Cardiology

Subclinical changes in cardiac structure and diastolic function in early adulthood may serve as risk markers for cognitive decline in midlife, new research suggests.

Cardiovascular disease risk factors such as high blood pressure, high cholesterol, and diabetes have been associated with an increased risk for cognitive impairment, but much less is known about heart structure and function and the risks for cognition.

“We showed for the first time that, even before the occurrence of cardiovascular disease, people with abnormalities in cardiac structure and function as early as in young adulthood have lower midlife cognition,” investigators Laure Rouch, PharmD, PhD, and Kristine Yaffe, MD, both with the department of psychiatry, University of California, San Francisco, said in a joint email.

“This study reminds us that heart health is key to brain health and that the overlap and interplay between the two is not limited to patients with end-stage heart disease,” Dr. Rouch and Dr. Yaffe said.

The findings were published online Jan. 26, 2022, in Neurology.
 

Heart/brain connection

The analysis included 2,653 participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study.

Echocardiograms were obtained at year 5, 25, and 30 study visits – at mean ages of 30, 50, and 55 years, respectively. At year 30, participants underwent a standard battery of tests measuring global cognition, processing speed, executive function, delayed verbal memory, and verbal fluency.

Over 25 years, there was an average increase in left ventricular mass of 0.27 g/m2 per year – from a mean of 80.5 g/m² in year 5 to 86.0 g/m² in year 30.

Left atrial volume increased by an average of 0.42 mL/m2 per year, from 16 mL/m² in year 5 to 26 mL/m² in year 30.

Left ventricular ejection fraction (LVEF) decreased by 0.11% per year, from 63.3% in year 5 to 59.7% in year 30.

After adjustment for demographics and education, an increase in left ventricular mass of at least 1 standard deviation over 25 years was associated with lower cognition on most tests (P ≤ .02).

An increase in left atrial volume over the study period was associated with lower global cognition (P = .04), whereas a decrease in LVEF was not associated with cognition. Further adjustment for cardiovascular risk factors yielded similar results.

“A more effective collaboration is needed between cardiologists and neurologists to promote healthy brain aging,” Dr. Rouch and Dr. Yaffe said.

“Echocardiography is a widely available, relatively inexpensive, and noninvasive imaging method that could be integrated into a risk assessment for cognitive impairment,” they added.

Looking ahead, the investigators noted there is a need for further research to determine whether interventions to improve cardiac structure and diastolic function could also benefit brain health.

They should also investigate the role of arterial stiffness and cerebral small vessel disease in the relationship between cardiac structure, function, and cognition, the researchers added.
 

First structural biomarker

Commenting on the study, Shaheen E. Lakhan, MD, PhD, a neurologist in Newton, Mass., said the study is important because, “thus far, the connections have really been physiological parameters,” such as blood pressure and cognitive health.

“This is really strong evidence of a structural cardiac biomarker that can be measured before and independent of changes in physiology or diseased state,” said Dr. Lakhan, who was not involved with the research.

As more and more interventions are being introduced for addressing disorders of cognition, “this potential structural finding may serve as a solid biomarker to determine” what lifestyle or drug therapy should be taken, he added.

Also weighing in on the findings, Pierre Fayad, MD, professor in the department of neurological sciences and director of the Nebraska Stroke Center, University of Nebraska Medical Center, Omaha, said CARDIA is “an important study” providing “precious data.”

The reported changes in cardiac structure and function “precede the clinical symptomatology, as the follow-up stops before they enter into later adulthood, where the risk of clinical events dramatically rises. Meaning these patients still have not had stroke, congestive heart failure, heart attack or dementia, but some of them could be on that trajectory later in their life,” Dr. Fayad told this news organization.

Documenting such changes over time is “valuable to give an insight into what leads us to such progression,” he noted.

How reliably predictive the findings are for eventual clinical cognitive impairment “will need to be confirmed and verified” in future studies, he added.

“If verified, it could be helpful to provide interventions to those with the left atrial volume enlargement marker and see their effectiveness at preventing eventual clinical cognitive impairment,” said Dr. Fayad.

The CARDIA study is supported by the National Heart, Lung, and Blood Institute in collaboration with the University of Alabama at Birmingham, Northwestern University, the University of Minnesota, and the Kaiser Foundation Research Institute. Rouch, Lakhan, and Dr. Fayad have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Subclinical changes in cardiac structure and diastolic function in early adulthood may serve as risk markers for cognitive decline in midlife, new research suggests.

Cardiovascular disease risk factors such as high blood pressure, high cholesterol, and diabetes have been associated with an increased risk for cognitive impairment, but much less is known about heart structure and function and the risks for cognition.

“We showed for the first time that, even before the occurrence of cardiovascular disease, people with abnormalities in cardiac structure and function as early as in young adulthood have lower midlife cognition,” investigators Laure Rouch, PharmD, PhD, and Kristine Yaffe, MD, both with the department of psychiatry, University of California, San Francisco, said in a joint email.

“This study reminds us that heart health is key to brain health and that the overlap and interplay between the two is not limited to patients with end-stage heart disease,” Dr. Rouch and Dr. Yaffe said.

The findings were published online Jan. 26, 2022, in Neurology.
 

Heart/brain connection

The analysis included 2,653 participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study.

Echocardiograms were obtained at year 5, 25, and 30 study visits – at mean ages of 30, 50, and 55 years, respectively. At year 30, participants underwent a standard battery of tests measuring global cognition, processing speed, executive function, delayed verbal memory, and verbal fluency.

Over 25 years, there was an average increase in left ventricular mass of 0.27 g/m2 per year – from a mean of 80.5 g/m² in year 5 to 86.0 g/m² in year 30.

Left atrial volume increased by an average of 0.42 mL/m2 per year, from 16 mL/m² in year 5 to 26 mL/m² in year 30.

Left ventricular ejection fraction (LVEF) decreased by 0.11% per year, from 63.3% in year 5 to 59.7% in year 30.

After adjustment for demographics and education, an increase in left ventricular mass of at least 1 standard deviation over 25 years was associated with lower cognition on most tests (P ≤ .02).

An increase in left atrial volume over the study period was associated with lower global cognition (P = .04), whereas a decrease in LVEF was not associated with cognition. Further adjustment for cardiovascular risk factors yielded similar results.

“A more effective collaboration is needed between cardiologists and neurologists to promote healthy brain aging,” Dr. Rouch and Dr. Yaffe said.

“Echocardiography is a widely available, relatively inexpensive, and noninvasive imaging method that could be integrated into a risk assessment for cognitive impairment,” they added.

Looking ahead, the investigators noted there is a need for further research to determine whether interventions to improve cardiac structure and diastolic function could also benefit brain health.

They should also investigate the role of arterial stiffness and cerebral small vessel disease in the relationship between cardiac structure, function, and cognition, the researchers added.
 

First structural biomarker

Commenting on the study, Shaheen E. Lakhan, MD, PhD, a neurologist in Newton, Mass., said the study is important because, “thus far, the connections have really been physiological parameters,” such as blood pressure and cognitive health.

“This is really strong evidence of a structural cardiac biomarker that can be measured before and independent of changes in physiology or diseased state,” said Dr. Lakhan, who was not involved with the research.

As more and more interventions are being introduced for addressing disorders of cognition, “this potential structural finding may serve as a solid biomarker to determine” what lifestyle or drug therapy should be taken, he added.

Also weighing in on the findings, Pierre Fayad, MD, professor in the department of neurological sciences and director of the Nebraska Stroke Center, University of Nebraska Medical Center, Omaha, said CARDIA is “an important study” providing “precious data.”

The reported changes in cardiac structure and function “precede the clinical symptomatology, as the follow-up stops before they enter into later adulthood, where the risk of clinical events dramatically rises. Meaning these patients still have not had stroke, congestive heart failure, heart attack or dementia, but some of them could be on that trajectory later in their life,” Dr. Fayad told this news organization.

Documenting such changes over time is “valuable to give an insight into what leads us to such progression,” he noted.

How reliably predictive the findings are for eventual clinical cognitive impairment “will need to be confirmed and verified” in future studies, he added.

“If verified, it could be helpful to provide interventions to those with the left atrial volume enlargement marker and see their effectiveness at preventing eventual clinical cognitive impairment,” said Dr. Fayad.

The CARDIA study is supported by the National Heart, Lung, and Blood Institute in collaboration with the University of Alabama at Birmingham, Northwestern University, the University of Minnesota, and the Kaiser Foundation Research Institute. Rouch, Lakhan, and Dr. Fayad have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Subclinical changes in cardiac structure and diastolic function in early adulthood may serve as risk markers for cognitive decline in midlife, new research suggests.

Cardiovascular disease risk factors such as high blood pressure, high cholesterol, and diabetes have been associated with an increased risk for cognitive impairment, but much less is known about heart structure and function and the risks for cognition.

“We showed for the first time that, even before the occurrence of cardiovascular disease, people with abnormalities in cardiac structure and function as early as in young adulthood have lower midlife cognition,” investigators Laure Rouch, PharmD, PhD, and Kristine Yaffe, MD, both with the department of psychiatry, University of California, San Francisco, said in a joint email.

“This study reminds us that heart health is key to brain health and that the overlap and interplay between the two is not limited to patients with end-stage heart disease,” Dr. Rouch and Dr. Yaffe said.

The findings were published online Jan. 26, 2022, in Neurology.
 

Heart/brain connection

The analysis included 2,653 participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study.

Echocardiograms were obtained at year 5, 25, and 30 study visits – at mean ages of 30, 50, and 55 years, respectively. At year 30, participants underwent a standard battery of tests measuring global cognition, processing speed, executive function, delayed verbal memory, and verbal fluency.

Over 25 years, there was an average increase in left ventricular mass of 0.27 g/m2 per year – from a mean of 80.5 g/m² in year 5 to 86.0 g/m² in year 30.

Left atrial volume increased by an average of 0.42 mL/m2 per year, from 16 mL/m² in year 5 to 26 mL/m² in year 30.

Left ventricular ejection fraction (LVEF) decreased by 0.11% per year, from 63.3% in year 5 to 59.7% in year 30.

After adjustment for demographics and education, an increase in left ventricular mass of at least 1 standard deviation over 25 years was associated with lower cognition on most tests (P ≤ .02).

An increase in left atrial volume over the study period was associated with lower global cognition (P = .04), whereas a decrease in LVEF was not associated with cognition. Further adjustment for cardiovascular risk factors yielded similar results.

“A more effective collaboration is needed between cardiologists and neurologists to promote healthy brain aging,” Dr. Rouch and Dr. Yaffe said.

“Echocardiography is a widely available, relatively inexpensive, and noninvasive imaging method that could be integrated into a risk assessment for cognitive impairment,” they added.

Looking ahead, the investigators noted there is a need for further research to determine whether interventions to improve cardiac structure and diastolic function could also benefit brain health.

They should also investigate the role of arterial stiffness and cerebral small vessel disease in the relationship between cardiac structure, function, and cognition, the researchers added.
 

First structural biomarker

Commenting on the study, Shaheen E. Lakhan, MD, PhD, a neurologist in Newton, Mass., said the study is important because, “thus far, the connections have really been physiological parameters,” such as blood pressure and cognitive health.

“This is really strong evidence of a structural cardiac biomarker that can be measured before and independent of changes in physiology or diseased state,” said Dr. Lakhan, who was not involved with the research.

As more and more interventions are being introduced for addressing disorders of cognition, “this potential structural finding may serve as a solid biomarker to determine” what lifestyle or drug therapy should be taken, he added.

Also weighing in on the findings, Pierre Fayad, MD, professor in the department of neurological sciences and director of the Nebraska Stroke Center, University of Nebraska Medical Center, Omaha, said CARDIA is “an important study” providing “precious data.”

The reported changes in cardiac structure and function “precede the clinical symptomatology, as the follow-up stops before they enter into later adulthood, where the risk of clinical events dramatically rises. Meaning these patients still have not had stroke, congestive heart failure, heart attack or dementia, but some of them could be on that trajectory later in their life,” Dr. Fayad told this news organization.

Documenting such changes over time is “valuable to give an insight into what leads us to such progression,” he noted.

How reliably predictive the findings are for eventual clinical cognitive impairment “will need to be confirmed and verified” in future studies, he added.

“If verified, it could be helpful to provide interventions to those with the left atrial volume enlargement marker and see their effectiveness at preventing eventual clinical cognitive impairment,” said Dr. Fayad.

The CARDIA study is supported by the National Heart, Lung, and Blood Institute in collaboration with the University of Alabama at Birmingham, Northwestern University, the University of Minnesota, and the Kaiser Foundation Research Institute. Rouch, Lakhan, and Dr. Fayad have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Why some COVID-19 vaccines seem occasionally to cause a distinctive form of myocarditis, and why adolescent boys and young men appear most vulnerable, remain a mystery. But the entity’s prevalence, nuances of presentation, and likely clinical course have come into sharper view after recent additions to the literature.  

Two new publications all but confirm that the rare cases of myocarditis closely following vaccination against SARS-CoV-2, primarily with one of the mRNA-based vaccines from Pfizer-BioNTech and Moderna, is a clinically different creature from myocarditis physicians were likely to see before the pandemic.

A third report unveils rates of hospitalization for myocarditis linked to Pfizer-BioNTech vaccination in the 12- to 15-year age group, based on active surveillance across Israel. Of note, the rates were lower than corresponding numbers among the country’s 16- to 19-year-olds published in late 2021 by the same authors.
 

No link with CoronaVac

A case-control study covering almost the entire population of Hong Kong from February to August 2021 confirms a slight but significant excess risk for myocarditis and, to a lesser degree, pericarditis, after injections of the Pfizer-BioNTech vaccine. As consistently reported from other studies, the risks were highest in adolescent and young adult males and after a second dose.

The study estimated an overall carditis incidence of 5.7 cases per million doses of Pfizer-BioNTech, for a risk 3.5 times that in the unvaccinated Hong Kong population. Carditis rates after a first dose were about 2.5 per million and 10 per million after a second dose.

Hong Kong launched its public SARS-CoV-2 immunization program in late February 2021 with the Chinese-made CoronaVac (Sinovac) inactivated-virus vaccine, and introduced the mRNA-based alternative several weeks later. By August 2021, the vaccines had reached about 3.3 million people in the region – 49% of the Hong Kong population at least 12 years of age.

In a novel finding, there were no excesses in carditis cases after CoronaVac vaccination. The difference between vaccines likely isn’t caused by chance, because three-fourths of the carditis-associated Pfizer-BioNTech injections arose within a week, whereas “71% of cases following the use of CoronaVac occurred more than 30 days after vaccination,” senior author Ian Chi Kei Wong, PhD, University of Hong Kong, said in an interview.

“This onset distribution for cases having received CoronaVac demonstrates that it is highly unlikely the carditis cases are related to the vaccine,” he said. And that “plausibly implies a specific underlying mechanism between vaccination and carditis that may only be applicable to mRNA vaccines.”

That inference is in line with case reports and other research, including large population-based studies from Israel and Denmark, although a recent study from the United Kingdom hinted at a potential excess myocarditis risk associated with the adenovirus-based AstraZeneca-Oxford vaccine.

The Hong Kong study identified 160 patients age 12 or older with a first diagnosis of carditis during February to August 2021, in electronic health records covering nearly the entire region.

“We used laboratory test results of troponin levels to further eliminate unlikely cases of carditis,” Dr. Wong said. The health records were linked to a “population-based vaccination record” maintained by the government’s department of health.

About 10 control patients from among all hospitalized patients without carditis were matched by age, sex, and admission date to each of the 160 carditis cases. About 83% of cases and 92% of the controls were unvaccinated.

Among those who received the Pfizer-BioNTech vaccine, representing 12.5% of cases and 4.2% of controls, the estimated carditis incidence was 0.57 per 100,000 doses. For those who received CoronaVac, representing 4.4% of cases and 3.9% of controls, it was 0.31 per 100,000 doses.

In adjusted analysis, the odds ratios for carditis among Pfizer-BioNTech vaccine recipients, compared with unvaccinated controls, were 3.57 (95% confidence interval, 1.93-6.60) overall, 4.68 (95% CI, 2.25-9.71) for males, 2.22 (95% CI, 0.57-8.69) for females, 2.41 (95% CI, 1.18-4.90) for ages 18 and older, and 13.8 (95% CI, 2.86-110.4) for ages 12-17

Myocarditis accounted for most of the excess cases, with an overall OR of 9.29 (95% CI, 3.94-21.9). The OR reached only 1.06 (95% CI, 0.35-3.22) for pericarditis alone.

The case-control study is noteworthy for its design, which contrasts with the many recent case series and passive or active surveillance studies, and even the more robust population-based studies of vaccine-related myocarditis, observed Dongngan Truong, MD, University of Utah and Primary Children’s Hospital, both in Salt Lake City, who wasn’t part of the study.

Among its strengths, she said in an interview, are its linkage of comprehensive hospital and vaccination data sets for two different vaccines; and that it corroborates other research suggesting there is “something in particular about mRNA vaccination that seems to be associated with the development of myocarditis.”

Active surveillance in Israel

In an October 2021 report based on an Israeli Ministry of Health database covering up to May 2021, rates of myocarditis arising within 21 days of a second Pfizer-BioNTech dose in 16- to 19-year-olds reached about 1 per 6,637 males and 1 per 99,853 females. Those numbers compared with 1 per 26,000 males and 1 per 218,000 females across all age groups.

Now authors led by Dror Mevorach, MD, Hadassah Medical Center, Jerusalem, have published corresponding numbers from the same data base for myocarditis associated with the same vaccine in males and females aged 12-15.  

Their research covers 404,407 people in that age group who received a first dose of the mRNA-based vaccine and 326,463 who received the second dose from June to October, 2021. Only 18 cases of myocarditis were observed within 21 days of either dose.

The estimated rates for males were 0.56 cases per 100,000 after a first dose and 8.09 cases per 100,000 after a second dose.

For females, the estimates were 0 cases per 100,000 after a first dose and 0.69 cases per 100,000 after a second dose.

“The pattern observed, mainly following the second vaccination in males, suggests causality,” the group wrote.
 

Leveraging passive surveillance reports

Another new report adds a twist to updated numbers from the U.S. Vaccine Adverse Event Reporting System (VAERS).

Prevalences derived from the passive-surveillance data base, known for including case records of inconsistent quality or completeness, are considered especially prone to reporting bias, the authors acknowledged.

The current analysis, however, plunges deep into VAERS-reported cases of presumed SARS-CoV-2 vaccine-associated myocarditis to help clarify “more of the characteristics of the patients and some of the treatments and short-term outcomes,” Matthew E. Oster, MD, MPH, said in an interview.

Dr. Oster, from the Centers for Disease Control and Prevention and Emory University, Atlanta, is lead author on the study’s Jan. 25, 2022, publication in JAMA.

The group reviewed charts and interviewed involved clinicians to adjudicate and document presentations, therapies, and the clinical course of cases reported as SARS-CoV-2 vaccine–associated myocarditis from December 2020 to August 2021. Out of the nearly 2000 reports, which were limited to patients younger than 30, the group identified 1,626 likely cases of such myocarditis arising within 7 days of a second mRNA vaccine dose.

The confirmed cases consistently represented higher prevalences than expected compared with prepandemic myocarditis claims data for both sexes and across age groups spanning 12-29 years.

For example, rates were highest for adolescent males – about 106 and 71 cases per million second doses of the Pfizer-BioNTech vaccine in those aged 16-17 and 12-16, respectively, for example. They were lowest for women aged 25-29, at 2.23 cases per million second Pfizer-BioNTech doses; the highest rate among females was about 11 per million for the 16-17 age group.

The observed rates, Dr. Oster said, represent an update to VAERS numbers published June 2021 in Morbidity and Mortality Weekly Report covering cases through June 2021.

“Overall, the general risk of having myocarditis from the vaccines is still extremely low. Even in the highest risk groups, it is still extremely low, and still lower than the risk of having cardiac complications from COVID,” he noted.
 

How do patients fare clinically?

From their chart reviews and interviews with case clinicians, Dr. Oster said, “we started to learn quickly that this is really a different type of myocarditis.”

For example, its onset, typically within a few days of the potential immunologic cause, was more rapid than in viral myocarditis, and its symptoms resolved faster, the report notes. Clinical presentations tended to be less severe, treatments not as intensive, and outcomes not as serious, compared with “the kind of typical viral myocarditis that most of the providers were used to taking care of in the past,” he said. “The pattern for these cases was very consistent.”

The study covered VAERS reports of suspected myocarditis arising within a week of first dose of a mRNA-based vaccine from the United States launch of public vaccination in December 2020 to August 2021, the CDC-based group reported. By then, more than 192 million people in the country had received either the Pfizer-BioNTech (age 12 or older) or Moderna (age 18 or older) vaccines.

Of the 1,991 reports of myocarditis, including 391 also involving pericarditis, 1,626 met the study’s definition for myocarditis on adjudication; about 82% of the latter cases were in males.

Based on the investigators’ review of charts and clinician interviews connected with 826 cases that met their definition of myocarditis in patients younger than 30, 89% reported “chest pain, pressure, or discomfort” and 30% reported dyspnea or shortness of breath. Troponin levels were elevated in 98%, 72% of patients who underwent electrocardiography showed abnormalities, and 12% of those with echocardiography had left ventricular ejection fractions less than 50%.

