al. Prediction of lifetime risk for cardiovascular disease by risk factor burden at 50 years of age. Circulation 2006;113(6):791–798. doi:10.1161/CIRCULATIONAHA.105.548206
Expert Panel on Detection and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001; 285:24862497. pmid:11368702
Akosah KO, Gower E, Groon L, Rooney BL, Schaper A. Mild hypercholesterolemia and premature heart disease: do the national criteria underestimate disease risk? J Am Coll Cardiol 2000; 35(5):1178–1184. doi:10.1016/S0735-1097(00)00556-8
Steinberg D, Grundy SM. The case for treating hypercholesterolemia at an earlier age: moving toward consensus. J Am Coll Cardiol 2012; 60(25):2640–2641. doi:10.1016/j.jacc.2012.09.016
Martin SS, Blaha MJ, Blankstein R, et al. Dyslipidemia, coronary artery calcium, and incident atherosclerotic cardiovascular disease: Implications for statin therapy from the multi-ethnic study of atherosclerosis. Circulation 2014; 129(1):77–86. doi:10.1161/CIRCULATIONAHA.113.003625
Goff DC, Lloyd-Jones DM, Bennett G, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice guidelines. Circulation 2014; 129(25 suppl 2):S49–S73. doi:10.1161/01.cir.0000437741.48606.98
Yeboah J, McClelland RL, Polonsky TS, et al. Comparison of novel risk markers for improvement in cardiovascular risk assessment in intermediate-risk individuals. JAMA 2012; 308(8):788–795. doi:10.1001/jama.2012.9624
Nasir K, Bittencourt MS, Blaha MJ, et al. Implications of coronary artery calcium testing among statin candidates according to American College of Cardiology/American Heart Association cholesterol management guidelines MESA (Multi-Ethnic Study of Atherosclerosis). J Am Coll Cardiol 2015; 66(15):1657–1668. doi:10.1016/j.jacc.2015.07.066
Hecht H, Blaha MJ, Berman DS, et al. Clinical indications for coronary artery calcium scoring in asymptomatic patients: expert consensus statement from the Society of Cardiovascular Computed Tomography. J Cardiovasc Comput Tomogr 2017; 11(2):157–168. doi:10.1016/j.jcct.2017.02.010
Miedema MD, Duprez DA, Misialek JR, et al. Use of coronary artery calcium testing to guide aspirin utilization for primary prevention: estimates from the multi-ethnic study of atherosclerosis. Circ Cardiovasc Qual Outcomes 2014; 7(3):453–460. doi:10.1161/CIRCOUTCOMES.113.000690
McClelland RL, Jorgensen NW, Budoff M, et al. 10-year coronary heart disease risk prediction using coronary artery calcium and traditional risk factors. J Am Coll Cardiol 2015; 66(15):1643–1653. doi:10.1016/j.jacc.2015.08.035
Hong JC, Blankstein R, Shaw LJ, et al. Implications of coronary artery calcium testing for treatment decisions among statin candidates according to the ACC/AHA cholesterol management guidelines: a cost-effectiveness analysis. JACC Cardiovasc Imaging 2017; 10(8):938–952. doi:10.1016/j.jcmg.2017.04.014
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Lehnert BE, Bree RL. Analysis of appropriateness of outpatient CT and MRI referred from primary care clinics at an academic medical center: how critical is the need for improved decision support? J Am Coll Radiol 2010; 7(3):192–197. doi:10.1016/j.jacr.2009.11.010
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Hecht HS. Coronary artery calcium scanning: past, present, and future. JACC Cardiovasc Imaging 2015; 8(5):579–596. doi:10.1016/j.jcmg.2015.02.006
MacHaalany J, Yam Y, Ruddy TD, et al. Potential clinical and economic consequences of noncardiac incidental findings on cardiac computed tomography. J Am Coll Cardiol 2009; 54(16):1533–1541. doi:10.1016/j.jacc.2009.06.026
McEvoy JW, Martin SS, Blaha MJ, et al. The case for and against a coronary artery calcium trial: means, motive, and opportunity. JACC Cardiovasc Imaging 2016; 9(8):994–1002. doi:10.1016/j.jcmg.2016.03.012
Patel MR, Bailey SR, Bonow RO, et al. ACCF/SCAI/AATS/AHA/ASE/ASNC/HFSA/HRS/SCCM/SCCT/SCMR/STS 2012 appropriate use criteria for diagnostic catheterization. J Thorac Cardiovasc Surg 2012; 144(1):39–71. doi:10.1016/j.jtcvs.2012.04.013
Villines TC, Hulten EA, Shaw LJ, et al. Prevalence and severity of coronary artery disease and adverse events among symptomatic patients with coronary artery calcification scores of zero undergoing coronary computed tomography angiography. J Am Coll Cardiol 2011; 58(24):2533–2540. doi:10.1016/j.jacc.2011.10.851
Hecht HS, Cronin P, Blaha MJ, et al. 2016 SCCT/STR guidelines for coronary artery calcium scoring of noncontrast noncardiac chest CT scans: a report of the Society of Cardiovascular Computed Tomography and Society of Thoracic Radiology. J Thorac Imaging 2017; 32(5):W54–W66. doi:10.1097/RTI.0000000000000287
Greenland P, Alpert JS, Beller GA, et al. 2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults: executive summary: a report of the American College of Cardiology foundation/American Heart Association task force on practice guidelines. Circulation 2010; 122(25):2748–2764. doi:10.1161/CIR.0b013e3182051bab
Martin SS, Sperling LS, Blaha MJ, et al. Clinician-patient risk discussion for atherosclerotic cardiovascular disease prevention: importance to implementation of the 2013 ACC/AHA guidelines. J Am Coll Cardiol 2015; 65(13):1361–1368. doi:10.1016/j.jacc.2015.01.043
Gupta A, Lau E, Varshney R, et al. The identification of calcified coronary plaque is associated with initiation and continuation of pharmacologic and lifestyle preventive therapies: a systematic review and meta-analysis. JACC Cardiovasc Imaging 2017; 10(8):833–842. doi:10.1016/j.jcmg.2017.01.030
Rozanski A, Gransar H, Shaw LJ, et al. Impact of coronary artery calcium scanning on coronary risk factors and downstream testing: The EISNER (Early Identification of Subclinical Atherosclerosis by Noninvasive Imaging Research) prospective randomized trial. J Am Coll Cardiol 2011; 57(15):1622–1632. doi:10.1016/j.jacc.2011.01.019

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Coronary artery calcium scoring: Its practicality and clinical utility in primary care

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Coronary artery calcium testing is useful in diagnosing subclinical coronary artery disease and in predicting the risk of future cardiovascular events and death.

Given the high negative predictive value of the test, it can also serve to reclassify risk in patients beyond traditional risk factors.
Along with shared decision-making, elevated calcium scores can guide the initiation of statin or aspirin therapy.
A high score in an asymptomatic patient should not trigger further testing without a comprehensive discussion of the risks and benefits.

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What can we do about musculoskeletal pain from bisphosphonates?

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What can we do about musculoskeletal pain from bisphosphonates?

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Sian Yik Lim, MD

Marcy B. Bolster, MD

Bisphosphonates, especially intravenous zoledronic acid, often cause influenza-like symptoms such as severe musculoskeletal pain, fever, headache, malaise, and fatigue, sometimes accompanied by nausea, vomiting, and diarrhea. As many as 30% of patients experience these symptoms, which are usually transient, last up to 1 week, and, in most patients, only rarely recur with subsequent infusions.

It is essential to counsel and reassure patients about these reactions before starting treatment. We recommend that patients take acetaminophen before intravenous bisphosphonate infusions, and if an acute-phase reaction occurs, we provide adequate supportive care with acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs). If patients report severe musculoskeletal pain, then consider discontinuing the bisphosphonate treatment.

INFLUENZA-LIKE SYMPTOMS

The acute-phase reaction is a transient inflammatory state characterized by influenza-like symptoms such as fever, myalgia, joint pain, and nausea. It often occurs within the first few days after initial exposure to a bisphosphonate. Patients tend to rate the symptoms as mild to moderate. Symptoms may recur with subsequent doses; however, the incidence rate decreases substantially with each subsequent dose.

With intravenous bisphosphonates

Reid et al1 analyzed data from a trial in which 7,765 postmenopausal women with osteoporosis were randomized to receive intravenous zoledronic acid or placebo; 42.4% of the zoledronic acid group experienced symptoms that could be attributed to an acute-phase reaction after the first infusion, compared with 11.7% of the placebo group (P < .0001). Statistically significant differences (P < .0001) in symptoms between the groups included the following:

Fever 20.3% vs 2.5%
Musculoskeletal symptoms 19.9% vs 4.7%
Gastrointestinal symptoms 7.8% vs 2.1%.

Of the patients describing musculoskeletal symptoms after receiving zoledronic acid, most (79%) described them as generalized pain or discomfort, while about 25% said they were regional, usually localized to the back, neck, chest, and shoulders, 5% described joint stiffness, and 2.5% reported joint swelling.¹

In this and other studies,^1–3 acute-phase reactions most commonly occurred within the first few days after the infusion and were rated as mild to moderate in 90% of cases.^1,2 Patients who reported an acute-phase reaction were not more likely to opt out of subsequent infusions. The authors postulated that this was most likely because acute-phase reactions were mild and transient, and most resolved within 1 week.¹ The incidence decreased with each subsequent infusion of zoledronic acid^1–3; rates of the acute-phase reaction at years 1, 2, and 3 were 30%, 7%, and 3%, respectively.¹

With oral bisphosphonates

The acute-phase reaction is less common with oral bisphosphonates (occurring in 5.6% of patients in a retrospective study4) and is usually less severe.^4,5

AMINOBISPHOSPHONATES INDUCE INFLAMMATORY CYTOKINES

Musculoskeletal pain related to the acute-phase reaction is thought to be due to transient release of inflammatory cytokines such as interleukin 6, interferon gamma, and tumor necrosis factor alpha from macrophages, monocytes, and gamma-delta T cells.⁶

Bisphosphonates are taken up by osteoclasts and inhibit their function. But bisphosphonates are not all the same: they can be divided into aminobisphosphonates (eg, alendronate, pamidronate, risedronate, zoledronic acid) and nonaminobisphosphonates (eg, clodronate, etidronate).

Inside the osteoclasts, aminobisphosphonates inhibit farnesyl diphosphate synthase in the mevalonate pathways, thus disrupting cell signaling and leading to apoptosis.⁷ However, inhibition of farnesyl diphosphate synthase also increases intracellular levels of isopentyl pyrophosphate, which induces T-cell activation; this is thought to result in release of inflammatory cytokines, leading to the acute-phase reaction.^7,8

In contrast, nonaminobisphosphonates such as clodronate and etidronate, after being internalized, are metabolized into nonhydrolyzable adenosine triphosphate, which is toxic to the osteoclast. The acute-phase reaction or influenza-like illness is unique to aminobisphosphonates; nonaminobisphosphonates have not been associated with an acute-phase reaction.

TRIALS OF PREVENTIVE TREATMENT

With NSAIDs, acetaminophen

Wark et al⁹ randomized 481 postmenopausal women who had osteopenia but who had never received bisphosphonates to 4 treatment groups:

Zoledronic acid 5 mg intravenously plus acetaminophen 1,000 mg every 6 hours for 3 days
Zoledronic acid 5 mg intravenously plus ibuprofen 400 mg every 6 hours for 3 days
Zoledronic acid 5 mg intravenously plus 2 placebo capsules every 6 hours for 3 days
Placebo infusion plus 2 placebo capsules every 6 hours for 3 days.

Patients were assessed for fever and worsening symptoms over 3 days after the infusion. The group that got zoledronic acid infusion and placebo capsules had the highest rates of fever (64%) and worsening symptoms (76%); acetaminophen and ibuprofen reduced these rates to an approximately equal extent, to 37% for fever and 46% (acetaminophen) and 49% (ibuprofen) for worsening symptoms. The group that received placebo bisphosphonate infusions had the lowest rates of fever (11%) and worsening symptoms (17%).

Silverman et al¹⁰ found that acetaminophen 650 mg taken 45 minutes before intravenous zoledronic acid infusion and continued every 6 hours for 3 days led to an absolute risk reduction of 21% in the incidence of fever or use of rescue medication compared with placebo.

Trials of other agents

In a study of 60 women,¹¹ 30 received an oral bolus of cholecalciferol 300,000 IU 5 days before zoledronic acid 5 mg infusion plus daily calcium 1,000 mg and vitamin D 800 IU, and 30 received a placebo pill 5 days before the same infusion and vitamin regimen as the other group. The preinfusion oral bolus did not decrease the incidence of acute-phase reactions, although it led to a small decrease in the severity of musculoskeletal pain (the median pain score was reduced from 2 to 1 on a scale of 0 to 10).

Other interventions such as fluvastatin and oral dexamethasone given before intravenous zoledronic acid did not reduce the severity or incidence of the acute-phase reaction.^10,12,13

OUR APPROACH

Before starting bisphosphonate therapy, patients should be counseled about the possibility of acute musculoskeletal pain and other symptoms of the acute-phase reaction.

For intravenous bisphosphonates

We advise all patients scheduled to receive intravenous bisphosphonates to take acetaminophen 650 to 1,000 mg once on the morning of the infusion. We prefer acetaminophen over NSAIDs for prophylaxis to avoid the gastric mucosal and renal toxicity more common with NSAIDs, especially in the elderly.

If the patient has a history of acute musculoskeletal pain or other symptoms of an acute-phase reaction after bisphosphonate infusion, we advise a more aggressive approach to prophylaxis: acetaminophen 650 mg 1 hour before the infusion, then every 6 hours for up to 3 days. This approach, with acetaminophen or NSAIDs, has been shown in large randomized controlled trials to reduce the incidence and severity of the acute-phase reaction.

If an acute-phase reaction occurs, we inform patients that the likelihood decreases and is quite low with subsequent doses. We provide correct and honest information, so that patients who experience an acute-phase reaction can make an informed decision about continuing bisphosphonate treatment or switching to another treatment. If the patient decides to continue with intravenous bisphosphonate treatment, we recommend more-aggressive prophylaxis with acetaminophen or NSAIDs with subsequent infusions.

For oral bisphosphonates

We do not prescribe prophylactic treatment with acetaminophen or NSAIDs with oral bisphosphonates, but we do advise patients to take acetaminophen or NSAIDs as needed for mild to moderate musculoskeletal pain, should this occur.

We try to continue treatment in mild to moderate cases, while monitoring the patient closely to see if the musculoskeletal pain resolves within 1 to 2 weeks.

If the pain is severe or does not resolve in 1 to 2 weeks, we offer switching to another drug class. Since musculoskeletal pain with oral bisphosphonates does not represent an allergic reaction, we have switched patients from oral to intravenous bisphosphonates without recurrence of musculoskeletal pain.

SEVERE MUSCULOSKELETAL PAIN BEYOND THE ACUTE PHASE

Severe musculoskeletal pain that may not be related to the acute-phase reaction, although rare, has been reported.^5,14 From 1995, when alendronate was approved for osteoporosis, through 2002, the US Food and Drug Administration received reports of severe musculoskeletal pain in 117 patients.¹⁵

This severe musculoskeletal pain related to bisphosphonate use remains poorly characterized. It has been reported to occur days or months (median time 14 days, range same day to 52 months) after starting bisphosphonate therapy and to resolve only if the bisphosphonate is stopped.^5,15 It differs from typical acute-phase reactions, which tend to occur with the initial dose (intravenous or oral) and resolve within several days. There are case reports of polyarthritis with synovitis that recurred with each bisphosphonate dose (oral or intravenous) and led to discontinuation of the bisphosphonate.^14,16–18

Clinicians need to be aware of the possibility of severe musculoskeletal pain and consider stopping bisphosphonate treatment in these cases. Besides discontinuation, acetaminophen, NSAIDs, and, in rare cases, glucocorticoids or short-term opiate therapy may be used for symptom control. In patients with a severe or persistent acute-phase reaction or musculoskeletal pain, discontinuation of bisphosphonates is warranted.

References

Reid IR, Gamble GD, Mesenbrink P, Lakatos P, Black DM. Characterization of and risk factors for the acute-phase response after zoledronic acid. J Clin Endocrinol Metab 2010; 95(9):4380–4387. doi:10.1210/jc.2010-0597
Black DM, Delmas PD, Eastell R, et al; HORIZON Pivotal Fracture Trial. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 2007; 356(18):1809–1822. doi:10.1056/NEJMoa067312
Lyles KW, Colon-Emeric CS, Magaziner JS, et al; HORIZON Recurrent Fracture Trial. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med 2007; 357(18):1799–1809. doi:10.1056/NEJMoa074941
Bock O, Boerst H, Thomasius FE, et al. Common musculoskeletal adverse effects of oral treatment with once weekly alendronate and risedronate in patients with osteoporosis and ways for their prevention. J Musculoskelet Neuronal Interact 2007; 7(2):144–148. pmid:17627083
US Food and Drug Administration (FDA). Information for healthcare professionals: Bisphosphonates (marketed as Actonel, Actonel+Ca, Aredia, Boniva, Didronel, Fosamax, Fosamax+D, Reclast, Skelid, and Zometa). https://wayback.archive-it.org/7993/20170722190245/https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm124165.htm. Accessed August 1, 2018.
Dicuonzo G, Vincenzi B, Santini D, et al. Fever after zoledronic acid administration is due to increase in TNF-alpha and IL-6. J Interferon Cytokine Res 2003; 23(11):649–654. doi:10.1089/107999003322558782
Olson K, Van Poznak C. Significance and impact of bisphosphonate-induced acute phase responses. J Oncol Pharm Pract 2007; 13(4):223–229. doi:10.1177/1078155207080806
Roelofs AJ, Jauhiainen M, Monkkonen H, Rogers MJ, Monkkonen J, Thompson K. Peripheral blood monocytes are responsible for gammadelta T cell activation induced by zoledronic acid through accumulation of IPP/DMAPP. Br J Haematol 2009; 144(2):245–250. doi:10.1111/j.1365-2141.2008.07435.x
Wark JD, Bensen W, Recknor C, et al. Treatment with acetaminophen/paracetamol or ibuprofen alleviates post-dose symptoms related to intravenous infusion with zoledronic acid 5 mg. Osteoporos Int 2012; 23(2):503–512. doi:10.1007/s00198-011-1563-8
Silverman SL, Kriegman A, Goncalves J, Kianifard F, Carlson T, Leary E. Effect of acetaminophen and fluvastatin on post-dose symptoms following infusion of zoledronic acid. Osteoporos Int 2011; 22(8):2337–2345. doi:10.1007/s00198-010-1448-2
Catalano A, Morabito N, Atteritano M, Basile G, Cucinotta D, Lasco A. Vitamin D reduces musculoskeletal pain after infusion of zoledronic acid for postmenopausal osteoporosis. Calcif Tissue Int 2012; 90(4):279–285. doi:10.1007/s00223-012-9577-6
Thompson K, Keech F, McLernon DJ, et al. Fluvastatin does not prevent the acute-phase response to intravenous zoledronic acid in post-menopausal women. Bone 2011; 49(1):140–145. doi:10.1016/j.bone.2010.10.177
Billington EO, Horne A, Gamble GD, Maslowski K, House M, Reid IR. Effect of single-dose dexamethasone on acute phase response following zoledronic aacid: a randomized controlled trial. Osteoporos Int 2017; 28(6):1867–1874. doi:10.1007/s00198-017-3960-0
Ugurlar M. Alendronate- and risedronate-induced acute polyarthritis. Osteoporos Int 2016; 27(11):3383–3385. doi:10.1007/s00198-016-3695-3
Wysowski DK, Chang JT. Alendronate and risedronate: reports of severe bone, joint, and muscle pain. Arch Intern Med 2005; 165(3):346–347.
Gwynne Jones DP, Savage RL, Highton J. Alendronate-induced synovitis. J Rheumatol 2008; 35(3):537–538. pmid:18203307
Gokkus K, Yazicioglu G, Sagtas E, Uyan A, Aydin AT. Possible alendronate-induced polyarticular synovitis. J Postgrad Med 2016; 62(2):126–128. doi:10.4103/0022-3859.174160
White SL, Jacob A, Gregson C, Bhalla A. Severe polyarthritis secondary to zolendronic acid: a case report and literature review. Clin Cases Miner Bone Metab 2015 ; 12(1):69–74. doi:10.11138/ccmbm/2015.12.1.069

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Sian Yik Lim, MD
Bone and Joint Center, Straub Clinic, Honolulu, HI

Marcy B. Bolster, MD
Associate Professor of Medicine, Harvard Medical School; Director, Rheumatology Fellowship Training Program, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Boston, MA

Address: Sian Yik Lim, MD, Bone and Joint Center, Straub Clinic, 800 S. King Street, Honolulu, HI 96813; limsianyik@gmail.com

Dr. Bolster has disclosed grant support from AbbVie Pharmaceuticals and remuneration for clinical trial research from Cumberland Pharmaceuticals.

