Heart Failure

A scoring system that predicts risk for new heart failure over 5 years that is based solely on a few familiar, readily available biomarkers could potentially help steer patients with diabetes or even prediabetes toward HF-preventive therapies, researchers proposed based on a new study.

They foresee the risk-stratification tool, based on data pooled from three major community-based cohort studies but not independently validated, as a way to select patients with diabetes and prediabetes for treatment with SGLT2 inhibitors.

Several members of that drug class, conceived as antidiabetic agents, have been shown to help in prevention or treatment of HF in patients with diabetes and those without diabetes but at increased cardiovascular (CV) risk. Yet their uptake in practice has been lagging, the group noted.

Most HF benefits in the SGLT2 inhibitor trials “were seen in patients who have established cardiovascular disease – basically a history of heart attack or stroke,” Ambarish Pandey, MD, MSCS, University of Texas Southwestern Medical Center, Dallas, said in an interview.

“So we wanted to see how we can identify high-risk patients without a history of cardiovascular disease using these biomarkers, as an approach to targeting SGLT2 inhibitors, which are fairly expensive therapies,” he said. Without such risk stratification, “you end up treating so many more patients to get very modest returns.”

The group developed a scoring system based on four biomarkers that are “easily measured with inexpensive tests,” Dr. Pandey said: high-sensitivity-assay cardiac troponin T (hs-cTnT) and C-reactive protein (hs-CRP) levels, N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) levels, and electrocardiography for evidence of left-ventricular hypertrophy (ECG-LVH).

The derivation cohort consisted of participants in the Atherosclerosis Risk in Communities RIC, Dallas Heart Study, and Multi-Ethnic Study of Atherosclerosis Multi-Ethnic Study of Atherosclerosis epidemiologic studies who were free of coronary heart disease, stroke, or HF for whom there were sufficient data on CV risk factors and the four biomarkers. None were taking SGLT2 inhibitors at enrollment in their respective studies, the researchers noted.

Members of the pooled cohorts who had diabetes or prediabetes were assigned 1 point for each abnormal biomarker. The 5-year risk for incident HF went up continuously along with the score in people with diabetes and in those with prediabetes, the latter defined as a fasting plasma glucose level from 100 mg/dL to less than 126 mg/dL.

For those with a score of 1, compared with 0, for example, the risk for HF went up 82% with diabetes and 40% with prediabetes. But for those with a score of 3 or 4, the risk went up more than four and a half times with diabetes and more than three and a half times for those with prediabetes. Risk increases were independent of other likely HF risk factors and consistently significant.

The analysis was published Jan. 6 in JACC: Heart Failure.

The biomarker score should be especially useful in patients considered at low to intermediate risk, based on clinical characteristics, as a means to identify residual HF risk and, potentially, select candidates for SGLT2-inhibitor therapy, Dr. Pandey said.

“The other purpose of the study was to broaden the scope of heart failure prevention in dysglycemia by looking also at prediabetes, not just diabetes,” he said. There isn’t much high-quality evidence supporting SGLT2-inhibitor therapy in prediabetes, but it follows that the drugs may be helpful in prediabetes because they are protective in patients with and without diabetes.

“Our work suggests that prediabetes patients who have elevated biomarkers are at a higher risk of heart failure,” Dr. Pandey said, suggesting that the HF risk score could potentially help select their drug therapy as well.

The current study seems “to provide a proof of concept that one can use circulating biomarkers to more precisely identify patients in whom therapies might be expected to exert greatest benefit,” which is especially important for potentially expensive agents like the SGLT2 inhibitors, James L. Januzzi, MD, Massachusetts General Hospital, Boston, said in an interview.

Importantly in the analysis, a greater number of biomarker abnormalities not only corresponded to rising levels of risk, the risk increases were “dramatic,” and therefore so was the supposed potential benefit of SGLT2-inhibitor therapy, said Dr. Januzzi, who isn’t a coauthor but was an editor for its publication in JACC: Heart Failure.

The uptake of SGLT2 inhibitors for heart failure in practice has been less rapid than hoped, he observed, so if “this hypothetical construct holds up” for the drug class, “it might actually help kick-start focusing on who might optimally receive the drugs.”

Elevated levels of hs-cTnT, hs-CRP, and NT-proBNP, as well as presence of ECG-LVH, were each independently associated with a significantly increased 5-year risk for HF in unadjusted and adjusted analyses of the 6,799 people in the pooled cohort, 33.2% of whom had diabetes and 66.8% of whom had prediabetes, the group writes.

The scoring system would require validation in other cohorts before it could be used, Dr. Pandey observed; once there is “robust validation,” it might be applied first to patients with dysglycemia at intermediate CV risk by standard clinical measures.

Certainly the HF risk-stratification scoring system requires validation in other studies, Dr. Januzzi agreed. But it is intuitively appealing, and the study’s results are consistent with “data that we’re submitting for publication imminently” based on the CANVAS CV-outcomes trial of the SGLT2 inhibitor canagliflozin (Invokana) in patients with diabetes.

Dr. Pandey disclosed receiving support from the Gilead Sciences Research Scholar Program and serving on an advisory board of Roche Diagnostics. Dr. Januzzi disclosed receiving grant support from Novartis, Applied Therapeutics, and Innolife; consulting for Abbott Diagnostics, Janssen, Novartis, Quidel, and Roche Diagnostics; and serving on end-point committees or data safety monitoring boards for trials supported by Abbott, AbbVie, Amgen, CVRx, Janssen, MyoKardia, and Takeda.

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

A scoring system that predicts risk for new heart failure over 5 years that is based solely on a few familiar, readily available biomarkers could potentially help steer patients with diabetes or even prediabetes toward HF-preventive therapies, researchers proposed based on a new study.

They foresee the risk-stratification tool, based on data pooled from three major community-based cohort studies but not independently validated, as a way to select patients with diabetes and prediabetes for treatment with SGLT2 inhibitors.

Several members of that drug class, conceived as antidiabetic agents, have been shown to help in prevention or treatment of HF in patients with diabetes and those without diabetes but at increased cardiovascular (CV) risk. Yet their uptake in practice has been lagging, the group noted.

Most HF benefits in the SGLT2 inhibitor trials “were seen in patients who have established cardiovascular disease – basically a history of heart attack or stroke,” Ambarish Pandey, MD, MSCS, University of Texas Southwestern Medical Center, Dallas, said in an interview.

“So we wanted to see how we can identify high-risk patients without a history of cardiovascular disease using these biomarkers, as an approach to targeting SGLT2 inhibitors, which are fairly expensive therapies,” he said. Without such risk stratification, “you end up treating so many more patients to get very modest returns.”

The group developed a scoring system based on four biomarkers that are “easily measured with inexpensive tests,” Dr. Pandey said: high-sensitivity-assay cardiac troponin T (hs-cTnT) and C-reactive protein (hs-CRP) levels, N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) levels, and electrocardiography for evidence of left-ventricular hypertrophy (ECG-LVH).

The derivation cohort consisted of participants in the Atherosclerosis Risk in Communities RIC, Dallas Heart Study, and Multi-Ethnic Study of Atherosclerosis Multi-Ethnic Study of Atherosclerosis epidemiologic studies who were free of coronary heart disease, stroke, or HF for whom there were sufficient data on CV risk factors and the four biomarkers. None were taking SGLT2 inhibitors at enrollment in their respective studies, the researchers noted.

Members of the pooled cohorts who had diabetes or prediabetes were assigned 1 point for each abnormal biomarker. The 5-year risk for incident HF went up continuously along with the score in people with diabetes and in those with prediabetes, the latter defined as a fasting plasma glucose level from 100 mg/dL to less than 126 mg/dL.

