Heart Failure

Interrogating the cardiac implantable electronic device (CIED) after death can yield important information about critical device malfunction, premortem abnormalities, and the mechanism and timing of death, a new study suggests.

Postmortem CIED interrogation is “richly informative” in assisting both cardiac and forensic investigations and “should be considered for select patients with CIEDs undergoing autopsy,” say Elizabeth Paratz, MBBS, department of cardiology, Baker Heart and Diabetes Institute, Prahran, Australia, and colleagues.

Their study results were published online in JACC: Clinical Electrophysiology. 

Cause of death revealed in half of cases

They reviewed CIED interrogations in 260 deceased individuals undergoing medicolegal investigation of sudden death (162 patients) or unexplained death (98 patients) by the Victorian Institute of Forensic Medicine between 2005 and 2020.

Roughly two-thirds were male (68.8%) and their median age was 72.8 years; 202 patients had pacemakers, 56 had defibrillators, and 2 had loop recorders. The cause of death was cardiac in 79.6% of cases.

Postmortem CIED interrogation was successful in 98.5% cases and directly informed cause of death in 131 cases (50.4%), with fatal ventricular arrhythmias identified in 121 patients.

CIED interrogation assisted in determining the cause of death in 63.6% of cases of sudden death and 28.6% of nonsudden death cases.

In 20 cases (7.7%), CIED interrogation uncovered potential device malfunction. Issues included failure to appropriately treat ventricular arrhythmias in 13 cases; lead issues in 3 cases, including 2 cases resulting in failure to treat ventricular arrhythmias; as well as battery depletion in 6 cases.

In 72 patients (27.7%), the device recorded abnormalities in the 30 days before death. These abnormalities included nonsustained ventricular tachycardia in 26 cases, rapid atrial fibrillation in 17, elective replacement indicator or end-of-life status in 22, intrathoracic impedance alarms or lead issues in 3 each, and therapy delivered in 1 instance.

“In several cases, the absence of an arrhythmia carried medicolegal implications: For example, in eight fatal motor vehicle accident cases, only one patient had a ventricular arrhythmia documented on their CIED,” Dr. Paratz and colleagues report.

And in six cases in which the patient was found dead after a prolonged period, CIED interrogation determined time of death. And in one case, CIED interrogation was the primary means of identifying the patient.

Still, postmortem CIED interrogation remains uncommon, the study team notes.

They point to a 2007 survey of Chicago morticians that found roughly 370 CIEDs were explanted per year prior to cremation, but only 4% of morticians had ever returned a CIED to the manufacturer for analysis.

“Encouraging postmortem interrogation of CIEDs may assist in postmarketing surveillance for critical faults, as well as in providing an electrophysiological appraisal of terminal rhythms and device responses in a variety of physiological scenarios,” the researchers say.

The study had no commercial funding. Dr. Paratz is supported by a National Health and Medical Research Council/National Heart Foundation cofunded Postgraduate Scholarship, Royal Australasian College of Physicians JJ Billings Scholarship, and PSA Insurance Cardiovascular Scholarship. The authors have disclosed no relevant financial relationships.

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

Interrogating the cardiac implantable electronic device (CIED) after death can yield important information about critical device malfunction, premortem abnormalities, and the mechanism and timing of death, a new study suggests.

Postmortem CIED interrogation is “richly informative” in assisting both cardiac and forensic investigations and “should be considered for select patients with CIEDs undergoing autopsy,” say Elizabeth Paratz, MBBS, department of cardiology, Baker Heart and Diabetes Institute, Prahran, Australia, and colleagues.

Their study results were published online in JACC: Clinical Electrophysiology. 

Cause of death revealed in half of cases

They reviewed CIED interrogations in 260 deceased individuals undergoing medicolegal investigation of sudden death (162 patients) or unexplained death (98 patients) by the Victorian Institute of Forensic Medicine between 2005 and 2020.

Roughly two-thirds were male (68.8%) and their median age was 72.8 years; 202 patients had pacemakers, 56 had defibrillators, and 2 had loop recorders. The cause of death was cardiac in 79.6% of cases.

Postmortem CIED interrogation was successful in 98.5% cases and directly informed cause of death in 131 cases (50.4%), with fatal ventricular arrhythmias identified in 121 patients.

CIED interrogation assisted in determining the cause of death in 63.6% of cases of sudden death and 28.6% of nonsudden death cases.

In 20 cases (7.7%), CIED interrogation uncovered potential device malfunction. Issues included failure to appropriately treat ventricular arrhythmias in 13 cases; lead issues in 3 cases, including 2 cases resulting in failure to treat ventricular arrhythmias; as well as battery depletion in 6 cases.

In 72 patients (27.7%), the device recorded abnormalities in the 30 days before death. These abnormalities included nonsustained ventricular tachycardia in 26 cases, rapid atrial fibrillation in 17, elective replacement indicator or end-of-life status in 22, intrathoracic impedance alarms or lead issues in 3 each, and therapy delivered in 1 instance.

“In several cases, the absence of an arrhythmia carried medicolegal implications: For example, in eight fatal motor vehicle accident cases, only one patient had a ventricular arrhythmia documented on their CIED,” Dr. Paratz and colleagues report.

And in six cases in which the patient was found dead after a prolonged period, CIED interrogation determined time of death. And in one case, CIED interrogation was the primary means of identifying the patient.

Still, postmortem CIED interrogation remains uncommon, the study team notes.

They point to a 2007 survey of Chicago morticians that found roughly 370 CIEDs were explanted per year prior to cremation, but only 4% of morticians had ever returned a CIED to the manufacturer for analysis.

“Encouraging postmortem interrogation of CIEDs may assist in postmarketing surveillance for critical faults, as well as in providing an electrophysiological appraisal of terminal rhythms and device responses in a variety of physiological scenarios,” the researchers say.

The study had no commercial funding. Dr. Paratz is supported by a National Health and Medical Research Council/National Heart Foundation cofunded Postgraduate Scholarship, Royal Australasian College of Physicians JJ Billings Scholarship, and PSA Insurance Cardiovascular Scholarship. The authors have disclosed no relevant financial relationships.

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

Interrogating the cardiac implantable electronic device (CIED) after death can yield important information about critical device malfunction, premortem abnormalities, and the mechanism and timing of death, a new study suggests.

Postmortem CIED interrogation is “richly informative” in assisting both cardiac and forensic investigations and “should be considered for select patients with CIEDs undergoing autopsy,” say Elizabeth Paratz, MBBS, department of cardiology, Baker Heart and Diabetes Institute, Prahran, Australia, and colleagues.

Their study results were published online in JACC: Clinical Electrophysiology. 

Cause of death revealed in half of cases

They reviewed CIED interrogations in 260 deceased individuals undergoing medicolegal investigation of sudden death (162 patients) or unexplained death (98 patients) by the Victorian Institute of Forensic Medicine between 2005 and 2020.

Roughly two-thirds were male (68.8%) and their median age was 72.8 years; 202 patients had pacemakers, 56 had defibrillators, and 2 had loop recorders. The cause of death was cardiac in 79.6% of cases.

Postmortem CIED interrogation was successful in 98.5% cases and directly informed cause of death in 131 cases (50.4%), with fatal ventricular arrhythmias identified in 121 patients.

CIED interrogation assisted in determining the cause of death in 63.6% of cases of sudden death and 28.6% of nonsudden death cases.

In 20 cases (7.7%), CIED interrogation uncovered potential device malfunction. Issues included failure to appropriately treat ventricular arrhythmias in 13 cases; lead issues in 3 cases, including 2 cases resulting in failure to treat ventricular arrhythmias; as well as battery depletion in 6 cases.

In 72 patients (27.7%), the device recorded abnormalities in the 30 days before death. These abnormalities included nonsustained ventricular tachycardia in 26 cases, rapid atrial fibrillation in 17, elective replacement indicator or end-of-life status in 22, intrathoracic impedance alarms or lead issues in 3 each, and therapy delivered in 1 instance.

“In several cases, the absence of an arrhythmia carried medicolegal implications: For example, in eight fatal motor vehicle accident cases, only one patient had a ventricular arrhythmia documented on their CIED,” Dr. Paratz and colleagues report.

And in six cases in which the patient was found dead after a prolonged period, CIED interrogation determined time of death. And in one case, CIED interrogation was the primary means of identifying the patient.

Still, postmortem CIED interrogation remains uncommon, the study team notes.

They point to a 2007 survey of Chicago morticians that found roughly 370 CIEDs were explanted per year prior to cremation, but only 4% of morticians had ever returned a CIED to the manufacturer for analysis.

“Encouraging postmortem interrogation of CIEDs may assist in postmarketing surveillance for critical faults, as well as in providing an electrophysiological appraisal of terminal rhythms and device responses in a variety of physiological scenarios,” the researchers say.

The study had no commercial funding. Dr. Paratz is supported by a National Health and Medical Research Council/National Heart Foundation cofunded Postgraduate Scholarship, Royal Australasian College of Physicians JJ Billings Scholarship, and PSA Insurance Cardiovascular Scholarship. The authors have disclosed no relevant financial relationships.

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

The first large population study to investigate the association between different COVID-19 vaccines types and cardiac effects and adverse events shows a small increase in the risk for acute myocarditis with both the mRNA-based vaccines and – in what may a first in the literature – an adenovirus-vector vaccine.

Ivan Pantic/Getty Images

The excess risk was seen following the first dose of the ChAdOc1 (AstraZeneca/Oxford), the adenovirus-based vaccine, and the mRNA-based BNT162b2 (Pfizer/BioNTech). It was observed after first and second doses of the mRNA-1273 (Moderna) vaccine.

The incidence rate ratios for myocarditis 1-7 days after the first AstraZeneca, Pfizer, and Moderna injections were 1.76, 1.45, and 8.38, respectively, and 23.1 after the second dose of the Moderna vaccine.

“There’s a bit more uncertainty and worry about mRNA vaccines because it’s quite a new vector for vaccination and, therefore, there’s been more focus on the potential side effects,” said Nicholas Mills, MD.

“But it doesn’t surprise me the signal is present for all types of vaccines because they’re designed to generate a systemic immune response and that is, unfortunately, where you can cause small risks for immune-mediated illnesses like myocarditis,” Dr. Mills, from the University of Edinburgh, told this news organization. Dr. Mills is a coauthor on the study, published Dec. 14 in Nature Medicine.

To put the risks in context, the group estimated between 1 and 10 additional myocarditis hospitalizations or deaths per 1 million people vaccinated, but 40 excess myocarditis events per million following a positive SARS-CoV-2 test result.

As reported, rates of excess myocarditis events associated with a first dose were 2 per million injections of the AstraZeneca vaccine, 1 per million for the Pfizer vaccine, and 6 per million with the Moderna vaccine.

Following a second dose, there were 10 additional myocarditis events per million people receiving the Moderna vaccine and none among recipients of the AstraZeneca or Pfizer vaccines.

“It was particularly seen within the first 7 days of the first dose, which is very consistent with what we see in people who have viral myocarditis,” Dr. Mills said. “So it looks like a real signal but it’s very small.”

The results are in line with previous studies of the Pfizer vaccine in Israel and studies of the Moderna vaccine in the United States, Biykem Bozkurt, MD, PhD, professor of medicine at Baylor College of Medicine, Houston, told this news organization.

“What this paper does is confirm that cardiovascular complications – and they are only looking at a small component of those cardiovascular complications – are markedly higher with the COVID-19 infection than with the vaccines,” she said.

It also adds a new twist to the search for the mechanisms of myocarditis, which has focused on the immunogenicity of the RNA in the Pfizer and Moderna vaccines but also hypothesized that molecular mimicry between the SARS-CoV-2 spike glycoprotein and cell antigens, antibody production against cardiac proteins, and testosterone may play a role.

“But now it doesn’t look like the risk is solely confined to the mRNA vaccine platform because it’s also happening with the adenovirus,” Dr. Bozkurt said. “The mechanisms require future experimental and clinical research and we’ll need more granular data with cohorts that are closely followed up as well as subclinical follow-up.”

James de Lemos, MD, professor of medicine at the University of Texas Southwestern Medical Center, Dallas, and cochair of the American Heart Association’s COVID-19 CVD Registry, said he was also not surprised by a myocarditis signal with AstraZeneca’s adenovirus vaccine.

“Looking at relative risks has biological implications, but the clinical and public health implications are that the absolute risk with the adenovirus is trivial. And you see that with their estimations of absolute risk where it’s literally sort of a needle in the haystack of 1 or 2 per million,” he said in an interview.
 

Large-scale data

The investigators examined the rates of hospital admission or death from myocarditis, pericarditis, and cardiac arrhythmia in the 28 days following SARS-CoV-2 vaccination or infection by linking the English National Immunisation Database of COVID-19 vaccination with a national patient-level health care database of 38.6 million people, aged 16 years or older, vaccinated from Dec.1, 2020, to Aug. 24, 2021.

The number of people admitted to the hospital or who died during the study period was 1,615 for myocarditis, 1,574 for pericarditis, and 385,508 for cardiac arrhythmia.

There was no evidence of an increased risk for pericarditis or cardiac arrhythmia following vaccination, except for arrhythmia in the 28 days following a second dose of the Moderna vaccine (IRR, 1.46).

In contrast, the risk was increased for pericarditis (IRR, 2.79) and cardiac arrhythmia (IRR, 5.35) in the 28 days following a positive SARS-CoV-2 test result.

Although the scale of the analysis allows for more precise estimates than what’s been possible in smaller data sets, there is the challenge of diagnosing COVID-19 from billing codes and the potential for ascertainment bias, noted Dr. de Lemos.  

“Having said that, I think it’s a really important study, because it’s the first study to put the incidence in context in the same general population the risks of myocarditis with various vaccines and with COVID-19,” he said.

“That’s really important and provides a lot of reassurance for those who are trying to balance the risks and benefits of vaccination.”
 

Analyses by sex and age

A subgroup analysis by age showed increased risks for myocarditis with the mRNA vaccines only in those younger than 40, whereas no association was found with the Oxford adenovirus vaccine.

“We’re not seeing any signal here that would make us change the recommendation for vaccination in children as a consequence of this risk,” Dr. Mills said during a press briefing.

Dr. Bozkurt pointed out, however, that the estimated excess in myocarditis events following a second dose of the Moderna vaccine in these younger adults reportedly exceeded that for SARS-CoV-2 infection (15 per million vs. 10 per million).

“For that age group, it’s concerning and needs further clarification. This hasn’t been seen before,” she said.

The average age was 39 years for those receiving two doses of the Moderna vaccine and 55 for recipients of the Pfizer and Oxford vaccines. The Moderna vaccine wasn’t rolled out until April 2021 in the United Kingdom, the authors noted, so the number of patients who received this vaccine is lower.

Although reports have suggested young males are at greater risk for myocarditis after vaccination, an analysis by sex found that women had an increased risk for myocarditis after a first dose of the AstraZeneca (IRR, 1.40) and Pfizer (IRR, 1.54) vaccines and following a positive COVID-19 test result (IRR, 11.00).

“Women being at increased risk is rather a new message,” Dr. Bozkurt said. “But the incidence rate ratios are being compared against the unvaccinated, so when you see the increase in women, it doesn’t mean it’s increased against men. It would be helpful for sex-specific incidence rate ratios to be reported for younger age subgroups, such as ages 16-20 and 20-30, to determine whether there’s an increased risk for males compared to females at younger ages.”

Age and sex differences are huge questions, but “I think we’ll learn a lot about myocarditis in general from what is going to be an explosion of research into the vaccine-associated causes,” Dr. de Lemos said.

“That will help us understand myocarditis more broadly and prepare us for the next generation of vaccines, which inevitably will be mRNA based.”

Dr. Mills reported having no relevant disclosures. Dr. Bozkurt reported consulting for Bayer and scPharmaceuticals and serving on a clinical-events committee for a trial supported by Abbott Pharmaceuticals and on a data and safety monitoring board for a trial supported by Liva Nova Pharmaceuticals. Dr. De Lemos reported having no relevant conflicts of interest.

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

The first large population study to investigate the association between different COVID-19 vaccines types and cardiac effects and adverse events shows a small increase in the risk for acute myocarditis with both the mRNA-based vaccines and – in what may a first in the literature – an adenovirus-vector vaccine.