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bisphosphonates, musculoskeletal pain, acute phase reaction, zoledronic acid, zolendronate, fever, cytokines, nonsteroidal anti-inflammatory drugs, NSAIDs, acetaminophen, aminobisphosphonates, osteoporosis, osteopenia, bone health, Sian Lim, Marcy Bolster

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Bone and Joint Center, Straub Clinic, Honolulu, HI

Address: Sian Yik Lim, MD, Bone and Joint Center, Straub Clinic, 800 S. King Street, Honolulu, HI 96813; limsianyik@gmail.com

Dr. Bolster has disclosed grant support from AbbVie Pharmaceuticals and remuneration for clinical trial research from Cumberland Pharmaceuticals.

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Bone and Joint Center, Straub Clinic, Honolulu, HI

Address: Sian Yik Lim, MD, Bone and Joint Center, Straub Clinic, 800 S. King Street, Honolulu, HI 96813; limsianyik@gmail.com

Dr. Bolster has disclosed grant support from AbbVie Pharmaceuticals and remuneration for clinical trial research from Cumberland Pharmaceuticals.

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INFLUENZA-LIKE SYMPTOMS

With intravenous bisphosphonates

Fever 20.3% vs 2.5%
Musculoskeletal symptoms 19.9% vs 4.7%
Gastrointestinal symptoms 7.8% vs 2.1%.

With oral bisphosphonates

The acute-phase reaction is less common with oral bisphosphonates (occurring in 5.6% of patients in a retrospective study4) and is usually less severe.^4,5

AMINOBISPHOSPHONATES INDUCE INFLAMMATORY CYTOKINES

TRIALS OF PREVENTIVE TREATMENT

With NSAIDs, acetaminophen

Wark et al⁹ randomized 481 postmenopausal women who had osteopenia but who had never received bisphosphonates to 4 treatment groups:

Zoledronic acid 5 mg intravenously plus acetaminophen 1,000 mg every 6 hours for 3 days
Zoledronic acid 5 mg intravenously plus ibuprofen 400 mg every 6 hours for 3 days
Zoledronic acid 5 mg intravenously plus 2 placebo capsules every 6 hours for 3 days
Placebo infusion plus 2 placebo capsules every 6 hours for 3 days.

Trials of other agents

Other interventions such as fluvastatin and oral dexamethasone given before intravenous zoledronic acid did not reduce the severity or incidence of the acute-phase reaction.^10,12,13

OUR APPROACH

Before starting bisphosphonate therapy, patients should be counseled about the possibility of acute musculoskeletal pain and other symptoms of the acute-phase reaction.

For intravenous bisphosphonates

For oral bisphosphonates

We try to continue treatment in mild to moderate cases, while monitoring the patient closely to see if the musculoskeletal pain resolves within 1 to 2 weeks.

SEVERE MUSCULOSKELETAL PAIN BEYOND THE ACUTE PHASE

INFLUENZA-LIKE SYMPTOMS

With intravenous bisphosphonates

Fever 20.3% vs 2.5%
Musculoskeletal symptoms 19.9% vs 4.7%
Gastrointestinal symptoms 7.8% vs 2.1%.

With oral bisphosphonates

The acute-phase reaction is less common with oral bisphosphonates (occurring in 5.6% of patients in a retrospective study4) and is usually less severe.^4,5

AMINOBISPHOSPHONATES INDUCE INFLAMMATORY CYTOKINES

TRIALS OF PREVENTIVE TREATMENT

With NSAIDs, acetaminophen

Wark et al⁹ randomized 481 postmenopausal women who had osteopenia but who had never received bisphosphonates to 4 treatment groups:

Zoledronic acid 5 mg intravenously plus acetaminophen 1,000 mg every 6 hours for 3 days
Zoledronic acid 5 mg intravenously plus ibuprofen 400 mg every 6 hours for 3 days
Zoledronic acid 5 mg intravenously plus 2 placebo capsules every 6 hours for 3 days
Placebo infusion plus 2 placebo capsules every 6 hours for 3 days.

Trials of other agents

Other interventions such as fluvastatin and oral dexamethasone given before intravenous zoledronic acid did not reduce the severity or incidence of the acute-phase reaction.^10,12,13

OUR APPROACH

Before starting bisphosphonate therapy, patients should be counseled about the possibility of acute musculoskeletal pain and other symptoms of the acute-phase reaction.

For intravenous bisphosphonates

For oral bisphosphonates

We try to continue treatment in mild to moderate cases, while monitoring the patient closely to see if the musculoskeletal pain resolves within 1 to 2 weeks.

SEVERE MUSCULOSKELETAL PAIN BEYOND THE ACUTE PHASE

References

Reid IR, Gamble GD, Mesenbrink P, Lakatos P, Black DM. Characterization of and risk factors for the acute-phase response after zoledronic acid. J Clin Endocrinol Metab 2010; 95(9):4380–4387. doi:10.1210/jc.2010-0597
Black DM, Delmas PD, Eastell R, et al; HORIZON Pivotal Fracture Trial. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 2007; 356(18):1809–1822. doi:10.1056/NEJMoa067312
Lyles KW, Colon-Emeric CS, Magaziner JS, et al; HORIZON Recurrent Fracture Trial. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med 2007; 357(18):1799–1809. doi:10.1056/NEJMoa074941
Bock O, Boerst H, Thomasius FE, et al. Common musculoskeletal adverse effects of oral treatment with once weekly alendronate and risedronate in patients with osteoporosis and ways for their prevention. J Musculoskelet Neuronal Interact 2007; 7(2):144–148. pmid:17627083
US Food and Drug Administration (FDA). Information for healthcare professionals: Bisphosphonates (marketed as Actonel, Actonel+Ca, Aredia, Boniva, Didronel, Fosamax, Fosamax+D, Reclast, Skelid, and Zometa). https://wayback.archive-it.org/7993/20170722190245/https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm124165.htm. Accessed August 1, 2018.
Dicuonzo G, Vincenzi B, Santini D, et al. Fever after zoledronic acid administration is due to increase in TNF-alpha and IL-6. J Interferon Cytokine Res 2003; 23(11):649–654. doi:10.1089/107999003322558782
Olson K, Van Poznak C. Significance and impact of bisphosphonate-induced acute phase responses. J Oncol Pharm Pract 2007; 13(4):223–229. doi:10.1177/1078155207080806
Roelofs AJ, Jauhiainen M, Monkkonen H, Rogers MJ, Monkkonen J, Thompson K. Peripheral blood monocytes are responsible for gammadelta T cell activation induced by zoledronic acid through accumulation of IPP/DMAPP. Br J Haematol 2009; 144(2):245–250. doi:10.1111/j.1365-2141.2008.07435.x
Wark JD, Bensen W, Recknor C, et al. Treatment with acetaminophen/paracetamol or ibuprofen alleviates post-dose symptoms related to intravenous infusion with zoledronic acid 5 mg. Osteoporos Int 2012; 23(2):503–512. doi:10.1007/s00198-011-1563-8
Silverman SL, Kriegman A, Goncalves J, Kianifard F, Carlson T, Leary E. Effect of acetaminophen and fluvastatin on post-dose symptoms following infusion of zoledronic acid. Osteoporos Int 2011; 22(8):2337–2345. doi:10.1007/s00198-010-1448-2
Catalano A, Morabito N, Atteritano M, Basile G, Cucinotta D, Lasco A. Vitamin D reduces musculoskeletal pain after infusion of zoledronic acid for postmenopausal osteoporosis. Calcif Tissue Int 2012; 90(4):279–285. doi:10.1007/s00223-012-9577-6
Thompson K, Keech F, McLernon DJ, et al. Fluvastatin does not prevent the acute-phase response to intravenous zoledronic acid in post-menopausal women. Bone 2011; 49(1):140–145. doi:10.1016/j.bone.2010.10.177
Billington EO, Horne A, Gamble GD, Maslowski K, House M, Reid IR. Effect of single-dose dexamethasone on acute phase response following zoledronic aacid: a randomized controlled trial. Osteoporos Int 2017; 28(6):1867–1874. doi:10.1007/s00198-017-3960-0
Ugurlar M. Alendronate- and risedronate-induced acute polyarthritis. Osteoporos Int 2016; 27(11):3383–3385. doi:10.1007/s00198-016-3695-3
Wysowski DK, Chang JT. Alendronate and risedronate: reports of severe bone, joint, and muscle pain. Arch Intern Med 2005; 165(3):346–347.
Gwynne Jones DP, Savage RL, Highton J. Alendronate-induced synovitis. J Rheumatol 2008; 35(3):537–538. pmid:18203307
Gokkus K, Yazicioglu G, Sagtas E, Uyan A, Aydin AT. Possible alendronate-induced polyarticular synovitis. J Postgrad Med 2016; 62(2):126–128. doi:10.4103/0022-3859.174160
White SL, Jacob A, Gregson C, Bhalla A. Severe polyarthritis secondary to zolendronic acid: a case report and literature review. Clin Cases Miner Bone Metab 2015 ; 12(1):69–74. doi:10.11138/ccmbm/2015.12.1.069

References

Reid IR, Gamble GD, Mesenbrink P, Lakatos P, Black DM. Characterization of and risk factors for the acute-phase response after zoledronic acid. J Clin Endocrinol Metab 2010; 95(9):4380–4387. doi:10.1210/jc.2010-0597
Black DM, Delmas PD, Eastell R, et al; HORIZON Pivotal Fracture Trial. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 2007; 356(18):1809–1822. doi:10.1056/NEJMoa067312
Lyles KW, Colon-Emeric CS, Magaziner JS, et al; HORIZON Recurrent Fracture Trial. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med 2007; 357(18):1799–1809. doi:10.1056/NEJMoa074941
Bock O, Boerst H, Thomasius FE, et al. Common musculoskeletal adverse effects of oral treatment with once weekly alendronate and risedronate in patients with osteoporosis and ways for their prevention. J Musculoskelet Neuronal Interact 2007; 7(2):144–148. pmid:17627083
US Food and Drug Administration (FDA). Information for healthcare professionals: Bisphosphonates (marketed as Actonel, Actonel+Ca, Aredia, Boniva, Didronel, Fosamax, Fosamax+D, Reclast, Skelid, and Zometa). https://wayback.archive-it.org/7993/20170722190245/https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm124165.htm. Accessed August 1, 2018.
Dicuonzo G, Vincenzi B, Santini D, et al. Fever after zoledronic acid administration is due to increase in TNF-alpha and IL-6. J Interferon Cytokine Res 2003; 23(11):649–654. doi:10.1089/107999003322558782
Olson K, Van Poznak C. Significance and impact of bisphosphonate-induced acute phase responses. J Oncol Pharm Pract 2007; 13(4):223–229. doi:10.1177/1078155207080806
Roelofs AJ, Jauhiainen M, Monkkonen H, Rogers MJ, Monkkonen J, Thompson K. Peripheral blood monocytes are responsible for gammadelta T cell activation induced by zoledronic acid through accumulation of IPP/DMAPP. Br J Haematol 2009; 144(2):245–250. doi:10.1111/j.1365-2141.2008.07435.x
Wark JD, Bensen W, Recknor C, et al. Treatment with acetaminophen/paracetamol or ibuprofen alleviates post-dose symptoms related to intravenous infusion with zoledronic acid 5 mg. Osteoporos Int 2012; 23(2):503–512. doi:10.1007/s00198-011-1563-8
Silverman SL, Kriegman A, Goncalves J, Kianifard F, Carlson T, Leary E. Effect of acetaminophen and fluvastatin on post-dose symptoms following infusion of zoledronic acid. Osteoporos Int 2011; 22(8):2337–2345. doi:10.1007/s00198-010-1448-2
Catalano A, Morabito N, Atteritano M, Basile G, Cucinotta D, Lasco A. Vitamin D reduces musculoskeletal pain after infusion of zoledronic acid for postmenopausal osteoporosis. Calcif Tissue Int 2012; 90(4):279–285. doi:10.1007/s00223-012-9577-6
Thompson K, Keech F, McLernon DJ, et al. Fluvastatin does not prevent the acute-phase response to intravenous zoledronic acid in post-menopausal women. Bone 2011; 49(1):140–145. doi:10.1016/j.bone.2010.10.177
Billington EO, Horne A, Gamble GD, Maslowski K, House M, Reid IR. Effect of single-dose dexamethasone on acute phase response following zoledronic aacid: a randomized controlled trial. Osteoporos Int 2017; 28(6):1867–1874. doi:10.1007/s00198-017-3960-0
Ugurlar M. Alendronate- and risedronate-induced acute polyarthritis. Osteoporos Int 2016; 27(11):3383–3385. doi:10.1007/s00198-016-3695-3
Wysowski DK, Chang JT. Alendronate and risedronate: reports of severe bone, joint, and muscle pain. Arch Intern Med 2005; 165(3):346–347.
Gwynne Jones DP, Savage RL, Highton J. Alendronate-induced synovitis. J Rheumatol 2008; 35(3):537–538. pmid:18203307
Gokkus K, Yazicioglu G, Sagtas E, Uyan A, Aydin AT. Possible alendronate-induced polyarticular synovitis. J Postgrad Med 2016; 62(2):126–128. doi:10.4103/0022-3859.174160
White SL, Jacob A, Gregson C, Bhalla A. Severe polyarthritis secondary to zolendronic acid: a case report and literature review. Clin Cases Miner Bone Metab 2015 ; 12(1):69–74. doi:10.11138/ccmbm/2015.12.1.069

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How should we diagnose and manage checkpoint inhibitor-associated colitis?

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How should we diagnose and manage checkpoint inhibitor-associated colitis?

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If a patient experiences diarrhea, hematochezia, or abdominal pain within the first 6 weeks of therapy with one of the anticancer drugs known as immune checkpoint inhibitors (ICIs), the first step is to rule out infection, especially with Clostridium difficile. The next step is colonosocopy with biopsy or computed tomography.

Figure 1. Proposed diagnosis and management of immune checkpoint inhibitor (ICI)-associated colitis.

Patients with mild ICI-associated colitis may need only supportive care, and the ICI can be continued. In moderate or severe cases, the agent may need to be stopped and corticosteroids and other colitis-targeted agents may be needed. Figure 1 shows our algorithm for diagnosing and treating ICI-associated colitis.

POWERFUL ANTICANCER DRUGS

ICIs are monoclonal antibodies used in treating metastatic melanoma, non-small-cell lung cancer, metastatic prostate cancer, Hodgkin lymphoma, renal cell carcinoma, and other advanced malignancies.^1,2 They act by binding to and blocking proteins on T cells, antigen-presenting cells, and tumor cells that keep immune responses in check and prevent T cells from killing cancer cells.¹ For example:

Ipilimumab blocks cytotoxic T lymphocyte-associated antigen 4
Nivolumab and pembrolizumab block programmed cell death protein 1
Atezolizumab blocks programmed death ligand 1.¹

With these proteins blocked, T cells can do their job, often producing dramatic regression of cancer. However, ICIs can cause a range of immune-related adverse effects, including endocrine and cutaneous toxicities, iridocyclitis, lymphadenopathy, neuropathy, nephritis, immune-mediated pneumonitis, pancreatitis, hepatitis, and colitis.³

ICI-ASSOCIATED COLITIS IS COMMON

ICI-associated colitis is common; it is estimated to affect about 30% of patients receiving ipilimumab, for example.⁴ Clinical presentations range from watery bowel movements, blood or mucus in the stool, abdominal cramping, and flatulence to ileus, colectasia, intestinal perforation, and even death.⁵

Incidence of diarrhea and colitis, and time to onset

The incidence appears to increase with the dosage and duration of ICI therapy. The onset of colitis typically occurs 6 to 7 weeks after starting ipilimumab,⁶ and 6 to 18 weeks after starting nivolumab or pembrolizumab.⁷ Table 1 lists the incidence of diarrhea and colitis and time of onset to colitis with common ICIs. However, colitis, like other immune-related adverse events, can occur at any point, even after ICI therapy has been discontinued.⁸

It is best to detect side effects of ICIs promptly, as acute inflammation can progress to chronic inflammation within 1 month of onset.⁹ We believe that early intervention and close monitoring may prevent complications and the need for long-term immunosuppressive treatment.

Patients, family members, and caregivers should be informed of possible gastrointestinal along with systemic side effects. Severe gastrointestinal symptoms such as increased stool frequency and change in stool consistency should trigger appropriate investigation and the withholding of ICI therapy.

COLITIS IS A SPECTRUM

The colon appears to be the gastrointestinal organ most affected by ICIs. Of patients with intestinal side effects, including diarrhea, only some develop colitis. The severity of ICI-associated colitis ranges from mild bowel illness to fulminant colitis.

Hodi et al,¹⁰ in a randomized trial in which 511 patients with melanoma received ipilimumab, reported that approximately 30% had mild diarrhea, while fewer than 10% had severe diarrhea, fever, ileus, or peritoneal signs. Five patients (1%) developed intestinal perforation, 4 (0.8%) died of complications, and 26 (5%) required hospitalization for severe enterocolitis.

The pathophysiology of ICI-mediated colitis is unclear. Most cases are diagnosed clinically.

Colitis is graded based on the Montreal classification system¹¹:

Mild colitis is defined as passage of fewer than 4 stools per day (with or without blood) over baseline and absence of any systemic illness.

Moderate is passage of more than 4 stools per day but with minimal signs of systemic toxicity.

Severe is defined as passage of at least 6 stools per day, heart rate at least 90 beats per minute, temperature at least 37.5°C (99.5°F), hemoglobin less than 10.5 g/dL, and erythrocyte sedimentation rate at least 30 mm/h.¹¹

RULE OUT INFECTION

If symptoms such as diarrhea or abdominal pain arise within 6 weeks of starting ICI therapy, then we should check for an infectious cause. The differential diagnosis of suspected ICI-associated colitis includes infections with C difficile, cytomegalovirus, opportunistic organisms, and other bacteria and viruses. ICI-induced celiac disease and immune hyperthyroidism should also be ruled out.⁴

CONSIDER COLONOSCOPY AND BIOPSY

Once infection is ruled out, colonoscopy should be considered if symptoms persist or are severe. Colonoscopy with biopsy remains the gold standard for diagnosis, and it is also helpful in assessing severity of mucosal inflammation and monitoring response to medical treatment.

Table 2 lists common endoscopic and histologic features of ICI-mediated colitis; however, none of them is specific for this disease.

Common endoscopic features are loss of vascular pattern, edema, friability, spontaneous bleeding, and deep ulcerations.¹² A recent study suggested that colonic ulcerations predict a steroid-refractory course in patients with immune-mediated colitis.⁴

Figure 2. Histologic features of immune checkpoint inhibitor-associated colitis. High-resolution images of the colon showing normal histopathology (A), and colonic mucosa with intraepithelial lymphocytosis and occasional apoptosis in crypt epithelium (B) (hematoxylin and eosin, × 200).

Histologically, ICI-associated colitis is characterized by both acute and chronic changes, including an increased number of neutrophils and lymphocytes in the epithelium and lamina propria, erosions, ulcers, crypt abscess, crypt apoptosis, crypt distortion, and even noncaseating granulomas.¹³ However, transmural disease is rare. Figure 2 compares the histopathologic features of ICI-associated colitis and a normal colon.

COMPUTED TOMOGRAPHY CAN BE USEFUL

Computed tomography (CT) can also be useful for the diagnosis and measurement of severity.

Garcia-Neuer et al1⁴ analyzed 303 patients with advanced melanoma who developed gastrointestinal symptoms while being treated with ipilimumab. Ninety-nine (33%) of them reported diarrhea during therapy, of whom 34 underwent both CT and colonoscopy with biopsy. CT was highly predictive of colitis on biopsy, with a positive predictive value of 96% and a negative likelihood ratio of 0.2.¹⁴

TREATMENT

Supportive care may be enough when treating mild ICI-related colitis. This can include oral and intravenous hydration⁴ and an antidiarrheal drug such as loperamide in a low dose.

Corticosteroids. For moderate ICI-associated colitis with stool frequency of 4 or more per day, patients should be started on an oral corticosteroid such as prednisone 0.5 to 1 mg/kg per day. If symptoms do not improve within 72 hours of starting an oral corticosteroid, the patient should be admitted to the hospital for observation and escalation to higher doses or possibly intravenous corticosteroids.

Infliximab has been used in severe and steroid-refractory cases,¹³ although there has been concern about using anti-tumor necrosis factor (TNF) agents such as this in patients with malignancies, especially melanoma. Since melanoma can be very aggressive and anti-TNF agents may promote it, it is prudent to try not to use this class of agents.

Other biologic agents such as vedolizumab, a gut-specific anti-integrin agent, are safer, have theoretic advantages over anti-TNF agents, and can be considered in patients with steroid-dependent or steroid-refractory ICI-associated enterocolitis. A recent study suggested that 2 to 4 infusions of vedolizumab are adequate to achieve steroid-free remission.¹⁵ Results from 6 clinical trials of vedolizumab in 2,830 patients with Crohn disease or ulcerative colitis did not show any increased risk of serious infections or malignancies over placebo.^16,17 A drawback is its slow onset of action.