For those with a score of 1, compared with 0, for example, the risk for HF went up 82% with diabetes and 40% with prediabetes. But for those with a score of 3 or 4, the risk went up more than four and a half times with diabetes and more than three and a half times for those with prediabetes. Risk increases were independent of other likely HF risk factors and consistently significant.

The analysis was published Jan. 6 in JACC: Heart Failure.

The biomarker score should be especially useful in patients considered at low to intermediate risk, based on clinical characteristics, as a means to identify residual HF risk and, potentially, select candidates for SGLT2-inhibitor therapy, Dr. Pandey said.

“The other purpose of the study was to broaden the scope of heart failure prevention in dysglycemia by looking also at prediabetes, not just diabetes,” he said. There isn’t much high-quality evidence supporting SGLT2-inhibitor therapy in prediabetes, but it follows that the drugs may be helpful in prediabetes because they are protective in patients with and without diabetes.

“Our work suggests that prediabetes patients who have elevated biomarkers are at a higher risk of heart failure,” Dr. Pandey said, suggesting that the HF risk score could potentially help select their drug therapy as well.

The current study seems “to provide a proof of concept that one can use circulating biomarkers to more precisely identify patients in whom therapies might be expected to exert greatest benefit,” which is especially important for potentially expensive agents like the SGLT2 inhibitors, James L. Januzzi, MD, Massachusetts General Hospital, Boston, said in an interview.

Importantly in the analysis, a greater number of biomarker abnormalities not only corresponded to rising levels of risk, the risk increases were “dramatic,” and therefore so was the supposed potential benefit of SGLT2-inhibitor therapy, said Dr. Januzzi, who isn’t a coauthor but was an editor for its publication in JACC: Heart Failure.

The uptake of SGLT2 inhibitors for heart failure in practice has been less rapid than hoped, he observed, so if “this hypothetical construct holds up” for the drug class, “it might actually help kick-start focusing on who might optimally receive the drugs.”

Elevated levels of hs-cTnT, hs-CRP, and NT-proBNP, as well as presence of ECG-LVH, were each independently associated with a significantly increased 5-year risk for HF in unadjusted and adjusted analyses of the 6,799 people in the pooled cohort, 33.2% of whom had diabetes and 66.8% of whom had prediabetes, the group writes.

The scoring system would require validation in other cohorts before it could be used, Dr. Pandey observed; once there is “robust validation,” it might be applied first to patients with dysglycemia at intermediate CV risk by standard clinical measures.

Certainly the HF risk-stratification scoring system requires validation in other studies, Dr. Januzzi agreed. But it is intuitively appealing, and the study’s results are consistent with “data that we’re submitting for publication imminently” based on the CANVAS CV-outcomes trial of the SGLT2 inhibitor canagliflozin (Invokana) in patients with diabetes.

Dr. Pandey disclosed receiving support from the Gilead Sciences Research Scholar Program and serving on an advisory board of Roche Diagnostics. Dr. Januzzi disclosed receiving grant support from Novartis, Applied Therapeutics, and Innolife; consulting for Abbott Diagnostics, Janssen, Novartis, Quidel, and Roche Diagnostics; and serving on end-point committees or data safety monitoring boards for trials supported by Abbott, AbbVie, Amgen, CVRx, Janssen, MyoKardia, and Takeda.

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

A scoring system that predicts risk for new heart failure over 5 years that is based solely on a few familiar, readily available biomarkers could potentially help steer patients with diabetes or even prediabetes toward HF-preventive therapies, researchers proposed based on a new study.

They foresee the risk-stratification tool, based on data pooled from three major community-based cohort studies but not independently validated, as a way to select patients with diabetes and prediabetes for treatment with SGLT2 inhibitors.

Several members of that drug class, conceived as antidiabetic agents, have been shown to help in prevention or treatment of HF in patients with diabetes and those without diabetes but at increased cardiovascular (CV) risk. Yet their uptake in practice has been lagging, the group noted.

Most HF benefits in the SGLT2 inhibitor trials “were seen in patients who have established cardiovascular disease – basically a history of heart attack or stroke,” Ambarish Pandey, MD, MSCS, University of Texas Southwestern Medical Center, Dallas, said in an interview.

“So we wanted to see how we can identify high-risk patients without a history of cardiovascular disease using these biomarkers, as an approach to targeting SGLT2 inhibitors, which are fairly expensive therapies,” he said. Without such risk stratification, “you end up treating so many more patients to get very modest returns.”

The group developed a scoring system based on four biomarkers that are “easily measured with inexpensive tests,” Dr. Pandey said: high-sensitivity-assay cardiac troponin T (hs-cTnT) and C-reactive protein (hs-CRP) levels, N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) levels, and electrocardiography for evidence of left-ventricular hypertrophy (ECG-LVH).

The derivation cohort consisted of participants in the Atherosclerosis Risk in Communities RIC, Dallas Heart Study, and Multi-Ethnic Study of Atherosclerosis Multi-Ethnic Study of Atherosclerosis epidemiologic studies who were free of coronary heart disease, stroke, or HF for whom there were sufficient data on CV risk factors and the four biomarkers. None were taking SGLT2 inhibitors at enrollment in their respective studies, the researchers noted.

Members of the pooled cohorts who had diabetes or prediabetes were assigned 1 point for each abnormal biomarker. The 5-year risk for incident HF went up continuously along with the score in people with diabetes and in those with prediabetes, the latter defined as a fasting plasma glucose level from 100 mg/dL to less than 126 mg/dL.

For those with a score of 1, compared with 0, for example, the risk for HF went up 82% with diabetes and 40% with prediabetes. But for those with a score of 3 or 4, the risk went up more than four and a half times with diabetes and more than three and a half times for those with prediabetes. Risk increases were independent of other likely HF risk factors and consistently significant.

The analysis was published Jan. 6 in JACC: Heart Failure.

The biomarker score should be especially useful in patients considered at low to intermediate risk, based on clinical characteristics, as a means to identify residual HF risk and, potentially, select candidates for SGLT2-inhibitor therapy, Dr. Pandey said.

“The other purpose of the study was to broaden the scope of heart failure prevention in dysglycemia by looking also at prediabetes, not just diabetes,” he said. There isn’t much high-quality evidence supporting SGLT2-inhibitor therapy in prediabetes, but it follows that the drugs may be helpful in prediabetes because they are protective in patients with and without diabetes.

“Our work suggests that prediabetes patients who have elevated biomarkers are at a higher risk of heart failure,” Dr. Pandey said, suggesting that the HF risk score could potentially help select their drug therapy as well.

The current study seems “to provide a proof of concept that one can use circulating biomarkers to more precisely identify patients in whom therapies might be expected to exert greatest benefit,” which is especially important for potentially expensive agents like the SGLT2 inhibitors, James L. Januzzi, MD, Massachusetts General Hospital, Boston, said in an interview.

Importantly in the analysis, a greater number of biomarker abnormalities not only corresponded to rising levels of risk, the risk increases were “dramatic,” and therefore so was the supposed potential benefit of SGLT2-inhibitor therapy, said Dr. Januzzi, who isn’t a coauthor but was an editor for its publication in JACC: Heart Failure.

The uptake of SGLT2 inhibitors for heart failure in practice has been less rapid than hoped, he observed, so if “this hypothetical construct holds up” for the drug class, “it might actually help kick-start focusing on who might optimally receive the drugs.”

Elevated levels of hs-cTnT, hs-CRP, and NT-proBNP, as well as presence of ECG-LVH, were each independently associated with a significantly increased 5-year risk for HF in unadjusted and adjusted analyses of the 6,799 people in the pooled cohort, 33.2% of whom had diabetes and 66.8% of whom had prediabetes, the group writes.

