Heart Failure

A once-daily polypill containing four drugs to lower blood pressure and LDL cholesterol reduced major adverse cardiovascular events by 21% relative to placebo in people at intermediate cardiovascular risk in the landmark TIPS-3 trial.

And with the addition of aspirin at 75 mg per day the combination achieved an even more robust 31% relative risk reduction, investigators reported at the.

“Aspirin contributes importantly to the benefits,” Salim Yusuf, MD, DPhil, emphasized in presenting the International Polycap Study (TIPS-3) results jointly with study coprincipal investigator Prem Pais, MD, at the virtual American Heart Association scientific sessions.

The multinational study provides powerful new support for a broad, population health–based approach to primary cardiovascular prevention.

“If half of eligible people [were to] use a polypill with aspirin, 3-5 million cardiovascular events per year would be avoided globally,” according to Dr. Yusuf, professor of medicine and director of the Population Health Research Institute at McMaster University in Hamilton, Ont.

“This is likely a cost-effective strategy to meet global targets of reducing cardiovascular disease by 30% by 2020,” added Dr. Pais of St. John’s Research Institute in Bangalore, India.

TIPS-3 included 5,713 participants at intermediate cardiovascular risk, with an estimated event risk of 1.8% per year using the INTERHEART Risk Score. Half were women. More than 80% of participants had hypertension, and nearly 40% had diabetes or impaired fasting glucose. Nearly 90% of participants came from India, the Philippines, Malaysia, Indonesia, or Bangladesh. All participants received advice about lifestyle management.

They were then randomized to receive a polypill or placebo, and then each group was further randomized to receive 75 mg/day of aspirin or matching placebo. The polypill contained 40 mg of simvastatin, 100 mg of atenolol, 25 mg of hydrochlorothiazide, and 10 mg of ramipril.

During a mean 4.6 years of follow-up, the primary composite major adverse cardiovascular event rate occurred in 4.4% of the polypill group, 4.1% of the polypill-plus-aspirin group, and 5.8% of the double-placebo group. This translated to a 21% reduction in cardiovascular disease with the polypill, a 31% reduction with polypill plus aspirin, and a 14% reduction in the composite of cardiovascular death, MI, or stroke with aspirin alone.

The polypill and placebo groups diverged in terms of the primary outcome starting about 6 months into the study, Dr. Pais noted.

Serious adverse events were less common with the polypill than with placebo. Importantly, there was no difference in major, minor, or GI bleeding between the polypill-plus-aspirin group and placebo-treated controls. Dr. Yusuf attributed the lack of excess bleeding in aspirin recipients to two factors: people with a history of bleeding or GI symptoms were excluded from TIPS-3, and the dose of aspirin used was lower than in other primary prevention trials, where bleeding offset the reduction in cardiovascular events.

Nonadherence was a major issue in TIPS-3, mainly because of delays in polypill production and distribution, coupled late in the trial with the COVID-19 pandemic. The nonadherence rate was 19% at 2 years, 32% at 4 years, and 43% at the study’s end. Only 5% of discontinuations were due to side effects. In a sensitivity analysis carried out in participants without discontinuation for nonmedical reasons, the benefits of the polypill plus aspirin were larger than in the overall study: a 39% relative risk reduction in the primary endpoint that probably offers a more accurate picture of the combination’s likely real-world performance.

Discussant Anushka Patel, MBBS, PhD, noted that TIPS-3 is the third randomized trial to provide direct evidence that a polypill-based strategy improves clinical outcomes. The effect sizes of the benefits – a 20%-30% reduction in major cardiovascular events – has been consistent in TIPS-3, PolyIran, and HOPE-3, each of which tested a different polypill drug combination.

“If implementation and adherence challenges can be addressed at the system, prescriber, and patient levels, and if high-quality polypills can be made affordable, the public health impact could actually be enormous,” said Dr. Patel, chief scientist at the George Institute for Global Health and professor of medicine at the University of New South Wales in Sydney, Australia.

However, she parted company with Dr. Yusuf regarding routine incorporation of aspirin into polypills.

“I think the totality of evidence would still probably favor taking an individualized approach that also considers bleeding risk,” the cardiologist said.

Donald Lloyd-Jones, MD, who chaired a press conference highlighting TIPS-3, declared, “You’re seeing a paradigm shift right here in front of your eyes today. This could be a game changer in terms of preventing large numbers of cardiovascular events.”

While TIPS-3 was conducted mainly in low- and middle-income countries, it’s important to recognize that’s where 75% of cardiovascular events and cardiovascular deaths now occur.

“This is very much a disease that has emerged in the developing world,” commented Dr. Lloyd-Jones, the AHA president-elect, chair of the AHA Council on Scientific Sessions Programming, and professor and chair of the department of preventive medicine at Northwestern University, Chicago.

He also sees a polypill strategy for primary cardiovascular prevention as highly viable in high-resource countries. It makes sense to employ it there initially in underserved communities, where a polypill-based approach sidesteps difficulties in monitoring care and adjusting medication doses due to reduced access to health care while minimizing cost and adherence issues, he added.

Dr. Yusuf and Dr. Pais reported receiving institutional research support from the TIPS-3 major sponsors: the Wellcome Trust, Cadila Pharmaceuticals, the Canadian Institutes of Health Research, and the Heart and Stroke Foundation of Canada.

Simultaneously with their presentation at AHA 2020, the TIPS-3 results were published online in the New England Journal of Medicine.
 

bjancin@mdedge.com

SOURCE: Yusuf, S. AHA 2020. Session LBS.02.

A once-daily polypill containing four drugs to lower blood pressure and LDL cholesterol reduced major adverse cardiovascular events by 21% relative to placebo in people at intermediate cardiovascular risk in the landmark TIPS-3 trial.

And with the addition of aspirin at 75 mg per day the combination achieved an even more robust 31% relative risk reduction, investigators reported at the.

“Aspirin contributes importantly to the benefits,” Salim Yusuf, MD, DPhil, emphasized in presenting the International Polycap Study (TIPS-3) results jointly with study coprincipal investigator Prem Pais, MD, at the virtual American Heart Association scientific sessions.

The multinational study provides powerful new support for a broad, population health–based approach to primary cardiovascular prevention.

“If half of eligible people [were to] use a polypill with aspirin, 3-5 million cardiovascular events per year would be avoided globally,” according to Dr. Yusuf, professor of medicine and director of the Population Health Research Institute at McMaster University in Hamilton, Ont.

“This is likely a cost-effective strategy to meet global targets of reducing cardiovascular disease by 30% by 2020,” added Dr. Pais of St. John’s Research Institute in Bangalore, India.

TIPS-3 included 5,713 participants at intermediate cardiovascular risk, with an estimated event risk of 1.8% per year using the INTERHEART Risk Score. Half were women. More than 80% of participants had hypertension, and nearly 40% had diabetes or impaired fasting glucose. Nearly 90% of participants came from India, the Philippines, Malaysia, Indonesia, or Bangladesh. All participants received advice about lifestyle management.

They were then randomized to receive a polypill or placebo, and then each group was further randomized to receive 75 mg/day of aspirin or matching placebo. The polypill contained 40 mg of simvastatin, 100 mg of atenolol, 25 mg of hydrochlorothiazide, and 10 mg of ramipril.

During a mean 4.6 years of follow-up, the primary composite major adverse cardiovascular event rate occurred in 4.4% of the polypill group, 4.1% of the polypill-plus-aspirin group, and 5.8% of the double-placebo group. This translated to a 21% reduction in cardiovascular disease with the polypill, a 31% reduction with polypill plus aspirin, and a 14% reduction in the composite of cardiovascular death, MI, or stroke with aspirin alone.

The polypill and placebo groups diverged in terms of the primary outcome starting about 6 months into the study, Dr. Pais noted.

Serious adverse events were less common with the polypill than with placebo. Importantly, there was no difference in major, minor, or GI bleeding between the polypill-plus-aspirin group and placebo-treated controls. Dr. Yusuf attributed the lack of excess bleeding in aspirin recipients to two factors: people with a history of bleeding or GI symptoms were excluded from TIPS-3, and the dose of aspirin used was lower than in other primary prevention trials, where bleeding offset the reduction in cardiovascular events.

Nonadherence was a major issue in TIPS-3, mainly because of delays in polypill production and distribution, coupled late in the trial with the COVID-19 pandemic. The nonadherence rate was 19% at 2 years, 32% at 4 years, and 43% at the study’s end. Only 5% of discontinuations were due to side effects. In a sensitivity analysis carried out in participants without discontinuation for nonmedical reasons, the benefits of the polypill plus aspirin were larger than in the overall study: a 39% relative risk reduction in the primary endpoint that probably offers a more accurate picture of the combination’s likely real-world performance.

Discussant Anushka Patel, MBBS, PhD, noted that TIPS-3 is the third randomized trial to provide direct evidence that a polypill-based strategy improves clinical outcomes. The effect sizes of the benefits – a 20%-30% reduction in major cardiovascular events – has been consistent in TIPS-3, PolyIran, and HOPE-3, each of which tested a different polypill drug combination.

“If implementation and adherence challenges can be addressed at the system, prescriber, and patient levels, and if high-quality polypills can be made affordable, the public health impact could actually be enormous,” said Dr. Patel, chief scientist at the George Institute for Global Health and professor of medicine at the University of New South Wales in Sydney, Australia.

However, she parted company with Dr. Yusuf regarding routine incorporation of aspirin into polypills.

“I think the totality of evidence would still probably favor taking an individualized approach that also considers bleeding risk,” the cardiologist said.

Donald Lloyd-Jones, MD, who chaired a press conference highlighting TIPS-3, declared, “You’re seeing a paradigm shift right here in front of your eyes today. This could be a game changer in terms of preventing large numbers of cardiovascular events.”

While TIPS-3 was conducted mainly in low- and middle-income countries, it’s important to recognize that’s where 75% of cardiovascular events and cardiovascular deaths now occur.

“This is very much a disease that has emerged in the developing world,” commented Dr. Lloyd-Jones, the AHA president-elect, chair of the AHA Council on Scientific Sessions Programming, and professor and chair of the department of preventive medicine at Northwestern University, Chicago.

He also sees a polypill strategy for primary cardiovascular prevention as highly viable in high-resource countries. It makes sense to employ it there initially in underserved communities, where a polypill-based approach sidesteps difficulties in monitoring care and adjusting medication doses due to reduced access to health care while minimizing cost and adherence issues, he added.

Dr. Yusuf and Dr. Pais reported receiving institutional research support from the TIPS-3 major sponsors: the Wellcome Trust, Cadila Pharmaceuticals, the Canadian Institutes of Health Research, and the Heart and Stroke Foundation of Canada.

Simultaneously with their presentation at AHA 2020, the TIPS-3 results were published online in the New England Journal of Medicine.
 

bjancin@mdedge.com

SOURCE: Yusuf, S. AHA 2020. Session LBS.02.

A once-daily polypill containing four drugs to lower blood pressure and LDL cholesterol reduced major adverse cardiovascular events by 21% relative to placebo in people at intermediate cardiovascular risk in the landmark TIPS-3 trial.

And with the addition of aspirin at 75 mg per day the combination achieved an even more robust 31% relative risk reduction, investigators reported at the.

“Aspirin contributes importantly to the benefits,” Salim Yusuf, MD, DPhil, emphasized in presenting the International Polycap Study (TIPS-3) results jointly with study coprincipal investigator Prem Pais, MD, at the virtual American Heart Association scientific sessions.

The multinational study provides powerful new support for a broad, population health–based approach to primary cardiovascular prevention.

“If half of eligible people [were to] use a polypill with aspirin, 3-5 million cardiovascular events per year would be avoided globally,” according to Dr. Yusuf, professor of medicine and director of the Population Health Research Institute at McMaster University in Hamilton, Ont.

“This is likely a cost-effective strategy to meet global targets of reducing cardiovascular disease by 30% by 2020,” added Dr. Pais of St. John’s Research Institute in Bangalore, India.

TIPS-3 included 5,713 participants at intermediate cardiovascular risk, with an estimated event risk of 1.8% per year using the INTERHEART Risk Score. Half were women. More than 80% of participants had hypertension, and nearly 40% had diabetes or impaired fasting glucose. Nearly 90% of participants came from India, the Philippines, Malaysia, Indonesia, or Bangladesh. All participants received advice about lifestyle management.

They were then randomized to receive a polypill or placebo, and then each group was further randomized to receive 75 mg/day of aspirin or matching placebo. The polypill contained 40 mg of simvastatin, 100 mg of atenolol, 25 mg of hydrochlorothiazide, and 10 mg of ramipril.

During a mean 4.6 years of follow-up, the primary composite major adverse cardiovascular event rate occurred in 4.4% of the polypill group, 4.1% of the polypill-plus-aspirin group, and 5.8% of the double-placebo group. This translated to a 21% reduction in cardiovascular disease with the polypill, a 31% reduction with polypill plus aspirin, and a 14% reduction in the composite of cardiovascular death, MI, or stroke with aspirin alone.

The polypill and placebo groups diverged in terms of the primary outcome starting about 6 months into the study, Dr. Pais noted.

Serious adverse events were less common with the polypill than with placebo. Importantly, there was no difference in major, minor, or GI bleeding between the polypill-plus-aspirin group and placebo-treated controls. Dr. Yusuf attributed the lack of excess bleeding in aspirin recipients to two factors: people with a history of bleeding or GI symptoms were excluded from TIPS-3, and the dose of aspirin used was lower than in other primary prevention trials, where bleeding offset the reduction in cardiovascular events.

Nonadherence was a major issue in TIPS-3, mainly because of delays in polypill production and distribution, coupled late in the trial with the COVID-19 pandemic. The nonadherence rate was 19% at 2 years, 32% at 4 years, and 43% at the study’s end. Only 5% of discontinuations were due to side effects. In a sensitivity analysis carried out in participants without discontinuation for nonmedical reasons, the benefits of the polypill plus aspirin were larger than in the overall study: a 39% relative risk reduction in the primary endpoint that probably offers a more accurate picture of the combination’s likely real-world performance.

Discussant Anushka Patel, MBBS, PhD, noted that TIPS-3 is the third randomized trial to provide direct evidence that a polypill-based strategy improves clinical outcomes. The effect sizes of the benefits – a 20%-30% reduction in major cardiovascular events – has been consistent in TIPS-3, PolyIran, and HOPE-3, each of which tested a different polypill drug combination.

“If implementation and adherence challenges can be addressed at the system, prescriber, and patient levels, and if high-quality polypills can be made affordable, the public health impact could actually be enormous,” said Dr. Patel, chief scientist at the George Institute for Global Health and professor of medicine at the University of New South Wales in Sydney, Australia.

However, she parted company with Dr. Yusuf regarding routine incorporation of aspirin into polypills.

“I think the totality of evidence would still probably favor taking an individualized approach that also considers bleeding risk,” the cardiologist said.

Donald Lloyd-Jones, MD, who chaired a press conference highlighting TIPS-3, declared, “You’re seeing a paradigm shift right here in front of your eyes today. This could be a game changer in terms of preventing large numbers of cardiovascular events.”

While TIPS-3 was conducted mainly in low- and middle-income countries, it’s important to recognize that’s where 75% of cardiovascular events and cardiovascular deaths now occur.

“This is very much a disease that has emerged in the developing world,” commented Dr. Lloyd-Jones, the AHA president-elect, chair of the AHA Council on Scientific Sessions Programming, and professor and chair of the department of preventive medicine at Northwestern University, Chicago.

He also sees a polypill strategy for primary cardiovascular prevention as highly viable in high-resource countries. It makes sense to employ it there initially in underserved communities, where a polypill-based approach sidesteps difficulties in monitoring care and adjusting medication doses due to reduced access to health care while minimizing cost and adherence issues, he added.

Dr. Yusuf and Dr. Pais reported receiving institutional research support from the TIPS-3 major sponsors: the Wellcome Trust, Cadila Pharmaceuticals, the Canadian Institutes of Health Research, and the Heart and Stroke Foundation of Canada.

Simultaneously with their presentation at AHA 2020, the TIPS-3 results were published online in the New England Journal of Medicine.
 

bjancin@mdedge.com

SOURCE: Yusuf, S. AHA 2020. Session LBS.02.

Omecamtiv mecarbil, a member of the novel myotropic drug class that improves cardiac performance, safely produced a significant but modest improvement in heart failure events or cardiovascular death in a pivotal trial with HFrEF patients, leaving experts unsure about the role this drug could have on top of an already crowded list of four first-line drug classes for this condition.

“It remains to be investigated and discussed where omecamtiv mecarbil fits in” the overall approach to treating patients with heart failure with reduced ejection fraction (HFrEF), commented Paul Heidenreich, MD, designated discussant for the report at the virtual scientific sessions of the American Heart Association.

Room for a fifth HFrEF drug?

In addition to the limited benefit, another question raised by the trial is how OM would perform when used on top of what is now considered standard, quadruple therapy for most HFrEF patients: a beta-blocker, a mineralocorticoid receptor antagonist, sacubitril-valsartan (Entresto), and an agent from the sodium glucose co-transporter 2 (SGLT2) inhibitor class, specifically dapagliflozin (Farxiga) or empagliflozin (Jardiance). During the period when the new OM trial was run, 2017-2019, the SGLT2 inhibitors had not yet been established as a key part of standard HFrEF treatment, and hence fewer than 3% of enrolled patients were on one of these drugs.

Because of this evidence gap, OM “can’t be across the board a fifth drug on top of standard treatment,” based on the new results, cautioned Dr. Heidenreich, a cardiologist and professor of medicine at Stanford (Calif.) University School of Medicine.

The positives of omecamtiv mercarbil

But in addition to its positive result in the GALACTIC-HF trial, treatment with OM showed other attractive characteristics in a study that treated a wide spectrum of 4,120 patients with HFrEF as well as including 4,112 patients randomized to placebo. Most notably, OM had a very clean safety profile, with adverse event rates similar to placebo patients across all adverse event subtypes, as well as causing no drop in blood pressure and actually an average 2.0–mm Hg increase in systolic blood pressure, no increase in potassium, no apparent impact on renal function, and a small but significant decline in N-terminal pro-B-type natriuretic peptide (NT-proBNP) compared with placebo.

This coupled with the novel mechanism of action of OM – direct augmentation of cardiac sarcomere function by increasing myosin attachment to actin – suggests that OM can be safely added on top of existing HFrEF treatment to provide an unique and incremental benefit.

“Other heart failure drugs [like beta-blockers and sacubitril-valsartan] lower blood pressure, so what can happen is that clinicians run out of room to add full dosages” when patients’ pressures fall too low, commented Gregory D. Lewis, MD, head of Heart Failure at Massachusetts General Hospital in Boston. He is principle investigator for another OM trial, METEORIC-HF, which is examining the possible impact of the drug on exercise capacity in a randomized study with about 270 HFrEF patients.

If the METEORIC-HF results can could confirm some of the GALACTIC-HF results that suggested improvements in patient function, the combined data could potentially lead to regulatory approval for U.S. marketing of the drug, Dr. Lewis suggested. Results from that study are expected in 2021, he said in an interview.

The GALACTIC-HF results hinted at possible functional improvement after 24 weeks on treatment among patients who required hospitalization as measured by the Kansas City Cardiomyopathy Questionnaire, which measures quality life. However, this difference failed to meet the study’s prespecified definition of a significant effect.

Another intriguing suggestion of focused benefit was in patients with a left ventricular ejection fraction at or below the median in GALACTIC-HF of 28%. In that subgroup, OM treatment was linked with a significant 16% relative reduction in the primary endpoint compared with placebo, while it had no significant effect in the other 50% of patients with higher ejection fractions. (The maximum left ventricular ejection fraction for enrollment was 35%.) This apparent subgroup interaction was statistically significant, reported Dr. Teerlink, a professor of medicine at the University of California, San Francisco, and director of Heart Failure at the San Francisco V.A. Medical Center.

Further analysis of the study data “will provide greater insight into subgroups who may demonstrate greater benefit, such as patients with lower ejection fraction in whom improving cardiac function may have a greater role,” he said. The idea that a drug that improves myocyte function at the molecular level could especially benefit patients with the lowest ejection fractions is “biologically plausible,” Dr. Teerlink said.

This scenario looks reasonable, and could make OM something of a niche drug for at least the near term, said Dr. Mann.

The world’s first myotropic drug

Possibly the most notable aspect of GALACTIC-HF is that it proved the efficacy, modest though it was, of a novel drug mechanism that fulfills a decades-long quest of heart failure researchers: a safe way to improve the heart’s pumping action.

“For years, the heart failure community struggled with treatment to improve cardiac performance, but invariably it ended in disaster by worsening cardiac deaths,” problems that led to abandonment of early inotropic drugs more than a generation ago, noted Dr. Mann.

