Cardiology

An electronic nudge explaining the cardiovascular benefits of the influenza vaccine increased vaccination rates, particularly among people who had previously had a heart attack, showed the NUDGE FLU series of clinical trials.

Influenza has the potential to be a dangerous infection on its own, but it increases the risk for cardiovascular events among people with a history of heart attack, said the study’s lead author, Ankeet Bhatt, MD, a cardiologist at Kaiser Permanente San Francisco Medical Center, San Francisco.

“Yearly influenza vaccines help prevent influenza infection and, in patients with a heart attack, are potentially cardioprotective,” he said during his presentation at the American Heart Association (AHA) Scientific Sessions 2024 in Chicago. The NUDGE FLU results were simultaneously published online in JAMA Cardiology.

In Denmark, where the trials were conducted, about 80% of older adults get flu shots, but only about 40% of younger adults with chronic diseases do, Bhatt reported. In the United States, about 45% of adults and 55% of children received at least one dose of the flu vaccine in the 2023/24 flu season, according to the US Centers for Disease Control and Prevention (CDC).

 

The NUDGE FLU Trials

Bhatt and his colleagues conducted three related clinical trials during the 2022/23 and 2023/24 flu seasons: NUDGE-FLU and NUDGE-FLU-2 targeted older adults, whereas NUDGE-FLU-CHRONIC targeted younger adults with chronic diseases. Nearly 2 million people were involved in the three trials.

Participants were randomized to receive one of a series of different behavioral-science-informed letters, delivered through a government-run electronic communication system, or no reminder.

People who received any of the nudges had higher rates of vaccination; among heart attack survivors, there was a 1.8% improvement and among adults without a history of heart attack, there was a 1.3% improvement. But a nudge that explained the potential cardiovascular benefits of flu shots was even more effective, leading to a 3.9% increase among people with a history of heart attack and a 2% increase among those with no heart attack history.

“A simple sentence resulted in a durable improvement in the vaccination rate,” said Bhatt.

The effect was even greater among those who had not been vaccinated in the previous flu season. Among heart attack survivors, nearly 14% more people got the vaccine compared with just 1.5% more survivors who were previously vaccinated. And it was most effective among younger adults who had experienced a recent heart attack, resulting in a 26% increase.

“The impact was larger in patients with a history of acute myocardial infarction, in those who were vaccine-hesitant, and in younger people” — all groups with the most to gain from vaccination in terms of cardiovascular protection — Bhatt reported.

About 25% of people in the United States are unsure about whether to get a flu shot, said Orly Vardeny, PharmD, professor of medicine at the University of Minnesota Medical School in Minneapolis, who was not involved in the study. The fact that previously unvaccinated people were convinced by the nudges is reassuring. “That’s the group where this intervention is most likely to move the needle,” she said.

Around half of all people hospitalized for flu in the United States have cardiovascular disease, CDC data showed, so “even a small increase in the number of patients who get vaccinated has substantial public health benefits,” Vardeny said.

The NUDGE FLU series showed that nudges like this should be employed as a simple tool to improve vaccination rates, but the system would be much more difficult to implement in the United States, Bhatt said.

Denmark has a national health service and a preexisting government electronic communication system, whereas the US system is privately run and more fractured. It would be possible to make it work, he pointed out, but would take some effort.

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

An electronic nudge explaining the cardiovascular benefits of the influenza vaccine increased vaccination rates, particularly among people who had previously had a heart attack, showed the NUDGE FLU series of clinical trials.

Influenza has the potential to be a dangerous infection on its own, but it increases the risk for cardiovascular events among people with a history of heart attack, said the study’s lead author, Ankeet Bhatt, MD, a cardiologist at Kaiser Permanente San Francisco Medical Center, San Francisco.

“Yearly influenza vaccines help prevent influenza infection and, in patients with a heart attack, are potentially cardioprotective,” he said during his presentation at the American Heart Association (AHA) Scientific Sessions 2024 in Chicago. The NUDGE FLU results were simultaneously published online in JAMA Cardiology.

In Denmark, where the trials were conducted, about 80% of older adults get flu shots, but only about 40% of younger adults with chronic diseases do, Bhatt reported. In the United States, about 45% of adults and 55% of children received at least one dose of the flu vaccine in the 2023/24 flu season, according to the US Centers for Disease Control and Prevention (CDC).

 

The NUDGE FLU Trials

Bhatt and his colleagues conducted three related clinical trials during the 2022/23 and 2023/24 flu seasons: NUDGE-FLU and NUDGE-FLU-2 targeted older adults, whereas NUDGE-FLU-CHRONIC targeted younger adults with chronic diseases. Nearly 2 million people were involved in the three trials.

Participants were randomized to receive one of a series of different behavioral-science-informed letters, delivered through a government-run electronic communication system, or no reminder.

People who received any of the nudges had higher rates of vaccination; among heart attack survivors, there was a 1.8% improvement and among adults without a history of heart attack, there was a 1.3% improvement. But a nudge that explained the potential cardiovascular benefits of flu shots was even more effective, leading to a 3.9% increase among people with a history of heart attack and a 2% increase among those with no heart attack history.

“A simple sentence resulted in a durable improvement in the vaccination rate,” said Bhatt.

The effect was even greater among those who had not been vaccinated in the previous flu season. Among heart attack survivors, nearly 14% more people got the vaccine compared with just 1.5% more survivors who were previously vaccinated. And it was most effective among younger adults who had experienced a recent heart attack, resulting in a 26% increase.

“The impact was larger in patients with a history of acute myocardial infarction, in those who were vaccine-hesitant, and in younger people” — all groups with the most to gain from vaccination in terms of cardiovascular protection — Bhatt reported.

About 25% of people in the United States are unsure about whether to get a flu shot, said Orly Vardeny, PharmD, professor of medicine at the University of Minnesota Medical School in Minneapolis, who was not involved in the study. The fact that previously unvaccinated people were convinced by the nudges is reassuring. “That’s the group where this intervention is most likely to move the needle,” she said.

Around half of all people hospitalized for flu in the United States have cardiovascular disease, CDC data showed, so “even a small increase in the number of patients who get vaccinated has substantial public health benefits,” Vardeny said.

The NUDGE FLU series showed that nudges like this should be employed as a simple tool to improve vaccination rates, but the system would be much more difficult to implement in the United States, Bhatt said.

Denmark has a national health service and a preexisting government electronic communication system, whereas the US system is privately run and more fractured. It would be possible to make it work, he pointed out, but would take some effort.

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

An electronic nudge explaining the cardiovascular benefits of the influenza vaccine increased vaccination rates, particularly among people who had previously had a heart attack, showed the NUDGE FLU series of clinical trials.

Influenza has the potential to be a dangerous infection on its own, but it increases the risk for cardiovascular events among people with a history of heart attack, said the study’s lead author, Ankeet Bhatt, MD, a cardiologist at Kaiser Permanente San Francisco Medical Center, San Francisco.

“Yearly influenza vaccines help prevent influenza infection and, in patients with a heart attack, are potentially cardioprotective,” he said during his presentation at the American Heart Association (AHA) Scientific Sessions 2024 in Chicago. The NUDGE FLU results were simultaneously published online in JAMA Cardiology.

In Denmark, where the trials were conducted, about 80% of older adults get flu shots, but only about 40% of younger adults with chronic diseases do, Bhatt reported. In the United States, about 45% of adults and 55% of children received at least one dose of the flu vaccine in the 2023/24 flu season, according to the US Centers for Disease Control and Prevention (CDC).

 

The NUDGE FLU Trials

Bhatt and his colleagues conducted three related clinical trials during the 2022/23 and 2023/24 flu seasons: NUDGE-FLU and NUDGE-FLU-2 targeted older adults, whereas NUDGE-FLU-CHRONIC targeted younger adults with chronic diseases. Nearly 2 million people were involved in the three trials.

Participants were randomized to receive one of a series of different behavioral-science-informed letters, delivered through a government-run electronic communication system, or no reminder.

People who received any of the nudges had higher rates of vaccination; among heart attack survivors, there was a 1.8% improvement and among adults without a history of heart attack, there was a 1.3% improvement. But a nudge that explained the potential cardiovascular benefits of flu shots was even more effective, leading to a 3.9% increase among people with a history of heart attack and a 2% increase among those with no heart attack history.

“A simple sentence resulted in a durable improvement in the vaccination rate,” said Bhatt.

The effect was even greater among those who had not been vaccinated in the previous flu season. Among heart attack survivors, nearly 14% more people got the vaccine compared with just 1.5% more survivors who were previously vaccinated. And it was most effective among younger adults who had experienced a recent heart attack, resulting in a 26% increase.

“The impact was larger in patients with a history of acute myocardial infarction, in those who were vaccine-hesitant, and in younger people” — all groups with the most to gain from vaccination in terms of cardiovascular protection — Bhatt reported.

About 25% of people in the United States are unsure about whether to get a flu shot, said Orly Vardeny, PharmD, professor of medicine at the University of Minnesota Medical School in Minneapolis, who was not involved in the study. The fact that previously unvaccinated people were convinced by the nudges is reassuring. “That’s the group where this intervention is most likely to move the needle,” she said.

Around half of all people hospitalized for flu in the United States have cardiovascular disease, CDC data showed, so “even a small increase in the number of patients who get vaccinated has substantial public health benefits,” Vardeny said.

The NUDGE FLU series showed that nudges like this should be employed as a simple tool to improve vaccination rates, but the system would be much more difficult to implement in the United States, Bhatt said.

Denmark has a national health service and a preexisting government electronic communication system, whereas the US system is privately run and more fractured. It would be possible to make it work, he pointed out, but would take some effort.

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

New questions about the landmark trial that launched the antiplatelet drug ticagrelor worldwide are being raised after an investigation uncovered more information about how the PLATO study was conducted.

Peter Doshi, PhD, senior editor at The BMJ, obtained primary records for the trial and unpublished data through a Freedom of Information Act request, and has detailed inconsistencies and omissions in data reporting from the 2009 trial originally published in The New England Journal of Medicine (NEJM). The new investigation into the Platelet Inhibition and Patient Outcomes (PLATO) trial is published in The BMJ.

The findings come as generic versions of ticagrelor (Brilinta) are expected to become available soon in the United States. Ticagrelor is the only P2Y12 inhibitor still under patent, and in 2022, the United States spent more than $750 million on it, according to the report.

PLATO, sponsored by ticagrelor manufacturer AstraZeneca, included more than 18,000 patients in 43 countries. Investigators reported that ticagrelor reduced deaths from vascular causes, heart attack, or stroke compared with clopidogrel (Plavix). However, in a subgroup analysis, among US patients, there were more deaths in the ticagrelor group, and AstraZeneca failed its first bid for approval from the US Food and Drug Administration (FDA).

 

Failed First Bid for FDA Approval

AstraZeneca resubmitted its application, which was met with objections by some FDA staff members, including medical officer Thomas Marciniak, who called the resubmission “the worst in my experience regarding completeness of the submissions and the sponsor responding completely and accurately to requests,” Doshi reports.

Despite the objections, the FDA in 2011 approved ticagrelor for acute coronary syndrome, kicking off intense controversy over the trial, as several other studies have failed to replicate PLATO’s positive results.

Doubts have grown about its apparent advantage over cheaper, off-patent P2Y12 inhibitors such as clopidogrel and prasugrel.

“Critics said it was noteworthy that ticagrelor failed in the US,” Doshi writes, “the only high enrolling country where sites were not monitored by the sponsor itself.” Doshi’s report points out that critics of the trial “highlight that AstraZeneca itself carried out the data monitoring for PLATO except for sites that were monitored by third party contract research organizations. In the four countries exclusively monitored by non-sponsor personnel—Georgia, Israel, Russia, and the US—ticagrelor fared worse.”

Victor Serebruany, MD, from Johns Hopkins University, said he was initially impressed by the trial results but became skeptical after noticing inconsistencies and anomalies in the data. He filed a complaint with the US District Court in the District of Columbia, suggesting that the cardiovascular events in the study “may have been manipulated.”

 

US Department of Justice Investigation

The US Department of Justice (DOJ) opened an investigation in 2013 and closed it in 2014 with no further action. Serebruany continues to publish critiques of the trial 15 years later but told The BMJ he has little hope that the questions will be resolved unless the DOJ re-engages with an investigation.

Doshi also points out discrepancies in the data reported. In the 2009 paper, published as an intent-to-treat analysis, investigators said there were 905 total deaths from any cause among all randomized patients. “An internal company report states, however, that 983 patients had died at this point. While 33 deaths occurred after the follow-up period, the NEJM tally still leaves out 45 deaths ‘discovered after withdrawal of consent,’” he reports.

The NEJM responded to Doshi that while it didn’t dispute the error in the number of deaths, it was uncertain about publishing a correction, citing new — not yet published — guidelines from the International Committee of Medical Journal Editors. NEJM Editor-in-Chief Eric Rubin told The BMJ that “for older manuscripts, correction is not necessarily appropriate unless there would be an effect on clinical practice.”

Doshi’s investigation includes an interview with Eric Bates, MD, professor of internal medicine at the University of Michigan in Ann Arbor, and a co-author of the US guidelines that recommend ticagrelor, who said he was “increasingly disturbed by how trial after trial came out as being not dramatically positive in any way.” Bates is now calling for a review of ticagrelor’s recommendation in guidelines, according to the report.

AstraZeneca declined to be interviewed for the BMJ investigation, according to Doshi, and a spokesperson from the company told the journal by email that they have “nothing to add,” directing editors to its 2014 public statement after the DOJ’s investigation into PLATO. The BMJ said PLATO trial co-chairs Robert A. Harrington, MD, and Lars Wallentin, MD, did not respond to The BMJ’s requests for comment.

 

Will the Guidelines Be Changed Now?

“I know and have worked with Drs Wallentin and Harrington,” Bates told Medscape Medical News, “and find them to be honest, intelligent clinical scientists with the highest ethical standards who manage conflicts of interest as well as can be done in the clinical research arena, where industry support is required to develop new knowledge,” he said.

“If there is a concern that AstraZeneca was manipulating the dataset and FDA submission, that is an important issue,” Bates said. “The US paradox and the failure of any other antiplatelet trial to find a comparative mortality advantage are two unexplained issues with PLATO that provide good fodder for conspiracy theories. I agree with the NEJM that this trial is 15 years old and may not be worth readjudicating in the current treatment era.”

Other calls for revisiting guidelines have come after disappointing postlicensure studies have repeatedly demonstrated that ticagrelor has “similar efficacy to clopidogrel but with increased bleeding and [dyspnea],” Doshi reports.

“My concern is the marketing spin by AstraZeneca and the promotion of ticagrelor by six to eight ‘thought leaders’ consistently funded by AstraZeneca over the past 10 years,” said Bates. “They have flooded the literature with supportive subset and post hoc analyses, review articles, and ‘meta-analyses’ flawed by selection and intellectual bias, and public interviews that consistently discount the findings of the many subsequent randomized controlled trials that have not supported the superiority of ticagrelor over clopidogrel or prasugrel.”

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

New questions about the landmark trial that launched the antiplatelet drug ticagrelor worldwide are being raised after an investigation uncovered more information about how the PLATO study was conducted.

Peter Doshi, PhD, senior editor at The BMJ, obtained primary records for the trial and unpublished data through a Freedom of Information Act request, and has detailed inconsistencies and omissions in data reporting from the 2009 trial originally published in The New England Journal of Medicine (NEJM). The new investigation into the Platelet Inhibition and Patient Outcomes (PLATO) trial is published in The BMJ.

The findings come as generic versions of ticagrelor (Brilinta) are expected to become available soon in the United States. Ticagrelor is the only P2Y12 inhibitor still under patent, and in 2022, the United States spent more than $750 million on it, according to the report.

PLATO, sponsored by ticagrelor manufacturer AstraZeneca, included more than 18,000 patients in 43 countries. Investigators reported that ticagrelor reduced deaths from vascular causes, heart attack, or stroke compared with clopidogrel (Plavix). However, in a subgroup analysis, among US patients, there were more deaths in the ticagrelor group, and AstraZeneca failed its first bid for approval from the US Food and Drug Administration (FDA).

 

Failed First Bid for FDA Approval

AstraZeneca resubmitted its application, which was met with objections by some FDA staff members, including medical officer Thomas Marciniak, who called the resubmission “the worst in my experience regarding completeness of the submissions and the sponsor responding completely and accurately to requests,” Doshi reports.