The scoring system would require validation in other cohorts before it could be used, Dr. Pandey observed; once there is “robust validation,” it might be applied first to patients with dysglycemia at intermediate CV risk by standard clinical measures.

Certainly the HF risk-stratification scoring system requires validation in other studies, Dr. Januzzi agreed. But it is intuitively appealing, and the study’s results are consistent with “data that we’re submitting for publication imminently” based on the CANVAS CV-outcomes trial of the SGLT2 inhibitor canagliflozin (Invokana) in patients with diabetes.

Dr. Pandey disclosed receiving support from the Gilead Sciences Research Scholar Program and serving on an advisory board of Roche Diagnostics. Dr. Januzzi disclosed receiving grant support from Novartis, Applied Therapeutics, and Innolife; consulting for Abbott Diagnostics, Janssen, Novartis, Quidel, and Roche Diagnostics; and serving on end-point committees or data safety monitoring boards for trials supported by Abbott, AbbVie, Amgen, CVRx, Janssen, MyoKardia, and Takeda.

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

The Food and Drug Administration has determined that data collected on the dual SGLT1/2 inhibitor sotagliflozin (Zynquista) for treating patients with type 2 diabetes in the SOLOIST and SCORED pivotal trials can help support a New Drug Application (NDA) submission, according to a statement released on Jan. 14 by Lexicon Pharmaceuticals, the company developing this drug. Lexicon concurrently said that it hopes to potentially file this NDA later in 2021.

The statement said the FDA’s decision related to an NDA for “an indication to reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent visits for heart failure in adult patients with type 2 diabetes with either worsening heart failure or additional risk factors for heart failure.”

Results from SOLOIST and SCORED, first reported in November 2020 at the American Heart Association scientific sessions, showed statistically significant benefits for their respective primary endpoints.

The findings also demonstrated several novel benefits from the first advanced clinical trials of an SGLT inhibitor that blocks both the SGLT2 protein in kidneys as well as the SGLT1 protein, which resides primarily in the gastrointestinal system and is the main route for glucose out of the gut.

In both SOLOIST and SCORED, patient outcomes on sotagliflozin tracked the benefits and adverse effects previously seen with several SGLT2 inhibitors (canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin), but in addition showed several unprecedented benefits: An ability to lower hemoglobin A1c in patients with severely depressed renal function, safe initiation in patients recently hospitalized for heart failure, the first prospective data to show improvements in patients with heart failure with preserved ejection fraction, and a higher level of protection against MIs and strokes than the SGLT2 inhibitors.

The FDA’s willingness to consider data from both trials in an NDA was not a given, as the primary endpoints for both trials underwent tweaking while they were underway to compensate for an unexpectedly early end to patient enrollment and follow-up caused by changes in drug company sponsorship and challenges introduced by the COVID-19 pandemic.

In 2019, the FDA denied the NDA for sotagliflozin as a treatment for patients with type 1 diabetes, but this indication received approval in Europe.

SOLOIST and SCORED were sponsored initially by Sanofi, and more recently by Lexicon.

mzoler@mdedge.com

The Food and Drug Administration has determined that data collected on the dual SGLT1/2 inhibitor sotagliflozin (Zynquista) for treating patients with type 2 diabetes in the SOLOIST and SCORED pivotal trials can help support a New Drug Application (NDA) submission, according to a statement released on Jan. 14 by Lexicon Pharmaceuticals, the company developing this drug. Lexicon concurrently said that it hopes to potentially file this NDA later in 2021.

The statement said the FDA’s decision related to an NDA for “an indication to reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent visits for heart failure in adult patients with type 2 diabetes with either worsening heart failure or additional risk factors for heart failure.”

Results from SOLOIST and SCORED, first reported in November 2020 at the American Heart Association scientific sessions, showed statistically significant benefits for their respective primary endpoints.

The findings also demonstrated several novel benefits from the first advanced clinical trials of an SGLT inhibitor that blocks both the SGLT2 protein in kidneys as well as the SGLT1 protein, which resides primarily in the gastrointestinal system and is the main route for glucose out of the gut.

In both SOLOIST and SCORED, patient outcomes on sotagliflozin tracked the benefits and adverse effects previously seen with several SGLT2 inhibitors (canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin), but in addition showed several unprecedented benefits: An ability to lower hemoglobin A1c in patients with severely depressed renal function, safe initiation in patients recently hospitalized for heart failure, the first prospective data to show improvements in patients with heart failure with preserved ejection fraction, and a higher level of protection against MIs and strokes than the SGLT2 inhibitors.

The FDA’s willingness to consider data from both trials in an NDA was not a given, as the primary endpoints for both trials underwent tweaking while they were underway to compensate for an unexpectedly early end to patient enrollment and follow-up caused by changes in drug company sponsorship and challenges introduced by the COVID-19 pandemic.

In 2019, the FDA denied the NDA for sotagliflozin as a treatment for patients with type 1 diabetes, but this indication received approval in Europe.

SOLOIST and SCORED were sponsored initially by Sanofi, and more recently by Lexicon.

mzoler@mdedge.com

The Food and Drug Administration has determined that data collected on the dual SGLT1/2 inhibitor sotagliflozin (Zynquista) for treating patients with type 2 diabetes in the SOLOIST and SCORED pivotal trials can help support a New Drug Application (NDA) submission, according to a statement released on Jan. 14 by Lexicon Pharmaceuticals, the company developing this drug. Lexicon concurrently said that it hopes to potentially file this NDA later in 2021.

The statement said the FDA’s decision related to an NDA for “an indication to reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent visits for heart failure in adult patients with type 2 diabetes with either worsening heart failure or additional risk factors for heart failure.”

Results from SOLOIST and SCORED, first reported in November 2020 at the American Heart Association scientific sessions, showed statistically significant benefits for their respective primary endpoints.

The findings also demonstrated several novel benefits from the first advanced clinical trials of an SGLT inhibitor that blocks both the SGLT2 protein in kidneys as well as the SGLT1 protein, which resides primarily in the gastrointestinal system and is the main route for glucose out of the gut.

In both SOLOIST and SCORED, patient outcomes on sotagliflozin tracked the benefits and adverse effects previously seen with several SGLT2 inhibitors (canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin), but in addition showed several unprecedented benefits: An ability to lower hemoglobin A1c in patients with severely depressed renal function, safe initiation in patients recently hospitalized for heart failure, the first prospective data to show improvements in patients with heart failure with preserved ejection fraction, and a higher level of protection against MIs and strokes than the SGLT2 inhibitors.

The FDA’s willingness to consider data from both trials in an NDA was not a given, as the primary endpoints for both trials underwent tweaking while they were underway to compensate for an unexpectedly early end to patient enrollment and follow-up caused by changes in drug company sponsorship and challenges introduced by the COVID-19 pandemic.

In 2019, the FDA denied the NDA for sotagliflozin as a treatment for patients with type 1 diabetes, but this indication received approval in Europe.

SOLOIST and SCORED were sponsored initially by Sanofi, and more recently by Lexicon.

mzoler@mdedge.com

A newly updated expert consensus from the American College of Cardiology for management of heart failure with reduced ejection fraction includes several new guideline-directed medical therapies among other substantial changes relative to its 2017 predecessor.

The advances in treatment of heart failure with reduced ejection fraction (HFrEF) have resulted in a substantial increase in complexity in reaching treatment goals, according to the authors of the new guidance. Structured similarly to the 2017 ACC Expert Consensus Decision Pathway, the update accommodates a series of practical tips to bring all patients on board with the newer as well as the established therapies with lifesaving potential.