About 96% were hospitalized, and presenting symptoms resolved by discharge in 87% of those with available data, the group noted. Among patients with data on in-hospital therapy, they wrote, NSAIDs were the most common therapy, in 87%.

‘Mild and self-limiting’

The case-control study from Hong Kong didn’t specifically examine patients’ treatment and clinical course, but it does portray their vaccine-associated myocarditis as contrasting with more familiar viral myocarditis.

Patients with “typical” myocarditis tend to be “overall much sicker than what we’re seeing with myocarditis following vaccination,” Dr. Truong agreed. None of the 20 patients with myocarditis after Pfizer-BioNTech vaccination in Hong Kong were admitted to the intensive care unit. That, she added, suggests none required extracorporeal membrane oxygenation or vasoactive support, often necessary in viral myocarditis. “And they had shorter hospital stays.”

In contrast, Dr. Wong noted, 14 of the study’s unvaccinated patients required ICU admission; 12 of them died during the follow-up period. None with vaccine-related carditis died during the study’s follow-up. “We also showed that cases following [Pfizer-BioNTech] vaccination were all mild and self-limiting.”

Dr. Truong largely agreed that SARS-CoV-2 vaccine myocarditis and most myocarditis seen before the pandemic can be viewed as distinct clinical entities, “at least in the short term. I think we do need to follow these patients to look at more long-term outcomes, because at this point I don’t think we know the long-term implications. But at least in the short term, it seems like these patients are different, are much less sick, and recover pretty quickly overall.”

Dr. Oster emphasized that the many and varied acute and long-term hazards from contracting COVID-19 far outweigh any risk for myocarditis from vaccination. But for individuals who were hit with myocarditis soon after their first mRNA vaccine dose, who have already established their susceptibility, he and his colleagues would recommend that they “consider alternatives and not get the vaccine again.”

Dr. Oster reported no relevant financial relationships. Dr. Wong and colleagues did not report any relevant disclosures. Dr. Truong has previously disclosed serving as a consultant to Pfizer.

A version of this article first appeared on Medscape.com.

Why some COVID-19 vaccines seem occasionally to cause a distinctive form of myocarditis, and why adolescent boys and young men appear most vulnerable, remain a mystery. But the entity’s prevalence, nuances of presentation, and likely clinical course have come into sharper view after recent additions to the literature.  

Two new publications all but confirm that the rare cases of myocarditis closely following vaccination against SARS-CoV-2, primarily with one of the mRNA-based vaccines from Pfizer-BioNTech and Moderna, is a clinically different creature from myocarditis physicians were likely to see before the pandemic.

A third report unveils rates of hospitalization for myocarditis linked to Pfizer-BioNTech vaccination in the 12- to 15-year age group, based on active surveillance across Israel. Of note, the rates were lower than corresponding numbers among the country’s 16- to 19-year-olds published in late 2021 by the same authors.
 

No link with CoronaVac

A case-control study covering almost the entire population of Hong Kong from February to August 2021 confirms a slight but significant excess risk for myocarditis and, to a lesser degree, pericarditis, after injections of the Pfizer-BioNTech vaccine. As consistently reported from other studies, the risks were highest in adolescent and young adult males and after a second dose.

The study estimated an overall carditis incidence of 5.7 cases per million doses of Pfizer-BioNTech, for a risk 3.5 times that in the unvaccinated Hong Kong population. Carditis rates after a first dose were about 2.5 per million and 10 per million after a second dose.

Hong Kong launched its public SARS-CoV-2 immunization program in late February 2021 with the Chinese-made CoronaVac (Sinovac) inactivated-virus vaccine, and introduced the mRNA-based alternative several weeks later. By August 2021, the vaccines had reached about 3.3 million people in the region – 49% of the Hong Kong population at least 12 years of age.

In a novel finding, there were no excesses in carditis cases after CoronaVac vaccination. The difference between vaccines likely isn’t caused by chance, because three-fourths of the carditis-associated Pfizer-BioNTech injections arose within a week, whereas “71% of cases following the use of CoronaVac occurred more than 30 days after vaccination,” senior author Ian Chi Kei Wong, PhD, University of Hong Kong, said in an interview.

“This onset distribution for cases having received CoronaVac demonstrates that it is highly unlikely the carditis cases are related to the vaccine,” he said. And that “plausibly implies a specific underlying mechanism between vaccination and carditis that may only be applicable to mRNA vaccines.”

That inference is in line with case reports and other research, including large population-based studies from Israel and Denmark, although a recent study from the United Kingdom hinted at a potential excess myocarditis risk associated with the adenovirus-based AstraZeneca-Oxford vaccine.

The Hong Kong study identified 160 patients age 12 or older with a first diagnosis of carditis during February to August 2021, in electronic health records covering nearly the entire region.

“We used laboratory test results of troponin levels to further eliminate unlikely cases of carditis,” Dr. Wong said. The health records were linked to a “population-based vaccination record” maintained by the government’s department of health.

About 10 control patients from among all hospitalized patients without carditis were matched by age, sex, and admission date to each of the 160 carditis cases. About 83% of cases and 92% of the controls were unvaccinated.

Among those who received the Pfizer-BioNTech vaccine, representing 12.5% of cases and 4.2% of controls, the estimated carditis incidence was 0.57 per 100,000 doses. For those who received CoronaVac, representing 4.4% of cases and 3.9% of controls, it was 0.31 per 100,000 doses.

In adjusted analysis, the odds ratios for carditis among Pfizer-BioNTech vaccine recipients, compared with unvaccinated controls, were 3.57 (95% confidence interval, 1.93-6.60) overall, 4.68 (95% CI, 2.25-9.71) for males, 2.22 (95% CI, 0.57-8.69) for females, 2.41 (95% CI, 1.18-4.90) for ages 18 and older, and 13.8 (95% CI, 2.86-110.4) for ages 12-17

Myocarditis accounted for most of the excess cases, with an overall OR of 9.29 (95% CI, 3.94-21.9). The OR reached only 1.06 (95% CI, 0.35-3.22) for pericarditis alone.

The case-control study is noteworthy for its design, which contrasts with the many recent case series and passive or active surveillance studies, and even the more robust population-based studies of vaccine-related myocarditis, observed Dongngan Truong, MD, University of Utah and Primary Children’s Hospital, both in Salt Lake City, who wasn’t part of the study.

Among its strengths, she said in an interview, are its linkage of comprehensive hospital and vaccination data sets for two different vaccines; and that it corroborates other research suggesting there is “something in particular about mRNA vaccination that seems to be associated with the development of myocarditis.”

Active surveillance in Israel

In an October 2021 report based on an Israeli Ministry of Health database covering up to May 2021, rates of myocarditis arising within 21 days of a second Pfizer-BioNTech dose in 16- to 19-year-olds reached about 1 per 6,637 males and 1 per 99,853 females. Those numbers compared with 1 per 26,000 males and 1 per 218,000 females across all age groups.

Now authors led by Dror Mevorach, MD, Hadassah Medical Center, Jerusalem, have published corresponding numbers from the same data base for myocarditis associated with the same vaccine in males and females aged 12-15.  

Their research covers 404,407 people in that age group who received a first dose of the mRNA-based vaccine and 326,463 who received the second dose from June to October, 2021. Only 18 cases of myocarditis were observed within 21 days of either dose.

The estimated rates for males were 0.56 cases per 100,000 after a first dose and 8.09 cases per 100,000 after a second dose.

For females, the estimates were 0 cases per 100,000 after a first dose and 0.69 cases per 100,000 after a second dose.

“The pattern observed, mainly following the second vaccination in males, suggests causality,” the group wrote.
 

Leveraging passive surveillance reports

Another new report adds a twist to updated numbers from the U.S. Vaccine Adverse Event Reporting System (VAERS).

Prevalences derived from the passive-surveillance data base, known for including case records of inconsistent quality or completeness, are considered especially prone to reporting bias, the authors acknowledged.

The current analysis, however, plunges deep into VAERS-reported cases of presumed SARS-CoV-2 vaccine-associated myocarditis to help clarify “more of the characteristics of the patients and some of the treatments and short-term outcomes,” Matthew E. Oster, MD, MPH, said in an interview.

Dr. Oster, from the Centers for Disease Control and Prevention and Emory University, Atlanta, is lead author on the study’s Jan. 25, 2022, publication in JAMA.

The group reviewed charts and interviewed involved clinicians to adjudicate and document presentations, therapies, and the clinical course of cases reported as SARS-CoV-2 vaccine–associated myocarditis from December 2020 to August 2021. Out of the nearly 2000 reports, which were limited to patients younger than 30, the group identified 1,626 likely cases of such myocarditis arising within 7 days of a second mRNA vaccine dose.

The confirmed cases consistently represented higher prevalences than expected compared with prepandemic myocarditis claims data for both sexes and across age groups spanning 12-29 years.

For example, rates were highest for adolescent males – about 106 and 71 cases per million second doses of the Pfizer-BioNTech vaccine in those aged 16-17 and 12-16, respectively, for example. They were lowest for women aged 25-29, at 2.23 cases per million second Pfizer-BioNTech doses; the highest rate among females was about 11 per million for the 16-17 age group.

The observed rates, Dr. Oster said, represent an update to VAERS numbers published June 2021 in Morbidity and Mortality Weekly Report covering cases through June 2021.

“Overall, the general risk of having myocarditis from the vaccines is still extremely low. Even in the highest risk groups, it is still extremely low, and still lower than the risk of having cardiac complications from COVID,” he noted.
 

How do patients fare clinically?

From their chart reviews and interviews with case clinicians, Dr. Oster said, “we started to learn quickly that this is really a different type of myocarditis.”

For example, its onset, typically within a few days of the potential immunologic cause, was more rapid than in viral myocarditis, and its symptoms resolved faster, the report notes. Clinical presentations tended to be less severe, treatments not as intensive, and outcomes not as serious, compared with “the kind of typical viral myocarditis that most of the providers were used to taking care of in the past,” he said. “The pattern for these cases was very consistent.”

The study covered VAERS reports of suspected myocarditis arising within a week of first dose of a mRNA-based vaccine from the United States launch of public vaccination in December 2020 to August 2021, the CDC-based group reported. By then, more than 192 million people in the country had received either the Pfizer-BioNTech (age 12 or older) or Moderna (age 18 or older) vaccines.

Of the 1,991 reports of myocarditis, including 391 also involving pericarditis, 1,626 met the study’s definition for myocarditis on adjudication; about 82% of the latter cases were in males.

Based on the investigators’ review of charts and clinician interviews connected with 826 cases that met their definition of myocarditis in patients younger than 30, 89% reported “chest pain, pressure, or discomfort” and 30% reported dyspnea or shortness of breath. Troponin levels were elevated in 98%, 72% of patients who underwent electrocardiography showed abnormalities, and 12% of those with echocardiography had left ventricular ejection fractions less than 50%.

About 96% were hospitalized, and presenting symptoms resolved by discharge in 87% of those with available data, the group noted. Among patients with data on in-hospital therapy, they wrote, NSAIDs were the most common therapy, in 87%.

‘Mild and self-limiting’

The case-control study from Hong Kong didn’t specifically examine patients’ treatment and clinical course, but it does portray their vaccine-associated myocarditis as contrasting with more familiar viral myocarditis.

Patients with “typical” myocarditis tend to be “overall much sicker than what we’re seeing with myocarditis following vaccination,” Dr. Truong agreed. None of the 20 patients with myocarditis after Pfizer-BioNTech vaccination in Hong Kong were admitted to the intensive care unit. That, she added, suggests none required extracorporeal membrane oxygenation or vasoactive support, often necessary in viral myocarditis. “And they had shorter hospital stays.”

In contrast, Dr. Wong noted, 14 of the study’s unvaccinated patients required ICU admission; 12 of them died during the follow-up period. None with vaccine-related carditis died during the study’s follow-up. “We also showed that cases following [Pfizer-BioNTech] vaccination were all mild and self-limiting.”

Dr. Truong largely agreed that SARS-CoV-2 vaccine myocarditis and most myocarditis seen before the pandemic can be viewed as distinct clinical entities, “at least in the short term. I think we do need to follow these patients to look at more long-term outcomes, because at this point I don’t think we know the long-term implications. But at least in the short term, it seems like these patients are different, are much less sick, and recover pretty quickly overall.”

Dr. Oster emphasized that the many and varied acute and long-term hazards from contracting COVID-19 far outweigh any risk for myocarditis from vaccination. But for individuals who were hit with myocarditis soon after their first mRNA vaccine dose, who have already established their susceptibility, he and his colleagues would recommend that they “consider alternatives and not get the vaccine again.”

Dr. Oster reported no relevant financial relationships. Dr. Wong and colleagues did not report any relevant disclosures. Dr. Truong has previously disclosed serving as a consultant to Pfizer.

A version of this article first appeared on Medscape.com.

Why some COVID-19 vaccines seem occasionally to cause a distinctive form of myocarditis, and why adolescent boys and young men appear most vulnerable, remain a mystery. But the entity’s prevalence, nuances of presentation, and likely clinical course have come into sharper view after recent additions to the literature.  

Two new publications all but confirm that the rare cases of myocarditis closely following vaccination against SARS-CoV-2, primarily with one of the mRNA-based vaccines from Pfizer-BioNTech and Moderna, is a clinically different creature from myocarditis physicians were likely to see before the pandemic.

A third report unveils rates of hospitalization for myocarditis linked to Pfizer-BioNTech vaccination in the 12- to 15-year age group, based on active surveillance across Israel. Of note, the rates were lower than corresponding numbers among the country’s 16- to 19-year-olds published in late 2021 by the same authors.
 

No link with CoronaVac

A case-control study covering almost the entire population of Hong Kong from February to August 2021 confirms a slight but significant excess risk for myocarditis and, to a lesser degree, pericarditis, after injections of the Pfizer-BioNTech vaccine. As consistently reported from other studies, the risks were highest in adolescent and young adult males and after a second dose.

The study estimated an overall carditis incidence of 5.7 cases per million doses of Pfizer-BioNTech, for a risk 3.5 times that in the unvaccinated Hong Kong population. Carditis rates after a first dose were about 2.5 per million and 10 per million after a second dose.

Hong Kong launched its public SARS-CoV-2 immunization program in late February 2021 with the Chinese-made CoronaVac (Sinovac) inactivated-virus vaccine, and introduced the mRNA-based alternative several weeks later. By August 2021, the vaccines had reached about 3.3 million people in the region – 49% of the Hong Kong population at least 12 years of age.

In a novel finding, there were no excesses in carditis cases after CoronaVac vaccination. The difference between vaccines likely isn’t caused by chance, because three-fourths of the carditis-associated Pfizer-BioNTech injections arose within a week, whereas “71% of cases following the use of CoronaVac occurred more than 30 days after vaccination,” senior author Ian Chi Kei Wong, PhD, University of Hong Kong, said in an interview.

“This onset distribution for cases having received CoronaVac demonstrates that it is highly unlikely the carditis cases are related to the vaccine,” he said. And that “plausibly implies a specific underlying mechanism between vaccination and carditis that may only be applicable to mRNA vaccines.”

That inference is in line with case reports and other research, including large population-based studies from Israel and Denmark, although a recent study from the United Kingdom hinted at a potential excess myocarditis risk associated with the adenovirus-based AstraZeneca-Oxford vaccine.

The Hong Kong study identified 160 patients age 12 or older with a first diagnosis of carditis during February to August 2021, in electronic health records covering nearly the entire region.

“We used laboratory test results of troponin levels to further eliminate unlikely cases of carditis,” Dr. Wong said. The health records were linked to a “population-based vaccination record” maintained by the government’s department of health.

About 10 control patients from among all hospitalized patients without carditis were matched by age, sex, and admission date to each of the 160 carditis cases. About 83% of cases and 92% of the controls were unvaccinated.

Among those who received the Pfizer-BioNTech vaccine, representing 12.5% of cases and 4.2% of controls, the estimated carditis incidence was 0.57 per 100,000 doses. For those who received CoronaVac, representing 4.4% of cases and 3.9% of controls, it was 0.31 per 100,000 doses.

In adjusted analysis, the odds ratios for carditis among Pfizer-BioNTech vaccine recipients, compared with unvaccinated controls, were 3.57 (95% confidence interval, 1.93-6.60) overall, 4.68 (95% CI, 2.25-9.71) for males, 2.22 (95% CI, 0.57-8.69) for females, 2.41 (95% CI, 1.18-4.90) for ages 18 and older, and 13.8 (95% CI, 2.86-110.4) for ages 12-17

Myocarditis accounted for most of the excess cases, with an overall OR of 9.29 (95% CI, 3.94-21.9). The OR reached only 1.06 (95% CI, 0.35-3.22) for pericarditis alone.

The case-control study is noteworthy for its design, which contrasts with the many recent case series and passive or active surveillance studies, and even the more robust population-based studies of vaccine-related myocarditis, observed Dongngan Truong, MD, University of Utah and Primary Children’s Hospital, both in Salt Lake City, who wasn’t part of the study.

Among its strengths, she said in an interview, are its linkage of comprehensive hospital and vaccination data sets for two different vaccines; and that it corroborates other research suggesting there is “something in particular about mRNA vaccination that seems to be associated with the development of myocarditis.”

Active surveillance in Israel

In an October 2021 report based on an Israeli Ministry of Health database covering up to May 2021, rates of myocarditis arising within 21 days of a second Pfizer-BioNTech dose in 16- to 19-year-olds reached about 1 per 6,637 males and 1 per 99,853 females. Those numbers compared with 1 per 26,000 males and 1 per 218,000 females across all age groups.

Now authors led by Dror Mevorach, MD, Hadassah Medical Center, Jerusalem, have published corresponding numbers from the same data base for myocarditis associated with the same vaccine in males and females aged 12-15.  

Their research covers 404,407 people in that age group who received a first dose of the mRNA-based vaccine and 326,463 who received the second dose from June to October, 2021. Only 18 cases of myocarditis were observed within 21 days of either dose.

The estimated rates for males were 0.56 cases per 100,000 after a first dose and 8.09 cases per 100,000 after a second dose.

For females, the estimates were 0 cases per 100,000 after a first dose and 0.69 cases per 100,000 after a second dose.

“The pattern observed, mainly following the second vaccination in males, suggests causality,” the group wrote.
 

Leveraging passive surveillance reports

Another new report adds a twist to updated numbers from the U.S. Vaccine Adverse Event Reporting System (VAERS).

Prevalences derived from the passive-surveillance data base, known for including case records of inconsistent quality or completeness, are considered especially prone to reporting bias, the authors acknowledged.

The current analysis, however, plunges deep into VAERS-reported cases of presumed SARS-CoV-2 vaccine-associated myocarditis to help clarify “more of the characteristics of the patients and some of the treatments and short-term outcomes,” Matthew E. Oster, MD, MPH, said in an interview.

Dr. Oster, from the Centers for Disease Control and Prevention and Emory University, Atlanta, is lead author on the study’s Jan. 25, 2022, publication in JAMA.

The group reviewed charts and interviewed involved clinicians to adjudicate and document presentations, therapies, and the clinical course of cases reported as SARS-CoV-2 vaccine–associated myocarditis from December 2020 to August 2021. Out of the nearly 2000 reports, which were limited to patients younger than 30, the group identified 1,626 likely cases of such myocarditis arising within 7 days of a second mRNA vaccine dose.

The confirmed cases consistently represented higher prevalences than expected compared with prepandemic myocarditis claims data for both sexes and across age groups spanning 12-29 years.

For example, rates were highest for adolescent males – about 106 and 71 cases per million second doses of the Pfizer-BioNTech vaccine in those aged 16-17 and 12-16, respectively, for example. They were lowest for women aged 25-29, at 2.23 cases per million second Pfizer-BioNTech doses; the highest rate among females was about 11 per million for the 16-17 age group.

The observed rates, Dr. Oster said, represent an update to VAERS numbers published June 2021 in Morbidity and Mortality Weekly Report covering cases through June 2021.

“Overall, the general risk of having myocarditis from the vaccines is still extremely low. Even in the highest risk groups, it is still extremely low, and still lower than the risk of having cardiac complications from COVID,” he noted.
 

How do patients fare clinically?

From their chart reviews and interviews with case clinicians, Dr. Oster said, “we started to learn quickly that this is really a different type of myocarditis.”

For example, its onset, typically within a few days of the potential immunologic cause, was more rapid than in viral myocarditis, and its symptoms resolved faster, the report notes. Clinical presentations tended to be less severe, treatments not as intensive, and outcomes not as serious, compared with “the kind of typical viral myocarditis that most of the providers were used to taking care of in the past,” he said. “The pattern for these cases was very consistent.”

The study covered VAERS reports of suspected myocarditis arising within a week of first dose of a mRNA-based vaccine from the United States launch of public vaccination in December 2020 to August 2021, the CDC-based group reported. By then, more than 192 million people in the country had received either the Pfizer-BioNTech (age 12 or older) or Moderna (age 18 or older) vaccines.

Of the 1,991 reports of myocarditis, including 391 also involving pericarditis, 1,626 met the study’s definition for myocarditis on adjudication; about 82% of the latter cases were in males.

Based on the investigators’ review of charts and clinician interviews connected with 826 cases that met their definition of myocarditis in patients younger than 30, 89% reported “chest pain, pressure, or discomfort” and 30% reported dyspnea or shortness of breath. Troponin levels were elevated in 98%, 72% of patients who underwent electrocardiography showed abnormalities, and 12% of those with echocardiography had left ventricular ejection fractions less than 50%.