Despite the objections, the FDA in 2011 approved ticagrelor for acute coronary syndrome, kicking off intense controversy over the trial, as several other studies have failed to replicate PLATO’s positive results.

Doubts have grown about its apparent advantage over cheaper, off-patent P2Y12 inhibitors such as clopidogrel and prasugrel.

“Critics said it was noteworthy that ticagrelor failed in the US,” Doshi writes, “the only high enrolling country where sites were not monitored by the sponsor itself.” Doshi’s report points out that critics of the trial “highlight that AstraZeneca itself carried out the data monitoring for PLATO except for sites that were monitored by third party contract research organizations. In the four countries exclusively monitored by non-sponsor personnel—Georgia, Israel, Russia, and the US—ticagrelor fared worse.”

Victor Serebruany, MD, from Johns Hopkins University, said he was initially impressed by the trial results but became skeptical after noticing inconsistencies and anomalies in the data. He filed a complaint with the US District Court in the District of Columbia, suggesting that the cardiovascular events in the study “may have been manipulated.”

 

US Department of Justice Investigation

The US Department of Justice (DOJ) opened an investigation in 2013 and closed it in 2014 with no further action. Serebruany continues to publish critiques of the trial 15 years later but told The BMJ he has little hope that the questions will be resolved unless the DOJ re-engages with an investigation.

Doshi also points out discrepancies in the data reported. In the 2009 paper, published as an intent-to-treat analysis, investigators said there were 905 total deaths from any cause among all randomized patients. “An internal company report states, however, that 983 patients had died at this point. While 33 deaths occurred after the follow-up period, the NEJM tally still leaves out 45 deaths ‘discovered after withdrawal of consent,’” he reports.

The NEJM responded to Doshi that while it didn’t dispute the error in the number of deaths, it was uncertain about publishing a correction, citing new — not yet published — guidelines from the International Committee of Medical Journal Editors. NEJM Editor-in-Chief Eric Rubin told The BMJ that “for older manuscripts, correction is not necessarily appropriate unless there would be an effect on clinical practice.”

Doshi’s investigation includes an interview with Eric Bates, MD, professor of internal medicine at the University of Michigan in Ann Arbor, and a co-author of the US guidelines that recommend ticagrelor, who said he was “increasingly disturbed by how trial after trial came out as being not dramatically positive in any way.” Bates is now calling for a review of ticagrelor’s recommendation in guidelines, according to the report.

AstraZeneca declined to be interviewed for the BMJ investigation, according to Doshi, and a spokesperson from the company told the journal by email that they have “nothing to add,” directing editors to its 2014 public statement after the DOJ’s investigation into PLATO. The BMJ said PLATO trial co-chairs Robert A. Harrington, MD, and Lars Wallentin, MD, did not respond to The BMJ’s requests for comment.

 

Will the Guidelines Be Changed Now?

“I know and have worked with Drs Wallentin and Harrington,” Bates told Medscape Medical News, “and find them to be honest, intelligent clinical scientists with the highest ethical standards who manage conflicts of interest as well as can be done in the clinical research arena, where industry support is required to develop new knowledge,” he said.

“If there is a concern that AstraZeneca was manipulating the dataset and FDA submission, that is an important issue,” Bates said. “The US paradox and the failure of any other antiplatelet trial to find a comparative mortality advantage are two unexplained issues with PLATO that provide good fodder for conspiracy theories. I agree with the NEJM that this trial is 15 years old and may not be worth readjudicating in the current treatment era.”

Other calls for revisiting guidelines have come after disappointing postlicensure studies have repeatedly demonstrated that ticagrelor has “similar efficacy to clopidogrel but with increased bleeding and [dyspnea],” Doshi reports.

“My concern is the marketing spin by AstraZeneca and the promotion of ticagrelor by six to eight ‘thought leaders’ consistently funded by AstraZeneca over the past 10 years,” said Bates. “They have flooded the literature with supportive subset and post hoc analyses, review articles, and ‘meta-analyses’ flawed by selection and intellectual bias, and public interviews that consistently discount the findings of the many subsequent randomized controlled trials that have not supported the superiority of ticagrelor over clopidogrel or prasugrel.”

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

New questions about the landmark trial that launched the antiplatelet drug ticagrelor worldwide are being raised after an investigation uncovered more information about how the PLATO study was conducted.

Peter Doshi, PhD, senior editor at The BMJ, obtained primary records for the trial and unpublished data through a Freedom of Information Act request, and has detailed inconsistencies and omissions in data reporting from the 2009 trial originally published in The New England Journal of Medicine (NEJM). The new investigation into the Platelet Inhibition and Patient Outcomes (PLATO) trial is published in The BMJ.

The findings come as generic versions of ticagrelor (Brilinta) are expected to become available soon in the United States. Ticagrelor is the only P2Y12 inhibitor still under patent, and in 2022, the United States spent more than $750 million on it, according to the report.

PLATO, sponsored by ticagrelor manufacturer AstraZeneca, included more than 18,000 patients in 43 countries. Investigators reported that ticagrelor reduced deaths from vascular causes, heart attack, or stroke compared with clopidogrel (Plavix). However, in a subgroup analysis, among US patients, there were more deaths in the ticagrelor group, and AstraZeneca failed its first bid for approval from the US Food and Drug Administration (FDA).

 

Failed First Bid for FDA Approval

AstraZeneca resubmitted its application, which was met with objections by some FDA staff members, including medical officer Thomas Marciniak, who called the resubmission “the worst in my experience regarding completeness of the submissions and the sponsor responding completely and accurately to requests,” Doshi reports.

Despite the objections, the FDA in 2011 approved ticagrelor for acute coronary syndrome, kicking off intense controversy over the trial, as several other studies have failed to replicate PLATO’s positive results.

Doubts have grown about its apparent advantage over cheaper, off-patent P2Y12 inhibitors such as clopidogrel and prasugrel.

“Critics said it was noteworthy that ticagrelor failed in the US,” Doshi writes, “the only high enrolling country where sites were not monitored by the sponsor itself.” Doshi’s report points out that critics of the trial “highlight that AstraZeneca itself carried out the data monitoring for PLATO except for sites that were monitored by third party contract research organizations. In the four countries exclusively monitored by non-sponsor personnel—Georgia, Israel, Russia, and the US—ticagrelor fared worse.”

Victor Serebruany, MD, from Johns Hopkins University, said he was initially impressed by the trial results but became skeptical after noticing inconsistencies and anomalies in the data. He filed a complaint with the US District Court in the District of Columbia, suggesting that the cardiovascular events in the study “may have been manipulated.”

 

US Department of Justice Investigation

The US Department of Justice (DOJ) opened an investigation in 2013 and closed it in 2014 with no further action. Serebruany continues to publish critiques of the trial 15 years later but told The BMJ he has little hope that the questions will be resolved unless the DOJ re-engages with an investigation.

Doshi also points out discrepancies in the data reported. In the 2009 paper, published as an intent-to-treat analysis, investigators said there were 905 total deaths from any cause among all randomized patients. “An internal company report states, however, that 983 patients had died at this point. While 33 deaths occurred after the follow-up period, the NEJM tally still leaves out 45 deaths ‘discovered after withdrawal of consent,’” he reports.

The NEJM responded to Doshi that while it didn’t dispute the error in the number of deaths, it was uncertain about publishing a correction, citing new — not yet published — guidelines from the International Committee of Medical Journal Editors. NEJM Editor-in-Chief Eric Rubin told The BMJ that “for older manuscripts, correction is not necessarily appropriate unless there would be an effect on clinical practice.”

Doshi’s investigation includes an interview with Eric Bates, MD, professor of internal medicine at the University of Michigan in Ann Arbor, and a co-author of the US guidelines that recommend ticagrelor, who said he was “increasingly disturbed by how trial after trial came out as being not dramatically positive in any way.” Bates is now calling for a review of ticagrelor’s recommendation in guidelines, according to the report.

AstraZeneca declined to be interviewed for the BMJ investigation, according to Doshi, and a spokesperson from the company told the journal by email that they have “nothing to add,” directing editors to its 2014 public statement after the DOJ’s investigation into PLATO. The BMJ said PLATO trial co-chairs Robert A. Harrington, MD, and Lars Wallentin, MD, did not respond to The BMJ’s requests for comment.

 

Will the Guidelines Be Changed Now?

“I know and have worked with Drs Wallentin and Harrington,” Bates told Medscape Medical News, “and find them to be honest, intelligent clinical scientists with the highest ethical standards who manage conflicts of interest as well as can be done in the clinical research arena, where industry support is required to develop new knowledge,” he said.

“If there is a concern that AstraZeneca was manipulating the dataset and FDA submission, that is an important issue,” Bates said. “The US paradox and the failure of any other antiplatelet trial to find a comparative mortality advantage are two unexplained issues with PLATO that provide good fodder for conspiracy theories. I agree with the NEJM that this trial is 15 years old and may not be worth readjudicating in the current treatment era.”

Other calls for revisiting guidelines have come after disappointing postlicensure studies have repeatedly demonstrated that ticagrelor has “similar efficacy to clopidogrel but with increased bleeding and [dyspnea],” Doshi reports.

“My concern is the marketing spin by AstraZeneca and the promotion of ticagrelor by six to eight ‘thought leaders’ consistently funded by AstraZeneca over the past 10 years,” said Bates. “They have flooded the literature with supportive subset and post hoc analyses, review articles, and ‘meta-analyses’ flawed by selection and intellectual bias, and public interviews that consistently discount the findings of the many subsequent randomized controlled trials that have not supported the superiority of ticagrelor over clopidogrel or prasugrel.”

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

TOPLINE:

Elevated levels of N-terminal pro–B-type natriuretic peptide (NT-proBNP), a key biomarker for diagnosing heart failure, show a nearly fourfold increased risk for atrial fibrillation (AF) in at-risk individuals. The utility of this biomarker was particularly evident in older adults and when serum-based measurements were used.

METHODOLOGY:

• Researchers conducted a meta-analysis of prospective cohort, case-cohort, or nested case-control studies to examine the association between NT-proBNP and the incidence of AF.
• They also explored the potential of NT-proBNP in improving risk prediction models for AF.
• Overall, 136,089 adults were included from 16 cohorts, and 8017 cases of incident AF were reported over a median follow-up of 4-20 years.
• Most of the included cohorts were from Europe (n = 12), followed by America (n = 3) and Asia (n = 1).
• The accuracy of the risk prediction models was evaluated using C-indexes, with values in the range of 0.50-0.70, low accuracy; 0.70-0.90, moderate accuracy; and > 0.90, high accuracy.

TAKEAWAY:

• Elevated NT-proBNP levels showed a strong association with the risk for AF, with individuals in the highest quintile of NT-proBNP facing a 3.84-fold higher risk for incident AF (pooled relative risk [RR], 3.84; 95% CI, 3.03-4.87) than those in the lowest quintile.
• The risk increased by 9% for each 10 pg/mL increase in NT-proBNP (RR, 1.09; 95% CI, 1.04-1.14), with a significant nonlinear dose-response association found between NT-proBNP and the risk for AF (P for nonlinearity < .001).
• The association was stronger in the subgroups of older adults and when the biomarker was measured in serum samples.
• The addition of NT-proBNP to traditional risk prediction models for AF may improve predictive accuracy, with the ΔC-indexes ranging from 0.010 to 0.060.

IN PRACTICE:

“The significance of NT-proBNP in enhancing AF risk stratification deserves greater attention, with potential expansion to routine health screening,” the authors wrote.

SOURCE:

The study was led by Wanyue Wang, Department of Epidemiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China, and was published online on December 06, 2024, in Heart.

LIMITATIONS:

Significant heterogeneity was observed in this meta-analysis, with the subgroup articles only providing exploratory and indicative findings. Due to the observational nature of this study, residual confounding could not be excluded. None of the prospective studies included differentiated subtypes of AF, such as paroxysmal and asymptomatic forms, which might have influenced the observed outcomes.

DISCLOSURES:

This study was supported by grants from the National Key Research and Development Program of China, Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, National Natural Science Foundation of China, and National High Level Hospital Clinical Research Funding. The authors declared no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Elevated levels of N-terminal pro–B-type natriuretic peptide (NT-proBNP), a key biomarker for diagnosing heart failure, show a nearly fourfold increased risk for atrial fibrillation (AF) in at-risk individuals. The utility of this biomarker was particularly evident in older adults and when serum-based measurements were used.

METHODOLOGY:

• Researchers conducted a meta-analysis of prospective cohort, case-cohort, or nested case-control studies to examine the association between NT-proBNP and the incidence of AF.
• They also explored the potential of NT-proBNP in improving risk prediction models for AF.
• Overall, 136,089 adults were included from 16 cohorts, and 8017 cases of incident AF were reported over a median follow-up of 4-20 years.
• Most of the included cohorts were from Europe (n = 12), followed by America (n = 3) and Asia (n = 1).
• The accuracy of the risk prediction models was evaluated using C-indexes, with values in the range of 0.50-0.70, low accuracy; 0.70-0.90, moderate accuracy; and > 0.90, high accuracy.

TAKEAWAY:

• Elevated NT-proBNP levels showed a strong association with the risk for AF, with individuals in the highest quintile of NT-proBNP facing a 3.84-fold higher risk for incident AF (pooled relative risk [RR], 3.84; 95% CI, 3.03-4.87) than those in the lowest quintile.
• The risk increased by 9% for each 10 pg/mL increase in NT-proBNP (RR, 1.09; 95% CI, 1.04-1.14), with a significant nonlinear dose-response association found between NT-proBNP and the risk for AF (P for nonlinearity < .001).
• The association was stronger in the subgroups of older adults and when the biomarker was measured in serum samples.
• The addition of NT-proBNP to traditional risk prediction models for AF may improve predictive accuracy, with the ΔC-indexes ranging from 0.010 to 0.060.

IN PRACTICE:

“The significance of NT-proBNP in enhancing AF risk stratification deserves greater attention, with potential expansion to routine health screening,” the authors wrote.

SOURCE:

The study was led by Wanyue Wang, Department of Epidemiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China, and was published online on December 06, 2024, in Heart.

LIMITATIONS:

Significant heterogeneity was observed in this meta-analysis, with the subgroup articles only providing exploratory and indicative findings. Due to the observational nature of this study, residual confounding could not be excluded. None of the prospective studies included differentiated subtypes of AF, such as paroxysmal and asymptomatic forms, which might have influenced the observed outcomes.

DISCLOSURES:

This study was supported by grants from the National Key Research and Development Program of China, Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, National Natural Science Foundation of China, and National High Level Hospital Clinical Research Funding. The authors declared no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Elevated levels of N-terminal pro–B-type natriuretic peptide (NT-proBNP), a key biomarker for diagnosing heart failure, show a nearly fourfold increased risk for atrial fibrillation (AF) in at-risk individuals. The utility of this biomarker was particularly evident in older adults and when serum-based measurements were used.

METHODOLOGY:

• Researchers conducted a meta-analysis of prospective cohort, case-cohort, or nested case-control studies to examine the association between NT-proBNP and the incidence of AF.
• They also explored the potential of NT-proBNP in improving risk prediction models for AF.
• Overall, 136,089 adults were included from 16 cohorts, and 8017 cases of incident AF were reported over a median follow-up of 4-20 years.
• Most of the included cohorts were from Europe (n = 12), followed by America (n = 3) and Asia (n = 1).
• The accuracy of the risk prediction models was evaluated using C-indexes, with values in the range of 0.50-0.70, low accuracy; 0.70-0.90, moderate accuracy; and > 0.90, high accuracy.

TAKEAWAY:

• Elevated NT-proBNP levels showed a strong association with the risk for AF, with individuals in the highest quintile of NT-proBNP facing a 3.84-fold higher risk for incident AF (pooled relative risk [RR], 3.84; 95% CI, 3.03-4.87) than those in the lowest quintile.
• The risk increased by 9% for each 10 pg/mL increase in NT-proBNP (RR, 1.09; 95% CI, 1.04-1.14), with a significant nonlinear dose-response association found between NT-proBNP and the risk for AF (P for nonlinearity < .001).
• The association was stronger in the subgroups of older adults and when the biomarker was measured in serum samples.
• The addition of NT-proBNP to traditional risk prediction models for AF may improve predictive accuracy, with the ΔC-indexes ranging from 0.010 to 0.060.

IN PRACTICE:

“The significance of NT-proBNP in enhancing AF risk stratification deserves greater attention, with potential expansion to routine health screening,” the authors wrote.