The potential return from implementing these recommendations is not trivial. Relative to an ACE inhibitor and a beta-blocker alone, optimal implementation of the current guideline-directed medical therapies (GDMT) “can extend medical survival by more than 6 years,” according to Gregg C. Fonarow, MD, chief of cardiology at the University of California, Los Angeles.

A member of the writing committee for the 2021 update, Dr. Fonarow explained that the consensus pathway is more than a list of therapies and recommended doses. The detailed advice on how to overcome the barriers to GDMT is meant to close the substantial gap between current practice and unmet opportunities for inhibiting HFrEF progression.

“Optimal GDMT among HFrEF patients is distressingly low, due in part to the number and complexity of medications that now constitute GDMT,” said the chair of the writing committee, Thomas M. Maddox, MD, executive director, Healthcare Innovation Lab, BJC HealthCare/Washington University, St. Louis. Like Dr. Fonarow, Dr. Maddox emphasized that the importance of the update for the practical strategies it offers to place patients on optimal care.

SOURCE: Maddox TM et al. J Am Coll Cardiol. 2021 Jan 11. doi: 10.1016/j.jacc.2020.11.022.

A newly updated expert consensus from the American College of Cardiology for management of heart failure with reduced ejection fraction includes several new guideline-directed medical therapies among other substantial changes relative to its 2017 predecessor.

The advances in treatment of heart failure with reduced ejection fraction (HFrEF) have resulted in a substantial increase in complexity in reaching treatment goals, according to the authors of the new guidance. Structured similarly to the 2017 ACC Expert Consensus Decision Pathway, the update accommodates a series of practical tips to bring all patients on board with the newer as well as the established therapies with lifesaving potential.

The potential return from implementing these recommendations is not trivial. Relative to an ACE inhibitor and a beta-blocker alone, optimal implementation of the current guideline-directed medical therapies (GDMT) “can extend medical survival by more than 6 years,” according to Gregg C. Fonarow, MD, chief of cardiology at the University of California, Los Angeles.

A member of the writing committee for the 2021 update, Dr. Fonarow explained that the consensus pathway is more than a list of therapies and recommended doses. The detailed advice on how to overcome the barriers to GDMT is meant to close the substantial gap between current practice and unmet opportunities for inhibiting HFrEF progression.

“Optimal GDMT among HFrEF patients is distressingly low, due in part to the number and complexity of medications that now constitute GDMT,” said the chair of the writing committee, Thomas M. Maddox, MD, executive director, Healthcare Innovation Lab, BJC HealthCare/Washington University, St. Louis. Like Dr. Fonarow, Dr. Maddox emphasized that the importance of the update for the practical strategies it offers to place patients on optimal care.

SOURCE: Maddox TM et al. J Am Coll Cardiol. 2021 Jan 11. doi: 10.1016/j.jacc.2020.11.022.

A newly updated expert consensus from the American College of Cardiology for management of heart failure with reduced ejection fraction includes several new guideline-directed medical therapies among other substantial changes relative to its 2017 predecessor.

The advances in treatment of heart failure with reduced ejection fraction (HFrEF) have resulted in a substantial increase in complexity in reaching treatment goals, according to the authors of the new guidance. Structured similarly to the 2017 ACC Expert Consensus Decision Pathway, the update accommodates a series of practical tips to bring all patients on board with the newer as well as the established therapies with lifesaving potential.

The potential return from implementing these recommendations is not trivial. Relative to an ACE inhibitor and a beta-blocker alone, optimal implementation of the current guideline-directed medical therapies (GDMT) “can extend medical survival by more than 6 years,” according to Gregg C. Fonarow, MD, chief of cardiology at the University of California, Los Angeles.

A member of the writing committee for the 2021 update, Dr. Fonarow explained that the consensus pathway is more than a list of therapies and recommended doses. The detailed advice on how to overcome the barriers to GDMT is meant to close the substantial gap between current practice and unmet opportunities for inhibiting HFrEF progression.

“Optimal GDMT among HFrEF patients is distressingly low, due in part to the number and complexity of medications that now constitute GDMT,” said the chair of the writing committee, Thomas M. Maddox, MD, executive director, Healthcare Innovation Lab, BJC HealthCare/Washington University, St. Louis. Like Dr. Fonarow, Dr. Maddox emphasized that the importance of the update for the practical strategies it offers to place patients on optimal care.

SOURCE: Maddox TM et al. J Am Coll Cardiol. 2021 Jan 11. doi: 10.1016/j.jacc.2020.11.022.

Patients with heart failure who are infected with SARS-CoV-2 are at high risk for complications, with nearly 1 in 4 dying during hospitalization, according to a large database analysis that included more than 8,000 patients who had heart failure and COVID-19.

Floaria Bicher/iStock/Getty Images Plus

In-hospital mortality was 24.2% for patients who had a history of heart failure and were hospitalized with COVID-19, as compared with 14.2% for individuals without heart failure who were hospitalized with COVID-19.

For perspective, the researchers compared the patients with heart failure and COVID-19 with patients who had a history of heart failure and were hospitalized for an acute worsening episode: the risk for death was about 10-fold higher with COVID-19.

“These patients really face remarkably high risk, and when we compare that to the risk of in-hospital death with something we are a lot more familiar with – acute heart failure – we see that the risk was about 10-fold greater,” said first author Ankeet S. Bhatt, MD, MBA, from Brigham and Women’s Hospital and Harvard Medical School, both in Boston.

In an article published online in JACC Heart Failure on Dec. 28, a group led by Dr. Bhatt and senior author Scott D. Solomon, MD, reported an analysis of administrative data on a total of 2,041,855 incident hospitalizations logged in the Premier Healthcare Database between April 1, 2020, and Sept. 30, 2020.

The Premier Healthcare Database comprises data from more than 1 billion patient encounters, which equates to approximately 1 in every 5 of all inpatient discharges in the United States.

Of 132,312 hospitalizations of patients with a history of heart failure, 23,843 (18.0%) were hospitalized with acute heart failure, 8,383 patients (6.4%) were hospitalized with COVID-19, and 100,068 (75.6%) were hospitalized for other reasons.

Outcomes and resource utilization were compared with 141,895 COVID-19 hospitalizations of patients who did not have heart failure.

Patients were deemed to have a history of heart failure if they were hospitalized at least once for heart failure from Jan. 1, 2019, to March 21, 2020, or had at least two heart failure outpatient visits during that period.

In a comment, Dr. Solomon noted some of the pros and cons of the data used in this study.

“Premier is a huge database, encompassing about one-quarter of all the health care facilities in the United States and one-fifth of all inpatient visits, so for that reason we’re able to look at things that are very difficult to look at in smaller hospital systems, but the data are also limited in that you don’t have as much granular detail as you might in smaller datasets,” said Dr. Solomon.

“One thing to recognize is that our data start at the point of hospital admission, so were looking only at individuals who have crossed the threshold in terms of their illness and been admitted,” he added.

Use of in-hospital resources was significantly greater for patients with heart failure hospitalized for COVID-19, compared with patients hospitalized for acute heart failure or for other reasons. This included “multifold” higher rates of ICU care (29% vs. 15%), mechanical ventilation (17% vs. 6%), and central venous catheter insertion (19% vs. 7%; P < .001 for all).

The proportion of patients who required mechanical ventilation and care in the ICU in the group with COVID-19 but who did not have no heart failure was similar to those who had both conditions.