Ivan Pantic/Getty Images

The excess risk was seen following the first dose of the ChAdOc1 (AstraZeneca/Oxford), the adenovirus-based vaccine, and the mRNA-based BNT162b2 (Pfizer/BioNTech). It was observed after first and second doses of the mRNA-1273 (Moderna) vaccine.

The incidence rate ratios for myocarditis 1-7 days after the first AstraZeneca, Pfizer, and Moderna injections were 1.76, 1.45, and 8.38, respectively, and 23.1 after the second dose of the Moderna vaccine.

“There’s a bit more uncertainty and worry about mRNA vaccines because it’s quite a new vector for vaccination and, therefore, there’s been more focus on the potential side effects,” said Nicholas Mills, MD.

“But it doesn’t surprise me the signal is present for all types of vaccines because they’re designed to generate a systemic immune response and that is, unfortunately, where you can cause small risks for immune-mediated illnesses like myocarditis,” Dr. Mills, from the University of Edinburgh, told this news organization. Dr. Mills is a coauthor on the study, published Dec. 14 in Nature Medicine.

To put the risks in context, the group estimated between 1 and 10 additional myocarditis hospitalizations or deaths per 1 million people vaccinated, but 40 excess myocarditis events per million following a positive SARS-CoV-2 test result.

As reported, rates of excess myocarditis events associated with a first dose were 2 per million injections of the AstraZeneca vaccine, 1 per million for the Pfizer vaccine, and 6 per million with the Moderna vaccine.

Following a second dose, there were 10 additional myocarditis events per million people receiving the Moderna vaccine and none among recipients of the AstraZeneca or Pfizer vaccines.

“It was particularly seen within the first 7 days of the first dose, which is very consistent with what we see in people who have viral myocarditis,” Dr. Mills said. “So it looks like a real signal but it’s very small.”

The results are in line with previous studies of the Pfizer vaccine in Israel and studies of the Moderna vaccine in the United States, Biykem Bozkurt, MD, PhD, professor of medicine at Baylor College of Medicine, Houston, told this news organization.

“What this paper does is confirm that cardiovascular complications – and they are only looking at a small component of those cardiovascular complications – are markedly higher with the COVID-19 infection than with the vaccines,” she said.

It also adds a new twist to the search for the mechanisms of myocarditis, which has focused on the immunogenicity of the RNA in the Pfizer and Moderna vaccines but also hypothesized that molecular mimicry between the SARS-CoV-2 spike glycoprotein and cell antigens, antibody production against cardiac proteins, and testosterone may play a role.

“But now it doesn’t look like the risk is solely confined to the mRNA vaccine platform because it’s also happening with the adenovirus,” Dr. Bozkurt said. “The mechanisms require future experimental and clinical research and we’ll need more granular data with cohorts that are closely followed up as well as subclinical follow-up.”

James de Lemos, MD, professor of medicine at the University of Texas Southwestern Medical Center, Dallas, and cochair of the American Heart Association’s COVID-19 CVD Registry, said he was also not surprised by a myocarditis signal with AstraZeneca’s adenovirus vaccine.

“Looking at relative risks has biological implications, but the clinical and public health implications are that the absolute risk with the adenovirus is trivial. And you see that with their estimations of absolute risk where it’s literally sort of a needle in the haystack of 1 or 2 per million,” he said in an interview.
 

Large-scale data

The investigators examined the rates of hospital admission or death from myocarditis, pericarditis, and cardiac arrhythmia in the 28 days following SARS-CoV-2 vaccination or infection by linking the English National Immunisation Database of COVID-19 vaccination with a national patient-level health care database of 38.6 million people, aged 16 years or older, vaccinated from Dec.1, 2020, to Aug. 24, 2021.

The number of people admitted to the hospital or who died during the study period was 1,615 for myocarditis, 1,574 for pericarditis, and 385,508 for cardiac arrhythmia.

There was no evidence of an increased risk for pericarditis or cardiac arrhythmia following vaccination, except for arrhythmia in the 28 days following a second dose of the Moderna vaccine (IRR, 1.46).

In contrast, the risk was increased for pericarditis (IRR, 2.79) and cardiac arrhythmia (IRR, 5.35) in the 28 days following a positive SARS-CoV-2 test result.

Although the scale of the analysis allows for more precise estimates than what’s been possible in smaller data sets, there is the challenge of diagnosing COVID-19 from billing codes and the potential for ascertainment bias, noted Dr. de Lemos.  

“Having said that, I think it’s a really important study, because it’s the first study to put the incidence in context in the same general population the risks of myocarditis with various vaccines and with COVID-19,” he said.

“That’s really important and provides a lot of reassurance for those who are trying to balance the risks and benefits of vaccination.”
 

Analyses by sex and age

A subgroup analysis by age showed increased risks for myocarditis with the mRNA vaccines only in those younger than 40, whereas no association was found with the Oxford adenovirus vaccine.

“We’re not seeing any signal here that would make us change the recommendation for vaccination in children as a consequence of this risk,” Dr. Mills said during a press briefing.

Dr. Bozkurt pointed out, however, that the estimated excess in myocarditis events following a second dose of the Moderna vaccine in these younger adults reportedly exceeded that for SARS-CoV-2 infection (15 per million vs. 10 per million).

“For that age group, it’s concerning and needs further clarification. This hasn’t been seen before,” she said.

The average age was 39 years for those receiving two doses of the Moderna vaccine and 55 for recipients of the Pfizer and Oxford vaccines. The Moderna vaccine wasn’t rolled out until April 2021 in the United Kingdom, the authors noted, so the number of patients who received this vaccine is lower.

Although reports have suggested young males are at greater risk for myocarditis after vaccination, an analysis by sex found that women had an increased risk for myocarditis after a first dose of the AstraZeneca (IRR, 1.40) and Pfizer (IRR, 1.54) vaccines and following a positive COVID-19 test result (IRR, 11.00).

“Women being at increased risk is rather a new message,” Dr. Bozkurt said. “But the incidence rate ratios are being compared against the unvaccinated, so when you see the increase in women, it doesn’t mean it’s increased against men. It would be helpful for sex-specific incidence rate ratios to be reported for younger age subgroups, such as ages 16-20 and 20-30, to determine whether there’s an increased risk for males compared to females at younger ages.”

Age and sex differences are huge questions, but “I think we’ll learn a lot about myocarditis in general from what is going to be an explosion of research into the vaccine-associated causes,” Dr. de Lemos said.

“That will help us understand myocarditis more broadly and prepare us for the next generation of vaccines, which inevitably will be mRNA based.”

Dr. Mills reported having no relevant disclosures. Dr. Bozkurt reported consulting for Bayer and scPharmaceuticals and serving on a clinical-events committee for a trial supported by Abbott Pharmaceuticals and on a data and safety monitoring board for a trial supported by Liva Nova Pharmaceuticals. Dr. De Lemos reported having no relevant conflicts of interest.

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

The first large population study to investigate the association between different COVID-19 vaccines types and cardiac effects and adverse events shows a small increase in the risk for acute myocarditis with both the mRNA-based vaccines and – in what may a first in the literature – an adenovirus-vector vaccine.

Ivan Pantic/Getty Images

The excess risk was seen following the first dose of the ChAdOc1 (AstraZeneca/Oxford), the adenovirus-based vaccine, and the mRNA-based BNT162b2 (Pfizer/BioNTech). It was observed after first and second doses of the mRNA-1273 (Moderna) vaccine.

The incidence rate ratios for myocarditis 1-7 days after the first AstraZeneca, Pfizer, and Moderna injections were 1.76, 1.45, and 8.38, respectively, and 23.1 after the second dose of the Moderna vaccine.

“There’s a bit more uncertainty and worry about mRNA vaccines because it’s quite a new vector for vaccination and, therefore, there’s been more focus on the potential side effects,” said Nicholas Mills, MD.

“But it doesn’t surprise me the signal is present for all types of vaccines because they’re designed to generate a systemic immune response and that is, unfortunately, where you can cause small risks for immune-mediated illnesses like myocarditis,” Dr. Mills, from the University of Edinburgh, told this news organization. Dr. Mills is a coauthor on the study, published Dec. 14 in Nature Medicine.

To put the risks in context, the group estimated between 1 and 10 additional myocarditis hospitalizations or deaths per 1 million people vaccinated, but 40 excess myocarditis events per million following a positive SARS-CoV-2 test result.

As reported, rates of excess myocarditis events associated with a first dose were 2 per million injections of the AstraZeneca vaccine, 1 per million for the Pfizer vaccine, and 6 per million with the Moderna vaccine.

Following a second dose, there were 10 additional myocarditis events per million people receiving the Moderna vaccine and none among recipients of the AstraZeneca or Pfizer vaccines.

“It was particularly seen within the first 7 days of the first dose, which is very consistent with what we see in people who have viral myocarditis,” Dr. Mills said. “So it looks like a real signal but it’s very small.”

The results are in line with previous studies of the Pfizer vaccine in Israel and studies of the Moderna vaccine in the United States, Biykem Bozkurt, MD, PhD, professor of medicine at Baylor College of Medicine, Houston, told this news organization.

“What this paper does is confirm that cardiovascular complications – and they are only looking at a small component of those cardiovascular complications – are markedly higher with the COVID-19 infection than with the vaccines,” she said.

It also adds a new twist to the search for the mechanisms of myocarditis, which has focused on the immunogenicity of the RNA in the Pfizer and Moderna vaccines but also hypothesized that molecular mimicry between the SARS-CoV-2 spike glycoprotein and cell antigens, antibody production against cardiac proteins, and testosterone may play a role.

“But now it doesn’t look like the risk is solely confined to the mRNA vaccine platform because it’s also happening with the adenovirus,” Dr. Bozkurt said. “The mechanisms require future experimental and clinical research and we’ll need more granular data with cohorts that are closely followed up as well as subclinical follow-up.”

James de Lemos, MD, professor of medicine at the University of Texas Southwestern Medical Center, Dallas, and cochair of the American Heart Association’s COVID-19 CVD Registry, said he was also not surprised by a myocarditis signal with AstraZeneca’s adenovirus vaccine.

“Looking at relative risks has biological implications, but the clinical and public health implications are that the absolute risk with the adenovirus is trivial. And you see that with their estimations of absolute risk where it’s literally sort of a needle in the haystack of 1 or 2 per million,” he said in an interview.
 

Large-scale data

The investigators examined the rates of hospital admission or death from myocarditis, pericarditis, and cardiac arrhythmia in the 28 days following SARS-CoV-2 vaccination or infection by linking the English National Immunisation Database of COVID-19 vaccination with a national patient-level health care database of 38.6 million people, aged 16 years or older, vaccinated from Dec.1, 2020, to Aug. 24, 2021.

The number of people admitted to the hospital or who died during the study period was 1,615 for myocarditis, 1,574 for pericarditis, and 385,508 for cardiac arrhythmia.

There was no evidence of an increased risk for pericarditis or cardiac arrhythmia following vaccination, except for arrhythmia in the 28 days following a second dose of the Moderna vaccine (IRR, 1.46).

In contrast, the risk was increased for pericarditis (IRR, 2.79) and cardiac arrhythmia (IRR, 5.35) in the 28 days following a positive SARS-CoV-2 test result.

Although the scale of the analysis allows for more precise estimates than what’s been possible in smaller data sets, there is the challenge of diagnosing COVID-19 from billing codes and the potential for ascertainment bias, noted Dr. de Lemos.  

“Having said that, I think it’s a really important study, because it’s the first study to put the incidence in context in the same general population the risks of myocarditis with various vaccines and with COVID-19,” he said.

“That’s really important and provides a lot of reassurance for those who are trying to balance the risks and benefits of vaccination.”
 

Analyses by sex and age

A subgroup analysis by age showed increased risks for myocarditis with the mRNA vaccines only in those younger than 40, whereas no association was found with the Oxford adenovirus vaccine.

“We’re not seeing any signal here that would make us change the recommendation for vaccination in children as a consequence of this risk,” Dr. Mills said during a press briefing.

Dr. Bozkurt pointed out, however, that the estimated excess in myocarditis events following a second dose of the Moderna vaccine in these younger adults reportedly exceeded that for SARS-CoV-2 infection (15 per million vs. 10 per million).

“For that age group, it’s concerning and needs further clarification. This hasn’t been seen before,” she said.

The average age was 39 years for those receiving two doses of the Moderna vaccine and 55 for recipients of the Pfizer and Oxford vaccines. The Moderna vaccine wasn’t rolled out until April 2021 in the United Kingdom, the authors noted, so the number of patients who received this vaccine is lower.

Although reports have suggested young males are at greater risk for myocarditis after vaccination, an analysis by sex found that women had an increased risk for myocarditis after a first dose of the AstraZeneca (IRR, 1.40) and Pfizer (IRR, 1.54) vaccines and following a positive COVID-19 test result (IRR, 11.00).

“Women being at increased risk is rather a new message,” Dr. Bozkurt said. “But the incidence rate ratios are being compared against the unvaccinated, so when you see the increase in women, it doesn’t mean it’s increased against men. It would be helpful for sex-specific incidence rate ratios to be reported for younger age subgroups, such as ages 16-20 and 20-30, to determine whether there’s an increased risk for males compared to females at younger ages.”

Age and sex differences are huge questions, but “I think we’ll learn a lot about myocarditis in general from what is going to be an explosion of research into the vaccine-associated causes,” Dr. de Lemos said.

“That will help us understand myocarditis more broadly and prepare us for the next generation of vaccines, which inevitably will be mRNA based.”

Dr. Mills reported having no relevant disclosures. Dr. Bozkurt reported consulting for Bayer and scPharmaceuticals and serving on a clinical-events committee for a trial supported by Abbott Pharmaceuticals and on a data and safety monitoring board for a trial supported by Liva Nova Pharmaceuticals. Dr. De Lemos reported having no relevant conflicts of interest.

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

Adolescents and adults younger than age 21 who develop myocarditis after mRNA COVID-19 vaccination frequently have abnormal findings on cardiac MRI (cMRI) but most have a mild clinical course with rapid resolution of symptoms, a new study concludes.

• Most patients were male (90.6%), White (66.2%) and with a median age of 15.8 years.
• Suspected myocarditis occurred in 136 patients (97.8%) following mRNA vaccine, with 131 (94.2%) following the Pfizer-BioNTech vaccine; 128 cases (91.4%) occurred after the second dose.
• Symptoms started a median of 2 days (range 0 to 22 days) following vaccination administration.
• Chest pain was the most common symptom (99.3%), with fever present in 30.9% of patients and shortness of breath in 27.3%.
• Patients were treated with nonsteroidal anti-inflammatory drugs (81.3%), intravenous immunoglobulin (21.6%), glucocorticoids (21.6%), colchicine (7.9%) or no anti-inflammatory therapies (8.6%).
• Twenty-six patients (18.7%) were admitted to the intensive care unit; 2 received inotropic/vasoactive support; none required extracorporeal membrane oxygenation or died.
• Median time spent in the hospital was 2 days.
• A total of 111 patients had elevated troponin I (8.12 ng/mL) and 28 had elevated troponin T (0.61 ng/mL).
• More than two-thirds (69.8%) had abnormal electrocardiograms and/or arrhythmias (7 with nonsustained ventricular tachycardia).
• Twenty-six patients (18.7%) had left ventricular ejection fraction (LVEF) less than 55% on echocardiogram; LVEF had returned to normal in the 25 who returned for follow-up.
• 75 of 97 patients (77.3%) who underwent cMRI at a median of 5 days from symptom onset had abnormal findings; 74 (76.3%) had late gadolinium enhancement, 54 (55.7%) had myocardial edema, and 49 (50.5%) met Lake Louise criteria for myocarditis.

“These data suggest that most cases of suspected COVID-19 vaccine–related myocarditis in people younger than 21 are mild and resolve quickly,” corresponding author Dongngan Truong, MD, Division of Pediatric Cardiology, University of Utah and Primary Children’s Hospital, Salt Lake City, said in a statement.