SOURCE:

The study was led by Wanyue Wang, Department of Epidemiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China, and was published online on December 06, 2024, in Heart.

LIMITATIONS:

Significant heterogeneity was observed in this meta-analysis, with the subgroup articles only providing exploratory and indicative findings. Due to the observational nature of this study, residual confounding could not be excluded. None of the prospective studies included differentiated subtypes of AF, such as paroxysmal and asymptomatic forms, which might have influenced the observed outcomes.

DISCLOSURES:

This study was supported by grants from the National Key Research and Development Program of China, Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, National Natural Science Foundation of China, and National High Level Hospital Clinical Research Funding. The authors declared no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

The question may seem simple: Could paying for weight loss medications — especially the pricey glucagon-like peptide 1 receptor agonists (GLP-1s), tirzepatide (Zepbound) and semaglutide (Wegovy) — be more cost-effective than paying for obesity care and the complications of obesity, such as cardiovascular disease and diabetes?

It’s a question that’s getting an increased amount of attention.

And for good reason — more than two in five US adults have obesity, according to the Centers for Disease Control and Prevention, and costs to treat obesity, in 2019 dollars, approached $173 billion, including productivity losses. Adults with obesity have annual healthcare costs of $1861 more than those at healthier weights.

Among recent developments:

• A proposed new rule, announced on November 26 by the Biden administration, expands coverage of anti-obesity medication for Americans who have Medicare and Medicaid. If it takes effect, an estimated 3.4 million Medicare recipients and about 4 million adult Medicaid enrollees could get access to the medications.
• As Medicare coverage goes, private insurers often follow. Observers predict that if the Centers for Medicare & Medicaid Services (CMS) covers anti-obesity drugs, more private employers may soon do the same. Recently, however, some private plans have done the opposite and dropped coverage of the pricey GLP-1s, which can cost $1000 a month or more out-of-pocket, citing excess costs for their company.
• Among the analyses about the value of weight loss on healthcare cost savings is a report published on December 5 in JAMA Network Open. Emory University experts looked at privately insured adults and adult Medicare beneficiaries with a body mass index (BMI) of ≥ 25 (classified as overweight). The conclusion: Projected annual savings from weight loss among US adults with obesity were substantial for both employee-based insurance and Medicare recipients.
• Besides helping obesity and obesity-related conditions, access to GLP-1s could have a favorable effect on productivity, others claim. That’s one focus of a 5-year partnership between the University of Manchester in England, and Eli Lilly and Company. Called SURMOUNT-REAL UK, the study will evaluate the effectiveness of tirzepatide in weight loss, diabetes prevention, and prevention of obesity-related complications in adults with obesity. It also aims to look at changes in health-related quality of life with weight loss and with changes in employment status and sick days.

CMS Proposal

In a statement announcing the proposal for Medicare and Medicaid to offer weight loss drugs, the White House noted that “tens of millions of Americans struggle with obesity” but that currently Medicare only covers the anti-obesity medications for certain conditions such as diabetes. The new proposal would expand that access to those with obesity. As of August, just 13 states cover GLP-1s in Medicaid programs, and North Carolina was the latest to do so.

Organizations advocating for health equity and recognition that obesity is a chronic disease came out in strong support of the proposal.

Kenneth E. Thorpe, PhD, a health policy expert at Emory University in Atlanta, who coauthored the recent analysis finding that weight loss offsets healthcare costs on an individual basis, told this news organization: “If finalized, this broad new coverage [by Medicare and Medicaid] would have a profound impact on the ability of Americans to access these novel medications that could significantly reduce obesity-related healthcare spending and improve overall health.”

The proposal “is modernizing the coverage of Medicare and Medicaid for obesity treatment,” agreed John Cawley, PhD, professor of economics and public policy at Cornell University in Ithaca, New York, who has researched the direct medical costs of obesity in the United States. “In this HHS rule, they talk about the scientific and medical consensus that having obesity is a chronic condition.”

The proposal requires a 60-day comment period that ends January 27, 2025, taking the timeline into the beginning of the Trump administration. Cawley and others pointed out that Trump’s pick for Health and Human Services Secretary, Robert F. Kennedy Jr, has been an outspoken opponent of the anti-obesity medicines, suggesting instead that Americans simply eat better.

 

Expert Analyses: Emory, Cornell, Southern California

So would paying for the pricey GLP-1s be smart in the long term? Analyses don’t agree.

Weight loss among those with obesity produces healthcare cost savings, said Thorpe and Peter Joski, MSPH, an associate research professor at Emory University. The two compared annual healthcare spending among privately insured adults and adult Medicare beneficiaries with a BMI of ≥ 25, using data from the Medical Expenditure Panel Survey — Household Component from April 1 to June 20, 2024.

The researchers looked at 3774 adults insured with Medicare and 13,435 with employer-sponsored insurance. Overall, those with private insurance with a weight loss of 5% spent an estimated average of $670 less on healthcare. Those with a weight loss of 25% spent an estimated $2849 less on healthcare. Among those with Medicare who had one or more comorbidities, a 5% weight loss reduced spending by $1262 on average; a 25% loss reduced it by an estimated $5442, or 31%.

Thorpe called the savings substantial. In an email interview, Thorpe said, “So yes, weight loss for people living with obesity does lower healthcare costs, as my research shows, but it also lowers other costs as well.”

These include costs associated with disability, workers’ compensation, presenteeism/absenteeism, and everyday costs, he said. He contends that “those other costs should factor into decisions about preventing and treating obesity of payors and policymakers and enhance the case for cost-effectiveness of treating obesity.”

Other research suggests it’s important to target the use of the anti-obesity medications to the BMI range that would get the most benefit. For people just barely above the BMI threshold of 30, no cost savings are expected, Cawley found in his research. But he has found substantial cost reduction if the BMI was 35-40.

However, as Cawley pointed out, as the drugs get cheaper and more options become available, the entire scenario is expected to shift.

 

The Congressional Budget Office View

In October, the nonpartisan Congressional Budget Office issued a report, “How Would Authorizing Medicare to Cover Anti-Obesity Medications Affect the Federal Budget?” Among the conclusions: Covering the anti-obesity medications would increase federal spending, on net, by about $35 billion from 2026 to 2034. Total direct federal costs of covering the medication would increase from $1.6 billion in 2026 to $7.1 billion in 2034. And it said total savings from improved health of the beneficiaries would be small, less than $50 million in 2026 and rising to $1 billion in 2034.

Covering the medications would cost $5600 per user in 2026, then down to $4300 in 2034. The offset of savings per user would be about $50 in 2026, then $650 in 2034.

 

Expert Analysis: USC Schaeffer Center

“The costs offsets come over time,” said Alison Sexton Ward, PhD, an economist at the University of Southern California’s Leonard D. Schaeffer Center, Los Angeles, and an expert on the topic. “If we look at the average annual medical cost over a lifetime, we do see cost offsets there.”

However, treating obesity means people will live longer, “and living longer costs more,” she said.

She took issue with some of the calculations in the CBO report, such as not considering the effect of semaglutide’s patent expiring in 2033.

In a white paper published in April 2023, Sexton Ward and her coauthors modeled potential social benefits and medical cost offsets from granting access to the newer weight loss drugs. The cumulative social benefits of providing coverage over the next decade would reach nearly $1 trillion, they said. Benefits would increase if private insurance expanded coverage. “In the first 10 years alone, covering weight loss therapies would save Medicare $175 billion-$245 billion, depending on whether private insurance joins Medicare in providing coverage for younger populations.”

While much focus is on Medicare coverage, Sexton Ward and others pointed out the need to expand coverage to younger ages, with the aim of preventing or delaying obesity-related complications.

 

Lilly UK Trial

A spokesperson for Lilly declined to comment further on the UK study, explaining that the study was just launching.

Besides tracking weight loss, researchers will evaluate the effect of the weight loss on sick days from work and employment. Obesity is shown to affect a person’s ability to work, leading to more absenteeism, so treating the obesity may improve productivity.

 

Beyond Health: The Value of Weight Loss

“I love the idea of studying whether access to obesity medications helps people stay employed and do their job,” said Cristy Gallagher, associate director of Research and Policy at STOP Obesity Alliance at the Milken Institute School of Public Health, George Washington University, Washington, DC. The alliance includes more than 50 organizations advocating for adult obesity treatment.

“One of our big arguments is [that] access to care, and to obesity care, will also help other conditions — comorbidities like heart disease and diabetes.”

However, access to the anti-obesity medications, by itself, is not enough, Gallagher said. Other components, such as intensive behavioral therapy and guidance about diet and exercise, are needed, she said. So, too, for those who need it, is access to bariatric surgery, she said. And medication access should include other options besides the GLP-1s, she said. “Not every medication is right for everybody.”

Cawley, Gallagher, Thorpe, and Sexton Ward had no disclosures.
 

A version of this article appeared on Medscape.com.

The question may seem simple: Could paying for weight loss medications — especially the pricey glucagon-like peptide 1 receptor agonists (GLP-1s), tirzepatide (Zepbound) and semaglutide (Wegovy) — be more cost-effective than paying for obesity care and the complications of obesity, such as cardiovascular disease and diabetes?

It’s a question that’s getting an increased amount of attention.

And for good reason — more than two in five US adults have obesity, according to the Centers for Disease Control and Prevention, and costs to treat obesity, in 2019 dollars, approached $173 billion, including productivity losses. Adults with obesity have annual healthcare costs of $1861 more than those at healthier weights.

Among recent developments:

• A proposed new rule, announced on November 26 by the Biden administration, expands coverage of anti-obesity medication for Americans who have Medicare and Medicaid. If it takes effect, an estimated 3.4 million Medicare recipients and about 4 million adult Medicaid enrollees could get access to the medications.
• As Medicare coverage goes, private insurers often follow. Observers predict that if the Centers for Medicare & Medicaid Services (CMS) covers anti-obesity drugs, more private employers may soon do the same. Recently, however, some private plans have done the opposite and dropped coverage of the pricey GLP-1s, which can cost $1000 a month or more out-of-pocket, citing excess costs for their company.
• Among the analyses about the value of weight loss on healthcare cost savings is a report published on December 5 in JAMA Network Open. Emory University experts looked at privately insured adults and adult Medicare beneficiaries with a body mass index (BMI) of ≥ 25 (classified as overweight). The conclusion: Projected annual savings from weight loss among US adults with obesity were substantial for both employee-based insurance and Medicare recipients.
• Besides helping obesity and obesity-related conditions, access to GLP-1s could have a favorable effect on productivity, others claim. That’s one focus of a 5-year partnership between the University of Manchester in England, and Eli Lilly and Company. Called SURMOUNT-REAL UK, the study will evaluate the effectiveness of tirzepatide in weight loss, diabetes prevention, and prevention of obesity-related complications in adults with obesity. It also aims to look at changes in health-related quality of life with weight loss and with changes in employment status and sick days.

CMS Proposal

In a statement announcing the proposal for Medicare and Medicaid to offer weight loss drugs, the White House noted that “tens of millions of Americans struggle with obesity” but that currently Medicare only covers the anti-obesity medications for certain conditions such as diabetes. The new proposal would expand that access to those with obesity. As of August, just 13 states cover GLP-1s in Medicaid programs, and North Carolina was the latest to do so.

Organizations advocating for health equity and recognition that obesity is a chronic disease came out in strong support of the proposal.

Kenneth E. Thorpe, PhD, a health policy expert at Emory University in Atlanta, who coauthored the recent analysis finding that weight loss offsets healthcare costs on an individual basis, told this news organization: “If finalized, this broad new coverage [by Medicare and Medicaid] would have a profound impact on the ability of Americans to access these novel medications that could significantly reduce obesity-related healthcare spending and improve overall health.”

The proposal “is modernizing the coverage of Medicare and Medicaid for obesity treatment,” agreed John Cawley, PhD, professor of economics and public policy at Cornell University in Ithaca, New York, who has researched the direct medical costs of obesity in the United States. “In this HHS rule, they talk about the scientific and medical consensus that having obesity is a chronic condition.”

The proposal requires a 60-day comment period that ends January 27, 2025, taking the timeline into the beginning of the Trump administration. Cawley and others pointed out that Trump’s pick for Health and Human Services Secretary, Robert F. Kennedy Jr, has been an outspoken opponent of the anti-obesity medicines, suggesting instead that Americans simply eat better.

 

Expert Analyses: Emory, Cornell, Southern California

So would paying for the pricey GLP-1s be smart in the long term? Analyses don’t agree.

Weight loss among those with obesity produces healthcare cost savings, said Thorpe and Peter Joski, MSPH, an associate research professor at Emory University. The two compared annual healthcare spending among privately insured adults and adult Medicare beneficiaries with a BMI of ≥ 25, using data from the Medical Expenditure Panel Survey — Household Component from April 1 to June 20, 2024.

The researchers looked at 3774 adults insured with Medicare and 13,435 with employer-sponsored insurance. Overall, those with private insurance with a weight loss of 5% spent an estimated average of $670 less on healthcare. Those with a weight loss of 25% spent an estimated $2849 less on healthcare. Among those with Medicare who had one or more comorbidities, a 5% weight loss reduced spending by $1262 on average; a 25% loss reduced it by an estimated $5442, or 31%.

Thorpe called the savings substantial. In an email interview, Thorpe said, “So yes, weight loss for people living with obesity does lower healthcare costs, as my research shows, but it also lowers other costs as well.”

These include costs associated with disability, workers’ compensation, presenteeism/absenteeism, and everyday costs, he said. He contends that “those other costs should factor into decisions about preventing and treating obesity of payors and policymakers and enhance the case for cost-effectiveness of treating obesity.”

Other research suggests it’s important to target the use of the anti-obesity medications to the BMI range that would get the most benefit. For people just barely above the BMI threshold of 30, no cost savings are expected, Cawley found in his research. But he has found substantial cost reduction if the BMI was 35-40.

However, as Cawley pointed out, as the drugs get cheaper and more options become available, the entire scenario is expected to shift.

 

The Congressional Budget Office View

In October, the nonpartisan Congressional Budget Office issued a report, “How Would Authorizing Medicare to Cover Anti-Obesity Medications Affect the Federal Budget?” Among the conclusions: Covering the anti-obesity medications would increase federal spending, on net, by about $35 billion from 2026 to 2034. Total direct federal costs of covering the medication would increase from $1.6 billion in 2026 to $7.1 billion in 2034. And it said total savings from improved health of the beneficiaries would be small, less than $50 million in 2026 and rising to $1 billion in 2034.

Covering the medications would cost $5600 per user in 2026, then down to $4300 in 2034. The offset of savings per user would be about $50 in 2026, then $650 in 2034.

 

Expert Analysis: USC Schaeffer Center

“The costs offsets come over time,” said Alison Sexton Ward, PhD, an economist at the University of Southern California’s Leonard D. Schaeffer Center, Los Angeles, and an expert on the topic. “If we look at the average annual medical cost over a lifetime, we do see cost offsets there.”

However, treating obesity means people will live longer, “and living longer costs more,” she said.

She took issue with some of the calculations in the CBO report, such as not considering the effect of semaglutide’s patent expiring in 2033.

In a white paper published in April 2023, Sexton Ward and her coauthors modeled potential social benefits and medical cost offsets from granting access to the newer weight loss drugs. The cumulative social benefits of providing coverage over the next decade would reach nearly $1 trillion, they said. Benefits would increase if private insurance expanded coverage. “In the first 10 years alone, covering weight loss therapies would save Medicare $175 billion-$245 billion, depending on whether private insurance joins Medicare in providing coverage for younger populations.”

While much focus is on Medicare coverage, Sexton Ward and others pointed out the need to expand coverage to younger ages, with the aim of preventing or delaying obesity-related complications.

 

Lilly UK Trial

A spokesperson for Lilly declined to comment further on the UK study, explaining that the study was just launching.

Besides tracking weight loss, researchers will evaluate the effect of the weight loss on sick days from work and employment. Obesity is shown to affect a person’s ability to work, leading to more absenteeism, so treating the obesity may improve productivity.

 

Beyond Health: The Value of Weight Loss

“I love the idea of studying whether access to obesity medications helps people stay employed and do their job,” said Cristy Gallagher, associate director of Research and Policy at STOP Obesity Alliance at the Milken Institute School of Public Health, George Washington University, Washington, DC. The alliance includes more than 50 organizations advocating for adult obesity treatment.