The greater odds of in-hospital mortality among patients with both heart failure and COVID-19, compared with individuals with heart failure hospitalized for other reasons, was strongest in April, with an adjusted odds ratio of 14.48, compared with subsequent months (adjusted OR for May-September, 10.11; P for interaction < .001).

“We’re obviously not able to say with certainty what was happening in April, but I think that maybe the patients who were most vulnerable to COVID-19 may be more represented in that population, so the patients with comorbidities or who are immunosuppressed or otherwise,” said Dr. Bhatt in an interview.

“The other thing we think is that there may be a learning curve in terms of how to care for patients with acute severe respiratory illness. That includes increased institutional knowledge – like the use of prone ventilation – but also therapies that were subsequently shown to have benefit in randomized clinical trials, such as dexamethasone,” he added.

“These results should remind us to be innovative and thoughtful in our management of patients with heart failure while trying to maintain equity and good health for all,” wrote Nasrien E. Ibrahim, MD, from Massachusetts General Hospital, Boston; Ersilia DeFillipis, MD, Columbia University, New York; and Mitchel Psotka, MD, PhD, Innova Heart and Vascular Institute, Falls Church, Va., in an editorial accompanying the study.

The data emphasize the importance of ensuring equal access to services such as telemedicine, virtual visits, home nursing visits, and remote monitoring, they noted.

“As the COVID-19 pandemic rages on and disproportionately ravages socioeconomically disadvantaged communities, we should focus our efforts on strategies that minimize these inequities,” the editorialists wrote.

Dr. Solomon noted that, although Black and Hispanic patients were overrepresented in the population of heart failure patients hospitalized with COVID-19, once in the hospital, race was not a predictor of in-hospital mortality or the need for mechanical ventilation.

Dr. Bhatt has received speaker fees from Sanofi Pasteur and is supported by a National Institutes of Health/National Heart, Lung, and Blood Institute postdoctoral training grant. Dr. Solomon has received grant support and/or speaking fees from a number of companies and from the NIH/NHLBI. The editorialists disclosed no relevant financial relationships.

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

Patients with heart failure who are infected with SARS-CoV-2 are at high risk for complications, with nearly 1 in 4 dying during hospitalization, according to a large database analysis that included more than 8,000 patients who had heart failure and COVID-19.

Floaria Bicher/iStock/Getty Images Plus

In-hospital mortality was 24.2% for patients who had a history of heart failure and were hospitalized with COVID-19, as compared with 14.2% for individuals without heart failure who were hospitalized with COVID-19.

For perspective, the researchers compared the patients with heart failure and COVID-19 with patients who had a history of heart failure and were hospitalized for an acute worsening episode: the risk for death was about 10-fold higher with COVID-19.

“These patients really face remarkably high risk, and when we compare that to the risk of in-hospital death with something we are a lot more familiar with – acute heart failure – we see that the risk was about 10-fold greater,” said first author Ankeet S. Bhatt, MD, MBA, from Brigham and Women’s Hospital and Harvard Medical School, both in Boston.

In an article published online in JACC Heart Failure on Dec. 28, a group led by Dr. Bhatt and senior author Scott D. Solomon, MD, reported an analysis of administrative data on a total of 2,041,855 incident hospitalizations logged in the Premier Healthcare Database between April 1, 2020, and Sept. 30, 2020.

The Premier Healthcare Database comprises data from more than 1 billion patient encounters, which equates to approximately 1 in every 5 of all inpatient discharges in the United States.

Of 132,312 hospitalizations of patients with a history of heart failure, 23,843 (18.0%) were hospitalized with acute heart failure, 8,383 patients (6.4%) were hospitalized with COVID-19, and 100,068 (75.6%) were hospitalized for other reasons.

Outcomes and resource utilization were compared with 141,895 COVID-19 hospitalizations of patients who did not have heart failure.

Patients were deemed to have a history of heart failure if they were hospitalized at least once for heart failure from Jan. 1, 2019, to March 21, 2020, or had at least two heart failure outpatient visits during that period.

In a comment, Dr. Solomon noted some of the pros and cons of the data used in this study.

“Premier is a huge database, encompassing about one-quarter of all the health care facilities in the United States and one-fifth of all inpatient visits, so for that reason we’re able to look at things that are very difficult to look at in smaller hospital systems, but the data are also limited in that you don’t have as much granular detail as you might in smaller datasets,” said Dr. Solomon.

“One thing to recognize is that our data start at the point of hospital admission, so were looking only at individuals who have crossed the threshold in terms of their illness and been admitted,” he added.

Use of in-hospital resources was significantly greater for patients with heart failure hospitalized for COVID-19, compared with patients hospitalized for acute heart failure or for other reasons. This included “multifold” higher rates of ICU care (29% vs. 15%), mechanical ventilation (17% vs. 6%), and central venous catheter insertion (19% vs. 7%; P < .001 for all).

The proportion of patients who required mechanical ventilation and care in the ICU in the group with COVID-19 but who did not have no heart failure was similar to those who had both conditions.

The greater odds of in-hospital mortality among patients with both heart failure and COVID-19, compared with individuals with heart failure hospitalized for other reasons, was strongest in April, with an adjusted odds ratio of 14.48, compared with subsequent months (adjusted OR for May-September, 10.11; P for interaction < .001).

“We’re obviously not able to say with certainty what was happening in April, but I think that maybe the patients who were most vulnerable to COVID-19 may be more represented in that population, so the patients with comorbidities or who are immunosuppressed or otherwise,” said Dr. Bhatt in an interview.

“The other thing we think is that there may be a learning curve in terms of how to care for patients with acute severe respiratory illness. That includes increased institutional knowledge – like the use of prone ventilation – but also therapies that were subsequently shown to have benefit in randomized clinical trials, such as dexamethasone,” he added.

“These results should remind us to be innovative and thoughtful in our management of patients with heart failure while trying to maintain equity and good health for all,” wrote Nasrien E. Ibrahim, MD, from Massachusetts General Hospital, Boston; Ersilia DeFillipis, MD, Columbia University, New York; and Mitchel Psotka, MD, PhD, Innova Heart and Vascular Institute, Falls Church, Va., in an editorial accompanying the study.

The data emphasize the importance of ensuring equal access to services such as telemedicine, virtual visits, home nursing visits, and remote monitoring, they noted.

“As the COVID-19 pandemic rages on and disproportionately ravages socioeconomically disadvantaged communities, we should focus our efforts on strategies that minimize these inequities,” the editorialists wrote.

Dr. Solomon noted that, although Black and Hispanic patients were overrepresented in the population of heart failure patients hospitalized with COVID-19, once in the hospital, race was not a predictor of in-hospital mortality or the need for mechanical ventilation.

Dr. Bhatt has received speaker fees from Sanofi Pasteur and is supported by a National Institutes of Health/National Heart, Lung, and Blood Institute postdoctoral training grant. Dr. Solomon has received grant support and/or speaking fees from a number of companies and from the NIH/NHLBI. The editorialists disclosed no relevant financial relationships.

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

Patients with heart failure who are infected with SARS-CoV-2 are at high risk for complications, with nearly 1 in 4 dying during hospitalization, according to a large database analysis that included more than 8,000 patients who had heart failure and COVID-19.

Floaria Bicher/iStock/Getty Images Plus

In-hospital mortality was 24.2% for patients who had a history of heart failure and were hospitalized with COVID-19, as compared with 14.2% for individuals without heart failure who were hospitalized with COVID-19.

For perspective, the researchers compared the patients with heart failure and COVID-19 with patients who had a history of heart failure and were hospitalized for an acute worsening episode: the risk for death was about 10-fold higher with COVID-19.