But a more nuanced approach to inotropic agents recently has emerged from Dr. Teerlink and his associates, built on the premise that the dangers seen years ago related to the calcium modulations they caused. Their new paradigm is that the dangers of these “calcitropic” agents can be sidestepped with different agents that either mediate their effects via myosin, the myotropes like OM, or mitochondrial effects from mitotropic drugs.

The inotrope debacle from the 1990s made that drug-class name “a dirty word that causes fear and loathing in the heart failure community,” observed Dr. Mann. While the term myotrope has not yet really caught on, “If omecamtiv mecarbil starts getting used in routine practice, then I think you’ll start seeing uptake of the term myotrope,” he predicted.

GALACTIC-HF was sponsored by Amgen, Cytokinetics, and Servier, the companies developing omecamtiv mecarbil. Dr. Teerlink has received research support from and been a consultant to Amgen, Cytokinetics, and Servier, as well as Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Medtronic, Merck, and Novartis. Dr. Heidenreich had no disclosures. Dr. Mann is on a steering committee for a trial sponsored by Novartis and has no other commercial disclosures. Dr. Lewis is principal investigator for a trial of omecamtiv mecarbil and has no other commercial disclosures.

mzoler@mdedge.com

On Twitter @mitchelzoler

Omecamtiv mecarbil, a member of the novel myotropic drug class that improves cardiac performance, safely produced a significant but modest improvement in heart failure events or cardiovascular death in a pivotal trial with HFrEF patients, leaving experts unsure about the role this drug could have on top of an already crowded list of four first-line drug classes for this condition.

“It remains to be investigated and discussed where omecamtiv mecarbil fits in” the overall approach to treating patients with heart failure with reduced ejection fraction (HFrEF), commented Paul Heidenreich, MD, designated discussant for the report at the virtual scientific sessions of the American Heart Association.

Room for a fifth HFrEF drug?

In addition to the limited benefit, another question raised by the trial is how OM would perform when used on top of what is now considered standard, quadruple therapy for most HFrEF patients: a beta-blocker, a mineralocorticoid receptor antagonist, sacubitril-valsartan (Entresto), and an agent from the sodium glucose co-transporter 2 (SGLT2) inhibitor class, specifically dapagliflozin (Farxiga) or empagliflozin (Jardiance). During the period when the new OM trial was run, 2017-2019, the SGLT2 inhibitors had not yet been established as a key part of standard HFrEF treatment, and hence fewer than 3% of enrolled patients were on one of these drugs.

Because of this evidence gap, OM “can’t be across the board a fifth drug on top of standard treatment,” based on the new results, cautioned Dr. Heidenreich, a cardiologist and professor of medicine at Stanford (Calif.) University School of Medicine.

The positives of omecamtiv mercarbil

But in addition to its positive result in the GALACTIC-HF trial, treatment with OM showed other attractive characteristics in a study that treated a wide spectrum of 4,120 patients with HFrEF as well as including 4,112 patients randomized to placebo. Most notably, OM had a very clean safety profile, with adverse event rates similar to placebo patients across all adverse event subtypes, as well as causing no drop in blood pressure and actually an average 2.0–mm Hg increase in systolic blood pressure, no increase in potassium, no apparent impact on renal function, and a small but significant decline in N-terminal pro-B-type natriuretic peptide (NT-proBNP) compared with placebo.

This coupled with the novel mechanism of action of OM – direct augmentation of cardiac sarcomere function by increasing myosin attachment to actin – suggests that OM can be safely added on top of existing HFrEF treatment to provide an unique and incremental benefit.

“Other heart failure drugs [like beta-blockers and sacubitril-valsartan] lower blood pressure, so what can happen is that clinicians run out of room to add full dosages” when patients’ pressures fall too low, commented Gregory D. Lewis, MD, head of Heart Failure at Massachusetts General Hospital in Boston. He is principle investigator for another OM trial, METEORIC-HF, which is examining the possible impact of the drug on exercise capacity in a randomized study with about 270 HFrEF patients.

If the METEORIC-HF results can could confirm some of the GALACTIC-HF results that suggested improvements in patient function, the combined data could potentially lead to regulatory approval for U.S. marketing of the drug, Dr. Lewis suggested. Results from that study are expected in 2021, he said in an interview.

The GALACTIC-HF results hinted at possible functional improvement after 24 weeks on treatment among patients who required hospitalization as measured by the Kansas City Cardiomyopathy Questionnaire, which measures quality life. However, this difference failed to meet the study’s prespecified definition of a significant effect.

Another intriguing suggestion of focused benefit was in patients with a left ventricular ejection fraction at or below the median in GALACTIC-HF of 28%. In that subgroup, OM treatment was linked with a significant 16% relative reduction in the primary endpoint compared with placebo, while it had no significant effect in the other 50% of patients with higher ejection fractions. (The maximum left ventricular ejection fraction for enrollment was 35%.) This apparent subgroup interaction was statistically significant, reported Dr. Teerlink, a professor of medicine at the University of California, San Francisco, and director of Heart Failure at the San Francisco V.A. Medical Center.

Further analysis of the study data “will provide greater insight into subgroups who may demonstrate greater benefit, such as patients with lower ejection fraction in whom improving cardiac function may have a greater role,” he said. The idea that a drug that improves myocyte function at the molecular level could especially benefit patients with the lowest ejection fractions is “biologically plausible,” Dr. Teerlink said.

This scenario looks reasonable, and could make OM something of a niche drug for at least the near term, said Dr. Mann.

The world’s first myotropic drug

Possibly the most notable aspect of GALACTIC-HF is that it proved the efficacy, modest though it was, of a novel drug mechanism that fulfills a decades-long quest of heart failure researchers: a safe way to improve the heart’s pumping action.

“For years, the heart failure community struggled with treatment to improve cardiac performance, but invariably it ended in disaster by worsening cardiac deaths,” problems that led to abandonment of early inotropic drugs more than a generation ago, noted Dr. Mann.

But a more nuanced approach to inotropic agents recently has emerged from Dr. Teerlink and his associates, built on the premise that the dangers seen years ago related to the calcium modulations they caused. Their new paradigm is that the dangers of these “calcitropic” agents can be sidestepped with different agents that either mediate their effects via myosin, the myotropes like OM, or mitochondrial effects from mitotropic drugs.

The inotrope debacle from the 1990s made that drug-class name “a dirty word that causes fear and loathing in the heart failure community,” observed Dr. Mann. While the term myotrope has not yet really caught on, “If omecamtiv mecarbil starts getting used in routine practice, then I think you’ll start seeing uptake of the term myotrope,” he predicted.

GALACTIC-HF was sponsored by Amgen, Cytokinetics, and Servier, the companies developing omecamtiv mecarbil. Dr. Teerlink has received research support from and been a consultant to Amgen, Cytokinetics, and Servier, as well as Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Medtronic, Merck, and Novartis. Dr. Heidenreich had no disclosures. Dr. Mann is on a steering committee for a trial sponsored by Novartis and has no other commercial disclosures. Dr. Lewis is principal investigator for a trial of omecamtiv mecarbil and has no other commercial disclosures.

mzoler@mdedge.com

On Twitter @mitchelzoler

Omecamtiv mecarbil, a member of the novel myotropic drug class that improves cardiac performance, safely produced a significant but modest improvement in heart failure events or cardiovascular death in a pivotal trial with HFrEF patients, leaving experts unsure about the role this drug could have on top of an already crowded list of four first-line drug classes for this condition.

“It remains to be investigated and discussed where omecamtiv mecarbil fits in” the overall approach to treating patients with heart failure with reduced ejection fraction (HFrEF), commented Paul Heidenreich, MD, designated discussant for the report at the virtual scientific sessions of the American Heart Association.

Room for a fifth HFrEF drug?

In addition to the limited benefit, another question raised by the trial is how OM would perform when used on top of what is now considered standard, quadruple therapy for most HFrEF patients: a beta-blocker, a mineralocorticoid receptor antagonist, sacubitril-valsartan (Entresto), and an agent from the sodium glucose co-transporter 2 (SGLT2) inhibitor class, specifically dapagliflozin (Farxiga) or empagliflozin (Jardiance). During the period when the new OM trial was run, 2017-2019, the SGLT2 inhibitors had not yet been established as a key part of standard HFrEF treatment, and hence fewer than 3% of enrolled patients were on one of these drugs.

Because of this evidence gap, OM “can’t be across the board a fifth drug on top of standard treatment,” based on the new results, cautioned Dr. Heidenreich, a cardiologist and professor of medicine at Stanford (Calif.) University School of Medicine.

The positives of omecamtiv mercarbil

But in addition to its positive result in the GALACTIC-HF trial, treatment with OM showed other attractive characteristics in a study that treated a wide spectrum of 4,120 patients with HFrEF as well as including 4,112 patients randomized to placebo. Most notably, OM had a very clean safety profile, with adverse event rates similar to placebo patients across all adverse event subtypes, as well as causing no drop in blood pressure and actually an average 2.0–mm Hg increase in systolic blood pressure, no increase in potassium, no apparent impact on renal function, and a small but significant decline in N-terminal pro-B-type natriuretic peptide (NT-proBNP) compared with placebo.

This coupled with the novel mechanism of action of OM – direct augmentation of cardiac sarcomere function by increasing myosin attachment to actin – suggests that OM can be safely added on top of existing HFrEF treatment to provide an unique and incremental benefit.

“Other heart failure drugs [like beta-blockers and sacubitril-valsartan] lower blood pressure, so what can happen is that clinicians run out of room to add full dosages” when patients’ pressures fall too low, commented Gregory D. Lewis, MD, head of Heart Failure at Massachusetts General Hospital in Boston. He is principle investigator for another OM trial, METEORIC-HF, which is examining the possible impact of the drug on exercise capacity in a randomized study with about 270 HFrEF patients.

If the METEORIC-HF results can could confirm some of the GALACTIC-HF results that suggested improvements in patient function, the combined data could potentially lead to regulatory approval for U.S. marketing of the drug, Dr. Lewis suggested. Results from that study are expected in 2021, he said in an interview.

The GALACTIC-HF results hinted at possible functional improvement after 24 weeks on treatment among patients who required hospitalization as measured by the Kansas City Cardiomyopathy Questionnaire, which measures quality life. However, this difference failed to meet the study’s prespecified definition of a significant effect.

Another intriguing suggestion of focused benefit was in patients with a left ventricular ejection fraction at or below the median in GALACTIC-HF of 28%. In that subgroup, OM treatment was linked with a significant 16% relative reduction in the primary endpoint compared with placebo, while it had no significant effect in the other 50% of patients with higher ejection fractions. (The maximum left ventricular ejection fraction for enrollment was 35%.) This apparent subgroup interaction was statistically significant, reported Dr. Teerlink, a professor of medicine at the University of California, San Francisco, and director of Heart Failure at the San Francisco V.A. Medical Center.

Further analysis of the study data “will provide greater insight into subgroups who may demonstrate greater benefit, such as patients with lower ejection fraction in whom improving cardiac function may have a greater role,” he said. The idea that a drug that improves myocyte function at the molecular level could especially benefit patients with the lowest ejection fractions is “biologically plausible,” Dr. Teerlink said.

This scenario looks reasonable, and could make OM something of a niche drug for at least the near term, said Dr. Mann.

The world’s first myotropic drug

Possibly the most notable aspect of GALACTIC-HF is that it proved the efficacy, modest though it was, of a novel drug mechanism that fulfills a decades-long quest of heart failure researchers: a safe way to improve the heart’s pumping action.

“For years, the heart failure community struggled with treatment to improve cardiac performance, but invariably it ended in disaster by worsening cardiac deaths,” problems that led to abandonment of early inotropic drugs more than a generation ago, noted Dr. Mann.

But a more nuanced approach to inotropic agents recently has emerged from Dr. Teerlink and his associates, built on the premise that the dangers seen years ago related to the calcium modulations they caused. Their new paradigm is that the dangers of these “calcitropic” agents can be sidestepped with different agents that either mediate their effects via myosin, the myotropes like OM, or mitochondrial effects from mitotropic drugs.

The inotrope debacle from the 1990s made that drug-class name “a dirty word that causes fear and loathing in the heart failure community,” observed Dr. Mann. While the term myotrope has not yet really caught on, “If omecamtiv mecarbil starts getting used in routine practice, then I think you’ll start seeing uptake of the term myotrope,” he predicted.

GALACTIC-HF was sponsored by Amgen, Cytokinetics, and Servier, the companies developing omecamtiv mecarbil. Dr. Teerlink has received research support from and been a consultant to Amgen, Cytokinetics, and Servier, as well as Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Medtronic, Merck, and Novartis. Dr. Heidenreich had no disclosures. Dr. Mann is on a steering committee for a trial sponsored by Novartis and has no other commercial disclosures. Dr. Lewis is principal investigator for a trial of omecamtiv mecarbil and has no other commercial disclosures.

mzoler@mdedge.com

On Twitter @mitchelzoler

Thyroid dysfunction had virtually no independent impact on survival in a retrospective study of nearly 5,000 English patients with chronic heart failure, adding to evidence that subclinical thyroid disorders in these patients requires no special management beyond ongoing monitoring.

Sebastian Kaulitzki/Fotolia

“Although thyroid dysfunction is related to outcome in patients with chronic heart failure, the association disappears when adjustment is made for established prognostic variables, such as age, NT-proBNP [N-terminal of the prohormone brain natriuretic peptide], and [New York Heart Association] class,” wrote Nathan A. Samuel, MBChB, and coauthors in the American Journal of Cardiology.

Results from several earlier studies had shown evidence for reduced survival in heart failure patients with thyroid dysfunction, but in analyses that did not adjust for heart failure severity, such as a 2013 report that used data from the Sudden Cardiac Death in Heart Failure Trial SCD-HeFT. Other studies that adjusted for heart failure severity based on serum level of natriuretic peptides did not show significant associations between thyroid function and mortality, and when those results couple with the new report they together minimize the immediate risk from subclinical thyroid dysfunction faced by heart failure patients, wrote the authors of the new report.

Don’t treat subclinical thyroid dysfunction

“Our results suggest that subclinical thyroid disease has little impact on outcomes, and that we should not treat subclinical hypothyroidism in the expectation of improving outlook,” said Andrew L. Clark, MD, senior author on the new report and professor and head of the department of academic cardiology at Hull (England) York Medical School.

“Both hyper-and hypothyroidism can cause heart failure, so thyroid function should always be checked in patients when they present with heart failure. A small proportion of patients have heart failure that is potentially reversible” with thyroid-directed treatment, Dr. Clark said in an interview.

But “subclinical disease should probably not be treated, although we have not conducted a clinical trial that proves this assertion. We speculate, based on our findings, that such a trial is unlikely to be positive.”

Patients with subclinical thyroid disorders, particularly subclinical hypothyroidism, “need to be followed and treated should they develop clinical disease,” he maintained. “Except in extreme circumstances, such as the handful of patients who might have gross myxedema and may be near coma, thyroid replacement therapy for those [with heart failure] who have clinical hypothyroidism should follow standard lines.”

It is important to monitor thyroid function,” agreed Dr. Samuel, a researcher in the department of academic cardiology at Hull York Medical School. “We found that thyroxine use was most common among patients with hyperthyroidism, suggesting that they were previously hypothyroid and had received inappropriate treatment.”

Confounder adjustment mitigates the thyroid link

The new analysis used data collected from 6,782 consecutive heart failure patients enrolled during 2000-2018 at a community heart failure clinic that serves patients in the region of Hull, England. The researchers identified 4,992 of these patients with confirmed heart failure and adequate data for their analyses, including 2,997 (60%) with heart failure with reduced ejection fraction (HFrEF) and 1,995 (40%) with heart failure with normal ejection fraction (HFnEF, the term used by the authors but often called heart failure with preserved ejection fraction).

Thyroid hormone levels showed that 90% of these patients were euthyroid, 6% were hyperthyroid, and 4% were hypothyroid, rates consistent with prior reports for both the general population and heart failure patients. Only 12 patients (0.2%) had overt hypothyroidism, and fewer that 1% (about 45 patients) had overt hyperthyroidism. Patients averaged about 73 years of age, and during a median 4.6 years of follow-up 58% died.

Both the hypo- and hyperthyroid patients showed significantly higher mortality rates than euthyroid patients in a univariate analysis. But the patients with thyroid dysfunction also had more comorbidities, more severe heart failure symptoms measured by NYHA functional class, and more severe heart failure measured as higher serum levels of NT-proBNP.

In a multivariate analysis that adjusted for these factors, the significant differences disappeared among the entire group of heart failure patients for the outcomes of all-cause mortality, and mortality or hospitalization with heart failure. The multivariate analysis also showed no significant association between higher levels of thyroid-stimulating hormone (TSH) and all-cause death or death plus heart failure hospitalization among the patients with HFrEF.

Among patients with HFnEF, the multivariate adjusted analysis showed a small increase in both mortality and mortality plus hospitalization for heart failure, a 2% rise for each of these two endpoints for each 1 mIU/L increase in TSH, the authors reported. Although the P value for each of these two significant differences among patients with HFnEF was .02, the 95% confidence interval included 1.00 and ranged from 1.00 to 1.04.

The multivariate analysis identified three variables with the strongest associations with all-cause mortality: older age, higher levels of NT-proBNP, and higher NYHA class indicating greater functional impairment.

The results support the hypothesis that “worsening heart failure can lead to down-regulation of thyroid hormone signaling,” the authors suggested. Their study is also “the first to examine the prognostic significance of thyroid dysfunction in a large population of patients with HFnEF.” This analysis showed a “weak but significant association between increasing TSH and both mortality and the composite endpoint in patients with HFnEF.”

“HFnEF is a heterogeneous group of conditions that are difficult to diagnose in many cases. Therefore, future studies are needed to provide further clarity on the effect of thyroid dysfunction in these patients,” Dr. Samuel said.

The study received no commercial funding. Dr. Samuel and Dr. Clark had no disclosures.

mzoler@mdedge.com

SOURCE: Samuel NA et al. Am J Cardiol. 2020 Oct 24. doi: 10.1016/j.amjcard.2020.10.034.

Thyroid dysfunction had virtually no independent impact on survival in a retrospective study of nearly 5,000 English patients with chronic heart failure, adding to evidence that subclinical thyroid disorders in these patients requires no special management beyond ongoing monitoring.

Sebastian Kaulitzki/Fotolia

“Although thyroid dysfunction is related to outcome in patients with chronic heart failure, the association disappears when adjustment is made for established prognostic variables, such as age, NT-proBNP [N-terminal of the prohormone brain natriuretic peptide], and [New York Heart Association] class,” wrote Nathan A. Samuel, MBChB, and coauthors in the American Journal of Cardiology.

Results from several earlier studies had shown evidence for reduced survival in heart failure patients with thyroid dysfunction, but in analyses that did not adjust for heart failure severity, such as a 2013 report that used data from the Sudden Cardiac Death in Heart Failure Trial SCD-HeFT. Other studies that adjusted for heart failure severity based on serum level of natriuretic peptides did not show significant associations between thyroid function and mortality, and when those results couple with the new report they together minimize the immediate risk from subclinical thyroid dysfunction faced by heart failure patients, wrote the authors of the new report.

Don’t treat subclinical thyroid dysfunction

“Our results suggest that subclinical thyroid disease has little impact on outcomes, and that we should not treat subclinical hypothyroidism in the expectation of improving outlook,” said Andrew L. Clark, MD, senior author on the new report and professor and head of the department of academic cardiology at Hull (England) York Medical School.

“Both hyper-and hypothyroidism can cause heart failure, so thyroid function should always be checked in patients when they present with heart failure. A small proportion of patients have heart failure that is potentially reversible” with thyroid-directed treatment, Dr. Clark said in an interview.

But “subclinical disease should probably not be treated, although we have not conducted a clinical trial that proves this assertion. We speculate, based on our findings, that such a trial is unlikely to be positive.”

Patients with subclinical thyroid disorders, particularly subclinical hypothyroidism, “need to be followed and treated should they develop clinical disease,” he maintained. “Except in extreme circumstances, such as the handful of patients who might have gross myxedema and may be near coma, thyroid replacement therapy for those [with heart failure] who have clinical hypothyroidism should follow standard lines.”

It is important to monitor thyroid function,” agreed Dr. Samuel, a researcher in the department of academic cardiology at Hull York Medical School. “We found that thyroxine use was most common among patients with hyperthyroidism, suggesting that they were previously hypothyroid and had received inappropriate treatment.”