“We were very happy to see that type of recovery. However, we are awaiting further studies to better understand the long-term outcomes of patients who have had COVID-19 vaccination-related myocarditis. We also need to study the risk factors and mechanisms for this rare complication,” Dr. Truong added.

Dr. Lloyd-Jones said these findings support the AHA’s position that COVID-19 vaccines are “safe, highly effective, and fundamental to saving lives, protecting our families and communities against COVID-19, and ending the pandemic.”

The study received no funding. Dr. Truong consults for Pfizer on vaccine-associated myocarditis. A complete list of author disclosures is available with the original article.

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

Adolescents and adults younger than age 21 who develop myocarditis after mRNA COVID-19 vaccination frequently have abnormal findings on cardiac MRI (cMRI) but most have a mild clinical course with rapid resolution of symptoms, a new study concludes.

• Most patients were male (90.6%), White (66.2%) and with a median age of 15.8 years.
• Suspected myocarditis occurred in 136 patients (97.8%) following mRNA vaccine, with 131 (94.2%) following the Pfizer-BioNTech vaccine; 128 cases (91.4%) occurred after the second dose.
• Symptoms started a median of 2 days (range 0 to 22 days) following vaccination administration.
• Chest pain was the most common symptom (99.3%), with fever present in 30.9% of patients and shortness of breath in 27.3%.
• Patients were treated with nonsteroidal anti-inflammatory drugs (81.3%), intravenous immunoglobulin (21.6%), glucocorticoids (21.6%), colchicine (7.9%) or no anti-inflammatory therapies (8.6%).
• Twenty-six patients (18.7%) were admitted to the intensive care unit; 2 received inotropic/vasoactive support; none required extracorporeal membrane oxygenation or died.
• Median time spent in the hospital was 2 days.
• A total of 111 patients had elevated troponin I (8.12 ng/mL) and 28 had elevated troponin T (0.61 ng/mL).
• More than two-thirds (69.8%) had abnormal electrocardiograms and/or arrhythmias (7 with nonsustained ventricular tachycardia).
• Twenty-six patients (18.7%) had left ventricular ejection fraction (LVEF) less than 55% on echocardiogram; LVEF had returned to normal in the 25 who returned for follow-up.
• 75 of 97 patients (77.3%) who underwent cMRI at a median of 5 days from symptom onset had abnormal findings; 74 (76.3%) had late gadolinium enhancement, 54 (55.7%) had myocardial edema, and 49 (50.5%) met Lake Louise criteria for myocarditis.

“These data suggest that most cases of suspected COVID-19 vaccine–related myocarditis in people younger than 21 are mild and resolve quickly,” corresponding author Dongngan Truong, MD, Division of Pediatric Cardiology, University of Utah and Primary Children’s Hospital, Salt Lake City, said in a statement.

“We were very happy to see that type of recovery. However, we are awaiting further studies to better understand the long-term outcomes of patients who have had COVID-19 vaccination-related myocarditis. We also need to study the risk factors and mechanisms for this rare complication,” Dr. Truong added.

Dr. Lloyd-Jones said these findings support the AHA’s position that COVID-19 vaccines are “safe, highly effective, and fundamental to saving lives, protecting our families and communities against COVID-19, and ending the pandemic.”

The study received no funding. Dr. Truong consults for Pfizer on vaccine-associated myocarditis. A complete list of author disclosures is available with the original article.

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

Adolescents and adults younger than age 21 who develop myocarditis after mRNA COVID-19 vaccination frequently have abnormal findings on cardiac MRI (cMRI) but most have a mild clinical course with rapid resolution of symptoms, a new study concludes.

• Most patients were male (90.6%), White (66.2%) and with a median age of 15.8 years.
• Suspected myocarditis occurred in 136 patients (97.8%) following mRNA vaccine, with 131 (94.2%) following the Pfizer-BioNTech vaccine; 128 cases (91.4%) occurred after the second dose.
• Symptoms started a median of 2 days (range 0 to 22 days) following vaccination administration.
• Chest pain was the most common symptom (99.3%), with fever present in 30.9% of patients and shortness of breath in 27.3%.
• Patients were treated with nonsteroidal anti-inflammatory drugs (81.3%), intravenous immunoglobulin (21.6%), glucocorticoids (21.6%), colchicine (7.9%) or no anti-inflammatory therapies (8.6%).
• Twenty-six patients (18.7%) were admitted to the intensive care unit; 2 received inotropic/vasoactive support; none required extracorporeal membrane oxygenation or died.
• Median time spent in the hospital was 2 days.
• A total of 111 patients had elevated troponin I (8.12 ng/mL) and 28 had elevated troponin T (0.61 ng/mL).
• More than two-thirds (69.8%) had abnormal electrocardiograms and/or arrhythmias (7 with nonsustained ventricular tachycardia).
• Twenty-six patients (18.7%) had left ventricular ejection fraction (LVEF) less than 55% on echocardiogram; LVEF had returned to normal in the 25 who returned for follow-up.
• 75 of 97 patients (77.3%) who underwent cMRI at a median of 5 days from symptom onset had abnormal findings; 74 (76.3%) had late gadolinium enhancement, 54 (55.7%) had myocardial edema, and 49 (50.5%) met Lake Louise criteria for myocarditis.

“These data suggest that most cases of suspected COVID-19 vaccine–related myocarditis in people younger than 21 are mild and resolve quickly,” corresponding author Dongngan Truong, MD, Division of Pediatric Cardiology, University of Utah and Primary Children’s Hospital, Salt Lake City, said in a statement.

“We were very happy to see that type of recovery. However, we are awaiting further studies to better understand the long-term outcomes of patients who have had COVID-19 vaccination-related myocarditis. We also need to study the risk factors and mechanisms for this rare complication,” Dr. Truong added.

Dr. Lloyd-Jones said these findings support the AHA’s position that COVID-19 vaccines are “safe, highly effective, and fundamental to saving lives, protecting our families and communities against COVID-19, and ending the pandemic.”

The study received no funding. Dr. Truong consults for Pfizer on vaccine-associated myocarditis. A complete list of author disclosures is available with the original article.

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

An abstract and poster presentation questioning the safety of mRNA-based COVID-19 vaccines, embraced by some and lambasted by others, has drawn an “expression of concern” from the American Heart Association, along with a bid for correction.

The abstract in question concludes that COVID vaccines “dramatically increase” levels of certain inflammatory biomarkers, and therefore, the 5-year risk of acute coronary syndromes (ACS), based on pre- and post-vaccination results of an obscure blood panel called the PULS Cardiac Test (GD Biosciences). The findings were presented at the AHA’s 2021 Scientific Sessionsas, an uncontrolled observational study of 566 patients in a preventive cardiology practice.

Some on social media have seized on the abstract as evidence of serious potential harm from the two available mRNA-based SARS-CoV-2 vaccines, BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna). But others contend that the study’s described design and findings are specious and its conclusions overstated.

They also point to the notoriety of its one listed author, Steven R. Gundry, MD, who promotes his diet books and supplements as well as fringe, highly criticized theories about diet and disease on several websites, including drgundry.com. Dr. Gundry has not responded to requests for an interview.

Dr. Gundry’s abstract from the AHA Scientific Sessions 2021, available on the meeting’s program planner, was marked with an “expression of concern” by the AHA that is to stand “until a suitable correction is published, to indicate that the abstract in its current version may not be reliable.”

The expression of concern statement, also published online Nov. 24 in Circulation, says “potential errors in the abstract” were brought to the attention of the meeting planners. “Specifically, there are several typographical errors, there is no data in the abstract regarding myocardial T-cell infiltration, there are no statistical analyses for significance provided, and the author is not clear that only anecdotal data was used.”

The biomarker elevations on which the abstract’s conclusions are based included hepatocyte growth factor, “which serves as a marker for chemotaxis of T-cells into epithelium and cardiac tissue,” it states.

“The expression of concern about the abstract will remain in place until a correction is accepted and published” in Circulation, AHA spokesperson Suzanne Grant told this news organization by email.

“The specific data needed will be up to the abstract author to determine and supply,” she said, noting that Dr. Gundry “has been in communication with the journal throughout this process.”

Submitting researchers “must always attest to the validity of the abstract,” Ms. Grant said. “Abstracts are then curated by independent review panels, blinded to the identities of the abstract authors, and are considered based on the potential to add to the diversity of scientific issues and views discussed at the meeting.”

Regarding the AHA’s system for vetting abstracts vying for acceptance to the scientific sessions, she said it is not primarily intended to “evaluate scientific validity” and that the organization is “currently reviewing its existing abstract submission processes.”

A recent Reuters report reviews the controversy and provides links to criticisms of the study on social media.

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

An abstract and poster presentation questioning the safety of mRNA-based COVID-19 vaccines, embraced by some and lambasted by others, has drawn an “expression of concern” from the American Heart Association, along with a bid for correction.

The abstract in question concludes that COVID vaccines “dramatically increase” levels of certain inflammatory biomarkers, and therefore, the 5-year risk of acute coronary syndromes (ACS), based on pre- and post-vaccination results of an obscure blood panel called the PULS Cardiac Test (GD Biosciences). The findings were presented at the AHA’s 2021 Scientific Sessionsas, an uncontrolled observational study of 566 patients in a preventive cardiology practice.

Some on social media have seized on the abstract as evidence of serious potential harm from the two available mRNA-based SARS-CoV-2 vaccines, BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna). But others contend that the study’s described design and findings are specious and its conclusions overstated.

They also point to the notoriety of its one listed author, Steven R. Gundry, MD, who promotes his diet books and supplements as well as fringe, highly criticized theories about diet and disease on several websites, including drgundry.com. Dr. Gundry has not responded to requests for an interview.

Dr. Gundry’s abstract from the AHA Scientific Sessions 2021, available on the meeting’s program planner, was marked with an “expression of concern” by the AHA that is to stand “until a suitable correction is published, to indicate that the abstract in its current version may not be reliable.”

The expression of concern statement, also published online Nov. 24 in Circulation, says “potential errors in the abstract” were brought to the attention of the meeting planners. “Specifically, there are several typographical errors, there is no data in the abstract regarding myocardial T-cell infiltration, there are no statistical analyses for significance provided, and the author is not clear that only anecdotal data was used.”

The biomarker elevations on which the abstract’s conclusions are based included hepatocyte growth factor, “which serves as a marker for chemotaxis of T-cells into epithelium and cardiac tissue,” it states.

“The expression of concern about the abstract will remain in place until a correction is accepted and published” in Circulation, AHA spokesperson Suzanne Grant told this news organization by email.

“The specific data needed will be up to the abstract author to determine and supply,” she said, noting that Dr. Gundry “has been in communication with the journal throughout this process.”

Submitting researchers “must always attest to the validity of the abstract,” Ms. Grant said. “Abstracts are then curated by independent review panels, blinded to the identities of the abstract authors, and are considered based on the potential to add to the diversity of scientific issues and views discussed at the meeting.”

Regarding the AHA’s system for vetting abstracts vying for acceptance to the scientific sessions, she said it is not primarily intended to “evaluate scientific validity” and that the organization is “currently reviewing its existing abstract submission processes.”

A recent Reuters report reviews the controversy and provides links to criticisms of the study on social media.

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

An abstract and poster presentation questioning the safety of mRNA-based COVID-19 vaccines, embraced by some and lambasted by others, has drawn an “expression of concern” from the American Heart Association, along with a bid for correction.

The abstract in question concludes that COVID vaccines “dramatically increase” levels of certain inflammatory biomarkers, and therefore, the 5-year risk of acute coronary syndromes (ACS), based on pre- and post-vaccination results of an obscure blood panel called the PULS Cardiac Test (GD Biosciences). The findings were presented at the AHA’s 2021 Scientific Sessionsas, an uncontrolled observational study of 566 patients in a preventive cardiology practice.

Some on social media have seized on the abstract as evidence of serious potential harm from the two available mRNA-based SARS-CoV-2 vaccines, BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna). But others contend that the study’s described design and findings are specious and its conclusions overstated.

They also point to the notoriety of its one listed author, Steven R. Gundry, MD, who promotes his diet books and supplements as well as fringe, highly criticized theories about diet and disease on several websites, including drgundry.com. Dr. Gundry has not responded to requests for an interview.

Dr. Gundry’s abstract from the AHA Scientific Sessions 2021, available on the meeting’s program planner, was marked with an “expression of concern” by the AHA that is to stand “until a suitable correction is published, to indicate that the abstract in its current version may not be reliable.”

The expression of concern statement, also published online Nov. 24 in Circulation, says “potential errors in the abstract” were brought to the attention of the meeting planners. “Specifically, there are several typographical errors, there is no data in the abstract regarding myocardial T-cell infiltration, there are no statistical analyses for significance provided, and the author is not clear that only anecdotal data was used.”

The biomarker elevations on which the abstract’s conclusions are based included hepatocyte growth factor, “which serves as a marker for chemotaxis of T-cells into epithelium and cardiac tissue,” it states.

“The expression of concern about the abstract will remain in place until a correction is accepted and published” in Circulation, AHA spokesperson Suzanne Grant told this news organization by email.

“The specific data needed will be up to the abstract author to determine and supply,” she said, noting that Dr. Gundry “has been in communication with the journal throughout this process.”

Submitting researchers “must always attest to the validity of the abstract,” Ms. Grant said. “Abstracts are then curated by independent review panels, blinded to the identities of the abstract authors, and are considered based on the potential to add to the diversity of scientific issues and views discussed at the meeting.”

Regarding the AHA’s system for vetting abstracts vying for acceptance to the scientific sessions, she said it is not primarily intended to “evaluate scientific validity” and that the organization is “currently reviewing its existing abstract submission processes.”

A recent Reuters report reviews the controversy and provides links to criticisms of the study on social media.

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

Dr Javed Butler, from the University of Mississippi Medical Center, reports on key presentations on heart failure from the 2021 annual meeting of the American Heart Association.  

Dr Butler starts with the EMPULSE trial, which looked at the use of empagliflozin in hospitalized patients with acute heart failure. The study found that patients randomly assigned to empagliflozin had a 36% chance of improved outcomes by 3 months. 

He next looks at two reports from the EMPEROR-Preserved trials, which examined the effects of empagliflozin on patients with ejection fraction greater than 50%. The study found a 17% relative risk reduction in cardiovascular death and a 22% reduction in risk for first heart failure hospitalization. The second EMPEROR report, which examined quality-of-life metrics, found a benefit in favor of empagliflozin over placebo. 

Next, Dr Butler discusses the CHIEF-HF trial, in which heart failure patients were randomly assigned to canagliflozin regardless of ejection fraction. Canagliflozin showed benefit in symptom improvement consistently, regardless of patients having diabetes or heart failure with reduced or preserved ejection fraction. 

Finally, Dr Butler examined the results of the FIGARO-DKD trial, which studied finerenone in patients with diabetic kidney disease. The study reported a 32% relative risk reduction in heart failure events, and reduced hospitalization and cardiovascular death in patients who had a history of heart failure events and those who did not.  

--

 Javed Butler, MD, Professor, Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi 

Javed Butler, MD, has disclosed the following relevant financial relationships: 
 
Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Abbott; Amgen; Array; AstraZeneca; Bayer; Boehringer-Ingelheim; Bristol-Myers Squibb; CVRx; Janssen; LivaNova; Luitpold; Medtronic; Merck; Novartis; Novo Nordisk; Vifor 
Serve(d) as a speaker or a member of a speakers bureau for: AstraZeneca; Novartis; Boehringer-Ingelheim; Eli Lilly; Janssen

Dr Javed Butler, from the University of Mississippi Medical Center, reports on key presentations on heart failure from the 2021 annual meeting of the American Heart Association.  

Dr Butler starts with the EMPULSE trial, which looked at the use of empagliflozin in hospitalized patients with acute heart failure. The study found that patients randomly assigned to empagliflozin had a 36% chance of improved outcomes by 3 months. 

He next looks at two reports from the EMPEROR-Preserved trials, which examined the effects of empagliflozin on patients with ejection fraction greater than 50%. The study found a 17% relative risk reduction in cardiovascular death and a 22% reduction in risk for first heart failure hospitalization. The second EMPEROR report, which examined quality-of-life metrics, found a benefit in favor of empagliflozin over placebo. 