“These patients really face remarkably high risk, and when we compare that to the risk of in-hospital death with something we are a lot more familiar with – acute heart failure – we see that the risk was about 10-fold greater,” said first author Ankeet S. Bhatt, MD, MBA, from Brigham and Women’s Hospital and Harvard Medical School, both in Boston.

In an article published online in JACC Heart Failure on Dec. 28, a group led by Dr. Bhatt and senior author Scott D. Solomon, MD, reported an analysis of administrative data on a total of 2,041,855 incident hospitalizations logged in the Premier Healthcare Database between April 1, 2020, and Sept. 30, 2020.

The Premier Healthcare Database comprises data from more than 1 billion patient encounters, which equates to approximately 1 in every 5 of all inpatient discharges in the United States.

Of 132,312 hospitalizations of patients with a history of heart failure, 23,843 (18.0%) were hospitalized with acute heart failure, 8,383 patients (6.4%) were hospitalized with COVID-19, and 100,068 (75.6%) were hospitalized for other reasons.

Outcomes and resource utilization were compared with 141,895 COVID-19 hospitalizations of patients who did not have heart failure.

Patients were deemed to have a history of heart failure if they were hospitalized at least once for heart failure from Jan. 1, 2019, to March 21, 2020, or had at least two heart failure outpatient visits during that period.

In a comment, Dr. Solomon noted some of the pros and cons of the data used in this study.

“Premier is a huge database, encompassing about one-quarter of all the health care facilities in the United States and one-fifth of all inpatient visits, so for that reason we’re able to look at things that are very difficult to look at in smaller hospital systems, but the data are also limited in that you don’t have as much granular detail as you might in smaller datasets,” said Dr. Solomon.

“One thing to recognize is that our data start at the point of hospital admission, so were looking only at individuals who have crossed the threshold in terms of their illness and been admitted,” he added.

Use of in-hospital resources was significantly greater for patients with heart failure hospitalized for COVID-19, compared with patients hospitalized for acute heart failure or for other reasons. This included “multifold” higher rates of ICU care (29% vs. 15%), mechanical ventilation (17% vs. 6%), and central venous catheter insertion (19% vs. 7%; P < .001 for all).

The proportion of patients who required mechanical ventilation and care in the ICU in the group with COVID-19 but who did not have no heart failure was similar to those who had both conditions.

The greater odds of in-hospital mortality among patients with both heart failure and COVID-19, compared with individuals with heart failure hospitalized for other reasons, was strongest in April, with an adjusted odds ratio of 14.48, compared with subsequent months (adjusted OR for May-September, 10.11; P for interaction < .001).

“We’re obviously not able to say with certainty what was happening in April, but I think that maybe the patients who were most vulnerable to COVID-19 may be more represented in that population, so the patients with comorbidities or who are immunosuppressed or otherwise,” said Dr. Bhatt in an interview.

“The other thing we think is that there may be a learning curve in terms of how to care for patients with acute severe respiratory illness. That includes increased institutional knowledge – like the use of prone ventilation – but also therapies that were subsequently shown to have benefit in randomized clinical trials, such as dexamethasone,” he added.

“These results should remind us to be innovative and thoughtful in our management of patients with heart failure while trying to maintain equity and good health for all,” wrote Nasrien E. Ibrahim, MD, from Massachusetts General Hospital, Boston; Ersilia DeFillipis, MD, Columbia University, New York; and Mitchel Psotka, MD, PhD, Innova Heart and Vascular Institute, Falls Church, Va., in an editorial accompanying the study.

The data emphasize the importance of ensuring equal access to services such as telemedicine, virtual visits, home nursing visits, and remote monitoring, they noted.

“As the COVID-19 pandemic rages on and disproportionately ravages socioeconomically disadvantaged communities, we should focus our efforts on strategies that minimize these inequities,” the editorialists wrote.

Dr. Solomon noted that, although Black and Hispanic patients were overrepresented in the population of heart failure patients hospitalized with COVID-19, once in the hospital, race was not a predictor of in-hospital mortality or the need for mechanical ventilation.

Dr. Bhatt has received speaker fees from Sanofi Pasteur and is supported by a National Institutes of Health/National Heart, Lung, and Blood Institute postdoctoral training grant. Dr. Solomon has received grant support and/or speaking fees from a number of companies and from the NIH/NHLBI. The editorialists disclosed no relevant financial relationships.

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

Elite American soccer players have, on average, larger, thicker, and heavier hearts than the general population, according to a new study that provides clinicians with normative echocardiogram and electrocardiogram (ECG) cutoffs to use when assessing the heart health of competitive athletes.

Nikada/Getty Images

To provide these age- and sex-specific reference values, a team from Massachusetts General Hospital, Boston, led by Timothy W. Churchill, MD, and Aaron L. Baggish, MD, analyzed data from 122 female and 116 male soccer players from the American national teams preparing for World Cup play and undergoing FIFA-mandated preparticipation screening.

The athletes frequently exceeded normal echocardiographic ranges for left ventricular (LV) mass, volume, and wall thickness – structural cardiac parameters responsive to exercise-induced remodeling – but with none showing pathologic findings that might indicate the need to restrict their participation in the sport.

Almost one-third (30%) of female athletes and 41% of male athletes exceeded the American Society of Echocardiography’s upper limit of normal for LV wall thickness, with a measure greater than 12 mm seen in 12% of men and 1% of women.

The majority (51% of females and 59% of males) exceeded normal ranges for body surface area–indexed LV mass, with 77% and 68%, respectively, having LV volumes above the normal range.

Dr. Baggish stressed in an interview, however, that these data tell a story about healthy hearts, not at-risk hearts.

“These are the healthiest, highest-performing elite soccer players that we have in the United States, and this is really a look at how adaptive the heart can be, how much it can grow and change in size, shape, structure, and function in response to sport,” said Dr. Baggish.

The mean age of screened athletes was 20 years (range, 15-40 years). The majority of the female players were White (71%), whereas the male players were more evenly divided between Black (34%), Hispanic (33%), and White (32%).

Screening was performed at U.S. Soccer training sites by experienced clinicians affiliated with the Massachusetts General Hospital cardiovascular performance program.

Interestingly, the study debunks the idea that women, on average, have smaller chamber sizes. “When we did body-size correction, the men and women actually looked pretty similar with respect to their ability to adapt to strenuous exercise,” noted Dr. Baggish.

They did see, however, that women were more likely than men to have abnormal ECG findings. Male athletes showed a higher prevalence of “normal” training-related ECG findings, whereas female athletes were more likely to have abnormal ECG patterns (11.5% vs. 0.0% in the male cohort), most often pathologic T-wave inversions (TWI) confined to the anterior precordial lead distribution.

“This is important because ECGs are the most common screening tool used and we wanted to alert people to the fact that these women who showed some abnormalities on ECG went on to have a total healthy-looking echo, so a false-positive ECG is something to consider,” said Dr. Baggish.

This excess in anterior TWIs has been seen in previous studies and is thought to be benign, although the mechanism remains unclear. Four of the nine female athletes with abnormal ECG findings on initial evaluation had normalized on repeat testing 2-4 years later. Serial data were available in only a subset of athletes.
 

Clarity needed after COVID

The data, published recently in JAMA Cardiology, are particularly valuable these days given concern over the effects of COVID-19 on the heart and return-to-play recommendations.

“Athletes who have had COVID are being sent for echocardiograms before they can return to play to check for COVID-induced heart disease – which is real – but what we’re seeing is that there’s confusion out there in terms of what is a COVID-related abnormality and what is a normal, adapted athletic heart,” said Dr. Baggish.