“One of our big arguments is [that] access to care, and to obesity care, will also help other conditions — comorbidities like heart disease and diabetes.”

However, access to the anti-obesity medications, by itself, is not enough, Gallagher said. Other components, such as intensive behavioral therapy and guidance about diet and exercise, are needed, she said. So, too, for those who need it, is access to bariatric surgery, she said. And medication access should include other options besides the GLP-1s, she said. “Not every medication is right for everybody.”

Cawley, Gallagher, Thorpe, and Sexton Ward had no disclosures.
 

A version of this article appeared on Medscape.com.

The question may seem simple: Could paying for weight loss medications — especially the pricey glucagon-like peptide 1 receptor agonists (GLP-1s), tirzepatide (Zepbound) and semaglutide (Wegovy) — be more cost-effective than paying for obesity care and the complications of obesity, such as cardiovascular disease and diabetes?

It’s a question that’s getting an increased amount of attention.

And for good reason — more than two in five US adults have obesity, according to the Centers for Disease Control and Prevention, and costs to treat obesity, in 2019 dollars, approached $173 billion, including productivity losses. Adults with obesity have annual healthcare costs of $1861 more than those at healthier weights.

Among recent developments:

• A proposed new rule, announced on November 26 by the Biden administration, expands coverage of anti-obesity medication for Americans who have Medicare and Medicaid. If it takes effect, an estimated 3.4 million Medicare recipients and about 4 million adult Medicaid enrollees could get access to the medications.
• As Medicare coverage goes, private insurers often follow. Observers predict that if the Centers for Medicare & Medicaid Services (CMS) covers anti-obesity drugs, more private employers may soon do the same. Recently, however, some private plans have done the opposite and dropped coverage of the pricey GLP-1s, which can cost $1000 a month or more out-of-pocket, citing excess costs for their company.
• Among the analyses about the value of weight loss on healthcare cost savings is a report published on December 5 in JAMA Network Open. Emory University experts looked at privately insured adults and adult Medicare beneficiaries with a body mass index (BMI) of ≥ 25 (classified as overweight). The conclusion: Projected annual savings from weight loss among US adults with obesity were substantial for both employee-based insurance and Medicare recipients.
• Besides helping obesity and obesity-related conditions, access to GLP-1s could have a favorable effect on productivity, others claim. That’s one focus of a 5-year partnership between the University of Manchester in England, and Eli Lilly and Company. Called SURMOUNT-REAL UK, the study will evaluate the effectiveness of tirzepatide in weight loss, diabetes prevention, and prevention of obesity-related complications in adults with obesity. It also aims to look at changes in health-related quality of life with weight loss and with changes in employment status and sick days.

CMS Proposal

In a statement announcing the proposal for Medicare and Medicaid to offer weight loss drugs, the White House noted that “tens of millions of Americans struggle with obesity” but that currently Medicare only covers the anti-obesity medications for certain conditions such as diabetes. The new proposal would expand that access to those with obesity. As of August, just 13 states cover GLP-1s in Medicaid programs, and North Carolina was the latest to do so.

Organizations advocating for health equity and recognition that obesity is a chronic disease came out in strong support of the proposal.

Kenneth E. Thorpe, PhD, a health policy expert at Emory University in Atlanta, who coauthored the recent analysis finding that weight loss offsets healthcare costs on an individual basis, told this news organization: “If finalized, this broad new coverage [by Medicare and Medicaid] would have a profound impact on the ability of Americans to access these novel medications that could significantly reduce obesity-related healthcare spending and improve overall health.”

The proposal “is modernizing the coverage of Medicare and Medicaid for obesity treatment,” agreed John Cawley, PhD, professor of economics and public policy at Cornell University in Ithaca, New York, who has researched the direct medical costs of obesity in the United States. “In this HHS rule, they talk about the scientific and medical consensus that having obesity is a chronic condition.”

The proposal requires a 60-day comment period that ends January 27, 2025, taking the timeline into the beginning of the Trump administration. Cawley and others pointed out that Trump’s pick for Health and Human Services Secretary, Robert F. Kennedy Jr, has been an outspoken opponent of the anti-obesity medicines, suggesting instead that Americans simply eat better.

 

Expert Analyses: Emory, Cornell, Southern California

So would paying for the pricey GLP-1s be smart in the long term? Analyses don’t agree.

Weight loss among those with obesity produces healthcare cost savings, said Thorpe and Peter Joski, MSPH, an associate research professor at Emory University. The two compared annual healthcare spending among privately insured adults and adult Medicare beneficiaries with a BMI of ≥ 25, using data from the Medical Expenditure Panel Survey — Household Component from April 1 to June 20, 2024.

The researchers looked at 3774 adults insured with Medicare and 13,435 with employer-sponsored insurance. Overall, those with private insurance with a weight loss of 5% spent an estimated average of $670 less on healthcare. Those with a weight loss of 25% spent an estimated $2849 less on healthcare. Among those with Medicare who had one or more comorbidities, a 5% weight loss reduced spending by $1262 on average; a 25% loss reduced it by an estimated $5442, or 31%.

Thorpe called the savings substantial. In an email interview, Thorpe said, “So yes, weight loss for people living with obesity does lower healthcare costs, as my research shows, but it also lowers other costs as well.”

These include costs associated with disability, workers’ compensation, presenteeism/absenteeism, and everyday costs, he said. He contends that “those other costs should factor into decisions about preventing and treating obesity of payors and policymakers and enhance the case for cost-effectiveness of treating obesity.”

Other research suggests it’s important to target the use of the anti-obesity medications to the BMI range that would get the most benefit. For people just barely above the BMI threshold of 30, no cost savings are expected, Cawley found in his research. But he has found substantial cost reduction if the BMI was 35-40.

However, as Cawley pointed out, as the drugs get cheaper and more options become available, the entire scenario is expected to shift.

 

The Congressional Budget Office View

In October, the nonpartisan Congressional Budget Office issued a report, “How Would Authorizing Medicare to Cover Anti-Obesity Medications Affect the Federal Budget?” Among the conclusions: Covering the anti-obesity medications would increase federal spending, on net, by about $35 billion from 2026 to 2034. Total direct federal costs of covering the medication would increase from $1.6 billion in 2026 to $7.1 billion in 2034. And it said total savings from improved health of the beneficiaries would be small, less than $50 million in 2026 and rising to $1 billion in 2034.

Covering the medications would cost $5600 per user in 2026, then down to $4300 in 2034. The offset of savings per user would be about $50 in 2026, then $650 in 2034.

 

Expert Analysis: USC Schaeffer Center

“The costs offsets come over time,” said Alison Sexton Ward, PhD, an economist at the University of Southern California’s Leonard D. Schaeffer Center, Los Angeles, and an expert on the topic. “If we look at the average annual medical cost over a lifetime, we do see cost offsets there.”

However, treating obesity means people will live longer, “and living longer costs more,” she said.

She took issue with some of the calculations in the CBO report, such as not considering the effect of semaglutide’s patent expiring in 2033.

In a white paper published in April 2023, Sexton Ward and her coauthors modeled potential social benefits and medical cost offsets from granting access to the newer weight loss drugs. The cumulative social benefits of providing coverage over the next decade would reach nearly $1 trillion, they said. Benefits would increase if private insurance expanded coverage. “In the first 10 years alone, covering weight loss therapies would save Medicare $175 billion-$245 billion, depending on whether private insurance joins Medicare in providing coverage for younger populations.”

While much focus is on Medicare coverage, Sexton Ward and others pointed out the need to expand coverage to younger ages, with the aim of preventing or delaying obesity-related complications.

 

Lilly UK Trial

A spokesperson for Lilly declined to comment further on the UK study, explaining that the study was just launching.

Besides tracking weight loss, researchers will evaluate the effect of the weight loss on sick days from work and employment. Obesity is shown to affect a person’s ability to work, leading to more absenteeism, so treating the obesity may improve productivity.

 

Beyond Health: The Value of Weight Loss

“I love the idea of studying whether access to obesity medications helps people stay employed and do their job,” said Cristy Gallagher, associate director of Research and Policy at STOP Obesity Alliance at the Milken Institute School of Public Health, George Washington University, Washington, DC. The alliance includes more than 50 organizations advocating for adult obesity treatment.

“One of our big arguments is [that] access to care, and to obesity care, will also help other conditions — comorbidities like heart disease and diabetes.”

However, access to the anti-obesity medications, by itself, is not enough, Gallagher said. Other components, such as intensive behavioral therapy and guidance about diet and exercise, are needed, she said. So, too, for those who need it, is access to bariatric surgery, she said. And medication access should include other options besides the GLP-1s, she said. “Not every medication is right for everybody.”

Cawley, Gallagher, Thorpe, and Sexton Ward had no disclosures.
 

A version of this article appeared on Medscape.com.

TOPLINE:

The beneficial effect of clopidogrel monotherapy over aspirin monotherapy in patients who underwent percutaneous coronary intervention (PCI) and remained event free for 6-18 months on dual antiplatelet therapy (DAPT) is consistent, regardless of bleeding risk or PCI complexity, according to a post hoc analysis of the HOST-EXAM trial.

METHODOLOGY:

• The HOST-EXAM Extended study conducted across 37 sites in South Korea included patients who underwent PCI with drug-eluting stents and remained free of clinical events for 6-18 months post-PCI, while receiving DAPT.
• This post hoc analysis of the HOST-EXAM Extended study compared the effectiveness of long-term daily clopidogrel (75 mg) with that of aspirin monotherapy (100 mg) after PCI, according to bleeding risk and procedural complexity in 3974 patients (mean age, 63 years; 75% men) who were followed for up to 5.9 years.
• High bleeding risk was reported in 866 patients, and 849 patients underwent complex PCI.
• Patients were classified into four distinct risk groups: No bleeding risk and noncomplex PCI, no bleeding risk and complex PCI, high bleeding risk and noncomplex PCI, and high bleeding risk and complex PCI.
• The co-primary endpoints were thrombotic composite events (cardiovascular death, nonfatal myocardial infarction, stroke, readmission due to acute coronary syndrome, and definite/probable stent thrombosis) and any bleeding event.

TAKEAWAY:

• Thrombotic composite events (hazard ratio [HR], 2.15; P < .001) and any bleeding event (HR, 3.64; P < .001) were more frequent in patients with a high bleeding risk than in those without.
• However, there was no difference in the risk for thrombotic composite events or any bleeding event by PCI complexity.
• The long-term benefits of clopidogrel monotherapy over aspirin monotherapy were seen in all patients, regardless of bleeding risks (P for interaction = .38 for thrombotic composite events and P for interaction = .20 for any bleeding event) or PCI complexity (P for interaction = .12 for thrombotic composite events and P for interaction = .62 for any bleeding event).
• The greatest risk reduction in thrombotic composite events with clopidogrel monotherapy occurred in patients with a high bleeding risk who underwent complex PCI (HR, 0.46; P = .03).

IN PRACTICE:

“[In this study], no significant interaction was found between treatment arms and risk groups, denoting that the beneficial impact of clopidogrel monotherapy was consistent regardless of HBR [high bleeding risk] or PCI complexity,” the authors wrote.

SOURCE:

This study was led by Jeehoon Kang, MD, Seoul National University College of Medicine and Seoul National University Hospital, Seoul, Republic of Korea. It was published online on November 27, 2024, in JAMA Cardiology.

LIMITATIONS:

As this study is a post hoc analysis, the findings should be considered primarily hypothesis generating. This study was conducted exclusively in an East Asian population and may not be generalizable to other ethnic groups. The definitions of high bleeding risk and complex PCI used in this analysis were not prespecified in the study protocol of the HOST-EXAM trial. Certain criteria defining high bleeding risk were not analyzed as they fell under the exclusion criteria of the HOST-EXAM trial or were not recorded in the study case report form.

DISCLOSURES:

This study was supported by grants from the Patient-Centered Clinical Research Coordinating Center and Seoul National University Hospital. One author reported receiving grants and personal fees from various pharmaceutical companies outside the submitted work.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

The beneficial effect of clopidogrel monotherapy over aspirin monotherapy in patients who underwent percutaneous coronary intervention (PCI) and remained event free for 6-18 months on dual antiplatelet therapy (DAPT) is consistent, regardless of bleeding risk or PCI complexity, according to a post hoc analysis of the HOST-EXAM trial.

METHODOLOGY:

• The HOST-EXAM Extended study conducted across 37 sites in South Korea included patients who underwent PCI with drug-eluting stents and remained free of clinical events for 6-18 months post-PCI, while receiving DAPT.
• This post hoc analysis of the HOST-EXAM Extended study compared the effectiveness of long-term daily clopidogrel (75 mg) with that of aspirin monotherapy (100 mg) after PCI, according to bleeding risk and procedural complexity in 3974 patients (mean age, 63 years; 75% men) who were followed for up to 5.9 years.
• High bleeding risk was reported in 866 patients, and 849 patients underwent complex PCI.
• Patients were classified into four distinct risk groups: No bleeding risk and noncomplex PCI, no bleeding risk and complex PCI, high bleeding risk and noncomplex PCI, and high bleeding risk and complex PCI.
• The co-primary endpoints were thrombotic composite events (cardiovascular death, nonfatal myocardial infarction, stroke, readmission due to acute coronary syndrome, and definite/probable stent thrombosis) and any bleeding event.

TAKEAWAY:

• Thrombotic composite events (hazard ratio [HR], 2.15; P < .001) and any bleeding event (HR, 3.64; P < .001) were more frequent in patients with a high bleeding risk than in those without.
• However, there was no difference in the risk for thrombotic composite events or any bleeding event by PCI complexity.
• The long-term benefits of clopidogrel monotherapy over aspirin monotherapy were seen in all patients, regardless of bleeding risks (P for interaction = .38 for thrombotic composite events and P for interaction = .20 for any bleeding event) or PCI complexity (P for interaction = .12 for thrombotic composite events and P for interaction = .62 for any bleeding event).
• The greatest risk reduction in thrombotic composite events with clopidogrel monotherapy occurred in patients with a high bleeding risk who underwent complex PCI (HR, 0.46; P = .03).

IN PRACTICE:

“[In this study], no significant interaction was found between treatment arms and risk groups, denoting that the beneficial impact of clopidogrel monotherapy was consistent regardless of HBR [high bleeding risk] or PCI complexity,” the authors wrote.

SOURCE:

This study was led by Jeehoon Kang, MD, Seoul National University College of Medicine and Seoul National University Hospital, Seoul, Republic of Korea. It was published online on November 27, 2024, in JAMA Cardiology.

LIMITATIONS:

As this study is a post hoc analysis, the findings should be considered primarily hypothesis generating. This study was conducted exclusively in an East Asian population and may not be generalizable to other ethnic groups. The definitions of high bleeding risk and complex PCI used in this analysis were not prespecified in the study protocol of the HOST-EXAM trial. Certain criteria defining high bleeding risk were not analyzed as they fell under the exclusion criteria of the HOST-EXAM trial or were not recorded in the study case report form.

DISCLOSURES:

This study was supported by grants from the Patient-Centered Clinical Research Coordinating Center and Seoul National University Hospital. One author reported receiving grants and personal fees from various pharmaceutical companies outside the submitted work.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

The beneficial effect of clopidogrel monotherapy over aspirin monotherapy in patients who underwent percutaneous coronary intervention (PCI) and remained event free for 6-18 months on dual antiplatelet therapy (DAPT) is consistent, regardless of bleeding risk or PCI complexity, according to a post hoc analysis of the HOST-EXAM trial.

METHODOLOGY:

• The HOST-EXAM Extended study conducted across 37 sites in South Korea included patients who underwent PCI with drug-eluting stents and remained free of clinical events for 6-18 months post-PCI, while receiving DAPT.
• This post hoc analysis of the HOST-EXAM Extended study compared the effectiveness of long-term daily clopidogrel (75 mg) with that of aspirin monotherapy (100 mg) after PCI, according to bleeding risk and procedural complexity in 3974 patients (mean age, 63 years; 75% men) who were followed for up to 5.9 years.
• High bleeding risk was reported in 866 patients, and 849 patients underwent complex PCI.
• Patients were classified into four distinct risk groups: No bleeding risk and noncomplex PCI, no bleeding risk and complex PCI, high bleeding risk and noncomplex PCI, and high bleeding risk and complex PCI.
• The co-primary endpoints were thrombotic composite events (cardiovascular death, nonfatal myocardial infarction, stroke, readmission due to acute coronary syndrome, and definite/probable stent thrombosis) and any bleeding event.