Surgery is an option for patients with severe colitis refractory to intravenous corticosteroids or biological agents, as severe colitis carries a risk of significant morbidity and even death. The incidence of bowel perforation leading to colectomy or death in patients receiving ICI therapy is 0.5% to 1%.^18,19

Fecal microbiota transplant was associated with mucosal healing after 1 month in a case report of ICI-associated colitis.⁹

Follow-up. In most patients, symptoms resolve with discontinuation of the ICI and brief use of corticosteroids or biological agents. Patients with recurrent or persistent symptoms while on long-term ICI therapy may need periodic endoscopic evaluation, especially if there are chronic structural changes on histologic study.

If patients have recurrent or persistent symptoms along with chronic inflammatory structural changes on histology, a sign of an inflammatory bowel diseaselike condition, long-term maintenance therapy with an anti-inflammatory or immunosuppressant agent may be considered. However, there is no consensus on the treatment of this condition. It can be treated in the same way as classic inflammatory bowel disease in the setting of concurrent or prior history of malignancy, especially melanoma. Certain agents used in inflammatory bowel disease such as methotrexate and vedolizumab carry a lower risk of malignancy than anti-TNF agents and can be considered. A multidisciplinary approach that includes an oncologist, gastroenterologist, infectious disease specialist, and colorectal surgeon is imperative.

References

Shih K, Arkenau HT, Infante JR. Clinical impact of checkpoint inhibitors as novel cancer therapies. Drugs 2014; 74(17):1993–2013. doi:10.1007/s40265-014-0305-6
Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature 2011; 480(7378):480–489. doi:10.1038/nature10673
Dine J, Gordon R, Shames Y, Kasler MK, Barton-Burke M. Immune checkpoint inhibitors: an innovation in immunotherapy for the treatment and management of patients with cancer. Asia Pac J Oncol Nurs 2017; 4(2):127–135. doi:10.4103/apjon.apjon_4_17
Prieux-Klotz C, Dior M, Damotte D, et al. Immune checkpoint inhibitor-induced colitis: diagnosis and management. Target Oncol 2017; 12(3):301–308. doi:10.1007/s11523-017-0495-4
Howell M, Lee R, Bowyer S, Fusi A, Lorigan P. Optimal management of immune-related toxicities associated with checkpoint inhibitors in lung cancer. Lung Cancer 2015; 88(2):117–123. doi:10.1016/j.lungcan.2015.02.007
Weber JS, Kähler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol 2012; 30(21):2691–2697. doi:10.1200/JCO.2012.41.6750
Eigentler TK, Hassel JC, Berking C, et al. Diagnosis, monitoring and management of immune-related adverse drug reactions of anti-PD-1 antibody therapy. Cancer Treat Rev 2016; 45:7–18. doi:10.1016/j.ctrv.2016.02.003
Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med 2018; 378(2):158–168. doi:10.1056/NEJMra1703481
Wang Y, DuPont H, Jiang ZD, Jenq R, Zuazua R, Shuttlesworth G. Fecal microbiota transplant for immune-checkpoint inhibitor-induced colitis in a 50 year old with bladder cancer. Gastroenterol 2018; 154(1 suppl). doi:10.1053/j.gastro.2017.11.075
Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363(8):711–723. doi:10.1056/NEJMoa1003466
Satsangi J, Silverberg MS, Vermeire S, Colombel JF. The Montreal classification of inflammatory bowel disease: controversies, consensus, and implications. Gut 2006; 55(6):749–753. doi:10.1136/gut.2005.082909
Rastogi P, Sultan M, Charabaty AJ, Atkins MB, Mattar MC. Ipilimumab associated colitis: an IpiColitis case series at MedStar Georgetown University Hospital. World J Gastroenterol 2015; 21(14):4373–4378. doi:10.3748/wjg.v21.i14.4373
Pocha C, Roat J, Viskocil K. Immune-mediated colitis: important to recognize and treat. J Crohns Colitis 2014; 8(2):181–182. doi:10.1016/j.crohns.2013.09.019
Garcia-Neuer M, Marmarelis ME, Jangi SR, et al. Diagnostic comparison of CT scans and colonoscopy for immune-related colitis in ipilimumab-treated advanced melanoma patients. Cancer Immunol Res 2017; 5(4):286–291. doi:10.1158/2326-6066.CIR-16-0302
Bergqvist V, Hertervig E, Gedeon P, et al. Vedolizumab treatment for immune checkpoint inhibitor-induced enterocolitis. Cancer Immunol Immunother 2017; 66(5):581–592. doi:10.1007/s00262-017-1962-6
Sandborn WJ, Feagan BG, Rutgeerts P, et al; GEMINI 2 Study Group. Vedolizumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med 2013; 369(8):711–721. doi:10.1056/NEJMoa1215739
Feagan BG, Rutgeerts P, Sands BE, et al; GEMINI 1 Study Group. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med 2013; 369(8):699–710. doi:10.1056/NEJMoa1215734
Kähler KC, Hauschild A. Treatment and side effect management of CTLA-4 antibody therapy in metastatic melanoma. J Dtsch Dermatol Ges 2011; 9(4):277–286. doi:10.1111/j.1610-0387.2010.07568.x
Ibrahim RA, Berman DM, DePril V, et al. Ipilimumab safety profile: summary of findings from completed trials in advanced melanoma. J Clin Onc 2011; 29(15 suppl):8583–8583. doi:10.1200/jco.2011.29.15_suppl.8583

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Pauline Funchain, MD
Department of Hematology and Medical Oncology, Cleveland Clinic; Clinical Assistant Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Ana Bennett, MD
Department of Anatomic Pathology and Transplantation Center, Cleveland Clinic; Clinical Assistant Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Tracy L. Hull, MD
Surgical Head, Section of Inflammatory Bowel DIsease, Department of Colorectal Surgery, Cleveland Clinic; Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Bo Shen, MD
Section Head, Center for Inflammatory Bowel Disease, Department of Gastroenterology, Hepatology, & Nutrition, Cleveland Clinic; Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Address: Bo Shen, MD, Center for Inflammatory Bowel Disease, Department of Gastroenterology and Hepatology, A31, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; shenb@ccf.org

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colitis, cancer drugs, immune checkpoint inhibitors, ICIs, ipilimumab, nivolumab, pembrolizumab, atrezolizumab, monocloncal antibodies, mabs, diarrhea, infection, Clostridium difficile, C difficile, C diff, colonoscopy, Freeha Khan, Pauline Funchain, Ana Bennett, Tracy Hull, Bo Shen

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POWERFUL ANTICANCER DRUGS

Ipilimumab blocks cytotoxic T lymphocyte-associated antigen 4
Nivolumab and pembrolizumab block programmed cell death protein 1
Atezolizumab blocks programmed death ligand 1.¹

ICI-ASSOCIATED COLITIS IS COMMON

COLITIS IS A SPECTRUM

The pathophysiology of ICI-mediated colitis is unclear. Most cases are diagnosed clinically.

Colitis is graded based on the Montreal classification system¹¹:

Mild colitis is defined as passage of fewer than 4 stools per day (with or without blood) over baseline and absence of any systemic illness.

Moderate is passage of more than 4 stools per day but with minimal signs of systemic toxicity.

RULE OUT INFECTION

CONSIDER COLONOSCOPY AND BIOPSY

Table 2 lists common endoscopic and histologic features of ICI-mediated colitis; however, none of them is specific for this disease.

COMPUTED TOMOGRAPHY CAN BE USEFUL

Computed tomography (CT) can also be useful for the diagnosis and measurement of severity.

TREATMENT

Supportive care may be enough when treating mild ICI-related colitis. This can include oral and intravenous hydration⁴ and an antidiarrheal drug such as loperamide in a low dose.

Fecal microbiota transplant was associated with mucosal healing after 1 month in a case report of ICI-associated colitis.⁹

POWERFUL ANTICANCER DRUGS

Ipilimumab blocks cytotoxic T lymphocyte-associated antigen 4
Nivolumab and pembrolizumab block programmed cell death protein 1
Atezolizumab blocks programmed death ligand 1.¹

ICI-ASSOCIATED COLITIS IS COMMON

COLITIS IS A SPECTRUM

The pathophysiology of ICI-mediated colitis is unclear. Most cases are diagnosed clinically.

Colitis is graded based on the Montreal classification system¹¹:

Mild colitis is defined as passage of fewer than 4 stools per day (with or without blood) over baseline and absence of any systemic illness.

Moderate is passage of more than 4 stools per day but with minimal signs of systemic toxicity.

RULE OUT INFECTION

CONSIDER COLONOSCOPY AND BIOPSY

Table 2 lists common endoscopic and histologic features of ICI-mediated colitis; however, none of them is specific for this disease.

COMPUTED TOMOGRAPHY CAN BE USEFUL

Computed tomography (CT) can also be useful for the diagnosis and measurement of severity.

TREATMENT

Supportive care may be enough when treating mild ICI-related colitis. This can include oral and intravenous hydration⁴ and an antidiarrheal drug such as loperamide in a low dose.

Fecal microbiota transplant was associated with mucosal healing after 1 month in a case report of ICI-associated colitis.⁹

References

Shih K, Arkenau HT, Infante JR. Clinical impact of checkpoint inhibitors as novel cancer therapies. Drugs 2014; 74(17):1993–2013. doi:10.1007/s40265-014-0305-6
Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature 2011; 480(7378):480–489. doi:10.1038/nature10673
Dine J, Gordon R, Shames Y, Kasler MK, Barton-Burke M. Immune checkpoint inhibitors: an innovation in immunotherapy for the treatment and management of patients with cancer. Asia Pac J Oncol Nurs 2017; 4(2):127–135. doi:10.4103/apjon.apjon_4_17
Prieux-Klotz C, Dior M, Damotte D, et al. Immune checkpoint inhibitor-induced colitis: diagnosis and management. Target Oncol 2017; 12(3):301–308. doi:10.1007/s11523-017-0495-4
Howell M, Lee R, Bowyer S, Fusi A, Lorigan P. Optimal management of immune-related toxicities associated with checkpoint inhibitors in lung cancer. Lung Cancer 2015; 88(2):117–123. doi:10.1016/j.lungcan.2015.02.007
Weber JS, Kähler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol 2012; 30(21):2691–2697. doi:10.1200/JCO.2012.41.6750
Eigentler TK, Hassel JC, Berking C, et al. Diagnosis, monitoring and management of immune-related adverse drug reactions of anti-PD-1 antibody therapy. Cancer Treat Rev 2016; 45:7–18. doi:10.1016/j.ctrv.2016.02.003
Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med 2018; 378(2):158–168. doi:10.1056/NEJMra1703481
Wang Y, DuPont H, Jiang ZD, Jenq R, Zuazua R, Shuttlesworth G. Fecal microbiota transplant for immune-checkpoint inhibitor-induced colitis in a 50 year old with bladder cancer. Gastroenterol 2018; 154(1 suppl). doi:10.1053/j.gastro.2017.11.075
Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363(8):711–723. doi:10.1056/NEJMoa1003466
Satsangi J, Silverberg MS, Vermeire S, Colombel JF. The Montreal classification of inflammatory bowel disease: controversies, consensus, and implications. Gut 2006; 55(6):749–753. doi:10.1136/gut.2005.082909
Rastogi P, Sultan M, Charabaty AJ, Atkins MB, Mattar MC. Ipilimumab associated colitis: an IpiColitis case series at MedStar Georgetown University Hospital. World J Gastroenterol 2015; 21(14):4373–4378. doi:10.3748/wjg.v21.i14.4373
Pocha C, Roat J, Viskocil K. Immune-mediated colitis: important to recognize and treat. J Crohns Colitis 2014; 8(2):181–182. doi:10.1016/j.crohns.2013.09.019
Garcia-Neuer M, Marmarelis ME, Jangi SR, et al. Diagnostic comparison of CT scans and colonoscopy for immune-related colitis in ipilimumab-treated advanced melanoma patients. Cancer Immunol Res 2017; 5(4):286–291. doi:10.1158/2326-6066.CIR-16-0302
Bergqvist V, Hertervig E, Gedeon P, et al. Vedolizumab treatment for immune checkpoint inhibitor-induced enterocolitis. Cancer Immunol Immunother 2017; 66(5):581–592. doi:10.1007/s00262-017-1962-6
Sandborn WJ, Feagan BG, Rutgeerts P, et al; GEMINI 2 Study Group. Vedolizumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med 2013; 369(8):711–721. doi:10.1056/NEJMoa1215739
Feagan BG, Rutgeerts P, Sands BE, et al; GEMINI 1 Study Group. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med 2013; 369(8):699–710. doi:10.1056/NEJMoa1215734
Kähler KC, Hauschild A. Treatment and side effect management of CTLA-4 antibody therapy in metastatic melanoma. J Dtsch Dermatol Ges 2011; 9(4):277–286. doi:10.1111/j.1610-0387.2010.07568.x
Ibrahim RA, Berman DM, DePril V, et al. Ipilimumab safety profile: summary of findings from completed trials in advanced melanoma. J Clin Onc 2011; 29(15 suppl):8583–8583. doi:10.1200/jco.2011.29.15_suppl.8583

References

Shih K, Arkenau HT, Infante JR. Clinical impact of checkpoint inhibitors as novel cancer therapies. Drugs 2014; 74(17):1993–2013. doi:10.1007/s40265-014-0305-6
Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature 2011; 480(7378):480–489. doi:10.1038/nature10673
Dine J, Gordon R, Shames Y, Kasler MK, Barton-Burke M. Immune checkpoint inhibitors: an innovation in immunotherapy for the treatment and management of patients with cancer. Asia Pac J Oncol Nurs 2017; 4(2):127–135. doi:10.4103/apjon.apjon_4_17
Prieux-Klotz C, Dior M, Damotte D, et al. Immune checkpoint inhibitor-induced colitis: diagnosis and management. Target Oncol 2017; 12(3):301–308. doi:10.1007/s11523-017-0495-4
Howell M, Lee R, Bowyer S, Fusi A, Lorigan P. Optimal management of immune-related toxicities associated with checkpoint inhibitors in lung cancer. Lung Cancer 2015; 88(2):117–123. doi:10.1016/j.lungcan.2015.02.007
Weber JS, Kähler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol 2012; 30(21):2691–2697. doi:10.1200/JCO.2012.41.6750
Eigentler TK, Hassel JC, Berking C, et al. Diagnosis, monitoring and management of immune-related adverse drug reactions of anti-PD-1 antibody therapy. Cancer Treat Rev 2016; 45:7–18. doi:10.1016/j.ctrv.2016.02.003
Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med 2018; 378(2):158–168. doi:10.1056/NEJMra1703481
Wang Y, DuPont H, Jiang ZD, Jenq R, Zuazua R, Shuttlesworth G. Fecal microbiota transplant for immune-checkpoint inhibitor-induced colitis in a 50 year old with bladder cancer. Gastroenterol 2018; 154(1 suppl). doi:10.1053/j.gastro.2017.11.075
Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363(8):711–723. doi:10.1056/NEJMoa1003466
Satsangi J, Silverberg MS, Vermeire S, Colombel JF. The Montreal classification of inflammatory bowel disease: controversies, consensus, and implications. Gut 2006; 55(6):749–753. doi:10.1136/gut.2005.082909
Rastogi P, Sultan M, Charabaty AJ, Atkins MB, Mattar MC. Ipilimumab associated colitis: an IpiColitis case series at MedStar Georgetown University Hospital. World J Gastroenterol 2015; 21(14):4373–4378. doi:10.3748/wjg.v21.i14.4373
Pocha C, Roat J, Viskocil K. Immune-mediated colitis: important to recognize and treat. J Crohns Colitis 2014; 8(2):181–182. doi:10.1016/j.crohns.2013.09.019
Garcia-Neuer M, Marmarelis ME, Jangi SR, et al. Diagnostic comparison of CT scans and colonoscopy for immune-related colitis in ipilimumab-treated advanced melanoma patients. Cancer Immunol Res 2017; 5(4):286–291. doi:10.1158/2326-6066.CIR-16-0302
Bergqvist V, Hertervig E, Gedeon P, et al. Vedolizumab treatment for immune checkpoint inhibitor-induced enterocolitis. Cancer Immunol Immunother 2017; 66(5):581–592. doi:10.1007/s00262-017-1962-6
Sandborn WJ, Feagan BG, Rutgeerts P, et al; GEMINI 2 Study Group. Vedolizumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med 2013; 369(8):711–721. doi:10.1056/NEJMoa1215739
Feagan BG, Rutgeerts P, Sands BE, et al; GEMINI 1 Study Group. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med 2013; 369(8):699–710. doi:10.1056/NEJMoa1215734
Kähler KC, Hauschild A. Treatment and side effect management of CTLA-4 antibody therapy in metastatic melanoma. J Dtsch Dermatol Ges 2011; 9(4):277–286. doi:10.1111/j.1610-0387.2010.07568.x
Ibrahim RA, Berman DM, DePril V, et al. Ipilimumab safety profile: summary of findings from completed trials in advanced melanoma. J Clin Onc 2011; 29(15 suppl):8583–8583. doi:10.1200/jco.2011.29.15_suppl.8583

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Fournier gangrene

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Fournier gangrene

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Hiroki Matsuura, MD

Kazuki Iwasa, MD

An 88-year-old man with a 1-day history of fever and altered mental status was transferred to the emergency department. He had been receiving conservative management for low-risk localized prostate cancer but had no previous cardiovascular or gastrointestinal problems.

Physical examination revealed black discoloration of the rectal wall and perineum and the entire penis and scrotum (Figure 1). Computed tomography demonstrated subcutaneous emphysema in the scrotum.

Based on these findings, the diagnosis was Fournier gangrene. Despite aggressive treatment, the patient’s condition deteriorated rapidly, and he died 2 hours after admission.

FOURNIER GANGRENE: NECROTIZING FASCIITIS OF THE PERINEUM

Fournier gangrene is a rare but rapidly progressive necrotizing fasciitis of the perineum with a high death rate.

Predisposing factors for Fournier gangrene include older age, diabetes mellitus, morbid obesity, cardiovascular disorders, chronic alcoholism, long-term corticosteroid treatment, malignancy, and human immunodeficiency virus infection.^1,2 Urethral obstruction, instrumentation, urinary extravasation, and trauma have also been associated with this condition.³

In general, organisms from the urinary tract spread along the fascial planes to involve the penis and scrotum.

The differential diagnosis of Fournier gangrene includes scrotal and perineal disorders, as well as intra-abdominal disorders such as cellulitis, abscess, strangulated hernia, pyoderma gangrenosum, allergic vasculitis, vascular occlusion syndromes, and warfarin necrosis.

Delay in the diagnosis of Fournier gangrene leads to an extremely high death rate due to rapid progression of the disease, leading to sepsis, multiple organ failure, and disseminated intravascular coagulation. Immediate diagnosis and appropriate treatment such as broad-spectrum antibiotics and extensive surgical debridement reduce morbidity and control the infection. Antibiotics for methicillin-resistant Staphylococcus aureus should be considered if there is a history of or risk factors for this organism.⁴

Necrotizing fasciitis, including Fournier gangrene, is a common indication for intravenous immunoglobulin, and this treatment has been reported to be effective in a few cases. However, a double-blind, placebo-controlled trial that evaluated the benefit of this treatment was terminated early due to slow patient recruitment.⁵

A delay of even a few hours from suspicion of Fournier gangrene to surgical debridement significantly increases the risk of death.⁶ Thus, when it is suspected, immediate surgical intervention may be necessary to confirm the diagnosis and to treat it. The usual combination of antibiotic therapy for Fournier gangrene includes penicillin for the streptococcal species, a third-generation cephalosporin with or without an aminoglycoside for the gram-negative organisms, and metronidazole for anaerobic bacteria.

References

Wang YK, Li YH, Wu ST, Meng E. Fournier’s gangrene. QJM 2017; 110(10):671–672. doi:10.1093/qjmed/hcx124
Yanar H, Taviloglu K, Ertekin C, et al. Fournier’s gangrene: risk factors and strategies for management. World J Surg 2006; 30(9):1750–1754. doi:10.1007/s00268-005-0777-3
Paonam SS, Bag S. Fournier gangrene with extensive necrosis of urethra and bladder mucosa: a rare occurrence in a patient with advanced prostate cancer. Urol Ann 2015; 7(4):507–509. doi:10.4103/0974-7796.157975
Brook I. Microbiology and management of soft tissue and muscle infections. Int J Surg 2008; 6(4):328–338. doi:10.1016/j.ijsu.2007.07.001
Koch C, Hecker A, Grau V, Padberg W, Wolff M, Henrich M. Intravenous immunoglobulin in necrotizing fasciitis—a case report and review of recent literature. Ann Med Surg (Lond) 2015; 4(3):260–263. doi:10.1016/j.amsu.2015.07.017
Singh A, Ahmed K, Aydin A, Khan MS, Dasgupta P. Fournier's gangrene. A clinical review. Arch Ital Urol Androl 2016; 88(3):157–164. doi:10.4081/aiua.2016.3.157

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Hiroki Matsuura, MD
Department of General Internal Medicine, Mitoyo General Hospital, Kagawa, Japan; Department of General Internal Medicine, Kurashiki Central Hospital, Okayama, Japan

Kazuki Iwasa, MD
Department of General Internal Medicine, Aso Iizuka Hospital, Fukuoka, Japan; Department of Gynecology, Shikoku Central Hospital, Ehime, Japan

Address: Hiroki Matsuura, MD, 708, Himehama, Toyohama-cho, Kanonji-city, Kagawa, 769-1695 Japan; superonewex0506@yahoo.co.jp

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Department of General Internal Medicine, Mitoyo General Hospital, Kagawa, Japan; Department of General Internal Medicine, Kurashiki Central Hospital, Okayama, Japan

Kazuki Iwasa, MD
Department of General Internal Medicine, Aso Iizuka Hospital, Fukuoka, Japan; Department of Gynecology, Shikoku Central Hospital, Ehime, Japan

Address: Hiroki Matsuura, MD, 708, Himehama, Toyohama-cho, Kanonji-city, Kagawa, 769-1695 Japan; superonewex0506@yahoo.co.jp

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Department of General Internal Medicine, Mitoyo General Hospital, Kagawa, Japan; Department of General Internal Medicine, Kurashiki Central Hospital, Okayama, Japan

Kazuki Iwasa, MD
Department of General Internal Medicine, Aso Iizuka Hospital, Fukuoka, Japan; Department of Gynecology, Shikoku Central Hospital, Ehime, Japan

Address: Hiroki Matsuura, MD, 708, Himehama, Toyohama-cho, Kanonji-city, Kagawa, 769-1695 Japan; superonewex0506@yahoo.co.jp

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Based on these findings, the diagnosis was Fournier gangrene. Despite aggressive treatment, the patient’s condition deteriorated rapidly, and he died 2 hours after admission.