About 96% were hospitalized, and presenting symptoms resolved by discharge in 87% of those with available data, the group noted. Among patients with data on in-hospital therapy, they wrote, NSAIDs were the most common therapy, in 87%.

‘Mild and self-limiting’

The case-control study from Hong Kong didn’t specifically examine patients’ treatment and clinical course, but it does portray their vaccine-associated myocarditis as contrasting with more familiar viral myocarditis.

Patients with “typical” myocarditis tend to be “overall much sicker than what we’re seeing with myocarditis following vaccination,” Dr. Truong agreed. None of the 20 patients with myocarditis after Pfizer-BioNTech vaccination in Hong Kong were admitted to the intensive care unit. That, she added, suggests none required extracorporeal membrane oxygenation or vasoactive support, often necessary in viral myocarditis. “And they had shorter hospital stays.”

In contrast, Dr. Wong noted, 14 of the study’s unvaccinated patients required ICU admission; 12 of them died during the follow-up period. None with vaccine-related carditis died during the study’s follow-up. “We also showed that cases following [Pfizer-BioNTech] vaccination were all mild and self-limiting.”

Dr. Truong largely agreed that SARS-CoV-2 vaccine myocarditis and most myocarditis seen before the pandemic can be viewed as distinct clinical entities, “at least in the short term. I think we do need to follow these patients to look at more long-term outcomes, because at this point I don’t think we know the long-term implications. But at least in the short term, it seems like these patients are different, are much less sick, and recover pretty quickly overall.”

Dr. Oster emphasized that the many and varied acute and long-term hazards from contracting COVID-19 far outweigh any risk for myocarditis from vaccination. But for individuals who were hit with myocarditis soon after their first mRNA vaccine dose, who have already established their susceptibility, he and his colleagues would recommend that they “consider alternatives and not get the vaccine again.”

Dr. Oster reported no relevant financial relationships. Dr. Wong and colleagues did not report any relevant disclosures. Dr. Truong has previously disclosed serving as a consultant to Pfizer.

A version of this article first appeared on Medscape.com.

The American Heart Association recently released a scientific statement concerning hypertension in pregnancy, which laid out the variety of disorders, the epidemiology, the future impact of pregnant persons, and the current debates regarding treatment and diagnosis.

This statement addresses all stages from preconception through post pregnancy and outlines the many prevention and treatment options available. Although family physicians were not specifically called out to be partners in the statement, we have a large role to play for both our pregnant patients and those of reproductive age who are not pregnant.

Preconception health

One of the first things pointed out was preconception health. Regardless of whether each individual family physician provides prenatal care, we can all focus on preconception health for those of reproductive age.

The statement from the AHA points out that “lifestyle changes before and during pregnancy may ameliorate both maternal and fetal risks.”

As many already do, family physicians should focus on encouraging their patients to practice healthy eating and exercise prior to pregnancy to help establish routines that will decrease the risk of hypertensive disorders in pregnancy.

Focusing on care prior to pregnancy also allows the primary care provider to be involved in quickly linking patients to prenatal care, as it is well established that early and complete prenatal care is important for improving outcomes.

Later-in-life pregnancy

The AHA also highlights that many are choosing to have pregnancies at older ages and with greater comorbidities than in past years. This is another area in which family physicians can provide important care.

We can help by first identifying the chronic conditions, such as hypertension and diabetes, that make the hypertensive disorders of pregnancy more likely. We should then focus on the treatment of these conditions during the preconception time so that they are well controlled prior to pregnancy.

We should also preferentially choose medications that our patients will be able to continue in pregnancy, so that control may be maintained throughout pregnancy.

The statement particularly highlights the avoidance of antihypertensives that are renin-angiotensin system blockers.

We can also help prepare our patients for the additional medications, testing, and precautions they will likely require during their pregnancy so that they know what to expect.

Family physicians are also already starting to utilize home blood pressure monitoring and can introduce this method so that patients may continue to monitor their blood pressures during pregnancy.

Throughout pregnancy, the new statement calls in the current debates of when prenatal care providers should be diagnosing hypertensive disorders and the goals of treatment.

Prenatal care providers can use shared decision-making for medication choices and blood pressure goals. They can also continue to encourage the healthy lifestyle choices such as diet and exercise to reduce the risk of poor outcomes.

This AHA also indicates that prenatal care providers can integrate the use of home blood pressure monitoring as they monitor the blood pressure for patients with hypertensive disorders of pregnancy.
 

Postpartum care

The postpartum period is another crucial time for family physicians and other primary care providers to greatly impact their patients with hypertensive diseases of pregnancy.

They can work to ensure that blood pressure is closely monitored and controlled, including by prescribing diuretics, which are typically not used during pregnancy.

If a patient’s blood pressure does not go down on its own, the primary care provider can begin treatment for hypertension outside of pregnancy. This can decrease their long-term cardiac risk factors and provide control prior to any future potential pregnancies.

Providing care during this postpartum time also offers a great opportunity to again encourage lifestyle options that may decrease risk.

Family physicians and other primary care providers can also encourage their patient to be involved in registries that gather data on hypertensive disorders in pregnancy.

In the new statement, the AHA acknowledges the great number of things that are not yet known or fully understood and the health inequities that many face.

Family physicians are positioned to help advocate for their patients and utilize a team-based approach to help provide resources to patients. We must continue to be there for our patients at every stage of their lives to help them live their healthiest lives possible.

The statement also indicates that there may be genetic factors at play more than social determinants of health. It is important to identify what those are for the best care of our patients while ensuring we are doing our best to provide our patients with the resources they need.

Dr. Wheat is a family physician at Erie Family Health Center and program director of Northwestern University’s McGaw Family Medicine residency program, both in Chicago. Dr. Wheat serves on the editorial advisory board of Family Practice News. You can contact her at fpnews@mdedge.com.

The American Heart Association recently released a scientific statement concerning hypertension in pregnancy, which laid out the variety of disorders, the epidemiology, the future impact of pregnant persons, and the current debates regarding treatment and diagnosis.

This statement addresses all stages from preconception through post pregnancy and outlines the many prevention and treatment options available. Although family physicians were not specifically called out to be partners in the statement, we have a large role to play for both our pregnant patients and those of reproductive age who are not pregnant.

Preconception health

One of the first things pointed out was preconception health. Regardless of whether each individual family physician provides prenatal care, we can all focus on preconception health for those of reproductive age.

The statement from the AHA points out that “lifestyle changes before and during pregnancy may ameliorate both maternal and fetal risks.”

As many already do, family physicians should focus on encouraging their patients to practice healthy eating and exercise prior to pregnancy to help establish routines that will decrease the risk of hypertensive disorders in pregnancy.

Focusing on care prior to pregnancy also allows the primary care provider to be involved in quickly linking patients to prenatal care, as it is well established that early and complete prenatal care is important for improving outcomes.

Later-in-life pregnancy

The AHA also highlights that many are choosing to have pregnancies at older ages and with greater comorbidities than in past years. This is another area in which family physicians can provide important care.

We can help by first identifying the chronic conditions, such as hypertension and diabetes, that make the hypertensive disorders of pregnancy more likely. We should then focus on the treatment of these conditions during the preconception time so that they are well controlled prior to pregnancy.

We should also preferentially choose medications that our patients will be able to continue in pregnancy, so that control may be maintained throughout pregnancy.

The statement particularly highlights the avoidance of antihypertensives that are renin-angiotensin system blockers.

We can also help prepare our patients for the additional medications, testing, and precautions they will likely require during their pregnancy so that they know what to expect.

Family physicians are also already starting to utilize home blood pressure monitoring and can introduce this method so that patients may continue to monitor their blood pressures during pregnancy.

Throughout pregnancy, the new statement calls in the current debates of when prenatal care providers should be diagnosing hypertensive disorders and the goals of treatment.

Prenatal care providers can use shared decision-making for medication choices and blood pressure goals. They can also continue to encourage the healthy lifestyle choices such as diet and exercise to reduce the risk of poor outcomes.

This AHA also indicates that prenatal care providers can integrate the use of home blood pressure monitoring as they monitor the blood pressure for patients with hypertensive disorders of pregnancy.
 

Postpartum care

The postpartum period is another crucial time for family physicians and other primary care providers to greatly impact their patients with hypertensive diseases of pregnancy.

They can work to ensure that blood pressure is closely monitored and controlled, including by prescribing diuretics, which are typically not used during pregnancy.

If a patient’s blood pressure does not go down on its own, the primary care provider can begin treatment for hypertension outside of pregnancy. This can decrease their long-term cardiac risk factors and provide control prior to any future potential pregnancies.

Providing care during this postpartum time also offers a great opportunity to again encourage lifestyle options that may decrease risk.

Family physicians and other primary care providers can also encourage their patient to be involved in registries that gather data on hypertensive disorders in pregnancy.

In the new statement, the AHA acknowledges the great number of things that are not yet known or fully understood and the health inequities that many face.

Family physicians are positioned to help advocate for their patients and utilize a team-based approach to help provide resources to patients. We must continue to be there for our patients at every stage of their lives to help them live their healthiest lives possible.

The statement also indicates that there may be genetic factors at play more than social determinants of health. It is important to identify what those are for the best care of our patients while ensuring we are doing our best to provide our patients with the resources they need.

Dr. Wheat is a family physician at Erie Family Health Center and program director of Northwestern University’s McGaw Family Medicine residency program, both in Chicago. Dr. Wheat serves on the editorial advisory board of Family Practice News. You can contact her at fpnews@mdedge.com.

The American Heart Association recently released a scientific statement concerning hypertension in pregnancy, which laid out the variety of disorders, the epidemiology, the future impact of pregnant persons, and the current debates regarding treatment and diagnosis.

This statement addresses all stages from preconception through post pregnancy and outlines the many prevention and treatment options available. Although family physicians were not specifically called out to be partners in the statement, we have a large role to play for both our pregnant patients and those of reproductive age who are not pregnant.

Preconception health

One of the first things pointed out was preconception health. Regardless of whether each individual family physician provides prenatal care, we can all focus on preconception health for those of reproductive age.

The statement from the AHA points out that “lifestyle changes before and during pregnancy may ameliorate both maternal and fetal risks.”

As many already do, family physicians should focus on encouraging their patients to practice healthy eating and exercise prior to pregnancy to help establish routines that will decrease the risk of hypertensive disorders in pregnancy.

Focusing on care prior to pregnancy also allows the primary care provider to be involved in quickly linking patients to prenatal care, as it is well established that early and complete prenatal care is important for improving outcomes.

Later-in-life pregnancy

The AHA also highlights that many are choosing to have pregnancies at older ages and with greater comorbidities than in past years. This is another area in which family physicians can provide important care.

We can help by first identifying the chronic conditions, such as hypertension and diabetes, that make the hypertensive disorders of pregnancy more likely. We should then focus on the treatment of these conditions during the preconception time so that they are well controlled prior to pregnancy.

We should also preferentially choose medications that our patients will be able to continue in pregnancy, so that control may be maintained throughout pregnancy.

The statement particularly highlights the avoidance of antihypertensives that are renin-angiotensin system blockers.

We can also help prepare our patients for the additional medications, testing, and precautions they will likely require during their pregnancy so that they know what to expect.

Family physicians are also already starting to utilize home blood pressure monitoring and can introduce this method so that patients may continue to monitor their blood pressures during pregnancy.

Throughout pregnancy, the new statement calls in the current debates of when prenatal care providers should be diagnosing hypertensive disorders and the goals of treatment.

Prenatal care providers can use shared decision-making for medication choices and blood pressure goals. They can also continue to encourage the healthy lifestyle choices such as diet and exercise to reduce the risk of poor outcomes.

This AHA also indicates that prenatal care providers can integrate the use of home blood pressure monitoring as they monitor the blood pressure for patients with hypertensive disorders of pregnancy.
 

Postpartum care

The postpartum period is another crucial time for family physicians and other primary care providers to greatly impact their patients with hypertensive diseases of pregnancy.

They can work to ensure that blood pressure is closely monitored and controlled, including by prescribing diuretics, which are typically not used during pregnancy.

If a patient’s blood pressure does not go down on its own, the primary care provider can begin treatment for hypertension outside of pregnancy. This can decrease their long-term cardiac risk factors and provide control prior to any future potential pregnancies.

Providing care during this postpartum time also offers a great opportunity to again encourage lifestyle options that may decrease risk.

Family physicians and other primary care providers can also encourage their patient to be involved in registries that gather data on hypertensive disorders in pregnancy.

In the new statement, the AHA acknowledges the great number of things that are not yet known or fully understood and the health inequities that many face.

Family physicians are positioned to help advocate for their patients and utilize a team-based approach to help provide resources to patients. We must continue to be there for our patients at every stage of their lives to help them live their healthiest lives possible.

The statement also indicates that there may be genetic factors at play more than social determinants of health. It is important to identify what those are for the best care of our patients while ensuring we are doing our best to provide our patients with the resources they need.

Dr. Wheat is a family physician at Erie Family Health Center and program director of Northwestern University’s McGaw Family Medicine residency program, both in Chicago. Dr. Wheat serves on the editorial advisory board of Family Practice News. You can contact her at fpnews@mdedge.com.

There’s overall agreement that iron deficiency is prevalent and portends a worse prognosis in patients with heart failure (HF), regardless of ejection fraction or anemia. What remains unclear, however, is which of the many definitions of iron deficiency most closely aligns with adverse outcomes.

Iron deficiency (ID) differs in chronic inflammatory conditions, such as chronic HF, and is defined in international guidelines as a ferritin less than 100 ng/mL or ferritin 100-299 ng/mL with a transferrin saturation (TSAT) less than 20%.

copyrightSaipg/iStockphoto

A new study examining four definitions of ID in more than 4,000 patients with HF revealed that TSAT and serum iron – but not guideline criteria – were independently associated with higher 5-year all-cause mortality, regardless of HF phenotype.

“The standard definition, the society guideline definition of iron deficiency, simply isn’t related to outcome at all. The lines for mortality are, more or less, superimposed,” senior author Andrew L. Clark, MD, Hull (England) University Teaching Hospital NHS Trust, told this news organization.

“So we do think, therefore, there’s a need for a rethink as to what constitutes a definition of iron definition in people with heart failure.”

The results were published in the Journal of the American College of Cardiology.

Previous studies have shown that guideline-defined ID is an independent predictor of mortality in chronic HF, but others have questioned its diagnostic and prognostic utility. A 2018 study using bone marrow iron staining as the gold standard showed that a TSAT of 19.8% or less or serum iron of 13 mcmol/L or less, but not ferritin, identified HF patients at the highest risk for death.

A 2016 report from the Hull LifeLab cohort also showed that the highest quintiles of ferritin had the worst all-cause and cardiovascular (CV) mortality.

Commenting on the new results, Maria Rosa Costanzo, MD, Midwest Cardiovascular Institute, Naperville, Ill., said “the first clinical implication is that we should not use these guidelines to define iron deficiency.

“The fundamental problem with the definition is that ferritin is not a good marker of iron deficiency because ferritin is an inflammatory marker,” she said. “So you could have high ferritin and still have iron deficiency because heart failure, like many other diseases, is an inflammatory state.”

In the present analysis of 4,422 patients referred to the Hull LifeLab clinic between 2001 and 2019, iron deficiency was defined using international guideline criteria, ferritin less than 100 ng/mL, TSAT less than 20%, and serum iron 13 mcmol/L or less.

In line with previous studies, the prevalence of ID was high, ranging from 44% to 68%, depending on the definition. ID was more common in women and in those with more severe symptoms, anemia, or preserved ejection fraction.

Overall, 5-year mortality was 34.5% (median follow-up, 49 months). Unadjusted mortality was lowest for patients with a serum ferritin less than 100 ng/mL and a TSAT greater than 20% and was highest for those with serum ferritin above 100 ng/mL with a TSAT less than 20%.

Serum iron levels and TSAT were highly correlated with each other (r = 0.92; P < .001). “Serum iron is almost entirely transferrin bound, and therefore a close association between serious iron and TSAT is not surprising,” noted the authors, led by Gabriele Masini, MD, University of Brescia (Italy).

After multivariate adjustment, TSAT less than 20% (hazard ratio, 1.27; P < .001) and serum iron of 13 mcmol/L or less (HR, 1.37; P < .001) were associated with greater all-cause mortality but not with CV mortality.

Serum ferritin less than 100 ng/mL tended to be associated with lower adjusted all-cause mortality (HR, 0.91; P = .09), whereas ferritin greater than 300 ng/mL was associated with lower all-cause (HR, 0.69, P < .001) and CV mortality (HR, 0.78; P = .048).

No association was found for guideline ID criteria and all-cause or CV mortality. Among patients fulfilling guideline ID criteria with a TSAT less than 20% and a ferritin 100 to 299 ng/mL, the adjusted hazard ratio for 5-year mortality was 1.82.
 

A ‘new iron age’

Although 3,011 (68%) patients met the guideline definition of ID, 32% of these patients had a TSAT of 20% or greater and serum iron above 13 mcmol/L, noted Dr. Costanzo.

“In other words, 30% of the patients do not have true iron deficiency,” she said. “If these patients are enrolled in trials of treatment for iron deficiency, they may spuriously reduce the efficacy of treatment.”

Intravenous iron has been shown to improve exercise capacity and quality of life in iron-deficient patients with HF in a series of trials, including FAIR-HF, CONFIRM-HF, and EFFECT-HF, and to reduce HF hospitalizations by 21% in the recent AFFIRM-AF trial.

Although from a single center, Dr. Clark said their findings are robust and hoped they spur a reanalysis of the data from older intravenous iron trials, as well as the IRONMAN trial expected later this year in patients with TSAT less than 20% or ferritin less than 100 ng/L.

“I would very much like to encourage industry to take our study and run with it a little bit and see if we can actually persuade them to rerun studies, maybe even very small-scale studies with a couple hundred patients, to see what the signal is using our definition of iron deficiency and seeing if we get a more striking immediate consequence from IV iron treatment as a result,” he said. “Because we think that we’ve now been able to define a group of patients whose iron deficiency is giving them a very poor prognosis and they, therefore, have much more to gain.”

In an accompanying editorial, Dr. Costanzo and coauthor James Januzzi, MD, of Massachusetts General Hospital and Harvard Medical School, both in Boston, also called for further research into better ID definitions and treatments.

“Diagnostically, soluble transferrin receptor levels may have the strongest correlation with the gold standard of bone marrow iron deficit, whereas new treatments, such as blockade of hepcidin, a key modulator of iron absorption and distribution, may emerge as an effective treatment for both absolute and functional ID,” they wrote.

“Ultimately, the study by Masini et al. places us squarely in a new iron age and underscores the great need for more investigation of the pathophysiology, clinical consequences, and treatment of iron deficiency in all patients with HF,” Dr. Costanzo and Dr. Januzzi concluded.

Dr. Masini reported having no relevant financial relationships. Dr. Januzzi is supported by the Hutter Family Professorship; is a trustee of the American College of Cardiology; is a board member of Imbria Pharmaceuticals; has received grant support from Abbott Diagnostics, Applied Therapeutics, Innolife, and Novartis; has received consulting income from Abbott Diagnostics, Boehringer Ingelheim, Janssen, Novartis, and Roche Diagnostics; and participates in clinical endpoint committees/data safety monitoring boards for AbbVie, Siemens, Takeda, and Vifor. Dr. Costanzo is a member of the board of directors for Nuwellis; is a consultant for Boehringer Ingelheim, V-Wave, and Nuwellis; and has received grant support from Novartis, Bayer, V-Wave, Nuwellis, and Abbott.

A version of this article first appeared on Medscape.com.

There’s overall agreement that iron deficiency is prevalent and portends a worse prognosis in patients with heart failure (HF), regardless of ejection fraction or anemia. What remains unclear, however, is which of the many definitions of iron deficiency most closely aligns with adverse outcomes.

Iron deficiency (ID) differs in chronic inflammatory conditions, such as chronic HF, and is defined in international guidelines as a ferritin less than 100 ng/mL or ferritin 100-299 ng/mL with a transferrin saturation (TSAT) less than 20%.

copyrightSaipg/iStockphoto

A new study examining four definitions of ID in more than 4,000 patients with HF revealed that TSAT and serum iron – but not guideline criteria – were independently associated with higher 5-year all-cause mortality, regardless of HF phenotype.

“The standard definition, the society guideline definition of iron deficiency, simply isn’t related to outcome at all. The lines for mortality are, more or less, superimposed,” senior author Andrew L. Clark, MD, Hull (England) University Teaching Hospital NHS Trust, told this news organization.

“So we do think, therefore, there’s a need for a rethink as to what constitutes a definition of iron definition in people with heart failure.”

The results were published in the Journal of the American College of Cardiology.

Previous studies have shown that guideline-defined ID is an independent predictor of mortality in chronic HF, but others have questioned its diagnostic and prognostic utility. A 2018 study using bone marrow iron staining as the gold standard showed that a TSAT of 19.8% or less or serum iron of 13 mcmol/L or less, but not ferritin, identified HF patients at the highest risk for death.

A 2016 report from the Hull LifeLab cohort also showed that the highest quintiles of ferritin had the worst all-cause and cardiovascular (CV) mortality.

Commenting on the new results, Maria Rosa Costanzo, MD, Midwest Cardiovascular Institute, Naperville, Ill., said “the first clinical implication is that we should not use these guidelines to define iron deficiency.