Confounder adjustment mitigates the thyroid link

The new analysis used data collected from 6,782 consecutive heart failure patients enrolled during 2000-2018 at a community heart failure clinic that serves patients in the region of Hull, England. The researchers identified 4,992 of these patients with confirmed heart failure and adequate data for their analyses, including 2,997 (60%) with heart failure with reduced ejection fraction (HFrEF) and 1,995 (40%) with heart failure with normal ejection fraction (HFnEF, the term used by the authors but often called heart failure with preserved ejection fraction).

Thyroid hormone levels showed that 90% of these patients were euthyroid, 6% were hyperthyroid, and 4% were hypothyroid, rates consistent with prior reports for both the general population and heart failure patients. Only 12 patients (0.2%) had overt hypothyroidism, and fewer that 1% (about 45 patients) had overt hyperthyroidism. Patients averaged about 73 years of age, and during a median 4.6 years of follow-up 58% died.

Both the hypo- and hyperthyroid patients showed significantly higher mortality rates than euthyroid patients in a univariate analysis. But the patients with thyroid dysfunction also had more comorbidities, more severe heart failure symptoms measured by NYHA functional class, and more severe heart failure measured as higher serum levels of NT-proBNP.

In a multivariate analysis that adjusted for these factors, the significant differences disappeared among the entire group of heart failure patients for the outcomes of all-cause mortality, and mortality or hospitalization with heart failure. The multivariate analysis also showed no significant association between higher levels of thyroid-stimulating hormone (TSH) and all-cause death or death plus heart failure hospitalization among the patients with HFrEF.

Among patients with HFnEF, the multivariate adjusted analysis showed a small increase in both mortality and mortality plus hospitalization for heart failure, a 2% rise for each of these two endpoints for each 1 mIU/L increase in TSH, the authors reported. Although the P value for each of these two significant differences among patients with HFnEF was .02, the 95% confidence interval included 1.00 and ranged from 1.00 to 1.04.

The multivariate analysis identified three variables with the strongest associations with all-cause mortality: older age, higher levels of NT-proBNP, and higher NYHA class indicating greater functional impairment.

The results support the hypothesis that “worsening heart failure can lead to down-regulation of thyroid hormone signaling,” the authors suggested. Their study is also “the first to examine the prognostic significance of thyroid dysfunction in a large population of patients with HFnEF.” This analysis showed a “weak but significant association between increasing TSH and both mortality and the composite endpoint in patients with HFnEF.”

“HFnEF is a heterogeneous group of conditions that are difficult to diagnose in many cases. Therefore, future studies are needed to provide further clarity on the effect of thyroid dysfunction in these patients,” Dr. Samuel said.

The study received no commercial funding. Dr. Samuel and Dr. Clark had no disclosures.

mzoler@mdedge.com

SOURCE: Samuel NA et al. Am J Cardiol. 2020 Oct 24. doi: 10.1016/j.amjcard.2020.10.034.

Thyroid dysfunction had virtually no independent impact on survival in a retrospective study of nearly 5,000 English patients with chronic heart failure, adding to evidence that subclinical thyroid disorders in these patients requires no special management beyond ongoing monitoring.

Sebastian Kaulitzki/Fotolia

“Although thyroid dysfunction is related to outcome in patients with chronic heart failure, the association disappears when adjustment is made for established prognostic variables, such as age, NT-proBNP [N-terminal of the prohormone brain natriuretic peptide], and [New York Heart Association] class,” wrote Nathan A. Samuel, MBChB, and coauthors in the American Journal of Cardiology.

Results from several earlier studies had shown evidence for reduced survival in heart failure patients with thyroid dysfunction, but in analyses that did not adjust for heart failure severity, such as a 2013 report that used data from the Sudden Cardiac Death in Heart Failure Trial SCD-HeFT. Other studies that adjusted for heart failure severity based on serum level of natriuretic peptides did not show significant associations between thyroid function and mortality, and when those results couple with the new report they together minimize the immediate risk from subclinical thyroid dysfunction faced by heart failure patients, wrote the authors of the new report.

Don’t treat subclinical thyroid dysfunction

“Our results suggest that subclinical thyroid disease has little impact on outcomes, and that we should not treat subclinical hypothyroidism in the expectation of improving outlook,” said Andrew L. Clark, MD, senior author on the new report and professor and head of the department of academic cardiology at Hull (England) York Medical School.

“Both hyper-and hypothyroidism can cause heart failure, so thyroid function should always be checked in patients when they present with heart failure. A small proportion of patients have heart failure that is potentially reversible” with thyroid-directed treatment, Dr. Clark said in an interview.

But “subclinical disease should probably not be treated, although we have not conducted a clinical trial that proves this assertion. We speculate, based on our findings, that such a trial is unlikely to be positive.”

Patients with subclinical thyroid disorders, particularly subclinical hypothyroidism, “need to be followed and treated should they develop clinical disease,” he maintained. “Except in extreme circumstances, such as the handful of patients who might have gross myxedema and may be near coma, thyroid replacement therapy for those [with heart failure] who have clinical hypothyroidism should follow standard lines.”

It is important to monitor thyroid function,” agreed Dr. Samuel, a researcher in the department of academic cardiology at Hull York Medical School. “We found that thyroxine use was most common among patients with hyperthyroidism, suggesting that they were previously hypothyroid and had received inappropriate treatment.”

Confounder adjustment mitigates the thyroid link

The new analysis used data collected from 6,782 consecutive heart failure patients enrolled during 2000-2018 at a community heart failure clinic that serves patients in the region of Hull, England. The researchers identified 4,992 of these patients with confirmed heart failure and adequate data for their analyses, including 2,997 (60%) with heart failure with reduced ejection fraction (HFrEF) and 1,995 (40%) with heart failure with normal ejection fraction (HFnEF, the term used by the authors but often called heart failure with preserved ejection fraction).

Thyroid hormone levels showed that 90% of these patients were euthyroid, 6% were hyperthyroid, and 4% were hypothyroid, rates consistent with prior reports for both the general population and heart failure patients. Only 12 patients (0.2%) had overt hypothyroidism, and fewer that 1% (about 45 patients) had overt hyperthyroidism. Patients averaged about 73 years of age, and during a median 4.6 years of follow-up 58% died.

Both the hypo- and hyperthyroid patients showed significantly higher mortality rates than euthyroid patients in a univariate analysis. But the patients with thyroid dysfunction also had more comorbidities, more severe heart failure symptoms measured by NYHA functional class, and more severe heart failure measured as higher serum levels of NT-proBNP.

In a multivariate analysis that adjusted for these factors, the significant differences disappeared among the entire group of heart failure patients for the outcomes of all-cause mortality, and mortality or hospitalization with heart failure. The multivariate analysis also showed no significant association between higher levels of thyroid-stimulating hormone (TSH) and all-cause death or death plus heart failure hospitalization among the patients with HFrEF.

Among patients with HFnEF, the multivariate adjusted analysis showed a small increase in both mortality and mortality plus hospitalization for heart failure, a 2% rise for each of these two endpoints for each 1 mIU/L increase in TSH, the authors reported. Although the P value for each of these two significant differences among patients with HFnEF was .02, the 95% confidence interval included 1.00 and ranged from 1.00 to 1.04.

The multivariate analysis identified three variables with the strongest associations with all-cause mortality: older age, higher levels of NT-proBNP, and higher NYHA class indicating greater functional impairment.

The results support the hypothesis that “worsening heart failure can lead to down-regulation of thyroid hormone signaling,” the authors suggested. Their study is also “the first to examine the prognostic significance of thyroid dysfunction in a large population of patients with HFnEF.” This analysis showed a “weak but significant association between increasing TSH and both mortality and the composite endpoint in patients with HFnEF.”

“HFnEF is a heterogeneous group of conditions that are difficult to diagnose in many cases. Therefore, future studies are needed to provide further clarity on the effect of thyroid dysfunction in these patients,” Dr. Samuel said.

The study received no commercial funding. Dr. Samuel and Dr. Clark had no disclosures.

mzoler@mdedge.com

SOURCE: Samuel NA et al. Am J Cardiol. 2020 Oct 24. doi: 10.1016/j.amjcard.2020.10.034.

The latest recommendations from sports cardiologists on getting athletes with COVID-19 back on the playing field safely emphasize a more judicious approach to screening for cardiac injury.

The new recommendations, made by the American College of Cardiology’s Sports and Exercise Cardiology Section, are for adult athletes in competitive sports and also for two important groups: younger athletes taking part in competitive high school sports and older athletes aged 35 and older, the Masters athletes, who continue to be active throughout their lives. The document was published online in JAMA Cardiology.

Because of the evolving nature of knowledge about COVID-19, updates on recommendations for safe return to play for athletes of all ages will continue to be made, senior author Aaron L. Baggish, MD, director of the cardiovascular performance program at Massachusetts General Hospital, Boston, said.

“The recommendations we released in May were entirely based on our experience taking care of hospitalized patients with COVID-19; we had no athletes in this population. We used a lot of conservative guesswork around how this would apply to otherwise healthy athletes,” Dr. Baggish said in an interview.

“But as sports started to open up, and we started to see large numbers of first professional and then college athletes come back into training, we realized that we needed to stop and ask whether the recommendations we put forward back in May were still appropriate,” Dr. Baggish said.

“Once we started to actually get into the trenches with these athletes, literally hundreds of them, and applying the testing strategies that we had initially recommended in everybody, we realized that we probably had some room for improvement, and that’s why we reconvened, to make these revisions,” he said.

Essentially, the recommendations now urge less cardiac testing. “Cardiac injury is not as common as we may have originally thought,” said Dr. Baggish.

“In the early days of COVID, people who were hospitalized had evidence of heart injury, and so we wondered if that prevalence would also be applicable to otherwise young, healthy people who got COVID. If that had been the case, we would have been in big trouble with respect to getting people back into sports. So this is why we started with a conservative screening approach and a lot of testing in order to not miss a huge burden of disease,” he said.

“But what we’ve learned over the past few months is that young people who get either asymptomatic or mild infection appear to have very, very low risk of having associated heart injury, so the need for testing in that population, when people who have infections recover fully, is almost certainly not going to be high yield,” Dr. Baggish said.
 

First iteration of the recommendations

Published in May in the early weeks of the pandemic, the first recommendations for safe return to play said that all athletes should stop training for at least 2 weeks after their symptoms resolve, then undergo “careful, clinical cardiovascular evaluation in combination with cardiac biomarkers and imaging.”

Additional testing with cardiac MRI, exercise testing, or ambulatory rhythm monitoring was to be done “based on the clinical course and initial testing.”

But experts caution that monitoring on such a scale in everyone is unnecessary and could even be counterproductive.

“Sending young athletes for extensive testing is not warranted and could send them to unnecessary testing, cardiac imaging, and so on,” Dr. Baggish said.

Only those athletes who continue to have symptoms or whose symptoms return when they get back to their athletic activities should go on for more screening.

“There, in essence, is the single main change from May, and that is a move away from screening with testing everyone, [and instead] confining that to the people who had moderate or greater severity disease,” he said.

Both iterations of the recommendations end with the same message.

“We are at the beginning of our knowledge about the cardiotoxic effects of COVID-19 but we are gathering evidence every day,” said Dr. Baggish. “Just as they did earlier, we acknowledge that our approaches are subject to change when we learn more about how COVID affects the heart, and specifically the hearts of athletes. This will be an ongoing process.”
 

Something to lean on

The recommendations are welcome, said James E. Udelson, MD, chief of the division of cardiology at Tufts Medical Center, Boston, coauthor of an accompanying editorial.

“It was a bit of the wild west out there, because each university, each college, all with good intentions, had been all struggling to figure out what to do, and how much to do. Probably the most important message from this new paper is the fact that now there is something out there that all coaches, athletes, families, schools, trainers can get some guidance from,” Dr. Udelson said in an interview.

Refining the cardiac screening criteria was a necessary step, Dr. Udelson said.

“How much cardiac imaging do you do? That is a matter of controversy,” said Dr. Udelson, who coauthored the commentary with Tufts cardiologist Ethan Rowin, MD, and Michael A. Curtis, MEd, a certified strength and conditioning specialist at the University of Virginia, Charlottesville. “The problem is that if you use a very sensitive imaging test on a lot of people, sometimes you find things that you really didn’t need to know about. They’re really not important. And now, the athlete is told he or she cannot play for 3 months because they might have myocarditis.

“Should we be too sensitive, meaning do we want to pick up anything no matter whether it’s important or not?” he added. “There will be a lot of false positives, and we are going to disqualify a lot of people. Or do you tune it a different way?”

Dr. Udelson said he would like to see commercial sports donate money to support research into the potential cardiotoxicity of COVID-19.

“If the organizations that benefit from these athletes, like the National Collegiate Athletic Association and professional sports leagues, can fund some of this research, that would be a huge help,” Dr. Udelson said.

“These are the top sports cardiologists in the country, and they have to start somewhere, and these are all based on what we know right now, as well as their own extensive experience. We all know that we are just at the beginning of our knowledge of this. But we have to have something to guide this huge community out there that is really thirsty for help.”

Dr. Baggish reports receiving research funding for the study of athletes in competitive sports from the National Heart, Lung, and Blood Institute; the National Football League Players Association; and the American Heart Association and receiving compensation for his role as team cardiologist from the US Olympic Committee/US Olympic Training Centers, US Soccer, US Rowing, the New England Patriots, the Boston Bruins, the New England Revolution, and Harvard University. Dr. Udelson has disclosed no relevant financial relationships.
 

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

The latest recommendations from sports cardiologists on getting athletes with COVID-19 back on the playing field safely emphasize a more judicious approach to screening for cardiac injury.

The new recommendations, made by the American College of Cardiology’s Sports and Exercise Cardiology Section, are for adult athletes in competitive sports and also for two important groups: younger athletes taking part in competitive high school sports and older athletes aged 35 and older, the Masters athletes, who continue to be active throughout their lives. The document was published online in JAMA Cardiology.

Because of the evolving nature of knowledge about COVID-19, updates on recommendations for safe return to play for athletes of all ages will continue to be made, senior author Aaron L. Baggish, MD, director of the cardiovascular performance program at Massachusetts General Hospital, Boston, said.

“The recommendations we released in May were entirely based on our experience taking care of hospitalized patients with COVID-19; we had no athletes in this population. We used a lot of conservative guesswork around how this would apply to otherwise healthy athletes,” Dr. Baggish said in an interview.

“But as sports started to open up, and we started to see large numbers of first professional and then college athletes come back into training, we realized that we needed to stop and ask whether the recommendations we put forward back in May were still appropriate,” Dr. Baggish said.

“Once we started to actually get into the trenches with these athletes, literally hundreds of them, and applying the testing strategies that we had initially recommended in everybody, we realized that we probably had some room for improvement, and that’s why we reconvened, to make these revisions,” he said.

Essentially, the recommendations now urge less cardiac testing. “Cardiac injury is not as common as we may have originally thought,” said Dr. Baggish.

“In the early days of COVID, people who were hospitalized had evidence of heart injury, and so we wondered if that prevalence would also be applicable to otherwise young, healthy people who got COVID. If that had been the case, we would have been in big trouble with respect to getting people back into sports. So this is why we started with a conservative screening approach and a lot of testing in order to not miss a huge burden of disease,” he said.

“But what we’ve learned over the past few months is that young people who get either asymptomatic or mild infection appear to have very, very low risk of having associated heart injury, so the need for testing in that population, when people who have infections recover fully, is almost certainly not going to be high yield,” Dr. Baggish said.
 

First iteration of the recommendations

Published in May in the early weeks of the pandemic, the first recommendations for safe return to play said that all athletes should stop training for at least 2 weeks after their symptoms resolve, then undergo “careful, clinical cardiovascular evaluation in combination with cardiac biomarkers and imaging.”

Additional testing with cardiac MRI, exercise testing, or ambulatory rhythm monitoring was to be done “based on the clinical course and initial testing.”

But experts caution that monitoring on such a scale in everyone is unnecessary and could even be counterproductive.

“Sending young athletes for extensive testing is not warranted and could send them to unnecessary testing, cardiac imaging, and so on,” Dr. Baggish said.

Only those athletes who continue to have symptoms or whose symptoms return when they get back to their athletic activities should go on for more screening.

“There, in essence, is the single main change from May, and that is a move away from screening with testing everyone, [and instead] confining that to the people who had moderate or greater severity disease,” he said.

Both iterations of the recommendations end with the same message.

“We are at the beginning of our knowledge about the cardiotoxic effects of COVID-19 but we are gathering evidence every day,” said Dr. Baggish. “Just as they did earlier, we acknowledge that our approaches are subject to change when we learn more about how COVID affects the heart, and specifically the hearts of athletes. This will be an ongoing process.”
 

Something to lean on

The recommendations are welcome, said James E. Udelson, MD, chief of the division of cardiology at Tufts Medical Center, Boston, coauthor of an accompanying editorial.

“It was a bit of the wild west out there, because each university, each college, all with good intentions, had been all struggling to figure out what to do, and how much to do. Probably the most important message from this new paper is the fact that now there is something out there that all coaches, athletes, families, schools, trainers can get some guidance from,” Dr. Udelson said in an interview.

Refining the cardiac screening criteria was a necessary step, Dr. Udelson said.

“How much cardiac imaging do you do? That is a matter of controversy,” said Dr. Udelson, who coauthored the commentary with Tufts cardiologist Ethan Rowin, MD, and Michael A. Curtis, MEd, a certified strength and conditioning specialist at the University of Virginia, Charlottesville. “The problem is that if you use a very sensitive imaging test on a lot of people, sometimes you find things that you really didn’t need to know about. They’re really not important. And now, the athlete is told he or she cannot play for 3 months because they might have myocarditis.

“Should we be too sensitive, meaning do we want to pick up anything no matter whether it’s important or not?” he added. “There will be a lot of false positives, and we are going to disqualify a lot of people. Or do you tune it a different way?”

Dr. Udelson said he would like to see commercial sports donate money to support research into the potential cardiotoxicity of COVID-19.

“If the organizations that benefit from these athletes, like the National Collegiate Athletic Association and professional sports leagues, can fund some of this research, that would be a huge help,” Dr. Udelson said.

“These are the top sports cardiologists in the country, and they have to start somewhere, and these are all based on what we know right now, as well as their own extensive experience. We all know that we are just at the beginning of our knowledge of this. But we have to have something to guide this huge community out there that is really thirsty for help.”

Dr. Baggish reports receiving research funding for the study of athletes in competitive sports from the National Heart, Lung, and Blood Institute; the National Football League Players Association; and the American Heart Association and receiving compensation for his role as team cardiologist from the US Olympic Committee/US Olympic Training Centers, US Soccer, US Rowing, the New England Patriots, the Boston Bruins, the New England Revolution, and Harvard University. Dr. Udelson has disclosed no relevant financial relationships.
 

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

The latest recommendations from sports cardiologists on getting athletes with COVID-19 back on the playing field safely emphasize a more judicious approach to screening for cardiac injury.

The new recommendations, made by the American College of Cardiology’s Sports and Exercise Cardiology Section, are for adult athletes in competitive sports and also for two important groups: younger athletes taking part in competitive high school sports and older athletes aged 35 and older, the Masters athletes, who continue to be active throughout their lives. The document was published online in JAMA Cardiology.

Because of the evolving nature of knowledge about COVID-19, updates on recommendations for safe return to play for athletes of all ages will continue to be made, senior author Aaron L. Baggish, MD, director of the cardiovascular performance program at Massachusetts General Hospital, Boston, said.

“The recommendations we released in May were entirely based on our experience taking care of hospitalized patients with COVID-19; we had no athletes in this population. We used a lot of conservative guesswork around how this would apply to otherwise healthy athletes,” Dr. Baggish said in an interview.

“But as sports started to open up, and we started to see large numbers of first professional and then college athletes come back into training, we realized that we needed to stop and ask whether the recommendations we put forward back in May were still appropriate,” Dr. Baggish said.

“Once we started to actually get into the trenches with these athletes, literally hundreds of them, and applying the testing strategies that we had initially recommended in everybody, we realized that we probably had some room for improvement, and that’s why we reconvened, to make these revisions,” he said.

Essentially, the recommendations now urge less cardiac testing. “Cardiac injury is not as common as we may have originally thought,” said Dr. Baggish.

“In the early days of COVID, people who were hospitalized had evidence of heart injury, and so we wondered if that prevalence would also be applicable to otherwise young, healthy people who got COVID. If that had been the case, we would have been in big trouble with respect to getting people back into sports. So this is why we started with a conservative screening approach and a lot of testing in order to not miss a huge burden of disease,” he said.

“But what we’ve learned over the past few months is that young people who get either asymptomatic or mild infection appear to have very, very low risk of having associated heart injury, so the need for testing in that population, when people who have infections recover fully, is almost certainly not going to be high yield,” Dr. Baggish said.
 