FOURNIER GANGRENE: NECROTIZING FASCIITIS OF THE PERINEUM

Fournier gangrene is a rare but rapidly progressive necrotizing fasciitis of the perineum with a high death rate.

In general, organisms from the urinary tract spread along the fascial planes to involve the penis and scrotum.

Based on these findings, the diagnosis was Fournier gangrene. Despite aggressive treatment, the patient’s condition deteriorated rapidly, and he died 2 hours after admission.

FOURNIER GANGRENE: NECROTIZING FASCIITIS OF THE PERINEUM

Fournier gangrene is a rare but rapidly progressive necrotizing fasciitis of the perineum with a high death rate.

In general, organisms from the urinary tract spread along the fascial planes to involve the penis and scrotum.

References

Wang YK, Li YH, Wu ST, Meng E. Fournier’s gangrene. QJM 2017; 110(10):671–672. doi:10.1093/qjmed/hcx124
Yanar H, Taviloglu K, Ertekin C, et al. Fournier’s gangrene: risk factors and strategies for management. World J Surg 2006; 30(9):1750–1754. doi:10.1007/s00268-005-0777-3
Paonam SS, Bag S. Fournier gangrene with extensive necrosis of urethra and bladder mucosa: a rare occurrence in a patient with advanced prostate cancer. Urol Ann 2015; 7(4):507–509. doi:10.4103/0974-7796.157975
Brook I. Microbiology and management of soft tissue and muscle infections. Int J Surg 2008; 6(4):328–338. doi:10.1016/j.ijsu.2007.07.001
Koch C, Hecker A, Grau V, Padberg W, Wolff M, Henrich M. Intravenous immunoglobulin in necrotizing fasciitis—a case report and review of recent literature. Ann Med Surg (Lond) 2015; 4(3):260–263. doi:10.1016/j.amsu.2015.07.017
Singh A, Ahmed K, Aydin A, Khan MS, Dasgupta P. Fournier's gangrene. A clinical review. Arch Ital Urol Androl 2016; 88(3):157–164. doi:10.4081/aiua.2016.3.157

References

Wang YK, Li YH, Wu ST, Meng E. Fournier’s gangrene. QJM 2017; 110(10):671–672. doi:10.1093/qjmed/hcx124
Yanar H, Taviloglu K, Ertekin C, et al. Fournier’s gangrene: risk factors and strategies for management. World J Surg 2006; 30(9):1750–1754. doi:10.1007/s00268-005-0777-3
Paonam SS, Bag S. Fournier gangrene with extensive necrosis of urethra and bladder mucosa: a rare occurrence in a patient with advanced prostate cancer. Urol Ann 2015; 7(4):507–509. doi:10.4103/0974-7796.157975
Brook I. Microbiology and management of soft tissue and muscle infections. Int J Surg 2008; 6(4):328–338. doi:10.1016/j.ijsu.2007.07.001
Koch C, Hecker A, Grau V, Padberg W, Wolff M, Henrich M. Intravenous immunoglobulin in necrotizing fasciitis—a case report and review of recent literature. Ann Med Surg (Lond) 2015; 4(3):260–263. doi:10.1016/j.amsu.2015.07.017
Singh A, Ahmed K, Aydin A, Khan MS, Dasgupta P. Fournier's gangrene. A clinical review. Arch Ital Urol Androl 2016; 88(3):157–164. doi:10.4081/aiua.2016.3.157

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Brain abscesses in a 60-year-old man

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Adam Fershko, MD, FACP

A 60-year-old man with hypertension and persistent atrial fibrillation refractory to radiofrequency ablation was brought to the hospital in status epilepticus requiring intubation. His wife said that during the past month he had experienced a number of episodic seizures, but due to his busy work schedule he had not sought medical attention. He had also been hospitalized 3 times during the past week for chills, tremors, and fevers with temperatures up to 101°F (38.3°C), and his symptoms had been ascribed to the amiodarone he had been taking for the past 11 days for atrial fibrillation. The amiodarone dose had been decreased to half a tablet after the first 7 days, but his symptoms had continued.

When the patient was able to speak, he denied intravenous drug abuse and claimed to be up to date with vaccinations. Colonoscopy 10 years earlier had been negative. He has no pets, but says that there are stray cats around his home and that he has had contact with cat feces while gardening. He works as a diesel mechanic and is exposed to motor oil and diesel fuel, but denies any direct exposure to carcinogenic chemicals.

On admission, his temperature was 37.7°C (99.9°F), blood pressure 92/69 mm Hg, heart rate 96 beats per minute, respiratory rate 21 per minute, and oxygen saturation 95% on room air and 100% on oxygen at 2 L per minute.

Decerebrate posturing and forced left visual gaze deviation was observed. Oral examination revealed severe decay of multiple teeth, with some teeth broken down to the level of the gingiva, and moderate generalized periodontal disease with heavy plaque and calculi in the gingiva.

Figure 1. Magnetic resonance imaging identified multiple ring-enhancing lesions (arrows) in the right hemisphere.

The patient underwent magnetic resonance imaging, which showed more than 20 ring-enhancing lesions in the right brain hemisphere, the largest lesion measuring 1.2 cm × 1.5 cm (Figure 1).

The differential diagnosis for intracranial ring-enhancing lesions includes metastasis, abscess, infection in an immunocompromised state (eg, toxoplasmosis), glioblastoma, subacute infarct, neurocysticercosis, lymphoma, demyelination, and resolving hematoma. In our patient, further testing to narrow the differential included lumbar puncture, with results within normal limits, and transthoracic echocardiography, which was negative for endocarditis. A biopsy obtained by craniotomy confirmed the diagnosis of abscess surrounded by reactive glioses.

During his hospitalization, the patient’s antiseizure regimen was lorazepam 1 to 2 mg as needed, levetiracetam 1,500 mg twice daily, and fosphenytoin infusion at 100 mg phenytoin sodium equivalents per minute. Initial antibiotic therapy included ampicillin 2 g intravenously (IV) 4 times daily.

Because of persistent nocturnal fevers with temperatures ranging from 37.8°C (100°F) to 41.2°C (106.2°F), antibiotic coverage was broadened to meropenem 2 g IV every 8 hours. Testing for Toxoplasma gondii, human immunodeficiency virus, and JC polyomavirus was negative. Cerebrospinal fluid culture and abscess cultures were also negative. Blood cultures were eventually positive for Peptostreptococcus micros and Streptococcus constellatus. Based on review of culture results, antibiotic therapy was switched to ceftriaxone 2 g IV twice daily and metronidazole 500 mg IV 3 times daily.

For the dental infection, the patient underwent surgical irrigation and debridement with full dental extraction for multiple dental abscesses.

His regimen for seizure control was changed to phenytoin and valproic acid, and he was discharged in stable condition on the following drug regimen: ceftriaxone 2 g IV twice daily, metronidazole 500 mg IV 3 times daily for 6 weeks, levetiracetam 1,500 mg twice daily, and valproic acid 750 mg 3 times daily.

At a 3-month follow-up visit, he reported no seizure-like activity but demonstrated persistent neurologic deficits (dysdiadochokinesia and mild ataxia).

A LESS COMMON CAUSE OF BRAIN ABSCESS

In the United States, 1,500 to 2,000 cases of brain abscess are diagnosed every year, and this condition is responsible for an estimated 1 in 10,000 hospitalizations. Most patients hospitalized are men over age 60 or children. Most patients with hematogenous or embolic spread of infection from a primary infection source are immunocompromised.

However, the lesions in our patient were not from compromised immunity, but rather from septic hematogenous spread of an odontogenic infection. Odontogenic bacteria are a common cause of pyogenic orofascial infection, including periapical abscess and infection of adjoining fascial spaces of the head and neck.¹

P micros and S constellatus have been commonly found in many types of odontogenic infection, including dentoalveolar infection, periodontitis, and pericoronitis.² Our patient was found to have several periodontal abscesses with bacteremia and spread to the brain. Although transthoracic echocardiography was negative for vegetations or patent foramen ovale, the quality and location of the brain abscesses suggested embolic spread of infection. Most of the suspected septic emboli were in the right hemisphere, consistent with patterns seen with cardioembolic phenomena, and a number of lesions appeared to be within the distribution of the right anterior cerebral artery and the middle cerebral artery.

EMPIRIC AND SPECIFIC THERAPIES

Empiric antibiotic therapy for local odontogenic infection includes amoxicillin with clavulanic acid and metronidazole.¹ Our patient’s treatment with ceftriaxone and metronidazole was based on the species and sensitivities of the bacteria in blood cultures.

Surgical irrigation with debridement is considered first-line therapy for local dental infection, with antimicrobials as adjunctive therapy. Initiation of antibiotic therapy before surgery has been associated with a shortened duration of infection and a reduced risk of bacteremia.³

First-line therapy for cerebral abscess is typically antibiotics, specifically ceftriaxone and metronidazole as in our patient. Ceftriaxone is selected for coverage against streptococci, enterobacteriacae, and most common anaerobes, whereas metronidazole is chosen for its efficacy against Bacteroides fragilis.

Computed tomography-guided stereotactic aspiration and open drainage are viable options for solitary and surgically accessible abscesses—typically those greater than 2 cm. Our patient had multiple small septic emboli in the right hemisphere, with the largest lesion measuring 1.5 cm, thus limiting the effectiveness of surgical intervention.

Some patients with mass effect or other evidence of increased intracranial pressure may benefit from high doses of a corticosteroid such as dexamethasone. However, since our patient had no clinical or diagnostic findings suggesting elevated intracranial pressure, we opted for nonsurgical management of the brain abscesses, with 6 weeks of intravenous antibiotics, an antiseizure regimen, and plans for repeat imaging in the outpatient setting.

References

Bahl R, Sandhu S, Singh K, Sahai N, Gupta M. Odontogenic infections: microbiology and management. Contemp Clin Dent 2014; 5(3):307–311. doi:10.4103/0976-237X.137921
Kuriyama T, Karasawa T, Nakagawa K, Yamamoto E, Nakamura S. Bacteriology and antimicrobial susceptibility of gram-positive cocci isolated from pus specimens of orofacial odontogenic infections. Oral Microbiol Immunol 2002; 17(2):132–135. pmid:11929563
Peedikayil FC. Antibiotics in odontogenic infections—an update. J Antimicro 2016; 2:(2)117. doi:10.4172/2472-1212.1000117

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Stella Pak, MD
Department of Medicine, Kettering Medical Center, Kettering, OH

Shawn Marein, DO
Department of Medicine, Kettering Medical Center, Kettering, OH

Victor Valencia
Northwestern University Feinberg School of Medicine, Chicago, IL

Damian Valencia, MD
Department of Medicine, Kettering Medical Center, Kettering, OH

Jessica Uhler, BS
Department of Medicine, Wright State University Boonshoft School of Medicine, Dayton, OH

Adam Fershko, MD, FACP
Department of Medicine, Kettering Medical Center, Kettering, OH

Address: Stella Pak, MD, Department of Medicine, Kettering Medical Center, 3535 Southern Boulevard, Kettering, OH 45429; stella.pak@ketteringhealth.org

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brain, abscess, magnetic resonance imaging, MRI, ring-enhancing lesions, bad teeth, periodontal abscesses, odontogenic infection, hematogenous spread, septic embolization, Stella Pak, Shawn Marein, Victor Valencia, Damian Valencia, Jessica Uhler, Adam Fershko

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Department of Medicine, Kettering Medical Center, Kettering, OH

Victor Valencia
Northwestern University Feinberg School of Medicine, Chicago, IL

Damian Valencia, MD
Department of Medicine, Kettering Medical Center, Kettering, OH

Jessica Uhler, BS
Department of Medicine, Wright State University Boonshoft School of Medicine, Dayton, OH

Adam Fershko, MD, FACP
Department of Medicine, Kettering Medical Center, Kettering, OH

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Northwestern University Feinberg School of Medicine, Chicago, IL

Damian Valencia, MD
Department of Medicine, Kettering Medical Center, Kettering, OH

Jessica Uhler, BS
Department of Medicine, Wright State University Boonshoft School of Medicine, Dayton, OH

Adam Fershko, MD, FACP
Department of Medicine, Kettering Medical Center, Kettering, OH

Address: Stella Pak, MD, Department of Medicine, Kettering Medical Center, 3535 Southern Boulevard, Kettering, OH 45429; stella.pak@ketteringhealth.org

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The patient underwent magnetic resonance imaging, which showed more than 20 ring-enhancing lesions in the right brain hemisphere, the largest lesion measuring 1.2 cm × 1.5 cm (Figure 1).

For the dental infection, the patient underwent surgical irrigation and debridement with full dental extraction for multiple dental abscesses.

At a 3-month follow-up visit, he reported no seizure-like activity but demonstrated persistent neurologic deficits (dysdiadochokinesia and mild ataxia).

A LESS COMMON CAUSE OF BRAIN ABSCESS

EMPIRIC AND SPECIFIC THERAPIES

The patient underwent magnetic resonance imaging, which showed more than 20 ring-enhancing lesions in the right brain hemisphere, the largest lesion measuring 1.2 cm × 1.5 cm (Figure 1).

For the dental infection, the patient underwent surgical irrigation and debridement with full dental extraction for multiple dental abscesses.

At a 3-month follow-up visit, he reported no seizure-like activity but demonstrated persistent neurologic deficits (dysdiadochokinesia and mild ataxia).

A LESS COMMON CAUSE OF BRAIN ABSCESS

EMPIRIC AND SPECIFIC THERAPIES

References

Bahl R, Sandhu S, Singh K, Sahai N, Gupta M. Odontogenic infections: microbiology and management. Contemp Clin Dent 2014; 5(3):307–311. doi:10.4103/0976-237X.137921
Kuriyama T, Karasawa T, Nakagawa K, Yamamoto E, Nakamura S. Bacteriology and antimicrobial susceptibility of gram-positive cocci isolated from pus specimens of orofacial odontogenic infections. Oral Microbiol Immunol 2002; 17(2):132–135. pmid:11929563
Peedikayil FC. Antibiotics in odontogenic infections—an update. J Antimicro 2016; 2:(2)117. doi:10.4172/2472-1212.1000117

References

Bahl R, Sandhu S, Singh K, Sahai N, Gupta M. Odontogenic infections: microbiology and management. Contemp Clin Dent 2014; 5(3):307–311. doi:10.4103/0976-237X.137921
Kuriyama T, Karasawa T, Nakagawa K, Yamamoto E, Nakamura S. Bacteriology and antimicrobial susceptibility of gram-positive cocci isolated from pus specimens of orofacial odontogenic infections. Oral Microbiol Immunol 2002; 17(2):132–135. pmid:11929563
Peedikayil FC. Antibiotics in odontogenic infections—an update. J Antimicro 2016; 2:(2)117. doi:10.4172/2472-1212.1000117

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We can learn a lot from drug adverse effects

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We can learn a lot from drug adverse effects

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Brian F. Mandell, MD, PhD

No one likes adverse effects from medications. Some seem to occur as random events; others are predictable based on known pharmacologic properties of a drug or its metabolites, or are monitored for after published reports of anecdotes. Adverse effects can also teach us important things about human biology.

Some drugs exhibit a dose-toxicity relationship that is sufficiently predictable to permit drug-level monitoring to limit renal or other toxicity. Others cause ocular or marrow toxicity that can be limited by weight-based dosing and careful monitoring. With azathioprine, some toxicity can be predicted by assessing the activity of the enzyme thiopurine methyltransferase, which metabolizes the drug. Other approaches to using pharmacogenomics have included HLA-B locus haplotyping to detect increased risk of immune-mediated toxicities of drugs such as carbamazepine and allopurinol. Both of these drugs exhibit serious systemic toxicities that are incompletely understood, but these are nascent and significant steps toward providing personalized (precision) medical care.

Adverse effects of some drugs may result from their intracellular effects, which are only partially predictable by drug levels or dosing. Colchicine, hydroxychloroquine, and amiodarone all affect intracellular vacuolar transport and lysosomal processing. Yet, although the footprints of drug effect can be seen in many histopathology samples, only some patients—but maybe more than currently recognized—suffer cardiac and skeletal muscle vacuolar myopathy, axonal neuropathies, or pulmonary or retinal cell toxicity from these drugs. But distinguishing the histopathologic footprints of drug exposure and the biologic effect from true drug toxicity with organ damage is not always straightforward.

Rare adverse effects may only become apparent with frequent use of a drug in the general community. These often remain mechanistically unexplained: Why can minoxidil cause pericardial effusions or a nonsteroidal anti-inflammatory drug cause aseptic meningitis? Some effects may be due to altering of the unique balance of biochemical pathways in a given patient, leading to unexpected drug metabolism with generation of toxic metabolites.

More interesting to me are effects that are seemingly off-target biologic outcomes caused by disrupting normal physiologic homeostasis and stimulating counterregulatory pathways in such a way that unexpected biologic effects occur. Angioedema and cough in some patients who have taken angiotensin-converting enzyme inhibitors are examples, but why the disturbed control mechanisms lead to these effects in only occasional patients is still incompletely elucidated.

Two additional classes of drugs with unique systemic adverse effects are discussed in this issue of the Journal. The “flulike” syndrome after bisphosphonate treatment, presumably resulting from selective cytokine release by macrophages that have ingested certain bisphosphonates, is a not uncommon and significant annoyance to many patients, and in my experience it is a reason patients discontinue the treatment. Lim and Bolster describe the reaction and their approach to its management, and comment on the fairly obscure pathway that may explain its occurrence. Again, it is not clear to me why only relatively few patients experience the reaction. Is there a genetic predisposition? Or is it influenced by the patient’s baseline “inflammatory tone,” as influenced by the state of his or her microbiome or other still uncharacterized factors? And why does this reaction often diminish with repeated dosing of the drug?

Most striking is the description and discussion by Khan et al of the management of autoimmune colitis after administration of immune checkpoint inhibitor anticancer therapies. These drugs represent important advances in the therapy of various cancers. They are novel in that they are not specific to tumor type, although certain drugs within this new class of immunotherapy seem to exhibit more dramatic and enduring responses against one type of cancer than against another. These therapies are not directly tumor-reactive, but act by down-regulating the normal “brakes” or checkpoints of the immune system that normally play a role in reigning in the immune-inflammatory system response to infection once the offending infective agent is neutralized. These checkpoints have also been thought to limit the development of autoimmunity. Many cancers seem to capitalize on the activation of these brakes to evade tumor immunity. That these checkpoint therapies are so effective in some patients with heretofore unresponsive cancers is obviously a major advance. But equally striking is the scientific proof of the immunologic concept that by inhibiting these normal brakes on inflammation there is loss of normal regulation of the immune response and autoimmunity ensues unchecked. Khan et al discuss the colitis that can occur with these therapies, but a host of fascinating and potentially life-threatening organ-specific complications can be invoked by the checkpoint inhibitors, including hypophysitis, myositis, nephritis, and pneumonitis. What determines which patient will suffer these immune complications, which organs will be affected in a given patient, and the relationships between preexisting autoimmune disease, antitumor response, and these autoimmune complications are still being unraveled.

If you have not yet encountered patients with these complications in your practice, it is quite likely you will. The topic is worth reading about now (see the review by June et al¹), and we will provide additional reviews in the future.