Next, Dr Butler discusses the CHIEF-HF trial, in which heart failure patients were randomly assigned to canagliflozin regardless of ejection fraction. Canagliflozin showed benefit in symptom improvement consistently, regardless of patients having diabetes or heart failure with reduced or preserved ejection fraction. 

Finally, Dr Butler examined the results of the FIGARO-DKD trial, which studied finerenone in patients with diabetic kidney disease. The study reported a 32% relative risk reduction in heart failure events, and reduced hospitalization and cardiovascular death in patients who had a history of heart failure events and those who did not.  

--

 Javed Butler, MD, Professor, Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi 

Javed Butler, MD, has disclosed the following relevant financial relationships: 
 
Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Abbott; Amgen; Array; AstraZeneca; Bayer; Boehringer-Ingelheim; Bristol-Myers Squibb; CVRx; Janssen; LivaNova; Luitpold; Medtronic; Merck; Novartis; Novo Nordisk; Vifor 
Serve(d) as a speaker or a member of a speakers bureau for: AstraZeneca; Novartis; Boehringer-Ingelheim; Eli Lilly; Janssen

Dr Javed Butler, from the University of Mississippi Medical Center, reports on key presentations on heart failure from the 2021 annual meeting of the American Heart Association.  

Dr Butler starts with the EMPULSE trial, which looked at the use of empagliflozin in hospitalized patients with acute heart failure. The study found that patients randomly assigned to empagliflozin had a 36% chance of improved outcomes by 3 months. 

He next looks at two reports from the EMPEROR-Preserved trials, which examined the effects of empagliflozin on patients with ejection fraction greater than 50%. The study found a 17% relative risk reduction in cardiovascular death and a 22% reduction in risk for first heart failure hospitalization. The second EMPEROR report, which examined quality-of-life metrics, found a benefit in favor of empagliflozin over placebo. 

Next, Dr Butler discusses the CHIEF-HF trial, in which heart failure patients were randomly assigned to canagliflozin regardless of ejection fraction. Canagliflozin showed benefit in symptom improvement consistently, regardless of patients having diabetes or heart failure with reduced or preserved ejection fraction. 

Finally, Dr Butler examined the results of the FIGARO-DKD trial, which studied finerenone in patients with diabetic kidney disease. The study reported a 32% relative risk reduction in heart failure events, and reduced hospitalization and cardiovascular death in patients who had a history of heart failure events and those who did not.  

--

 Javed Butler, MD, Professor, Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi 

Javed Butler, MD, has disclosed the following relevant financial relationships: 
 
Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Abbott; Amgen; Array; AstraZeneca; Bayer; Boehringer-Ingelheim; Bristol-Myers Squibb; CVRx; Janssen; LivaNova; Luitpold; Medtronic; Merck; Novartis; Novo Nordisk; Vifor 
Serve(d) as a speaker or a member of a speakers bureau for: AstraZeneca; Novartis; Boehringer-Ingelheim; Eli Lilly; Janssen

Patients with cardiac implantable electronic devices (CIEDs) who received treatment with an sodium-glucose cotransporter 2 inhibitor had significantly fewer atrial arrhythmia events, compared with those who never received such a drug, in a prospective analysis of nearly 14,000 patients with a device who were followed for an average of nearly 2 years.

The findings suggest that use of an agent from the class of SGLT2 inhibitors “is associated with a pronounced reduction in atrial arrhythmia burden and all-cause mortality in patients with a CIED in a real-world setting,” said Ilan Goldenberg, MD, at the American Heart Association scientific sessions. “These data indicate possible antiarrhythmic properties of SGLT2 inhibitors that are incremental to the beneficial effects of the drug on heart failure outcomes,” added Dr. Goldenberg, director of the Clinical Cardiovascular Research Center at the University of Rochester (N.Y.).

In a propensity score–matched analysis that included more than 5,000 of the enrolled patients with a CIED, treatment with an SGLT2 inhibitor was tied to a significant 23% relative reduction in atrial arrhythmia events and a 44% relative drop in all-cause death, he reported.
 

Effect mediated by reduced left atrial pressure?

“Other heart failure drugs have shown some decrease in the rate of sudden cardiac death, but this is the first [heart failure] drug to associate with a reduction in atrial arrhythmias,” Dr. Goldenberg noted. “We think that a reduction in left atrial pressure” produced by treatment with an SGLT2 inhibitor “may be linked to the reduction in atrial arrhythmias.”

The study did not show an association of SGLT2-inhibitor use and a change in ventricular arrhythmias, compared with patients with CIEDs who did not receive an agent from this class.

The findings suggest “expanding the possible indications for SGLT2 inhibitors,” commented Harriette G.C. Van Spall, MD, a cardiologist at McMaster University, Hamilton, Ont., who moderated the session where Dr. Goldenberg gave his report.

The study included 13,890 consecutive, prospectively enrolled patients who received a CIED during January 2015–April 2020 at any of five hospitals operated by either of two tertiary health care systems, one run by the University of Rochester and the second based at Sheba Medical Center in Tel HaShomer, Israel. The devices that made patients eligible for the study included permanent pacemakers, implantable cardioverter defibrillators, cardiac resynchronization therapy devices, and implantable cardiac monitors. A blinded adjudication committee composed of electrophysiologists identified the arrhythmic episodes.

At entry into the study (the time of device implantation), 12,992 patients were not receiving an SGLT2 inhibitor (94%) and 898 (6%) were receiving a drug from this class. Of those, 39% were on dapagliflozin (Farxiga), 35% were on empagliflozin (Jardiance), and 26% were on canagliflozin (Invokana).

Patients receiving an SGLT2 inhibitor at baseline were on average substantially younger than the patients not on this drug class (59 years vs. 69 years); they had a substantially higher prevalence of diabetes (78% vs. 25%), and ischemic cardiomyopathy (63% vs. 39%). Patients on an SGLT2 inhibitor at baseline also had more modestly higher prevalence rates of prior heart failure (38% vs. 31%), and hypertension (69% vs. 63%). Prevalence of a history of atrial fibrillation (AFib) was nearly the same in both groups: 31% in patients on an SGLT2 inhibitor and 35% in those not on these drugs.

The study’s primary endpoint was the total number of arrhythmia events during follow-up of 24,442 patient-years, during which patients exhibited 19,633 atrial arrhythmia events and 3,231 ventricular arrhythmia events.
 

1% absolute reduction in atrial arrhythmias

A multivariate analysis of the entire population – adjusted for baseline differences in age, diabetes, sex, and history of AFib – showed that treatment with an SGLT2 inhibitor at baseline was linked with a significant 24% relative reduction in incident atrial arrhythmia events, a significant 24% reduction in both atrial and ventricular arrhythmia events, and a 42% relative reduction in all-cause deaths, compared with no SGLT2-inhibitor treatment.

The only analyzed endpoint that showed no significant between-group difference was incidence of ventricular arrhythmias, which was a relative 7% lower in the SGLT2-inhibitor group.

On an absolute basis, treatment with an SGLT2 inhibitor was tied to about a 1% lower rate of atrial arrhythmia events per year, a reduction from a 2.5% rate in those not on an SGLT2 inhibitor to about a 1.5% rate in those taking this drug class.

A second, confirmatory analysis used propensity score matching to identify 5,323 patients not on an SGLT2 inhibitor at baseline who closely matched the 898 patients on an SGLT2 inhibitor. The multivariate modeling for this analysis also adjusted for age, diabetes, sex, and history of AFib.

The results of these analyses closely matched the calculations that used the entire study population. Relative to patients not on an SGLT2 inhibitor those on a drug from this class had 23% fewer atrial arrhythmias, 44% fewer total death, and 22% fewer atrial or ventricular arrhythmias, all significant differences. However, ventricular arrhythmias only reduced by a relative 5%, a nonsignificant difference.

In the propensity score–matched analysis, the absolute reduction in atrial arrhythmias in those on an SGLT2 inhibitor at baseline was roughly 1.3% fewer per year, compared with those not on this drug class.

The study was funded by an unrestricted grant to the University of Rochester from AstraZeneca, the company that markets the SGLT2 inhibitor dapagliflozin (Farxiga). Dr. Goldenberg and Dr. Van Spall had no disclosures.

[email protected]

Patients with cardiac implantable electronic devices (CIEDs) who received treatment with an sodium-glucose cotransporter 2 inhibitor had significantly fewer atrial arrhythmia events, compared with those who never received such a drug, in a prospective analysis of nearly 14,000 patients with a device who were followed for an average of nearly 2 years.

The findings suggest that use of an agent from the class of SGLT2 inhibitors “is associated with a pronounced reduction in atrial arrhythmia burden and all-cause mortality in patients with a CIED in a real-world setting,” said Ilan Goldenberg, MD, at the American Heart Association scientific sessions. “These data indicate possible antiarrhythmic properties of SGLT2 inhibitors that are incremental to the beneficial effects of the drug on heart failure outcomes,” added Dr. Goldenberg, director of the Clinical Cardiovascular Research Center at the University of Rochester (N.Y.).

In a propensity score–matched analysis that included more than 5,000 of the enrolled patients with a CIED, treatment with an SGLT2 inhibitor was tied to a significant 23% relative reduction in atrial arrhythmia events and a 44% relative drop in all-cause death, he reported.
 

Effect mediated by reduced left atrial pressure?

“Other heart failure drugs have shown some decrease in the rate of sudden cardiac death, but this is the first [heart failure] drug to associate with a reduction in atrial arrhythmias,” Dr. Goldenberg noted. “We think that a reduction in left atrial pressure” produced by treatment with an SGLT2 inhibitor “may be linked to the reduction in atrial arrhythmias.”

The study did not show an association of SGLT2-inhibitor use and a change in ventricular arrhythmias, compared with patients with CIEDs who did not receive an agent from this class.

The findings suggest “expanding the possible indications for SGLT2 inhibitors,” commented Harriette G.C. Van Spall, MD, a cardiologist at McMaster University, Hamilton, Ont., who moderated the session where Dr. Goldenberg gave his report.

The study included 13,890 consecutive, prospectively enrolled patients who received a CIED during January 2015–April 2020 at any of five hospitals operated by either of two tertiary health care systems, one run by the University of Rochester and the second based at Sheba Medical Center in Tel HaShomer, Israel. The devices that made patients eligible for the study included permanent pacemakers, implantable cardioverter defibrillators, cardiac resynchronization therapy devices, and implantable cardiac monitors. A blinded adjudication committee composed of electrophysiologists identified the arrhythmic episodes.

At entry into the study (the time of device implantation), 12,992 patients were not receiving an SGLT2 inhibitor (94%) and 898 (6%) were receiving a drug from this class. Of those, 39% were on dapagliflozin (Farxiga), 35% were on empagliflozin (Jardiance), and 26% were on canagliflozin (Invokana).

Patients receiving an SGLT2 inhibitor at baseline were on average substantially younger than the patients not on this drug class (59 years vs. 69 years); they had a substantially higher prevalence of diabetes (78% vs. 25%), and ischemic cardiomyopathy (63% vs. 39%). Patients on an SGLT2 inhibitor at baseline also had more modestly higher prevalence rates of prior heart failure (38% vs. 31%), and hypertension (69% vs. 63%). Prevalence of a history of atrial fibrillation (AFib) was nearly the same in both groups: 31% in patients on an SGLT2 inhibitor and 35% in those not on these drugs.

The study’s primary endpoint was the total number of arrhythmia events during follow-up of 24,442 patient-years, during which patients exhibited 19,633 atrial arrhythmia events and 3,231 ventricular arrhythmia events.
 

1% absolute reduction in atrial arrhythmias

A multivariate analysis of the entire population – adjusted for baseline differences in age, diabetes, sex, and history of AFib – showed that treatment with an SGLT2 inhibitor at baseline was linked with a significant 24% relative reduction in incident atrial arrhythmia events, a significant 24% reduction in both atrial and ventricular arrhythmia events, and a 42% relative reduction in all-cause deaths, compared with no SGLT2-inhibitor treatment.

The only analyzed endpoint that showed no significant between-group difference was incidence of ventricular arrhythmias, which was a relative 7% lower in the SGLT2-inhibitor group.

On an absolute basis, treatment with an SGLT2 inhibitor was tied to about a 1% lower rate of atrial arrhythmia events per year, a reduction from a 2.5% rate in those not on an SGLT2 inhibitor to about a 1.5% rate in those taking this drug class.

A second, confirmatory analysis used propensity score matching to identify 5,323 patients not on an SGLT2 inhibitor at baseline who closely matched the 898 patients on an SGLT2 inhibitor. The multivariate modeling for this analysis also adjusted for age, diabetes, sex, and history of AFib.

The results of these analyses closely matched the calculations that used the entire study population. Relative to patients not on an SGLT2 inhibitor those on a drug from this class had 23% fewer atrial arrhythmias, 44% fewer total death, and 22% fewer atrial or ventricular arrhythmias, all significant differences. However, ventricular arrhythmias only reduced by a relative 5%, a nonsignificant difference.

In the propensity score–matched analysis, the absolute reduction in atrial arrhythmias in those on an SGLT2 inhibitor at baseline was roughly 1.3% fewer per year, compared with those not on this drug class.

The study was funded by an unrestricted grant to the University of Rochester from AstraZeneca, the company that markets the SGLT2 inhibitor dapagliflozin (Farxiga). Dr. Goldenberg and Dr. Van Spall had no disclosures.

[email protected]

Patients with cardiac implantable electronic devices (CIEDs) who received treatment with an sodium-glucose cotransporter 2 inhibitor had significantly fewer atrial arrhythmia events, compared with those who never received such a drug, in a prospective analysis of nearly 14,000 patients with a device who were followed for an average of nearly 2 years.

The findings suggest that use of an agent from the class of SGLT2 inhibitors “is associated with a pronounced reduction in atrial arrhythmia burden and all-cause mortality in patients with a CIED in a real-world setting,” said Ilan Goldenberg, MD, at the American Heart Association scientific sessions. “These data indicate possible antiarrhythmic properties of SGLT2 inhibitors that are incremental to the beneficial effects of the drug on heart failure outcomes,” added Dr. Goldenberg, director of the Clinical Cardiovascular Research Center at the University of Rochester (N.Y.).

In a propensity score–matched analysis that included more than 5,000 of the enrolled patients with a CIED, treatment with an SGLT2 inhibitor was tied to a significant 23% relative reduction in atrial arrhythmia events and a 44% relative drop in all-cause death, he reported.
 

Effect mediated by reduced left atrial pressure?

“Other heart failure drugs have shown some decrease in the rate of sudden cardiac death, but this is the first [heart failure] drug to associate with a reduction in atrial arrhythmias,” Dr. Goldenberg noted. “We think that a reduction in left atrial pressure” produced by treatment with an SGLT2 inhibitor “may be linked to the reduction in atrial arrhythmias.”

The study did not show an association of SGLT2-inhibitor use and a change in ventricular arrhythmias, compared with patients with CIEDs who did not receive an agent from this class.

The findings suggest “expanding the possible indications for SGLT2 inhibitors,” commented Harriette G.C. Van Spall, MD, a cardiologist at McMaster University, Hamilton, Ont., who moderated the session where Dr. Goldenberg gave his report.

The study included 13,890 consecutive, prospectively enrolled patients who received a CIED during January 2015–April 2020 at any of five hospitals operated by either of two tertiary health care systems, one run by the University of Rochester and the second based at Sheba Medical Center in Tel HaShomer, Israel. The devices that made patients eligible for the study included permanent pacemakers, implantable cardioverter defibrillators, cardiac resynchronization therapy devices, and implantable cardiac monitors. A blinded adjudication committee composed of electrophysiologists identified the arrhythmic episodes.

At entry into the study (the time of device implantation), 12,992 patients were not receiving an SGLT2 inhibitor (94%) and 898 (6%) were receiving a drug from this class. Of those, 39% were on dapagliflozin (Farxiga), 35% were on empagliflozin (Jardiance), and 26% were on canagliflozin (Invokana).