First iteration of the recommendations

Published in May in the early weeks of the pandemic, the first recommendations for safe return to play said that all athletes should stop training for at least 2 weeks after their symptoms resolve, then undergo “careful, clinical cardiovascular evaluation in combination with cardiac biomarkers and imaging.”

Additional testing with cardiac MRI, exercise testing, or ambulatory rhythm monitoring was to be done “based on the clinical course and initial testing.”

But experts caution that monitoring on such a scale in everyone is unnecessary and could even be counterproductive.

“Sending young athletes for extensive testing is not warranted and could send them to unnecessary testing, cardiac imaging, and so on,” Dr. Baggish said.

Only those athletes who continue to have symptoms or whose symptoms return when they get back to their athletic activities should go on for more screening.

“There, in essence, is the single main change from May, and that is a move away from screening with testing everyone, [and instead] confining that to the people who had moderate or greater severity disease,” he said.

Both iterations of the recommendations end with the same message.

“We are at the beginning of our knowledge about the cardiotoxic effects of COVID-19 but we are gathering evidence every day,” said Dr. Baggish. “Just as they did earlier, we acknowledge that our approaches are subject to change when we learn more about how COVID affects the heart, and specifically the hearts of athletes. This will be an ongoing process.”
 

Something to lean on

The recommendations are welcome, said James E. Udelson, MD, chief of the division of cardiology at Tufts Medical Center, Boston, coauthor of an accompanying editorial.

“It was a bit of the wild west out there, because each university, each college, all with good intentions, had been all struggling to figure out what to do, and how much to do. Probably the most important message from this new paper is the fact that now there is something out there that all coaches, athletes, families, schools, trainers can get some guidance from,” Dr. Udelson said in an interview.

Refining the cardiac screening criteria was a necessary step, Dr. Udelson said.

“How much cardiac imaging do you do? That is a matter of controversy,” said Dr. Udelson, who coauthored the commentary with Tufts cardiologist Ethan Rowin, MD, and Michael A. Curtis, MEd, a certified strength and conditioning specialist at the University of Virginia, Charlottesville. “The problem is that if you use a very sensitive imaging test on a lot of people, sometimes you find things that you really didn’t need to know about. They’re really not important. And now, the athlete is told he or she cannot play for 3 months because they might have myocarditis.

“Should we be too sensitive, meaning do we want to pick up anything no matter whether it’s important or not?” he added. “There will be a lot of false positives, and we are going to disqualify a lot of people. Or do you tune it a different way?”

Dr. Udelson said he would like to see commercial sports donate money to support research into the potential cardiotoxicity of COVID-19.

“If the organizations that benefit from these athletes, like the National Collegiate Athletic Association and professional sports leagues, can fund some of this research, that would be a huge help,” Dr. Udelson said.

“These are the top sports cardiologists in the country, and they have to start somewhere, and these are all based on what we know right now, as well as their own extensive experience. We all know that we are just at the beginning of our knowledge of this. But we have to have something to guide this huge community out there that is really thirsty for help.”

Dr. Baggish reports receiving research funding for the study of athletes in competitive sports from the National Heart, Lung, and Blood Institute; the National Football League Players Association; and the American Heart Association and receiving compensation for his role as team cardiologist from the US Olympic Committee/US Olympic Training Centers, US Soccer, US Rowing, the New England Patriots, the Boston Bruins, the New England Revolution, and Harvard University. Dr. Udelson has disclosed no relevant financial relationships.
 

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

Nearly half the nation’s hospitals, many of which are still wrestling with the financial fallout of the unexpected coronavirus, will get lower payments for all Medicare patients because of their history of readmitting patients, federal records show.

The penalties are the ninth annual round of the Hospital Readmissions Reduction Program created as part of the Affordable Care Act’s broader effort to improve quality and lower costs. The latest penalties are calculated using each hospital case history between July 2016 and June 2019, so the flood of coronavirus patients that have swamped hospitals this year were not included.

The Centers for Medicare & Medicaid Services announced in September it may suspend the penalty program in the future if the chaos surrounding the pandemic, including the spring’s moratorium on elective surgeries, makes it too difficult to assess hospital performance.

For this year, the penalties remain in effect. Retroactive to the federal fiscal year that began Oct. 1, Medicare will lower a year’s worth of payments to 2,545 hospitals, the data show. The average reduction is 0.69%, with 613 hospitals receiving a penalty of 1% or more.

Out of 5,267 hospitals in the country, Congress has exempted 2,176 from the threat of penalties, either because they are critical access hospitals – defined as the only inpatient facility in an area – or hospitals that specialize in psychiatric patients, children, veterans, rehabilitation or long-term care. Of the 3,080 hospitals CMS evaluated, 83% received a penalty.

The number and severity of penalties were comparable to those of recent years, although the number of hospitals receiving the maximum penalty of 3% dropped from 56 to 39. Because the penalties are applied to new admission payments, the total dollar amount each hospital will lose will not be known until after the fiscal year ends on July 30.

“It’s unfortunate that hospitals will face readmission penalties in fiscal year 2021,” said Akin Demehin, director of policy at the American Hospital Association. “Given the financial strain that hospitals are under, every dollar counts, and the impact of any penalty is significant.”

The penalties are based on readmissions of Medicare patients who initially came to the hospital with diagnoses of congestive heart failure, heart attack, pneumonia, chronic obstructive pulmonary disease, hip or knee replacement, or coronary artery bypass graft surgery. Medicare counts as a readmission any of those patients who ended up back in any hospital within 30 days of discharge, except for planned returns like a second phase of surgery.

A hospital will be penalized if its readmission rate is higher than expected given the national trends in any one of those categories.

The industry has disapproved of the program since its inception, complaining the measures aren’t precise and it unfairly punishes hospitals that treat low-income patients, who often don’t have the resources to ensure their recoveries are successful.

Michael Millenson, a health quality consultant who focuses on patient safety, said the penalties are a useful but imperfect mechanism to push hospitals to improve their care. The designers of the penalty system envisioned it as a way to neutralize the economic benefit hospitals get from readmitted patients under Medicare’s fee-for-service payment model, as they are otherwise paid for two stays instead of just one.

“Every industry complains the penalties are too harsh,” he said. “if you’re going to tell me we don’t need any economic incentives to do the right thing because we’re always doing the right thing – that’s not true.”

KHN (Kaiser Health News) is a nonprofit news service covering health issues. It is an editorially independent program of KFF (Kaiser Family Foundation), which is not affiliated with Kaiser Permanente.

Nearly half the nation’s hospitals, many of which are still wrestling with the financial fallout of the unexpected coronavirus, will get lower payments for all Medicare patients because of their history of readmitting patients, federal records show.

The penalties are the ninth annual round of the Hospital Readmissions Reduction Program created as part of the Affordable Care Act’s broader effort to improve quality and lower costs. The latest penalties are calculated using each hospital case history between July 2016 and June 2019, so the flood of coronavirus patients that have swamped hospitals this year were not included.

The Centers for Medicare & Medicaid Services announced in September it may suspend the penalty program in the future if the chaos surrounding the pandemic, including the spring’s moratorium on elective surgeries, makes it too difficult to assess hospital performance.

For this year, the penalties remain in effect. Retroactive to the federal fiscal year that began Oct. 1, Medicare will lower a year’s worth of payments to 2,545 hospitals, the data show. The average reduction is 0.69%, with 613 hospitals receiving a penalty of 1% or more.

Out of 5,267 hospitals in the country, Congress has exempted 2,176 from the threat of penalties, either because they are critical access hospitals – defined as the only inpatient facility in an area – or hospitals that specialize in psychiatric patients, children, veterans, rehabilitation or long-term care. Of the 3,080 hospitals CMS evaluated, 83% received a penalty.

The number and severity of penalties were comparable to those of recent years, although the number of hospitals receiving the maximum penalty of 3% dropped from 56 to 39. Because the penalties are applied to new admission payments, the total dollar amount each hospital will lose will not be known until after the fiscal year ends on July 30.

“It’s unfortunate that hospitals will face readmission penalties in fiscal year 2021,” said Akin Demehin, director of policy at the American Hospital Association. “Given the financial strain that hospitals are under, every dollar counts, and the impact of any penalty is significant.”

The penalties are based on readmissions of Medicare patients who initially came to the hospital with diagnoses of congestive heart failure, heart attack, pneumonia, chronic obstructive pulmonary disease, hip or knee replacement, or coronary artery bypass graft surgery. Medicare counts as a readmission any of those patients who ended up back in any hospital within 30 days of discharge, except for planned returns like a second phase of surgery.

A hospital will be penalized if its readmission rate is higher than expected given the national trends in any one of those categories.

The industry has disapproved of the program since its inception, complaining the measures aren’t precise and it unfairly punishes hospitals that treat low-income patients, who often don’t have the resources to ensure their recoveries are successful.

Michael Millenson, a health quality consultant who focuses on patient safety, said the penalties are a useful but imperfect mechanism to push hospitals to improve their care. The designers of the penalty system envisioned it as a way to neutralize the economic benefit hospitals get from readmitted patients under Medicare’s fee-for-service payment model, as they are otherwise paid for two stays instead of just one.

“Every industry complains the penalties are too harsh,” he said. “if you’re going to tell me we don’t need any economic incentives to do the right thing because we’re always doing the right thing – that’s not true.”

KHN (Kaiser Health News) is a nonprofit news service covering health issues. It is an editorially independent program of KFF (Kaiser Family Foundation), which is not affiliated with Kaiser Permanente.

Nearly half the nation’s hospitals, many of which are still wrestling with the financial fallout of the unexpected coronavirus, will get lower payments for all Medicare patients because of their history of readmitting patients, federal records show.

The penalties are the ninth annual round of the Hospital Readmissions Reduction Program created as part of the Affordable Care Act’s broader effort to improve quality and lower costs. The latest penalties are calculated using each hospital case history between July 2016 and June 2019, so the flood of coronavirus patients that have swamped hospitals this year were not included.

The Centers for Medicare & Medicaid Services announced in September it may suspend the penalty program in the future if the chaos surrounding the pandemic, including the spring’s moratorium on elective surgeries, makes it too difficult to assess hospital performance.

For this year, the penalties remain in effect. Retroactive to the federal fiscal year that began Oct. 1, Medicare will lower a year’s worth of payments to 2,545 hospitals, the data show. The average reduction is 0.69%, with 613 hospitals receiving a penalty of 1% or more.

Out of 5,267 hospitals in the country, Congress has exempted 2,176 from the threat of penalties, either because they are critical access hospitals – defined as the only inpatient facility in an area – or hospitals that specialize in psychiatric patients, children, veterans, rehabilitation or long-term care. Of the 3,080 hospitals CMS evaluated, 83% received a penalty.

The number and severity of penalties were comparable to those of recent years, although the number of hospitals receiving the maximum penalty of 3% dropped from 56 to 39. Because the penalties are applied to new admission payments, the total dollar amount each hospital will lose will not be known until after the fiscal year ends on July 30.

“It’s unfortunate that hospitals will face readmission penalties in fiscal year 2021,” said Akin Demehin, director of policy at the American Hospital Association. “Given the financial strain that hospitals are under, every dollar counts, and the impact of any penalty is significant.”

The penalties are based on readmissions of Medicare patients who initially came to the hospital with diagnoses of congestive heart failure, heart attack, pneumonia, chronic obstructive pulmonary disease, hip or knee replacement, or coronary artery bypass graft surgery. Medicare counts as a readmission any of those patients who ended up back in any hospital within 30 days of discharge, except for planned returns like a second phase of surgery.

A hospital will be penalized if its readmission rate is higher than expected given the national trends in any one of those categories.

The industry has disapproved of the program since its inception, complaining the measures aren’t precise and it unfairly punishes hospitals that treat low-income patients, who often don’t have the resources to ensure their recoveries are successful.

Michael Millenson, a health quality consultant who focuses on patient safety, said the penalties are a useful but imperfect mechanism to push hospitals to improve their care. The designers of the penalty system envisioned it as a way to neutralize the economic benefit hospitals get from readmitted patients under Medicare’s fee-for-service payment model, as they are otherwise paid for two stays instead of just one.

“Every industry complains the penalties are too harsh,” he said. “if you’re going to tell me we don’t need any economic incentives to do the right thing because we’re always doing the right thing – that’s not true.”

KHN (Kaiser Health News) is a nonprofit news service covering health issues. It is an editorially independent program of KFF (Kaiser Family Foundation), which is not affiliated with Kaiser Permanente.

Patients with mild heart failure who received a cardiac resynchronization device had significantly reduced rates of hospitalizations for heart failure during follow-up of 1,820 patients for an average of 5.6 years, identifying in this post hoc analysis another benefit from this device that patients potentially receive in addition to an established survival advantage.

Extended follow-up of patients enrolled in the MADIT-CRT trial showed that patients with either New York Heart Association (NYHA) class I or II cardiomyopathy who received a cardiac resynchronization device with a defibrillator (CRT-D) had a significant reduction in all-cause hospitalization during follow-up, compared with control patients randomized to receive an implantable cardioverter defibrillator (ICD) device. This reduction in all hospitalizations was specifically driven by a significant reduction in cardiovascular hospitalizations, and the drop in cardiovascular hospitalizations was specifically driven by a cut in hospitalizations for heart failure (HHF), Sabu Thomas, MD, said at the annual scientific meeting of the Heart Failure Society of America.

The data showed that during follow-up all-cause hospitalizations occurred in 73% of the CRT-D patients and 83% of those who received an ICD; cardiovascular hospitalizations happened in 29% of the CRT-D patients and in 43% of those with an ICD; and HHF occurred in 12% of the CRT-D patients and in 22% of those with an ICD, reported Dr. Thomas, a heart failure cardiologist at the University of Rochester (N.Y.) Medical Center. All three between-group differences were statistically significant for these post hoc endpoints.

These reduced hospitalizations also linked with better survival. Patients in the trial database with cardiovascular hospitalizations had a nearly fourfold higher rate of death, compared with nonhospitalized patients, Dr. Thomas said.

The findings “suggest that this device [CRT-D] has sustained benefit in these patients for up to 7 years,” said Dr. Thomas and his collaborator, Valentina Kutyifa, MD, in an interview. “However, this was only seen in patients with left bundle branch block [LBBB].” In patients with non-LBBB, CRT-D was not associated with a reduction in [cardiovascular] hospitalizations.

The LBBB connection

In a multivariate analysis, the 1,281 patients with LBBB (70% of the study cohort) who were more than 6 months out from device placement had a significant 43% relative cut in their incidence of cardiovascular hospitalizations, compared with that of control patients who received an ICD, while the 537 patients with non-LBBB showed no benefit from CRT-D treatment, compared with those who received an ICD, for reducing cardiovascular hospitalizations. (Data from two enrolled patients weren’t available for the analyses.) This finding that the HHF benefit focused in patients with LBBB was consistent with many prior observations that CRT-D was most effective in this patient subgroup.

The researchers also highlighted that their findings apply only to patients with NYHA functional class I or II heart failure with reduced ejection fraction (HFrEF), the only types of patients enrolled in the MADIT-CRT trial (15% had class I disease).

The results also showed that, during the first 6 months on CRT-D treatment, patients with a LBBB showed a significant 43% increase in their cardiovascular hospitalizations, compared with control patients, which may have been driven by device-related events. “We did not investigate this in detail, and it needs more study,” said Dr. Thomas and Dr. Kutyifa, a cardiac electrophysiologist at the University of Rochester.Their new findings extend the initial, prespecified results of the MADIT-CRT (Multicenter Automatic Defibrillator Implantation With Cardiac Resynchronization Therapy) trial, which was designed to examine a primary endpoint of death from any cause or a nonfatal heart failure event. During the initial average follow-up of 2.4 years, patients who received a CRT-D device had a significant relative reduction in this endpoint of 34%, compared with patients on ICD treatment, exclusively in patients with LBBB. Extended follow-up for as long as 7 years of the same cohort showed a continued significant reduction of all-cause death compared with controls, a 41% relative risk reduction, that again was only apparent in patients with LBBB.

The MADIT-CRT findings are generally consistent with prevailing CRT-D recommendations from the American College of Cardiology and American Heart Association from 2013 that give a class I indication (“is indicated”) for using the device in heart failure patients with LBBB, a QRS interval of at least 150 msec, NYHA class II-IV function, and a left ventricular ejection fraction no greater than 35%. A lesser, class IIa recommendation (“can be useful”) exists for patients with a narrower QRS of 120-149 msec with the other class I criteria, and for patients with non-LBBB the recommendation drops to class IIb (“may be considered”).
 

CRT-D ‘is mysterious,’ especially for non-LBBB patients

“Every time researchers have tried to move beyond the [existing] paradigm of who benefits from CRT-D, it’s never panned out,” commented Jeffrey J. Goldberger, MD, an electrophysiologist, professor, and chief of the cardiovascular division at the University of Miami. “The guidelines are pretty correct on who should get CRT-D. I wouldn’t say that no patients with non-LBBB should get it, but they are less likely to benefit,” although he conceded that responses to CRT-D are highly individualized and hard to predict.

“CRT is mysterious. I’ve had patients who did incredibly well on it,” but “once you start getting outside of where the benefits are proven, you start to run into issues,” Dr. Goldberger said in an interview. “The only solid predictor of a CRT-D response is in patients with LBBB.”

The hospitalizations for heart failure that the University of Rochester investigators assessed as an additional study outcome represent an “important endpoint, but one that is much more subjective than survival,” making its reliability “a bit of a gray area,” he said. The analyses are also limited by being post hoc and, hence, just hypothesis generating.

A recently published analysis of the same dataset by many of the same investigators hinted that CRT-D might reduce HHF in non-LBBB patients when the focus is on recurrent hospitalizations.

Despite the evidence of a survival benefit from CRT-D placement in selected patients, especially those with LBBB, “registry data have shown that use of CRT-D varies widely and has been as low as 27% of eligible patients,” noted Dr. Thomas and Dr. Kutyifa. “There is an opportunity here to understand the barriers to more widespread adoption of CRT-D in appropriate patients,” they said. It is also “possible that CRT-D is overused in non-LBBB patients” given that this subgroup receives about a third of CRT-D devices now. “Future studies should carefully investigate the role of CRT-D in non-LBBB patients.”

MADIT-CRT was funded by Boston Scientific, which markets several CRT-D devices. Dr. Thomas had no disclosures. Dr. Kutyifa has been a consultant to Biotronik and Zoll and has received research funding from Biotronik, Boston Scientific, Spire, and Zoll. Dr Goldberger is director of a not-for-profit think tank on risk stratification for sudden cardiac death that has received unrestricted educational grants from Abbott, Biotronik, Boston Scientific, and Medtronic.

mzoler@mdedge.com

SOURCE: Thomas S et al. HFSA 2020, Abstract 019.

Patients with mild heart failure who received a cardiac resynchronization device had significantly reduced rates of hospitalizations for heart failure during follow-up of 1,820 patients for an average of 5.6 years, identifying in this post hoc analysis another benefit from this device that patients potentially receive in addition to an established survival advantage.

Extended follow-up of patients enrolled in the MADIT-CRT trial showed that patients with either New York Heart Association (NYHA) class I or II cardiomyopathy who received a cardiac resynchronization device with a defibrillator (CRT-D) had a significant reduction in all-cause hospitalization during follow-up, compared with control patients randomized to receive an implantable cardioverter defibrillator (ICD) device. This reduction in all hospitalizations was specifically driven by a significant reduction in cardiovascular hospitalizations, and the drop in cardiovascular hospitalizations was specifically driven by a cut in hospitalizations for heart failure (HHF), Sabu Thomas, MD, said at the annual scientific meeting of the Heart Failure Society of America.

The data showed that during follow-up all-cause hospitalizations occurred in 73% of the CRT-D patients and 83% of those who received an ICD; cardiovascular hospitalizations happened in 29% of the CRT-D patients and in 43% of those with an ICD; and HHF occurred in 12% of the CRT-D patients and in 22% of those with an ICD, reported Dr. Thomas, a heart failure cardiologist at the University of Rochester (N.Y.) Medical Center. All three between-group differences were statistically significant for these post hoc endpoints.

These reduced hospitalizations also linked with better survival. Patients in the trial database with cardiovascular hospitalizations had a nearly fourfold higher rate of death, compared with nonhospitalized patients, Dr. Thomas said.

The findings “suggest that this device [CRT-D] has sustained benefit in these patients for up to 7 years,” said Dr. Thomas and his collaborator, Valentina Kutyifa, MD, in an interview. “However, this was only seen in patients with left bundle branch block [LBBB].” In patients with non-LBBB, CRT-D was not associated with a reduction in [cardiovascular] hospitalizations.