“The fundamental problem with the definition is that ferritin is not a good marker of iron deficiency because ferritin is an inflammatory marker,” she said. “So you could have high ferritin and still have iron deficiency because heart failure, like many other diseases, is an inflammatory state.”

In the present analysis of 4,422 patients referred to the Hull LifeLab clinic between 2001 and 2019, iron deficiency was defined using international guideline criteria, ferritin less than 100 ng/mL, TSAT less than 20%, and serum iron 13 mcmol/L or less.

In line with previous studies, the prevalence of ID was high, ranging from 44% to 68%, depending on the definition. ID was more common in women and in those with more severe symptoms, anemia, or preserved ejection fraction.

Overall, 5-year mortality was 34.5% (median follow-up, 49 months). Unadjusted mortality was lowest for patients with a serum ferritin less than 100 ng/mL and a TSAT greater than 20% and was highest for those with serum ferritin above 100 ng/mL with a TSAT less than 20%.

Serum iron levels and TSAT were highly correlated with each other (r = 0.92; P < .001). “Serum iron is almost entirely transferrin bound, and therefore a close association between serious iron and TSAT is not surprising,” noted the authors, led by Gabriele Masini, MD, University of Brescia (Italy).

After multivariate adjustment, TSAT less than 20% (hazard ratio, 1.27; P < .001) and serum iron of 13 mcmol/L or less (HR, 1.37; P < .001) were associated with greater all-cause mortality but not with CV mortality.

Serum ferritin less than 100 ng/mL tended to be associated with lower adjusted all-cause mortality (HR, 0.91; P = .09), whereas ferritin greater than 300 ng/mL was associated with lower all-cause (HR, 0.69, P < .001) and CV mortality (HR, 0.78; P = .048).

No association was found for guideline ID criteria and all-cause or CV mortality. Among patients fulfilling guideline ID criteria with a TSAT less than 20% and a ferritin 100 to 299 ng/mL, the adjusted hazard ratio for 5-year mortality was 1.82.
 

A ‘new iron age’

Although 3,011 (68%) patients met the guideline definition of ID, 32% of these patients had a TSAT of 20% or greater and serum iron above 13 mcmol/L, noted Dr. Costanzo.

“In other words, 30% of the patients do not have true iron deficiency,” she said. “If these patients are enrolled in trials of treatment for iron deficiency, they may spuriously reduce the efficacy of treatment.”

Intravenous iron has been shown to improve exercise capacity and quality of life in iron-deficient patients with HF in a series of trials, including FAIR-HF, CONFIRM-HF, and EFFECT-HF, and to reduce HF hospitalizations by 21% in the recent AFFIRM-AF trial.

Although from a single center, Dr. Clark said their findings are robust and hoped they spur a reanalysis of the data from older intravenous iron trials, as well as the IRONMAN trial expected later this year in patients with TSAT less than 20% or ferritin less than 100 ng/L.

“I would very much like to encourage industry to take our study and run with it a little bit and see if we can actually persuade them to rerun studies, maybe even very small-scale studies with a couple hundred patients, to see what the signal is using our definition of iron deficiency and seeing if we get a more striking immediate consequence from IV iron treatment as a result,” he said. “Because we think that we’ve now been able to define a group of patients whose iron deficiency is giving them a very poor prognosis and they, therefore, have much more to gain.”

In an accompanying editorial, Dr. Costanzo and coauthor James Januzzi, MD, of Massachusetts General Hospital and Harvard Medical School, both in Boston, also called for further research into better ID definitions and treatments.

“Diagnostically, soluble transferrin receptor levels may have the strongest correlation with the gold standard of bone marrow iron deficit, whereas new treatments, such as blockade of hepcidin, a key modulator of iron absorption and distribution, may emerge as an effective treatment for both absolute and functional ID,” they wrote.

“Ultimately, the study by Masini et al. places us squarely in a new iron age and underscores the great need for more investigation of the pathophysiology, clinical consequences, and treatment of iron deficiency in all patients with HF,” Dr. Costanzo and Dr. Januzzi concluded.

Dr. Masini reported having no relevant financial relationships. Dr. Januzzi is supported by the Hutter Family Professorship; is a trustee of the American College of Cardiology; is a board member of Imbria Pharmaceuticals; has received grant support from Abbott Diagnostics, Applied Therapeutics, Innolife, and Novartis; has received consulting income from Abbott Diagnostics, Boehringer Ingelheim, Janssen, Novartis, and Roche Diagnostics; and participates in clinical endpoint committees/data safety monitoring boards for AbbVie, Siemens, Takeda, and Vifor. Dr. Costanzo is a member of the board of directors for Nuwellis; is a consultant for Boehringer Ingelheim, V-Wave, and Nuwellis; and has received grant support from Novartis, Bayer, V-Wave, Nuwellis, and Abbott.

A version of this article first appeared on Medscape.com.

There’s overall agreement that iron deficiency is prevalent and portends a worse prognosis in patients with heart failure (HF), regardless of ejection fraction or anemia. What remains unclear, however, is which of the many definitions of iron deficiency most closely aligns with adverse outcomes.

Iron deficiency (ID) differs in chronic inflammatory conditions, such as chronic HF, and is defined in international guidelines as a ferritin less than 100 ng/mL or ferritin 100-299 ng/mL with a transferrin saturation (TSAT) less than 20%.

copyrightSaipg/iStockphoto

A new study examining four definitions of ID in more than 4,000 patients with HF revealed that TSAT and serum iron – but not guideline criteria – were independently associated with higher 5-year all-cause mortality, regardless of HF phenotype.

“The standard definition, the society guideline definition of iron deficiency, simply isn’t related to outcome at all. The lines for mortality are, more or less, superimposed,” senior author Andrew L. Clark, MD, Hull (England) University Teaching Hospital NHS Trust, told this news organization.

“So we do think, therefore, there’s a need for a rethink as to what constitutes a definition of iron definition in people with heart failure.”

The results were published in the Journal of the American College of Cardiology.

Previous studies have shown that guideline-defined ID is an independent predictor of mortality in chronic HF, but others have questioned its diagnostic and prognostic utility. A 2018 study using bone marrow iron staining as the gold standard showed that a TSAT of 19.8% or less or serum iron of 13 mcmol/L or less, but not ferritin, identified HF patients at the highest risk for death.

A 2016 report from the Hull LifeLab cohort also showed that the highest quintiles of ferritin had the worst all-cause and cardiovascular (CV) mortality.

Commenting on the new results, Maria Rosa Costanzo, MD, Midwest Cardiovascular Institute, Naperville, Ill., said “the first clinical implication is that we should not use these guidelines to define iron deficiency.

“The fundamental problem with the definition is that ferritin is not a good marker of iron deficiency because ferritin is an inflammatory marker,” she said. “So you could have high ferritin and still have iron deficiency because heart failure, like many other diseases, is an inflammatory state.”

In the present analysis of 4,422 patients referred to the Hull LifeLab clinic between 2001 and 2019, iron deficiency was defined using international guideline criteria, ferritin less than 100 ng/mL, TSAT less than 20%, and serum iron 13 mcmol/L or less.

In line with previous studies, the prevalence of ID was high, ranging from 44% to 68%, depending on the definition. ID was more common in women and in those with more severe symptoms, anemia, or preserved ejection fraction.

Overall, 5-year mortality was 34.5% (median follow-up, 49 months). Unadjusted mortality was lowest for patients with a serum ferritin less than 100 ng/mL and a TSAT greater than 20% and was highest for those with serum ferritin above 100 ng/mL with a TSAT less than 20%.

Serum iron levels and TSAT were highly correlated with each other (r = 0.92; P < .001). “Serum iron is almost entirely transferrin bound, and therefore a close association between serious iron and TSAT is not surprising,” noted the authors, led by Gabriele Masini, MD, University of Brescia (Italy).

After multivariate adjustment, TSAT less than 20% (hazard ratio, 1.27; P < .001) and serum iron of 13 mcmol/L or less (HR, 1.37; P < .001) were associated with greater all-cause mortality but not with CV mortality.

Serum ferritin less than 100 ng/mL tended to be associated with lower adjusted all-cause mortality (HR, 0.91; P = .09), whereas ferritin greater than 300 ng/mL was associated with lower all-cause (HR, 0.69, P < .001) and CV mortality (HR, 0.78; P = .048).

No association was found for guideline ID criteria and all-cause or CV mortality. Among patients fulfilling guideline ID criteria with a TSAT less than 20% and a ferritin 100 to 299 ng/mL, the adjusted hazard ratio for 5-year mortality was 1.82.
 

A ‘new iron age’

Although 3,011 (68%) patients met the guideline definition of ID, 32% of these patients had a TSAT of 20% or greater and serum iron above 13 mcmol/L, noted Dr. Costanzo.

“In other words, 30% of the patients do not have true iron deficiency,” she said. “If these patients are enrolled in trials of treatment for iron deficiency, they may spuriously reduce the efficacy of treatment.”

Intravenous iron has been shown to improve exercise capacity and quality of life in iron-deficient patients with HF in a series of trials, including FAIR-HF, CONFIRM-HF, and EFFECT-HF, and to reduce HF hospitalizations by 21% in the recent AFFIRM-AF trial.

Although from a single center, Dr. Clark said their findings are robust and hoped they spur a reanalysis of the data from older intravenous iron trials, as well as the IRONMAN trial expected later this year in patients with TSAT less than 20% or ferritin less than 100 ng/L.

“I would very much like to encourage industry to take our study and run with it a little bit and see if we can actually persuade them to rerun studies, maybe even very small-scale studies with a couple hundred patients, to see what the signal is using our definition of iron deficiency and seeing if we get a more striking immediate consequence from IV iron treatment as a result,” he said. “Because we think that we’ve now been able to define a group of patients whose iron deficiency is giving them a very poor prognosis and they, therefore, have much more to gain.”

In an accompanying editorial, Dr. Costanzo and coauthor James Januzzi, MD, of Massachusetts General Hospital and Harvard Medical School, both in Boston, also called for further research into better ID definitions and treatments.

“Diagnostically, soluble transferrin receptor levels may have the strongest correlation with the gold standard of bone marrow iron deficit, whereas new treatments, such as blockade of hepcidin, a key modulator of iron absorption and distribution, may emerge as an effective treatment for both absolute and functional ID,” they wrote.

“Ultimately, the study by Masini et al. places us squarely in a new iron age and underscores the great need for more investigation of the pathophysiology, clinical consequences, and treatment of iron deficiency in all patients with HF,” Dr. Costanzo and Dr. Januzzi concluded.

Dr. Masini reported having no relevant financial relationships. Dr. Januzzi is supported by the Hutter Family Professorship; is a trustee of the American College of Cardiology; is a board member of Imbria Pharmaceuticals; has received grant support from Abbott Diagnostics, Applied Therapeutics, Innolife, and Novartis; has received consulting income from Abbott Diagnostics, Boehringer Ingelheim, Janssen, Novartis, and Roche Diagnostics; and participates in clinical endpoint committees/data safety monitoring boards for AbbVie, Siemens, Takeda, and Vifor. Dr. Costanzo is a member of the board of directors for Nuwellis; is a consultant for Boehringer Ingelheim, V-Wave, and Nuwellis; and has received grant support from Novartis, Bayer, V-Wave, Nuwellis, and Abbott.

A version of this article first appeared on Medscape.com.

As inclisiran, a first-in-class LDL-cholesterol lowering drug, enters the U.S. market following Food and Drug Administration approval in December 2021, several issues muddy how popular inclisiran will be in actual practice. That’s despite stellar phase 3 trial evidence for safety, tolerability, and a potent lipid-lowering effect.

The active ingredient of inclisiran (Leqvio) is a small interfering RNA (siRNA) molecule that shuts down production of the PCSK9 (proprotein convertase subtilisin/kexin type 9) protein, an enzyme that’s made and functions primarily in the liver and degrades cellular receptors for LDL cholesterol. Inhibiting PCSK9 production means LDL-cholesterol receptors accumulate and boost the ability of liver cells to pull more LDL cholesterol out of blood.

PCSK9 inhibition is the most potent LDL-cholesterol lowering method now available, and it works well in patients who have maxed out LDL reduction by diet and statin treatment. The siRNA of inclisiran is tweaked to target the molecule to the surface of liver cells following subcutaneous injection. Other modifications of the siRNA give it stability that allows twice-a-year dosing, although patients receive a third injection during their first year to hasten a maximum treatment effect.

Inclisiran’s FDA approval relied on results from three pivotal trials that together enrolled 3,660 patients with either atherosclerotic cardiovascular disease (ASCVD), ASCVD risk equivalents, or heterozygous familial hypercholesterolemia (HeFH), and LDL-cholesterol levels of at least 70 mg/dL in those with established ASCVD, or at least 100 mg/dL in other patients. (HeFH and ASCVD are the drug’s approved indications.) Pooled data from the three trials showed that inclisiran was safe and well tolerated during 18 months and produced an average LDL-cholesterol reduction after 510 days (1.4 years) of about 51% compared to baseline after correction for placebo effects (J Am Coll Cardiol. 2021 Mar 9;77 [9]:1182-93).

These data showed inclisiran was about as safe and effective for reducing LDL-cholesterol as agents from another class of PCSK9 inhibitors that rely on injected antibodies to inactivate PCSK9. Two agents from this class, alirocumab (Praluent) and evolocumab (Repatha), both came on the U.S. market in 2015. Although their performance in routine practice during the ensuing 6-plus years has been as safe and effective as what they showed in their respective registration trials, they have faced a rocky uptake road that’s been primarily hindered by the hefty price tag that both drugs carry.
 

Prior-authorization blues

When they first came out, evolocumab and alirocumab were burdened by annual drug costs of roughly $14,000, a fact that led to widespread prior-authorization and copay barriers set up by U.S. insurers. Although these barriers gradually lessened over time, in part aided by a substantial price cut for both drugs that led to annual drug costs more in the range of $6,000/year, they remain relatively pricey and are still not easy to start in patients because of prior-authorization requirements, said clinicians.

Recent penetration of the older PCSK9 inhibitors into eligible U.S. patients “is only about 1%-2%, based on the latest data,” said Michael H. Davidson, MD, a lipid specialist and director of Preventive Cardiology at the University of Chicago.

“We have these great, effective drugs, but they haven’t really made an impact over the past 5 years,” because of very limited uptake, a situation Dr. Davidson called “very disappointing,” during an interview.

Given this recent history, inclisiran, another expensive PCSK9 inhibitor, may face similar coverage pushback as it hits the U.S. market with a retail price, announced by its manufacturer Novartis, of $3,250/dose. This means that patients who start the drug and receive their initial dose, a second dose after 3 months, and then additional doses every 6 months, rack up a drug cost of close to $10,000 the first year on the drug and $6,500 each subsequent year.

This treatment schedule highlights the major logistical difference that distinguishes inclisiran from the antibody-based PCSK9 inhibitors, which are given by repeated subcutaneous injection every 2 or 4 weeks, usually with patients self-injecting the drugs at home. The less-frequent dosing schedule for inclisiran prompted the drug’s developers to schedule injections by a clinician in an office setting in the pivotal trials, which led to labeling for inclisiran that specifies administration only by a health care professional.
 

The ‘buy-and-bill’ coverage model

This difference in drug administration between inclisiran and the antibody-based PCSK9 inhibitors set up Novartis to promote insurance reimbursement for inclisiran using a “buy-and-bill” paradigm that was first developed for oncology drugs and which may provide a loophole around the prior-authorization roadblocks that hindered early uptake of the antibody-based PCSK9 inhibitors.

It’s also an approach that has made U.S. clinicians unsure how it will play out in practice. Infrequent inclisiran dosing may also boost patient compliance.

“Adherence is the greatest challenge in preventive cardiology, and thus inclisiran has the potential to be a game changer,” commented Christie M. Ballantyne, MD, professor and chief of cardiology at Baylor College of Medicine, Houston.

“Will it be easier for physicians to write a prescription and for patients to get the medication without a demanding and frustrating prior-authorization process?” he wondered during an interview. “I’m waiting to see how this unfolds, especially in systems where pharmacy is not fully integrated with the outpatient setting. In some ways, this is as big of an experiment as was development of the drug,” Dr. Ballantyne said.

Although the prior-authorization hoops for evolocumab and alirocumab have become easier to jump through, “most physicians don’t have the resources to handle it and don’t bother,” noted Dr. Davidson, and he’s concerned that infrastructure challenges will also hamper the buy-and-bill strategy for inclisiran.

He also expressed skepticism that the prior-authorization barrier will disappear. “Payers don’t want to open a large population to a very expensive drug without some gatekeeping,” he said, while acknowledging that in late January 2022 he did not yet have personal experience administering inclisiran or navigating its insurance reimbursement.
 

Boosting patient compliance

Dr. Davidson agreed that the prospect for enhanced patient compliance with inclisiran was intriguing and had already drawn the interest of some of his patients.

“There is a lot of appeal” to a treatment that’s only given once every 6 months, he said. “Compliance is a major issue, and this is less work for patients.”

“The biggest possible attraction of inclisiran is that it is given twice a year, but whether this plays out as anticipated in the real world need to be seen,” cautioned Vijay Nambi, MD, a cardiologist at the Michael E. DeBakey VA Hospital, Houston, and at Baylor College of Medicine who has written about inclisiran. He noted that while two doses a year is “on paper very attractive,” this scheme opens the door to missed or delayed appointments because of vacations, other patient travel, or events like a pandemic.

“The biggest pro for inclisiran is the dosing schedule,” said Chandni Bardolia, PharmD, a drug information specialist at Tabula Rasa Healthcare, Moorestown, N.J., who has analyzed and written about inclisiran and other lipid-lowering medications. “Twice yearly dosing following initiation will be a huge benefit to improve adherence and reduce the number of injections.”

However, inclisiran’s attractive dosing schedule as well as its safety and potent efficacy do not tell the whole story, she highlighted in an interview.

Inclisiran’s clinical evidence still cooking

“I see inclisiran as a last-line drug, mainly because the current alternatives have more safety and efficacy data,” Dr. Bardolia said.

Inclisiran’s “cost and the fact that there are other agents with clinical outcome data already available [alirocumab and evolocumab] means inclisiran is not a first-line agent after statins,” agreed Dr. Nambi.

The FDA based its inclisiran approval entirely on the drug’s demonstrated safety and LDL-lowering efficacy. The cardiovascular outcomes trial for inclisiran, ORION-4, with about 15,000 enrolled patients, started in 2018 and remains in progress with full results expected in 2026.

The lack of clinical outcomes data for inclisiran is a major limitation, said Neil J. Stone, MD, a cardiologist and professor at Northwestern University, Chicago, and vice chair of the panel that wrote the most recent cholesterol guideline for the American College of Cardiology and American Heart Association.

“My greatest concern is the lack of outcome trial data. That’s very important,” Dr. Stone said in an interview.

But others minimize this limitation given the overwhelming evidence that links lower levels of LDL-cholesterol to reduced clinical events.

Most clinicians “support lower LDL as a surrogate” for reduced clinical events, “just like blood pressure and hemoglobin A1c,” noted Dr. Davidson, although he conceded that a “substantial minority wants to wait to see inclisiran’s outcome benefits.”
 

It’s all about price

While opinions are mixed on the need for clinical outcomes data, experts are more uniform in seeing drug prices that run to several thousands per year as the main uptake issue.

“We need to look at the cost-efficacy with inclisiran, and we need benefit data to determine this,” said Dr. Stone.

“Outcomes data are central to characterizing value. I imagine that costs will impact adoption and dissemination” of inclisiran, commented Paul L. Hess, MD, a cardiologist at the Rocky Mountain Regional VA Medical Center, Denver.

Patient interest in less frequent dosing will be important for driving use, but “ultimately cost will be the most important driving factor,” for inclisiran uptake, commented Robert H. Eckel, MD, an endocrinologist affiliated with the University of Colorado School of Medicine, Aurora.

Dr. Davidson has ties to New Amsterdam Pharma and Amgen, which markets evolocumab (Repatha). Dr. Ballantyne is a consultant to numerous companies, including Amgen and Regeneron, which market alirocumab (Praluent). Dr. Nambi has been a site investigator for studies sponsored by Amgen, and by Merck, which markets the LDL-cholesterol drug ezetimibe (Zetia) and is developing an oral PCSK9 inhibitor (he said that the views he expressed are his own and don’t represent that of the department of Veterans Affairs or Baylor.) Dr. Bardolia had no disclosures beyond her employment at Tabula Rasa Healthcare. Dr. Stone, Dr. Hess, and Dr. Eckel had no relevant disclosures.


 

As inclisiran, a first-in-class LDL-cholesterol lowering drug, enters the U.S. market following Food and Drug Administration approval in December 2021, several issues muddy how popular inclisiran will be in actual practice. That’s despite stellar phase 3 trial evidence for safety, tolerability, and a potent lipid-lowering effect.

The active ingredient of inclisiran (Leqvio) is a small interfering RNA (siRNA) molecule that shuts down production of the PCSK9 (proprotein convertase subtilisin/kexin type 9) protein, an enzyme that’s made and functions primarily in the liver and degrades cellular receptors for LDL cholesterol. Inhibiting PCSK9 production means LDL-cholesterol receptors accumulate and boost the ability of liver cells to pull more LDL cholesterol out of blood.

PCSK9 inhibition is the most potent LDL-cholesterol lowering method now available, and it works well in patients who have maxed out LDL reduction by diet and statin treatment. The siRNA of inclisiran is tweaked to target the molecule to the surface of liver cells following subcutaneous injection. Other modifications of the siRNA give it stability that allows twice-a-year dosing, although patients receive a third injection during their first year to hasten a maximum treatment effect.