Patients receiving an SGLT2 inhibitor at baseline were on average substantially younger than the patients not on this drug class (59 years vs. 69 years); they had a substantially higher prevalence of diabetes (78% vs. 25%), and ischemic cardiomyopathy (63% vs. 39%). Patients on an SGLT2 inhibitor at baseline also had more modestly higher prevalence rates of prior heart failure (38% vs. 31%), and hypertension (69% vs. 63%). Prevalence of a history of atrial fibrillation (AFib) was nearly the same in both groups: 31% in patients on an SGLT2 inhibitor and 35% in those not on these drugs.

The study’s primary endpoint was the total number of arrhythmia events during follow-up of 24,442 patient-years, during which patients exhibited 19,633 atrial arrhythmia events and 3,231 ventricular arrhythmia events.
 

1% absolute reduction in atrial arrhythmias

A multivariate analysis of the entire population – adjusted for baseline differences in age, diabetes, sex, and history of AFib – showed that treatment with an SGLT2 inhibitor at baseline was linked with a significant 24% relative reduction in incident atrial arrhythmia events, a significant 24% reduction in both atrial and ventricular arrhythmia events, and a 42% relative reduction in all-cause deaths, compared with no SGLT2-inhibitor treatment.

The only analyzed endpoint that showed no significant between-group difference was incidence of ventricular arrhythmias, which was a relative 7% lower in the SGLT2-inhibitor group.

On an absolute basis, treatment with an SGLT2 inhibitor was tied to about a 1% lower rate of atrial arrhythmia events per year, a reduction from a 2.5% rate in those not on an SGLT2 inhibitor to about a 1.5% rate in those taking this drug class.

A second, confirmatory analysis used propensity score matching to identify 5,323 patients not on an SGLT2 inhibitor at baseline who closely matched the 898 patients on an SGLT2 inhibitor. The multivariate modeling for this analysis also adjusted for age, diabetes, sex, and history of AFib.

The results of these analyses closely matched the calculations that used the entire study population. Relative to patients not on an SGLT2 inhibitor those on a drug from this class had 23% fewer atrial arrhythmias, 44% fewer total death, and 22% fewer atrial or ventricular arrhythmias, all significant differences. However, ventricular arrhythmias only reduced by a relative 5%, a nonsignificant difference.

In the propensity score–matched analysis, the absolute reduction in atrial arrhythmias in those on an SGLT2 inhibitor at baseline was roughly 1.3% fewer per year, compared with those not on this drug class.

The study was funded by an unrestricted grant to the University of Rochester from AstraZeneca, the company that markets the SGLT2 inhibitor dapagliflozin (Farxiga). Dr. Goldenberg and Dr. Van Spall had no disclosures.

[email protected]

The investigational PCSK9 inhibitor that Merck showcased recently would be more than a “me-too” drug if it ultimately wins approval, despite competition from several approved agents that slash elevated cholesterol levels by targeting the same protein.

BananaStock/thinkstockphotos.com

In fact, it would be something of a breakthrough. The new agent under study – now called MK-0616 – comes in pill form, in contrast to the three currently available PCSK9-lowering drugs that must be given in injections separated by weeks to months.

The drug faces an uncertain road to regulatory review and any approval, but MK-0616 at least seems to be starting out in the right direction.

In two phase 1 studies with a total of 100 participants, plasma PCSK9 levels plunged more than 90% after a single dose of the drug; and low-density-lipoprotein cholesterol (LDL-C) levels dropped about 65% when MK-0616 was given daily for 2 weeks on a background of statin therapy.

Moreover, “MK-0616 was generally well tolerated at up to and including single doses of 300 milligrams,” the maximum tested in the studies, Douglas G. Johns, PhD, reported at the virtual American Heart Association scientific sessions.

The collective results from the oral agent’s earliest human experience are “definitely encouraging” and support MK-0616 as a potential LDL-lowering agent that would be more convenient and arguably more accessible to patients compared to current injectable PCSK9 inhibitors, proposed Dr. Johns, clinical director of translational medicine for Merck in Kenilworth, N.J.

Available PCSK9-targeting agents include alirocumab (Praluent, Sanofi/Regeneron), Food and Drug Administration–approved in July 2015, and evolocumab (Repatha, Amgen), approved by the agency the following month. Both are monoclonal antibodies with neutralizing specificity for the PCSK9 protein; whereas the third such agent, inclisiran (Leqvio, Novartis) is a small-molecule interfering-RNA that suppresses PCSK9 synthesis. Inclisiran is approved in the European Union but its case to the FDA was turned down in 2020.

Dr. Johns said MK-0616 is a cyclic peptide that is “about one-hundredth the size of a monoclonal antibody, but we’re able to achieve monoclonal antibody-like potency and selectivity with this much smaller footprint.”

Added to statin therapy, the current PCSK9-targeting agents reduce LDL-C by an additional one-half or more, and the two antibody-based agents “also decrease atherosclerotic cardiovascular events. They are, however, expensive and not always available, requiring insurance or other approval,” observed Anne C. Goldberg, MD, as invited discussant after Dr. Johns’ presentation.

“They require every 2- to 4-week injections. They’re generally reserved for secondary prevention, and sometimes primary prevention as in familial hypercholesterolemia,” said Dr. Goldberg, of Washington University, St. Louis. Inclisiran, she noted, requires injections every 6 months and has yet to show its mettle in cardiovascular outcomes trials.

“Certainly, an oral form would be easier to use,” she said. “This would be particularly helpful in patients averse to injections,” especially, perhaps, in children. “Children with familial hypercholesterolemia could benefit with greater cholesterol lowering and might be better off with a pill than an injection.” That would be good reason to emphasize the enrollment of children in the drug’s upcoming clinical trials, Dr. Goldberg said.

But cost could potentially become restrictive for MK-0616 as well, should it ever be approved. “If it’s priced too high, then are you really going to see the increased use?” she posed. “Certainly, there’s a high bar for therapies that are add-on to statins in terms of cost effectiveness.”

In the first of the two trials, 60 predominantly White male participants aged 50 or younger were randomly assigned to receive a single dose of MK-0616, at different levels ranging from 10 mg to 300 mg, or placebo. They subsequently crossed over to a different group for a second round of dosing. Both times, three participants took the drug for every one who received placebo.

Participants who took the active drug, regardless of dosage, showed greater than 90% reductions in circulating PCSK9 levels compared to baseline. Six participants discontinued the study before its completion.

In the second trial, 40 White adults aged 65 or younger (mean, 58), including 13 women, with LDL-C of 60 mg/dL to 160 mg/dL (mean, 87 mg/dL) on statin therapy for at least 3 months were randomly assigned 3-to-1 to add-on MK-0616, either 10 mg or 20 mg daily, or placebo for 14 days.

LDL-C levels fell an average of about 65% over the 2 weeks among those taking the active drug; they declined less than 5% for those who took placebo.

There were no deaths or serious adverse events in either trial, Dr. Johns reported. On the other hand, pharmacokinetics studies showed that exposure to the drug fell by “about 50%-60%” when dosing was preceded by food intake within the previous 30 minutes. “However, if a meal is consumed 30 minutes after the dose, this food effect is much, much less prominent, almost negligible.”

These preliminary results show the drug is “orally bioavailable and exerts a clinically meaningful effect,” Dr. Johns said. “However, there’s definitely more to be done. And we are planning the next phase of clinical development, a phase 2 trial, sometime next year.”

The research was funded by Merck. Dr. Johns disclosed employment with and equity ownership in Merck, as did all the study’s coauthors. Dr. Goldberg disclosed holding research contracts through her institution with Regeneron/Sanofi-Aventis, Amarin, Amgen, Pfizer, IONIS/Akcea, Regeneron, Novartis, Arrowroot Pharmaceuticals, and the FH Foundation; and consulting for Novartis, Akcea, Regeneron, and Esperion.

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

The investigational PCSK9 inhibitor that Merck showcased recently would be more than a “me-too” drug if it ultimately wins approval, despite competition from several approved agents that slash elevated cholesterol levels by targeting the same protein.

BananaStock/thinkstockphotos.com

In fact, it would be something of a breakthrough. The new agent under study – now called MK-0616 – comes in pill form, in contrast to the three currently available PCSK9-lowering drugs that must be given in injections separated by weeks to months.

The drug faces an uncertain road to regulatory review and any approval, but MK-0616 at least seems to be starting out in the right direction.

In two phase 1 studies with a total of 100 participants, plasma PCSK9 levels plunged more than 90% after a single dose of the drug; and low-density-lipoprotein cholesterol (LDL-C) levels dropped about 65% when MK-0616 was given daily for 2 weeks on a background of statin therapy.

Moreover, “MK-0616 was generally well tolerated at up to and including single doses of 300 milligrams,” the maximum tested in the studies, Douglas G. Johns, PhD, reported at the virtual American Heart Association scientific sessions.

The collective results from the oral agent’s earliest human experience are “definitely encouraging” and support MK-0616 as a potential LDL-lowering agent that would be more convenient and arguably more accessible to patients compared to current injectable PCSK9 inhibitors, proposed Dr. Johns, clinical director of translational medicine for Merck in Kenilworth, N.J.

Available PCSK9-targeting agents include alirocumab (Praluent, Sanofi/Regeneron), Food and Drug Administration–approved in July 2015, and evolocumab (Repatha, Amgen), approved by the agency the following month. Both are monoclonal antibodies with neutralizing specificity for the PCSK9 protein; whereas the third such agent, inclisiran (Leqvio, Novartis) is a small-molecule interfering-RNA that suppresses PCSK9 synthesis. Inclisiran is approved in the European Union but its case to the FDA was turned down in 2020.

Dr. Johns said MK-0616 is a cyclic peptide that is “about one-hundredth the size of a monoclonal antibody, but we’re able to achieve monoclonal antibody-like potency and selectivity with this much smaller footprint.”

Added to statin therapy, the current PCSK9-targeting agents reduce LDL-C by an additional one-half or more, and the two antibody-based agents “also decrease atherosclerotic cardiovascular events. They are, however, expensive and not always available, requiring insurance or other approval,” observed Anne C. Goldberg, MD, as invited discussant after Dr. Johns’ presentation.

“They require every 2- to 4-week injections. They’re generally reserved for secondary prevention, and sometimes primary prevention as in familial hypercholesterolemia,” said Dr. Goldberg, of Washington University, St. Louis. Inclisiran, she noted, requires injections every 6 months and has yet to show its mettle in cardiovascular outcomes trials.

“Certainly, an oral form would be easier to use,” she said. “This would be particularly helpful in patients averse to injections,” especially, perhaps, in children. “Children with familial hypercholesterolemia could benefit with greater cholesterol lowering and might be better off with a pill than an injection.” That would be good reason to emphasize the enrollment of children in the drug’s upcoming clinical trials, Dr. Goldberg said.

But cost could potentially become restrictive for MK-0616 as well, should it ever be approved. “If it’s priced too high, then are you really going to see the increased use?” she posed. “Certainly, there’s a high bar for therapies that are add-on to statins in terms of cost effectiveness.”

In the first of the two trials, 60 predominantly White male participants aged 50 or younger were randomly assigned to receive a single dose of MK-0616, at different levels ranging from 10 mg to 300 mg, or placebo. They subsequently crossed over to a different group for a second round of dosing. Both times, three participants took the drug for every one who received placebo.

Participants who took the active drug, regardless of dosage, showed greater than 90% reductions in circulating PCSK9 levels compared to baseline. Six participants discontinued the study before its completion.

In the second trial, 40 White adults aged 65 or younger (mean, 58), including 13 women, with LDL-C of 60 mg/dL to 160 mg/dL (mean, 87 mg/dL) on statin therapy for at least 3 months were randomly assigned 3-to-1 to add-on MK-0616, either 10 mg or 20 mg daily, or placebo for 14 days.

LDL-C levels fell an average of about 65% over the 2 weeks among those taking the active drug; they declined less than 5% for those who took placebo.

There were no deaths or serious adverse events in either trial, Dr. Johns reported. On the other hand, pharmacokinetics studies showed that exposure to the drug fell by “about 50%-60%” when dosing was preceded by food intake within the previous 30 minutes. “However, if a meal is consumed 30 minutes after the dose, this food effect is much, much less prominent, almost negligible.”

These preliminary results show the drug is “orally bioavailable and exerts a clinically meaningful effect,” Dr. Johns said. “However, there’s definitely more to be done. And we are planning the next phase of clinical development, a phase 2 trial, sometime next year.”

The research was funded by Merck. Dr. Johns disclosed employment with and equity ownership in Merck, as did all the study’s coauthors. Dr. Goldberg disclosed holding research contracts through her institution with Regeneron/Sanofi-Aventis, Amarin, Amgen, Pfizer, IONIS/Akcea, Regeneron, Novartis, Arrowroot Pharmaceuticals, and the FH Foundation; and consulting for Novartis, Akcea, Regeneron, and Esperion.

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

The investigational PCSK9 inhibitor that Merck showcased recently would be more than a “me-too” drug if it ultimately wins approval, despite competition from several approved agents that slash elevated cholesterol levels by targeting the same protein.

BananaStock/thinkstockphotos.com

In fact, it would be something of a breakthrough. The new agent under study – now called MK-0616 – comes in pill form, in contrast to the three currently available PCSK9-lowering drugs that must be given in injections separated by weeks to months.

The drug faces an uncertain road to regulatory review and any approval, but MK-0616 at least seems to be starting out in the right direction.

In two phase 1 studies with a total of 100 participants, plasma PCSK9 levels plunged more than 90% after a single dose of the drug; and low-density-lipoprotein cholesterol (LDL-C) levels dropped about 65% when MK-0616 was given daily for 2 weeks on a background of statin therapy.

Moreover, “MK-0616 was generally well tolerated at up to and including single doses of 300 milligrams,” the maximum tested in the studies, Douglas G. Johns, PhD, reported at the virtual American Heart Association scientific sessions.

The collective results from the oral agent’s earliest human experience are “definitely encouraging” and support MK-0616 as a potential LDL-lowering agent that would be more convenient and arguably more accessible to patients compared to current injectable PCSK9 inhibitors, proposed Dr. Johns, clinical director of translational medicine for Merck in Kenilworth, N.J.

Available PCSK9-targeting agents include alirocumab (Praluent, Sanofi/Regeneron), Food and Drug Administration–approved in July 2015, and evolocumab (Repatha, Amgen), approved by the agency the following month. Both are monoclonal antibodies with neutralizing specificity for the PCSK9 protein; whereas the third such agent, inclisiran (Leqvio, Novartis) is a small-molecule interfering-RNA that suppresses PCSK9 synthesis. Inclisiran is approved in the European Union but its case to the FDA was turned down in 2020.

Dr. Johns said MK-0616 is a cyclic peptide that is “about one-hundredth the size of a monoclonal antibody, but we’re able to achieve monoclonal antibody-like potency and selectivity with this much smaller footprint.”

Added to statin therapy, the current PCSK9-targeting agents reduce LDL-C by an additional one-half or more, and the two antibody-based agents “also decrease atherosclerotic cardiovascular events. They are, however, expensive and not always available, requiring insurance or other approval,” observed Anne C. Goldberg, MD, as invited discussant after Dr. Johns’ presentation.

“They require every 2- to 4-week injections. They’re generally reserved for secondary prevention, and sometimes primary prevention as in familial hypercholesterolemia,” said Dr. Goldberg, of Washington University, St. Louis. Inclisiran, she noted, requires injections every 6 months and has yet to show its mettle in cardiovascular outcomes trials.

“Certainly, an oral form would be easier to use,” she said. “This would be particularly helpful in patients averse to injections,” especially, perhaps, in children. “Children with familial hypercholesterolemia could benefit with greater cholesterol lowering and might be better off with a pill than an injection.” That would be good reason to emphasize the enrollment of children in the drug’s upcoming clinical trials, Dr. Goldberg said.

But cost could potentially become restrictive for MK-0616 as well, should it ever be approved. “If it’s priced too high, then are you really going to see the increased use?” she posed. “Certainly, there’s a high bar for therapies that are add-on to statins in terms of cost effectiveness.”

In the first of the two trials, 60 predominantly White male participants aged 50 or younger were randomly assigned to receive a single dose of MK-0616, at different levels ranging from 10 mg to 300 mg, or placebo. They subsequently crossed over to a different group for a second round of dosing. Both times, three participants took the drug for every one who received placebo.