The LBBB connection

In a multivariate analysis, the 1,281 patients with LBBB (70% of the study cohort) who were more than 6 months out from device placement had a significant 43% relative cut in their incidence of cardiovascular hospitalizations, compared with that of control patients who received an ICD, while the 537 patients with non-LBBB showed no benefit from CRT-D treatment, compared with those who received an ICD, for reducing cardiovascular hospitalizations. (Data from two enrolled patients weren’t available for the analyses.) This finding that the HHF benefit focused in patients with LBBB was consistent with many prior observations that CRT-D was most effective in this patient subgroup.

The researchers also highlighted that their findings apply only to patients with NYHA functional class I or II heart failure with reduced ejection fraction (HFrEF), the only types of patients enrolled in the MADIT-CRT trial (15% had class I disease).

The results also showed that, during the first 6 months on CRT-D treatment, patients with a LBBB showed a significant 43% increase in their cardiovascular hospitalizations, compared with control patients, which may have been driven by device-related events. “We did not investigate this in detail, and it needs more study,” said Dr. Thomas and Dr. Kutyifa, a cardiac electrophysiologist at the University of Rochester.Their new findings extend the initial, prespecified results of the MADIT-CRT (Multicenter Automatic Defibrillator Implantation With Cardiac Resynchronization Therapy) trial, which was designed to examine a primary endpoint of death from any cause or a nonfatal heart failure event. During the initial average follow-up of 2.4 years, patients who received a CRT-D device had a significant relative reduction in this endpoint of 34%, compared with patients on ICD treatment, exclusively in patients with LBBB. Extended follow-up for as long as 7 years of the same cohort showed a continued significant reduction of all-cause death compared with controls, a 41% relative risk reduction, that again was only apparent in patients with LBBB.

The MADIT-CRT findings are generally consistent with prevailing CRT-D recommendations from the American College of Cardiology and American Heart Association from 2013 that give a class I indication (“is indicated”) for using the device in heart failure patients with LBBB, a QRS interval of at least 150 msec, NYHA class II-IV function, and a left ventricular ejection fraction no greater than 35%. A lesser, class IIa recommendation (“can be useful”) exists for patients with a narrower QRS of 120-149 msec with the other class I criteria, and for patients with non-LBBB the recommendation drops to class IIb (“may be considered”).
 

CRT-D ‘is mysterious,’ especially for non-LBBB patients

“Every time researchers have tried to move beyond the [existing] paradigm of who benefits from CRT-D, it’s never panned out,” commented Jeffrey J. Goldberger, MD, an electrophysiologist, professor, and chief of the cardiovascular division at the University of Miami. “The guidelines are pretty correct on who should get CRT-D. I wouldn’t say that no patients with non-LBBB should get it, but they are less likely to benefit,” although he conceded that responses to CRT-D are highly individualized and hard to predict.

“CRT is mysterious. I’ve had patients who did incredibly well on it,” but “once you start getting outside of where the benefits are proven, you start to run into issues,” Dr. Goldberger said in an interview. “The only solid predictor of a CRT-D response is in patients with LBBB.”

The hospitalizations for heart failure that the University of Rochester investigators assessed as an additional study outcome represent an “important endpoint, but one that is much more subjective than survival,” making its reliability “a bit of a gray area,” he said. The analyses are also limited by being post hoc and, hence, just hypothesis generating.

A recently published analysis of the same dataset by many of the same investigators hinted that CRT-D might reduce HHF in non-LBBB patients when the focus is on recurrent hospitalizations.

Despite the evidence of a survival benefit from CRT-D placement in selected patients, especially those with LBBB, “registry data have shown that use of CRT-D varies widely and has been as low as 27% of eligible patients,” noted Dr. Thomas and Dr. Kutyifa. “There is an opportunity here to understand the barriers to more widespread adoption of CRT-D in appropriate patients,” they said. It is also “possible that CRT-D is overused in non-LBBB patients” given that this subgroup receives about a third of CRT-D devices now. “Future studies should carefully investigate the role of CRT-D in non-LBBB patients.”

MADIT-CRT was funded by Boston Scientific, which markets several CRT-D devices. Dr. Thomas had no disclosures. Dr. Kutyifa has been a consultant to Biotronik and Zoll and has received research funding from Biotronik, Boston Scientific, Spire, and Zoll. Dr Goldberger is director of a not-for-profit think tank on risk stratification for sudden cardiac death that has received unrestricted educational grants from Abbott, Biotronik, Boston Scientific, and Medtronic.

mzoler@mdedge.com

SOURCE: Thomas S et al. HFSA 2020, Abstract 019.

Patients with mild heart failure who received a cardiac resynchronization device had significantly reduced rates of hospitalizations for heart failure during follow-up of 1,820 patients for an average of 5.6 years, identifying in this post hoc analysis another benefit from this device that patients potentially receive in addition to an established survival advantage.

Extended follow-up of patients enrolled in the MADIT-CRT trial showed that patients with either New York Heart Association (NYHA) class I or II cardiomyopathy who received a cardiac resynchronization device with a defibrillator (CRT-D) had a significant reduction in all-cause hospitalization during follow-up, compared with control patients randomized to receive an implantable cardioverter defibrillator (ICD) device. This reduction in all hospitalizations was specifically driven by a significant reduction in cardiovascular hospitalizations, and the drop in cardiovascular hospitalizations was specifically driven by a cut in hospitalizations for heart failure (HHF), Sabu Thomas, MD, said at the annual scientific meeting of the Heart Failure Society of America.

The data showed that during follow-up all-cause hospitalizations occurred in 73% of the CRT-D patients and 83% of those who received an ICD; cardiovascular hospitalizations happened in 29% of the CRT-D patients and in 43% of those with an ICD; and HHF occurred in 12% of the CRT-D patients and in 22% of those with an ICD, reported Dr. Thomas, a heart failure cardiologist at the University of Rochester (N.Y.) Medical Center. All three between-group differences were statistically significant for these post hoc endpoints.

These reduced hospitalizations also linked with better survival. Patients in the trial database with cardiovascular hospitalizations had a nearly fourfold higher rate of death, compared with nonhospitalized patients, Dr. Thomas said.

The findings “suggest that this device [CRT-D] has sustained benefit in these patients for up to 7 years,” said Dr. Thomas and his collaborator, Valentina Kutyifa, MD, in an interview. “However, this was only seen in patients with left bundle branch block [LBBB].” In patients with non-LBBB, CRT-D was not associated with a reduction in [cardiovascular] hospitalizations.

The LBBB connection

In a multivariate analysis, the 1,281 patients with LBBB (70% of the study cohort) who were more than 6 months out from device placement had a significant 43% relative cut in their incidence of cardiovascular hospitalizations, compared with that of control patients who received an ICD, while the 537 patients with non-LBBB showed no benefit from CRT-D treatment, compared with those who received an ICD, for reducing cardiovascular hospitalizations. (Data from two enrolled patients weren’t available for the analyses.) This finding that the HHF benefit focused in patients with LBBB was consistent with many prior observations that CRT-D was most effective in this patient subgroup.

The researchers also highlighted that their findings apply only to patients with NYHA functional class I or II heart failure with reduced ejection fraction (HFrEF), the only types of patients enrolled in the MADIT-CRT trial (15% had class I disease).

The results also showed that, during the first 6 months on CRT-D treatment, patients with a LBBB showed a significant 43% increase in their cardiovascular hospitalizations, compared with control patients, which may have been driven by device-related events. “We did not investigate this in detail, and it needs more study,” said Dr. Thomas and Dr. Kutyifa, a cardiac electrophysiologist at the University of Rochester.Their new findings extend the initial, prespecified results of the MADIT-CRT (Multicenter Automatic Defibrillator Implantation With Cardiac Resynchronization Therapy) trial, which was designed to examine a primary endpoint of death from any cause or a nonfatal heart failure event. During the initial average follow-up of 2.4 years, patients who received a CRT-D device had a significant relative reduction in this endpoint of 34%, compared with patients on ICD treatment, exclusively in patients with LBBB. Extended follow-up for as long as 7 years of the same cohort showed a continued significant reduction of all-cause death compared with controls, a 41% relative risk reduction, that again was only apparent in patients with LBBB.

The MADIT-CRT findings are generally consistent with prevailing CRT-D recommendations from the American College of Cardiology and American Heart Association from 2013 that give a class I indication (“is indicated”) for using the device in heart failure patients with LBBB, a QRS interval of at least 150 msec, NYHA class II-IV function, and a left ventricular ejection fraction no greater than 35%. A lesser, class IIa recommendation (“can be useful”) exists for patients with a narrower QRS of 120-149 msec with the other class I criteria, and for patients with non-LBBB the recommendation drops to class IIb (“may be considered”).
 

CRT-D ‘is mysterious,’ especially for non-LBBB patients

“Every time researchers have tried to move beyond the [existing] paradigm of who benefits from CRT-D, it’s never panned out,” commented Jeffrey J. Goldberger, MD, an electrophysiologist, professor, and chief of the cardiovascular division at the University of Miami. “The guidelines are pretty correct on who should get CRT-D. I wouldn’t say that no patients with non-LBBB should get it, but they are less likely to benefit,” although he conceded that responses to CRT-D are highly individualized and hard to predict.

“CRT is mysterious. I’ve had patients who did incredibly well on it,” but “once you start getting outside of where the benefits are proven, you start to run into issues,” Dr. Goldberger said in an interview. “The only solid predictor of a CRT-D response is in patients with LBBB.”

The hospitalizations for heart failure that the University of Rochester investigators assessed as an additional study outcome represent an “important endpoint, but one that is much more subjective than survival,” making its reliability “a bit of a gray area,” he said. The analyses are also limited by being post hoc and, hence, just hypothesis generating.

A recently published analysis of the same dataset by many of the same investigators hinted that CRT-D might reduce HHF in non-LBBB patients when the focus is on recurrent hospitalizations.

Despite the evidence of a survival benefit from CRT-D placement in selected patients, especially those with LBBB, “registry data have shown that use of CRT-D varies widely and has been as low as 27% of eligible patients,” noted Dr. Thomas and Dr. Kutyifa. “There is an opportunity here to understand the barriers to more widespread adoption of CRT-D in appropriate patients,” they said. It is also “possible that CRT-D is overused in non-LBBB patients” given that this subgroup receives about a third of CRT-D devices now. “Future studies should carefully investigate the role of CRT-D in non-LBBB patients.”

MADIT-CRT was funded by Boston Scientific, which markets several CRT-D devices. Dr. Thomas had no disclosures. Dr. Kutyifa has been a consultant to Biotronik and Zoll and has received research funding from Biotronik, Boston Scientific, Spire, and Zoll. Dr Goldberger is director of a not-for-profit think tank on risk stratification for sudden cardiac death that has received unrestricted educational grants from Abbott, Biotronik, Boston Scientific, and Medtronic.

mzoler@mdedge.com

SOURCE: Thomas S et al. HFSA 2020, Abstract 019.

Safety measures for lab monitoring of mineralocorticoid receptor agonist therapy, performance measures for sacubitril/valsartan, cardiac resynchronization therapy and titration of medications, and quality measures based on patient-reported outcomes are among the updates the joint task force of the American College of Cardiology and the American Heart Association have made to performance and quality measures for managing adults with heart failure.

The revisions, published online Nov. 2 in the Journal of the American College of Cardiology, update the 2011 ACC/AHA heart failure measure set, writing committee vice chair Gregg C. Fonarow, MD, said in an interview. The 2011 measure set predates the 2015 approval of the angiotensin receptor neprilysin inhibitor (ARNI) sacubitril/valsartan for heart failure in adults.
 

Measures stress dosages, strength of evidence

“For the first time the heart failure performance measure sets also focus on not just the use of guideline-recommended medication at any dose, but on utilizing the doses that are evidence-based and guideline recommended so long as they are well tolerated,” said Dr. Fonarow, interim chief of cardiology at the University of California, Los Angeles. “The measure set now includes assessment of patients being treated with doses of medications at 50% or greater of target dose in the absence of contraindications or documented intolerance.”

The update includes seven new performance measures, two quality measures, and one structural measure. The performance measures come from the strongest recommendations – that is, a class of recommendation of 1 (strong) or 3 (no benefit or harmful, process to be avoided) – in the 2017 ACC/AHA/Heart Failure Society of American heart failure guideline update published in Circulation.

In addition to the 2017 update, the writing committee also reviewed existing performance measures. “Those management strategies, diagnostic testing, medications, and devices with the strongest evidence and highest level of guideline recommendations were further considered for inclusion in the performance measure set,” Dr. Fonarow said. “The measures went through extensive review by peer reviewers and approval from the organizations represented.”

Specifically, the update includes measures for monitoring serum potassium after starting mineralocorticoid receptor antagonists therapy, and cardiac resynchronization therapy for patients with heart failure with reduced ejection fraction already on guideline-directed therapy. “This therapy can significantly improve functional capacity and outcomes in appropriately selected patients,” Dr. Fonarow said.
 

New and retired measures

The update adds two performance measures for titration of medications based on dose, either reaching 50% of the recommended dose for a variety of medications, including ARNI, or documenting that the dose wasn’t tolerated for other reason for not using the dose.

The new structural measure calls for facility participation in a heart failure registry. The revised measure set now consists of 18 measures in all.

The update retired one measure from the 2011 set: left ventricular ejection fraction assessment for inpatients. The committee cited its use above 97% as the reason, but LVEF in outpatients remains a measure.

The following tree measures have been revised:

• Patient self-care education has moved from performance measure to quality measure because of concerns about the accuracy of self-care education documentation and limited evidence of improved outcomes with better documentation.
• ACE inhibitor or angiotensin receptor blocker therapy for left ventricular systolic dysfunction adds ARNI therapy to align with the 2017 ACC/AHA/HFSA update.
• Postdischarge appointments shifts from performance to quality measure and include a 7-day limit.

Measures future research should focus on, noted Dr. Fonarow, include the use of sodium glucose cotransporter 2 (SGLT2) inhibitors for heart failure, including in patients without diabetes. “Since the ACC/AHA heart failure guidelines had not yet been updated to recommend these therapies they could not be included in this performance measure set,” he said.

He also said “an urgent need” exists for further research into treatments for heart failure with preserved ejection fraction along with optimal implementation strategies.  

“If these ACC/AHA heart failure performance measures were applied in all settings in which patients with heart failure in the United States are being cared for, and optimal and equitable conformity with each of these measures were achieved, over 100,000 lives a year of patients with heart failure could be saved,” he said. “There’s in an urgent need to measure and improve heart failure care quality.”

Dr. Fonarow reported financial relationships with Abbott, Amgen, AstraZeneca, CHF Solutions, Janssen, Medtronic, Merck, and Novartis.

SOURCE: American College of Cardiology/American Heart Association Task Force on Performance Measures. J Am Coll Cardiol. 2020 Nov 2;76:2527-64.

Safety measures for lab monitoring of mineralocorticoid receptor agonist therapy, performance measures for sacubitril/valsartan, cardiac resynchronization therapy and titration of medications, and quality measures based on patient-reported outcomes are among the updates the joint task force of the American College of Cardiology and the American Heart Association have made to performance and quality measures for managing adults with heart failure.

The revisions, published online Nov. 2 in the Journal of the American College of Cardiology, update the 2011 ACC/AHA heart failure measure set, writing committee vice chair Gregg C. Fonarow, MD, said in an interview. The 2011 measure set predates the 2015 approval of the angiotensin receptor neprilysin inhibitor (ARNI) sacubitril/valsartan for heart failure in adults.
 

Measures stress dosages, strength of evidence

“For the first time the heart failure performance measure sets also focus on not just the use of guideline-recommended medication at any dose, but on utilizing the doses that are evidence-based and guideline recommended so long as they are well tolerated,” said Dr. Fonarow, interim chief of cardiology at the University of California, Los Angeles. “The measure set now includes assessment of patients being treated with doses of medications at 50% or greater of target dose in the absence of contraindications or documented intolerance.”

The update includes seven new performance measures, two quality measures, and one structural measure. The performance measures come from the strongest recommendations – that is, a class of recommendation of 1 (strong) or 3 (no benefit or harmful, process to be avoided) – in the 2017 ACC/AHA/Heart Failure Society of American heart failure guideline update published in Circulation.

In addition to the 2017 update, the writing committee also reviewed existing performance measures. “Those management strategies, diagnostic testing, medications, and devices with the strongest evidence and highest level of guideline recommendations were further considered for inclusion in the performance measure set,” Dr. Fonarow said. “The measures went through extensive review by peer reviewers and approval from the organizations represented.”

Specifically, the update includes measures for monitoring serum potassium after starting mineralocorticoid receptor antagonists therapy, and cardiac resynchronization therapy for patients with heart failure with reduced ejection fraction already on guideline-directed therapy. “This therapy can significantly improve functional capacity and outcomes in appropriately selected patients,” Dr. Fonarow said.
 

New and retired measures

The update adds two performance measures for titration of medications based on dose, either reaching 50% of the recommended dose for a variety of medications, including ARNI, or documenting that the dose wasn’t tolerated for other reason for not using the dose.

The new structural measure calls for facility participation in a heart failure registry. The revised measure set now consists of 18 measures in all.

The update retired one measure from the 2011 set: left ventricular ejection fraction assessment for inpatients. The committee cited its use above 97% as the reason, but LVEF in outpatients remains a measure.

The following tree measures have been revised:

• Patient self-care education has moved from performance measure to quality measure because of concerns about the accuracy of self-care education documentation and limited evidence of improved outcomes with better documentation.
• ACE inhibitor or angiotensin receptor blocker therapy for left ventricular systolic dysfunction adds ARNI therapy to align with the 2017 ACC/AHA/HFSA update.
• Postdischarge appointments shifts from performance to quality measure and include a 7-day limit.

Measures future research should focus on, noted Dr. Fonarow, include the use of sodium glucose cotransporter 2 (SGLT2) inhibitors for heart failure, including in patients without diabetes. “Since the ACC/AHA heart failure guidelines had not yet been updated to recommend these therapies they could not be included in this performance measure set,” he said.

He also said “an urgent need” exists for further research into treatments for heart failure with preserved ejection fraction along with optimal implementation strategies.  

“If these ACC/AHA heart failure performance measures were applied in all settings in which patients with heart failure in the United States are being cared for, and optimal and equitable conformity with each of these measures were achieved, over 100,000 lives a year of patients with heart failure could be saved,” he said. “There’s in an urgent need to measure and improve heart failure care quality.”

Dr. Fonarow reported financial relationships with Abbott, Amgen, AstraZeneca, CHF Solutions, Janssen, Medtronic, Merck, and Novartis.

SOURCE: American College of Cardiology/American Heart Association Task Force on Performance Measures. J Am Coll Cardiol. 2020 Nov 2;76:2527-64.

Safety measures for lab monitoring of mineralocorticoid receptor agonist therapy, performance measures for sacubitril/valsartan, cardiac resynchronization therapy and titration of medications, and quality measures based on patient-reported outcomes are among the updates the joint task force of the American College of Cardiology and the American Heart Association have made to performance and quality measures for managing adults with heart failure.

The revisions, published online Nov. 2 in the Journal of the American College of Cardiology, update the 2011 ACC/AHA heart failure measure set, writing committee vice chair Gregg C. Fonarow, MD, said in an interview. The 2011 measure set predates the 2015 approval of the angiotensin receptor neprilysin inhibitor (ARNI) sacubitril/valsartan for heart failure in adults.
 

Measures stress dosages, strength of evidence

“For the first time the heart failure performance measure sets also focus on not just the use of guideline-recommended medication at any dose, but on utilizing the doses that are evidence-based and guideline recommended so long as they are well tolerated,” said Dr. Fonarow, interim chief of cardiology at the University of California, Los Angeles. “The measure set now includes assessment of patients being treated with doses of medications at 50% or greater of target dose in the absence of contraindications or documented intolerance.”

The update includes seven new performance measures, two quality measures, and one structural measure. The performance measures come from the strongest recommendations – that is, a class of recommendation of 1 (strong) or 3 (no benefit or harmful, process to be avoided) – in the 2017 ACC/AHA/Heart Failure Society of American heart failure guideline update published in Circulation.

In addition to the 2017 update, the writing committee also reviewed existing performance measures. “Those management strategies, diagnostic testing, medications, and devices with the strongest evidence and highest level of guideline recommendations were further considered for inclusion in the performance measure set,” Dr. Fonarow said. “The measures went through extensive review by peer reviewers and approval from the organizations represented.”

Specifically, the update includes measures for monitoring serum potassium after starting mineralocorticoid receptor antagonists therapy, and cardiac resynchronization therapy for patients with heart failure with reduced ejection fraction already on guideline-directed therapy. “This therapy can significantly improve functional capacity and outcomes in appropriately selected patients,” Dr. Fonarow said.
 