Inclisiran’s FDA approval relied on results from three pivotal trials that together enrolled 3,660 patients with either atherosclerotic cardiovascular disease (ASCVD), ASCVD risk equivalents, or heterozygous familial hypercholesterolemia (HeFH), and LDL-cholesterol levels of at least 70 mg/dL in those with established ASCVD, or at least 100 mg/dL in other patients. (HeFH and ASCVD are the drug’s approved indications.) Pooled data from the three trials showed that inclisiran was safe and well tolerated during 18 months and produced an average LDL-cholesterol reduction after 510 days (1.4 years) of about 51% compared to baseline after correction for placebo effects (J Am Coll Cardiol. 2021 Mar 9;77 [9]:1182-93).

These data showed inclisiran was about as safe and effective for reducing LDL-cholesterol as agents from another class of PCSK9 inhibitors that rely on injected antibodies to inactivate PCSK9. Two agents from this class, alirocumab (Praluent) and evolocumab (Repatha), both came on the U.S. market in 2015. Although their performance in routine practice during the ensuing 6-plus years has been as safe and effective as what they showed in their respective registration trials, they have faced a rocky uptake road that’s been primarily hindered by the hefty price tag that both drugs carry.
 

Prior-authorization blues

When they first came out, evolocumab and alirocumab were burdened by annual drug costs of roughly $14,000, a fact that led to widespread prior-authorization and copay barriers set up by U.S. insurers. Although these barriers gradually lessened over time, in part aided by a substantial price cut for both drugs that led to annual drug costs more in the range of $6,000/year, they remain relatively pricey and are still not easy to start in patients because of prior-authorization requirements, said clinicians.

Recent penetration of the older PCSK9 inhibitors into eligible U.S. patients “is only about 1%-2%, based on the latest data,” said Michael H. Davidson, MD, a lipid specialist and director of Preventive Cardiology at the University of Chicago.

“We have these great, effective drugs, but they haven’t really made an impact over the past 5 years,” because of very limited uptake, a situation Dr. Davidson called “very disappointing,” during an interview.

Given this recent history, inclisiran, another expensive PCSK9 inhibitor, may face similar coverage pushback as it hits the U.S. market with a retail price, announced by its manufacturer Novartis, of $3,250/dose. This means that patients who start the drug and receive their initial dose, a second dose after 3 months, and then additional doses every 6 months, rack up a drug cost of close to $10,000 the first year on the drug and $6,500 each subsequent year.

This treatment schedule highlights the major logistical difference that distinguishes inclisiran from the antibody-based PCSK9 inhibitors, which are given by repeated subcutaneous injection every 2 or 4 weeks, usually with patients self-injecting the drugs at home. The less-frequent dosing schedule for inclisiran prompted the drug’s developers to schedule injections by a clinician in an office setting in the pivotal trials, which led to labeling for inclisiran that specifies administration only by a health care professional.
 

The ‘buy-and-bill’ coverage model

This difference in drug administration between inclisiran and the antibody-based PCSK9 inhibitors set up Novartis to promote insurance reimbursement for inclisiran using a “buy-and-bill” paradigm that was first developed for oncology drugs and which may provide a loophole around the prior-authorization roadblocks that hindered early uptake of the antibody-based PCSK9 inhibitors.

It’s also an approach that has made U.S. clinicians unsure how it will play out in practice. Infrequent inclisiran dosing may also boost patient compliance.

“Adherence is the greatest challenge in preventive cardiology, and thus inclisiran has the potential to be a game changer,” commented Christie M. Ballantyne, MD, professor and chief of cardiology at Baylor College of Medicine, Houston.

“Will it be easier for physicians to write a prescription and for patients to get the medication without a demanding and frustrating prior-authorization process?” he wondered during an interview. “I’m waiting to see how this unfolds, especially in systems where pharmacy is not fully integrated with the outpatient setting. In some ways, this is as big of an experiment as was development of the drug,” Dr. Ballantyne said.

Although the prior-authorization hoops for evolocumab and alirocumab have become easier to jump through, “most physicians don’t have the resources to handle it and don’t bother,” noted Dr. Davidson, and he’s concerned that infrastructure challenges will also hamper the buy-and-bill strategy for inclisiran.

He also expressed skepticism that the prior-authorization barrier will disappear. “Payers don’t want to open a large population to a very expensive drug without some gatekeeping,” he said, while acknowledging that in late January 2022 he did not yet have personal experience administering inclisiran or navigating its insurance reimbursement.
 

Boosting patient compliance

Dr. Davidson agreed that the prospect for enhanced patient compliance with inclisiran was intriguing and had already drawn the interest of some of his patients.

“There is a lot of appeal” to a treatment that’s only given once every 6 months, he said. “Compliance is a major issue, and this is less work for patients.”

“The biggest possible attraction of inclisiran is that it is given twice a year, but whether this plays out as anticipated in the real world need to be seen,” cautioned Vijay Nambi, MD, a cardiologist at the Michael E. DeBakey VA Hospital, Houston, and at Baylor College of Medicine who has written about inclisiran. He noted that while two doses a year is “on paper very attractive,” this scheme opens the door to missed or delayed appointments because of vacations, other patient travel, or events like a pandemic.

“The biggest pro for inclisiran is the dosing schedule,” said Chandni Bardolia, PharmD, a drug information specialist at Tabula Rasa Healthcare, Moorestown, N.J., who has analyzed and written about inclisiran and other lipid-lowering medications. “Twice yearly dosing following initiation will be a huge benefit to improve adherence and reduce the number of injections.”

However, inclisiran’s attractive dosing schedule as well as its safety and potent efficacy do not tell the whole story, she highlighted in an interview.

Inclisiran’s clinical evidence still cooking

“I see inclisiran as a last-line drug, mainly because the current alternatives have more safety and efficacy data,” Dr. Bardolia said.

Inclisiran’s “cost and the fact that there are other agents with clinical outcome data already available [alirocumab and evolocumab] means inclisiran is not a first-line agent after statins,” agreed Dr. Nambi.

The FDA based its inclisiran approval entirely on the drug’s demonstrated safety and LDL-lowering efficacy. The cardiovascular outcomes trial for inclisiran, ORION-4, with about 15,000 enrolled patients, started in 2018 and remains in progress with full results expected in 2026.

The lack of clinical outcomes data for inclisiran is a major limitation, said Neil J. Stone, MD, a cardiologist and professor at Northwestern University, Chicago, and vice chair of the panel that wrote the most recent cholesterol guideline for the American College of Cardiology and American Heart Association.

“My greatest concern is the lack of outcome trial data. That’s very important,” Dr. Stone said in an interview.

But others minimize this limitation given the overwhelming evidence that links lower levels of LDL-cholesterol to reduced clinical events.

Most clinicians “support lower LDL as a surrogate” for reduced clinical events, “just like blood pressure and hemoglobin A1c,” noted Dr. Davidson, although he conceded that a “substantial minority wants to wait to see inclisiran’s outcome benefits.”
 

It’s all about price

While opinions are mixed on the need for clinical outcomes data, experts are more uniform in seeing drug prices that run to several thousands per year as the main uptake issue.

“We need to look at the cost-efficacy with inclisiran, and we need benefit data to determine this,” said Dr. Stone.

“Outcomes data are central to characterizing value. I imagine that costs will impact adoption and dissemination” of inclisiran, commented Paul L. Hess, MD, a cardiologist at the Rocky Mountain Regional VA Medical Center, Denver.

Patient interest in less frequent dosing will be important for driving use, but “ultimately cost will be the most important driving factor,” for inclisiran uptake, commented Robert H. Eckel, MD, an endocrinologist affiliated with the University of Colorado School of Medicine, Aurora.

Dr. Davidson has ties to New Amsterdam Pharma and Amgen, which markets evolocumab (Repatha). Dr. Ballantyne is a consultant to numerous companies, including Amgen and Regeneron, which market alirocumab (Praluent). Dr. Nambi has been a site investigator for studies sponsored by Amgen, and by Merck, which markets the LDL-cholesterol drug ezetimibe (Zetia) and is developing an oral PCSK9 inhibitor (he said that the views he expressed are his own and don’t represent that of the department of Veterans Affairs or Baylor.) Dr. Bardolia had no disclosures beyond her employment at Tabula Rasa Healthcare. Dr. Stone, Dr. Hess, and Dr. Eckel had no relevant disclosures.


 

As inclisiran, a first-in-class LDL-cholesterol lowering drug, enters the U.S. market following Food and Drug Administration approval in December 2021, several issues muddy how popular inclisiran will be in actual practice. That’s despite stellar phase 3 trial evidence for safety, tolerability, and a potent lipid-lowering effect.

The active ingredient of inclisiran (Leqvio) is a small interfering RNA (siRNA) molecule that shuts down production of the PCSK9 (proprotein convertase subtilisin/kexin type 9) protein, an enzyme that’s made and functions primarily in the liver and degrades cellular receptors for LDL cholesterol. Inhibiting PCSK9 production means LDL-cholesterol receptors accumulate and boost the ability of liver cells to pull more LDL cholesterol out of blood.

PCSK9 inhibition is the most potent LDL-cholesterol lowering method now available, and it works well in patients who have maxed out LDL reduction by diet and statin treatment. The siRNA of inclisiran is tweaked to target the molecule to the surface of liver cells following subcutaneous injection. Other modifications of the siRNA give it stability that allows twice-a-year dosing, although patients receive a third injection during their first year to hasten a maximum treatment effect.

Inclisiran’s FDA approval relied on results from three pivotal trials that together enrolled 3,660 patients with either atherosclerotic cardiovascular disease (ASCVD), ASCVD risk equivalents, or heterozygous familial hypercholesterolemia (HeFH), and LDL-cholesterol levels of at least 70 mg/dL in those with established ASCVD, or at least 100 mg/dL in other patients. (HeFH and ASCVD are the drug’s approved indications.) Pooled data from the three trials showed that inclisiran was safe and well tolerated during 18 months and produced an average LDL-cholesterol reduction after 510 days (1.4 years) of about 51% compared to baseline after correction for placebo effects (J Am Coll Cardiol. 2021 Mar 9;77 [9]:1182-93).

These data showed inclisiran was about as safe and effective for reducing LDL-cholesterol as agents from another class of PCSK9 inhibitors that rely on injected antibodies to inactivate PCSK9. Two agents from this class, alirocumab (Praluent) and evolocumab (Repatha), both came on the U.S. market in 2015. Although their performance in routine practice during the ensuing 6-plus years has been as safe and effective as what they showed in their respective registration trials, they have faced a rocky uptake road that’s been primarily hindered by the hefty price tag that both drugs carry.
 

Prior-authorization blues

When they first came out, evolocumab and alirocumab were burdened by annual drug costs of roughly $14,000, a fact that led to widespread prior-authorization and copay barriers set up by U.S. insurers. Although these barriers gradually lessened over time, in part aided by a substantial price cut for both drugs that led to annual drug costs more in the range of $6,000/year, they remain relatively pricey and are still not easy to start in patients because of prior-authorization requirements, said clinicians.

Recent penetration of the older PCSK9 inhibitors into eligible U.S. patients “is only about 1%-2%, based on the latest data,” said Michael H. Davidson, MD, a lipid specialist and director of Preventive Cardiology at the University of Chicago.

“We have these great, effective drugs, but they haven’t really made an impact over the past 5 years,” because of very limited uptake, a situation Dr. Davidson called “very disappointing,” during an interview.

Given this recent history, inclisiran, another expensive PCSK9 inhibitor, may face similar coverage pushback as it hits the U.S. market with a retail price, announced by its manufacturer Novartis, of $3,250/dose. This means that patients who start the drug and receive their initial dose, a second dose after 3 months, and then additional doses every 6 months, rack up a drug cost of close to $10,000 the first year on the drug and $6,500 each subsequent year.

This treatment schedule highlights the major logistical difference that distinguishes inclisiran from the antibody-based PCSK9 inhibitors, which are given by repeated subcutaneous injection every 2 or 4 weeks, usually with patients self-injecting the drugs at home. The less-frequent dosing schedule for inclisiran prompted the drug’s developers to schedule injections by a clinician in an office setting in the pivotal trials, which led to labeling for inclisiran that specifies administration only by a health care professional.
 

The ‘buy-and-bill’ coverage model

This difference in drug administration between inclisiran and the antibody-based PCSK9 inhibitors set up Novartis to promote insurance reimbursement for inclisiran using a “buy-and-bill” paradigm that was first developed for oncology drugs and which may provide a loophole around the prior-authorization roadblocks that hindered early uptake of the antibody-based PCSK9 inhibitors.

It’s also an approach that has made U.S. clinicians unsure how it will play out in practice. Infrequent inclisiran dosing may also boost patient compliance.

“Adherence is the greatest challenge in preventive cardiology, and thus inclisiran has the potential to be a game changer,” commented Christie M. Ballantyne, MD, professor and chief of cardiology at Baylor College of Medicine, Houston.

“Will it be easier for physicians to write a prescription and for patients to get the medication without a demanding and frustrating prior-authorization process?” he wondered during an interview. “I’m waiting to see how this unfolds, especially in systems where pharmacy is not fully integrated with the outpatient setting. In some ways, this is as big of an experiment as was development of the drug,” Dr. Ballantyne said.

Although the prior-authorization hoops for evolocumab and alirocumab have become easier to jump through, “most physicians don’t have the resources to handle it and don’t bother,” noted Dr. Davidson, and he’s concerned that infrastructure challenges will also hamper the buy-and-bill strategy for inclisiran.

He also expressed skepticism that the prior-authorization barrier will disappear. “Payers don’t want to open a large population to a very expensive drug without some gatekeeping,” he said, while acknowledging that in late January 2022 he did not yet have personal experience administering inclisiran or navigating its insurance reimbursement.
 

Boosting patient compliance

Dr. Davidson agreed that the prospect for enhanced patient compliance with inclisiran was intriguing and had already drawn the interest of some of his patients.

“There is a lot of appeal” to a treatment that’s only given once every 6 months, he said. “Compliance is a major issue, and this is less work for patients.”

“The biggest possible attraction of inclisiran is that it is given twice a year, but whether this plays out as anticipated in the real world need to be seen,” cautioned Vijay Nambi, MD, a cardiologist at the Michael E. DeBakey VA Hospital, Houston, and at Baylor College of Medicine who has written about inclisiran. He noted that while two doses a year is “on paper very attractive,” this scheme opens the door to missed or delayed appointments because of vacations, other patient travel, or events like a pandemic.

“The biggest pro for inclisiran is the dosing schedule,” said Chandni Bardolia, PharmD, a drug information specialist at Tabula Rasa Healthcare, Moorestown, N.J., who has analyzed and written about inclisiran and other lipid-lowering medications. “Twice yearly dosing following initiation will be a huge benefit to improve adherence and reduce the number of injections.”

However, inclisiran’s attractive dosing schedule as well as its safety and potent efficacy do not tell the whole story, she highlighted in an interview.

Inclisiran’s clinical evidence still cooking

“I see inclisiran as a last-line drug, mainly because the current alternatives have more safety and efficacy data,” Dr. Bardolia said.

Inclisiran’s “cost and the fact that there are other agents with clinical outcome data already available [alirocumab and evolocumab] means inclisiran is not a first-line agent after statins,” agreed Dr. Nambi.

The FDA based its inclisiran approval entirely on the drug’s demonstrated safety and LDL-lowering efficacy. The cardiovascular outcomes trial for inclisiran, ORION-4, with about 15,000 enrolled patients, started in 2018 and remains in progress with full results expected in 2026.

The lack of clinical outcomes data for inclisiran is a major limitation, said Neil J. Stone, MD, a cardiologist and professor at Northwestern University, Chicago, and vice chair of the panel that wrote the most recent cholesterol guideline for the American College of Cardiology and American Heart Association.

“My greatest concern is the lack of outcome trial data. That’s very important,” Dr. Stone said in an interview.

But others minimize this limitation given the overwhelming evidence that links lower levels of LDL-cholesterol to reduced clinical events.

Most clinicians “support lower LDL as a surrogate” for reduced clinical events, “just like blood pressure and hemoglobin A1c,” noted Dr. Davidson, although he conceded that a “substantial minority wants to wait to see inclisiran’s outcome benefits.”
 

It’s all about price

While opinions are mixed on the need for clinical outcomes data, experts are more uniform in seeing drug prices that run to several thousands per year as the main uptake issue.

“We need to look at the cost-efficacy with inclisiran, and we need benefit data to determine this,” said Dr. Stone.

“Outcomes data are central to characterizing value. I imagine that costs will impact adoption and dissemination” of inclisiran, commented Paul L. Hess, MD, a cardiologist at the Rocky Mountain Regional VA Medical Center, Denver.

Patient interest in less frequent dosing will be important for driving use, but “ultimately cost will be the most important driving factor,” for inclisiran uptake, commented Robert H. Eckel, MD, an endocrinologist affiliated with the University of Colorado School of Medicine, Aurora.

Dr. Davidson has ties to New Amsterdam Pharma and Amgen, which markets evolocumab (Repatha). Dr. Ballantyne is a consultant to numerous companies, including Amgen and Regeneron, which market alirocumab (Praluent). Dr. Nambi has been a site investigator for studies sponsored by Amgen, and by Merck, which markets the LDL-cholesterol drug ezetimibe (Zetia) and is developing an oral PCSK9 inhibitor (he said that the views he expressed are his own and don’t represent that of the department of Veterans Affairs or Baylor.) Dr. Bardolia had no disclosures beyond her employment at Tabula Rasa Healthcare. Dr. Stone, Dr. Hess, and Dr. Eckel had no relevant disclosures.


 

A new statement from the U.S. Preventive Services Task Force concludes that current evidence is insufficient to assess the balance of benefits and harms of screening for atrial fibrillation (AFib) in asymptomatic adults.

The guidance is similar to the task force’s 2018 statement on screening for AFib with electrocardiography in asymptomatic adults 65 years or older, but lowers the inclusion age to adults 50 years or older.

“This 2021 evidence review included searching for evidence on additional screening methods such as automated blood pressure cuffs, pulse oximeters, and consumer devices such as smartwatches and smartphone apps. However, even with this expanded scope, the USPSTF did not find evidence to recommend for or against screening for AF,” the task force states.

The prevalence of increases in age from less than 0.2% in adults younger than 55 years to about 10% in those 85 years or older, the group says. The prevalence is higher in men than in women, but it is uncertain if it differs by race and ethnicity.

Although AFib substantially increases the risk for stroke, the stroke risk associated with subclinical AFib, particularly that of shorter duration lasting less than 24 hours or of lower burden, as might be detected by some screening approaches, is “uncertain,” the task force adds.

The updated recommendations were published online in JAMA, along with a separate evidence report and editorial.

The task force reviewed 26 studies in 113,784 patients, including 12 new to the update.

Studies showed that systematic screening detected significantly more AFib than no screening or pulse palpation (absolute difference, 1.0%-4.8% over up to 12 months). In two of the trials, however, only 10.7% and 44.5% of participants actually received the screening test.

The review included three randomized trials of screening vs. no screening that reported on health outcomes, but only one, STROKESTOP, was powered for health outcomes. It found a significantly lower risk for the primary composite endpoint of ischemic or hemorrhagic stroke, system embolism, bleeding leading to hospitalization, and all-cause mortality with twice-daily intermittent single-lead ECG monitoring for 14 days, compared with no screening. However, there were no significant differences in any of the individual outcomes of the composite endpoint.

“Additionally, and probably the most important thing to appreciate for the STROKESTOP study is that it has several limitations,” task force member Gbenga Ogedegbe, MD, MPH, of New York University told this news organization. The intervention was not masked, and outcomes weren’t centrally adjudicated.

Further, “about 11% of patients in the trial had a history of transient ischemic attack (TIA), stroke, or embolism and the population that we’re looking at within the task force are people without symptoms or history of stroke or ischemic attack,” he said. “That’s the fundamental difference here. So those limitations make it difficult to say that STROKESTOP actually has benefit.”

Notably absent from the review was the recent LOOP study, which found no significant benefit on outcomes with continuous monitoring with an implantable loop recorder (ILR) over usual care in older adults.

While it “offers some context for this issue,” it was not eligible for inclusion because 25% of the population had a prior history of stroke, TIA, or embolism and “because this screening approach may not be feasible for primary care settings,” lead author of the Evidence Report Leila Kahwati, MD, MPH, from RTI International’s Social and Health Organizational Research and Evaluation Program and the University of North Carolina at Chapel Hill, explained in an email.

Treatment with warfarin (mean, 1.5 years) was associated with a lower risk for ischemic stroke (relative risk, 0.32) and all-cause mortality (relative risk, 0.68), while direct oral anticoagulants were associated with a lower incidence of stroke (adjusted odds ratio range, 0.32-0.44). Patients had an increased risk for major bleeding with both warfarin (pooled relative risk, 1.8) and direct-acting oral anticoagulants (odds ratio, 1.38-2.21), but confidence intervals did not exclude a null effect.

The USPSTF found no trials that reported on the benefits of anticoagulation therapy in screen-detected patients.

In an accompanying editorial Philip Greenland, MD, points out that the task force’s conclusion differs from the 2020 European Society of Cardiology AFib guideline, which endorses opportunistic screening for AFib by pulse palpation or ECG rhythm strip in patients 65 years or older (class I recommendation) and advises that clinicians consider systematic ECG screening to detect AFib in people 75 years or older, or those at high risk for stroke (class IIa).