“In this paper, we provide a dataset of normal values – generated before COVID was on anyone’s radar – to let cardiologists know what’s ‘big good’ and not ‘big bad.’ ”
 

More sport-specific data needed

“Although these numbers are still small, this dataset is an important step forward in our understanding of athletic adaptations,” said Matthew Martinez, MD, in an interview. “Many factors impact physiologic athletic changes, and the study aids in our understanding of gender- and sport-specific changes in athletes.”

Dr. Martinez, who is the director of sports cardiology at Atlantic Health–Morristown (N.J.) Medical Center and the Gagnon Cardiovascular Institute, also in Morristown, and the chair of Sports and Exercise Cardiology Section Leadership Council for the American College of Cardiology, noted the relatively young mean age of screened athletes.

“The data represent collegiate-age athletes with some older groups mixed in, but it does not represent older established elite athlete changes,” he said.

Mean age was 21 years in the female players but only 18 years in the males because the men’s senior national team failed to qualify for the World Cup during the study period and was therefore not screened. The authors acknowledged the “dearth of older men in the cohort.”

There is, overall, little age-, sport-, and sex-specific normative data for differentiating training-related cardiovascular adaptations from potentially pathologic phenotypes, wrote the authors.

It exists for men playing in the National Football League and for both sexes participating in the National Basketball Association, but most other studies have mixed the sports and focused mainly on men. That said, Dr. Baggish does not consider these data to be applicable to all elite athletes.

“Soccer is kind of in a league of its own with respect to the mixed amount of explosive or resistant and aerobic work that these athletes have to do, and also it’s the most popular sport in the world, so we really wanted to focus on them,” said Dr. Baggish.

Although the findings are perhaps applicable to athletes from other team sports characterized by explosive spurts of high-intensity activity – like hockey, lacrosse, and field hockey – he would not suggest they be applied to, say, long-distance runners, cyclists, or other sports that require a similar type of aerobic output.

Dr. Baggish reported no relevant conflict of interest. Dr. Martinez is league cardiologist for Major League Soccer.

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

Elite American soccer players have, on average, larger, thicker, and heavier hearts than the general population, according to a new study that provides clinicians with normative echocardiogram and electrocardiogram (ECG) cutoffs to use when assessing the heart health of competitive athletes.

Nikada/Getty Images

To provide these age- and sex-specific reference values, a team from Massachusetts General Hospital, Boston, led by Timothy W. Churchill, MD, and Aaron L. Baggish, MD, analyzed data from 122 female and 116 male soccer players from the American national teams preparing for World Cup play and undergoing FIFA-mandated preparticipation screening.

The athletes frequently exceeded normal echocardiographic ranges for left ventricular (LV) mass, volume, and wall thickness – structural cardiac parameters responsive to exercise-induced remodeling – but with none showing pathologic findings that might indicate the need to restrict their participation in the sport.

Almost one-third (30%) of female athletes and 41% of male athletes exceeded the American Society of Echocardiography’s upper limit of normal for LV wall thickness, with a measure greater than 12 mm seen in 12% of men and 1% of women.

The majority (51% of females and 59% of males) exceeded normal ranges for body surface area–indexed LV mass, with 77% and 68%, respectively, having LV volumes above the normal range.

Dr. Baggish stressed in an interview, however, that these data tell a story about healthy hearts, not at-risk hearts.

“These are the healthiest, highest-performing elite soccer players that we have in the United States, and this is really a look at how adaptive the heart can be, how much it can grow and change in size, shape, structure, and function in response to sport,” said Dr. Baggish.

The mean age of screened athletes was 20 years (range, 15-40 years). The majority of the female players were White (71%), whereas the male players were more evenly divided between Black (34%), Hispanic (33%), and White (32%).

Screening was performed at U.S. Soccer training sites by experienced clinicians affiliated with the Massachusetts General Hospital cardiovascular performance program.

Interestingly, the study debunks the idea that women, on average, have smaller chamber sizes. “When we did body-size correction, the men and women actually looked pretty similar with respect to their ability to adapt to strenuous exercise,” noted Dr. Baggish.

They did see, however, that women were more likely than men to have abnormal ECG findings. Male athletes showed a higher prevalence of “normal” training-related ECG findings, whereas female athletes were more likely to have abnormal ECG patterns (11.5% vs. 0.0% in the male cohort), most often pathologic T-wave inversions (TWI) confined to the anterior precordial lead distribution.

“This is important because ECGs are the most common screening tool used and we wanted to alert people to the fact that these women who showed some abnormalities on ECG went on to have a total healthy-looking echo, so a false-positive ECG is something to consider,” said Dr. Baggish.

This excess in anterior TWIs has been seen in previous studies and is thought to be benign, although the mechanism remains unclear. Four of the nine female athletes with abnormal ECG findings on initial evaluation had normalized on repeat testing 2-4 years later. Serial data were available in only a subset of athletes.
 

Clarity needed after COVID

The data, published recently in JAMA Cardiology, are particularly valuable these days given concern over the effects of COVID-19 on the heart and return-to-play recommendations.

“Athletes who have had COVID are being sent for echocardiograms before they can return to play to check for COVID-induced heart disease – which is real – but what we’re seeing is that there’s confusion out there in terms of what is a COVID-related abnormality and what is a normal, adapted athletic heart,” said Dr. Baggish.

“In this paper, we provide a dataset of normal values – generated before COVID was on anyone’s radar – to let cardiologists know what’s ‘big good’ and not ‘big bad.’ ”
 

More sport-specific data needed

“Although these numbers are still small, this dataset is an important step forward in our understanding of athletic adaptations,” said Matthew Martinez, MD, in an interview. “Many factors impact physiologic athletic changes, and the study aids in our understanding of gender- and sport-specific changes in athletes.”

Dr. Martinez, who is the director of sports cardiology at Atlantic Health–Morristown (N.J.) Medical Center and the Gagnon Cardiovascular Institute, also in Morristown, and the chair of Sports and Exercise Cardiology Section Leadership Council for the American College of Cardiology, noted the relatively young mean age of screened athletes.

“The data represent collegiate-age athletes with some older groups mixed in, but it does not represent older established elite athlete changes,” he said.

Mean age was 21 years in the female players but only 18 years in the males because the men’s senior national team failed to qualify for the World Cup during the study period and was therefore not screened. The authors acknowledged the “dearth of older men in the cohort.”

There is, overall, little age-, sport-, and sex-specific normative data for differentiating training-related cardiovascular adaptations from potentially pathologic phenotypes, wrote the authors.

It exists for men playing in the National Football League and for both sexes participating in the National Basketball Association, but most other studies have mixed the sports and focused mainly on men. That said, Dr. Baggish does not consider these data to be applicable to all elite athletes.

“Soccer is kind of in a league of its own with respect to the mixed amount of explosive or resistant and aerobic work that these athletes have to do, and also it’s the most popular sport in the world, so we really wanted to focus on them,” said Dr. Baggish.

Although the findings are perhaps applicable to athletes from other team sports characterized by explosive spurts of high-intensity activity – like hockey, lacrosse, and field hockey – he would not suggest they be applied to, say, long-distance runners, cyclists, or other sports that require a similar type of aerobic output.

Dr. Baggish reported no relevant conflict of interest. Dr. Martinez is league cardiologist for Major League Soccer.

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

Elite American soccer players have, on average, larger, thicker, and heavier hearts than the general population, according to a new study that provides clinicians with normative echocardiogram and electrocardiogram (ECG) cutoffs to use when assessing the heart health of competitive athletes.

Nikada/Getty Images

To provide these age- and sex-specific reference values, a team from Massachusetts General Hospital, Boston, led by Timothy W. Churchill, MD, and Aaron L. Baggish, MD, analyzed data from 122 female and 116 male soccer players from the American national teams preparing for World Cup play and undergoing FIFA-mandated preparticipation screening.