TAKEAWAY:

• Thrombotic composite events (hazard ratio [HR], 2.15; P < .001) and any bleeding event (HR, 3.64; P < .001) were more frequent in patients with a high bleeding risk than in those without.
• However, there was no difference in the risk for thrombotic composite events or any bleeding event by PCI complexity.
• The long-term benefits of clopidogrel monotherapy over aspirin monotherapy were seen in all patients, regardless of bleeding risks (P for interaction = .38 for thrombotic composite events and P for interaction = .20 for any bleeding event) or PCI complexity (P for interaction = .12 for thrombotic composite events and P for interaction = .62 for any bleeding event).
• The greatest risk reduction in thrombotic composite events with clopidogrel monotherapy occurred in patients with a high bleeding risk who underwent complex PCI (HR, 0.46; P = .03).

IN PRACTICE:

“[In this study], no significant interaction was found between treatment arms and risk groups, denoting that the beneficial impact of clopidogrel monotherapy was consistent regardless of HBR [high bleeding risk] or PCI complexity,” the authors wrote.

SOURCE:

This study was led by Jeehoon Kang, MD, Seoul National University College of Medicine and Seoul National University Hospital, Seoul, Republic of Korea. It was published online on November 27, 2024, in JAMA Cardiology.

LIMITATIONS:

As this study is a post hoc analysis, the findings should be considered primarily hypothesis generating. This study was conducted exclusively in an East Asian population and may not be generalizable to other ethnic groups. The definitions of high bleeding risk and complex PCI used in this analysis were not prespecified in the study protocol of the HOST-EXAM trial. Certain criteria defining high bleeding risk were not analyzed as they fell under the exclusion criteria of the HOST-EXAM trial or were not recorded in the study case report form.

DISCLOSURES:

This study was supported by grants from the Patient-Centered Clinical Research Coordinating Center and Seoul National University Hospital. One author reported receiving grants and personal fees from various pharmaceutical companies outside the submitted work.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Among pregnant patients with chronic hypertension, delivery at 39 weeks of gestation provides an optimal balance between stillbirth risk and neonatal outcomes. Analysis of 227,977 term singleton deliveries shows consistent findings across different patient subgroups.

METHODOLOGY:

• A population-based retrospective cohort study analyzed 227,977 nonanomalous singleton term births in the United States from 2014 to 2018 among patients with chronic hypertension.
• Researchers excluded pregnancies with superimposed preeclampsia, eclampsia, pregestational diabetes, and deliveries occurring before 37 weeks or at 43 or more weeks of gestation.
• Analysis compared rates of stillbirth, infant death within 1 year of life, and neonatal morbidity at each week of term pregnancy.
• Neonatal morbidity was defined as a composite of neonatal intensive care unit admission, ventilation for 6 hours or longer, a low 5-minute Apgar score (≤ 3), and seizures.

TAKEAWAY:

• The rate of stillbirth per 10,000 ongoing pregnancies increased with gestational age and was lowest at 38 weeks (6.5; 95% CI, 5.4-7.7).
• Rates of infant death and neonatal morbidity were lowest at 40 weeks (18.0/10,000 live births; 95% CI, 13.7-23.6) and 39 weeks (637/10,000 live births; 95% CI, 619-654), respectively.
• At 39 weeks of gestation, the risk for delivery was lower (651/10,000; 95% CI, 633-670) than the composite risk for expectant management (750/10,000; 95% CI, 720-781).
• According to the authors, findings were consistent for non-Hispanic Black patients and pregnancies complicated by fetal growth restriction.

IN PRACTICE:

“To prevent one case of stillbirth, infant death, or neonatal morbidity, an estimated 101 patients with chronic hypertension would need to deliver at 39 weeks of gestation as opposed to 40 weeks. Given the approximately 45,000 patients with chronic hypertension who deliver at term each year in the United States, a policy of delivery at 39 weeks of gestation theoretically would prevent 450 adverse perinatal events per year,” wrote the authors of the study.

SOURCE:

The study was led by Ira Hamilton, James Liu, Labeena Wajahat, and Robert Rossi, University of Cincinnati College of Medicine in Cincinnati. It was published online in O&G Open.

LIMITATIONS:

According to the authors, the study could not stratify chronic hypertension based on medication use, number of medications, or degree of control. The researchers note that exact timing of delivery in weeks and days was not reported, limiting precise understanding of optimal delivery timing. Additionally, the study could not examine rates of neonatal morbidity and mortality in patients who developed superimposed preeclampsia during expectant management.

DISCLOSURES:

The authors did not report any potential conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Among pregnant patients with chronic hypertension, delivery at 39 weeks of gestation provides an optimal balance between stillbirth risk and neonatal outcomes. Analysis of 227,977 term singleton deliveries shows consistent findings across different patient subgroups.

METHODOLOGY:

• A population-based retrospective cohort study analyzed 227,977 nonanomalous singleton term births in the United States from 2014 to 2018 among patients with chronic hypertension.
• Researchers excluded pregnancies with superimposed preeclampsia, eclampsia, pregestational diabetes, and deliveries occurring before 37 weeks or at 43 or more weeks of gestation.
• Analysis compared rates of stillbirth, infant death within 1 year of life, and neonatal morbidity at each week of term pregnancy.
• Neonatal morbidity was defined as a composite of neonatal intensive care unit admission, ventilation for 6 hours or longer, a low 5-minute Apgar score (≤ 3), and seizures.

TAKEAWAY:

• The rate of stillbirth per 10,000 ongoing pregnancies increased with gestational age and was lowest at 38 weeks (6.5; 95% CI, 5.4-7.7).
• Rates of infant death and neonatal morbidity were lowest at 40 weeks (18.0/10,000 live births; 95% CI, 13.7-23.6) and 39 weeks (637/10,000 live births; 95% CI, 619-654), respectively.
• At 39 weeks of gestation, the risk for delivery was lower (651/10,000; 95% CI, 633-670) than the composite risk for expectant management (750/10,000; 95% CI, 720-781).
• According to the authors, findings were consistent for non-Hispanic Black patients and pregnancies complicated by fetal growth restriction.

IN PRACTICE:

“To prevent one case of stillbirth, infant death, or neonatal morbidity, an estimated 101 patients with chronic hypertension would need to deliver at 39 weeks of gestation as opposed to 40 weeks. Given the approximately 45,000 patients with chronic hypertension who deliver at term each year in the United States, a policy of delivery at 39 weeks of gestation theoretically would prevent 450 adverse perinatal events per year,” wrote the authors of the study.

SOURCE:

The study was led by Ira Hamilton, James Liu, Labeena Wajahat, and Robert Rossi, University of Cincinnati College of Medicine in Cincinnati. It was published online in O&G Open.

LIMITATIONS:

According to the authors, the study could not stratify chronic hypertension based on medication use, number of medications, or degree of control. The researchers note that exact timing of delivery in weeks and days was not reported, limiting precise understanding of optimal delivery timing. Additionally, the study could not examine rates of neonatal morbidity and mortality in patients who developed superimposed preeclampsia during expectant management.

DISCLOSURES:

The authors did not report any potential conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Among pregnant patients with chronic hypertension, delivery at 39 weeks of gestation provides an optimal balance between stillbirth risk and neonatal outcomes. Analysis of 227,977 term singleton deliveries shows consistent findings across different patient subgroups.

METHODOLOGY:

• A population-based retrospective cohort study analyzed 227,977 nonanomalous singleton term births in the United States from 2014 to 2018 among patients with chronic hypertension.
• Researchers excluded pregnancies with superimposed preeclampsia, eclampsia, pregestational diabetes, and deliveries occurring before 37 weeks or at 43 or more weeks of gestation.
• Analysis compared rates of stillbirth, infant death within 1 year of life, and neonatal morbidity at each week of term pregnancy.
• Neonatal morbidity was defined as a composite of neonatal intensive care unit admission, ventilation for 6 hours or longer, a low 5-minute Apgar score (≤ 3), and seizures.

TAKEAWAY:

• The rate of stillbirth per 10,000 ongoing pregnancies increased with gestational age and was lowest at 38 weeks (6.5; 95% CI, 5.4-7.7).
• Rates of infant death and neonatal morbidity were lowest at 40 weeks (18.0/10,000 live births; 95% CI, 13.7-23.6) and 39 weeks (637/10,000 live births; 95% CI, 619-654), respectively.
• At 39 weeks of gestation, the risk for delivery was lower (651/10,000; 95% CI, 633-670) than the composite risk for expectant management (750/10,000; 95% CI, 720-781).
• According to the authors, findings were consistent for non-Hispanic Black patients and pregnancies complicated by fetal growth restriction.

IN PRACTICE:

“To prevent one case of stillbirth, infant death, or neonatal morbidity, an estimated 101 patients with chronic hypertension would need to deliver at 39 weeks of gestation as opposed to 40 weeks. Given the approximately 45,000 patients with chronic hypertension who deliver at term each year in the United States, a policy of delivery at 39 weeks of gestation theoretically would prevent 450 adverse perinatal events per year,” wrote the authors of the study.

SOURCE:

The study was led by Ira Hamilton, James Liu, Labeena Wajahat, and Robert Rossi, University of Cincinnati College of Medicine in Cincinnati. It was published online in O&G Open.

LIMITATIONS:

According to the authors, the study could not stratify chronic hypertension based on medication use, number of medications, or degree of control. The researchers note that exact timing of delivery in weeks and days was not reported, limiting precise understanding of optimal delivery timing. Additionally, the study could not examine rates of neonatal morbidity and mortality in patients who developed superimposed preeclampsia during expectant management.

DISCLOSURES:

The authors did not report any potential conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Atherosclerotic cardiovascular disease (ASCVD) risk is higher with cutaneous lupus erythematosus (CLE) or systemic lupus erythematosus (SLE) than with psoriasis.

METHODOLOGY:

• A retrospective matched longitudinal study compared the incidence and prevalence of ASCVD of 8138 individuals with CLE; 24,675 with SLE; 192,577 with psoriasis; and 81,380 control individuals.
• The disease-free control population was matched in a 10:1 ratio to the CLE population on the basis of age, sex, insurance type, and enrollment duration.
• Prevalent ASCVD was defined as coronary artery disease, prior myocardial infarction, or cerebrovascular accident, with ASCVD incidence assessed by number of hospitalizations over 3 years.

TAKEAWAY:

• Persons with CLE had higher ASCVD risk than control individuals (odds ratio [OR], 1.72; P < .001), similar to those with SLE (OR, 2.41; P < .001) but unlike those with psoriasis (OR, 1.03; P = .48).
• ASCVD incidence at 3 years was 24.8 per 1000 person-years for SLE, 15.2 per 1000 person-years for CLE, 14.0 per 1000 person-years for psoriasis, and 10.3 per 1000 person-years for controls.
• Multivariable Cox proportional regression modeling showed ASCVD risk was highest in those with SLE (hazard ratio [HR], 2.23; P < .001) vs CLE (HR, 1.32; P < .001) and psoriasis (HR, 1.06; P = .09).
• ASCVD prevalence was higher in individuals with CLE receiving systemic therapy (2.7%) than in those receiving no therapy (1.6%), suggesting a potential link between disease severity and CVD risk.

IN PRACTICE:

“Persons with CLE are at higher risk for ASCVD, and guidelines for the evaluation and management of ASCVD may improve their quality of care,” the authors wrote.

SOURCE:

The study was led by Henry W. Chen, MD, Department of Dermatology, University of Texas Southwestern Medical Center, Dallas. It was published online on December 4, 2024, in JAMA Dermatology.

LIMITATIONS: 

The study was limited by its relatively young population (median age, 49 years) and the exclusion of adults aged > 65 years on Medicare insurance plans. The database lacked race and ethnicity data, and the analysis was restricted to a shorter 3-year period. The study could not fully evaluate detailed risk factors such as blood pressure levels, cholesterol measurements, or glycemic control, nor could it accurately assess smoking status.

DISCLOSURES:

The research was supported by the Department of Dermatology at the University of Texas Southwestern Medical Center and a grant from the National Institutes of Health. Several authors reported receiving grants or personal fees from various pharmaceutical companies. One author reported being a deputy editor for diversity, equity, and inclusion at JAMA Cardiology. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Atherosclerotic cardiovascular disease (ASCVD) risk is higher with cutaneous lupus erythematosus (CLE) or systemic lupus erythematosus (SLE) than with psoriasis.

METHODOLOGY:

• A retrospective matched longitudinal study compared the incidence and prevalence of ASCVD of 8138 individuals with CLE; 24,675 with SLE; 192,577 with psoriasis; and 81,380 control individuals.
• The disease-free control population was matched in a 10:1 ratio to the CLE population on the basis of age, sex, insurance type, and enrollment duration.
• Prevalent ASCVD was defined as coronary artery disease, prior myocardial infarction, or cerebrovascular accident, with ASCVD incidence assessed by number of hospitalizations over 3 years.

TAKEAWAY:

• Persons with CLE had higher ASCVD risk than control individuals (odds ratio [OR], 1.72; P < .001), similar to those with SLE (OR, 2.41; P < .001) but unlike those with psoriasis (OR, 1.03; P = .48).
• ASCVD incidence at 3 years was 24.8 per 1000 person-years for SLE, 15.2 per 1000 person-years for CLE, 14.0 per 1000 person-years for psoriasis, and 10.3 per 1000 person-years for controls.
• Multivariable Cox proportional regression modeling showed ASCVD risk was highest in those with SLE (hazard ratio [HR], 2.23; P < .001) vs CLE (HR, 1.32; P < .001) and psoriasis (HR, 1.06; P = .09).
• ASCVD prevalence was higher in individuals with CLE receiving systemic therapy (2.7%) than in those receiving no therapy (1.6%), suggesting a potential link between disease severity and CVD risk.

IN PRACTICE:

“Persons with CLE are at higher risk for ASCVD, and guidelines for the evaluation and management of ASCVD may improve their quality of care,” the authors wrote.

SOURCE:

The study was led by Henry W. Chen, MD, Department of Dermatology, University of Texas Southwestern Medical Center, Dallas. It was published online on December 4, 2024, in JAMA Dermatology.

LIMITATIONS: 

The study was limited by its relatively young population (median age, 49 years) and the exclusion of adults aged > 65 years on Medicare insurance plans. The database lacked race and ethnicity data, and the analysis was restricted to a shorter 3-year period. The study could not fully evaluate detailed risk factors such as blood pressure levels, cholesterol measurements, or glycemic control, nor could it accurately assess smoking status.

DISCLOSURES:

The research was supported by the Department of Dermatology at the University of Texas Southwestern Medical Center and a grant from the National Institutes of Health. Several authors reported receiving grants or personal fees from various pharmaceutical companies. One author reported being a deputy editor for diversity, equity, and inclusion at JAMA Cardiology. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Atherosclerotic cardiovascular disease (ASCVD) risk is higher with cutaneous lupus erythematosus (CLE) or systemic lupus erythematosus (SLE) than with psoriasis.

METHODOLOGY:

• A retrospective matched longitudinal study compared the incidence and prevalence of ASCVD of 8138 individuals with CLE; 24,675 with SLE; 192,577 with psoriasis; and 81,380 control individuals.
• The disease-free control population was matched in a 10:1 ratio to the CLE population on the basis of age, sex, insurance type, and enrollment duration.
• Prevalent ASCVD was defined as coronary artery disease, prior myocardial infarction, or cerebrovascular accident, with ASCVD incidence assessed by number of hospitalizations over 3 years.

TAKEAWAY:

• Persons with CLE had higher ASCVD risk than control individuals (odds ratio [OR], 1.72; P < .001), similar to those with SLE (OR, 2.41; P < .001) but unlike those with psoriasis (OR, 1.03; P = .48).
• ASCVD incidence at 3 years was 24.8 per 1000 person-years for SLE, 15.2 per 1000 person-years for CLE, 14.0 per 1000 person-years for psoriasis, and 10.3 per 1000 person-years for controls.
• Multivariable Cox proportional regression modeling showed ASCVD risk was highest in those with SLE (hazard ratio [HR], 2.23; P < .001) vs CLE (HR, 1.32; P < .001) and psoriasis (HR, 1.06; P = .09).
• ASCVD prevalence was higher in individuals with CLE receiving systemic therapy (2.7%) than in those receiving no therapy (1.6%), suggesting a potential link between disease severity and CVD risk.