Participants who took the active drug, regardless of dosage, showed greater than 90% reductions in circulating PCSK9 levels compared to baseline. Six participants discontinued the study before its completion.

In the second trial, 40 White adults aged 65 or younger (mean, 58), including 13 women, with LDL-C of 60 mg/dL to 160 mg/dL (mean, 87 mg/dL) on statin therapy for at least 3 months were randomly assigned 3-to-1 to add-on MK-0616, either 10 mg or 20 mg daily, or placebo for 14 days.

LDL-C levels fell an average of about 65% over the 2 weeks among those taking the active drug; they declined less than 5% for those who took placebo.

There were no deaths or serious adverse events in either trial, Dr. Johns reported. On the other hand, pharmacokinetics studies showed that exposure to the drug fell by “about 50%-60%” when dosing was preceded by food intake within the previous 30 minutes. “However, if a meal is consumed 30 minutes after the dose, this food effect is much, much less prominent, almost negligible.”

These preliminary results show the drug is “orally bioavailable and exerts a clinically meaningful effect,” Dr. Johns said. “However, there’s definitely more to be done. And we are planning the next phase of clinical development, a phase 2 trial, sometime next year.”

The research was funded by Merck. Dr. Johns disclosed employment with and equity ownership in Merck, as did all the study’s coauthors. Dr. Goldberg disclosed holding research contracts through her institution with Regeneron/Sanofi-Aventis, Amarin, Amgen, Pfizer, IONIS/Akcea, Regeneron, Novartis, Arrowroot Pharmaceuticals, and the FH Foundation; and consulting for Novartis, Akcea, Regeneron, and Esperion.

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

Daily aspirin is associated with new onset heart failure independent of other risk factors, according to data derived from a database with follow-up from more than 30,000 patients who did not have HF when they were enrolled.

Patrice Wendling/MDedge News

These data are not relevant to primary or secondary prevention of cardiovascular events but “refer only to starting aspirin for secondary prevention of HF in patients at high risk of HF or with symptomatic HF,” according to the senior investigator, Jan A. Staessen, MD, PhD, professor emeritus at the University of Leuven (Belgium).

In data from 30,827 patients at risk for HF enrolled in six observational studies, the hazard ratio (HR) for developing HF among those taking daily aspirin at baseline relative to those who were not was 1.26 (P ≤ .001) over 5.3 years of follow-up. In the 22,690 patients without a prior history cardiovascular disease (CVD), the HF risk increase for exposure to daily aspirin was about the same (HR 1.27; P = .001).

This study was launched because multiple conflicting studies have made the relationship between aspirin and HF risk unclear, according to the multinational team of authors, whose finding were published in ESC Heart Failure.

In principle, HF is recognized as a prothrombotic condition for which an antithrombotic therapy such as aspirin would be expected to have a protective role, but the investigators pointed out that the evidence is mixed. In a population-based Danish study of 12,277 patients with new-onset HF, for example, there was no relationship seen between aspirin use and a reduction in the composite outcome of all-cause mortality, myocardial infarction, or stroke.

Aspirin use linked to HF admissions

“Interestingly, this study reported that aspirin use was associated with an increased risk of readmissions for HF,” wrote the authors of the newly published data. “Uncertainty on aspirin use has been reflected in current guideline recommendations,” they added.

The population studied was drawn from the HOMAGE database, which has collated data on 46,437 participants in 21 studies. After the exclusion of studies with patients who already had HF as well as studies without information on HF incidence over time, six studies with 30,827 participants provided the basis for this analysis.

One study, ASCOT, which was randomized and blinded, served as the derivation data set. The remaining five studies, FLEMENGHO, HEALTH ABC, HULL LIFE LAB, PREDICTOR, and PROSPER, served as the validation data set.

In addition to identifying participants as aspirin users or nonusers at baseline, all of the studies had detailed baseline data on a wide variety of patient characteristics and risk factors, such as body mass index, blood cholesterol levels, blood glucose concentrations, blood pressure, and creatinine.

No patient in any trial was on an antithrombotic therapy other than aspirin at baseline.

Of the minority of patients with CVD at baseline, more than 80% had coronary heart disease. Only 2.8% of the total population had a prior myocardial infarction. In the study population overall, most (86%) had hypertension, and there was a sizeable proportion with diabetes (22%). The average age was 67 years, and 34% were women.
 

HF incidence on aspirin: 14.5/1000 person-years

Overall, the incidence rate of HF per 1,000 person-years for the entire population before adjustment was 14.5 in the group on daily aspirin versus 5.9 in the non-aspirin group. These absolute rates were lower in the discovery data set than in the validation set, but the relative differences in HF incidence rates for those who were versus those who were not on aspirin at baseline were similar.

Numerous sensitivity analyses supported the basic conclusions. This not only included one omitting patients with a history of CVD, but another that excluded patients who developed HF within the first 2 years. Stratified analyses looking for overall consistency across variables showed increased risk of new onset heart failure among those taking daily aspirin regardless of relative age, body weight, or blood pressure levels.

The most important limitation of this study was that it evaluated data taken from studies not originally designed to test the study hypothesis. In addition, only baseline data were available, so the drugs that patients took over the course of follow-up are unknown. However, the authors believe these data have a clinical message.

Given the consistency of these results, “our observations suggest that aspirin should be prescribed with caution in patients at risk of HF or having HF,” the investigators concluded.

“If such treatment is initiated in these patients, use low-dose aspirin,” Dr. Staessen told this news organization.
 

Aspirin for CVD versus HF risk

Many patients take low-dose aspirin to prevent the types of cardiovascular events, such as MI, that lead to heart failure. In attempting to address a controversy regarding aspirin and risk of new onset heart failure, it appears to create another regarding CVD risk reduction.

Deepak L. Bhatt, MD, executive director of Interventional Cardiovascular Programs at Brigham and Women’s Health, Boston, expressed some reluctance in applying these data to routine practice.

“It is important to emphasize that this pooled analysis draws upon six observational studies, not randomized trials of aspirin,” Dr. Bhatt said.

He called these findings “provocative,” but he said they “would need to be confirmed in databases of already completed randomized trials of aspirin versus a control before being actionable.” For Dr. Bhatt, one obstacle to a change in practice based on these data is that, “to my knowledge, no such signal [of a relationship between aspirin and incident heart failure] exists in the cumulative randomized data.”

Dr. Staessen reports no potential conflicts of interest for this study. Dr. Bhatt has a financial relationship with a large number of pharmaceutical companies, including PLx Pharma, for which he performs aspirin-related research.
 

Daily aspirin is associated with new onset heart failure independent of other risk factors, according to data derived from a database with follow-up from more than 30,000 patients who did not have HF when they were enrolled.

Patrice Wendling/MDedge News

These data are not relevant to primary or secondary prevention of cardiovascular events but “refer only to starting aspirin for secondary prevention of HF in patients at high risk of HF or with symptomatic HF,” according to the senior investigator, Jan A. Staessen, MD, PhD, professor emeritus at the University of Leuven (Belgium).

In data from 30,827 patients at risk for HF enrolled in six observational studies, the hazard ratio (HR) for developing HF among those taking daily aspirin at baseline relative to those who were not was 1.26 (P ≤ .001) over 5.3 years of follow-up. In the 22,690 patients without a prior history cardiovascular disease (CVD), the HF risk increase for exposure to daily aspirin was about the same (HR 1.27; P = .001).

This study was launched because multiple conflicting studies have made the relationship between aspirin and HF risk unclear, according to the multinational team of authors, whose finding were published in ESC Heart Failure.

In principle, HF is recognized as a prothrombotic condition for which an antithrombotic therapy such as aspirin would be expected to have a protective role, but the investigators pointed out that the evidence is mixed. In a population-based Danish study of 12,277 patients with new-onset HF, for example, there was no relationship seen between aspirin use and a reduction in the composite outcome of all-cause mortality, myocardial infarction, or stroke.

Aspirin use linked to HF admissions

“Interestingly, this study reported that aspirin use was associated with an increased risk of readmissions for HF,” wrote the authors of the newly published data. “Uncertainty on aspirin use has been reflected in current guideline recommendations,” they added.

The population studied was drawn from the HOMAGE database, which has collated data on 46,437 participants in 21 studies. After the exclusion of studies with patients who already had HF as well as studies without information on HF incidence over time, six studies with 30,827 participants provided the basis for this analysis.

One study, ASCOT, which was randomized and blinded, served as the derivation data set. The remaining five studies, FLEMENGHO, HEALTH ABC, HULL LIFE LAB, PREDICTOR, and PROSPER, served as the validation data set.

In addition to identifying participants as aspirin users or nonusers at baseline, all of the studies had detailed baseline data on a wide variety of patient characteristics and risk factors, such as body mass index, blood cholesterol levels, blood glucose concentrations, blood pressure, and creatinine.

No patient in any trial was on an antithrombotic therapy other than aspirin at baseline.

Of the minority of patients with CVD at baseline, more than 80% had coronary heart disease. Only 2.8% of the total population had a prior myocardial infarction. In the study population overall, most (86%) had hypertension, and there was a sizeable proportion with diabetes (22%). The average age was 67 years, and 34% were women.
 

HF incidence on aspirin: 14.5/1000 person-years

Overall, the incidence rate of HF per 1,000 person-years for the entire population before adjustment was 14.5 in the group on daily aspirin versus 5.9 in the non-aspirin group. These absolute rates were lower in the discovery data set than in the validation set, but the relative differences in HF incidence rates for those who were versus those who were not on aspirin at baseline were similar.

Numerous sensitivity analyses supported the basic conclusions. This not only included one omitting patients with a history of CVD, but another that excluded patients who developed HF within the first 2 years. Stratified analyses looking for overall consistency across variables showed increased risk of new onset heart failure among those taking daily aspirin regardless of relative age, body weight, or blood pressure levels.

The most important limitation of this study was that it evaluated data taken from studies not originally designed to test the study hypothesis. In addition, only baseline data were available, so the drugs that patients took over the course of follow-up are unknown. However, the authors believe these data have a clinical message.

Given the consistency of these results, “our observations suggest that aspirin should be prescribed with caution in patients at risk of HF or having HF,” the investigators concluded.

“If such treatment is initiated in these patients, use low-dose aspirin,” Dr. Staessen told this news organization.
 

Aspirin for CVD versus HF risk

Many patients take low-dose aspirin to prevent the types of cardiovascular events, such as MI, that lead to heart failure. In attempting to address a controversy regarding aspirin and risk of new onset heart failure, it appears to create another regarding CVD risk reduction.

Deepak L. Bhatt, MD, executive director of Interventional Cardiovascular Programs at Brigham and Women’s Health, Boston, expressed some reluctance in applying these data to routine practice.

“It is important to emphasize that this pooled analysis draws upon six observational studies, not randomized trials of aspirin,” Dr. Bhatt said.

He called these findings “provocative,” but he said they “would need to be confirmed in databases of already completed randomized trials of aspirin versus a control before being actionable.” For Dr. Bhatt, one obstacle to a change in practice based on these data is that, “to my knowledge, no such signal [of a relationship between aspirin and incident heart failure] exists in the cumulative randomized data.”

Dr. Staessen reports no potential conflicts of interest for this study. Dr. Bhatt has a financial relationship with a large number of pharmaceutical companies, including PLx Pharma, for which he performs aspirin-related research.
 

Daily aspirin is associated with new onset heart failure independent of other risk factors, according to data derived from a database with follow-up from more than 30,000 patients who did not have HF when they were enrolled.

Patrice Wendling/MDedge News

These data are not relevant to primary or secondary prevention of cardiovascular events but “refer only to starting aspirin for secondary prevention of HF in patients at high risk of HF or with symptomatic HF,” according to the senior investigator, Jan A. Staessen, MD, PhD, professor emeritus at the University of Leuven (Belgium).

In data from 30,827 patients at risk for HF enrolled in six observational studies, the hazard ratio (HR) for developing HF among those taking daily aspirin at baseline relative to those who were not was 1.26 (P ≤ .001) over 5.3 years of follow-up. In the 22,690 patients without a prior history cardiovascular disease (CVD), the HF risk increase for exposure to daily aspirin was about the same (HR 1.27; P = .001).

This study was launched because multiple conflicting studies have made the relationship between aspirin and HF risk unclear, according to the multinational team of authors, whose finding were published in ESC Heart Failure.

In principle, HF is recognized as a prothrombotic condition for which an antithrombotic therapy such as aspirin would be expected to have a protective role, but the investigators pointed out that the evidence is mixed. In a population-based Danish study of 12,277 patients with new-onset HF, for example, there was no relationship seen between aspirin use and a reduction in the composite outcome of all-cause mortality, myocardial infarction, or stroke.

Aspirin use linked to HF admissions

“Interestingly, this study reported that aspirin use was associated with an increased risk of readmissions for HF,” wrote the authors of the newly published data. “Uncertainty on aspirin use has been reflected in current guideline recommendations,” they added.

The population studied was drawn from the HOMAGE database, which has collated data on 46,437 participants in 21 studies. After the exclusion of studies with patients who already had HF as well as studies without information on HF incidence over time, six studies with 30,827 participants provided the basis for this analysis.

One study, ASCOT, which was randomized and blinded, served as the derivation data set. The remaining five studies, FLEMENGHO, HEALTH ABC, HULL LIFE LAB, PREDICTOR, and PROSPER, served as the validation data set.

In addition to identifying participants as aspirin users or nonusers at baseline, all of the studies had detailed baseline data on a wide variety of patient characteristics and risk factors, such as body mass index, blood cholesterol levels, blood glucose concentrations, blood pressure, and creatinine.

No patient in any trial was on an antithrombotic therapy other than aspirin at baseline.

Of the minority of patients with CVD at baseline, more than 80% had coronary heart disease. Only 2.8% of the total population had a prior myocardial infarction. In the study population overall, most (86%) had hypertension, and there was a sizeable proportion with diabetes (22%). The average age was 67 years, and 34% were women.
 

HF incidence on aspirin: 14.5/1000 person-years

Overall, the incidence rate of HF per 1,000 person-years for the entire population before adjustment was 14.5 in the group on daily aspirin versus 5.9 in the non-aspirin group. These absolute rates were lower in the discovery data set than in the validation set, but the relative differences in HF incidence rates for those who were versus those who were not on aspirin at baseline were similar.

Numerous sensitivity analyses supported the basic conclusions. This not only included one omitting patients with a history of CVD, but another that excluded patients who developed HF within the first 2 years. Stratified analyses looking for overall consistency across variables showed increased risk of new onset heart failure among those taking daily aspirin regardless of relative age, body weight, or blood pressure levels.

The most important limitation of this study was that it evaluated data taken from studies not originally designed to test the study hypothesis. In addition, only baseline data were available, so the drugs that patients took over the course of follow-up are unknown. However, the authors believe these data have a clinical message.

Given the consistency of these results, “our observations suggest that aspirin should be prescribed with caution in patients at risk of HF or having HF,” the investigators concluded.

“If such treatment is initiated in these patients, use low-dose aspirin,” Dr. Staessen told this news organization.
 

Aspirin for CVD versus HF risk

Many patients take low-dose aspirin to prevent the types of cardiovascular events, such as MI, that lead to heart failure. In attempting to address a controversy regarding aspirin and risk of new onset heart failure, it appears to create another regarding CVD risk reduction.

Deepak L. Bhatt, MD, executive director of Interventional Cardiovascular Programs at Brigham and Women’s Health, Boston, expressed some reluctance in applying these data to routine practice.

“It is important to emphasize that this pooled analysis draws upon six observational studies, not randomized trials of aspirin,” Dr. Bhatt said.

He called these findings “provocative,” but he said they “would need to be confirmed in databases of already completed randomized trials of aspirin versus a control before being actionable.” For Dr. Bhatt, one obstacle to a change in practice based on these data is that, “to my knowledge, no such signal [of a relationship between aspirin and incident heart failure] exists in the cumulative randomized data.”

Dr. Staessen reports no potential conflicts of interest for this study. Dr. Bhatt has a financial relationship with a large number of pharmaceutical companies, including PLx Pharma, for which he performs aspirin-related research.
 