References

June CH, Warshauer JT, Bluestone JA. Is autoimmunity the Achilles’ heel of cancer immunotherapy? Nat Med 2017; 23(5):540–547. doi:10.1038/nm.4321. Correction in Nat Med 2017; 23(8):1004. doi:10.1038/nm0817-1004b

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References

June CH, Warshauer JT, Bluestone JA. Is autoimmunity the Achilles’ heel of cancer immunotherapy? Nat Med 2017; 23(5):540–547. doi:10.1038/nm.4321. Correction in Nat Med 2017; 23(8):1004. doi:10.1038/nm0817-1004b

References

June CH, Warshauer JT, Bluestone JA. Is autoimmunity the Achilles’ heel of cancer immunotherapy? Nat Med 2017; 23(5):540–547. doi:10.1038/nm.4321. Correction in Nat Med 2017; 23(8):1004. doi:10.1038/nm0817-1004b

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Shortness of breath, fever, cough, and more in an elderly woman

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Brody D. Slostad, MD

Megha Prasad, MD

Nandan S. Anavekar, MD

An 87-year-old woman was brought to the intensive care unit with worsening shortness of breath on exertion, fatigue, orthopnea, paroxysmal nocturnal dyspnea, lower extremity swelling, subjective fever, productive cough, and rhinorrhea over the last week. She reported no chest pain, lightheadedness, or palpitations. Her medical history included the following:

Coronary artery disease requiring coronary artery bypass grafting
Ischemic cardiomyopathy
Severe mitral regurgitation
Moderate tricuspid regurgitation
Pulmonary hypertension
Cardiac arrest with recurrent ventricular tachycardia requiring an implanted cardioverter-defibrillator and amiodarone therapy
Hypothyroidism requiring levothyroxine
Asthma with a moderate obstructive pattern: forced expiratory volume in 1 second (FEV₁) 60% of predicted, forced vital capacity (FVC) 2.06 L, FEV₁/FVC 54%, diffusing capacity for carbon monoxide (DLCO) 72% of predicted with positive bronchodilator response
Long-standing essential thrombocythemia treated with hydroxyurea.

Before admission, she had been reliably taking guideline-directed heart failure therapy as well as amiodarone for her recurrent ventricular tachycardia. Her levothyroxine had recently been increased as well.

Physical examination. On admission, her blood pressure was 95/53 mm Hg, heart rate 73 beats per minute, temperature 36.7ºC (98.1ºF), and oxygen saturation 81% requiring supplemental oxygen 15 L/min by nonrebreather face mask. Physical examination revealed elevated jugular venous pressure, bibasilar crackles, lower extremity edema, and a grade 3 of 6 holosystolic murmur both at the left sternal border and at the apex radiating to the axilla. There was no evidence of wheezing or pulsus paradoxus.

Initial laboratory evaluation revealed abnormal values (Table 1).

Electrocardiography showed sinus rhythm and an old left bundle branch block.

Chest radiography showed cardiomegaly, bilateral pleural effusions, and pulmonary edema.

WHAT IS THE CAUSE OF HER SYMPTOMS?

1. Based on the available information, which of the following is the most likely cause of this patient’s clinical presentation?

Acute decompensated heart failure
Pulmonary embolism
Exacerbation of asthma
Exacerbation of chronic obstructive pulmonary disease (COPD)

Heart failure is a clinical diagnosis based on careful history-taking and physical examination. Major criteria include paroxysmal nocturnal dyspnea, orthopnea, elevated jugular venous pressure, pulmonary crackles, a third heart sound, cardiomegaly, pulmonary edema, and weight loss of more than 4.5 kg with diuretic therapy.¹ N-terminal pro-B-type natriuretic peptide (NT-proBNP) is also an effective marker of acute decompensated heart failure in the proper clinical setting.²

Our patient’s elevated jugular venous pressure, bibasilar crackles, lower extremity edema, chest radiography findings consistent with pulmonary edema, markedly elevated NT-proBNP, history of orthopnea, paroxysmal nocturnal dyspnea, and dyspnea on exertion were most consistent with acute decompensated heart failure. Her cough and subjective fevers were thought to be due to an upper respiratory tract viral infection.

Pulmonary embolism causes pleuritic chest pain, dyspnea, and, occasionally, elevated troponin. The most common feature on electrocardiography is sinus tachycardia; nonspecific ST-segment and T-wave changes may also be seen.³

Although pulmonary embolism remained in the differential diagnosis, our patient’s lack of typical features of pulmonary embolism made this less likely.

Asthma is characterized by recurrent airflow obstruction and bronchial hyperresponsiveness.⁴ Asthma exacerbations present with wheezing, tachypnea, tachycardia, and pulsus paradoxus.⁵

Despite her previous asthma diagnosis, our patient’s lack of typical features of asthma exacerbation made this diagnosis unlikely.

COPD exacerbations present with increased dyspnea, cough, sputum production, wheezing, lung resonance to percussion, and distant heart sounds, and are characterized by airflow obstruction.^6,7

Although our patient presented with cough and dyspnea, she had no history of COPD and her other signs and symptoms (elevated jugular venous pressure, elevated NT-proBNP, and peripheral edema) could not be explained by COPD exacerbation.

OUR PATIENT UNDERWENT FURTHER TESTING

Echocardiography revealed severe left ventricular enlargement, an ejection fraction of 20% (which was near her baseline value), diffuse regional wall-motion abnormalities, severe mitral regurgitation, and moderate tricuspid regurgitation consistent with an exacerbation of heart failure.

We considered the possibility that her heart failure symptoms might be due to precipitous up-titration of her levothyroxine dose, given her borderline-elevated free thyroxine (T₄) and increase in cardiac index (currently 4.45 L/min/m², previously 2.20 L/min/m² by the left ventricular outflow tract velocity time integral method). However, given her reduced ejection fraction, this clinical presentation most likely represented an acute exacerbation of her chronic heart failure. Her subjective fevers were thought to be due to a viral infection of the upper respiratory tract. The macrocytic anemia and thrombocytopenia were thought to be a side effect of her long-standing treatment with hydroxyurea for essential thrombocythemia, although amiodarone has also been associated with cytopenia.⁸

Treatment was started with intravenous diuretics and positive pressure ventilation with oxygen supplementation. Her levothyroxine dose was reduced, and her hydroxyurea was stopped.

Figure 1. Chest computed tomography axial views demonstrated increased attenuation in the liver (A, arrow) and left pleural base (B, arrow). Evaluation of the right lung base revealed ground-glass opacities (C, arrow) and honeycombing (D, arrow). These findings were consistent with amiodarone pulmonary toxicity.

After aggressive diuresis, our patient returned to euvolemia. However, she had persistent fine crackles and hypoxia. She had no further fever, and her vital signs were otherwise stable. Her cytopenia improved with cessation of hydroxyurea. Chest computed tomography (CT) showed bibasilar ground-glass infiltrates with areas of interstitial fibrosis, high-attenuation pleural lesions, and increased liver attenuation (Figure 1).

Further testing for connective tissue disease and hypersensitivity pneumonitis was also done, and the results were negative. To exclude an atypical infection, bronchoalveolar lavage was performed; preliminary microbial testing was negative, and the white blood cell count in the lavage fluid was 90% macrophages (pigment-laden), 7% neutrophils, and 3% lymphocytes.

WHAT IS THE CAUSE OF HER PERSISTENT PULMONARY FINDINGS?

2. Given the CT findings and laboratory results, what is the most likely cause of our patient’s persistent crackles and hypoxia?

Heart failure with reduced ejection fraction
Bacterial pneumonia
Idiopathic pulmonary fibrosis
Amiodarone pulmonary toxicity

Heart failure with reduced ejection fraction can cause ground-glass opacities on CT due to increased pulmonary edema. Although our patient initially presented with acute decompensation of heart failure with reduced ejection fraction decompensation, she had returned to euvolemia after aggressive diuresis. Moreover, increased pleural and liver attenuation are not typically seen as a result of heart failure with reduced ejection fraction, making this diagnosis less likely.

Bacterial pneumonia typically presents with cough, fever, and purulent sputum production.⁹ Further evaluation usually reveals decreased breath sounds, dullness to percussion, and leukocytosis.¹⁰ Chest CT in bacterial pneumonia commonly shows a focal area of consolidation, which was not seen in our patient.¹¹

Idiopathic pulmonary fibrosis usually presents with slowly progressive dyspnea and nonproductive cough.¹² Physical examination usually reveals fine crackles and occasionally end-inspiratory “squeaks” if traction bronchiectasis is present.¹² The diagnosis of idiopathic pulmonary fibrosis requires chest CT findings compatible with it (ie, basal fibrosis, reticular abnormalities, and honeycombing). However, it remains a diagnosis of exclusion and requires ruling out conditions known to cause pulmonary fibrosis such as hypersensitivity pneumonitis, connective tissue disease, and certain medications.¹²

Although idiopathic pulmonary fibrosis remained in the differential diagnosis, our patient remained on amiodarone, a known cause of pulmonary fibrosis.¹³ Similarly, the high-attenuation pleural lesions likely represented organizing pneumonia, which is more common in amiodarone pulmonary toxicity. And the ground-glass opacities made idiopathic pulmonary fibrosis unlikely, although they may be seen in an acute exacerbation of this disease.¹⁴ Thus, a diagnosis of idiopathic pulmonary fibrosis could not be made definitively.

Amiodarone pulmonary toxicity most commonly presents with acute to subacute cough and progressive dyspnea.¹³ Physical findings are similar to those in idiopathic pulmonary fibrosis and commonly include bibasilar crackles. Chest CT shows diffuse ground-glass opacities, reticular abnormalities, fibrosis, and increased attenuation of multiple organs, including the lungs, liver, and spleen.¹⁴ Bronchoalveolar lavage findings of lipid-laden macrophages suggest but do not definitively diagnose amiodarone pulmonary toxicity.¹⁵ And patients with acute amiodarone pulmonary toxicity may present with pigment-laden macrophages on bronchoalveolar lavage, as in our patient.¹⁶

Exclusion of hypersensitivity pneumonitis, connective tissue disease, and infection made our patient’s progressive dyspnea and chest CT findings of ground-glass opacities, fibrosis, and increased pulmonary and liver attenuation most consistent with amiodarone pulmonary toxicity.

Amiodarone was therefore discontinued. However, the test result of her lavage fluid for influenza A by polymerase chain reaction came back positive a few hours later.

WHAT IS THE NEXT STEP?

3. Given the positive influenza A polymerase chain reaction test, which of the following is the best next step in this patient’s management?

Surgical lung biopsy
Stop amiodarone and start supportive influenza management
Stop amiodarone and start dronedarone
Start an intravenous corticosteroid

Surgical lung biopsy is typically not required for diagnosis in patients with suspected amiodarone pulmonary toxicity. In addition, acute respiratory distress syndrome has been documented in patients who have undergone surgical biopsy for suspected amiodarone pulmonary toxicity.¹⁷

Thus, surgical biopsy is typically only done in cases of persistent symptoms despite withdrawal of amiodarone and initiation of steroid therapy.

Stopping amiodarone and starting supportive influenza management are the best next steps, as our patient’s fevers, cough, dyspnea, and laboratory test results were consistent with influenza.¹⁸ Moreover, CT findings of ground-glass opacities and reticular abnormalities can be seen in influenza.¹⁹

However, concomitant amiodarone pulmonary toxicity could not be ruled out, as CT showed increased lung and liver attenuation and fibrosis that could not be explained by influenza. And the elevation in aminotransferase levels more than 2 times the upper limit of normal and CT findings of increased liver attenuation suggested amiodarone hepatotoxicity. However, definitive diagnosis would require exclusion of other causes such as congestive hepatopathy, in some cases with liver biopsy.¹³

Our patient’s persistent hypoxia was thought to be due in part to influenza, and thus the best next step in management was to stop amiodarone and provide supportive care for influenza.

Dronedarone is an antiarrhythmic drug structurally and functionally similar to amiodarone. There are far fewer reports of pulmonary toxicity with dronedarone than with amiodarone.²⁰ However, lack of data on dronedarone in amiodarone pulmonary toxicity, increased rates of hospitalization and death associated with dronedarone in patients like ours with advanced heart failure, and our patient’s previously implanted cardioverter-defibrillator for recurrent ventricular tachycardia all made dronedarone an undesirable alternative to amiodarone.²¹

Corticosteroids are useful in the treatment of amiodarone pulmonary toxicity when hypoxia and dyspnea are present at diagnosis.¹³ Our patient’s hypoxia and dyspnea were thought to be due in part to her acute influenza infection, and therefore corticosteroids were not used at the outset.

However, concomitant amiodarone pulmonary toxicity could not be excluded, and the elevation in aminotransferases of more than 2 times the upper limit of normal and CT findings of increased liver attenuation suggested amiodarone hepatotoxicity—though congestive hepatopathy remained in the differential diagnosis. Therefore, supportive therapy for influenza was instituted, and amiodarone was withheld. Her condition subsequently improved, and she was discharged.

FOLLOW-UP 1 MONTH LATER

At a follow-up visit 1 month later, our patient continued to have dyspnea and hypoxia. She did not have signs or symptoms consistent with decompensated heart failure.

Pulmonary function testing revealed the following values:

FEV₁ 0.69 L (56% of predicted)
FVC 1.08 L (64% of predicted)
Figure 2. In A, repeat chest computed tomography demonstrated increased liver attenuation (arrow); in B, it showed persistent ground-glass opacities (white arrow), increased pulmonary attenuation (black arrowhead), and worsening pleural effusions (black arrows). These findings supported the diagnosis of amiodarone pulmonary toxicity.

FEV₁/FVC ratio 64%
DLCO 2.20 mL/min/mm Hg (12% of predicted).

Aminotransferase levels had also normalized. Repeat chest CT showed persistent bibasilar interstitial fibrotic changes, enlarging bilateral pleural effusions, and persistent peripheral ground-glass opacities (Figure 2).

WHAT FURTHER TREATMENT IS APPROPRIATE?

4. Given the chest CT findings, which of the following is the most appropriate treatment strategy for this patient?

No further management, continue to hold amiodarone
Corticosteroids
Repeat bronchoalveolar lavage
Intravenous antibiotics

No further management of amiodarone pulmonary toxicity would be appropriate if our patient did not have a high burden of symptoms. However, when patients with amiodarone pulmonary toxicity present with hypoxia and dyspnea, corticosteroids should be started.¹³ Our patient remained symptomatic after discontinuation of amiodarone and resolution of her influenza infection, and CT showed persistent signs of amiodarone pulmonary toxicity, which required further management.

Corticosteroids are useful in treating amiodarone pulmonary toxicity when hypoxia and dyspnea are present at diagnosis. Our patient’s persistent ground-glass opacities, fibrotic changes, and increased attenuation in multiple organs on CT, coupled with a confirmed reduction in FVC of greater than 15% and reduction in DLCO of greater than 20% after recovery from influenza, were most consistent with persistent amiodarone pulmonary toxicity.¹³

Although our patient’s amiodarone had been discontinued, the long half-life of the drug (45 days) allowed pulmonary toxicity to progress even after the drug was discontinued.²² Because our patient continued to have hypoxia and dyspnea on exertion, the most appropriate next step in management (in addition to managing her pleural effusions) was to start corticosteroids.

For amiodarone pulmonary toxicity, prednisone is typically started at 40 to 60 mg daily and can result in rapid improvement in symptoms.¹³ Tapering should be slow and may take several months.

Bronchoalveolar lavage is typically used in suspected cases of amiodarone pulmonary toxicity only to rule out an alternative diagnosis such as infection. Lipid-laden macrophages may be seen in the fluid. However, lipid-laden macrophages are not diagnostic of amiodarone pulmonary toxicity, as this finding may also be seen in patients taking amiodarone who do not develop pulmonary toxicity.¹⁵ Other findings on bronchoalveolar lavage in amiodarone pulmonary toxicity are nonspecific and are not diagnostically useful.¹³

Intravenous antibiotics are appropriate if bacterial pneumonia is suspected. However, bacterial pneumonia typically presents with cough, fever, purulent sputum production, and focal consolidation on chest imaging.⁹ Our patient’s CT findings of persistent peripheral ground-glass opacities and lack of cough, fever, or purulent sputum production were not consistent with bacterial pneumonia, and therefore intravenous antibiotics were not indicated.

CASE CONCLUSION

Given our patient’s persistent dyspnea, hypoxia, and chest CT findings consistent with amiodarone pulmonary toxicity, it was recommended that she start corticosteroids. However, before starting therapy, she suffered a femoral fracture that required surgical intervention. Around the time of the procedure, she had an ST-segment elevation myocardial infarction requiring vasopressor support and mechanical ventilation. At that time, the patient and family decided to pursue comfort measures, and she died peacefully.

MORE ABOUT AMIODARONE PULMONARY TOXICITY

Pulmonary toxicity is a well-described consequence of amiodarone therapy.²³ Amiodarone carries a 2% risk of pulmonary toxicity.²⁴ Although higher doses are more likely to cause pulmonary toxicity, lower doses also have been implicated.^22,24 Preexisting pulmonary disease may predispose patients taking amiodarone to pulmonary toxicity; however, this is not uniformly seen.²⁵

Mortality rates as high as 10% from amiodarone pulmonary toxicity have been reported. Thus, diligent surveillance for pulmonary toxicity with pulmonary function tests in patients taking amiodarone is mandatory. In particular, a reduction in FVC of greater than 15% or in DLCO of greater than 20% from baseline may be seen in amiodarone pulmonary toxicity.²⁶

Amiodarone pulmonary toxicity can present at any time after the start of therapy, but it occurs most often after 6 to 12 months.¹³ Patients typically experience insidious dyspnea; however, presentation with acute to subacute cough and progressive dyspnea can occur, especially with high concentrations of supplemental oxygen with or without mechanical ventilation.^12,27 Findings on physical examination include bibasilar crackles. CT chest findings include diffuse ground-glass opacities, reticular abnormalities, fibrosis, and increased attenuation in multiple organs, including the lung, liver, and spleen.¹⁴

The diagnosis of amiodarone pulmonary toxicity requires ruling out hypersensitivity pneumonitis, connective tissue disease, heart failure, and infection. Surgical biopsy and bronchoalveolar lavage are not commonly used to establish the diagnosis of amiodarone pulmonary toxicity, as surgical biopsy increases the risk of acute respiratory distress syndrome, and the results of bronchoalveolar lavage are usually nonspecific.^13,15

Initial treatment involves discontinuing the amiodarone once the diagnosis is suspected. If patients have worsening hypoxia or dyspnea at the time of diagnosis, corticosteroids can be used. Prednisone is typically started at 40 to 60 mg daily and can result in rapid improvement in symptoms.¹³ Tapering of corticosteroids should occur slowly and may take several months.