IN PRACTICE:

“Persons with CLE are at higher risk for ASCVD, and guidelines for the evaluation and management of ASCVD may improve their quality of care,” the authors wrote.

SOURCE:

The study was led by Henry W. Chen, MD, Department of Dermatology, University of Texas Southwestern Medical Center, Dallas. It was published online on December 4, 2024, in JAMA Dermatology.

LIMITATIONS: 

The study was limited by its relatively young population (median age, 49 years) and the exclusion of adults aged > 65 years on Medicare insurance plans. The database lacked race and ethnicity data, and the analysis was restricted to a shorter 3-year period. The study could not fully evaluate detailed risk factors such as blood pressure levels, cholesterol measurements, or glycemic control, nor could it accurately assess smoking status.

DISCLOSURES:

The research was supported by the Department of Dermatology at the University of Texas Southwestern Medical Center and a grant from the National Institutes of Health. Several authors reported receiving grants or personal fees from various pharmaceutical companies. One author reported being a deputy editor for diversity, equity, and inclusion at JAMA Cardiology. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, lipid-lowering drugs, were associated with a 22% lower risk for nonmelanoma skin cancer (NMSC) in patients with atherosclerotic cardiovascular disease (ASCVD), an effect that was particularly significant among men, those older than 65 years, and those with immunosuppression.

METHODOLOGY:

• To evaluate the risk for NMSC — basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) — in patients with ASCVD on PCSK9 inhibitors, researchers analyzed data from the US Collaborative Network in the TriNetX database of adults aged ≥ 40 years with ASCVD who received statin therapy between 2016 and 2022.
• A total of 73,636 patients were included, divided equally between those receiving a PCSK9 inhibitor (evolocumab, alirocumab, or inclisiran) plus statin therapy and the control group (those on statin therapy only).
• The analysis used propensity score matching for head-to-head comparisons, with hazard ratios (HRs) estimated using Cox proportional hazard models.
• Stratified analyses examined outcomes by age, sex, Fitzpatrick skin type, and immune status. (Immunosuppressed patients were those treated with immunosuppressants for more than 90 days in the year before the index date — the date when exposed patients were first prescribed a PCSK9 inhibitor, which was also index date for matched patients in the statin-only group.)

TAKEAWAY:

• Patients with ASCVD in the PCSK9 group showed significantly lower risks for NMSC (HR, 0.78; 95% CI, 0.71-0.87), BCC (HR, 0.78; 95% CI, 0.69-0.89), and SCC (HR, 0.79; 95% CI, 0.67-0.93) than control individuals on a statin only (P < .001 for all three).
• Both evolocumab and alirocumab demonstrated similar protective effects against the development of NMSC.
• The reduced risk for NMSC was particularly notable among patients aged 65-79 years (HR, 0.75; 95% CI, 0.66-0.86) and those aged ≥ 80 years (HR, 0.74; 95% CI, 0.60-0.91).
• Men showed a more pronounced reduction in the risk for NMSC (HR, 0.73; 95% CI, 0.64-0.83) than women (HR, 0.93; 95% CI, 0.78-1.11). The effect on lowering NMSC risk was also evident among immunosuppressed patients in the PCSK9 group (HR, 0.68; 95% CI, 0.60-0.75).

IN PRACTICE:

“The findings suggest the promising pleiotropic effect of PCSK9 inhibitors on the chemoprevention of NMSC,” the study authors wrote. Referring to previous studies that “provided mechanistic clues to our findings,” they added that “further studies are required to investigate the underlying mechanisms and establish causality.”

SOURCE:

The study was led by Cheng-Yuan Li, Taipei Veterans General Hospital, Taipei, Taiwan, and was published online in The British Journal of Dermatology.

LIMITATIONS:

Electronic health records lack information on sun protection habits, family history of skin cancer, diet, body mass index, and air pollution exposure, risk factors for NMSC. The study also lacked detailed information on enrollees’ lipid profiles and was focused mostly on patients in the United States, limiting the generalizability of the findings to other regions.

DISCLOSURES:

The study was supported by grants from Taipei Veterans General Hospital and the Ministry of Science and Technology, Taiwan. The authors reported no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, lipid-lowering drugs, were associated with a 22% lower risk for nonmelanoma skin cancer (NMSC) in patients with atherosclerotic cardiovascular disease (ASCVD), an effect that was particularly significant among men, those older than 65 years, and those with immunosuppression.

METHODOLOGY:

• To evaluate the risk for NMSC — basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) — in patients with ASCVD on PCSK9 inhibitors, researchers analyzed data from the US Collaborative Network in the TriNetX database of adults aged ≥ 40 years with ASCVD who received statin therapy between 2016 and 2022.
• A total of 73,636 patients were included, divided equally between those receiving a PCSK9 inhibitor (evolocumab, alirocumab, or inclisiran) plus statin therapy and the control group (those on statin therapy only).
• The analysis used propensity score matching for head-to-head comparisons, with hazard ratios (HRs) estimated using Cox proportional hazard models.
• Stratified analyses examined outcomes by age, sex, Fitzpatrick skin type, and immune status. (Immunosuppressed patients were those treated with immunosuppressants for more than 90 days in the year before the index date — the date when exposed patients were first prescribed a PCSK9 inhibitor, which was also index date for matched patients in the statin-only group.)

TAKEAWAY:

• Patients with ASCVD in the PCSK9 group showed significantly lower risks for NMSC (HR, 0.78; 95% CI, 0.71-0.87), BCC (HR, 0.78; 95% CI, 0.69-0.89), and SCC (HR, 0.79; 95% CI, 0.67-0.93) than control individuals on a statin only (P < .001 for all three).
• Both evolocumab and alirocumab demonstrated similar protective effects against the development of NMSC.
• The reduced risk for NMSC was particularly notable among patients aged 65-79 years (HR, 0.75; 95% CI, 0.66-0.86) and those aged ≥ 80 years (HR, 0.74; 95% CI, 0.60-0.91).
• Men showed a more pronounced reduction in the risk for NMSC (HR, 0.73; 95% CI, 0.64-0.83) than women (HR, 0.93; 95% CI, 0.78-1.11). The effect on lowering NMSC risk was also evident among immunosuppressed patients in the PCSK9 group (HR, 0.68; 95% CI, 0.60-0.75).

IN PRACTICE:

“The findings suggest the promising pleiotropic effect of PCSK9 inhibitors on the chemoprevention of NMSC,” the study authors wrote. Referring to previous studies that “provided mechanistic clues to our findings,” they added that “further studies are required to investigate the underlying mechanisms and establish causality.”

SOURCE:

The study was led by Cheng-Yuan Li, Taipei Veterans General Hospital, Taipei, Taiwan, and was published online in The British Journal of Dermatology.

LIMITATIONS:

Electronic health records lack information on sun protection habits, family history of skin cancer, diet, body mass index, and air pollution exposure, risk factors for NMSC. The study also lacked detailed information on enrollees’ lipid profiles and was focused mostly on patients in the United States, limiting the generalizability of the findings to other regions.

DISCLOSURES:

The study was supported by grants from Taipei Veterans General Hospital and the Ministry of Science and Technology, Taiwan. The authors reported no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, lipid-lowering drugs, were associated with a 22% lower risk for nonmelanoma skin cancer (NMSC) in patients with atherosclerotic cardiovascular disease (ASCVD), an effect that was particularly significant among men, those older than 65 years, and those with immunosuppression.

METHODOLOGY:

• To evaluate the risk for NMSC — basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) — in patients with ASCVD on PCSK9 inhibitors, researchers analyzed data from the US Collaborative Network in the TriNetX database of adults aged ≥ 40 years with ASCVD who received statin therapy between 2016 and 2022.
• A total of 73,636 patients were included, divided equally between those receiving a PCSK9 inhibitor (evolocumab, alirocumab, or inclisiran) plus statin therapy and the control group (those on statin therapy only).
• The analysis used propensity score matching for head-to-head comparisons, with hazard ratios (HRs) estimated using Cox proportional hazard models.
• Stratified analyses examined outcomes by age, sex, Fitzpatrick skin type, and immune status. (Immunosuppressed patients were those treated with immunosuppressants for more than 90 days in the year before the index date — the date when exposed patients were first prescribed a PCSK9 inhibitor, which was also index date for matched patients in the statin-only group.)

TAKEAWAY:

• Patients with ASCVD in the PCSK9 group showed significantly lower risks for NMSC (HR, 0.78; 95% CI, 0.71-0.87), BCC (HR, 0.78; 95% CI, 0.69-0.89), and SCC (HR, 0.79; 95% CI, 0.67-0.93) than control individuals on a statin only (P < .001 for all three).
• Both evolocumab and alirocumab demonstrated similar protective effects against the development of NMSC.
• The reduced risk for NMSC was particularly notable among patients aged 65-79 years (HR, 0.75; 95% CI, 0.66-0.86) and those aged ≥ 80 years (HR, 0.74; 95% CI, 0.60-0.91).
• Men showed a more pronounced reduction in the risk for NMSC (HR, 0.73; 95% CI, 0.64-0.83) than women (HR, 0.93; 95% CI, 0.78-1.11). The effect on lowering NMSC risk was also evident among immunosuppressed patients in the PCSK9 group (HR, 0.68; 95% CI, 0.60-0.75).

IN PRACTICE:

“The findings suggest the promising pleiotropic effect of PCSK9 inhibitors on the chemoprevention of NMSC,” the study authors wrote. Referring to previous studies that “provided mechanistic clues to our findings,” they added that “further studies are required to investigate the underlying mechanisms and establish causality.”

SOURCE:

The study was led by Cheng-Yuan Li, Taipei Veterans General Hospital, Taipei, Taiwan, and was published online in The British Journal of Dermatology.

LIMITATIONS:

Electronic health records lack information on sun protection habits, family history of skin cancer, diet, body mass index, and air pollution exposure, risk factors for NMSC. The study also lacked detailed information on enrollees’ lipid profiles and was focused mostly on patients in the United States, limiting the generalizability of the findings to other regions.

DISCLOSURES:

The study was supported by grants from Taipei Veterans General Hospital and the Ministry of Science and Technology, Taiwan. The authors reported no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

Lung cancer screening with low-dose CT can detect extensive coronary artery calcium (CAC), an independent predictor of all-cause death and cardiovascular events, new research suggested.

“The high prevalence of asymptomatic coronary artery disease (83%) was surprising, as was the prevalence of extensive CAC (30%),” principal investigator Gary Small, MBChB, PhD, a cardiologist at the University of Ottawa Heart Institute in Ontario, Canada, said in an interview.

“The size of effect was also surprising, as was the persistence of the effect even in the presence of elevated mortality risk from other causes,” he said. “Extensive coronary disease was associated with a twofold increase in risk for death or cardiovascular events over 4 years of follow-up,” even after adjustment for risk for death from cancer and other comorbidities such as chronic obstructive pulmonary disease.

“CAC as reported on chest CT exams is often ignored and not factored into clinical practice,” he noted. “The presence of CAC, however, provides a very real and very personal perspective on an individual’s cardiovascular risk. It is a true example of personalized medicine.”

The study was published online in The Canadian Medical Association Journal.

 

Potential Risk Reduction 

In March 2017, Ontario Health launched a pilot low-dose CT lung cancer screening program for high-risk individuals between the ages of 55 and 74 years, Small explained. As CAC, a marker of coronary artery disease, is seen easily during such a scan, the researchers analyzed the lung CTs to determine the prevalence of coronary artery disease and whether CAC was associated with increased risk.

The team quantified CAC using an estimated Agatston score and identified the composite primary outcome of all-cause death and cardiovascular events using linked electronic medical record data from Ottawa Hospital up to December 2023. Among the 1486 people who underwent screening (mean age, 66 years; 52% men; 68% current smokers), CAC was detected in 1232 (82.9%). CAC was mild to moderate in 793 participants (53.4%) and extensive in 439 (29.5%). No CAC was detected in 254 (17.1%) participants.

At follow-up, 78 participants (5.2%) experienced the primary composite outcome, including 39 (8.9%) with extensive CAC, 32 (4.0%) with mild to moderate CAC, and 7 (2.8%) with no CAC.

A total of 49 deaths occurred, including 16 cardiovascular deaths and 19 cancer deaths, of which 10 were from lung cancer. Cardiovascular events included sudden cardiac death (eight participants), fatal stroke (six participants), and one each from heart failure and peripheral vascular disease.

On multivariable analysis, extensive CAC was associated with the composite primary outcome (adjusted hazard ratio [aHR], 2.13), all-cause mortality (aHR, 2.39), and cardiovascular events (aHR, 2.06).

Extensive CAC remained predictive of cardiovascular events even after adjustment for noncardiovascular death as a competing risk (HR, 2.05).

“Our data highlight to lung cancer screening professionals the prevalence of this silent risk factor and re-emphasize the importance of this finding [ie, CAC] as an opportunity for risk reduction,” Small said.

“In terms of next steps, the journey toward cardiovascular risk reduction begins with a clear report of CAC on the lung cancer screening record,” he noted. “Following this step, professionals involved in the lung cancer screening program might consider a local management pathway to ensure that this opportunity for health improvement is not lost or ignored. Preventive medicine of this type would typically involve primary care.”

 

Managing Other Findings

Commenting on the study, Anna Bader, MD, assistant professor of radiology and biomedical imaging at the Yale School of Medicine in New Haven, Connecticut, said that “low-dose CT for lung cancer screening offers valuable insights beyond nodule detection, with CAC being among the most significant incidental findings.”

However, she added, a “robust mechanism” to effectively manage other findings — such as thoracic aortic disease, low bone density, and abnormalities in the thyroid or upper abdominal organs — without overdiagnosis, is needed. A mechanism also is needed to notify cardiologists or primary care providers about severe CAC findings.

Challenges that need to be overcome before such mechanisms can be put in place, she said, “include ensuring standardized CAC reporting, avoiding overburdening healthcare providers, mitigating the risk of excessive downstream testing, and ensuring equitable access to follow-up care for underserved and rural communities.”

Providers involved in lung cancer screening “must be trained to recognize the importance of CAC findings and act upon them,” she added. “Awareness campaigns or continuing medical education modules could address this.”

Multidisciplinary lung cancer screening programs can help with patient education, she noted. “Clear communication about potential findings, including the significance of incidental CAC, should be prioritized and addressed proactively, ideally before the exam, to enhance patient understanding and engagement.”

Matthew Tomey, MD, assistant professor of medicine at the Icahn School of Medicine at Mount Sinai in New York City, said that, “as a practicing cardiologist, I find it very helpful to look at my patients’ recent or past CT scans to look for vascular calcification. Whether or not a scan is specifically protocoled as a cardiac study, we can often appreciate vascular calcification when it is present. I would encourage every physician involved in helping their patients to prevent heart disease to take advantage of looking at any prior CT scans for evidence of vascular calcification.

“Systems of care to facilitate recognition of patients with incidentally discovered vascular calcification would be welcome and, on a large scale, could help prevent cardiovascular events,” he noted. “Such a system might involve facilitating referral to a prevention specialist. It could involve evidence-based guidance for referring physicians who ordered scans.”

Like Bader, he noted the importance of patient education, adding that it could be quite powerful. “We should be doing more to empower our patients to understand the findings of their imaging and to give them actionable, evidence-based guidance on how they can promote their own cardiovascular health,” he concluded.

No funding for the study was reported. Small reported receiving a research grant for amyloid research from Pfizer and honoraria from Pfizer and Alnylam (all paid to the institution, outside the submitted work). Bader and Tomey declared no relevant conflicts.

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

Lung cancer screening with low-dose CT can detect extensive coronary artery calcium (CAC), an independent predictor of all-cause death and cardiovascular events, new research suggested.

“The high prevalence of asymptomatic coronary artery disease (83%) was surprising, as was the prevalence of extensive CAC (30%),” principal investigator Gary Small, MBChB, PhD, a cardiologist at the University of Ottawa Heart Institute in Ontario, Canada, said in an interview.

“The size of effect was also surprising, as was the persistence of the effect even in the presence of elevated mortality risk from other causes,” he said. “Extensive coronary disease was associated with a twofold increase in risk for death or cardiovascular events over 4 years of follow-up,” even after adjustment for risk for death from cancer and other comorbidities such as chronic obstructive pulmonary disease.

“CAC as reported on chest CT exams is often ignored and not factored into clinical practice,” he noted. “The presence of CAC, however, provides a very real and very personal perspective on an individual’s cardiovascular risk. It is a true example of personalized medicine.”