Chronic kidney disease (CKD) had no impact on the efficacy or safety of the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (Jardiance, Boehringer Ingelheim) for patients with heart failure with preserved ejection fraction (HFpEF) in the EMPEROR-Preserved trial, showing once again that agents in this class are appropriate for patients with heart failure even when their kidney function is severely compromised.

More than half of the nearly 6,000 patients with heart failure and HFpEF enrolled in EMPEROR-Preserved had CKD (although renal function was not an enrollment criterion), including 10% with an estimated glomerular filtration rate (eGFR) that fell in the range of 20-29 mL/min/1.73 m2, which categorized them as having stage 4 CKD.

The results showed, in a prespecified analysis, that treatment with empagliflozin led to a consistent, significant relative risk reduction compared with placebo in the primary endpoint of cardiovascular death or hospitalization for heart failure “across the full spectrum of kidney function, down to an eGFR of 20 mL/min/1.73m2,” said Faiez Zannad, MD, PhD, who presented the findings at the annual meeting of the American Society of Nephrology.

Among the 46.5% of enrolled patients without CKD, empagliflozin produced a significant 20% drop in the primary outcome relative to those who received placebo. Among the 53.5% of patients with CKD at time of randomization (defined as an eGFR <60 mL/min/1/73 m2 or a urinary albumin to creatinine ratio >300 mg/g), treatment with empagliflozin was associated with a significant 25% cut in the primary endpoint compared with placebo.

Empagliflozin was also “well tolerated” by patients with HFpEF, whether or not they also had CKD, “including patients with severely impaired kidney function,” said Dr. Zannad, a professor of cardiology therapeutics at the University of Lorraine in Nancy, France, at the virtual meeting.
 

An end to ‘renalism’

“This is a nail in the coffin for the concept of ‘renalism,’” the erroneous notion held by many clinicians and researchers that various treatments are not as effective and potentially more likely to cause adverse effects in patients with CKD compared with those with better renal function, commented Janani Rangaswami, MD, a nephrologist who is a professor and director of the cardiorenal program at George Washington University, Washington, D.C.   

In addition to EMPEROR-Preserved, other large trials of agents from the SGLT2 inhibitor class bucked the premise of renalism and took the “groundbreaking step” of enrolling patients with moderate-severe CKD, noted Dr. Rangaswami in an interview. In particular, two trials took this approach when enrolling patients with heart failure with reduced ejection fraction (HFrEF), EMPEROR-Reduced (which also tested empagliflozin and matched the design of EMPEROR-Preserved) and DAPA-HF (which tested the SGLT2 inhibitor dapagliflozin [Farxiga, AstraZeneca]).

“It was a huge, bold step, especially in EMPEROR-Preserved and in EMPEROR-Reduced, which both enrolled patients with eGFRs as low as 20 mL/min/1.73m2,” Dr. Rangaswami said. DAPA-HF included patients with eGFRs as low as 30 mL/min/1.73m2.

EMPEROR-Reduced and DAPA-HF – published earlier this year – both had similar findings as EMPEROR-Preserved as reported by Dr. Zannad: consistent benefit from empagliflozin or dapagliflozin regardless of eGFR level and no signal of increased adverse events from treatment.

In fact, all three analyses show that patients with worse renal function had the highest risk for cardiovascular death and hospitalization for heart failure; hence, the beneficial impact from SGLT2 inhibitors is greatest in these patients.

These observations “make it easier to focus on the group with moderate-to-severe CKD,” both in the routine care setting as well as in future trials, said Dr. Rangaswami.

“This is a welcome trend that paves the way to test more treatments in patients with stage 4 and even stage 5 CKD, patients ... excluded from trials in the past,” she said.

In addition, the consistent benefit from SGLT2 inhibitors in these three heart failure trials regardless of CKD “means there is simply no room for renalism. There is no room for clinicians to say that because a patient’s eGFR is 30 mL/min/1.73m2 they are worried about starting an SGLT2 inhibitor,” she stressed.
 

More CKD-independent effects of empagliflozin

Results of other new analyses from EMPEROR-Preserved, also reported by Dr. Zannad, included the finding that empagliflozin was associated with a similar slowing of loss of renal function over time compared with placebo, regardless of CKD status.

In patients with CKD, empagliflozin slowed eGFR loss by 1.4 mL/min/1.73 m2/year, and in those without CKD, by 1.3 mL/min/1.73 m2/year, relative to placebo.

“Even in patients without CKD, there was a relevant eGFR decline in the placebo group that was attenuated by empagliflozin,” Dr. Zannad said.

At the end of the study, when empagliflozin was stopped, patients with or without CKD had their eGFR bounce back by an identical 2.4 mL/min/1.73 m2 relative to placebo.

Empagliflozin slowed progression to macroalbuminuria and significantly reduced the incidence of acute kidney injury by a similar amount regardless of CKD status compared with placebo.

EMPEROR-Preserved enrolled patients with function-limiting HFpEF, a left ventricular ejection fraction >40%, and a minimum level of a reliable serum marker of heart failure, N-terminal pro-B-type natriuretic peptide (NT-proBNP). Compared with placebo, empagliflozin reduced the trial’s primary outcome by an absolute 3.3 percentage points and by a significant relative risk reduction of 21% after a median 26 months of follow-up, according to a report published in October 2021.

EMPEROR-Preserved is the first prospective, randomized trial to unequivocally show the efficacy and safety of a drug for improving outcomes in patients with HFpEF.

EMPEROR-Preserved was sponsored by Boehringer-Ingelheim and Lilly, which market empagliflozin (Jardiance). Dr. Zannad has reported financial relationships with Boehringer Ingelheim as well as other companies. Dr. Rangaswami has reported being a consultant for Boehringer Ingelheim, Lilly, and AstraZeneca.

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

Chronic kidney disease (CKD) had no impact on the efficacy or safety of the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (Jardiance, Boehringer Ingelheim) for patients with heart failure with preserved ejection fraction (HFpEF) in the EMPEROR-Preserved trial, showing once again that agents in this class are appropriate for patients with heart failure even when their kidney function is severely compromised.

More than half of the nearly 6,000 patients with heart failure and HFpEF enrolled in EMPEROR-Preserved had CKD (although renal function was not an enrollment criterion), including 10% with an estimated glomerular filtration rate (eGFR) that fell in the range of 20-29 mL/min/1.73 m2, which categorized them as having stage 4 CKD.

The results showed, in a prespecified analysis, that treatment with empagliflozin led to a consistent, significant relative risk reduction compared with placebo in the primary endpoint of cardiovascular death or hospitalization for heart failure “across the full spectrum of kidney function, down to an eGFR of 20 mL/min/1.73m2,” said Faiez Zannad, MD, PhD, who presented the findings at the annual meeting of the American Society of Nephrology.

Among the 46.5% of enrolled patients without CKD, empagliflozin produced a significant 20% drop in the primary outcome relative to those who received placebo. Among the 53.5% of patients with CKD at time of randomization (defined as an eGFR <60 mL/min/1/73 m2 or a urinary albumin to creatinine ratio >300 mg/g), treatment with empagliflozin was associated with a significant 25% cut in the primary endpoint compared with placebo.

Empagliflozin was also “well tolerated” by patients with HFpEF, whether or not they also had CKD, “including patients with severely impaired kidney function,” said Dr. Zannad, a professor of cardiology therapeutics at the University of Lorraine in Nancy, France, at the virtual meeting.
 

An end to ‘renalism’

“This is a nail in the coffin for the concept of ‘renalism,’” the erroneous notion held by many clinicians and researchers that various treatments are not as effective and potentially more likely to cause adverse effects in patients with CKD compared with those with better renal function, commented Janani Rangaswami, MD, a nephrologist who is a professor and director of the cardiorenal program at George Washington University, Washington, D.C.   

In addition to EMPEROR-Preserved, other large trials of agents from the SGLT2 inhibitor class bucked the premise of renalism and took the “groundbreaking step” of enrolling patients with moderate-severe CKD, noted Dr. Rangaswami in an interview. In particular, two trials took this approach when enrolling patients with heart failure with reduced ejection fraction (HFrEF), EMPEROR-Reduced (which also tested empagliflozin and matched the design of EMPEROR-Preserved) and DAPA-HF (which tested the SGLT2 inhibitor dapagliflozin [Farxiga, AstraZeneca]).

“It was a huge, bold step, especially in EMPEROR-Preserved and in EMPEROR-Reduced, which both enrolled patients with eGFRs as low as 20 mL/min/1.73m2,” Dr. Rangaswami said. DAPA-HF included patients with eGFRs as low as 30 mL/min/1.73m2.

EMPEROR-Reduced and DAPA-HF – published earlier this year – both had similar findings as EMPEROR-Preserved as reported by Dr. Zannad: consistent benefit from empagliflozin or dapagliflozin regardless of eGFR level and no signal of increased adverse events from treatment.

In fact, all three analyses show that patients with worse renal function had the highest risk for cardiovascular death and hospitalization for heart failure; hence, the beneficial impact from SGLT2 inhibitors is greatest in these patients.

These observations “make it easier to focus on the group with moderate-to-severe CKD,” both in the routine care setting as well as in future trials, said Dr. Rangaswami.

“This is a welcome trend that paves the way to test more treatments in patients with stage 4 and even stage 5 CKD, patients ... excluded from trials in the past,” she said.

In addition, the consistent benefit from SGLT2 inhibitors in these three heart failure trials regardless of CKD “means there is simply no room for renalism. There is no room for clinicians to say that because a patient’s eGFR is 30 mL/min/1.73m2 they are worried about starting an SGLT2 inhibitor,” she stressed.
 

More CKD-independent effects of empagliflozin

Results of other new analyses from EMPEROR-Preserved, also reported by Dr. Zannad, included the finding that empagliflozin was associated with a similar slowing of loss of renal function over time compared with placebo, regardless of CKD status.

In patients with CKD, empagliflozin slowed eGFR loss by 1.4 mL/min/1.73 m2/year, and in those without CKD, by 1.3 mL/min/1.73 m2/year, relative to placebo.

“Even in patients without CKD, there was a relevant eGFR decline in the placebo group that was attenuated by empagliflozin,” Dr. Zannad said.

At the end of the study, when empagliflozin was stopped, patients with or without CKD had their eGFR bounce back by an identical 2.4 mL/min/1.73 m2 relative to placebo.

Empagliflozin slowed progression to macroalbuminuria and significantly reduced the incidence of acute kidney injury by a similar amount regardless of CKD status compared with placebo.

EMPEROR-Preserved enrolled patients with function-limiting HFpEF, a left ventricular ejection fraction >40%, and a minimum level of a reliable serum marker of heart failure, N-terminal pro-B-type natriuretic peptide (NT-proBNP). Compared with placebo, empagliflozin reduced the trial’s primary outcome by an absolute 3.3 percentage points and by a significant relative risk reduction of 21% after a median 26 months of follow-up, according to a report published in October 2021.

EMPEROR-Preserved is the first prospective, randomized trial to unequivocally show the efficacy and safety of a drug for improving outcomes in patients with HFpEF.

EMPEROR-Preserved was sponsored by Boehringer-Ingelheim and Lilly, which market empagliflozin (Jardiance). Dr. Zannad has reported financial relationships with Boehringer Ingelheim as well as other companies. Dr. Rangaswami has reported being a consultant for Boehringer Ingelheim, Lilly, and AstraZeneca.

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

Chronic kidney disease (CKD) had no impact on the efficacy or safety of the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (Jardiance, Boehringer Ingelheim) for patients with heart failure with preserved ejection fraction (HFpEF) in the EMPEROR-Preserved trial, showing once again that agents in this class are appropriate for patients with heart failure even when their kidney function is severely compromised.

More than half of the nearly 6,000 patients with heart failure and HFpEF enrolled in EMPEROR-Preserved had CKD (although renal function was not an enrollment criterion), including 10% with an estimated glomerular filtration rate (eGFR) that fell in the range of 20-29 mL/min/1.73 m2, which categorized them as having stage 4 CKD.

The results showed, in a prespecified analysis, that treatment with empagliflozin led to a consistent, significant relative risk reduction compared with placebo in the primary endpoint of cardiovascular death or hospitalization for heart failure “across the full spectrum of kidney function, down to an eGFR of 20 mL/min/1.73m2,” said Faiez Zannad, MD, PhD, who presented the findings at the annual meeting of the American Society of Nephrology.

Among the 46.5% of enrolled patients without CKD, empagliflozin produced a significant 20% drop in the primary outcome relative to those who received placebo. Among the 53.5% of patients with CKD at time of randomization (defined as an eGFR <60 mL/min/1/73 m2 or a urinary albumin to creatinine ratio >300 mg/g), treatment with empagliflozin was associated with a significant 25% cut in the primary endpoint compared with placebo.

Empagliflozin was also “well tolerated” by patients with HFpEF, whether or not they also had CKD, “including patients with severely impaired kidney function,” said Dr. Zannad, a professor of cardiology therapeutics at the University of Lorraine in Nancy, France, at the virtual meeting.
 

An end to ‘renalism’

“This is a nail in the coffin for the concept of ‘renalism,’” the erroneous notion held by many clinicians and researchers that various treatments are not as effective and potentially more likely to cause adverse effects in patients with CKD compared with those with better renal function, commented Janani Rangaswami, MD, a nephrologist who is a professor and director of the cardiorenal program at George Washington University, Washington, D.C.   

In addition to EMPEROR-Preserved, other large trials of agents from the SGLT2 inhibitor class bucked the premise of renalism and took the “groundbreaking step” of enrolling patients with moderate-severe CKD, noted Dr. Rangaswami in an interview. In particular, two trials took this approach when enrolling patients with heart failure with reduced ejection fraction (HFrEF), EMPEROR-Reduced (which also tested empagliflozin and matched the design of EMPEROR-Preserved) and DAPA-HF (which tested the SGLT2 inhibitor dapagliflozin [Farxiga, AstraZeneca]).

“It was a huge, bold step, especially in EMPEROR-Preserved and in EMPEROR-Reduced, which both enrolled patients with eGFRs as low as 20 mL/min/1.73m2,” Dr. Rangaswami said. DAPA-HF included patients with eGFRs as low as 30 mL/min/1.73m2.

EMPEROR-Reduced and DAPA-HF – published earlier this year – both had similar findings as EMPEROR-Preserved as reported by Dr. Zannad: consistent benefit from empagliflozin or dapagliflozin regardless of eGFR level and no signal of increased adverse events from treatment.

In fact, all three analyses show that patients with worse renal function had the highest risk for cardiovascular death and hospitalization for heart failure; hence, the beneficial impact from SGLT2 inhibitors is greatest in these patients.

These observations “make it easier to focus on the group with moderate-to-severe CKD,” both in the routine care setting as well as in future trials, said Dr. Rangaswami.

“This is a welcome trend that paves the way to test more treatments in patients with stage 4 and even stage 5 CKD, patients ... excluded from trials in the past,” she said.

In addition, the consistent benefit from SGLT2 inhibitors in these three heart failure trials regardless of CKD “means there is simply no room for renalism. There is no room for clinicians to say that because a patient’s eGFR is 30 mL/min/1.73m2 they are worried about starting an SGLT2 inhibitor,” she stressed.
 

More CKD-independent effects of empagliflozin

Results of other new analyses from EMPEROR-Preserved, also reported by Dr. Zannad, included the finding that empagliflozin was associated with a similar slowing of loss of renal function over time compared with placebo, regardless of CKD status.

In patients with CKD, empagliflozin slowed eGFR loss by 1.4 mL/min/1.73 m2/year, and in those without CKD, by 1.3 mL/min/1.73 m2/year, relative to placebo.

“Even in patients without CKD, there was a relevant eGFR decline in the placebo group that was attenuated by empagliflozin,” Dr. Zannad said.

At the end of the study, when empagliflozin was stopped, patients with or without CKD had their eGFR bounce back by an identical 2.4 mL/min/1.73 m2 relative to placebo.

Empagliflozin slowed progression to macroalbuminuria and significantly reduced the incidence of acute kidney injury by a similar amount regardless of CKD status compared with placebo.