New and retired measures

The update adds two performance measures for titration of medications based on dose, either reaching 50% of the recommended dose for a variety of medications, including ARNI, or documenting that the dose wasn’t tolerated for other reason for not using the dose.

The new structural measure calls for facility participation in a heart failure registry. The revised measure set now consists of 18 measures in all.

The update retired one measure from the 2011 set: left ventricular ejection fraction assessment for inpatients. The committee cited its use above 97% as the reason, but LVEF in outpatients remains a measure.

The following tree measures have been revised:

• Patient self-care education has moved from performance measure to quality measure because of concerns about the accuracy of self-care education documentation and limited evidence of improved outcomes with better documentation.
• ACE inhibitor or angiotensin receptor blocker therapy for left ventricular systolic dysfunction adds ARNI therapy to align with the 2017 ACC/AHA/HFSA update.
• Postdischarge appointments shifts from performance to quality measure and include a 7-day limit.

Measures future research should focus on, noted Dr. Fonarow, include the use of sodium glucose cotransporter 2 (SGLT2) inhibitors for heart failure, including in patients without diabetes. “Since the ACC/AHA heart failure guidelines had not yet been updated to recommend these therapies they could not be included in this performance measure set,” he said.

He also said “an urgent need” exists for further research into treatments for heart failure with preserved ejection fraction along with optimal implementation strategies.  

“If these ACC/AHA heart failure performance measures were applied in all settings in which patients with heart failure in the United States are being cared for, and optimal and equitable conformity with each of these measures were achieved, over 100,000 lives a year of patients with heart failure could be saved,” he said. “There’s in an urgent need to measure and improve heart failure care quality.”

Dr. Fonarow reported financial relationships with Abbott, Amgen, AstraZeneca, CHF Solutions, Janssen, Medtronic, Merck, and Novartis.

SOURCE: American College of Cardiology/American Heart Association Task Force on Performance Measures. J Am Coll Cardiol. 2020 Nov 2;76:2527-64.

For patients with diabetic kidney disease, finerenone, an agent from a new class of selective, nonsteroidal mineralocorticoid receptor antagonists, led to significant reductions in combined adverse renal outcomes and in combined adverse cardiovascular outcomes in the pivotal FIDELIO-DKD trial.

And the safety results showed a good level of tolerability. The rate of hyperkalemia was higher with finerenone than with placebo, but the rate of drug discontinuations for elevated potassium was lower than that seen with spironolactone, a steroidal mineralocorticoid receptor antagonist (MRA).

“An ideal drug would cause no hyperkalemia, but the absolute risk we saw is a fraction of what we see with spironolactone in this vulnerable patient population,” said Rajiv Agarwal, MD, from Indiana in Indianapolis, during a press briefing.

After a median follow-up of 2.6 years, finerenone was associated with a 3.4% absolute reduction in the rate of combined adverse renal events, the study’s primary end point, which comprised kidney failure, renal death, and a drop in estimated glomerular filtration rate (eGFR) of at least 40% from baseline. This produced a significant relative risk reduction of 18%, with a number needed to treat of 32 to prevent one of these events, Dr. Agarwal reported at Kidney Week 2020. Findings from the FIDELIO-DKD trial were published simultaneously in the New England Journal of Medicine.

Finerenone was also associated with an absolute 2.4% reduction in the rate of combined adverse cardiovascular events, the study’s “key secondary end point,” which included cardiovascular death, nonfatal MI, nonfatal stroke, and hospitalization for heart failure. This translated into a significant relative risk reduction of 14% and a number needed to treat of 42 to prevent one of these events.

FIDELIO-DKD assessed 5,734 patients with type 2 diabetes and chronic kidney disease from more than 1,000 sites in 48 countries, including the United States, from 2015 to 2018. In the study cohort, average age was slightly more than 65 years, average baseline systolic blood pressure was 138 mm Hg, average duration of diabetes was nearly 17 years, average baseline glycated hemoglobin (A1c) was 7.7%, and fewer than 5% of patients were Black, 25% were Asian, and about 63% were White.
 

A suggestion of less severe hyperkalemia

Finerenone was well tolerated by the participants, and the findings suggest that it caused less clinically meaningful hyperkalemia than spironolactone, the most established and widely used MRA.

Like all MRA drugs, finerenone led to an increase in serum potassium in all patient subgroups – in this case 0.2 mmol/L – unlike placebo, said Dr. Agarwal.

The overall incidence of hyperkalemia was 16% in the 2,827 evaluable patients in the finerenone group and 8% in the 2,831 evaluable patients in the placebo group. Fewer than 10% of patients in the trial received a potassium-binding agent.

The rate of hyperkalemia leading to treatment discontinuation was higher in the finerenone group than in the placebo group (2.3% vs. 0.9%).

That 2.3% rate is 10 times lower than the 23.0% rate of hyperkalemia-related treatment discontinuation in patients who received spironolactone and no potassium-binding agent, said Dr. Agarwal, citing a previous study he was involved with.

He hypothesized that finerenone might cause less clinically meaningful hyperkalemia because it creates no active metabolites that linger in the body, whereas spironolactone produces active metabolites with a half life of about 1 week.

“The risk for hyperkalemia is clearly increased with finerenone compared with placebo, and in the absence of head-to-head studies, it’s hard to know how it compares with spironolactone or eplerenone [Inspra],” the other agents in the MRA class, said Mikhail N. Kosiborod, MD, from the University of Missouri–Kansas City.

“The rates of hyperkalemia observed in FIDELIO-DKD were overall comparable to what we would expect from eplerenone. But the rate of serious hyperkalemia was quite low with finerenone, which is reassuring,” Dr. Kosiborod said in an interview.

And the adverse-effect profile showed that finerenone “is as safe as you could expect from an MRA,” said Janani Rangaswami, MD, from the Einstein Medical Center in Philadelphia.

The rate of hyperkalemia should be interpreted in the context of the high risk the enrolled patients faced, given that they all had moderate to severe diabetic kidney disease with albuminuria and, in some cases, eGFR rates as low as 25 mL/min per 1.73m², she explained. In addition, all patients were on maximally tolerated treatment with either an angiotensin-converting–enzyme inhibitor or an angiotensin receptor blocker to inhibit the renin angiotensin system (RAS).

“Considering this background, it’s a very acceptable adverse-event profile,” Dr. Rangaswami said in an interview.
 

Renal drugs that could work together

More than 99% of patients in FIDELIO-DKD were on an RAS inhibitor, but fewer than 5% were on a sodium glucose cotransporter 2 (SGLT2) inhibitor at baseline, and fewer than 10% started on this drug class during the course of the study.

Despite that, both Dr. Kosiborod and Dr. Rangaswami are enthusiastic about the prospect of using the three drugs in combination to maximize renal and cardiovascular benefits in FIDELIO-DKD–type patients. Recent results from the CREDENCE study of canagliflozin (Invokana) and from the DAPA-CKD study of dapagluflozin (Farxiga) have established SGLT2 inhibitors – at least those two – as key agents for patients with chronic kidney disease.

Dual treatment with an RAS inhibitor and an SGLT2 inhibitor is “clearly established” for patients with diabetic kidney disease, said Dr. Agarwal.

“After CREDENCE, DAPA-CKD, and now FIDELIO-DKD, we need to seriously consider triple therapy as the future of treatment for diabetic kidney disease to prevent both cardiovascular and kidney complications,” said Dr. Kosiborod. The approach will mimic the multidrug therapy that’s now standard for patients with heart failure with reduced ejection fraction (HFrEF). But he cautioned that this triple combination needs further testing.

“Triple therapy will be the standard of care” for patients with diabetic kidney disease, Dr. Rangaswami agreed, but she cautioned that she would not currently expand the target population for finerenone to patients without type 2 diabetes or to patients without the level of albuminuria required for entry into FIDELIO-DKD: at least 30 mg/g of creatinine per day. And patients with HFrEF were excluded from FIDELIO-DKD, so that limitation on finerenone use should remain for the time being, she added.

Dr. Rangaswami said she is optimistic about the potential efficacy of finerenone added to an SGLT2 inhibitor because of the likelihood that the two drug classes work in different but complementary ways. SGLT2 inhibitors seem to exert their renal protective effects largely through hemodynamic effects, whereas it is likely that finerenone exerts its effects largely as an anti-inflammatory and antifibrotic agent, she speculated. The FIDELIO-DKD results appear to rule out any major effect of finerenone on blood pressure lowering because average systolic pressure fell by only about 2 mm Hg in the treatment group.

“The benefits of finerenone for cardiorenal outcomes are substantial and clinically meaningful,” Dr. Kosiborod said. “We cannot assume that other MRAs, such as spironolactone, provide similar benefits,” he cautioned, but the results are “very good news for patients with type 2 diabetes and chronic kidney disease. We now have another effective intervention with a different mechanism of action.”

FIDELIO-DKD was sponsored by Bayer, the company developing finerenone (BAY 94-8862). Dr. Agarwal has been a consultant to and has received honoraria from Bayer and from several other companies. Dr. Kosiborod has been a consultant to Bayer and to AstraZeneca, Boehringer Ingelheim, Jansse, Merck, and Vifor and has received research funding from AstraZeneca and Boehringer Ingelheim. Dr. Rangaswami has disclosed no relevant financial relationships.
 

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

For patients with diabetic kidney disease, finerenone, an agent from a new class of selective, nonsteroidal mineralocorticoid receptor antagonists, led to significant reductions in combined adverse renal outcomes and in combined adverse cardiovascular outcomes in the pivotal FIDELIO-DKD trial.

And the safety results showed a good level of tolerability. The rate of hyperkalemia was higher with finerenone than with placebo, but the rate of drug discontinuations for elevated potassium was lower than that seen with spironolactone, a steroidal mineralocorticoid receptor antagonist (MRA).

“An ideal drug would cause no hyperkalemia, but the absolute risk we saw is a fraction of what we see with spironolactone in this vulnerable patient population,” said Rajiv Agarwal, MD, from Indiana in Indianapolis, during a press briefing.

After a median follow-up of 2.6 years, finerenone was associated with a 3.4% absolute reduction in the rate of combined adverse renal events, the study’s primary end point, which comprised kidney failure, renal death, and a drop in estimated glomerular filtration rate (eGFR) of at least 40% from baseline. This produced a significant relative risk reduction of 18%, with a number needed to treat of 32 to prevent one of these events, Dr. Agarwal reported at Kidney Week 2020. Findings from the FIDELIO-DKD trial were published simultaneously in the New England Journal of Medicine.

Finerenone was also associated with an absolute 2.4% reduction in the rate of combined adverse cardiovascular events, the study’s “key secondary end point,” which included cardiovascular death, nonfatal MI, nonfatal stroke, and hospitalization for heart failure. This translated into a significant relative risk reduction of 14% and a number needed to treat of 42 to prevent one of these events.

FIDELIO-DKD assessed 5,734 patients with type 2 diabetes and chronic kidney disease from more than 1,000 sites in 48 countries, including the United States, from 2015 to 2018. In the study cohort, average age was slightly more than 65 years, average baseline systolic blood pressure was 138 mm Hg, average duration of diabetes was nearly 17 years, average baseline glycated hemoglobin (A1c) was 7.7%, and fewer than 5% of patients were Black, 25% were Asian, and about 63% were White.
 

A suggestion of less severe hyperkalemia

Finerenone was well tolerated by the participants, and the findings suggest that it caused less clinically meaningful hyperkalemia than spironolactone, the most established and widely used MRA.

Like all MRA drugs, finerenone led to an increase in serum potassium in all patient subgroups – in this case 0.2 mmol/L – unlike placebo, said Dr. Agarwal.

The overall incidence of hyperkalemia was 16% in the 2,827 evaluable patients in the finerenone group and 8% in the 2,831 evaluable patients in the placebo group. Fewer than 10% of patients in the trial received a potassium-binding agent.

The rate of hyperkalemia leading to treatment discontinuation was higher in the finerenone group than in the placebo group (2.3% vs. 0.9%).

That 2.3% rate is 10 times lower than the 23.0% rate of hyperkalemia-related treatment discontinuation in patients who received spironolactone and no potassium-binding agent, said Dr. Agarwal, citing a previous study he was involved with.

He hypothesized that finerenone might cause less clinically meaningful hyperkalemia because it creates no active metabolites that linger in the body, whereas spironolactone produces active metabolites with a half life of about 1 week.

“The risk for hyperkalemia is clearly increased with finerenone compared with placebo, and in the absence of head-to-head studies, it’s hard to know how it compares with spironolactone or eplerenone [Inspra],” the other agents in the MRA class, said Mikhail N. Kosiborod, MD, from the University of Missouri–Kansas City.

“The rates of hyperkalemia observed in FIDELIO-DKD were overall comparable to what we would expect from eplerenone. But the rate of serious hyperkalemia was quite low with finerenone, which is reassuring,” Dr. Kosiborod said in an interview.

And the adverse-effect profile showed that finerenone “is as safe as you could expect from an MRA,” said Janani Rangaswami, MD, from the Einstein Medical Center in Philadelphia.

The rate of hyperkalemia should be interpreted in the context of the high risk the enrolled patients faced, given that they all had moderate to severe diabetic kidney disease with albuminuria and, in some cases, eGFR rates as low as 25 mL/min per 1.73m², she explained. In addition, all patients were on maximally tolerated treatment with either an angiotensin-converting–enzyme inhibitor or an angiotensin receptor blocker to inhibit the renin angiotensin system (RAS).

“Considering this background, it’s a very acceptable adverse-event profile,” Dr. Rangaswami said in an interview.
 

Renal drugs that could work together

More than 99% of patients in FIDELIO-DKD were on an RAS inhibitor, but fewer than 5% were on a sodium glucose cotransporter 2 (SGLT2) inhibitor at baseline, and fewer than 10% started on this drug class during the course of the study.

Despite that, both Dr. Kosiborod and Dr. Rangaswami are enthusiastic about the prospect of using the three drugs in combination to maximize renal and cardiovascular benefits in FIDELIO-DKD–type patients. Recent results from the CREDENCE study of canagliflozin (Invokana) and from the DAPA-CKD study of dapagluflozin (Farxiga) have established SGLT2 inhibitors – at least those two – as key agents for patients with chronic kidney disease.

Dual treatment with an RAS inhibitor and an SGLT2 inhibitor is “clearly established” for patients with diabetic kidney disease, said Dr. Agarwal.

“After CREDENCE, DAPA-CKD, and now FIDELIO-DKD, we need to seriously consider triple therapy as the future of treatment for diabetic kidney disease to prevent both cardiovascular and kidney complications,” said Dr. Kosiborod. The approach will mimic the multidrug therapy that’s now standard for patients with heart failure with reduced ejection fraction (HFrEF). But he cautioned that this triple combination needs further testing.

“Triple therapy will be the standard of care” for patients with diabetic kidney disease, Dr. Rangaswami agreed, but she cautioned that she would not currently expand the target population for finerenone to patients without type 2 diabetes or to patients without the level of albuminuria required for entry into FIDELIO-DKD: at least 30 mg/g of creatinine per day. And patients with HFrEF were excluded from FIDELIO-DKD, so that limitation on finerenone use should remain for the time being, she added.

Dr. Rangaswami said she is optimistic about the potential efficacy of finerenone added to an SGLT2 inhibitor because of the likelihood that the two drug classes work in different but complementary ways. SGLT2 inhibitors seem to exert their renal protective effects largely through hemodynamic effects, whereas it is likely that finerenone exerts its effects largely as an anti-inflammatory and antifibrotic agent, she speculated. The FIDELIO-DKD results appear to rule out any major effect of finerenone on blood pressure lowering because average systolic pressure fell by only about 2 mm Hg in the treatment group.

“The benefits of finerenone for cardiorenal outcomes are substantial and clinically meaningful,” Dr. Kosiborod said. “We cannot assume that other MRAs, such as spironolactone, provide similar benefits,” he cautioned, but the results are “very good news for patients with type 2 diabetes and chronic kidney disease. We now have another effective intervention with a different mechanism of action.”

FIDELIO-DKD was sponsored by Bayer, the company developing finerenone (BAY 94-8862). Dr. Agarwal has been a consultant to and has received honoraria from Bayer and from several other companies. Dr. Kosiborod has been a consultant to Bayer and to AstraZeneca, Boehringer Ingelheim, Jansse, Merck, and Vifor and has received research funding from AstraZeneca and Boehringer Ingelheim. Dr. Rangaswami has disclosed no relevant financial relationships.
 

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

For patients with diabetic kidney disease, finerenone, an agent from a new class of selective, nonsteroidal mineralocorticoid receptor antagonists, led to significant reductions in combined adverse renal outcomes and in combined adverse cardiovascular outcomes in the pivotal FIDELIO-DKD trial.

And the safety results showed a good level of tolerability. The rate of hyperkalemia was higher with finerenone than with placebo, but the rate of drug discontinuations for elevated potassium was lower than that seen with spironolactone, a steroidal mineralocorticoid receptor antagonist (MRA).

“An ideal drug would cause no hyperkalemia, but the absolute risk we saw is a fraction of what we see with spironolactone in this vulnerable patient population,” said Rajiv Agarwal, MD, from Indiana in Indianapolis, during a press briefing.

After a median follow-up of 2.6 years, finerenone was associated with a 3.4% absolute reduction in the rate of combined adverse renal events, the study’s primary end point, which comprised kidney failure, renal death, and a drop in estimated glomerular filtration rate (eGFR) of at least 40% from baseline. This produced a significant relative risk reduction of 18%, with a number needed to treat of 32 to prevent one of these events, Dr. Agarwal reported at Kidney Week 2020. Findings from the FIDELIO-DKD trial were published simultaneously in the New England Journal of Medicine.

Finerenone was also associated with an absolute 2.4% reduction in the rate of combined adverse cardiovascular events, the study’s “key secondary end point,” which included cardiovascular death, nonfatal MI, nonfatal stroke, and hospitalization for heart failure. This translated into a significant relative risk reduction of 14% and a number needed to treat of 42 to prevent one of these events.

FIDELIO-DKD assessed 5,734 patients with type 2 diabetes and chronic kidney disease from more than 1,000 sites in 48 countries, including the United States, from 2015 to 2018. In the study cohort, average age was slightly more than 65 years, average baseline systolic blood pressure was 138 mm Hg, average duration of diabetes was nearly 17 years, average baseline glycated hemoglobin (A1c) was 7.7%, and fewer than 5% of patients were Black, 25% were Asian, and about 63% were White.
 

A suggestion of less severe hyperkalemia

Finerenone was well tolerated by the participants, and the findings suggest that it caused less clinically meaningful hyperkalemia than spironolactone, the most established and widely used MRA.

Like all MRA drugs, finerenone led to an increase in serum potassium in all patient subgroups – in this case 0.2 mmol/L – unlike placebo, said Dr. Agarwal.

The overall incidence of hyperkalemia was 16% in the 2,827 evaluable patients in the finerenone group and 8% in the 2,831 evaluable patients in the placebo group. Fewer than 10% of patients in the trial received a potassium-binding agent.

The rate of hyperkalemia leading to treatment discontinuation was higher in the finerenone group than in the placebo group (2.3% vs. 0.9%).

That 2.3% rate is 10 times lower than the 23.0% rate of hyperkalemia-related treatment discontinuation in patients who received spironolactone and no potassium-binding agent, said Dr. Agarwal, citing a previous study he was involved with.

He hypothesized that finerenone might cause less clinically meaningful hyperkalemia because it creates no active metabolites that linger in the body, whereas spironolactone produces active metabolites with a half life of about 1 week.

“The risk for hyperkalemia is clearly increased with finerenone compared with placebo, and in the absence of head-to-head studies, it’s hard to know how it compares with spironolactone or eplerenone [Inspra],” the other agents in the MRA class, said Mikhail N. Kosiborod, MD, from the University of Missouri–Kansas City.

“The rates of hyperkalemia observed in FIDELIO-DKD were overall comparable to what we would expect from eplerenone. But the rate of serious hyperkalemia was quite low with finerenone, which is reassuring,” Dr. Kosiborod said in an interview.

And the adverse-effect profile showed that finerenone “is as safe as you could expect from an MRA,” said Janani Rangaswami, MD, from the Einstein Medical Center in Philadelphia.

The rate of hyperkalemia should be interpreted in the context of the high risk the enrolled patients faced, given that they all had moderate to severe diabetic kidney disease with albuminuria and, in some cases, eGFR rates as low as 25 mL/min per 1.73m², she explained. In addition, all patients were on maximally tolerated treatment with either an angiotensin-converting–enzyme inhibitor or an angiotensin receptor blocker to inhibit the renin angiotensin system (RAS).