The study was published online in The Canadian Medical Association Journal.

 

Potential Risk Reduction 

In March 2017, Ontario Health launched a pilot low-dose CT lung cancer screening program for high-risk individuals between the ages of 55 and 74 years, Small explained. As CAC, a marker of coronary artery disease, is seen easily during such a scan, the researchers analyzed the lung CTs to determine the prevalence of coronary artery disease and whether CAC was associated with increased risk.

The team quantified CAC using an estimated Agatston score and identified the composite primary outcome of all-cause death and cardiovascular events using linked electronic medical record data from Ottawa Hospital up to December 2023. Among the 1486 people who underwent screening (mean age, 66 years; 52% men; 68% current smokers), CAC was detected in 1232 (82.9%). CAC was mild to moderate in 793 participants (53.4%) and extensive in 439 (29.5%). No CAC was detected in 254 (17.1%) participants.

At follow-up, 78 participants (5.2%) experienced the primary composite outcome, including 39 (8.9%) with extensive CAC, 32 (4.0%) with mild to moderate CAC, and 7 (2.8%) with no CAC.

A total of 49 deaths occurred, including 16 cardiovascular deaths and 19 cancer deaths, of which 10 were from lung cancer. Cardiovascular events included sudden cardiac death (eight participants), fatal stroke (six participants), and one each from heart failure and peripheral vascular disease.

On multivariable analysis, extensive CAC was associated with the composite primary outcome (adjusted hazard ratio [aHR], 2.13), all-cause mortality (aHR, 2.39), and cardiovascular events (aHR, 2.06).

Extensive CAC remained predictive of cardiovascular events even after adjustment for noncardiovascular death as a competing risk (HR, 2.05).

“Our data highlight to lung cancer screening professionals the prevalence of this silent risk factor and re-emphasize the importance of this finding [ie, CAC] as an opportunity for risk reduction,” Small said.

“In terms of next steps, the journey toward cardiovascular risk reduction begins with a clear report of CAC on the lung cancer screening record,” he noted. “Following this step, professionals involved in the lung cancer screening program might consider a local management pathway to ensure that this opportunity for health improvement is not lost or ignored. Preventive medicine of this type would typically involve primary care.”

 

Managing Other Findings

Commenting on the study, Anna Bader, MD, assistant professor of radiology and biomedical imaging at the Yale School of Medicine in New Haven, Connecticut, said that “low-dose CT for lung cancer screening offers valuable insights beyond nodule detection, with CAC being among the most significant incidental findings.”

However, she added, a “robust mechanism” to effectively manage other findings — such as thoracic aortic disease, low bone density, and abnormalities in the thyroid or upper abdominal organs — without overdiagnosis, is needed. A mechanism also is needed to notify cardiologists or primary care providers about severe CAC findings.

Challenges that need to be overcome before such mechanisms can be put in place, she said, “include ensuring standardized CAC reporting, avoiding overburdening healthcare providers, mitigating the risk of excessive downstream testing, and ensuring equitable access to follow-up care for underserved and rural communities.”

Providers involved in lung cancer screening “must be trained to recognize the importance of CAC findings and act upon them,” she added. “Awareness campaigns or continuing medical education modules could address this.”

Multidisciplinary lung cancer screening programs can help with patient education, she noted. “Clear communication about potential findings, including the significance of incidental CAC, should be prioritized and addressed proactively, ideally before the exam, to enhance patient understanding and engagement.”

Matthew Tomey, MD, assistant professor of medicine at the Icahn School of Medicine at Mount Sinai in New York City, said that, “as a practicing cardiologist, I find it very helpful to look at my patients’ recent or past CT scans to look for vascular calcification. Whether or not a scan is specifically protocoled as a cardiac study, we can often appreciate vascular calcification when it is present. I would encourage every physician involved in helping their patients to prevent heart disease to take advantage of looking at any prior CT scans for evidence of vascular calcification.

“Systems of care to facilitate recognition of patients with incidentally discovered vascular calcification would be welcome and, on a large scale, could help prevent cardiovascular events,” he noted. “Such a system might involve facilitating referral to a prevention specialist. It could involve evidence-based guidance for referring physicians who ordered scans.”

Like Bader, he noted the importance of patient education, adding that it could be quite powerful. “We should be doing more to empower our patients to understand the findings of their imaging and to give them actionable, evidence-based guidance on how they can promote their own cardiovascular health,” he concluded.

No funding for the study was reported. Small reported receiving a research grant for amyloid research from Pfizer and honoraria from Pfizer and Alnylam (all paid to the institution, outside the submitted work). Bader and Tomey declared no relevant conflicts.

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

Lung cancer screening with low-dose CT can detect extensive coronary artery calcium (CAC), an independent predictor of all-cause death and cardiovascular events, new research suggested.

“The high prevalence of asymptomatic coronary artery disease (83%) was surprising, as was the prevalence of extensive CAC (30%),” principal investigator Gary Small, MBChB, PhD, a cardiologist at the University of Ottawa Heart Institute in Ontario, Canada, said in an interview.

“The size of effect was also surprising, as was the persistence of the effect even in the presence of elevated mortality risk from other causes,” he said. “Extensive coronary disease was associated with a twofold increase in risk for death or cardiovascular events over 4 years of follow-up,” even after adjustment for risk for death from cancer and other comorbidities such as chronic obstructive pulmonary disease.

“CAC as reported on chest CT exams is often ignored and not factored into clinical practice,” he noted. “The presence of CAC, however, provides a very real and very personal perspective on an individual’s cardiovascular risk. It is a true example of personalized medicine.”

The study was published online in The Canadian Medical Association Journal.

 

Potential Risk Reduction 

In March 2017, Ontario Health launched a pilot low-dose CT lung cancer screening program for high-risk individuals between the ages of 55 and 74 years, Small explained. As CAC, a marker of coronary artery disease, is seen easily during such a scan, the researchers analyzed the lung CTs to determine the prevalence of coronary artery disease and whether CAC was associated with increased risk.

The team quantified CAC using an estimated Agatston score and identified the composite primary outcome of all-cause death and cardiovascular events using linked electronic medical record data from Ottawa Hospital up to December 2023. Among the 1486 people who underwent screening (mean age, 66 years; 52% men; 68% current smokers), CAC was detected in 1232 (82.9%). CAC was mild to moderate in 793 participants (53.4%) and extensive in 439 (29.5%). No CAC was detected in 254 (17.1%) participants.

At follow-up, 78 participants (5.2%) experienced the primary composite outcome, including 39 (8.9%) with extensive CAC, 32 (4.0%) with mild to moderate CAC, and 7 (2.8%) with no CAC.

A total of 49 deaths occurred, including 16 cardiovascular deaths and 19 cancer deaths, of which 10 were from lung cancer. Cardiovascular events included sudden cardiac death (eight participants), fatal stroke (six participants), and one each from heart failure and peripheral vascular disease.

On multivariable analysis, extensive CAC was associated with the composite primary outcome (adjusted hazard ratio [aHR], 2.13), all-cause mortality (aHR, 2.39), and cardiovascular events (aHR, 2.06).

Extensive CAC remained predictive of cardiovascular events even after adjustment for noncardiovascular death as a competing risk (HR, 2.05).

“Our data highlight to lung cancer screening professionals the prevalence of this silent risk factor and re-emphasize the importance of this finding [ie, CAC] as an opportunity for risk reduction,” Small said.

“In terms of next steps, the journey toward cardiovascular risk reduction begins with a clear report of CAC on the lung cancer screening record,” he noted. “Following this step, professionals involved in the lung cancer screening program might consider a local management pathway to ensure that this opportunity for health improvement is not lost or ignored. Preventive medicine of this type would typically involve primary care.”

 

Managing Other Findings

Commenting on the study, Anna Bader, MD, assistant professor of radiology and biomedical imaging at the Yale School of Medicine in New Haven, Connecticut, said that “low-dose CT for lung cancer screening offers valuable insights beyond nodule detection, with CAC being among the most significant incidental findings.”

However, she added, a “robust mechanism” to effectively manage other findings — such as thoracic aortic disease, low bone density, and abnormalities in the thyroid or upper abdominal organs — without overdiagnosis, is needed. A mechanism also is needed to notify cardiologists or primary care providers about severe CAC findings.

Challenges that need to be overcome before such mechanisms can be put in place, she said, “include ensuring standardized CAC reporting, avoiding overburdening healthcare providers, mitigating the risk of excessive downstream testing, and ensuring equitable access to follow-up care for underserved and rural communities.”

Providers involved in lung cancer screening “must be trained to recognize the importance of CAC findings and act upon them,” she added. “Awareness campaigns or continuing medical education modules could address this.”

Multidisciplinary lung cancer screening programs can help with patient education, she noted. “Clear communication about potential findings, including the significance of incidental CAC, should be prioritized and addressed proactively, ideally before the exam, to enhance patient understanding and engagement.”

Matthew Tomey, MD, assistant professor of medicine at the Icahn School of Medicine at Mount Sinai in New York City, said that, “as a practicing cardiologist, I find it very helpful to look at my patients’ recent or past CT scans to look for vascular calcification. Whether or not a scan is specifically protocoled as a cardiac study, we can often appreciate vascular calcification when it is present. I would encourage every physician involved in helping their patients to prevent heart disease to take advantage of looking at any prior CT scans for evidence of vascular calcification.

“Systems of care to facilitate recognition of patients with incidentally discovered vascular calcification would be welcome and, on a large scale, could help prevent cardiovascular events,” he noted. “Such a system might involve facilitating referral to a prevention specialist. It could involve evidence-based guidance for referring physicians who ordered scans.”

Like Bader, he noted the importance of patient education, adding that it could be quite powerful. “We should be doing more to empower our patients to understand the findings of their imaging and to give them actionable, evidence-based guidance on how they can promote their own cardiovascular health,” he concluded.

No funding for the study was reported. Small reported receiving a research grant for amyloid research from Pfizer and honoraria from Pfizer and Alnylam (all paid to the institution, outside the submitted work). Bader and Tomey declared no relevant conflicts.

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

The results of the SUMMIT trial of the long-acting agonist of glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptors, tirzepatide, in patients with heart failure with preserved ejection fraction (HFpEF) and obesity are positive. But the trial design leaves clinicians and regulators with big doses of uncertainty.

Known Facts About HFpEF

HFpEF has exceeded heart failure with reduced ejection fraction (HFrEF) as the most common form of heart failure. HFpEF differs from HFrEF in that patients with preserved ejection fraction often present later in life with more comorbidities.

Some of these comorbidities are on the causal pathway of heart failure. Obesity, for instance, both associates with HFpEF and surely causes the diastolic dysfunction central to the condition. This may be a direct effect via high excess adipose tissue or an indirect effect via pro-inflammatory pathways.

GLP-1 agonists and the dual-acting GIP/GLP1 agonist tirzepatide have proven efficacy for weight loss. Semaglutide has previously been shown to improve quality of life and physical functioning in two small trials of patients with HFpEF and obesity. Semaglutide also reduced hard clinical outcomes in patients with obesity and these other conditions: chronic kidney disease, diabetes, and established atherosclerotic vascular disease.

This class of drugs is costly. The combination of both high drug costs and highly prevalent conditions such as obesity and HFpEF forces clinicians to make both value and clinical judgments when translating evidence.

 

The SUMMIT Trial

The SUMMIT trial aimed to evaluate tirzepatide’s effect on typical heart failure events, health status and functional capacity in patients with obesity and HFpEF. A total of 731 patients were randomly assigned to receive to tirzepatide or placebo.

Investigators chose two co-primary endpoints. The first was a composite of cardiovascular (CV) death and worsening heart failure events—the latter could be a hospitalization for heart failure, a visit for intravenous diuretics, or intensification of oral diuretics. The idea behind this rather unique composite was to capture all heart failure events. The second co-primary endpoint was a change in baseline Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS) at 1 year.

Characteristics of the patients included an average age of 65 years, 55% were female, the average body mass index was 38, and the mean left ventricular ejection fraction was 61% (the minimum for trial entry was 50%). Just under half had been hospitalized for heart failure in the year before trial entry.

 

Tirzepatide Results

The primary outcome of CV death and first heart failure event occurred in 36 patients (9.9%) in the tirzepatide group and 56 patients (15.3%) in the placebo group, for a hazard ratio of 0.62 (95% CI, 0.41-0.95; P =.026).

The 5.4% absolute risk reduction in the primary endpoint was completely driven by lower rates of heart failure events (8% vs 14.2%). CV death was actually higher in the tirzepatide arm, but the number of deaths was low in both arms (8 vs 5).

The rate of hospitalizations due to heart failure was lower with tirzepatide (3.3% vs 7.1%), as was intensification of oral diuretics (4.7% vs 5.7%).

The second co-primary endpoint of change from baseline in KCCQ-CSS favored tirzepatide.

Other secondary endpoints also favored tirzepatide: longer 6-minute walk distance, greater change in body weight (-11.6%), and lower high-sensitivity C-reactive protein levels and systolic blood pressure (-4.7 mm Hg).

 

Authors’ Conclusions and Expert Comments

At the American Heart Association Scientific Sessions, the primary investigator Milton Packer, MD, said SUMMIT was the first trial of patients with obesity and HFpEF that had major heart failure outcomes as the primary endpoint. And that tirzepatide changed the clinical trajectory of the disease.

Jennifer Ho, MD, associate professor of medicine at Harvard Medical School, Boston, Massachusetts, said, “This really is a practice-changing trial and cements this type of therapy as one of the cornerstones of obesity and HFpEF treatment.”

Other experts cited a recently published pooled analysis of semaglutide trials looking specifically at patients with HFpEF and found lower rates of HF events with the GLP-1 agonist.

The SUMMIT trial results were covered in 53 news outlets— nearly all with glowing headlines.

 

My Six Concerns With SUMMIT

The trial delivered statistically positive findings. What’s more, patients lost weight, and a greater than 11% weight loss difference is meaningful. Patients with a baseline weight of more than 100 kg who lose this much weight are bound to feel and function better.

The first problem comes when we ask whether the results are disease-modifying. There was no difference in CV death. And the number of hospitalizations for heart failure — the more standard endpoint — was low, at only 12 and 26, respectively. Contrast this with the DELIVER trial of the sodium-glucose cotransporter 2 inhibitor dapagliflozin in HFpEF where there were nearly 750 hospitalizations for heart failure and PARAGON-HF of sacubitril-valsartan vs valsartan in HFpEF, where there were nearly 1500. SUMMIT simply had too few events to make conclusions — a point Packer has made regarding AF ablation trials in patients with heart failure.

I have previously called GLP-1 drugs disease-modifying in patients with obesity and atherosclerotic disease. This is because the SELECT trial of semaglutide randomized more than 17,000 patients and recorded a 20% reduction in hard outcomes. And there were more than 1200 primary outcome events. SUMMIT does not come close to this measure.

The second issue is short follow-up. These were 65-year-old patients and with only 2 years of follow-up, it is hard to make conclusions regarding whether or not these drugs can provide long-term benefit.

The third issue is that SUMMIT authors don’t tell us the number of all-cause hospitalizations. I was part of a recently published meta-analysis of more than 100 heart failure trials that raised questions regarding the value of hospitalizations for heart failure as a surrogate for heart failure outcomes.

For instance, we found that in large trials there was great variability in the ability of a reduction in HF hospitalizations to predict a reduction in all-cause hospitalization. In small trials, such as SUMMIT, it would likely be impossible to predict how the reduction in HF hospitalization would predict all-cause hospitalization. I believe all-cause hospitalization is a more inclusive endpoint because it is bias free; it captures benefits and potential harms of the therapy; and it is patient-centered, because patients probably do not care what type of hospitalization they avoid.

The fourth issue with SUMMIT is the difficulty in maintaining blinding, which reduces confidence in outcomes that require clinical decisions or patient judgments. Owing to gastrointestinal symptoms, decreased appetite, and weight loss, patients on this class of drugs are very likely to know their treatment assignment. This is a criticism of not only SUMMIT but all GLP-1 agonist trials. The fact that blinding is difficult to maintain argues for choosing endpoints less susceptible to bias, such as CV death or all-cause hospitalization.

Proponents of tirzepatide for this indication might argue that unblinding is less of an issue because of objective endpoints such as biomarkers. And they have a point, but nearly all other endpoints, especially the co-primary endpoint of KCCQ-CSS, are largely susceptible to bias.