To possibly resolve whether screening for AFib in asymptomatic patients is justified, “future trials may need to consider enrolling only higher risk patients and identifying those with AF of longer duration,” said Dr. Greenland, JAMA editor and professor of preventive medicine and medicine at Northwestern University, Chicago.

“One important point raised by the LOOP trial is whether there is a threshold for AF duration that is most strongly associated with stroke risk and therefore most likely to benefit from anticoagulation,” he writes. Indeed, the LOOP authors themselves questioned whether the trial’s short AFib duration of 6 minutes may have led to many low-risk patients being diagnosed and treated.

“Additionally, trials need to recognize the need for longer monitoring periods (preferably continuous), and perhaps novel wearables will allow long-term monitoring, with accurate interpretation of the ECG and long-term adherence,” Dr. Greenland said.

In a related editorial in JAMA Internal Medicine, John Mandrola, MD, Baptist Health Louisville, Ky., and Andrew Foy, MD, Pennsylvania State University, Hershey, point out that continuous ILR monitoring in the LOOP trial found threefold more AFib and led to 2.7-fold higher rates of oral anticoagulation use, compared with standard care. Yet, there was no statistically significant difference in stroke reduction, and the 20% relative reduction in thromboembolic complications in the screened group was offset by a 26% relative increase in major bleeding.

“Perhaps the most remarkable aspect of the AF screening trials is that as the tools for screening improve, from a single 12-lead ECG to 14-day recordings and then the always-on ILR, more AF is detected and more [oral anticoagulant] is used, yet there is little demonstrable improvement in outcomes,” Dr. Mandrola and Dr. Foy write.

The editorialists also point to the potential for rhythm monitoring to lead to misdiagnosis and downstream cascades of care. “If you assume a 2% AF prevalence, even a device with 98% specificity will misdiagnose approximately 2000 individuals for every million screened.”

Dr. Mandrola told this news organization that the “greatest value” of these reports on AF screening and the critical appraisal of them is as an exercise in thinking about the limits of screening for disease. As James Maxwell Glover Wilson and Gunner Jungner wrote in their 1968 textbook, “Principles and Practice of Screening for Disease”: “in theory, screening is an admirable method of combating disease … [but] in practice, there are snags.”

“It would be good for the public to understand these snags…because they also apply to cancer, coronary calcium testing, and vascular screening as well,” Dr. Mandrola said.

Asked whether it’s possible to put the genie back in the bottle now that every other patient in clinic may have an ECG on their wrist, Dr. Ogedegbe said, “if a patient has no history of stroke or TIA and is 50 years or older, really, monitoring with these devices for AFib, there’s no evidence for or against doing that. Ultimately, the clinician has got to use their clinical judgment in talking to these patients.”

A related editorial in JAMA Cardiology suggests that, to be effective, the movement toward consumer-based screening must first show that such an approach improves outcomes and must deal with the paradox that those at highest risk for AFib and AFib-related stroke may be the least likely to own these technologies unless supported by the healthcare system.

“In addition, appropriate care pathways for confirming the diagnosis and, if necessary, initiating appropriate treatment in individuals with positive findings will need to be established,” Rod Passman, MD, Northwestern University, and Ben Freedman, MBBS, PhD, University of Sydney, Australia, say. “It will also be critical to ensure that device costs and variable technological literacy do not create barriers to making screening accessible to all those at risk.”

Finally, in a related editorial in JAMA Network Open Matthew Kalscheur, MD, and Zachary D. Goldberger, MD, both from the University of Wisconsin-Madison, say the potential benefits of early AFib detection should extend beyond stroke prevention.

“Patients identified with AF likely would benefit from targeted management of modifiable risk factors that contribute to AF, including obesity, hypertension, alcohol use, sleep apnea, smoking, and diabetes,” they write.

All members of the USPSTF receive travel reimbursement and an honorarium for participating in USPSTF meetings. Dr. Ogedegbe has a study included in the Evidence-based Practice Center report for this topic. Dr. Kahwati reported no relevant financial conflicts of interest. Dr. Greenland reported receiving research grants from the National Institutes of Health and from the American Heart Association. Dr. Mandrola is a regular contributor to this news organization. Dr. Foy, Dr. Kalscheur, and Dr. Goldberger reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A new statement from the U.S. Preventive Services Task Force concludes that current evidence is insufficient to assess the balance of benefits and harms of screening for atrial fibrillation (AFib) in asymptomatic adults.

The guidance is similar to the task force’s 2018 statement on screening for AFib with electrocardiography in asymptomatic adults 65 years or older, but lowers the inclusion age to adults 50 years or older.

“This 2021 evidence review included searching for evidence on additional screening methods such as automated blood pressure cuffs, pulse oximeters, and consumer devices such as smartwatches and smartphone apps. However, even with this expanded scope, the USPSTF did not find evidence to recommend for or against screening for AF,” the task force states.

The prevalence of increases in age from less than 0.2% in adults younger than 55 years to about 10% in those 85 years or older, the group says. The prevalence is higher in men than in women, but it is uncertain if it differs by race and ethnicity.

Although AFib substantially increases the risk for stroke, the stroke risk associated with subclinical AFib, particularly that of shorter duration lasting less than 24 hours or of lower burden, as might be detected by some screening approaches, is “uncertain,” the task force adds.

The updated recommendations were published online in JAMA, along with a separate evidence report and editorial.

The task force reviewed 26 studies in 113,784 patients, including 12 new to the update.

Studies showed that systematic screening detected significantly more AFib than no screening or pulse palpation (absolute difference, 1.0%-4.8% over up to 12 months). In two of the trials, however, only 10.7% and 44.5% of participants actually received the screening test.

The review included three randomized trials of screening vs. no screening that reported on health outcomes, but only one, STROKESTOP, was powered for health outcomes. It found a significantly lower risk for the primary composite endpoint of ischemic or hemorrhagic stroke, system embolism, bleeding leading to hospitalization, and all-cause mortality with twice-daily intermittent single-lead ECG monitoring for 14 days, compared with no screening. However, there were no significant differences in any of the individual outcomes of the composite endpoint.

“Additionally, and probably the most important thing to appreciate for the STROKESTOP study is that it has several limitations,” task force member Gbenga Ogedegbe, MD, MPH, of New York University told this news organization. The intervention was not masked, and outcomes weren’t centrally adjudicated.

Further, “about 11% of patients in the trial had a history of transient ischemic attack (TIA), stroke, or embolism and the population that we’re looking at within the task force are people without symptoms or history of stroke or ischemic attack,” he said. “That’s the fundamental difference here. So those limitations make it difficult to say that STROKESTOP actually has benefit.”

Notably absent from the review was the recent LOOP study, which found no significant benefit on outcomes with continuous monitoring with an implantable loop recorder (ILR) over usual care in older adults.

While it “offers some context for this issue,” it was not eligible for inclusion because 25% of the population had a prior history of stroke, TIA, or embolism and “because this screening approach may not be feasible for primary care settings,” lead author of the Evidence Report Leila Kahwati, MD, MPH, from RTI International’s Social and Health Organizational Research and Evaluation Program and the University of North Carolina at Chapel Hill, explained in an email.

Treatment with warfarin (mean, 1.5 years) was associated with a lower risk for ischemic stroke (relative risk, 0.32) and all-cause mortality (relative risk, 0.68), while direct oral anticoagulants were associated with a lower incidence of stroke (adjusted odds ratio range, 0.32-0.44). Patients had an increased risk for major bleeding with both warfarin (pooled relative risk, 1.8) and direct-acting oral anticoagulants (odds ratio, 1.38-2.21), but confidence intervals did not exclude a null effect.

The USPSTF found no trials that reported on the benefits of anticoagulation therapy in screen-detected patients.

In an accompanying editorial Philip Greenland, MD, points out that the task force’s conclusion differs from the 2020 European Society of Cardiology AFib guideline, which endorses opportunistic screening for AFib by pulse palpation or ECG rhythm strip in patients 65 years or older (class I recommendation) and advises that clinicians consider systematic ECG screening to detect AFib in people 75 years or older, or those at high risk for stroke (class IIa).

To possibly resolve whether screening for AFib in asymptomatic patients is justified, “future trials may need to consider enrolling only higher risk patients and identifying those with AF of longer duration,” said Dr. Greenland, JAMA editor and professor of preventive medicine and medicine at Northwestern University, Chicago.

“One important point raised by the LOOP trial is whether there is a threshold for AF duration that is most strongly associated with stroke risk and therefore most likely to benefit from anticoagulation,” he writes. Indeed, the LOOP authors themselves questioned whether the trial’s short AFib duration of 6 minutes may have led to many low-risk patients being diagnosed and treated.

“Additionally, trials need to recognize the need for longer monitoring periods (preferably continuous), and perhaps novel wearables will allow long-term monitoring, with accurate interpretation of the ECG and long-term adherence,” Dr. Greenland said.

In a related editorial in JAMA Internal Medicine, John Mandrola, MD, Baptist Health Louisville, Ky., and Andrew Foy, MD, Pennsylvania State University, Hershey, point out that continuous ILR monitoring in the LOOP trial found threefold more AFib and led to 2.7-fold higher rates of oral anticoagulation use, compared with standard care. Yet, there was no statistically significant difference in stroke reduction, and the 20% relative reduction in thromboembolic complications in the screened group was offset by a 26% relative increase in major bleeding.

“Perhaps the most remarkable aspect of the AF screening trials is that as the tools for screening improve, from a single 12-lead ECG to 14-day recordings and then the always-on ILR, more AF is detected and more [oral anticoagulant] is used, yet there is little demonstrable improvement in outcomes,” Dr. Mandrola and Dr. Foy write.

The editorialists also point to the potential for rhythm monitoring to lead to misdiagnosis and downstream cascades of care. “If you assume a 2% AF prevalence, even a device with 98% specificity will misdiagnose approximately 2000 individuals for every million screened.”

Dr. Mandrola told this news organization that the “greatest value” of these reports on AF screening and the critical appraisal of them is as an exercise in thinking about the limits of screening for disease. As James Maxwell Glover Wilson and Gunner Jungner wrote in their 1968 textbook, “Principles and Practice of Screening for Disease”: “in theory, screening is an admirable method of combating disease … [but] in practice, there are snags.”

“It would be good for the public to understand these snags…because they also apply to cancer, coronary calcium testing, and vascular screening as well,” Dr. Mandrola said.

Asked whether it’s possible to put the genie back in the bottle now that every other patient in clinic may have an ECG on their wrist, Dr. Ogedegbe said, “if a patient has no history of stroke or TIA and is 50 years or older, really, monitoring with these devices for AFib, there’s no evidence for or against doing that. Ultimately, the clinician has got to use their clinical judgment in talking to these patients.”

A related editorial in JAMA Cardiology suggests that, to be effective, the movement toward consumer-based screening must first show that such an approach improves outcomes and must deal with the paradox that those at highest risk for AFib and AFib-related stroke may be the least likely to own these technologies unless supported by the healthcare system.

“In addition, appropriate care pathways for confirming the diagnosis and, if necessary, initiating appropriate treatment in individuals with positive findings will need to be established,” Rod Passman, MD, Northwestern University, and Ben Freedman, MBBS, PhD, University of Sydney, Australia, say. “It will also be critical to ensure that device costs and variable technological literacy do not create barriers to making screening accessible to all those at risk.”

Finally, in a related editorial in JAMA Network Open Matthew Kalscheur, MD, and Zachary D. Goldberger, MD, both from the University of Wisconsin-Madison, say the potential benefits of early AFib detection should extend beyond stroke prevention.

“Patients identified with AF likely would benefit from targeted management of modifiable risk factors that contribute to AF, including obesity, hypertension, alcohol use, sleep apnea, smoking, and diabetes,” they write.

All members of the USPSTF receive travel reimbursement and an honorarium for participating in USPSTF meetings. Dr. Ogedegbe has a study included in the Evidence-based Practice Center report for this topic. Dr. Kahwati reported no relevant financial conflicts of interest. Dr. Greenland reported receiving research grants from the National Institutes of Health and from the American Heart Association. Dr. Mandrola is a regular contributor to this news organization. Dr. Foy, Dr. Kalscheur, and Dr. Goldberger reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A new statement from the U.S. Preventive Services Task Force concludes that current evidence is insufficient to assess the balance of benefits and harms of screening for atrial fibrillation (AFib) in asymptomatic adults.

The guidance is similar to the task force’s 2018 statement on screening for AFib with electrocardiography in asymptomatic adults 65 years or older, but lowers the inclusion age to adults 50 years or older.

“This 2021 evidence review included searching for evidence on additional screening methods such as automated blood pressure cuffs, pulse oximeters, and consumer devices such as smartwatches and smartphone apps. However, even with this expanded scope, the USPSTF did not find evidence to recommend for or against screening for AF,” the task force states.

The prevalence of increases in age from less than 0.2% in adults younger than 55 years to about 10% in those 85 years or older, the group says. The prevalence is higher in men than in women, but it is uncertain if it differs by race and ethnicity.

Although AFib substantially increases the risk for stroke, the stroke risk associated with subclinical AFib, particularly that of shorter duration lasting less than 24 hours or of lower burden, as might be detected by some screening approaches, is “uncertain,” the task force adds.

The updated recommendations were published online in JAMA, along with a separate evidence report and editorial.

The task force reviewed 26 studies in 113,784 patients, including 12 new to the update.

Studies showed that systematic screening detected significantly more AFib than no screening or pulse palpation (absolute difference, 1.0%-4.8% over up to 12 months). In two of the trials, however, only 10.7% and 44.5% of participants actually received the screening test.

The review included three randomized trials of screening vs. no screening that reported on health outcomes, but only one, STROKESTOP, was powered for health outcomes. It found a significantly lower risk for the primary composite endpoint of ischemic or hemorrhagic stroke, system embolism, bleeding leading to hospitalization, and all-cause mortality with twice-daily intermittent single-lead ECG monitoring for 14 days, compared with no screening. However, there were no significant differences in any of the individual outcomes of the composite endpoint.

“Additionally, and probably the most important thing to appreciate for the STROKESTOP study is that it has several limitations,” task force member Gbenga Ogedegbe, MD, MPH, of New York University told this news organization. The intervention was not masked, and outcomes weren’t centrally adjudicated.

Further, “about 11% of patients in the trial had a history of transient ischemic attack (TIA), stroke, or embolism and the population that we’re looking at within the task force are people without symptoms or history of stroke or ischemic attack,” he said. “That’s the fundamental difference here. So those limitations make it difficult to say that STROKESTOP actually has benefit.”

Notably absent from the review was the recent LOOP study, which found no significant benefit on outcomes with continuous monitoring with an implantable loop recorder (ILR) over usual care in older adults.

While it “offers some context for this issue,” it was not eligible for inclusion because 25% of the population had a prior history of stroke, TIA, or embolism and “because this screening approach may not be feasible for primary care settings,” lead author of the Evidence Report Leila Kahwati, MD, MPH, from RTI International’s Social and Health Organizational Research and Evaluation Program and the University of North Carolina at Chapel Hill, explained in an email.

Treatment with warfarin (mean, 1.5 years) was associated with a lower risk for ischemic stroke (relative risk, 0.32) and all-cause mortality (relative risk, 0.68), while direct oral anticoagulants were associated with a lower incidence of stroke (adjusted odds ratio range, 0.32-0.44). Patients had an increased risk for major bleeding with both warfarin (pooled relative risk, 1.8) and direct-acting oral anticoagulants (odds ratio, 1.38-2.21), but confidence intervals did not exclude a null effect.

The USPSTF found no trials that reported on the benefits of anticoagulation therapy in screen-detected patients.

In an accompanying editorial Philip Greenland, MD, points out that the task force’s conclusion differs from the 2020 European Society of Cardiology AFib guideline, which endorses opportunistic screening for AFib by pulse palpation or ECG rhythm strip in patients 65 years or older (class I recommendation) and advises that clinicians consider systematic ECG screening to detect AFib in people 75 years or older, or those at high risk for stroke (class IIa).

To possibly resolve whether screening for AFib in asymptomatic patients is justified, “future trials may need to consider enrolling only higher risk patients and identifying those with AF of longer duration,” said Dr. Greenland, JAMA editor and professor of preventive medicine and medicine at Northwestern University, Chicago.

“One important point raised by the LOOP trial is whether there is a threshold for AF duration that is most strongly associated with stroke risk and therefore most likely to benefit from anticoagulation,” he writes. Indeed, the LOOP authors themselves questioned whether the trial’s short AFib duration of 6 minutes may have led to many low-risk patients being diagnosed and treated.

“Additionally, trials need to recognize the need for longer monitoring periods (preferably continuous), and perhaps novel wearables will allow long-term monitoring, with accurate interpretation of the ECG and long-term adherence,” Dr. Greenland said.

In a related editorial in JAMA Internal Medicine, John Mandrola, MD, Baptist Health Louisville, Ky., and Andrew Foy, MD, Pennsylvania State University, Hershey, point out that continuous ILR monitoring in the LOOP trial found threefold more AFib and led to 2.7-fold higher rates of oral anticoagulation use, compared with standard care. Yet, there was no statistically significant difference in stroke reduction, and the 20% relative reduction in thromboembolic complications in the screened group was offset by a 26% relative increase in major bleeding.

“Perhaps the most remarkable aspect of the AF screening trials is that as the tools for screening improve, from a single 12-lead ECG to 14-day recordings and then the always-on ILR, more AF is detected and more [oral anticoagulant] is used, yet there is little demonstrable improvement in outcomes,” Dr. Mandrola and Dr. Foy write.

The editorialists also point to the potential for rhythm monitoring to lead to misdiagnosis and downstream cascades of care. “If you assume a 2% AF prevalence, even a device with 98% specificity will misdiagnose approximately 2000 individuals for every million screened.”

Dr. Mandrola told this news organization that the “greatest value” of these reports on AF screening and the critical appraisal of them is as an exercise in thinking about the limits of screening for disease. As James Maxwell Glover Wilson and Gunner Jungner wrote in their 1968 textbook, “Principles and Practice of Screening for Disease”: “in theory, screening is an admirable method of combating disease … [but] in practice, there are snags.”

“It would be good for the public to understand these snags…because they also apply to cancer, coronary calcium testing, and vascular screening as well,” Dr. Mandrola said.

Asked whether it’s possible to put the genie back in the bottle now that every other patient in clinic may have an ECG on their wrist, Dr. Ogedegbe said, “if a patient has no history of stroke or TIA and is 50 years or older, really, monitoring with these devices for AFib, there’s no evidence for or against doing that. Ultimately, the clinician has got to use their clinical judgment in talking to these patients.”

A related editorial in JAMA Cardiology suggests that, to be effective, the movement toward consumer-based screening must first show that such an approach improves outcomes and must deal with the paradox that those at highest risk for AFib and AFib-related stroke may be the least likely to own these technologies unless supported by the healthcare system.

“In addition, appropriate care pathways for confirming the diagnosis and, if necessary, initiating appropriate treatment in individuals with positive findings will need to be established,” Rod Passman, MD, Northwestern University, and Ben Freedman, MBBS, PhD, University of Sydney, Australia, say. “It will also be critical to ensure that device costs and variable technological literacy do not create barriers to making screening accessible to all those at risk.”

Finally, in a related editorial in JAMA Network Open Matthew Kalscheur, MD, and Zachary D. Goldberger, MD, both from the University of Wisconsin-Madison, say the potential benefits of early AFib detection should extend beyond stroke prevention.

“Patients identified with AF likely would benefit from targeted management of modifiable risk factors that contribute to AF, including obesity, hypertension, alcohol use, sleep apnea, smoking, and diabetes,” they write.

All members of the USPSTF receive travel reimbursement and an honorarium for participating in USPSTF meetings. Dr. Ogedegbe has a study included in the Evidence-based Practice Center report for this topic. Dr. Kahwati reported no relevant financial conflicts of interest. Dr. Greenland reported receiving research grants from the National Institutes of Health and from the American Heart Association. Dr. Mandrola is a regular contributor to this news organization. Dr. Foy, Dr. Kalscheur, and Dr. Goldberger reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Some details have been changed to protect the patient’s identity.

The first thing I noticed about Mr. Barry as I entered the intensive care unit was his left foot: Half of it was black, shriveled, and gangrenous, jutting out from under the white blanket. The soft rays of the morning sun illuminated his gaunt, unshaven, hollow cheeks. Sedated on propofol, with a green endotracheal tube sticking out of his chapped lips, he looked frail. His nurse, Becky, had just cleaned him after he passed tarry, maroon-colored stool. As she turned him over, I saw that the skin over his tailbone was broken. He had a large decubitus ulcer, the edges of which were now dried and black. The Foley bag, hanging next to his bed, was empty; there had been no urine for several hours now.

No one knew much about Mr. Barry. I don’t mean his current medical status – I mean what he did in life, who he loved, whether he had kids, what he valued. All we knew was that he was 83 years old and lived alone. No prior records in our system. No advanced directives. No information on any family. One of his neighbors called 911 after he was not seen for at least 10 days. Emergency medical services found Mr. Barry in bed, nearly lifeless. In the emergency room, he was noted to be in shock, with a dangerously low blood pressure. He was dry as a bone with markedly elevated sodium levels. His laboratory makers for kidney and liver function were deranged. He was admitted to the medical ICU with a diagnosis of hypovolemic shock and/or septic shock with multiorgan dysfunction. With 48 hours of supportive management with intravenous fluids and antibiotics, he did not improve. Blood cultures were positive for gram-positive cocci. The doses for medications used to maintain the blood pressure increased steadily. He also developed gastrointestinal bleeding.
 