“Considering this background, it’s a very acceptable adverse-event profile,” Dr. Rangaswami said in an interview.
 

Renal drugs that could work together

More than 99% of patients in FIDELIO-DKD were on an RAS inhibitor, but fewer than 5% were on a sodium glucose cotransporter 2 (SGLT2) inhibitor at baseline, and fewer than 10% started on this drug class during the course of the study.

Despite that, both Dr. Kosiborod and Dr. Rangaswami are enthusiastic about the prospect of using the three drugs in combination to maximize renal and cardiovascular benefits in FIDELIO-DKD–type patients. Recent results from the CREDENCE study of canagliflozin (Invokana) and from the DAPA-CKD study of dapagluflozin (Farxiga) have established SGLT2 inhibitors – at least those two – as key agents for patients with chronic kidney disease.

Dual treatment with an RAS inhibitor and an SGLT2 inhibitor is “clearly established” for patients with diabetic kidney disease, said Dr. Agarwal.

“After CREDENCE, DAPA-CKD, and now FIDELIO-DKD, we need to seriously consider triple therapy as the future of treatment for diabetic kidney disease to prevent both cardiovascular and kidney complications,” said Dr. Kosiborod. The approach will mimic the multidrug therapy that’s now standard for patients with heart failure with reduced ejection fraction (HFrEF). But he cautioned that this triple combination needs further testing.

“Triple therapy will be the standard of care” for patients with diabetic kidney disease, Dr. Rangaswami agreed, but she cautioned that she would not currently expand the target population for finerenone to patients without type 2 diabetes or to patients without the level of albuminuria required for entry into FIDELIO-DKD: at least 30 mg/g of creatinine per day. And patients with HFrEF were excluded from FIDELIO-DKD, so that limitation on finerenone use should remain for the time being, she added.

Dr. Rangaswami said she is optimistic about the potential efficacy of finerenone added to an SGLT2 inhibitor because of the likelihood that the two drug classes work in different but complementary ways. SGLT2 inhibitors seem to exert their renal protective effects largely through hemodynamic effects, whereas it is likely that finerenone exerts its effects largely as an anti-inflammatory and antifibrotic agent, she speculated. The FIDELIO-DKD results appear to rule out any major effect of finerenone on blood pressure lowering because average systolic pressure fell by only about 2 mm Hg in the treatment group.

“The benefits of finerenone for cardiorenal outcomes are substantial and clinically meaningful,” Dr. Kosiborod said. “We cannot assume that other MRAs, such as spironolactone, provide similar benefits,” he cautioned, but the results are “very good news for patients with type 2 diabetes and chronic kidney disease. We now have another effective intervention with a different mechanism of action.”

FIDELIO-DKD was sponsored by Bayer, the company developing finerenone (BAY 94-8862). Dr. Agarwal has been a consultant to and has received honoraria from Bayer and from several other companies. Dr. Kosiborod has been a consultant to Bayer and to AstraZeneca, Boehringer Ingelheim, Jansse, Merck, and Vifor and has received research funding from AstraZeneca and Boehringer Ingelheim. Dr. Rangaswami has disclosed no relevant financial relationships.
 

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

Many student athletes who test positive for COVID-19 likely can have an uneventful return to their sports after they have rested for 2 weeks in quarantine, doctors suggest.

Canberk Sezer/Getty Images

There are reasons for caution, however, especially when a patient has symptoms that indicate possible cardiac involvement. In these cases, patients should undergo cardiac testing before a physician clears them to return to play, according to guidance from professional associations. Reports of myocarditis in college athletes who tested positive for SARS-CoV-2 but were asymptomatic are among the reasons for concern. Myocarditis may increase the risk of sudden death during exercise.

“The thing that you need to keep in mind is that this is not just a respiratory illness,” David T. Bernhardt, MD, professor of pediatrics, orthopedics, and rehabilitation at the University of Wisconsin in Madison, said in a presentation at the annual meeting of the American Academy of Pediatrics, held virtually this year. High school and college athletes have had cardiac, neurologic, hematologic, and renal problems that “can complicate their recovery and their return to sport.”

Still, children who test positive for COVID-19 tend to have mild illness and often are asymptomatic. “It is more than likely going to be safe for the majority of the student athletes who are in the elementary and middle school age to return to sport,” said Dr. Bernhardt. Given that 18-year-old college freshmen have had cardiac complications, there may be reason for more caution with high school students.
 

Limited data

The AAP has released interim guidance on returning to sports and recommends that primary care physicians clear all patients with COVID-19 before they resume training. Physicians should screen for cardiac symptoms such as chest pain, shortness of breath, fatigue, palpitations, or syncope.

Those with severe illness should be restricted from exercise and participation for 3-6 months. Primary care physicians, preferably in consultation with pediatric cardiologists, should clear athletes who experience severe illness.

“Most of the recommendations come from the fact that we simply do not know what we do not know with COVID-19,” Susannah Briskin, MD, a coauthor of the interim guidance, said in an interview. “We have to be cautious in returning individuals to play and closely monitor them as we learn more about the disease process and its effect on kids.”

Patients with severe illness could include those who were hospitalized and experienced hypotension or arrhythmias, required intubation or extracorporeal membrane oxygenation (ECMO) support, had kidney or cardiac failure, or developed multisystem inflammatory syndrome in children (MIS-C), said Dr. Briskin, a specialist in pediatric sports medicine at Case Western Reserve University, Cleveland.

“The majority of COVID-19 cases will not present like this in kids. We have no idea how common myocarditis is in kids post infection. We do know that, if anyone has chest pain, shortness of breath, excessive fatigue, syncope [passing out], or arrhythmia [feeling of their heart skipping beats], they should undergo further evaluation for myocarditis,” Dr. Briskin said.

Patients who are asymptomatic or have mild symptoms should rest for 14 days after their positive test. After their infectious period has passed, a doctor should assess for any concerning cardiac symptoms. “Anyone with prolonged fever or moderate symptoms should see their pediatrician and have an EKG performed, at a minimum, prior to return to sports,” Dr. Briskin said. “Anyone with an abnormal EKG or concerning signs or symptoms should be referred on to pediatric cardiology for a further assessment.”

Most patients who Dr. Briskin has seen have been asymptomatic or mildly symptomatic. “They have done well with a gradual return to physical activity,” she said. “We recommend a gradual return so individuals can be monitored for any signs or symptoms concerning for myocarditis. The far majority of individuals likely have an uneventful return to play.”

Mitigating risk

COVID-19 adds elements of uncertainty and complexity to the usual process of mitigating risk in sports, Dr. Bernhardt noted in his lecture. “You are dealing with an infection that we do not know a lot about,” he said. “And we are trying to mitigate risk not only for the individual who may or may not have underlying health problems, but you are also trying to mitigate risk for anybody else involved with the sport, including athletic trainers and team physicians, coaches, spectators, custodial staff, people working at a snack shack, and all the other people that can be involved in a typical sporting type of atmosphere.”

When patients do return to play after an illness, they should gradually increase the training load to avoid injury. In addition, clinicians should screen for depression and anxiety using tools such as the Four-Item Patient Health Questionnaire (PHQ-4) when they see patients. “The pandemic has been quite stressful for everybody, including our high school student athletes,” Dr. Bernhardt said. “Giving everybody a PHQ-4 when they come into clinic right now probably makes sense in terms of the stress levels that all of us are experiencing.”

If a patient screens positive, take additional history and refer for more in-depth mental health evaluation and treatment if warranted. Sharing breathing and relaxation exercises, promoting healthy behaviors, and paying attention to unhealthy strategies also may help, Dr. Bernhardt suggested.

Ultimately, determining when an athlete with COVID-19 can be medically cleared to return to play may be a challenge. There are limited data on epidemiology and clinical presentations that could help identify cardiac injury related to the disease, Dr. Bernhardt said. Guidance from the American College of Cardiology provides a framework for evaluating athletes for return to play, and pediatric cardiologists have discussed how the guidance relates to a pediatric population. Cardiac assessments may include measures of biomarkers such as troponin, B-type natriuretic peptide, and sedimentation rate, along with electrocardiograms, echocardiograms, and cardiac MRI.

Beyond return-to-play decisions, encourage the use of cloth face coverings on the sidelines and away from the playing field, and stress proper quarantining, Dr. Briskin added. Too often, she hears about children not quarantining properly. “Individuals with a known exposure should be quarantined in their house – ideally in a separate room from everyone else. ... When they come out of their room, they should wash their hands well and wear a cloth face covering. They should not be eating with other people.”

Dr. Bernhardt had no relevant disclosures.

jremaly@mdedge.com

Many student athletes who test positive for COVID-19 likely can have an uneventful return to their sports after they have rested for 2 weeks in quarantine, doctors suggest.

Canberk Sezer/Getty Images

There are reasons for caution, however, especially when a patient has symptoms that indicate possible cardiac involvement. In these cases, patients should undergo cardiac testing before a physician clears them to return to play, according to guidance from professional associations. Reports of myocarditis in college athletes who tested positive for SARS-CoV-2 but were asymptomatic are among the reasons for concern. Myocarditis may increase the risk of sudden death during exercise.

“The thing that you need to keep in mind is that this is not just a respiratory illness,” David T. Bernhardt, MD, professor of pediatrics, orthopedics, and rehabilitation at the University of Wisconsin in Madison, said in a presentation at the annual meeting of the American Academy of Pediatrics, held virtually this year. High school and college athletes have had cardiac, neurologic, hematologic, and renal problems that “can complicate their recovery and their return to sport.”

Still, children who test positive for COVID-19 tend to have mild illness and often are asymptomatic. “It is more than likely going to be safe for the majority of the student athletes who are in the elementary and middle school age to return to sport,” said Dr. Bernhardt. Given that 18-year-old college freshmen have had cardiac complications, there may be reason for more caution with high school students.
 

Limited data

The AAP has released interim guidance on returning to sports and recommends that primary care physicians clear all patients with COVID-19 before they resume training. Physicians should screen for cardiac symptoms such as chest pain, shortness of breath, fatigue, palpitations, or syncope.

Those with severe illness should be restricted from exercise and participation for 3-6 months. Primary care physicians, preferably in consultation with pediatric cardiologists, should clear athletes who experience severe illness.

“Most of the recommendations come from the fact that we simply do not know what we do not know with COVID-19,” Susannah Briskin, MD, a coauthor of the interim guidance, said in an interview. “We have to be cautious in returning individuals to play and closely monitor them as we learn more about the disease process and its effect on kids.”

Patients with severe illness could include those who were hospitalized and experienced hypotension or arrhythmias, required intubation or extracorporeal membrane oxygenation (ECMO) support, had kidney or cardiac failure, or developed multisystem inflammatory syndrome in children (MIS-C), said Dr. Briskin, a specialist in pediatric sports medicine at Case Western Reserve University, Cleveland.

“The majority of COVID-19 cases will not present like this in kids. We have no idea how common myocarditis is in kids post infection. We do know that, if anyone has chest pain, shortness of breath, excessive fatigue, syncope [passing out], or arrhythmia [feeling of their heart skipping beats], they should undergo further evaluation for myocarditis,” Dr. Briskin said.

Patients who are asymptomatic or have mild symptoms should rest for 14 days after their positive test. After their infectious period has passed, a doctor should assess for any concerning cardiac symptoms. “Anyone with prolonged fever or moderate symptoms should see their pediatrician and have an EKG performed, at a minimum, prior to return to sports,” Dr. Briskin said. “Anyone with an abnormal EKG or concerning signs or symptoms should be referred on to pediatric cardiology for a further assessment.”

Most patients who Dr. Briskin has seen have been asymptomatic or mildly symptomatic. “They have done well with a gradual return to physical activity,” she said. “We recommend a gradual return so individuals can be monitored for any signs or symptoms concerning for myocarditis. The far majority of individuals likely have an uneventful return to play.”

Mitigating risk

COVID-19 adds elements of uncertainty and complexity to the usual process of mitigating risk in sports, Dr. Bernhardt noted in his lecture. “You are dealing with an infection that we do not know a lot about,” he said. “And we are trying to mitigate risk not only for the individual who may or may not have underlying health problems, but you are also trying to mitigate risk for anybody else involved with the sport, including athletic trainers and team physicians, coaches, spectators, custodial staff, people working at a snack shack, and all the other people that can be involved in a typical sporting type of atmosphere.”

When patients do return to play after an illness, they should gradually increase the training load to avoid injury. In addition, clinicians should screen for depression and anxiety using tools such as the Four-Item Patient Health Questionnaire (PHQ-4) when they see patients. “The pandemic has been quite stressful for everybody, including our high school student athletes,” Dr. Bernhardt said. “Giving everybody a PHQ-4 when they come into clinic right now probably makes sense in terms of the stress levels that all of us are experiencing.”

If a patient screens positive, take additional history and refer for more in-depth mental health evaluation and treatment if warranted. Sharing breathing and relaxation exercises, promoting healthy behaviors, and paying attention to unhealthy strategies also may help, Dr. Bernhardt suggested.

Ultimately, determining when an athlete with COVID-19 can be medically cleared to return to play may be a challenge. There are limited data on epidemiology and clinical presentations that could help identify cardiac injury related to the disease, Dr. Bernhardt said. Guidance from the American College of Cardiology provides a framework for evaluating athletes for return to play, and pediatric cardiologists have discussed how the guidance relates to a pediatric population. Cardiac assessments may include measures of biomarkers such as troponin, B-type natriuretic peptide, and sedimentation rate, along with electrocardiograms, echocardiograms, and cardiac MRI.

Beyond return-to-play decisions, encourage the use of cloth face coverings on the sidelines and away from the playing field, and stress proper quarantining, Dr. Briskin added. Too often, she hears about children not quarantining properly. “Individuals with a known exposure should be quarantined in their house – ideally in a separate room from everyone else. ... When they come out of their room, they should wash their hands well and wear a cloth face covering. They should not be eating with other people.”

Dr. Bernhardt had no relevant disclosures.

jremaly@mdedge.com

Many student athletes who test positive for COVID-19 likely can have an uneventful return to their sports after they have rested for 2 weeks in quarantine, doctors suggest.

Canberk Sezer/Getty Images

There are reasons for caution, however, especially when a patient has symptoms that indicate possible cardiac involvement. In these cases, patients should undergo cardiac testing before a physician clears them to return to play, according to guidance from professional associations. Reports of myocarditis in college athletes who tested positive for SARS-CoV-2 but were asymptomatic are among the reasons for concern. Myocarditis may increase the risk of sudden death during exercise.

“The thing that you need to keep in mind is that this is not just a respiratory illness,” David T. Bernhardt, MD, professor of pediatrics, orthopedics, and rehabilitation at the University of Wisconsin in Madison, said in a presentation at the annual meeting of the American Academy of Pediatrics, held virtually this year. High school and college athletes have had cardiac, neurologic, hematologic, and renal problems that “can complicate their recovery and their return to sport.”

Still, children who test positive for COVID-19 tend to have mild illness and often are asymptomatic. “It is more than likely going to be safe for the majority of the student athletes who are in the elementary and middle school age to return to sport,” said Dr. Bernhardt. Given that 18-year-old college freshmen have had cardiac complications, there may be reason for more caution with high school students.
 

Limited data

The AAP has released interim guidance on returning to sports and recommends that primary care physicians clear all patients with COVID-19 before they resume training. Physicians should screen for cardiac symptoms such as chest pain, shortness of breath, fatigue, palpitations, or syncope.

Those with severe illness should be restricted from exercise and participation for 3-6 months. Primary care physicians, preferably in consultation with pediatric cardiologists, should clear athletes who experience severe illness.

“Most of the recommendations come from the fact that we simply do not know what we do not know with COVID-19,” Susannah Briskin, MD, a coauthor of the interim guidance, said in an interview. “We have to be cautious in returning individuals to play and closely monitor them as we learn more about the disease process and its effect on kids.”

Patients with severe illness could include those who were hospitalized and experienced hypotension or arrhythmias, required intubation or extracorporeal membrane oxygenation (ECMO) support, had kidney or cardiac failure, or developed multisystem inflammatory syndrome in children (MIS-C), said Dr. Briskin, a specialist in pediatric sports medicine at Case Western Reserve University, Cleveland.

“The majority of COVID-19 cases will not present like this in kids. We have no idea how common myocarditis is in kids post infection. We do know that, if anyone has chest pain, shortness of breath, excessive fatigue, syncope [passing out], or arrhythmia [feeling of their heart skipping beats], they should undergo further evaluation for myocarditis,” Dr. Briskin said.

Patients who are asymptomatic or have mild symptoms should rest for 14 days after their positive test. After their infectious period has passed, a doctor should assess for any concerning cardiac symptoms. “Anyone with prolonged fever or moderate symptoms should see their pediatrician and have an EKG performed, at a minimum, prior to return to sports,” Dr. Briskin said. “Anyone with an abnormal EKG or concerning signs or symptoms should be referred on to pediatric cardiology for a further assessment.”

Most patients who Dr. Briskin has seen have been asymptomatic or mildly symptomatic. “They have done well with a gradual return to physical activity,” she said. “We recommend a gradual return so individuals can be monitored for any signs or symptoms concerning for myocarditis. The far majority of individuals likely have an uneventful return to play.”

Mitigating risk

COVID-19 adds elements of uncertainty and complexity to the usual process of mitigating risk in sports, Dr. Bernhardt noted in his lecture. “You are dealing with an infection that we do not know a lot about,” he said. “And we are trying to mitigate risk not only for the individual who may or may not have underlying health problems, but you are also trying to mitigate risk for anybody else involved with the sport, including athletic trainers and team physicians, coaches, spectators, custodial staff, people working at a snack shack, and all the other people that can be involved in a typical sporting type of atmosphere.”

When patients do return to play after an illness, they should gradually increase the training load to avoid injury. In addition, clinicians should screen for depression and anxiety using tools such as the Four-Item Patient Health Questionnaire (PHQ-4) when they see patients. “The pandemic has been quite stressful for everybody, including our high school student athletes,” Dr. Bernhardt said. “Giving everybody a PHQ-4 when they come into clinic right now probably makes sense in terms of the stress levels that all of us are experiencing.”

If a patient screens positive, take additional history and refer for more in-depth mental health evaluation and treatment if warranted. Sharing breathing and relaxation exercises, promoting healthy behaviors, and paying attention to unhealthy strategies also may help, Dr. Bernhardt suggested.

Ultimately, determining when an athlete with COVID-19 can be medically cleared to return to play may be a challenge. There are limited data on epidemiology and clinical presentations that could help identify cardiac injury related to the disease, Dr. Bernhardt said. Guidance from the American College of Cardiology provides a framework for evaluating athletes for return to play, and pediatric cardiologists have discussed how the guidance relates to a pediatric population. Cardiac assessments may include measures of biomarkers such as troponin, B-type natriuretic peptide, and sedimentation rate, along with electrocardiograms, echocardiograms, and cardiac MRI.

Beyond return-to-play decisions, encourage the use of cloth face coverings on the sidelines and away from the playing field, and stress proper quarantining, Dr. Briskin added. Too often, she hears about children not quarantining properly. “Individuals with a known exposure should be quarantined in their house – ideally in a separate room from everyone else. ... When they come out of their room, they should wash their hands well and wear a cloth face covering. They should not be eating with other people.”

Dr. Bernhardt had no relevant disclosures.

jremaly@mdedge.com

Start most patients newly diagnosed with heart failure with reduced ejection fraction on the disorder’s four foundational drug regimens all at once, all on the day the diagnosis is made, Gregg C. Fonarow, MD, recommended.

Less than 2 months before Dr. Fonarow made that striking statement during the virtual annual meeting of the Heart Failure Society of America, investigators first reported results from the EMPEROR-Reduced trial at the European Society of Cardiology’s virtual annual meeting, showing that the sodium-glucose transporter 2 (SGLT2) inhibitor empagliflozin (Jardiance) successfully cut events in patients with heart failure with reduced ejection fraction (HFrEF). That report, a year after results from a similar trial (DAPA-HF) showed the same outcome using a different drug from the same class, dapagliflozin (Farxiga), cemented the SGLT2 inhibitor drug class as the fourth pillar for treating HFrEF, joining the angiotensin receptor neprilysin inhibitor (ARNI) class (sacubitril valsartan), beta-blockers (like carvedilol), and mineralocorticoid receptor antagonists (like spironolactone).

This rejiggering of the consensus expert approach for treating HFrEF left cardiologists wondering what sequence to use when starting this quadruple therapy. Within weeks, the answer from heart failure opinion leaders was clear:

“Start all four pillars simultaneously. Most patients can tolerate, and will benefit from, a simultaneous start,” declared Dr. Fonarow, professor and chief of cardiology at the University of California, Los Angeles.