The fifth and main problem comes in translating this evidence in the clinic. Should doctors give up on nondrug means of weight loss? All of the positive outcome trials in this class of drugs have also shown weight loss. I believe we should take these data and use them to re-invigorate our advocacy for weight loss without medication. I know the standard answer to this proposal is nihilism: It just will not work. And I cannot deny that we have failed previously in our efforts to help patients lose weight. But perhaps now, with the vast amount of data, we can be more persuasive. Imagine a world where key opinion leaders made weight loss the message rather than prescription of a drug.

Finally, if you approach SUMMIT from the view of a regulator, with its small numbers of outcome events and bias-susceptible endpoints, you cannot allow a disease-modifying claim. For that we would need a properly powered trial that shows that the drug reduces both CV death and all-cause hospitalization.

In the end, SUMMIT is not close to changing treatment norms in patients with HFpEF. As evidence-based clinicians, we should demand more from our partners in industry and academia.

Dr. Mandrola practices cardiac electrophysiology in Baptist Medical Associates, Louisville, Kentucky, and is a writer and podcaster for Medscape. He espouses a conservative approach to medical practice. He participates in clinical research and writes often about the state of medical evidence. He has disclosed no relevant financial relationships.

 

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

The results of the SUMMIT trial of the long-acting agonist of glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptors, tirzepatide, in patients with heart failure with preserved ejection fraction (HFpEF) and obesity are positive. But the trial design leaves clinicians and regulators with big doses of uncertainty.

Known Facts About HFpEF

HFpEF has exceeded heart failure with reduced ejection fraction (HFrEF) as the most common form of heart failure. HFpEF differs from HFrEF in that patients with preserved ejection fraction often present later in life with more comorbidities.

Some of these comorbidities are on the causal pathway of heart failure. Obesity, for instance, both associates with HFpEF and surely causes the diastolic dysfunction central to the condition. This may be a direct effect via high excess adipose tissue or an indirect effect via pro-inflammatory pathways.

GLP-1 agonists and the dual-acting GIP/GLP1 agonist tirzepatide have proven efficacy for weight loss. Semaglutide has previously been shown to improve quality of life and physical functioning in two small trials of patients with HFpEF and obesity. Semaglutide also reduced hard clinical outcomes in patients with obesity and these other conditions: chronic kidney disease, diabetes, and established atherosclerotic vascular disease.

This class of drugs is costly. The combination of both high drug costs and highly prevalent conditions such as obesity and HFpEF forces clinicians to make both value and clinical judgments when translating evidence.

 

The SUMMIT Trial

The SUMMIT trial aimed to evaluate tirzepatide’s effect on typical heart failure events, health status and functional capacity in patients with obesity and HFpEF. A total of 731 patients were randomly assigned to receive to tirzepatide or placebo.

Investigators chose two co-primary endpoints. The first was a composite of cardiovascular (CV) death and worsening heart failure events—the latter could be a hospitalization for heart failure, a visit for intravenous diuretics, or intensification of oral diuretics. The idea behind this rather unique composite was to capture all heart failure events. The second co-primary endpoint was a change in baseline Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS) at 1 year.

Characteristics of the patients included an average age of 65 years, 55% were female, the average body mass index was 38, and the mean left ventricular ejection fraction was 61% (the minimum for trial entry was 50%). Just under half had been hospitalized for heart failure in the year before trial entry.

 

Tirzepatide Results

The primary outcome of CV death and first heart failure event occurred in 36 patients (9.9%) in the tirzepatide group and 56 patients (15.3%) in the placebo group, for a hazard ratio of 0.62 (95% CI, 0.41-0.95; P =.026).

The 5.4% absolute risk reduction in the primary endpoint was completely driven by lower rates of heart failure events (8% vs 14.2%). CV death was actually higher in the tirzepatide arm, but the number of deaths was low in both arms (8 vs 5).

The rate of hospitalizations due to heart failure was lower with tirzepatide (3.3% vs 7.1%), as was intensification of oral diuretics (4.7% vs 5.7%).

The second co-primary endpoint of change from baseline in KCCQ-CSS favored tirzepatide.

Other secondary endpoints also favored tirzepatide: longer 6-minute walk distance, greater change in body weight (-11.6%), and lower high-sensitivity C-reactive protein levels and systolic blood pressure (-4.7 mm Hg).

 

Authors’ Conclusions and Expert Comments

At the American Heart Association Scientific Sessions, the primary investigator Milton Packer, MD, said SUMMIT was the first trial of patients with obesity and HFpEF that had major heart failure outcomes as the primary endpoint. And that tirzepatide changed the clinical trajectory of the disease.

Jennifer Ho, MD, associate professor of medicine at Harvard Medical School, Boston, Massachusetts, said, “This really is a practice-changing trial and cements this type of therapy as one of the cornerstones of obesity and HFpEF treatment.”

Other experts cited a recently published pooled analysis of semaglutide trials looking specifically at patients with HFpEF and found lower rates of HF events with the GLP-1 agonist.

The SUMMIT trial results were covered in 53 news outlets— nearly all with glowing headlines.

 

My Six Concerns With SUMMIT

The trial delivered statistically positive findings. What’s more, patients lost weight, and a greater than 11% weight loss difference is meaningful. Patients with a baseline weight of more than 100 kg who lose this much weight are bound to feel and function better.

The first problem comes when we ask whether the results are disease-modifying. There was no difference in CV death. And the number of hospitalizations for heart failure — the more standard endpoint — was low, at only 12 and 26, respectively. Contrast this with the DELIVER trial of the sodium-glucose cotransporter 2 inhibitor dapagliflozin in HFpEF where there were nearly 750 hospitalizations for heart failure and PARAGON-HF of sacubitril-valsartan vs valsartan in HFpEF, where there were nearly 1500. SUMMIT simply had too few events to make conclusions — a point Packer has made regarding AF ablation trials in patients with heart failure.

I have previously called GLP-1 drugs disease-modifying in patients with obesity and atherosclerotic disease. This is because the SELECT trial of semaglutide randomized more than 17,000 patients and recorded a 20% reduction in hard outcomes. And there were more than 1200 primary outcome events. SUMMIT does not come close to this measure.

The second issue is short follow-up. These were 65-year-old patients and with only 2 years of follow-up, it is hard to make conclusions regarding whether or not these drugs can provide long-term benefit.

The third issue is that SUMMIT authors don’t tell us the number of all-cause hospitalizations. I was part of a recently published meta-analysis of more than 100 heart failure trials that raised questions regarding the value of hospitalizations for heart failure as a surrogate for heart failure outcomes.

For instance, we found that in large trials there was great variability in the ability of a reduction in HF hospitalizations to predict a reduction in all-cause hospitalization. In small trials, such as SUMMIT, it would likely be impossible to predict how the reduction in HF hospitalization would predict all-cause hospitalization. I believe all-cause hospitalization is a more inclusive endpoint because it is bias free; it captures benefits and potential harms of the therapy; and it is patient-centered, because patients probably do not care what type of hospitalization they avoid.

The fourth issue with SUMMIT is the difficulty in maintaining blinding, which reduces confidence in outcomes that require clinical decisions or patient judgments. Owing to gastrointestinal symptoms, decreased appetite, and weight loss, patients on this class of drugs are very likely to know their treatment assignment. This is a criticism of not only SUMMIT but all GLP-1 agonist trials. The fact that blinding is difficult to maintain argues for choosing endpoints less susceptible to bias, such as CV death or all-cause hospitalization.

Proponents of tirzepatide for this indication might argue that unblinding is less of an issue because of objective endpoints such as biomarkers. And they have a point, but nearly all other endpoints, especially the co-primary endpoint of KCCQ-CSS, are largely susceptible to bias.

The fifth and main problem comes in translating this evidence in the clinic. Should doctors give up on nondrug means of weight loss? All of the positive outcome trials in this class of drugs have also shown weight loss. I believe we should take these data and use them to re-invigorate our advocacy for weight loss without medication. I know the standard answer to this proposal is nihilism: It just will not work. And I cannot deny that we have failed previously in our efforts to help patients lose weight. But perhaps now, with the vast amount of data, we can be more persuasive. Imagine a world where key opinion leaders made weight loss the message rather than prescription of a drug.

Finally, if you approach SUMMIT from the view of a regulator, with its small numbers of outcome events and bias-susceptible endpoints, you cannot allow a disease-modifying claim. For that we would need a properly powered trial that shows that the drug reduces both CV death and all-cause hospitalization.

In the end, SUMMIT is not close to changing treatment norms in patients with HFpEF. As evidence-based clinicians, we should demand more from our partners in industry and academia.

Dr. Mandrola practices cardiac electrophysiology in Baptist Medical Associates, Louisville, Kentucky, and is a writer and podcaster for Medscape. He espouses a conservative approach to medical practice. He participates in clinical research and writes often about the state of medical evidence. He has disclosed no relevant financial relationships.

 

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

The results of the SUMMIT trial of the long-acting agonist of glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptors, tirzepatide, in patients with heart failure with preserved ejection fraction (HFpEF) and obesity are positive. But the trial design leaves clinicians and regulators with big doses of uncertainty.

Known Facts About HFpEF

HFpEF has exceeded heart failure with reduced ejection fraction (HFrEF) as the most common form of heart failure. HFpEF differs from HFrEF in that patients with preserved ejection fraction often present later in life with more comorbidities.

Some of these comorbidities are on the causal pathway of heart failure. Obesity, for instance, both associates with HFpEF and surely causes the diastolic dysfunction central to the condition. This may be a direct effect via high excess adipose tissue or an indirect effect via pro-inflammatory pathways.

GLP-1 agonists and the dual-acting GIP/GLP1 agonist tirzepatide have proven efficacy for weight loss. Semaglutide has previously been shown to improve quality of life and physical functioning in two small trials of patients with HFpEF and obesity. Semaglutide also reduced hard clinical outcomes in patients with obesity and these other conditions: chronic kidney disease, diabetes, and established atherosclerotic vascular disease.

This class of drugs is costly. The combination of both high drug costs and highly prevalent conditions such as obesity and HFpEF forces clinicians to make both value and clinical judgments when translating evidence.

 

The SUMMIT Trial

The SUMMIT trial aimed to evaluate tirzepatide’s effect on typical heart failure events, health status and functional capacity in patients with obesity and HFpEF. A total of 731 patients were randomly assigned to receive to tirzepatide or placebo.

Investigators chose two co-primary endpoints. The first was a composite of cardiovascular (CV) death and worsening heart failure events—the latter could be a hospitalization for heart failure, a visit for intravenous diuretics, or intensification of oral diuretics. The idea behind this rather unique composite was to capture all heart failure events. The second co-primary endpoint was a change in baseline Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS) at 1 year.

Characteristics of the patients included an average age of 65 years, 55% were female, the average body mass index was 38, and the mean left ventricular ejection fraction was 61% (the minimum for trial entry was 50%). Just under half had been hospitalized for heart failure in the year before trial entry.

 

Tirzepatide Results

The primary outcome of CV death and first heart failure event occurred in 36 patients (9.9%) in the tirzepatide group and 56 patients (15.3%) in the placebo group, for a hazard ratio of 0.62 (95% CI, 0.41-0.95; P =.026).

The 5.4% absolute risk reduction in the primary endpoint was completely driven by lower rates of heart failure events (8% vs 14.2%). CV death was actually higher in the tirzepatide arm, but the number of deaths was low in both arms (8 vs 5).

The rate of hospitalizations due to heart failure was lower with tirzepatide (3.3% vs 7.1%), as was intensification of oral diuretics (4.7% vs 5.7%).

The second co-primary endpoint of change from baseline in KCCQ-CSS favored tirzepatide.

Other secondary endpoints also favored tirzepatide: longer 6-minute walk distance, greater change in body weight (-11.6%), and lower high-sensitivity C-reactive protein levels and systolic blood pressure (-4.7 mm Hg).

 

Authors’ Conclusions and Expert Comments

At the American Heart Association Scientific Sessions, the primary investigator Milton Packer, MD, said SUMMIT was the first trial of patients with obesity and HFpEF that had major heart failure outcomes as the primary endpoint. And that tirzepatide changed the clinical trajectory of the disease.

Jennifer Ho, MD, associate professor of medicine at Harvard Medical School, Boston, Massachusetts, said, “This really is a practice-changing trial and cements this type of therapy as one of the cornerstones of obesity and HFpEF treatment.”

Other experts cited a recently published pooled analysis of semaglutide trials looking specifically at patients with HFpEF and found lower rates of HF events with the GLP-1 agonist.

The SUMMIT trial results were covered in 53 news outlets— nearly all with glowing headlines.

 

My Six Concerns With SUMMIT

The trial delivered statistically positive findings. What’s more, patients lost weight, and a greater than 11% weight loss difference is meaningful. Patients with a baseline weight of more than 100 kg who lose this much weight are bound to feel and function better.

The first problem comes when we ask whether the results are disease-modifying. There was no difference in CV death. And the number of hospitalizations for heart failure — the more standard endpoint — was low, at only 12 and 26, respectively. Contrast this with the DELIVER trial of the sodium-glucose cotransporter 2 inhibitor dapagliflozin in HFpEF where there were nearly 750 hospitalizations for heart failure and PARAGON-HF of sacubitril-valsartan vs valsartan in HFpEF, where there were nearly 1500. SUMMIT simply had too few events to make conclusions — a point Packer has made regarding AF ablation trials in patients with heart failure.

I have previously called GLP-1 drugs disease-modifying in patients with obesity and atherosclerotic disease. This is because the SELECT trial of semaglutide randomized more than 17,000 patients and recorded a 20% reduction in hard outcomes. And there were more than 1200 primary outcome events. SUMMIT does not come close to this measure.

The second issue is short follow-up. These were 65-year-old patients and with only 2 years of follow-up, it is hard to make conclusions regarding whether or not these drugs can provide long-term benefit.

The third issue is that SUMMIT authors don’t tell us the number of all-cause hospitalizations. I was part of a recently published meta-analysis of more than 100 heart failure trials that raised questions regarding the value of hospitalizations for heart failure as a surrogate for heart failure outcomes.

For instance, we found that in large trials there was great variability in the ability of a reduction in HF hospitalizations to predict a reduction in all-cause hospitalization. In small trials, such as SUMMIT, it would likely be impossible to predict how the reduction in HF hospitalization would predict all-cause hospitalization. I believe all-cause hospitalization is a more inclusive endpoint because it is bias free; it captures benefits and potential harms of the therapy; and it is patient-centered, because patients probably do not care what type of hospitalization they avoid.

The fourth issue with SUMMIT is the difficulty in maintaining blinding, which reduces confidence in outcomes that require clinical decisions or patient judgments. Owing to gastrointestinal symptoms, decreased appetite, and weight loss, patients on this class of drugs are very likely to know their treatment assignment. This is a criticism of not only SUMMIT but all GLP-1 agonist trials. The fact that blinding is difficult to maintain argues for choosing endpoints less susceptible to bias, such as CV death or all-cause hospitalization.

Proponents of tirzepatide for this indication might argue that unblinding is less of an issue because of objective endpoints such as biomarkers. And they have a point, but nearly all other endpoints, especially the co-primary endpoint of KCCQ-CSS, are largely susceptible to bias.

The fifth and main problem comes in translating this evidence in the clinic. Should doctors give up on nondrug means of weight loss? All of the positive outcome trials in this class of drugs have also shown weight loss. I believe we should take these data and use them to re-invigorate our advocacy for weight loss without medication. I know the standard answer to this proposal is nihilism: It just will not work. And I cannot deny that we have failed previously in our efforts to help patients lose weight. But perhaps now, with the vast amount of data, we can be more persuasive. Imagine a world where key opinion leaders made weight loss the message rather than prescription of a drug.

Finally, if you approach SUMMIT from the view of a regulator, with its small numbers of outcome events and bias-susceptible endpoints, you cannot allow a disease-modifying claim. For that we would need a properly powered trial that shows that the drug reduces both CV death and all-cause hospitalization.

In the end, SUMMIT is not close to changing treatment norms in patients with HFpEF. As evidence-based clinicians, we should demand more from our partners in industry and academia.

Dr. Mandrola practices cardiac electrophysiology in Baptist Medical Associates, Louisville, Kentucky, and is a writer and podcaster for Medscape. He espouses a conservative approach to medical practice. He participates in clinical research and writes often about the state of medical evidence. He has disclosed no relevant financial relationships.

 

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