References

McKee PA, Castelli WP, McNamara PM, Kannel WB. The natural history of congestive heart failure: the Framingham study. N Engl J Med 1971; 285(26):1441–1446. doi:10.1056/NEJM197112232852601
Stein PD, Terrin ML, Hales CA, et al. Clinical, laboratory, roentgenographic, and electrocardiographic findings in patients with acute pulmonary embolism and no pre-existing cardiac or pulmonary disease. Chest 1991; 100(3):598–603. pmid:1909617
Baggish AL, Siebert U, Lainchbury JG, et al. A validated clinical and biochemical score for the diagnosis of acute heart failure: the ProBNP investigation of dyspnea in the emergency department (PRIDE) acute heart failure score. Am Heart J 2006; 151(1):48–54. doi:10.1016/j.ahj.2005.02.031
National Heart, Lung, and Blood Institute. National Asthma Education and Prevention Program. Expert panel report 3: Guidelines for the diagnosis and management of asthma. www.nhlbi.nih.gov/sites/default/files/media/docs/asthgdln_1.pdf. Accessed August 3, 2018.
Brenner BE, Abraham E, Simon RR. Position and diaphoresis in acute asthma. Am J Med 1983; 74(6):1005–1009. pmid:6407304
Badgett RG, Tanaka DJ, Hunt DK, et al. Can moderate chronic obstructive pulmonary disease be diagnosed by historical and physical findings alone? Am J Med 1993; 94(2):188–196. pmid:8430714
Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. https://goldcopd.org/wp-content/uploads/2017/11/GOLD-2018-v6.0-FINAL-revised-20-Nov_WMS.pdf. Accessed August 17, 2018.
Erie AJ, McClure RF, Wolanskyj AP. Amiodarone-induced bone marrow granulomas: an unusual cause of reversible pancytopenia. Hematol Rep 2010; 2(1):e6. doi:10.4081/hr.2010.e6
Marrie TJ. Community-acquired pneumonia. Clin Infect Dis 1994; 18(4):501–513. pmid:8038304
Metlay JP, Kapoor WN, Fine MJ. Does this patient have community-acquired pneumonia? Diagnosing pneumonia by history and physical examination. JAMA 1997; 278(17):1440–1445. pmid:9356004
Walker CM, Abbott GF, Greene RE, Shepard JA, Vummidi D, Digumarthy SR. Imaging pulmonary infection: classic signs and patterns. AJR Am J Roentgenol 2014; 202(3):479–492. doi:10.2214/AJR.13.11463
Raghu G, Collard HR, Egan JJ, et al; ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary Fibrosis. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med 2011; 183(6):788–824. doi:10.1164/rccm.2009-040GL
Goldschlager N, Epstein AE, Naccarelli GV, et al; Practice Guidelines Sub-committee, North American Society of Pacing and Electrophysiology (HRS). A practical guide for clinicians who treat patients with amiodarone: 2007. Heart Rhythm 2007; 4(9):1250–1259. doi:10.1016/j.hrthm.2007.07.020
Kuhlman JE, Teigen C, Ren H, Hruban RH, Hutchins GM, Fishman EK. Amiodarone pulmonary toxicity: CT findings in symptomatic patients. Radiology 1990; 177(1):121–125. doi:10.1148/radiology.177.1.2399310
Martin WJ 2nd, Rosenow EC 3rd. Amiodarone pulmonary toxicity: recognition and pathogenesis (Part I). Chest 1988; 93(5):1067–1075. pmid:3282816
Iskandar SB, Abi-Saleh B, Keith RL, Byrd RP Jr, Roy TM. Amiodarone-induced alveolar hemorrhage. South Med J 2006; 99(4):383–387.
Van Mieghem W, Coolen L, Malysse I, Lacquet LM, Deneffe GJ, Demedts MG. Amiodarone and the development of ARDS after lung surgery. Chest 1994; 105(6):1642–1645. pmid:8205854
Nicholson KG. Clinical features of influenza. Semin Respir Infect 1992; 7(1):26–37. pmid:1609165
Muller NL, Franquet T, Lee KS, Silva CIS. Viruses, mycoplasma, and chlamydia. In: Imaging of Pulmonary Infections. Philadelphia, PA: Lippincott Williams & Wilkins; 2007:94–114.
Stack S, Nguyen DV, Casto A, Ahuja N. Diffuse alveolar damage in a patient receiving dronedarone. Chest 2015; 147(4):e131–e133. doi:10.1378/chest.14-1849
De Ferrari GM, Dusi V. Drug safety evaluation of dronedarone in atrial fibrillation. Expert Opin Drug Saf 2012; 11(6):1023–1045. doi:10.1517/14740338.2012.722994
Okayasu K, Takeda Y, Kojima J, et al. Amiodarone pulmonary toxicity: a patient with three recurrences of pulmonary toxicity and consideration of the probable risk for relapse. Intern Med 2006; 45(22):1303–1307. pmid:17170505
Vorperian VR, Havighurst TC, Miller S, January CT. Adverse effects of low dose amiodarone: a meta-analysis. J Am Coll Cardiol 1997; 30(3):791–798. pmid:9283542
Amiodarone Trials Meta-Analysis Investigators. Effect of prophylactic amiodarone on mortality after acute myocardial infarction and in congestive heart failure: meta-analysis of individual data from 6500 patients in randomised trials. Lancet 1997; 350(9089):1417–1424. pmid:9371164
Olshansky B, Sami M, Rubin A, et al; NHLBI AFFIRM Investigators. Use of amiodarone for atrial fibrillation in patients with preexisting pulmonary disease in the AFFIRM study. Am J Cardiol 2005; 95(3):404–405. doi:10.1016/j.amjcard.2004.09.044
Camus P. Interstitial lung disease from drugs, biologics, and radiation. In: Schwartz MI, King TE Jr, eds. Interstitial Lung Disease. 5th ed. Shelton, CT: People’s Medical Publishing House; 2011:637–644.
Wolkove N, Baltzan M. Amiodarone pulmonary toxicity. Can Respir J 2009; 16(2):43–48. doi:10.1155/2009/282540

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Brody D. Slostad, MD
Department of Internal Medicine, Mayo Clinic, Rochester, MN

Megha Prasad, MD
Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN

Nandan S. Anavekar, MD
Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN

Address: Brody D. Slostad, MD, Department of Internal Medicine, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905; slostad.brody@mayo.edu

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Cleveland Clinic Journal of Medicine - 85(9)

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amiodarone, pulmonary toxicity, lung toxicity, shortness of breath, heart failure, ventricular tachycardia, Brody Slostad, Megha Prasad, Nandan Anavekar

Read more about Shortness of breath, fever, cough, and more in an elderly woman

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Author(s)

Brody D. Slostad, MD

Megha Prasad, MD

Nandan S. Anavekar, MD

Author(s)

Brody D. Slostad, MD

Megha Prasad, MD

Nandan S. Anavekar, MD

Author and Disclosure Information

Brody D. Slostad, MD
Department of Internal Medicine, Mayo Clinic, Rochester, MN

Megha Prasad, MD
Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN

Nandan S. Anavekar, MD
Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN

Address: Brody D. Slostad, MD, Department of Internal Medicine, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905; slostad.brody@mayo.edu

Author and Disclosure Information

Brody D. Slostad, MD
Department of Internal Medicine, Mayo Clinic, Rochester, MN

Megha Prasad, MD
Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN

Nandan S. Anavekar, MD
Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN

Address: Brody D. Slostad, MD, Department of Internal Medicine, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905; slostad.brody@mayo.edu

Article PDF

slostad_shortnessofbreath.pdf

Article PDF

slostad_shortnessofbreath.pdf

Coronary artery disease requiring coronary artery bypass grafting
Ischemic cardiomyopathy
Severe mitral regurgitation
Moderate tricuspid regurgitation
Pulmonary hypertension
Cardiac arrest with recurrent ventricular tachycardia requiring an implanted cardioverter-defibrillator and amiodarone therapy
Hypothyroidism requiring levothyroxine
Asthma with a moderate obstructive pattern: forced expiratory volume in 1 second (FEV₁) 60% of predicted, forced vital capacity (FVC) 2.06 L, FEV₁/FVC 54%, diffusing capacity for carbon monoxide (DLCO) 72% of predicted with positive bronchodilator response
Long-standing essential thrombocythemia treated with hydroxyurea.

Initial laboratory evaluation revealed abnormal values (Table 1).

Electrocardiography showed sinus rhythm and an old left bundle branch block.

Chest radiography showed cardiomegaly, bilateral pleural effusions, and pulmonary edema.

WHAT IS THE CAUSE OF HER SYMPTOMS?

1. Based on the available information, which of the following is the most likely cause of this patient’s clinical presentation?

Acute decompensated heart failure
Pulmonary embolism
Exacerbation of asthma
Exacerbation of chronic obstructive pulmonary disease (COPD)

Although pulmonary embolism remained in the differential diagnosis, our patient’s lack of typical features of pulmonary embolism made this less likely.

Asthma is characterized by recurrent airflow obstruction and bronchial hyperresponsiveness.⁴ Asthma exacerbations present with wheezing, tachypnea, tachycardia, and pulsus paradoxus.⁵

Despite her previous asthma diagnosis, our patient’s lack of typical features of asthma exacerbation made this diagnosis unlikely.

COPD exacerbations present with increased dyspnea, cough, sputum production, wheezing, lung resonance to percussion, and distant heart sounds, and are characterized by airflow obstruction.^6,7

OUR PATIENT UNDERWENT FURTHER TESTING

Treatment was started with intravenous diuretics and positive pressure ventilation with oxygen supplementation. Her levothyroxine dose was reduced, and her hydroxyurea was stopped.

WHAT IS THE CAUSE OF HER PERSISTENT PULMONARY FINDINGS?

2. Given the CT findings and laboratory results, what is the most likely cause of our patient’s persistent crackles and hypoxia?

Heart failure with reduced ejection fraction
Bacterial pneumonia
Idiopathic pulmonary fibrosis
Amiodarone pulmonary toxicity

Amiodarone was therefore discontinued. However, the test result of her lavage fluid for influenza A by polymerase chain reaction came back positive a few hours later.

WHAT IS THE NEXT STEP?

3. Given the positive influenza A polymerase chain reaction test, which of the following is the best next step in this patient’s management?

Surgical lung biopsy
Stop amiodarone and start supportive influenza management
Stop amiodarone and start dronedarone
Start an intravenous corticosteroid

Thus, surgical biopsy is typically only done in cases of persistent symptoms despite withdrawal of amiodarone and initiation of steroid therapy.

Our patient’s persistent hypoxia was thought to be due in part to influenza, and thus the best next step in management was to stop amiodarone and provide supportive care for influenza.

FOLLOW-UP 1 MONTH LATER

At a follow-up visit 1 month later, our patient continued to have dyspnea and hypoxia. She did not have signs or symptoms consistent with decompensated heart failure.

Pulmonary function testing revealed the following values:

FEV₁ 0.69 L (56% of predicted)
FVC 1.08 L (64% of predicted)
Figure 2. In A, repeat chest computed tomography demonstrated increased liver attenuation (arrow); in B, it showed persistent ground-glass opacities (white arrow), increased pulmonary attenuation (black arrowhead), and worsening pleural effusions (black arrows). These findings supported the diagnosis of amiodarone pulmonary toxicity.

FEV₁/FVC ratio 64%
DLCO 2.20 mL/min/mm Hg (12% of predicted).

WHAT FURTHER TREATMENT IS APPROPRIATE?

4. Given the chest CT findings, which of the following is the most appropriate treatment strategy for this patient?

No further management, continue to hold amiodarone
Corticosteroids
Repeat bronchoalveolar lavage
Intravenous antibiotics

For amiodarone pulmonary toxicity, prednisone is typically started at 40 to 60 mg daily and can result in rapid improvement in symptoms.¹³ Tapering should be slow and may take several months.

CASE CONCLUSION

MORE ABOUT AMIODARONE PULMONARY TOXICITY

Coronary artery disease requiring coronary artery bypass grafting
Ischemic cardiomyopathy
Severe mitral regurgitation
Moderate tricuspid regurgitation
Pulmonary hypertension
Cardiac arrest with recurrent ventricular tachycardia requiring an implanted cardioverter-defibrillator and amiodarone therapy
Hypothyroidism requiring levothyroxine
Asthma with a moderate obstructive pattern: forced expiratory volume in 1 second (FEV₁) 60% of predicted, forced vital capacity (FVC) 2.06 L, FEV₁/FVC 54%, diffusing capacity for carbon monoxide (DLCO) 72% of predicted with positive bronchodilator response
Long-standing essential thrombocythemia treated with hydroxyurea.

Initial laboratory evaluation revealed abnormal values (Table 1).

Electrocardiography showed sinus rhythm and an old left bundle branch block.

Chest radiography showed cardiomegaly, bilateral pleural effusions, and pulmonary edema.

WHAT IS THE CAUSE OF HER SYMPTOMS?

1. Based on the available information, which of the following is the most likely cause of this patient’s clinical presentation?

Acute decompensated heart failure
Pulmonary embolism
Exacerbation of asthma
Exacerbation of chronic obstructive pulmonary disease (COPD)

Although pulmonary embolism remained in the differential diagnosis, our patient’s lack of typical features of pulmonary embolism made this less likely.

Asthma is characterized by recurrent airflow obstruction and bronchial hyperresponsiveness.⁴ Asthma exacerbations present with wheezing, tachypnea, tachycardia, and pulsus paradoxus.⁵

Despite her previous asthma diagnosis, our patient’s lack of typical features of asthma exacerbation made this diagnosis unlikely.

COPD exacerbations present with increased dyspnea, cough, sputum production, wheezing, lung resonance to percussion, and distant heart sounds, and are characterized by airflow obstruction.^6,7

OUR PATIENT UNDERWENT FURTHER TESTING

Treatment was started with intravenous diuretics and positive pressure ventilation with oxygen supplementation. Her levothyroxine dose was reduced, and her hydroxyurea was stopped.

WHAT IS THE CAUSE OF HER PERSISTENT PULMONARY FINDINGS?

2. Given the CT findings and laboratory results, what is the most likely cause of our patient’s persistent crackles and hypoxia?

Heart failure with reduced ejection fraction
Bacterial pneumonia
Idiopathic pulmonary fibrosis
Amiodarone pulmonary toxicity

Amiodarone was therefore discontinued. However, the test result of her lavage fluid for influenza A by polymerase chain reaction came back positive a few hours later.

WHAT IS THE NEXT STEP?

3. Given the positive influenza A polymerase chain reaction test, which of the following is the best next step in this patient’s management?

Surgical lung biopsy
Stop amiodarone and start supportive influenza management
Stop amiodarone and start dronedarone
Start an intravenous corticosteroid

Thus, surgical biopsy is typically only done in cases of persistent symptoms despite withdrawal of amiodarone and initiation of steroid therapy.

Our patient’s persistent hypoxia was thought to be due in part to influenza, and thus the best next step in management was to stop amiodarone and provide supportive care for influenza.

FOLLOW-UP 1 MONTH LATER

At a follow-up visit 1 month later, our patient continued to have dyspnea and hypoxia. She did not have signs or symptoms consistent with decompensated heart failure.

Pulmonary function testing revealed the following values:

FEV₁ 0.69 L (56% of predicted)
FVC 1.08 L (64% of predicted)
Figure 2. In A, repeat chest computed tomography demonstrated increased liver attenuation (arrow); in B, it showed persistent ground-glass opacities (white arrow), increased pulmonary attenuation (black arrowhead), and worsening pleural effusions (black arrows). These findings supported the diagnosis of amiodarone pulmonary toxicity.

FEV₁/FVC ratio 64%
DLCO 2.20 mL/min/mm Hg (12% of predicted).

WHAT FURTHER TREATMENT IS APPROPRIATE?

4. Given the chest CT findings, which of the following is the most appropriate treatment strategy for this patient?

No further management, continue to hold amiodarone
Corticosteroids
Repeat bronchoalveolar lavage
Intravenous antibiotics

For amiodarone pulmonary toxicity, prednisone is typically started at 40 to 60 mg daily and can result in rapid improvement in symptoms.¹³ Tapering should be slow and may take several months.

CASE CONCLUSION

MORE ABOUT AMIODARONE PULMONARY TOXICITY

References

McKee PA, Castelli WP, McNamara PM, Kannel WB. The natural history of congestive heart failure: the Framingham study. N Engl J Med 1971; 285(26):1441–1446. doi:10.1056/NEJM197112232852601
Stein PD, Terrin ML, Hales CA, et al. Clinical, laboratory, roentgenographic, and electrocardiographic findings in patients with acute pulmonary embolism and no pre-existing cardiac or pulmonary disease. Chest 1991; 100(3):598–603. pmid:1909617
Baggish AL, Siebert U, Lainchbury JG, et al. A validated clinical and biochemical score for the diagnosis of acute heart failure: the ProBNP investigation of dyspnea in the emergency department (PRIDE) acute heart failure score. Am Heart J 2006; 151(1):48–54. doi:10.1016/j.ahj.2005.02.031
National Heart, Lung, and Blood Institute. National Asthma Education and Prevention Program. Expert panel report 3: Guidelines for the diagnosis and management of asthma. www.nhlbi.nih.gov/sites/default/files/media/docs/asthgdln_1.pdf. Accessed August 3, 2018.
Brenner BE, Abraham E, Simon RR. Position and diaphoresis in acute asthma. Am J Med 1983; 74(6):1005–1009. pmid:6407304
Badgett RG, Tanaka DJ, Hunt DK, et al. Can moderate chronic obstructive pulmonary disease be diagnosed by historical and physical findings alone? Am J Med 1993; 94(2):188–196. pmid:8430714
Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. https://goldcopd.org/wp-content/uploads/2017/11/GOLD-2018-v6.0-FINAL-revised-20-Nov_WMS.pdf. Accessed August 17, 2018.
Erie AJ, McClure RF, Wolanskyj AP. Amiodarone-induced bone marrow granulomas: an unusual cause of reversible pancytopenia. Hematol Rep 2010; 2(1):e6. doi:10.4081/hr.2010.e6
Marrie TJ. Community-acquired pneumonia. Clin Infect Dis 1994; 18(4):501–513. pmid:8038304
Metlay JP, Kapoor WN, Fine MJ. Does this patient have community-acquired pneumonia? Diagnosing pneumonia by history and physical examination. JAMA 1997; 278(17):1440–1445. pmid:9356004
Walker CM, Abbott GF, Greene RE, Shepard JA, Vummidi D, Digumarthy SR. Imaging pulmonary infection: classic signs and patterns. AJR Am J Roentgenol 2014; 202(3):479–492. doi:10.2214/AJR.13.11463
Raghu G, Collard HR, Egan JJ, et al; ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary Fibrosis. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med 2011; 183(6):788–824. doi:10.1164/rccm.2009-040GL
Goldschlager N, Epstein AE, Naccarelli GV, et al; Practice Guidelines Sub-committee, North American Society of Pacing and Electrophysiology (HRS). A practical guide for clinicians who treat patients with amiodarone: 2007. Heart Rhythm 2007; 4(9):1250–1259. doi:10.1016/j.hrthm.2007.07.020
Kuhlman JE, Teigen C, Ren H, Hruban RH, Hutchins GM, Fishman EK. Amiodarone pulmonary toxicity: CT findings in symptomatic patients. Radiology 1990; 177(1):121–125. doi:10.1148/radiology.177.1.2399310
Martin WJ 2nd, Rosenow EC 3rd. Amiodarone pulmonary toxicity: recognition and pathogenesis (Part I). Chest 1988; 93(5):1067–1075. pmid:3282816
Iskandar SB, Abi-Saleh B, Keith RL, Byrd RP Jr, Roy TM. Amiodarone-induced alveolar hemorrhage. South Med J 2006; 99(4):383–387.
Van Mieghem W, Coolen L, Malysse I, Lacquet LM, Deneffe GJ, Demedts MG. Amiodarone and the development of ARDS after lung surgery. Chest 1994; 105(6):1642–1645. pmid:8205854
Nicholson KG. Clinical features of influenza. Semin Respir Infect 1992; 7(1):26–37. pmid:1609165
Muller NL, Franquet T, Lee KS, Silva CIS. Viruses, mycoplasma, and chlamydia. In: Imaging of Pulmonary Infections. Philadelphia, PA: Lippincott Williams & Wilkins; 2007:94–114.
Stack S, Nguyen DV, Casto A, Ahuja N. Diffuse alveolar damage in a patient receiving dronedarone. Chest 2015; 147(4):e131–e133. doi:10.1378/chest.14-1849
De Ferrari GM, Dusi V. Drug safety evaluation of dronedarone in atrial fibrillation. Expert Opin Drug Saf 2012; 11(6):1023–1045. doi:10.1517/14740338.2012.722994
Okayasu K, Takeda Y, Kojima J, et al. Amiodarone pulmonary toxicity: a patient with three recurrences of pulmonary toxicity and consideration of the probable risk for relapse. Intern Med 2006; 45(22):1303–1307. pmid:17170505
Vorperian VR, Havighurst TC, Miller S, January CT. Adverse effects of low dose amiodarone: a meta-analysis. J Am Coll Cardiol 1997; 30(3):791–798. pmid:9283542
Amiodarone Trials Meta-Analysis Investigators. Effect of prophylactic amiodarone on mortality after acute myocardial infarction and in congestive heart failure: meta-analysis of individual data from 6500 patients in randomised trials. Lancet 1997; 350(9089):1417–1424. pmid:9371164
Olshansky B, Sami M, Rubin A, et al; NHLBI AFFIRM Investigators. Use of amiodarone for atrial fibrillation in patients with preexisting pulmonary disease in the AFFIRM study. Am J Cardiol 2005; 95(3):404–405. doi:10.1016/j.amjcard.2004.09.044
Camus P. Interstitial lung disease from drugs, biologics, and radiation. In: Schwartz MI, King TE Jr, eds. Interstitial Lung Disease. 5th ed. Shelton, CT: People’s Medical Publishing House; 2011:637–644.
Wolkove N, Baltzan M. Amiodarone pulmonary toxicity. Can Respir J 2009; 16(2):43–48. doi:10.1155/2009/282540