EMPEROR-Preserved enrolled patients with function-limiting HFpEF, a left ventricular ejection fraction >40%, and a minimum level of a reliable serum marker of heart failure, N-terminal pro-B-type natriuretic peptide (NT-proBNP). Compared with placebo, empagliflozin reduced the trial’s primary outcome by an absolute 3.3 percentage points and by a significant relative risk reduction of 21% after a median 26 months of follow-up, according to a report published in October 2021.

EMPEROR-Preserved is the first prospective, randomized trial to unequivocally show the efficacy and safety of a drug for improving outcomes in patients with HFpEF.

EMPEROR-Preserved was sponsored by Boehringer-Ingelheim and Lilly, which market empagliflozin (Jardiance). Dr. Zannad has reported financial relationships with Boehringer Ingelheim as well as other companies. Dr. Rangaswami has reported being a consultant for Boehringer Ingelheim, Lilly, and AstraZeneca.

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

The sodium-glucose transporter 2 inhibitors, relative newcomers among first-line agents for chronic heart failure (HF), could well attain the same go-to status in patients hospitalized with acute HF if the EMPULSE trial has anything to say about it.

Of the study’s 530 such patients, those started on daily empagliflozin (Jardiance) soon after they were stabilized, compared with a control group, were less likely to die or be rehospitalized for HF over the next 3 months.

Also, “we saw an improvement in quality of life, we saw a greater reduction in body weight, and we didn’t see any safety concerns in this very vulnerable and sick patient population,” Adriaan A. Voors, MD, University Medical Center Groningen (the Netherlands), said when presenting the trial at the American Heart Association scientific sessions.

Patients assigned to empagliflozin had a 36% greater likelihood of showing a benefit as reflected in the treatment’s win ratio when opposed by placebo, an emerging way to express outcomes in cardiovascular clinical trials. The SGLT2 inhibitor’s win ratio for the primary endpoint was 1.36 (95% confidence interval, 1.09-1.68, P = .0054), Dr. Voors reported. The outcome consisted of death, number of HF events, time to first HF event, and 90-day change in quality of life scores.

There is reluctance in practice to start patients that early after decompensation on drugs used in chronic HF, Dr. Voors said in an interview. Empagliflozin in the trial was initiated in the stabilized setting an average of 3 days after hospital admission, he said. The trial should reassure physicians that the drug “is not only safe to start early in hospital, but it’s also beneficial to start early in hospital.”

EMPULSE, combined with support from other recent trials, “should be clinical practice changing, with early in-hospital initiation of SGLT2 inhibitors in patients hospitalized with HF being the expectation, along with clear recognition that delaying SGLT2 inhibitor initiation may expose patients to unnecessary harms and delays in improved health status,” Gregg C. Fonarow, MD, University of California Los Angeles Medical Center, told this news organization.

“For patients with HF, irrespective of ejection fraction, early in-hospital initiation of SGLT2 inhibitors – once stabilized and in the absence of contraindications – should be considered a new standard of care,” said Fonarow, who was not part of EMPULSE.

The trial also lends new weight to the strategy of “simultaneous or rapid-sequence initiation” of the so-called four pillars of guideline-directed medical therapy of HF with reduced ejection fraction in patients hospitalized with HFrEF, once they are stabilized, Dr. Fonarow said. The four-pronged approach, he noted, consists of sacubitril/valsartan (Entresto), a beta-blocker, a mineralocorticoid receptor antagonist (MRA), and an SGLT2 inhibitor.

Indeed, the new findings “fill an important gap and are clearly practice changing,” agreed Nancy K. Sweitzer, MD, PhD, University of Arizona Sarver Heart Center, Tucson, as an invited discussant following Dr. Voors’ presentation. “Few therapies have been shown to impact the course of those hospitalized with acute decompensated heart failure.”

Of note in the trial, Dr. Sweitzer continued, patients were started on empagliflozin regardless of any drug therapy they might already be on for chronic HF. “Because patients in the EMPULSE trial could be enrolled with a new diagnosis of heart failure, they were, by definition, not all on chronic guideline-directed heart failure therapy. Nevertheless, such patients benefited equally from the study intervention,” she said.

“This is crucial, as it tells us these drugs have immediate and important effects and should not be withheld while other drug classes are initiated and optimized.”

EMPULSE entered patients hospitalized for acute HF, which could be de novo or a decompensation of chronic HF, without regard to ejection fraction or whether they had diabetes, and who were clinically stable after at least one dose of loop diuretics. Their ejection fractions averaged 35% and exceeded 40% in about one-third of the total cohort.

At 90 days in the win ratio analysis, the 265 patients assigned to empagliflozin 10 mg once daily were the “winners”; that is, they were more likely to show a clinical benefit about 54% of the time in paired match-ups of patient outcomes, compared with about 40% for the 265 in the control group. The match-ups were a tie 6.4% of the time.

The empagliflozin group also benefited significantly for the endpoint of death from any cause or first HF event, with a hazard ratio of 0.65 (95% CI, 0.43-0.99; P = .042). They also were less likely to experience acute renal failure (7.7% vs. 12.1% for the control group) or serious adverse events (32.3% vs. 43.6%), Dr. Voors reported.

Tempting as it might be, the findings can’t necessarily be generalized to other SGLT2 inhibitors without an evidence base. But as Dr. Voors observed, several ongoing trials are exploring dapagliflozin (Farxiga) in a similar clinical setting.

They include DICTATE-AHF in patients with diabetes admitted with acute HF, and DAPA ACT HF-TIMI 68, which is entering patients stabilized during hospitalization with acute decompensated HFrEF. The trials are scheduled for completion in 2022 and 2023, respectively.

EMPULSE was supported by the Boehringer Ingelheim–Eli Lilly Diabetes Alliance. Dr. Voors disclosed research support and consulting for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Merck, Myokardia, Novo Nordisk, Novartis, and Roche Diagnostics. Dr. Sweitzer disclosed honoraria from Acorda and Myokardia, and reported receiving research support from Novartis and Merck. Dr. Fonarow cited honoraria from Abbott, Amgen, Janssen, Medtronic, Bayer, Merck, AstraZeneca, Cytokinetics, and Novartis.

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

The sodium-glucose transporter 2 inhibitors, relative newcomers among first-line agents for chronic heart failure (HF), could well attain the same go-to status in patients hospitalized with acute HF if the EMPULSE trial has anything to say about it.

Of the study’s 530 such patients, those started on daily empagliflozin (Jardiance) soon after they were stabilized, compared with a control group, were less likely to die or be rehospitalized for HF over the next 3 months.

Also, “we saw an improvement in quality of life, we saw a greater reduction in body weight, and we didn’t see any safety concerns in this very vulnerable and sick patient population,” Adriaan A. Voors, MD, University Medical Center Groningen (the Netherlands), said when presenting the trial at the American Heart Association scientific sessions.

Patients assigned to empagliflozin had a 36% greater likelihood of showing a benefit as reflected in the treatment’s win ratio when opposed by placebo, an emerging way to express outcomes in cardiovascular clinical trials. The SGLT2 inhibitor’s win ratio for the primary endpoint was 1.36 (95% confidence interval, 1.09-1.68, P = .0054), Dr. Voors reported. The outcome consisted of death, number of HF events, time to first HF event, and 90-day change in quality of life scores.

There is reluctance in practice to start patients that early after decompensation on drugs used in chronic HF, Dr. Voors said in an interview. Empagliflozin in the trial was initiated in the stabilized setting an average of 3 days after hospital admission, he said. The trial should reassure physicians that the drug “is not only safe to start early in hospital, but it’s also beneficial to start early in hospital.”

EMPULSE, combined with support from other recent trials, “should be clinical practice changing, with early in-hospital initiation of SGLT2 inhibitors in patients hospitalized with HF being the expectation, along with clear recognition that delaying SGLT2 inhibitor initiation may expose patients to unnecessary harms and delays in improved health status,” Gregg C. Fonarow, MD, University of California Los Angeles Medical Center, told this news organization.

“For patients with HF, irrespective of ejection fraction, early in-hospital initiation of SGLT2 inhibitors – once stabilized and in the absence of contraindications – should be considered a new standard of care,” said Fonarow, who was not part of EMPULSE.

The trial also lends new weight to the strategy of “simultaneous or rapid-sequence initiation” of the so-called four pillars of guideline-directed medical therapy of HF with reduced ejection fraction in patients hospitalized with HFrEF, once they are stabilized, Dr. Fonarow said. The four-pronged approach, he noted, consists of sacubitril/valsartan (Entresto), a beta-blocker, a mineralocorticoid receptor antagonist (MRA), and an SGLT2 inhibitor.

Indeed, the new findings “fill an important gap and are clearly practice changing,” agreed Nancy K. Sweitzer, MD, PhD, University of Arizona Sarver Heart Center, Tucson, as an invited discussant following Dr. Voors’ presentation. “Few therapies have been shown to impact the course of those hospitalized with acute decompensated heart failure.”

Of note in the trial, Dr. Sweitzer continued, patients were started on empagliflozin regardless of any drug therapy they might already be on for chronic HF. “Because patients in the EMPULSE trial could be enrolled with a new diagnosis of heart failure, they were, by definition, not all on chronic guideline-directed heart failure therapy. Nevertheless, such patients benefited equally from the study intervention,” she said.

“This is crucial, as it tells us these drugs have immediate and important effects and should not be withheld while other drug classes are initiated and optimized.”

EMPULSE entered patients hospitalized for acute HF, which could be de novo or a decompensation of chronic HF, without regard to ejection fraction or whether they had diabetes, and who were clinically stable after at least one dose of loop diuretics. Their ejection fractions averaged 35% and exceeded 40% in about one-third of the total cohort.

At 90 days in the win ratio analysis, the 265 patients assigned to empagliflozin 10 mg once daily were the “winners”; that is, they were more likely to show a clinical benefit about 54% of the time in paired match-ups of patient outcomes, compared with about 40% for the 265 in the control group. The match-ups were a tie 6.4% of the time.

The empagliflozin group also benefited significantly for the endpoint of death from any cause or first HF event, with a hazard ratio of 0.65 (95% CI, 0.43-0.99; P = .042). They also were less likely to experience acute renal failure (7.7% vs. 12.1% for the control group) or serious adverse events (32.3% vs. 43.6%), Dr. Voors reported.

Tempting as it might be, the findings can’t necessarily be generalized to other SGLT2 inhibitors without an evidence base. But as Dr. Voors observed, several ongoing trials are exploring dapagliflozin (Farxiga) in a similar clinical setting.

They include DICTATE-AHF in patients with diabetes admitted with acute HF, and DAPA ACT HF-TIMI 68, which is entering patients stabilized during hospitalization with acute decompensated HFrEF. The trials are scheduled for completion in 2022 and 2023, respectively.

EMPULSE was supported by the Boehringer Ingelheim–Eli Lilly Diabetes Alliance. Dr. Voors disclosed research support and consulting for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Merck, Myokardia, Novo Nordisk, Novartis, and Roche Diagnostics. Dr. Sweitzer disclosed honoraria from Acorda and Myokardia, and reported receiving research support from Novartis and Merck. Dr. Fonarow cited honoraria from Abbott, Amgen, Janssen, Medtronic, Bayer, Merck, AstraZeneca, Cytokinetics, and Novartis.

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

The sodium-glucose transporter 2 inhibitors, relative newcomers among first-line agents for chronic heart failure (HF), could well attain the same go-to status in patients hospitalized with acute HF if the EMPULSE trial has anything to say about it.

Of the study’s 530 such patients, those started on daily empagliflozin (Jardiance) soon after they were stabilized, compared with a control group, were less likely to die or be rehospitalized for HF over the next 3 months.

Also, “we saw an improvement in quality of life, we saw a greater reduction in body weight, and we didn’t see any safety concerns in this very vulnerable and sick patient population,” Adriaan A. Voors, MD, University Medical Center Groningen (the Netherlands), said when presenting the trial at the American Heart Association scientific sessions.

Patients assigned to empagliflozin had a 36% greater likelihood of showing a benefit as reflected in the treatment’s win ratio when opposed by placebo, an emerging way to express outcomes in cardiovascular clinical trials. The SGLT2 inhibitor’s win ratio for the primary endpoint was 1.36 (95% confidence interval, 1.09-1.68, P = .0054), Dr. Voors reported. The outcome consisted of death, number of HF events, time to first HF event, and 90-day change in quality of life scores.

There is reluctance in practice to start patients that early after decompensation on drugs used in chronic HF, Dr. Voors said in an interview. Empagliflozin in the trial was initiated in the stabilized setting an average of 3 days after hospital admission, he said. The trial should reassure physicians that the drug “is not only safe to start early in hospital, but it’s also beneficial to start early in hospital.”

EMPULSE, combined with support from other recent trials, “should be clinical practice changing, with early in-hospital initiation of SGLT2 inhibitors in patients hospitalized with HF being the expectation, along with clear recognition that delaying SGLT2 inhibitor initiation may expose patients to unnecessary harms and delays in improved health status,” Gregg C. Fonarow, MD, University of California Los Angeles Medical Center, told this news organization.

“For patients with HF, irrespective of ejection fraction, early in-hospital initiation of SGLT2 inhibitors – once stabilized and in the absence of contraindications – should be considered a new standard of care,” said Fonarow, who was not part of EMPULSE.

The trial also lends new weight to the strategy of “simultaneous or rapid-sequence initiation” of the so-called four pillars of guideline-directed medical therapy of HF with reduced ejection fraction in patients hospitalized with HFrEF, once they are stabilized, Dr. Fonarow said. The four-pronged approach, he noted, consists of sacubitril/valsartan (Entresto), a beta-blocker, a mineralocorticoid receptor antagonist (MRA), and an SGLT2 inhibitor.

Indeed, the new findings “fill an important gap and are clearly practice changing,” agreed Nancy K. Sweitzer, MD, PhD, University of Arizona Sarver Heart Center, Tucson, as an invited discussant following Dr. Voors’ presentation. “Few therapies have been shown to impact the course of those hospitalized with acute decompensated heart failure.”

Of note in the trial, Dr. Sweitzer continued, patients were started on empagliflozin regardless of any drug therapy they might already be on for chronic HF. “Because patients in the EMPULSE trial could be enrolled with a new diagnosis of heart failure, they were, by definition, not all on chronic guideline-directed heart failure therapy. Nevertheless, such patients benefited equally from the study intervention,” she said.

“This is crucial, as it tells us these drugs have immediate and important effects and should not be withheld while other drug classes are initiated and optimized.”

EMPULSE entered patients hospitalized for acute HF, which could be de novo or a decompensation of chronic HF, without regard to ejection fraction or whether they had diabetes, and who were clinically stable after at least one dose of loop diuretics. Their ejection fractions averaged 35% and exceeded 40% in about one-third of the total cohort.

At 90 days in the win ratio analysis, the 265 patients assigned to empagliflozin 10 mg once daily were the “winners”; that is, they were more likely to show a clinical benefit about 54% of the time in paired match-ups of patient outcomes, compared with about 40% for the 265 in the control group. The match-ups were a tie 6.4% of the time.

The empagliflozin group also benefited significantly for the endpoint of death from any cause or first HF event, with a hazard ratio of 0.65 (95% CI, 0.43-0.99; P = .042). They also were less likely to experience acute renal failure (7.7% vs. 12.1% for the control group) or serious adverse events (32.3% vs. 43.6%), Dr. Voors reported.

Tempting as it might be, the findings can’t necessarily be generalized to other SGLT2 inhibitors without an evidence base. But as Dr. Voors observed, several ongoing trials are exploring dapagliflozin (Farxiga) in a similar clinical setting.

They include DICTATE-AHF in patients with diabetes admitted with acute HF, and DAPA ACT HF-TIMI 68, which is entering patients stabilized during hospitalization with acute decompensated HFrEF. The trials are scheduled for completion in 2022 and 2023, respectively.

EMPULSE was supported by the Boehringer Ingelheim–Eli Lilly Diabetes Alliance. Dr. Voors disclosed research support and consulting for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Merck, Myokardia, Novo Nordisk, Novartis, and Roche Diagnostics. Dr. Sweitzer disclosed honoraria from Acorda and Myokardia, and reported receiving research support from Novartis and Merck. Dr. Fonarow cited honoraria from Abbott, Amgen, Janssen, Medtronic, Bayer, Merck, AstraZeneca, Cytokinetics, and Novartis.

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