Futile vs. potentially inappropriate

I was called for a cardiology consult because he had transient ST elevation in inferolateral leads on the monitor. Given his clinical scenario, the likelihood of type 1 myocardial infarction from plaque rupture was low; the ST elevations were probably related to vasospasm from increasing pressor requirement. Diagnostic cardiac catheterization showed clean coronary arteries. Continuous renal replacement therapy was soon started. Given Mr Barry’s multiorgan dysfunction and extremely poor prognosis, I recommended making all efforts to find his family or surrogate decision-maker to discuss goals of care or having a two-physician sign-off to place a DNR order.

Despite all efforts, we could not trace the family. We physicians vary individually on how we define value as related to life. We also vary on the degree of uncertainty about prognostication that we are comfortable with. This is one of the reasons the term “futility” is controversial and there is a push to use “potentially inappropriate” instead. The primary team had a different threshold for placing a DNR order and did not do it. That night, after I left the hospital, Mr Barry had a PEA (pulseless electrical activity) arrest and was resuscitated after 10 minutes of CPR. The next day, I noticed his bruised chest. He was on multiple medications to support his blood pressure.
 

My patient and a Hemingway protagonist

Whether by coincidence or irony, I started reading Ernest Hemingway’s short story “The Snows of Kilimanjaro” the same day that I met Mr. Barry. He reminded me of the story’s protagonist, Harry, lying on the cot with a gangrenous leg, waiting to die. Harry could sense death approaching. He reminisced about his past. All he wanted was to drink his “whiskey-soda.” “Darling, don’t drink that. We have to do everything we can,” his wife said. “You do it. I am tired,” Harry said, and continued to drink his whiskey-soda.

Mr. Barry looked tired. Tired of life? I can’t say with certainty. However, if I had to guess, the medical team’s heroics meant nothing to him. Unfortunately, he was not awake like Harry and could not do what he wished. I wondered what snippets of his life flashed before him as he lay on his bed at home for days. Did he want to have a whiskey-soda before dying? But we are not letting him die. Not easily anyway. We have to do everything we can: medications, coronary angiogram, dialysis, multiple rounds of CPR. Why?

In this country, we need permission to forgo CPR. If there are no advanced directives or next of kin available to discuss end-of-life care, performing CPR is the default status for all hospitalized patients, irrespective of the underlying severity of the illness. A unilateral DNR order written by a physician in good conscience (in a medically futile situation), but to which the patient has not consented, is generally invalid in most U.S. states. If health directives are not available, CPR will be administered on the presumption that the patient would want us to “do everything we can.” The medicolegal consequences and fear of not administering CPR is more profound than being found wrong and defying a patient’s wishes against CPR.

In patients with outside-hospital cardiac arrest, especially if related to ventricular fibrillation, early bystander CPR improves the survival rate. Hence, it makes sense for first responders and paramedics to administer CPR as the default option, focusing on the technique, rather than thinking about its utility based on the patient’s underlying comorbidities.

In the inpatient setting, however, physicians have enough information to comprehensively evaluate the patient. In a cohort of 5,690 critically ill ICU patients, obtained from a U.S. registry, the rate of survival to discharge after inpatient cardiac arrest is very low at 12.5%. Chronic health conditions, malignancy, end-stage renal disease, multiorgan dysfunction, need for vasopressor support, prior CPR, initial rhythm of asystole, or PEA advanced age were all associated with a less than 10% survival rate after CPR.

Dying is a process. Administering CPR to a dying patient is of little to no value. For Mr. Barry, it resulted in a bruised chest and broken ribs. James R. Jude, MD, one of the pioneers of closed chest compression, or modern-day CPR, wrote in 1965 that “resuscitation of the dying patient with irreparable damage to lungs, heart, kidneys, brain or any other vital system of the body has no medical, ethical, or moral justification. The techniques described in this monograph were designed to resuscitate the victim of acute insult, whether be it from drowning, electrical shock, untoward effect of drugs, anesthetic accident, heart block, acute myocardial infarction, or surgery.”

Yet, doctors continue to provide futile treatments at end of life for a variety of reasons: concerns about medico-legal risks, discomfort or inexperience with death and dying, uncertainty in prognostication, family requests, and organizational barriers such as lack of palliative services that can help lead end-of-life care discussions. Despite knowing that CPR has little benefit in critically ill patients with terminal illness and multiorgan dysfunction, we often ask the patient and their surrogate decision-makers: “If your heart stops, do you want us to restore your heart by pressing on the chest and giving electric shocks?” The very act of asking the question implies that CPR may be beneficial. We often do not go over the risks or offer an opinion on whether CPR should be performed. We take a neutral stance.

Anoxic brain injury, pain from broken ribs, and low likelihood of survival to discharge with acceptable neurologic recovery are rarely discussed in detail. Laypeople may overestimate the chances of survival after CPR and they may not comprehend that it does not reverse the dying process in patients with a terminal illness. When you ask about CPR, most families hear: “Do you want your loved one to live?” and the answer is nearly always “Yes.” We then administer CPR, thinking that we are respecting the patient’s autonomy in the medical decision-making process. However, in end-of-life care, elderly patients or surrogates may not fully understand the complexities involved or the outcomes of CPR. So, are we truly respecting their autonomy?
 

When to offer CPR?

In 2011, Billings and Krakauer, palliative care specialists from Massachusetts General Hospital, Boston, suggested that we focus on understanding our patient’s values and goals of care, and then decide whether to offer CPR, rather than taking a neutral stance. With this approach, we continue to respect the patient’s autonomy and also affirm our responsibility in providing care consistent with medical reality. We need to have the humility to accept that death is inevitable. Taking care of the dying to ensure a peaceful and dignified death is as much our moral and ethical responsibility as respecting a patient’s autonomy.

It has been 10 years since a group of physicians from Columbia University Medical Center, Harvard Medical School, MGH, and Boston Children’s Hospital proposed changes to how we determine resuscitation status. Instead of assuming that CPR is always wanted, they suggested three distinct approaches: consider CPR when the benefits versus risks are uncertain, and the patient is not end stage; recommend against CPR when there is a low likelihood of benefit and high likelihood of harm (e.g., patients with anoxic brain injury, advanced incurable cancer, or end-stage multiorgan dysfunction); and do not offer CPR to patients who will die imminently and have no chance of surviving CPR (e.g., patients with multiorgan dysfunction, increasing pressor requirements, and those who are actively dying without a single immediately reversible cause). I agree with their proposal.

Mr. Barry was actively dying. Unfortunately, we had neither his advanced directives nor access to family members or surrogates to discuss values and goals of care. Given the futility of administering CPR again, and based on our humanitarian principles, a moral and ethical responsibility to ensure a peaceful dying process, I and another ICU attending placed the DNR order. He passed away, peacefully, within a few hours.

That evening, as I was sitting on my porch reading the last page of “The Snows of Kilimanjaro,” my phone pinged. It was an email asking me to complete the final attestation for the death certificate. I imagined that Mr. Barry knew where he was going. He probably had his own special place – something beautiful and majestic, great and tall, dazzlingly white in the hot sun, like the snow-capped mountain of Kilimanjaro that Harry saw at the time of his death.

Dr. Mallidi is a general cardiologist at Zuckerberg San Francisco General Hospital, UCSF. He disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Some details have been changed to protect the patient’s identity.

The first thing I noticed about Mr. Barry as I entered the intensive care unit was his left foot: Half of it was black, shriveled, and gangrenous, jutting out from under the white blanket. The soft rays of the morning sun illuminated his gaunt, unshaven, hollow cheeks. Sedated on propofol, with a green endotracheal tube sticking out of his chapped lips, he looked frail. His nurse, Becky, had just cleaned him after he passed tarry, maroon-colored stool. As she turned him over, I saw that the skin over his tailbone was broken. He had a large decubitus ulcer, the edges of which were now dried and black. The Foley bag, hanging next to his bed, was empty; there had been no urine for several hours now.

No one knew much about Mr. Barry. I don’t mean his current medical status – I mean what he did in life, who he loved, whether he had kids, what he valued. All we knew was that he was 83 years old and lived alone. No prior records in our system. No advanced directives. No information on any family. One of his neighbors called 911 after he was not seen for at least 10 days. Emergency medical services found Mr. Barry in bed, nearly lifeless. In the emergency room, he was noted to be in shock, with a dangerously low blood pressure. He was dry as a bone with markedly elevated sodium levels. His laboratory makers for kidney and liver function were deranged. He was admitted to the medical ICU with a diagnosis of hypovolemic shock and/or septic shock with multiorgan dysfunction. With 48 hours of supportive management with intravenous fluids and antibiotics, he did not improve. Blood cultures were positive for gram-positive cocci. The doses for medications used to maintain the blood pressure increased steadily. He also developed gastrointestinal bleeding.
 

Futile vs. potentially inappropriate

I was called for a cardiology consult because he had transient ST elevation in inferolateral leads on the monitor. Given his clinical scenario, the likelihood of type 1 myocardial infarction from plaque rupture was low; the ST elevations were probably related to vasospasm from increasing pressor requirement. Diagnostic cardiac catheterization showed clean coronary arteries. Continuous renal replacement therapy was soon started. Given Mr Barry’s multiorgan dysfunction and extremely poor prognosis, I recommended making all efforts to find his family or surrogate decision-maker to discuss goals of care or having a two-physician sign-off to place a DNR order.

Despite all efforts, we could not trace the family. We physicians vary individually on how we define value as related to life. We also vary on the degree of uncertainty about prognostication that we are comfortable with. This is one of the reasons the term “futility” is controversial and there is a push to use “potentially inappropriate” instead. The primary team had a different threshold for placing a DNR order and did not do it. That night, after I left the hospital, Mr Barry had a PEA (pulseless electrical activity) arrest and was resuscitated after 10 minutes of CPR. The next day, I noticed his bruised chest. He was on multiple medications to support his blood pressure.
 

My patient and a Hemingway protagonist

Whether by coincidence or irony, I started reading Ernest Hemingway’s short story “The Snows of Kilimanjaro” the same day that I met Mr. Barry. He reminded me of the story’s protagonist, Harry, lying on the cot with a gangrenous leg, waiting to die. Harry could sense death approaching. He reminisced about his past. All he wanted was to drink his “whiskey-soda.” “Darling, don’t drink that. We have to do everything we can,” his wife said. “You do it. I am tired,” Harry said, and continued to drink his whiskey-soda.

Mr. Barry looked tired. Tired of life? I can’t say with certainty. However, if I had to guess, the medical team’s heroics meant nothing to him. Unfortunately, he was not awake like Harry and could not do what he wished. I wondered what snippets of his life flashed before him as he lay on his bed at home for days. Did he want to have a whiskey-soda before dying? But we are not letting him die. Not easily anyway. We have to do everything we can: medications, coronary angiogram, dialysis, multiple rounds of CPR. Why?

In this country, we need permission to forgo CPR. If there are no advanced directives or next of kin available to discuss end-of-life care, performing CPR is the default status for all hospitalized patients, irrespective of the underlying severity of the illness. A unilateral DNR order written by a physician in good conscience (in a medically futile situation), but to which the patient has not consented, is generally invalid in most U.S. states. If health directives are not available, CPR will be administered on the presumption that the patient would want us to “do everything we can.” The medicolegal consequences and fear of not administering CPR is more profound than being found wrong and defying a patient’s wishes against CPR.

In patients with outside-hospital cardiac arrest, especially if related to ventricular fibrillation, early bystander CPR improves the survival rate. Hence, it makes sense for first responders and paramedics to administer CPR as the default option, focusing on the technique, rather than thinking about its utility based on the patient’s underlying comorbidities.

In the inpatient setting, however, physicians have enough information to comprehensively evaluate the patient. In a cohort of 5,690 critically ill ICU patients, obtained from a U.S. registry, the rate of survival to discharge after inpatient cardiac arrest is very low at 12.5%. Chronic health conditions, malignancy, end-stage renal disease, multiorgan dysfunction, need for vasopressor support, prior CPR, initial rhythm of asystole, or PEA advanced age were all associated with a less than 10% survival rate after CPR.

Dying is a process. Administering CPR to a dying patient is of little to no value. For Mr. Barry, it resulted in a bruised chest and broken ribs. James R. Jude, MD, one of the pioneers of closed chest compression, or modern-day CPR, wrote in 1965 that “resuscitation of the dying patient with irreparable damage to lungs, heart, kidneys, brain or any other vital system of the body has no medical, ethical, or moral justification. The techniques described in this monograph were designed to resuscitate the victim of acute insult, whether be it from drowning, electrical shock, untoward effect of drugs, anesthetic accident, heart block, acute myocardial infarction, or surgery.”

Yet, doctors continue to provide futile treatments at end of life for a variety of reasons: concerns about medico-legal risks, discomfort or inexperience with death and dying, uncertainty in prognostication, family requests, and organizational barriers such as lack of palliative services that can help lead end-of-life care discussions. Despite knowing that CPR has little benefit in critically ill patients with terminal illness and multiorgan dysfunction, we often ask the patient and their surrogate decision-makers: “If your heart stops, do you want us to restore your heart by pressing on the chest and giving electric shocks?” The very act of asking the question implies that CPR may be beneficial. We often do not go over the risks or offer an opinion on whether CPR should be performed. We take a neutral stance.

Anoxic brain injury, pain from broken ribs, and low likelihood of survival to discharge with acceptable neurologic recovery are rarely discussed in detail. Laypeople may overestimate the chances of survival after CPR and they may not comprehend that it does not reverse the dying process in patients with a terminal illness. When you ask about CPR, most families hear: “Do you want your loved one to live?” and the answer is nearly always “Yes.” We then administer CPR, thinking that we are respecting the patient’s autonomy in the medical decision-making process. However, in end-of-life care, elderly patients or surrogates may not fully understand the complexities involved or the outcomes of CPR. So, are we truly respecting their autonomy?
 

When to offer CPR?

In 2011, Billings and Krakauer, palliative care specialists from Massachusetts General Hospital, Boston, suggested that we focus on understanding our patient’s values and goals of care, and then decide whether to offer CPR, rather than taking a neutral stance. With this approach, we continue to respect the patient’s autonomy and also affirm our responsibility in providing care consistent with medical reality. We need to have the humility to accept that death is inevitable. Taking care of the dying to ensure a peaceful and dignified death is as much our moral and ethical responsibility as respecting a patient’s autonomy.

It has been 10 years since a group of physicians from Columbia University Medical Center, Harvard Medical School, MGH, and Boston Children’s Hospital proposed changes to how we determine resuscitation status. Instead of assuming that CPR is always wanted, they suggested three distinct approaches: consider CPR when the benefits versus risks are uncertain, and the patient is not end stage; recommend against CPR when there is a low likelihood of benefit and high likelihood of harm (e.g., patients with anoxic brain injury, advanced incurable cancer, or end-stage multiorgan dysfunction); and do not offer CPR to patients who will die imminently and have no chance of surviving CPR (e.g., patients with multiorgan dysfunction, increasing pressor requirements, and those who are actively dying without a single immediately reversible cause). I agree with their proposal.

Mr. Barry was actively dying. Unfortunately, we had neither his advanced directives nor access to family members or surrogates to discuss values and goals of care. Given the futility of administering CPR again, and based on our humanitarian principles, a moral and ethical responsibility to ensure a peaceful dying process, I and another ICU attending placed the DNR order. He passed away, peacefully, within a few hours.

That evening, as I was sitting on my porch reading the last page of “The Snows of Kilimanjaro,” my phone pinged. It was an email asking me to complete the final attestation for the death certificate. I imagined that Mr. Barry knew where he was going. He probably had his own special place – something beautiful and majestic, great and tall, dazzlingly white in the hot sun, like the snow-capped mountain of Kilimanjaro that Harry saw at the time of his death.

Dr. Mallidi is a general cardiologist at Zuckerberg San Francisco General Hospital, UCSF. He disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Some details have been changed to protect the patient’s identity.

The first thing I noticed about Mr. Barry as I entered the intensive care unit was his left foot: Half of it was black, shriveled, and gangrenous, jutting out from under the white blanket. The soft rays of the morning sun illuminated his gaunt, unshaven, hollow cheeks. Sedated on propofol, with a green endotracheal tube sticking out of his chapped lips, he looked frail. His nurse, Becky, had just cleaned him after he passed tarry, maroon-colored stool. As she turned him over, I saw that the skin over his tailbone was broken. He had a large decubitus ulcer, the edges of which were now dried and black. The Foley bag, hanging next to his bed, was empty; there had been no urine for several hours now.

No one knew much about Mr. Barry. I don’t mean his current medical status – I mean what he did in life, who he loved, whether he had kids, what he valued. All we knew was that he was 83 years old and lived alone. No prior records in our system. No advanced directives. No information on any family. One of his neighbors called 911 after he was not seen for at least 10 days. Emergency medical services found Mr. Barry in bed, nearly lifeless. In the emergency room, he was noted to be in shock, with a dangerously low blood pressure. He was dry as a bone with markedly elevated sodium levels. His laboratory makers for kidney and liver function were deranged. He was admitted to the medical ICU with a diagnosis of hypovolemic shock and/or septic shock with multiorgan dysfunction. With 48 hours of supportive management with intravenous fluids and antibiotics, he did not improve. Blood cultures were positive for gram-positive cocci. The doses for medications used to maintain the blood pressure increased steadily. He also developed gastrointestinal bleeding.
 

Futile vs. potentially inappropriate

I was called for a cardiology consult because he had transient ST elevation in inferolateral leads on the monitor. Given his clinical scenario, the likelihood of type 1 myocardial infarction from plaque rupture was low; the ST elevations were probably related to vasospasm from increasing pressor requirement. Diagnostic cardiac catheterization showed clean coronary arteries. Continuous renal replacement therapy was soon started. Given Mr Barry’s multiorgan dysfunction and extremely poor prognosis, I recommended making all efforts to find his family or surrogate decision-maker to discuss goals of care or having a two-physician sign-off to place a DNR order.

Despite all efforts, we could not trace the family. We physicians vary individually on how we define value as related to life. We also vary on the degree of uncertainty about prognostication that we are comfortable with. This is one of the reasons the term “futility” is controversial and there is a push to use “potentially inappropriate” instead. The primary team had a different threshold for placing a DNR order and did not do it. That night, after I left the hospital, Mr Barry had a PEA (pulseless electrical activity) arrest and was resuscitated after 10 minutes of CPR. The next day, I noticed his bruised chest. He was on multiple medications to support his blood pressure.
 

My patient and a Hemingway protagonist

Whether by coincidence or irony, I started reading Ernest Hemingway’s short story “The Snows of Kilimanjaro” the same day that I met Mr. Barry. He reminded me of the story’s protagonist, Harry, lying on the cot with a gangrenous leg, waiting to die. Harry could sense death approaching. He reminisced about his past. All he wanted was to drink his “whiskey-soda.” “Darling, don’t drink that. We have to do everything we can,” his wife said. “You do it. I am tired,” Harry said, and continued to drink his whiskey-soda.

Mr. Barry looked tired. Tired of life? I can’t say with certainty. However, if I had to guess, the medical team’s heroics meant nothing to him. Unfortunately, he was not awake like Harry and could not do what he wished. I wondered what snippets of his life flashed before him as he lay on his bed at home for days. Did he want to have a whiskey-soda before dying? But we are not letting him die. Not easily anyway. We have to do everything we can: medications, coronary angiogram, dialysis, multiple rounds of CPR. Why?

In this country, we need permission to forgo CPR. If there are no advanced directives or next of kin available to discuss end-of-life care, performing CPR is the default status for all hospitalized patients, irrespective of the underlying severity of the illness. A unilateral DNR order written by a physician in good conscience (in a medically futile situation), but to which the patient has not consented, is generally invalid in most U.S. states. If health directives are not available, CPR will be administered on the presumption that the patient would want us to “do everything we can.” The medicolegal consequences and fear of not administering CPR is more profound than being found wrong and defying a patient’s wishes against CPR.

In patients with outside-hospital cardiac arrest, especially if related to ventricular fibrillation, early bystander CPR improves the survival rate. Hence, it makes sense for first responders and paramedics to administer CPR as the default option, focusing on the technique, rather than thinking about its utility based on the patient’s underlying comorbidities.

In the inpatient setting, however, physicians have enough information to comprehensively evaluate the patient. In a cohort of 5,690 critically ill ICU patients, obtained from a U.S. registry, the rate of survival to discharge after inpatient cardiac arrest is very low at 12.5%. Chronic health conditions, malignancy, end-stage renal disease, multiorgan dysfunction, need for vasopressor support, prior CPR, initial rhythm of asystole, or PEA advanced age were all associated with a less than 10% survival rate after CPR.

Dying is a process. Administering CPR to a dying patient is of little to no value. For Mr. Barry, it resulted in a bruised chest and broken ribs. James R. Jude, MD, one of the pioneers of closed chest compression, or modern-day CPR, wrote in 1965 that “resuscitation of the dying patient with irreparable damage to lungs, heart, kidneys, brain or any other vital system of the body has no medical, ethical, or moral justification. The techniques described in this monograph were designed to resuscitate the victim of acute insult, whether be it from drowning, electrical shock, untoward effect of drugs, anesthetic accident, heart block, acute myocardial infarction, or surgery.”