References

McKee PA, Castelli WP, McNamara PM, Kannel WB. The natural history of congestive heart failure: the Framingham study. N Engl J Med 1971; 285(26):1441–1446. doi:10.1056/NEJM197112232852601
Stein PD, Terrin ML, Hales CA, et al. Clinical, laboratory, roentgenographic, and electrocardiographic findings in patients with acute pulmonary embolism and no pre-existing cardiac or pulmonary disease. Chest 1991; 100(3):598–603. pmid:1909617
Baggish AL, Siebert U, Lainchbury JG, et al. A validated clinical and biochemical score for the diagnosis of acute heart failure: the ProBNP investigation of dyspnea in the emergency department (PRIDE) acute heart failure score. Am Heart J 2006; 151(1):48–54. doi:10.1016/j.ahj.2005.02.031
National Heart, Lung, and Blood Institute. National Asthma Education and Prevention Program. Expert panel report 3: Guidelines for the diagnosis and management of asthma. www.nhlbi.nih.gov/sites/default/files/media/docs/asthgdln_1.pdf. Accessed August 3, 2018.
Brenner BE, Abraham E, Simon RR. Position and diaphoresis in acute asthma. Am J Med 1983; 74(6):1005–1009. pmid:6407304
Badgett RG, Tanaka DJ, Hunt DK, et al. Can moderate chronic obstructive pulmonary disease be diagnosed by historical and physical findings alone? Am J Med 1993; 94(2):188–196. pmid:8430714
Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. https://goldcopd.org/wp-content/uploads/2017/11/GOLD-2018-v6.0-FINAL-revised-20-Nov_WMS.pdf. Accessed August 17, 2018.
Erie AJ, McClure RF, Wolanskyj AP. Amiodarone-induced bone marrow granulomas: an unusual cause of reversible pancytopenia. Hematol Rep 2010; 2(1):e6. doi:10.4081/hr.2010.e6
Marrie TJ. Community-acquired pneumonia. Clin Infect Dis 1994; 18(4):501–513. pmid:8038304
Metlay JP, Kapoor WN, Fine MJ. Does this patient have community-acquired pneumonia? Diagnosing pneumonia by history and physical examination. JAMA 1997; 278(17):1440–1445. pmid:9356004
Walker CM, Abbott GF, Greene RE, Shepard JA, Vummidi D, Digumarthy SR. Imaging pulmonary infection: classic signs and patterns. AJR Am J Roentgenol 2014; 202(3):479–492. doi:10.2214/AJR.13.11463
Raghu G, Collard HR, Egan JJ, et al; ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary Fibrosis. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med 2011; 183(6):788–824. doi:10.1164/rccm.2009-040GL
Goldschlager N, Epstein AE, Naccarelli GV, et al; Practice Guidelines Sub-committee, North American Society of Pacing and Electrophysiology (HRS). A practical guide for clinicians who treat patients with amiodarone: 2007. Heart Rhythm 2007; 4(9):1250–1259. doi:10.1016/j.hrthm.2007.07.020
Kuhlman JE, Teigen C, Ren H, Hruban RH, Hutchins GM, Fishman EK. Amiodarone pulmonary toxicity: CT findings in symptomatic patients. Radiology 1990; 177(1):121–125. doi:10.1148/radiology.177.1.2399310
Martin WJ 2nd, Rosenow EC 3rd. Amiodarone pulmonary toxicity: recognition and pathogenesis (Part I). Chest 1988; 93(5):1067–1075. pmid:3282816
Iskandar SB, Abi-Saleh B, Keith RL, Byrd RP Jr, Roy TM. Amiodarone-induced alveolar hemorrhage. South Med J 2006; 99(4):383–387.
Van Mieghem W, Coolen L, Malysse I, Lacquet LM, Deneffe GJ, Demedts MG. Amiodarone and the development of ARDS after lung surgery. Chest 1994; 105(6):1642–1645. pmid:8205854
Nicholson KG. Clinical features of influenza. Semin Respir Infect 1992; 7(1):26–37. pmid:1609165
Muller NL, Franquet T, Lee KS, Silva CIS. Viruses, mycoplasma, and chlamydia. In: Imaging of Pulmonary Infections. Philadelphia, PA: Lippincott Williams & Wilkins; 2007:94–114.
Stack S, Nguyen DV, Casto A, Ahuja N. Diffuse alveolar damage in a patient receiving dronedarone. Chest 2015; 147(4):e131–e133. doi:10.1378/chest.14-1849
De Ferrari GM, Dusi V. Drug safety evaluation of dronedarone in atrial fibrillation. Expert Opin Drug Saf 2012; 11(6):1023–1045. doi:10.1517/14740338.2012.722994
Okayasu K, Takeda Y, Kojima J, et al. Amiodarone pulmonary toxicity: a patient with three recurrences of pulmonary toxicity and consideration of the probable risk for relapse. Intern Med 2006; 45(22):1303–1307. pmid:17170505
Vorperian VR, Havighurst TC, Miller S, January CT. Adverse effects of low dose amiodarone: a meta-analysis. J Am Coll Cardiol 1997; 30(3):791–798. pmid:9283542
Amiodarone Trials Meta-Analysis Investigators. Effect of prophylactic amiodarone on mortality after acute myocardial infarction and in congestive heart failure: meta-analysis of individual data from 6500 patients in randomised trials. Lancet 1997; 350(9089):1417–1424. pmid:9371164
Olshansky B, Sami M, Rubin A, et al; NHLBI AFFIRM Investigators. Use of amiodarone for atrial fibrillation in patients with preexisting pulmonary disease in the AFFIRM study. Am J Cardiol 2005; 95(3):404–405. doi:10.1016/j.amjcard.2004.09.044
Camus P. Interstitial lung disease from drugs, biologics, and radiation. In: Schwartz MI, King TE Jr, eds. Interstitial Lung Disease. 5th ed. Shelton, CT: People’s Medical Publishing House; 2011:637–644.
Wolkove N, Baltzan M. Amiodarone pulmonary toxicity. Can Respir J 2009; 16(2):43–48. doi:10.1155/2009/282540

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Calcium and vitamin D: To supplement or not?

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Calcium and vitamin D: To supplement or not?

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Ian R. Reid, MD

We live in the era of evidence-based medicine, so new interventions must meet criteria for both safety and efficacy before they are adopted. However, we have inherited many practices adopted before the current standards were in place, and we have not always been rigorous in reevaluating traditional remedies. A conservative belief in established practice or the influence of vested interests may account for this lack of rigor in reappraisal.¹ Calcium and vitamin D supplements are possible examples of this phenomenon.

BONE METABOLISM IS TIGHTLY REGULATED

Bone is a connective tissue, its matrix composed principally of type 1 collagen, which provides tensile strength. Hydroxyapatite crystals, composed predominantly of calcium and phosphate, lie between the collagen fibers and provide compressive strength. In a tightly regulated process, osteoblasts lay down the collagenous matrix, and osteoclasts remove it. Mineralization of newly formed bone proceeds if normal levels of extracellular calcium and phosphate are present, in the absence of inhibitors of mineralization.

High calcium intake does not drive bone formation

The endocrine system is critical in maintaining normocalcemia. A decrease in calcium intake results in increased parathyroid hormone secretion, resulting in increased renal tubular calcium reabsorption, increased bone turnover (both formation and resorption), and increased activation of vitamin D leading to increased intestinal absorption of calcium. High calcium intake reverses these changes.

Figure 1. Absolute change in total body bone mineral content (BMC) over 5 years in normal postmenopausal women, as a function of each woman’s average calcium intake assessed at baseline and at year 5. The lines show the regression (with 95% confidence intervals) for this relationship (P = .53)

Thus, a normal serum calcium concentration can be maintained with calcium intake ranging from 200 to more than 2,000 mg/day, and rates of bone loss in postmenopausal women are unaffected by calcium intake (Figure 1).²

If calcium intake is very low, hypocalcemia and secondary hyperparathyroidism develop,³ and bone mineralization may be impaired. However, levels of calcium intake in Africa and in East and Southeast Asia are typically less than 400 mg/day,⁴ yet there is no evidence that these levels adversely affect skeletal health. In fact, fracture risk is lower in these regions than in North America, where calcium intake is several times greater.

Thus, some calcium intake is required to maintain circulating concentrations, but there is no mechanism by which high calcium intake can drive bone formation. Quite the opposite, in fact.

Vitamin D deficiency has little relationship with diet

Vitamin D is a biologically inactive secosteroid activated by hydroxylation in the liver and kidney to function as the key regulator of intestinal calcium absorption. As with calcium, its deficiency results in hypocalcemia and impaired bone mineralization.

Paradoxically, high levels of vitamin D stimulate bone resorption and inhibit bone mineralization in mice,⁵ and large doses increase bone resorption markers acutely in clinical studies.⁶ Thus, it is important to ensure an adequate vitamin D supply, but not an oversupply.

In the absence of supplements, most vitamin D is produced in the skin as a result of the action of ultraviolet light (from sunlight) on 7-dehydrocholesterol. Thus, vitamin D deficiency occurs in those deprived of skin exposure to sunlight (eg, due to veiling, living at high latitude, staying permanently indoors), but it has little relationship with diet.

ARE CALCIUM SUPPLEMENTS EFFECTIVE?

Calcium supplements are certainly biologically active. They transiently increase serum calcium concentrations, suppress parathyroid hormone, and reduce bone resorption.² In the first year of use, they increase bone density by about 1% compared with placebo.⁷ However, longer use does not result in further bone density advantage over placebo,⁷ suggesting that the response simply reflects a decreased number of osteoclastic resorption sites and does not indicate a sustained change in bone balance.

A 1% difference in bone density would not be expected to reduce fracture risk, and a number of large, carefully conducted randomized controlled trials published over the last 15 years have failed to demonstrate antifracture efficacy for calcium.^8–12 As a result, the US Preventive Services Task Force recommends against the routine use of calcium supplements in community-dwelling adults.¹³

In contrast, in a placebo-controlled trial published in 1992, Chapuy et al¹⁴ found that elderly women residing in nursing homes who received calcium and vitamin D supplements had fewer fractures. At 18 months, by intention-to-treat analysis, nonvertebral fractures had occurred in 160 (12%) of 1,387 women in the supplement group compared with 215 (15%) of 1,403 women in the placebo group (P < .001). However, these women were severely vitamin D-deficient (the mean serum 25-hydroxyvitamin D level at baseline in the placebo group was 13 ng/mL, normal range 15–50), to the extent that many must have had osteomalacia.

Thus, this study shows that calcium and vitamin D are effective in managing osteomalacia, but the subsequent trials^8–12 did not observe any benefit in community-dwelling cohorts. Meta-analyses that pool the Chapuy study with community-based studies generally find that calcium with vitamin D is beneficial, but the heterogeneity of these populations means that such pooling is inappropriate.¹⁵

It is sometimes stated that calcium and vitamin D should always be given with osteoporosis medications because the efficacy of these drugs has only been demonstrated when coadministered with these supplements. This is incorrect. The addition of calcium to alendronate does not alter its effects on bone density,¹⁶ and the antifracture efficacy of both bisphosphonates¹⁷ and estrogen^18,19 has been demonstrated in the absence of supplementation with calcium or vitamin D. The evidence that bisphosphonates prevent fractures in the absence of calcium supplements has recently been strengthened by the results of a randomized controlled trial comparing zoledronate with placebo in women over age 65 with osteopenia.²⁰

ARE CALCIUM SUPPLEMENTS SAFE?

Calcium supplements often cause gastrointestinal symptoms, particularly constipation. They have been shown to double the risk of hospital admission due to abdominal symptoms.²¹ In the absence of clear evidence of benefit, these facts alone should militate against their routine use. Calcium supplements also cause hypercalcemia and hypercalciuria²² and increase the risk of renal calculi (by 17% in the Women’s Health Initiative⁸).

Over the last decade, evidence has emerged that calcium supplements may also increase the risk of myocardial infarction, and possibly stroke. This finding was not statistically significant in any single study, but is consistently present in meta-analyses.²³

Evidence from the Women’s Health Initiative

When studies of calcium with vitamin D are added to these meta-analyses, the results are less consistent. This is because such meta-analyses are dominated by the Women's Health Initiative (because of its large size, with 36,282 participants). There have been 2 different analyses of this trial with respect to cardiovascular events.

When the Women’s Health Initiative as a whole was analyzed, there was no significant effect of calcium plus vitamin D on vascular end points. However, there is a significant interaction between body mass index and the effect of supplements, such that nonobese women demonstrated a 17% increase in myocardial infarction.²⁴ This study was unusual in that it included women already taking calcium and vitamin D supplements.

Figure 2. Effect of calcium supplements on cardiovascular events, with or without vitamin D. Data for 28,072 participants in 8 trials of calcium supplements with trial-level data, plus data for Women’s Health Initiative CaD study participants not taking calcium supplements at baseline.

There was a significant interaction between baseline use of supplements and the effects of the trial intervention on vascular events, justifying analyzing the supplement-naive individuals separately. In this group of 16,000 women, an increase in clinical myocardial infarction of 22% was found, similar to the findings with calcium supplements alone.²⁵

Thus, there is consistent evidence that introducing a calcium supplement de novo increases the risk of myocardial infarction (Figure 2).^16,25–31 We calculate that treating 1,000 patients with calcium or calcium plus vitamin D for 5 years would cause an additional 6 myocardial infarctions or strokes (number needed to harm 178) and prevent only 3 fractures (number needed to treat 302).²⁵

ARE VITAMIN D SUPPLEMENTS EFFECTIVE?

Vitamin D is highly effective in treating osteomalacia, improving symptoms within days and increasing bone density by as much as 50% over 1 year.^32,33 In contrast, randomized controlled trials of vitamin D supplements alone in people without osteomalacia have not shown increases in bone density or changes in fracture risk.^34–37

Figure 3. Changes in bone mineral density (BMD) from baseline to 2 years in the vitamin D and placebo groups of the Vitamin D Assessment study, according to baseline serum 25(OH)D (25-hydroxyvitamin D) concentrations. Data are mean ± 95% confidence intervals. P values are shown for between-group comparisons.

In 2017, my colleagues and I published a trial showing that vitamin D supplementation increases bone density by 2% to 3% in the spine and femoral neck in participants with baseline 25-hydroxyvitamin D levels below 30- nmol/L (12 ng/mL), but those starting above this level showed no effect (Figure 3).³⁸ And a reanalysis of an earlier study confirmed this 30 nmol/L threshold for an effect of vitamin D on bone density.³⁹ The finding of a clear-cut threshold for vitamin D effects is predicted by the physiologic considerations set out above.

Belief that higher levels of 25-hydroxyvitamin D are better is based on observational data. However, correlation does not prove causation, and it is likely that causation is reversed here. Those with better health are likely to spend more time exercising outdoors, are less likely to be obese, and are less likely to have inflammatory conditions; and as a result, they are more likely to have better vitamin D status. We should now be using trial-based definitions of vitamin D deficiency as opposed to thresholds derived from disease associations in observational studies.

Vitamin D supplements have also been suggested to benefit cardiovascular health and to reduce cancer risk, though current clinical trial data provide no support for these hypotheses.^36,40 Other trials addressing these questions are ongoing.

ARE VITAMIN D SUPPLEMENTS SAFE?

The safety of vitamin D supplements has generally been assessed with respect to the incidence of hypercalcemia. On this basis, very high doses have been promoted. However, there is now evidence that doses of 4,000 IU/day, 60,000 IU/month, and 500,000 IU/year increase the risk of falls and fractures.^41,42

The threshold for bone benefits discussed above (12 ng/mL) is easily exceeded with doses of vitamin D of 400 to 1,000 IU/day. At these levels, vitamin D supplements have no known adverse effects and can be widely endorsed for individuals at risk of deficiency. Supplement doses greater than 2,000 IU/day should be used only in exceptional circumstances, and with appropriate monitoring.

LITTLE USE FOR CALCIUM AND VITAMIN D SUPPLEMENTS

Extensive clinical trials have failed to demonstrate meaningful benefit from calcium supplements in the management of osteoporosis. Calcium supplements are often prescribed in patients who are receiving other treatments for osteoporosis, which may be justified with interventions that have the potential to cause hypocalcemia, but their coadministration with bisphosphonates has been shown to be unnecessary.

Calcium supplements commonly cause gastrointestinal symptoms that are sometimes severe and are likely to contribute to high levels of noncompliance with osteoporosis medications. They increase the risk of kidney stones,⁸ and there is reasonable evidence to suggest an adverse effect on vascular risk as well.²³

Vitamin D deficiency is common in frail elderly people, particularly those with dark skin or living at high latitudes. Low doses of vitamin D are safe and highly effective in preventing osteomalacia. But vitamin D supplements are unnecessary in those who regularly have sun exposure. And high doses of vitamin D have no demonstrated advantage and have been shown to increase the risk of falls and fractures.

Our decision to prescribe calcium and vitamin D supplements should be based on evidence that is of the same quality as for any other intervention we prescribe. Current evidence suggests that there is little reason to prescribe calcium, and that vitamin D should be targeted at those at risk of 25-hydroxyvitamin D levels less than 12 ng/mL.

References

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Reid IR, Bristow SM, Bolland MJ. Calcium supplements: benefits and risks. J Intern Med 2015; 278(4):354–368. doi:10.1111/joim.12394
Bolland MJ, Grey AB, Ames RW, Horne AM, Gamble GD, Reid IR. Fat mass is an important predictor of parathyroid hormone levels in postmenopausal women. Bone 2006; 38(3):317–321. doi:10.1016/j.bone.2005.08.018
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Rossini M, Gatti D, Viapiana O, et al. Short-term effects on bone turnover markers of a single high dose of oral vitamin D3. J Clin Endocrinol Metab 2012; 97(4):E622–E626. doi:10.1210/jc.2011-2448
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Grant AM, Avenell A, Campbell MK, et al; RECORD Trial Group. Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium or vitamin D, RECORD): a randomised placebo-controlled trial. Lancet 2005; 365(9471):1621–1628. doi:10.1016/S0140-6736(05)63013-9
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Reid I, Horne A, Mihov B, et al. Abstracts of the ECTS Congress 2018: Zoledronate every 18 months for 6 years in osteopenic postmenopausal women reduces non-vertebral fractures and height loss. Calcif Tissue Int 2018; 102:S1-S159. doi:10.1007/s00223-018-0418-0
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Gallagher JC, Smith LM, Yalamanchili V. Incidence of hypercalciuria and hypercalcemia during vitamin D and calcium supplementation in older women. Menopause 2014; 21(11):1173–1180. doi:10.1097/GME.0000000000000270
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Hsia J, Heiss G, Ren H, et al; Women’s Health Initiative Investigators. Calcium/vitamin D supplementation and cardiovascular events. Circulation 2007; 115(7):846–854. doi:10.1161/CIRCULATIONAHA.106.673491
Bolland MJ, Grey A, Avenell A, Gamble GD, Reid IR. Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women’s Health Initiative limited access dataset and meta-analysis. BMJ 2011; 342:d2040. doi:10.1136/bmj.d2040
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Reid IR, Ames RW, Evans MC,Gamble GD, Sharpe SJ. Effect of calcium supplementation on bone loss in postmenopausal women. N Engl J Med 1993; 328(7):460–464. doi:10.1056/NEJM199302183280702
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Bolland MJ, Grey A, Gamble GD, Reid IR. The effect of vitamin D supplementation on skeletal, vascular, or cancer outcomes: a trial sequential meta-analysis. Lancet Diabetes Endocrinol 2014; 2(4):307–320. doi:10.1016/S2213-8587(13)70212-2
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MacDonald HM, Reid IR, Gamble GD, Fraser WD, Tang JC, Wood AD. 25-Hydroxyvitamin D threshold for the effects of vitamin D supplements on bone density secondary analysis of a randomized controlled trial. J Bone Miner Res 2018. Epub ahead of print. doi:10.1002/jbmr.3442
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Address: Ian R. Reid, MD, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand; i.reid@auckland.ac.nz

Dr. Reid has disclosed consulting for Amgen and Merck and teaching and speaking for Amgen and Eli Lilly. He is supported by the Health Research Council of New Zealand.

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BONE METABOLISM IS TIGHTLY REGULATED

High calcium intake does not drive bone formation

Thus, some calcium intake is required to maintain circulating concentrations, but there is no mechanism by which high calcium intake can drive bone formation. Quite the opposite, in fact.

Vitamin D deficiency has little relationship with diet

ARE CALCIUM SUPPLEMENTS EFFECTIVE?

ARE CALCIUM SUPPLEMENTS SAFE?

Evidence from the Women’s Health Initiative

ARE VITAMIN D SUPPLEMENTS EFFECTIVE?

ARE VITAMIN D SUPPLEMENTS SAFE?

LITTLE USE FOR CALCIUM AND VITAMIN D SUPPLEMENTS

BONE METABOLISM IS TIGHTLY REGULATED

High calcium intake does not drive bone formation

Thus, some calcium intake is required to maintain circulating concentrations, but there is no mechanism by which high calcium intake can drive bone formation. Quite the opposite, in fact.

Vitamin D deficiency has little relationship with diet

ARE CALCIUM SUPPLEMENTS EFFECTIVE?

ARE CALCIUM SUPPLEMENTS SAFE?

Evidence from the Women’s Health Initiative

ARE VITAMIN D SUPPLEMENTS EFFECTIVE?

ARE VITAMIN D SUPPLEMENTS SAFE?