His rationale? Patients get benefits from each of these drug classes “surprisingly early,” with improved outcomes in clinical trials appearing within a few weeks, compared with patients in control arms. The consequence is that any delay in starting treatment denies patients time with improved health status, function, and survival.

Study results documented that the four foundational drug classes can produce rapid improvements in health status, left ventricular size and shape, and make clinically meaningful cuts in both first and recurrent hospitalizations for heart failure and in mortality, Dr. Fonarow said. After 30 days on quadruple treatment, a patient’s relative risk for death drops by more than three-quarters, compared with patients not on these medications.

The benefits from each of the four classes involve distinct physiologic pathways and hence are not diminished by concurrent treatment. And immediate initiation avoids the risk of clinical inertia and a negligence to prescribe one or more of the four important drug classes. Introducing the four classes in a sequential manner could mean spending as long as a year to get all four on board and up-titrated to optimal therapeutic levels, he noted.

“Overcome inertia by prescribing [all four drug classes] at the time of diagnosis,” Dr. Fonarow admonished his audience.

The challenge of prescribing inertia

The risk for inertia in prescribing heart failure medications is real. Data collected in the CHAMP-HF (Change the Management of Patients with Heart Failure) registry from more than 3,500 HFrEF patients managed at any of 150 U.S. primary care and cardiology practices starting in late 2015 and continuing through 2017 showed that, among patients eligible for treatment with renin-angiotensin system (RAS) inhibition (with either ARNI or a single RAS inhibiting drug), a beta-blocker, and a mineralocorticoid receptor antagonist (MRA), 22% received all three drug classes. A scant 1% were on target dosages of all three drug classes, noted Stephen J. Greene, MD, in a separate talk at the meeting when he cited his published findings.

The sole formulation currently in the ARNI class, sacubitril/valsartan (Entresto) has in recent years been the poster child for prescribing inertia in HFrEF patients after coming onto the U.S. market for routine use in 2015. A review run by Dr. Greene of more than 9,000 HFrEF patients who were at least 65 years old and discharged from a hospital participating in the Get With the Guidelines–Heart Failure registry during October 2015–September 2017 showed that 8% of eligible patients actually received a sacubitril/valsartan prescription. Separate assessment of outpatients with HFrEF from the same era showed 13% uptake, said D. Greene, a cardiologist at Duke University, Durham, N.C.

Substantial gaps in prescribing evidence-based treatments to HFrEF patients have existed for the past couple of decades, said Dr. Greene. “Even a blockbuster drug like sacubitril/valsartan has been slow to implement.”
 

Quadruple therapy adds an average of 6 years of life

One of the most strongest arguments favoring the start-four-at-once approach was detailed in what’s quickly become a widely cited analysis published in July 2020 by a team of researchers led by Muthiah Vaduganathan, MD. Using data from three key pivotal trials they estimated that timely treatment with all four drug classes would on average produce an extra 6 years of overall survival in a 55-year old HFrEF patient, and an added 8 years free from cardiovascular death or first hospitalization for heart failure, compared with less comprehensive treatment. The analysis also showed a significant 3-year average boost in overall survival among HFrEF patients who were 80 years old when using quadruple therapy compared with the “conventional medical therapy” used on control patients in the three trials examined.

Dr. Greene called these findings “remarkable.”

Mitchel L. Zoler/Frontline Medical News

“Four drugs use five mechanistic pathways to produce 6 added years of survival,” summed up Dr. Vaduganathan during a separate talk at the virtual meeting.

In addition to this substantial potential for a meaningful impact on patents’ lives, he cited other factors that add to the case for early prescription of the pharmaceutical gauntlet: avoiding missed treatment opportunities that occur with slower, step-wise drug introduction; simplifying, streamlining, and standardizing the care pathway, which helps avoid care inequities and disrupts the potential for inertia; magnifying benefit when comprehensive treatment starts sooner; and providing additive benefits without drug-drug interactions.

“Upfront treatment at the time of [HFrEF] diagnosis or hospitalization is an approach that disrupts treatment inertia,” emphasized Dr. Vaduganathan, a cardiologist at Brigham and Women’s Hospital in Boston.
 

New approaches needed to encourage quick uptake

“Efficacy alone has not been enough for efficient uptake in U.S. practice” of sacubitril/valsartan, other RAS inhibitors, beta-blockers, and MRAs, noted Dr. Greene.

He was more optimistic about prospects for relatively quick uptake of early SGLT2 inhibitor treatment as part of routine HFrEF management given all the positives that this new HFrEF treatment offers, including some “unique features” among HFrEF drugs. These include the simplicity of the regimen, which involves a single dosage for everyone that’s taken once daily; minimal blood pressure effects and no adverse renal effects while also producing substantial renal protection; and two SGLT2 inhibitors with proven HFrEF benefit (dapagliflozin and empagliflozin), which bodes well for an eventual price drop.

The SGLT2 inhibitors stack up as an “ideal” HFrEF treatment, concluded Dr. Greene, which should facilitate quick uptake. As far as getting clinicians to also add early on the other three members of the core four treatment classes in routine treatment, he conceded that “innovative and evidence-based approaches to improving real-world uptake of guideline-directed medical therapy are urgently needed.”

EMPEROR-Reduced was funded by Boehringer Ingelheim and Lilly, the companies that market empagliflozin (Jardiance). CHAMP-HF was funded by Novartis, the company that markets sacubitril/valsartan (Entresto). Dr. Fonarow has been a consultant or adviser to Novartis, as well as to Abbott, Amgen, AstraZeneca, Bayer, CHF Solutions, Edwards, Janssen, Medtronic, and Merck. Dr. Greene has received research funding from Novartis, has been a consultant to Amgen and Merck, an adviser to Amgen and Cytokinetics, and has received research funding from Amgen, AstraZeneca, Bristol-Myers Squibb, and Merck. Dr. Vaduganathan has had financial relationships with Boehringer Ingelheim and Novartis, as well as with Amgen, AstraZeneca, Baxter Healthcare, Bayer, Cytokinetics, and Relypsa.

mzoler@mdedge.com

Start most patients newly diagnosed with heart failure with reduced ejection fraction on the disorder’s four foundational drug regimens all at once, all on the day the diagnosis is made, Gregg C. Fonarow, MD, recommended.

Less than 2 months before Dr. Fonarow made that striking statement during the virtual annual meeting of the Heart Failure Society of America, investigators first reported results from the EMPEROR-Reduced trial at the European Society of Cardiology’s virtual annual meeting, showing that the sodium-glucose transporter 2 (SGLT2) inhibitor empagliflozin (Jardiance) successfully cut events in patients with heart failure with reduced ejection fraction (HFrEF). That report, a year after results from a similar trial (DAPA-HF) showed the same outcome using a different drug from the same class, dapagliflozin (Farxiga), cemented the SGLT2 inhibitor drug class as the fourth pillar for treating HFrEF, joining the angiotensin receptor neprilysin inhibitor (ARNI) class (sacubitril valsartan), beta-blockers (like carvedilol), and mineralocorticoid receptor antagonists (like spironolactone).

This rejiggering of the consensus expert approach for treating HFrEF left cardiologists wondering what sequence to use when starting this quadruple therapy. Within weeks, the answer from heart failure opinion leaders was clear:

“Start all four pillars simultaneously. Most patients can tolerate, and will benefit from, a simultaneous start,” declared Dr. Fonarow, professor and chief of cardiology at the University of California, Los Angeles.

His rationale? Patients get benefits from each of these drug classes “surprisingly early,” with improved outcomes in clinical trials appearing within a few weeks, compared with patients in control arms. The consequence is that any delay in starting treatment denies patients time with improved health status, function, and survival.

Study results documented that the four foundational drug classes can produce rapid improvements in health status, left ventricular size and shape, and make clinically meaningful cuts in both first and recurrent hospitalizations for heart failure and in mortality, Dr. Fonarow said. After 30 days on quadruple treatment, a patient’s relative risk for death drops by more than three-quarters, compared with patients not on these medications.

The benefits from each of the four classes involve distinct physiologic pathways and hence are not diminished by concurrent treatment. And immediate initiation avoids the risk of clinical inertia and a negligence to prescribe one or more of the four important drug classes. Introducing the four classes in a sequential manner could mean spending as long as a year to get all four on board and up-titrated to optimal therapeutic levels, he noted.

“Overcome inertia by prescribing [all four drug classes] at the time of diagnosis,” Dr. Fonarow admonished his audience.

The challenge of prescribing inertia

The risk for inertia in prescribing heart failure medications is real. Data collected in the CHAMP-HF (Change the Management of Patients with Heart Failure) registry from more than 3,500 HFrEF patients managed at any of 150 U.S. primary care and cardiology practices starting in late 2015 and continuing through 2017 showed that, among patients eligible for treatment with renin-angiotensin system (RAS) inhibition (with either ARNI or a single RAS inhibiting drug), a beta-blocker, and a mineralocorticoid receptor antagonist (MRA), 22% received all three drug classes. A scant 1% were on target dosages of all three drug classes, noted Stephen J. Greene, MD, in a separate talk at the meeting when he cited his published findings.

The sole formulation currently in the ARNI class, sacubitril/valsartan (Entresto) has in recent years been the poster child for prescribing inertia in HFrEF patients after coming onto the U.S. market for routine use in 2015. A review run by Dr. Greene of more than 9,000 HFrEF patients who were at least 65 years old and discharged from a hospital participating in the Get With the Guidelines–Heart Failure registry during October 2015–September 2017 showed that 8% of eligible patients actually received a sacubitril/valsartan prescription. Separate assessment of outpatients with HFrEF from the same era showed 13% uptake, said D. Greene, a cardiologist at Duke University, Durham, N.C.

Substantial gaps in prescribing evidence-based treatments to HFrEF patients have existed for the past couple of decades, said Dr. Greene. “Even a blockbuster drug like sacubitril/valsartan has been slow to implement.”
 

Quadruple therapy adds an average of 6 years of life

One of the most strongest arguments favoring the start-four-at-once approach was detailed in what’s quickly become a widely cited analysis published in July 2020 by a team of researchers led by Muthiah Vaduganathan, MD. Using data from three key pivotal trials they estimated that timely treatment with all four drug classes would on average produce an extra 6 years of overall survival in a 55-year old HFrEF patient, and an added 8 years free from cardiovascular death or first hospitalization for heart failure, compared with less comprehensive treatment. The analysis also showed a significant 3-year average boost in overall survival among HFrEF patients who were 80 years old when using quadruple therapy compared with the “conventional medical therapy” used on control patients in the three trials examined.

Dr. Greene called these findings “remarkable.”

Mitchel L. Zoler/Frontline Medical News

“Four drugs use five mechanistic pathways to produce 6 added years of survival,” summed up Dr. Vaduganathan during a separate talk at the virtual meeting.

In addition to this substantial potential for a meaningful impact on patents’ lives, he cited other factors that add to the case for early prescription of the pharmaceutical gauntlet: avoiding missed treatment opportunities that occur with slower, step-wise drug introduction; simplifying, streamlining, and standardizing the care pathway, which helps avoid care inequities and disrupts the potential for inertia; magnifying benefit when comprehensive treatment starts sooner; and providing additive benefits without drug-drug interactions.

“Upfront treatment at the time of [HFrEF] diagnosis or hospitalization is an approach that disrupts treatment inertia,” emphasized Dr. Vaduganathan, a cardiologist at Brigham and Women’s Hospital in Boston.
 

New approaches needed to encourage quick uptake

“Efficacy alone has not been enough for efficient uptake in U.S. practice” of sacubitril/valsartan, other RAS inhibitors, beta-blockers, and MRAs, noted Dr. Greene.

He was more optimistic about prospects for relatively quick uptake of early SGLT2 inhibitor treatment as part of routine HFrEF management given all the positives that this new HFrEF treatment offers, including some “unique features” among HFrEF drugs. These include the simplicity of the regimen, which involves a single dosage for everyone that’s taken once daily; minimal blood pressure effects and no adverse renal effects while also producing substantial renal protection; and two SGLT2 inhibitors with proven HFrEF benefit (dapagliflozin and empagliflozin), which bodes well for an eventual price drop.

The SGLT2 inhibitors stack up as an “ideal” HFrEF treatment, concluded Dr. Greene, which should facilitate quick uptake. As far as getting clinicians to also add early on the other three members of the core four treatment classes in routine treatment, he conceded that “innovative and evidence-based approaches to improving real-world uptake of guideline-directed medical therapy are urgently needed.”

EMPEROR-Reduced was funded by Boehringer Ingelheim and Lilly, the companies that market empagliflozin (Jardiance). CHAMP-HF was funded by Novartis, the company that markets sacubitril/valsartan (Entresto). Dr. Fonarow has been a consultant or adviser to Novartis, as well as to Abbott, Amgen, AstraZeneca, Bayer, CHF Solutions, Edwards, Janssen, Medtronic, and Merck. Dr. Greene has received research funding from Novartis, has been a consultant to Amgen and Merck, an adviser to Amgen and Cytokinetics, and has received research funding from Amgen, AstraZeneca, Bristol-Myers Squibb, and Merck. Dr. Vaduganathan has had financial relationships with Boehringer Ingelheim and Novartis, as well as with Amgen, AstraZeneca, Baxter Healthcare, Bayer, Cytokinetics, and Relypsa.

mzoler@mdedge.com

Start most patients newly diagnosed with heart failure with reduced ejection fraction on the disorder’s four foundational drug regimens all at once, all on the day the diagnosis is made, Gregg C. Fonarow, MD, recommended.

Less than 2 months before Dr. Fonarow made that striking statement during the virtual annual meeting of the Heart Failure Society of America, investigators first reported results from the EMPEROR-Reduced trial at the European Society of Cardiology’s virtual annual meeting, showing that the sodium-glucose transporter 2 (SGLT2) inhibitor empagliflozin (Jardiance) successfully cut events in patients with heart failure with reduced ejection fraction (HFrEF). That report, a year after results from a similar trial (DAPA-HF) showed the same outcome using a different drug from the same class, dapagliflozin (Farxiga), cemented the SGLT2 inhibitor drug class as the fourth pillar for treating HFrEF, joining the angiotensin receptor neprilysin inhibitor (ARNI) class (sacubitril valsartan), beta-blockers (like carvedilol), and mineralocorticoid receptor antagonists (like spironolactone).

This rejiggering of the consensus expert approach for treating HFrEF left cardiologists wondering what sequence to use when starting this quadruple therapy. Within weeks, the answer from heart failure opinion leaders was clear:

“Start all four pillars simultaneously. Most patients can tolerate, and will benefit from, a simultaneous start,” declared Dr. Fonarow, professor and chief of cardiology at the University of California, Los Angeles.

His rationale? Patients get benefits from each of these drug classes “surprisingly early,” with improved outcomes in clinical trials appearing within a few weeks, compared with patients in control arms. The consequence is that any delay in starting treatment denies patients time with improved health status, function, and survival.

Study results documented that the four foundational drug classes can produce rapid improvements in health status, left ventricular size and shape, and make clinically meaningful cuts in both first and recurrent hospitalizations for heart failure and in mortality, Dr. Fonarow said. After 30 days on quadruple treatment, a patient’s relative risk for death drops by more than three-quarters, compared with patients not on these medications.

The benefits from each of the four classes involve distinct physiologic pathways and hence are not diminished by concurrent treatment. And immediate initiation avoids the risk of clinical inertia and a negligence to prescribe one or more of the four important drug classes. Introducing the four classes in a sequential manner could mean spending as long as a year to get all four on board and up-titrated to optimal therapeutic levels, he noted.

“Overcome inertia by prescribing [all four drug classes] at the time of diagnosis,” Dr. Fonarow admonished his audience.

The challenge of prescribing inertia

The risk for inertia in prescribing heart failure medications is real. Data collected in the CHAMP-HF (Change the Management of Patients with Heart Failure) registry from more than 3,500 HFrEF patients managed at any of 150 U.S. primary care and cardiology practices starting in late 2015 and continuing through 2017 showed that, among patients eligible for treatment with renin-angiotensin system (RAS) inhibition (with either ARNI or a single RAS inhibiting drug), a beta-blocker, and a mineralocorticoid receptor antagonist (MRA), 22% received all three drug classes. A scant 1% were on target dosages of all three drug classes, noted Stephen J. Greene, MD, in a separate talk at the meeting when he cited his published findings.

The sole formulation currently in the ARNI class, sacubitril/valsartan (Entresto) has in recent years been the poster child for prescribing inertia in HFrEF patients after coming onto the U.S. market for routine use in 2015. A review run by Dr. Greene of more than 9,000 HFrEF patients who were at least 65 years old and discharged from a hospital participating in the Get With the Guidelines–Heart Failure registry during October 2015–September 2017 showed that 8% of eligible patients actually received a sacubitril/valsartan prescription. Separate assessment of outpatients with HFrEF from the same era showed 13% uptake, said D. Greene, a cardiologist at Duke University, Durham, N.C.

Substantial gaps in prescribing evidence-based treatments to HFrEF patients have existed for the past couple of decades, said Dr. Greene. “Even a blockbuster drug like sacubitril/valsartan has been slow to implement.”
 

Quadruple therapy adds an average of 6 years of life

One of the most strongest arguments favoring the start-four-at-once approach was detailed in what’s quickly become a widely cited analysis published in July 2020 by a team of researchers led by Muthiah Vaduganathan, MD. Using data from three key pivotal trials they estimated that timely treatment with all four drug classes would on average produce an extra 6 years of overall survival in a 55-year old HFrEF patient, and an added 8 years free from cardiovascular death or first hospitalization for heart failure, compared with less comprehensive treatment. The analysis also showed a significant 3-year average boost in overall survival among HFrEF patients who were 80 years old when using quadruple therapy compared with the “conventional medical therapy” used on control patients in the three trials examined.

Dr. Greene called these findings “remarkable.”

Mitchel L. Zoler/Frontline Medical News

“Four drugs use five mechanistic pathways to produce 6 added years of survival,” summed up Dr. Vaduganathan during a separate talk at the virtual meeting.

In addition to this substantial potential for a meaningful impact on patents’ lives, he cited other factors that add to the case for early prescription of the pharmaceutical gauntlet: avoiding missed treatment opportunities that occur with slower, step-wise drug introduction; simplifying, streamlining, and standardizing the care pathway, which helps avoid care inequities and disrupts the potential for inertia; magnifying benefit when comprehensive treatment starts sooner; and providing additive benefits without drug-drug interactions.

“Upfront treatment at the time of [HFrEF] diagnosis or hospitalization is an approach that disrupts treatment inertia,” emphasized Dr. Vaduganathan, a cardiologist at Brigham and Women’s Hospital in Boston.
 

New approaches needed to encourage quick uptake

“Efficacy alone has not been enough for efficient uptake in U.S. practice” of sacubitril/valsartan, other RAS inhibitors, beta-blockers, and MRAs, noted Dr. Greene.

He was more optimistic about prospects for relatively quick uptake of early SGLT2 inhibitor treatment as part of routine HFrEF management given all the positives that this new HFrEF treatment offers, including some “unique features” among HFrEF drugs. These include the simplicity of the regimen, which involves a single dosage for everyone that’s taken once daily; minimal blood pressure effects and no adverse renal effects while also producing substantial renal protection; and two SGLT2 inhibitors with proven HFrEF benefit (dapagliflozin and empagliflozin), which bodes well for an eventual price drop.

The SGLT2 inhibitors stack up as an “ideal” HFrEF treatment, concluded Dr. Greene, which should facilitate quick uptake. As far as getting clinicians to also add early on the other three members of the core four treatment classes in routine treatment, he conceded that “innovative and evidence-based approaches to improving real-world uptake of guideline-directed medical therapy are urgently needed.”

EMPEROR-Reduced was funded by Boehringer Ingelheim and Lilly, the companies that market empagliflozin (Jardiance). CHAMP-HF was funded by Novartis, the company that markets sacubitril/valsartan (Entresto). Dr. Fonarow has been a consultant or adviser to Novartis, as well as to Abbott, Amgen, AstraZeneca, Bayer, CHF Solutions, Edwards, Janssen, Medtronic, and Merck. Dr. Greene has received research funding from Novartis, has been a consultant to Amgen and Merck, an adviser to Amgen and Cytokinetics, and has received research funding from Amgen, AstraZeneca, Bristol-Myers Squibb, and Merck. Dr. Vaduganathan has had financial relationships with Boehringer Ingelheim and Novartis, as well as with Amgen, AstraZeneca, Baxter Healthcare, Bayer, Cytokinetics, and Relypsa.

mzoler@mdedge.com