Yet, doctors continue to provide futile treatments at end of life for a variety of reasons: concerns about medico-legal risks, discomfort or inexperience with death and dying, uncertainty in prognostication, family requests, and organizational barriers such as lack of palliative services that can help lead end-of-life care discussions. Despite knowing that CPR has little benefit in critically ill patients with terminal illness and multiorgan dysfunction, we often ask the patient and their surrogate decision-makers: “If your heart stops, do you want us to restore your heart by pressing on the chest and giving electric shocks?” The very act of asking the question implies that CPR may be beneficial. We often do not go over the risks or offer an opinion on whether CPR should be performed. We take a neutral stance.

Anoxic brain injury, pain from broken ribs, and low likelihood of survival to discharge with acceptable neurologic recovery are rarely discussed in detail. Laypeople may overestimate the chances of survival after CPR and they may not comprehend that it does not reverse the dying process in patients with a terminal illness. When you ask about CPR, most families hear: “Do you want your loved one to live?” and the answer is nearly always “Yes.” We then administer CPR, thinking that we are respecting the patient’s autonomy in the medical decision-making process. However, in end-of-life care, elderly patients or surrogates may not fully understand the complexities involved or the outcomes of CPR. So, are we truly respecting their autonomy?
 

When to offer CPR?

In 2011, Billings and Krakauer, palliative care specialists from Massachusetts General Hospital, Boston, suggested that we focus on understanding our patient’s values and goals of care, and then decide whether to offer CPR, rather than taking a neutral stance. With this approach, we continue to respect the patient’s autonomy and also affirm our responsibility in providing care consistent with medical reality. We need to have the humility to accept that death is inevitable. Taking care of the dying to ensure a peaceful and dignified death is as much our moral and ethical responsibility as respecting a patient’s autonomy.

It has been 10 years since a group of physicians from Columbia University Medical Center, Harvard Medical School, MGH, and Boston Children’s Hospital proposed changes to how we determine resuscitation status. Instead of assuming that CPR is always wanted, they suggested three distinct approaches: consider CPR when the benefits versus risks are uncertain, and the patient is not end stage; recommend against CPR when there is a low likelihood of benefit and high likelihood of harm (e.g., patients with anoxic brain injury, advanced incurable cancer, or end-stage multiorgan dysfunction); and do not offer CPR to patients who will die imminently and have no chance of surviving CPR (e.g., patients with multiorgan dysfunction, increasing pressor requirements, and those who are actively dying without a single immediately reversible cause). I agree with their proposal.

Mr. Barry was actively dying. Unfortunately, we had neither his advanced directives nor access to family members or surrogates to discuss values and goals of care. Given the futility of administering CPR again, and based on our humanitarian principles, a moral and ethical responsibility to ensure a peaceful dying process, I and another ICU attending placed the DNR order. He passed away, peacefully, within a few hours.

That evening, as I was sitting on my porch reading the last page of “The Snows of Kilimanjaro,” my phone pinged. It was an email asking me to complete the final attestation for the death certificate. I imagined that Mr. Barry knew where he was going. He probably had his own special place – something beautiful and majestic, great and tall, dazzlingly white in the hot sun, like the snow-capped mountain of Kilimanjaro that Harry saw at the time of his death.

Dr. Mallidi is a general cardiologist at Zuckerberg San Francisco General Hospital, UCSF. He disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Dietary guidelines provide scientifically sound and practical advice that, if followed by every person, would probably result in less obesity, type 2 diabetes, cardiovascular disease, cancer, and bone loss. But few US adults meet these recommendations, according to a recent report in the CDC’s Morbidity and Mortality Weekly Report (MMWR).¹

Data from the 2019 Behavioral Risk Factor Surveillance system indicate that only 12.3% of US adults consumed the recommended amount of fruit and 10% the recommended amount of vegetables (more on that shortly). Women were more likely than men to meet the requirements for fruit (14.5% vs 10.1%) and vegetable (12.4% vs 7.6%) intake. The vegetable recommendation was more likely to be met by those in higher income households than those in the lowest income categories (12.2% vs 6.8%).¹

Just what’s recommended? The most recent dietary guidelines from the Department of Agriculture suggest that adults should consume 1.5 to 2 cup-equivalents of fruits and 2 to 3 cup-equivalents of vegetables each day.² What is a cup-equivalent? Examples include: 1 cup of a raw, or cooked, vegetable or fruit; 1 cup of fruit juice; 2 cups of leafy salad greens; or 1/2 cup of a dried fruit or vegetable. Additional recommendations are that added sugar constitute < 10% of calories per day, saturated fat < 10% of calories per day, and sodium < 2300 mg per day.

Simplify the message to this … There’s an easy message for clinicians to provide to patients: Consume 2 cups of fruit and 2 to 3 cups of vegetables per day; increase intake of whole grains, seafood, nuts, and seeds; choose fat-free and low-fat dairy products; and avoid sugary beverages and foods. But as we know, recommending that patients do something and actually having them do it are often 2 different things. So how can we tip the scales in a healthier direction?

Advise patients not to go it alone. The US Preventive Services Task Force recommends intensive behavioral interventions to alter eating habits. These interventions include individual or group counseling sessions over extended periods (eg, 6 hours of contact time over 6 to 18 months), including some 1-on-1 time with a specially trained professional, such as a primary care physician, nurse, registered dietitian, or nutritionist. The good news is that, for those with cardiovascular risk factors (dyslipidemia, elevated blood pressure, type 2 diabetes, and hypertension), this is a level “B” recommendation—meaning these interventions should be covered by commercial health insurance with no out-of-pocket cost to patients.³

Dietary guidelines provide scientifically sound and practical advice that, if followed by every person, would probably result in less obesity, type 2 diabetes, cardiovascular disease, cancer, and bone loss. But few US adults meet these recommendations, according to a recent report in the CDC’s Morbidity and Mortality Weekly Report (MMWR).¹

Data from the 2019 Behavioral Risk Factor Surveillance system indicate that only 12.3% of US adults consumed the recommended amount of fruit and 10% the recommended amount of vegetables (more on that shortly). Women were more likely than men to meet the requirements for fruit (14.5% vs 10.1%) and vegetable (12.4% vs 7.6%) intake. The vegetable recommendation was more likely to be met by those in higher income households than those in the lowest income categories (12.2% vs 6.8%).¹

Just what’s recommended? The most recent dietary guidelines from the Department of Agriculture suggest that adults should consume 1.5 to 2 cup-equivalents of fruits and 2 to 3 cup-equivalents of vegetables each day.² What is a cup-equivalent? Examples include: 1 cup of a raw, or cooked, vegetable or fruit; 1 cup of fruit juice; 2 cups of leafy salad greens; or 1/2 cup of a dried fruit or vegetable. Additional recommendations are that added sugar constitute < 10% of calories per day, saturated fat < 10% of calories per day, and sodium < 2300 mg per day.

Simplify the message to this … There’s an easy message for clinicians to provide to patients: Consume 2 cups of fruit and 2 to 3 cups of vegetables per day; increase intake of whole grains, seafood, nuts, and seeds; choose fat-free and low-fat dairy products; and avoid sugary beverages and foods. But as we know, recommending that patients do something and actually having them do it are often 2 different things. So how can we tip the scales in a healthier direction?

Advise patients not to go it alone. The US Preventive Services Task Force recommends intensive behavioral interventions to alter eating habits. These interventions include individual or group counseling sessions over extended periods (eg, 6 hours of contact time over 6 to 18 months), including some 1-on-1 time with a specially trained professional, such as a primary care physician, nurse, registered dietitian, or nutritionist. The good news is that, for those with cardiovascular risk factors (dyslipidemia, elevated blood pressure, type 2 diabetes, and hypertension), this is a level “B” recommendation—meaning these interventions should be covered by commercial health insurance with no out-of-pocket cost to patients.³

Dietary guidelines provide scientifically sound and practical advice that, if followed by every person, would probably result in less obesity, type 2 diabetes, cardiovascular disease, cancer, and bone loss. But few US adults meet these recommendations, according to a recent report in the CDC’s Morbidity and Mortality Weekly Report (MMWR).¹

Data from the 2019 Behavioral Risk Factor Surveillance system indicate that only 12.3% of US adults consumed the recommended amount of fruit and 10% the recommended amount of vegetables (more on that shortly). Women were more likely than men to meet the requirements for fruit (14.5% vs 10.1%) and vegetable (12.4% vs 7.6%) intake. The vegetable recommendation was more likely to be met by those in higher income households than those in the lowest income categories (12.2% vs 6.8%).¹

Just what’s recommended? The most recent dietary guidelines from the Department of Agriculture suggest that adults should consume 1.5 to 2 cup-equivalents of fruits and 2 to 3 cup-equivalents of vegetables each day.² What is a cup-equivalent? Examples include: 1 cup of a raw, or cooked, vegetable or fruit; 1 cup of fruit juice; 2 cups of leafy salad greens; or 1/2 cup of a dried fruit or vegetable. Additional recommendations are that added sugar constitute < 10% of calories per day, saturated fat < 10% of calories per day, and sodium < 2300 mg per day.

Simplify the message to this … There’s an easy message for clinicians to provide to patients: Consume 2 cups of fruit and 2 to 3 cups of vegetables per day; increase intake of whole grains, seafood, nuts, and seeds; choose fat-free and low-fat dairy products; and avoid sugary beverages and foods. But as we know, recommending that patients do something and actually having them do it are often 2 different things. So how can we tip the scales in a healthier direction?

Advise patients not to go it alone. The US Preventive Services Task Force recommends intensive behavioral interventions to alter eating habits. These interventions include individual or group counseling sessions over extended periods (eg, 6 hours of contact time over 6 to 18 months), including some 1-on-1 time with a specially trained professional, such as a primary care physician, nurse, registered dietitian, or nutritionist. The good news is that, for those with cardiovascular risk factors (dyslipidemia, elevated blood pressure, type 2 diabetes, and hypertension), this is a level “B” recommendation—meaning these interventions should be covered by commercial health insurance with no out-of-pocket cost to patients.³

The widely held notion that consuming small to moderate amounts of alcohol is good for cardiovascular health is not supported by the data, the World Heart Federation says in a new policy brief.

In fact, the evidence is clear that any level of drinking can contribute to loss of a healthy life, the organization says.

“Over the past several decades, the prevalence of cardiovascular disease has nearly doubled, and alcohol has played a major role in the incidence of much of it,” the WHF said in the brief.

“The portrayal of alcohol as necessary for a vibrant social life has diverted attention from the harms of alcohol use, as have the frequent and widely publicized claims that moderate drinking, such as a glass of red wine a day, can offer protection against cardiovascular disease,” Monika Arora, PhD, member of the WHF advocacy committee and coauthor of the brief, said in a news release.

“These claims are at best misinformed and at worst an attempt by the alcohol industry to mislead the public about the danger of their product,” Dr. Arora added.

The WHF conclusions follow a report in the Lancet based on the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD), which found that there is no safe level of alcohol consumption.

In 2019, nearly 2.4 million deaths were attributed to alcohol, accounting for 4.3% of all deaths globally and 12.6% of deaths in men 15 to 49 years of age.

Even small amounts of alcohol have been shown to raise the risk for cardiovascular disease, including coronary disease, stroke, heart failure, hypertensive heart disease, cardiomyopathy, atrial fibrillation, and aneurysm, the WHF notes.

Studies that claim otherwise are largely based on purely observational research, which fails to account for relevant cofactors, the organization writes.

Based on their summary of the evidence to date, there is no reliable correlation between moderate alcohol consumption and a lower risk for cardiovascular disease.

Alcohol use is also a “major avoidable risk factor” for cancer, digestive diseases, intentional and unintentional injuries, and several infectious diseases, the WHF says.

Alcohol use also has significant economic and social costs, which include costs to individuals and health systems, productivity losses, as well as the increased risk for violence, homelessness, and criminal activity.

The WHF policy brief calls for “urgent and decisive action” to tackle the unprecedented rise in alcohol-related death and disability worldwide.

Recommended actions include boosting restrictions on alcohol availability; advancing and enforcing drinking and driving countermeasures; increasing access to screening, brief interventions, and treatment for alcohol use disorder; enforcing bans on alcohol advertising; establishing a uniform minimum legal drinking age; and mandating health warnings on alcohol products.

A version of this article first appeared on Medscape.com.

The widely held notion that consuming small to moderate amounts of alcohol is good for cardiovascular health is not supported by the data, the World Heart Federation says in a new policy brief.

In fact, the evidence is clear that any level of drinking can contribute to loss of a healthy life, the organization says.

“Over the past several decades, the prevalence of cardiovascular disease has nearly doubled, and alcohol has played a major role in the incidence of much of it,” the WHF said in the brief.

“The portrayal of alcohol as necessary for a vibrant social life has diverted attention from the harms of alcohol use, as have the frequent and widely publicized claims that moderate drinking, such as a glass of red wine a day, can offer protection against cardiovascular disease,” Monika Arora, PhD, member of the WHF advocacy committee and coauthor of the brief, said in a news release.

“These claims are at best misinformed and at worst an attempt by the alcohol industry to mislead the public about the danger of their product,” Dr. Arora added.

The WHF conclusions follow a report in the Lancet based on the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD), which found that there is no safe level of alcohol consumption.

In 2019, nearly 2.4 million deaths were attributed to alcohol, accounting for 4.3% of all deaths globally and 12.6% of deaths in men 15 to 49 years of age.

Even small amounts of alcohol have been shown to raise the risk for cardiovascular disease, including coronary disease, stroke, heart failure, hypertensive heart disease, cardiomyopathy, atrial fibrillation, and aneurysm, the WHF notes.

Studies that claim otherwise are largely based on purely observational research, which fails to account for relevant cofactors, the organization writes.

Based on their summary of the evidence to date, there is no reliable correlation between moderate alcohol consumption and a lower risk for cardiovascular disease.

Alcohol use is also a “major avoidable risk factor” for cancer, digestive diseases, intentional and unintentional injuries, and several infectious diseases, the WHF says.

Alcohol use also has significant economic and social costs, which include costs to individuals and health systems, productivity losses, as well as the increased risk for violence, homelessness, and criminal activity.

The WHF policy brief calls for “urgent and decisive action” to tackle the unprecedented rise in alcohol-related death and disability worldwide.

Recommended actions include boosting restrictions on alcohol availability; advancing and enforcing drinking and driving countermeasures; increasing access to screening, brief interventions, and treatment for alcohol use disorder; enforcing bans on alcohol advertising; establishing a uniform minimum legal drinking age; and mandating health warnings on alcohol products.

A version of this article first appeared on Medscape.com.

The widely held notion that consuming small to moderate amounts of alcohol is good for cardiovascular health is not supported by the data, the World Heart Federation says in a new policy brief.

In fact, the evidence is clear that any level of drinking can contribute to loss of a healthy life, the organization says.

“Over the past several decades, the prevalence of cardiovascular disease has nearly doubled, and alcohol has played a major role in the incidence of much of it,” the WHF said in the brief.

“The portrayal of alcohol as necessary for a vibrant social life has diverted attention from the harms of alcohol use, as have the frequent and widely publicized claims that moderate drinking, such as a glass of red wine a day, can offer protection against cardiovascular disease,” Monika Arora, PhD, member of the WHF advocacy committee and coauthor of the brief, said in a news release.

“These claims are at best misinformed and at worst an attempt by the alcohol industry to mislead the public about the danger of their product,” Dr. Arora added.

The WHF conclusions follow a report in the Lancet based on the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD), which found that there is no safe level of alcohol consumption.

In 2019, nearly 2.4 million deaths were attributed to alcohol, accounting for 4.3% of all deaths globally and 12.6% of deaths in men 15 to 49 years of age.

Even small amounts of alcohol have been shown to raise the risk for cardiovascular disease, including coronary disease, stroke, heart failure, hypertensive heart disease, cardiomyopathy, atrial fibrillation, and aneurysm, the WHF notes.

Studies that claim otherwise are largely based on purely observational research, which fails to account for relevant cofactors, the organization writes.

Based on their summary of the evidence to date, there is no reliable correlation between moderate alcohol consumption and a lower risk for cardiovascular disease.

Alcohol use is also a “major avoidable risk factor” for cancer, digestive diseases, intentional and unintentional injuries, and several infectious diseases, the WHF says.

Alcohol use also has significant economic and social costs, which include costs to individuals and health systems, productivity losses, as well as the increased risk for violence, homelessness, and criminal activity.

The WHF policy brief calls for “urgent and decisive action” to tackle the unprecedented rise in alcohol-related death and disability worldwide.

Recommended actions include boosting restrictions on alcohol availability; advancing and enforcing drinking and driving countermeasures; increasing access to screening, brief interventions, and treatment for alcohol use disorder; enforcing bans on alcohol advertising; establishing a uniform minimum legal drinking age; and mandating health warnings on alcohol products.

A version of this article first appeared on Medscape.com.

Medtronic has recalled 95,110 HawkOne Directional Atherectomy Systems because of the risk of the guidewire within the catheter moving downward or prolapsing during use, which may damage the tip of the catheter.

The U.S. Food and Drug Administration has identified this as a Class I recall, the most serious type, because of the potential for serious injury or death.

The HawkOne Directional Atherectomy system is used during procedures intended to remove blockage from peripheral arteries and improve blood flow.

If the guideline moves downward or prolapses during use, the “catheter tip may break off or separate, and this could lead to serious adverse events, including a tear along the inside wall of an artery (arterial dissection), a rupture or breakage of an artery (arterial rupture), decrease in blood flow to a part of the body because of a blocked artery (ischemia), and/or blood vessel complications that could require surgical repair and additional procedures to capture and remove the detached and/or migrated (embolized) tip,” the FDA says in a recall notice posted today on its website.

To date, there have been 55 injuries, no deaths, and 163 complaints reported for this device.

The recalled devices were distributed in the United States between Jan. 22, 2018 and Oct. 4, 2021. Product codes and lot numbers pertaining to the devices are listed on the FDA website.

Medtronic sent an urgent field safety notice to customers Dec. 6, 2021, requesting that they alert parties of the defect, review the instructions for use before using the device, and note the warnings and precautions listed in the letter.

Customers were also asked to complete the enclosed confirmation form and email to rs.cfqfca@medtronic.com.

Health care providers can report adverse reactions or quality problems they experience using these devices to the FDA’s MedWatch program.

A version of this article first appeared on Medscape.com.

Medtronic has recalled 95,110 HawkOne Directional Atherectomy Systems because of the risk of the guidewire within the catheter moving downward or prolapsing during use, which may damage the tip of the catheter.

The U.S. Food and Drug Administration has identified this as a Class I recall, the most serious type, because of the potential for serious injury or death.

The HawkOne Directional Atherectomy system is used during procedures intended to remove blockage from peripheral arteries and improve blood flow.

If the guideline moves downward or prolapses during use, the “catheter tip may break off or separate, and this could lead to serious adverse events, including a tear along the inside wall of an artery (arterial dissection), a rupture or breakage of an artery (arterial rupture), decrease in blood flow to a part of the body because of a blocked artery (ischemia), and/or blood vessel complications that could require surgical repair and additional procedures to capture and remove the detached and/or migrated (embolized) tip,” the FDA says in a recall notice posted today on its website.

To date, there have been 55 injuries, no deaths, and 163 complaints reported for this device.

The recalled devices were distributed in the United States between Jan. 22, 2018 and Oct. 4, 2021. Product codes and lot numbers pertaining to the devices are listed on the FDA website.

Medtronic sent an urgent field safety notice to customers Dec. 6, 2021, requesting that they alert parties of the defect, review the instructions for use before using the device, and note the warnings and precautions listed in the letter.

Customers were also asked to complete the enclosed confirmation form and email to rs.cfqfca@medtronic.com.

Health care providers can report adverse reactions or quality problems they experience using these devices to the FDA’s MedWatch program.

A version of this article first appeared on Medscape.com.

Medtronic has recalled 95,110 HawkOne Directional Atherectomy Systems because of the risk of the guidewire within the catheter moving downward or prolapsing during use, which may damage the tip of the catheter.

The U.S. Food and Drug Administration has identified this as a Class I recall, the most serious type, because of the potential for serious injury or death.

The HawkOne Directional Atherectomy system is used during procedures intended to remove blockage from peripheral arteries and improve blood flow.

If the guideline moves downward or prolapses during use, the “catheter tip may break off or separate, and this could lead to serious adverse events, including a tear along the inside wall of an artery (arterial dissection), a rupture or breakage of an artery (arterial rupture), decrease in blood flow to a part of the body because of a blocked artery (ischemia), and/or blood vessel complications that could require surgical repair and additional procedures to capture and remove the detached and/or migrated (embolized) tip,” the FDA says in a recall notice posted today on its website.

To date, there have been 55 injuries, no deaths, and 163 complaints reported for this device.

The recalled devices were distributed in the United States between Jan. 22, 2018 and Oct. 4, 2021. Product codes and lot numbers pertaining to the devices are listed on the FDA website.

Medtronic sent an urgent field safety notice to customers Dec. 6, 2021, requesting that they alert parties of the defect, review the instructions for use before using the device, and note the warnings and precautions listed in the letter.

Customers were also asked to complete the enclosed confirmation form and email to rs.cfqfca@medtronic.com.

Health care providers can report adverse reactions or quality problems they experience using these devices to the FDA’s MedWatch program.

A version of this article first appeared on Medscape.com.