LITTLE USE FOR CALCIUM AND VITAMIN D SUPPLEMENTS

References

Grey A, Bolland M. Web of industry, advocacy, and academia in the management of osteoporosis. BMJ 2015; 351:h3170. doi:10.1136/bmj.h3170
Reid IR, Bristow SM, Bolland MJ. Calcium supplements: benefits and risks. J Intern Med 2015; 278(4):354–368. doi:10.1111/joim.12394
Bolland MJ, Grey AB, Ames RW, Horne AM, Gamble GD, Reid IR. Fat mass is an important predictor of parathyroid hormone levels in postmenopausal women. Bone 2006; 38(3):317–321. doi:10.1016/j.bone.2005.08.018
International Osteoporosis Foundation. Calcium map. www.iofbonehealth.org/facts-and-statistics/calcium-map. Accessed July 10, 2018.
Lieben L, Masuyama R, Torrekens S, et al. Normocalcemia is maintained in mice under conditions of calcium malabsorption by vitamin D-induced inhibition of bone mineralization. J Clin Invest 2012; 122(5):1803–1815. doi:10.1172/JCI45890
Rossini M, Gatti D, Viapiana O, et al. Short-term effects on bone turnover markers of a single high dose of oral vitamin D3. J Clin Endocrinol Metab 2012; 97(4):E622–E626. doi:10.1210/jc.2011-2448
Tai V, Leung W, Grey A, Reid IR, Bolland MJ. Calcium intake and bone mineral density: systematic review and meta-analysis. BMJ 2015; 351:h4183. doi:10.1136/bmj.h4183
Jackson RD, LaCroix AZ, Gass M, et al; Women’s Health Initiative Investigators. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med 2006; 354(7):669–683. doi:10.1056/NEJMoa055218
Grant AM, Avenell A, Campbell MK, et al; RECORD Trial Group. Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium or vitamin D, RECORD): a randomised placebo-controlled trial. Lancet 2005; 365(9471):1621–1628. doi:10.1016/S0140-6736(05)63013-9
Prince RL, Devine A, Dhaliwal SS, Dick IM. Effects of calcium supplementation on clinical fracture and bone structure: results of a 5-year, double-blind, placebo-controlled trial in elderly women. Arch Intern Med 2006; 166(8):869–875. doi:10.1001/archinte.166.8.869
Reid IR, Mason B, Horne A, et al. Randomized controlled trial of calcium in healthy older women. Am J Med 2006; 119(9):777–785. doi:10.1016/j.amjmed.2006.02.038
Salovaara K, Tuppurainen M, Karkkainen M, et al. Effect of vitamin D-3 and calcium on fracture risk in 65-to 71-year-old women: a population-based 3-year randomized, controlled trial—the OSTPRE-FPS. J Bone Miner Res 2010; 25(7):1487–1495. doi:10.1002/jbmr.48
Moyer VA, US Preventive Services Task Force. Vitamin D and calcium supplementation to prevent fractures in adults: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2013; 158(9):691–696. doi:10.7326/0003-4819-158-9-201305070-00603
Chapuy MC, Arlot ME, Duboeuf F, et al. Vitamin D3 and calcium to prevent hip fractures in elderly women. N Engl J Med 1992; 327(23):1637–1642. doi:10.1056/NEJM199212033272305
Tang BMP, Eslick GD, Nowson C, Smith C, Bensoussan A. Use of calcium or calcium in combination with vitamin D supplementation to prevent fractures and bone loss in people aged 50 years and older: a meta-analysis. Lancet 2007; 370(9588):657–666. doi:10.1016/S0140-6736(07)61342-7
Bonnick S, Broy S, Kaiser F, et al. Treatment with alendronate plus calcium, alendronate alone, or calcium alone for postmenopausal low bone mineral density. Curr Med Res Opin 2007; 23(6):1341–1349. doi:10.1185/030079907X188035
McCloskey EV, Beneton M, Charlesworth D, et al. Clodronate reduces the incidence of fractures in community-dwelling elderly women unselected for osteoporosis: results of a double-blind, placebo-controlled randomized study. J Bone Miner Res 2007; 22(1):135–141. doi:10.1359/jbmr.061008
Lindsay R, Hart DM, Forrest C, Baird C. Prevention of spinal osteoporosis in oophorectomised women. Lancet 1980; 2(8205):1151–1154. pmid:6107766
Cauley JA, Robbins J, Chen Z, et al; Women’s Health Initiative Investigators. Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women’s Health Initiative randomized trial. JAMA 2003; 290(13):1729–1738. doi:10.1001/jama.290.13.1729
Reid I, Horne A, Mihov B, et al. Abstracts of the ECTS Congress 2018: Zoledronate every 18 months for 6 years in osteopenic postmenopausal women reduces non-vertebral fractures and height loss. Calcif Tissue Int 2018; 102:S1-S159. doi:10.1007/s00223-018-0418-0
Lewis JR, Zhu K, Prince RL. Adverse events from calcium supplementation: relationship to errors in myocardial infarction self-reporting in randomized controlled trials of calcium supplementation. J Bone Miner Res 2012; 27(3):719–722. doi:10.1002/jbmr.1484
Gallagher JC, Smith LM, Yalamanchili V. Incidence of hypercalciuria and hypercalcemia during vitamin D and calcium supplementation in older women. Menopause 2014; 21(11):1173–1180. doi:10.1097/GME.0000000000000270
Reid IR, Bristow SM, Bolland MJ. Calcium and cardiovascular disease. Endocrinol Metab (Seoul) 2017; 32(3):339–349. doi:10.3803/EnM.2017.32.3.339
Hsia J, Heiss G, Ren H, et al; Women’s Health Initiative Investigators. Calcium/vitamin D supplementation and cardiovascular events. Circulation 2007; 115(7):846–854. doi:10.1161/CIRCULATIONAHA.106.673491
Bolland MJ, Grey A, Avenell A, Gamble GD, Reid IR. Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women’s Health Initiative limited access dataset and meta-analysis. BMJ 2011; 342:d2040. doi:10.1136/bmj.d2040
Baron JA, Beach M, Mandel JS, et al. Calcium supplements for the prevention of colorectal adenomas. Calcium Polyp Prevention Study Group. N Engl J Med 1999; 340(3):101–107. doi:10.1056/NEJM199901143400204
Bolland MJ, Barber PA, Doughty RN, et al. Vascular events in healthy older women receiving calcium supplementation: randomised controlled trial. BMJ 2008; 336(7638):262–266. doi:10.1136/bmj.39440.525752.BE
Lappe JM, Travers-Gustafson D, Davies KM, Recker RR, Heaney RP. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr 2007; 85(6):1586–1591. doi:10.1093/ajcn/85.6.1586
Reid IR, Ames R, Mason B, et al. Randomized controlled trial of calcium supplementation in healthy, non-osteoporotic, older men. Arch Intern Med 2008; 168(20):2276–2282. doi:10.1001/archinte.168.20.2276
Reid IR, Ames RW, Evans MC,Gamble GD, Sharpe SJ. Effect of calcium supplementation on bone loss in postmenopausal women. N Engl J Med 1993; 328(7):460–464. doi:10.1056/NEJM199302183280702
Reid IR, Ames RW, Evans MC, Gamble GD, Sharpe SJ. Long-term effects of calcium supplementation on bone loss and fractures in postmenopausal women: a randomized controlled trial. Am J Med 1995; 98(4):331–335. doi:10.1016/S0002-9343(99)80310-6
Al-Ali H, Fuleihan GE. Nutritional osteomalacia: substantial clinical improvement and gain in bone density posttherapy. J Clin Densitom 2000; 3(1):97–101. pmid:10745306
El-Desouki MI, Othman SM, Fouda MA. Bone mineral density and bone scintigraphy in adult Saudi female patients with osteomalacia. Saudi Med J 2004; 25(3):355–358.
Reid IR, Bolland MJ, Grey A. Effects of vitamin D supplements on bone mineral density: a systematic review and meta-analysis. Lancet 2014; 383(9912):146–155. doi:10.1016/S0140-6736(13)61647-5
Avenell A, Mak JC, O’Connell D. Vitamin D and vitamin D analogues for preventing fractures in post-menopausal women and older men. Cochrane Database Syst Rev 2014; (4):CD000227. doi:10.1002/14651858.CD000227.pub4
Bolland MJ, Grey A, Gamble GD, Reid IR. The effect of vitamin D supplementation on skeletal, vascular, or cancer outcomes: a trial sequential meta-analysis. Lancet Diabetes Endocrinol 2014; 2(4):307–320. doi:10.1016/S2213-8587(13)70212-2
DIPART (Vitamin D Individual Patient Analysis of Randomized Trials) Group. Patient level pooled analysis of 68 500 patients from seven major vitamin D fracture trials in US and Europe. BMJ 2010; 340:b5463. doi:10.1136/bmj.b5463
Reid IR, Horne AM, Mihov B, et al. Effect of monthly high-dose vitamin D on bone density in community-dwelling older adults substudy of a randomized controlled trial. J Intern Med 2017; 282(5):452–460. doi:10.1111/joim.12651
MacDonald HM, Reid IR, Gamble GD, Fraser WD, Tang JC, Wood AD. 25-Hydroxyvitamin D threshold for the effects of vitamin D supplements on bone density secondary analysis of a randomized controlled trial. J Bone Miner Res 2018. Epub ahead of print. doi:10.1002/jbmr.3442
Scragg R, Stewart AW, Waayer D, et al. Effect of monthly high-dose vitamin D supplementation on cardiovascular disease in the vitamin D assessment study: a randomized clinical trial. JAMA Cardiol 2017; 2(6):608–616. doi:10.1001/jamacardio.2017.0175
Sanders KM, Stuart AL, Williamson EJ, et al. Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial. JAMA 2010; 303(18):1815–1822. doi:10.1001/jama.2010.594
Smith LM, Gallagher JC, Suiter C. Medium doses of daily vitamin D decrease falls and higher doses of daily vitamin D3 increase falls: a randomized clinical trial. J Steroid Biochem Mol Biol 2017; 173:317–322. doi:10.1016/j.jsbmb.2017.03.015

References

Grey A, Bolland M. Web of industry, advocacy, and academia in the management of osteoporosis. BMJ 2015; 351:h3170. doi:10.1136/bmj.h3170
Reid IR, Bristow SM, Bolland MJ. Calcium supplements: benefits and risks. J Intern Med 2015; 278(4):354–368. doi:10.1111/joim.12394
Bolland MJ, Grey AB, Ames RW, Horne AM, Gamble GD, Reid IR. Fat mass is an important predictor of parathyroid hormone levels in postmenopausal women. Bone 2006; 38(3):317–321. doi:10.1016/j.bone.2005.08.018
International Osteoporosis Foundation. Calcium map. www.iofbonehealth.org/facts-and-statistics/calcium-map. Accessed July 10, 2018.
Lieben L, Masuyama R, Torrekens S, et al. Normocalcemia is maintained in mice under conditions of calcium malabsorption by vitamin D-induced inhibition of bone mineralization. J Clin Invest 2012; 122(5):1803–1815. doi:10.1172/JCI45890
Rossini M, Gatti D, Viapiana O, et al. Short-term effects on bone turnover markers of a single high dose of oral vitamin D3. J Clin Endocrinol Metab 2012; 97(4):E622–E626. doi:10.1210/jc.2011-2448
Tai V, Leung W, Grey A, Reid IR, Bolland MJ. Calcium intake and bone mineral density: systematic review and meta-analysis. BMJ 2015; 351:h4183. doi:10.1136/bmj.h4183
Jackson RD, LaCroix AZ, Gass M, et al; Women’s Health Initiative Investigators. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med 2006; 354(7):669–683. doi:10.1056/NEJMoa055218
Grant AM, Avenell A, Campbell MK, et al; RECORD Trial Group. Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium or vitamin D, RECORD): a randomised placebo-controlled trial. Lancet 2005; 365(9471):1621–1628. doi:10.1016/S0140-6736(05)63013-9
Prince RL, Devine A, Dhaliwal SS, Dick IM. Effects of calcium supplementation on clinical fracture and bone structure: results of a 5-year, double-blind, placebo-controlled trial in elderly women. Arch Intern Med 2006; 166(8):869–875. doi:10.1001/archinte.166.8.869
Reid IR, Mason B, Horne A, et al. Randomized controlled trial of calcium in healthy older women. Am J Med 2006; 119(9):777–785. doi:10.1016/j.amjmed.2006.02.038
Salovaara K, Tuppurainen M, Karkkainen M, et al. Effect of vitamin D-3 and calcium on fracture risk in 65-to 71-year-old women: a population-based 3-year randomized, controlled trial—the OSTPRE-FPS. J Bone Miner Res 2010; 25(7):1487–1495. doi:10.1002/jbmr.48
Moyer VA, US Preventive Services Task Force. Vitamin D and calcium supplementation to prevent fractures in adults: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2013; 158(9):691–696. doi:10.7326/0003-4819-158-9-201305070-00603
Chapuy MC, Arlot ME, Duboeuf F, et al. Vitamin D3 and calcium to prevent hip fractures in elderly women. N Engl J Med 1992; 327(23):1637–1642. doi:10.1056/NEJM199212033272305
Tang BMP, Eslick GD, Nowson C, Smith C, Bensoussan A. Use of calcium or calcium in combination with vitamin D supplementation to prevent fractures and bone loss in people aged 50 years and older: a meta-analysis. Lancet 2007; 370(9588):657–666. doi:10.1016/S0140-6736(07)61342-7
Bonnick S, Broy S, Kaiser F, et al. Treatment with alendronate plus calcium, alendronate alone, or calcium alone for postmenopausal low bone mineral density. Curr Med Res Opin 2007; 23(6):1341–1349. doi:10.1185/030079907X188035
McCloskey EV, Beneton M, Charlesworth D, et al. Clodronate reduces the incidence of fractures in community-dwelling elderly women unselected for osteoporosis: results of a double-blind, placebo-controlled randomized study. J Bone Miner Res 2007; 22(1):135–141. doi:10.1359/jbmr.061008
Lindsay R, Hart DM, Forrest C, Baird C. Prevention of spinal osteoporosis in oophorectomised women. Lancet 1980; 2(8205):1151–1154. pmid:6107766
Cauley JA, Robbins J, Chen Z, et al; Women’s Health Initiative Investigators. Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women’s Health Initiative randomized trial. JAMA 2003; 290(13):1729–1738. doi:10.1001/jama.290.13.1729
Reid I, Horne A, Mihov B, et al. Abstracts of the ECTS Congress 2018: Zoledronate every 18 months for 6 years in osteopenic postmenopausal women reduces non-vertebral fractures and height loss. Calcif Tissue Int 2018; 102:S1-S159. doi:10.1007/s00223-018-0418-0
Lewis JR, Zhu K, Prince RL. Adverse events from calcium supplementation: relationship to errors in myocardial infarction self-reporting in randomized controlled trials of calcium supplementation. J Bone Miner Res 2012; 27(3):719–722. doi:10.1002/jbmr.1484
Gallagher JC, Smith LM, Yalamanchili V. Incidence of hypercalciuria and hypercalcemia during vitamin D and calcium supplementation in older women. Menopause 2014; 21(11):1173–1180. doi:10.1097/GME.0000000000000270
Reid IR, Bristow SM, Bolland MJ. Calcium and cardiovascular disease. Endocrinol Metab (Seoul) 2017; 32(3):339–349. doi:10.3803/EnM.2017.32.3.339
Hsia J, Heiss G, Ren H, et al; Women’s Health Initiative Investigators. Calcium/vitamin D supplementation and cardiovascular events. Circulation 2007; 115(7):846–854. doi:10.1161/CIRCULATIONAHA.106.673491
Bolland MJ, Grey A, Avenell A, Gamble GD, Reid IR. Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women’s Health Initiative limited access dataset and meta-analysis. BMJ 2011; 342:d2040. doi:10.1136/bmj.d2040
Baron JA, Beach M, Mandel JS, et al. Calcium supplements for the prevention of colorectal adenomas. Calcium Polyp Prevention Study Group. N Engl J Med 1999; 340(3):101–107. doi:10.1056/NEJM199901143400204
Bolland MJ, Barber PA, Doughty RN, et al. Vascular events in healthy older women receiving calcium supplementation: randomised controlled trial. BMJ 2008; 336(7638):262–266. doi:10.1136/bmj.39440.525752.BE
Lappe JM, Travers-Gustafson D, Davies KM, Recker RR, Heaney RP. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr 2007; 85(6):1586–1591. doi:10.1093/ajcn/85.6.1586
Reid IR, Ames R, Mason B, et al. Randomized controlled trial of calcium supplementation in healthy, non-osteoporotic, older men. Arch Intern Med 2008; 168(20):2276–2282. doi:10.1001/archinte.168.20.2276
Reid IR, Ames RW, Evans MC,Gamble GD, Sharpe SJ. Effect of calcium supplementation on bone loss in postmenopausal women. N Engl J Med 1993; 328(7):460–464. doi:10.1056/NEJM199302183280702
Reid IR, Ames RW, Evans MC, Gamble GD, Sharpe SJ. Long-term effects of calcium supplementation on bone loss and fractures in postmenopausal women: a randomized controlled trial. Am J Med 1995; 98(4):331–335. doi:10.1016/S0002-9343(99)80310-6
Al-Ali H, Fuleihan GE. Nutritional osteomalacia: substantial clinical improvement and gain in bone density posttherapy. J Clin Densitom 2000; 3(1):97–101. pmid:10745306
El-Desouki MI, Othman SM, Fouda MA. Bone mineral density and bone scintigraphy in adult Saudi female patients with osteomalacia. Saudi Med J 2004; 25(3):355–358.
Reid IR, Bolland MJ, Grey A. Effects of vitamin D supplements on bone mineral density: a systematic review and meta-analysis. Lancet 2014; 383(9912):146–155. doi:10.1016/S0140-6736(13)61647-5
Avenell A, Mak JC, O’Connell D. Vitamin D and vitamin D analogues for preventing fractures in post-menopausal women and older men. Cochrane Database Syst Rev 2014; (4):CD000227. doi:10.1002/14651858.CD000227.pub4
Bolland MJ, Grey A, Gamble GD, Reid IR. The effect of vitamin D supplementation on skeletal, vascular, or cancer outcomes: a trial sequential meta-analysis. Lancet Diabetes Endocrinol 2014; 2(4):307–320. doi:10.1016/S2213-8587(13)70212-2
DIPART (Vitamin D Individual Patient Analysis of Randomized Trials) Group. Patient level pooled analysis of 68 500 patients from seven major vitamin D fracture trials in US and Europe. BMJ 2010; 340:b5463. doi:10.1136/bmj.b5463
Reid IR, Horne AM, Mihov B, et al. Effect of monthly high-dose vitamin D on bone density in community-dwelling older adults substudy of a randomized controlled trial. J Intern Med 2017; 282(5):452–460. doi:10.1111/joim.12651
MacDonald HM, Reid IR, Gamble GD, Fraser WD, Tang JC, Wood AD. 25-Hydroxyvitamin D threshold for the effects of vitamin D supplements on bone density secondary analysis of a randomized controlled trial. J Bone Miner Res 2018. Epub ahead of print. doi:10.1002/jbmr.3442
Scragg R, Stewart AW, Waayer D, et al. Effect of monthly high-dose vitamin D supplementation on cardiovascular disease in the vitamin D assessment study: a randomized clinical trial. JAMA Cardiol 2017; 2(6):608–616. doi:10.1001/jamacardio.2017.0175
Sanders KM, Stuart AL, Williamson EJ, et al. Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial. JAMA 2010; 303(18):1815–1822. doi:10.1001/jama.2010.594
Smith LM, Gallagher JC, Suiter C. Medium doses of daily vitamin D decrease falls and higher doses of daily vitamin D3 increase falls: a randomized clinical trial. J Steroid Biochem Mol Biol 2017; 173:317–322. doi:10.1016/j.jsbmb.2017.03.015

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Calcium and vitamin D: To supplement or not?

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Calcium and vitamin D: To supplement or not?

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calcium, vitamin D, supplements, bone health, osteoporosis, myocardial infarction, stroke, Women’s Health Initiative, Ian Reid

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calcium, vitamin D, supplements, bone health, osteoporosis, myocardial infarction, stroke, Women’s Health Initiative, Ian Reid

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Patients with mRCC survive longer at high-volume centers

Obesity: Are shared medical appointments part of the answer?

Big benefits from small changes in weight

CURRENT APPROACHES

Counseling is important, but underused

Drugs and surgery also underused

ARE SHARED MEDICAL APPOINTMEMNTS AN ANSWER?

What can a shared medical appointment do?

BENEFITS OF SHARED APPOINTMENTS

Increased face time and access

Improved patient outcomes

Increased patient and provider satisfaction

Decreased costs

CHALLENGES TO STARTING SHARED APPOINTMENTS FOR OBESITY

Adequate resources and staff training

Maintaining patient attendance

Logistical challenges

Recruiting patients

Maintaining patient confidentiality

Ensuring insurance coverage

EVIDENCE OF EFFECTIVENESS IN OBESITY

WHO SHOULD BE ON THE TEAM?

WHAT ARE REALISTIC TARGETS?

Nutrition

Physical activity

Appetite control

Sleep

Stress management and mood disorders

IN FAVOR OF SHARED MEDICAL APPOINTMENTS FOR OBESITY

Big benefits from small changes in weight

CURRENT APPROACHES

Counseling is important, but underused

Drugs and surgery also underused

ARE SHARED MEDICAL APPOINTMEMNTS AN ANSWER?

What can a shared medical appointment do?

BENEFITS OF SHARED APPOINTMENTS

Increased face time and access

Improved patient outcomes

Increased patient and provider satisfaction

Decreased costs

CHALLENGES TO STARTING SHARED APPOINTMENTS FOR OBESITY

Adequate resources and staff training

Maintaining patient attendance

Logistical challenges

Recruiting patients

Maintaining patient confidentiality

Ensuring insurance coverage

EVIDENCE OF EFFECTIVENESS IN OBESITY

WHO SHOULD BE ON THE TEAM?

WHAT ARE REALISTIC TARGETS?

Nutrition

Physical activity

Appetite control

Sleep

Stress management and mood disorders

IN FAVOR OF SHARED MEDICAL APPOINTMENTS FOR OBESITY

Big benefits from small changes in weight

CURRENT APPROACHES

Counseling is important, but underused

Drugs and surgery also underused

ARE SHARED MEDICAL APPOINTMEMNTS AN ANSWER?

What can a shared medical appointment do?

BENEFITS OF SHARED APPOINTMENTS

Increased face time and access

Improved patient outcomes

Increased patient and provider satisfaction

Decreased costs

CHALLENGES TO STARTING SHARED APPOINTMENTS FOR OBESITY

Adequate resources and staff training

Maintaining patient attendance

Logistical challenges

Recruiting patients

Maintaining patient confidentiality

Ensuring insurance coverage

EVIDENCE OF EFFECTIVENESS IN OBESITY

WHO SHOULD BE ON THE TEAM?

WHAT ARE REALISTIC TARGETS?

Nutrition

Physical activity