The athletes frequently exceeded normal echocardiographic ranges for left ventricular (LV) mass, volume, and wall thickness – structural cardiac parameters responsive to exercise-induced remodeling – but with none showing pathologic findings that might indicate the need to restrict their participation in the sport.

Almost one-third (30%) of female athletes and 41% of male athletes exceeded the American Society of Echocardiography’s upper limit of normal for LV wall thickness, with a measure greater than 12 mm seen in 12% of men and 1% of women.

The majority (51% of females and 59% of males) exceeded normal ranges for body surface area–indexed LV mass, with 77% and 68%, respectively, having LV volumes above the normal range.

Dr. Baggish stressed in an interview, however, that these data tell a story about healthy hearts, not at-risk hearts.

“These are the healthiest, highest-performing elite soccer players that we have in the United States, and this is really a look at how adaptive the heart can be, how much it can grow and change in size, shape, structure, and function in response to sport,” said Dr. Baggish.

The mean age of screened athletes was 20 years (range, 15-40 years). The majority of the female players were White (71%), whereas the male players were more evenly divided between Black (34%), Hispanic (33%), and White (32%).

Screening was performed at U.S. Soccer training sites by experienced clinicians affiliated with the Massachusetts General Hospital cardiovascular performance program.

Interestingly, the study debunks the idea that women, on average, have smaller chamber sizes. “When we did body-size correction, the men and women actually looked pretty similar with respect to their ability to adapt to strenuous exercise,” noted Dr. Baggish.

They did see, however, that women were more likely than men to have abnormal ECG findings. Male athletes showed a higher prevalence of “normal” training-related ECG findings, whereas female athletes were more likely to have abnormal ECG patterns (11.5% vs. 0.0% in the male cohort), most often pathologic T-wave inversions (TWI) confined to the anterior precordial lead distribution.

“This is important because ECGs are the most common screening tool used and we wanted to alert people to the fact that these women who showed some abnormalities on ECG went on to have a total healthy-looking echo, so a false-positive ECG is something to consider,” said Dr. Baggish.

This excess in anterior TWIs has been seen in previous studies and is thought to be benign, although the mechanism remains unclear. Four of the nine female athletes with abnormal ECG findings on initial evaluation had normalized on repeat testing 2-4 years later. Serial data were available in only a subset of athletes.
 

Clarity needed after COVID

The data, published recently in JAMA Cardiology, are particularly valuable these days given concern over the effects of COVID-19 on the heart and return-to-play recommendations.

“Athletes who have had COVID are being sent for echocardiograms before they can return to play to check for COVID-induced heart disease – which is real – but what we’re seeing is that there’s confusion out there in terms of what is a COVID-related abnormality and what is a normal, adapted athletic heart,” said Dr. Baggish.

“In this paper, we provide a dataset of normal values – generated before COVID was on anyone’s radar – to let cardiologists know what’s ‘big good’ and not ‘big bad.’ ”
 

More sport-specific data needed

“Although these numbers are still small, this dataset is an important step forward in our understanding of athletic adaptations,” said Matthew Martinez, MD, in an interview. “Many factors impact physiologic athletic changes, and the study aids in our understanding of gender- and sport-specific changes in athletes.”

Dr. Martinez, who is the director of sports cardiology at Atlantic Health–Morristown (N.J.) Medical Center and the Gagnon Cardiovascular Institute, also in Morristown, and the chair of Sports and Exercise Cardiology Section Leadership Council for the American College of Cardiology, noted the relatively young mean age of screened athletes.

“The data represent collegiate-age athletes with some older groups mixed in, but it does not represent older established elite athlete changes,” he said.

Mean age was 21 years in the female players but only 18 years in the males because the men’s senior national team failed to qualify for the World Cup during the study period and was therefore not screened. The authors acknowledged the “dearth of older men in the cohort.”

There is, overall, little age-, sport-, and sex-specific normative data for differentiating training-related cardiovascular adaptations from potentially pathologic phenotypes, wrote the authors.

It exists for men playing in the National Football League and for both sexes participating in the National Basketball Association, but most other studies have mixed the sports and focused mainly on men. That said, Dr. Baggish does not consider these data to be applicable to all elite athletes.

“Soccer is kind of in a league of its own with respect to the mixed amount of explosive or resistant and aerobic work that these athletes have to do, and also it’s the most popular sport in the world, so we really wanted to focus on them,” said Dr. Baggish.

Although the findings are perhaps applicable to athletes from other team sports characterized by explosive spurts of high-intensity activity – like hockey, lacrosse, and field hockey – he would not suggest they be applied to, say, long-distance runners, cyclists, or other sports that require a similar type of aerobic output.

Dr. Baggish reported no relevant conflict of interest. Dr. Martinez is league cardiologist for Major League Soccer.

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

Heart transplant recipients infected with SARS-CoV-2 are about twice as likely to die from COVID-19 and should be immediately referred to a transplant center for care, according to transplant experts from Northern Italy.

In a COVID Rapid Report published Dec. 9 in JACC Heart Failure, a group led by Tomaso Bottio, MD, PhD, from the University of Padua, Italy, presented findings on 47 heart transplant recipients who tested positive for SARS-Cov-2 between Feb. 21 and June 30.

The investigators found a case fatality rate of 29.7%, compared with 15.4% in the general population. Prevalence of infection was also much higher at 18 cases (vs. 7) per 1,000 population.

“In our opinion, prompt referral to a heart transplant center is crucial for immunosuppressive therapy optimization and cardiologic follow-up,” Dr. Bottio said in an interview.

Beyond the need for careful adjustment of immunosuppression, graft function should be assessed to “avoid acute rejection or decompensation,” he added.

Dr. Bottio and colleagues tracked COVID-19 cases from among the 2,676 heart transplant recipients alive before the onset of the pandemic at seven heart transplant centers in Northern Italy.

Of the 47 recipients who contracted SARS-CoV-2, 38 required hospitalization while 9 remained at home and 14 died. Mean length of stay in hospital was 17.8 days, much longer in survivors than nonsurvivors (23.2 days vs. 8.5 days; P < .001).  

Nonsurvivors were significantly older than survivors (72 vs. 58 years; P = .002). Nonsurvivors were also more likely to present with diabetes (P = .04), extra-cardiac arteriopathy (P = .04), previous percutaneous coronary intervention (P = .04), more allograft vasculopathy (P = .04), and more symptoms of heart failure (P = .02).

Although the authors said the high case fatality rate was, unfortunately, expected, they did not expect so many patients to do well at home.

“What most surprised us was the proportion of a- or pauci-symptomatic heart transplanted patients who did well being treated at home without any therapy modifications,” Dr. Bottio shared. They were also surprised to see there were no cases of graft failure caused by infection-related myocarditis.

These findings from Northern Italy are not dissimilar from the 25% case fatality rate seen in a cohort of heart transplant recipients who caught COVID-19 in New York City early in the pandemic.

In another study, this time looking at a wider group of solid organ transplant recipients with SARS-CoV-2 infection at two centers during the first 3 weeks of the outbreak in New York City, 16 of 90 patients (18%) died.
 

Treatment recommendations?

Recognizing that there is no randomized trial data informing the treatment of this vulnerable patient population, Dr. Bottio and colleagues suggested that, based on their experience, no change in immunosuppression is needed in those who are “pauci-symptomatic” (mildly symptomatic).

“On the other hand, in hospitalized patients a partial reduction in immunosuppressive therapy avoiding full discontinuation and risk of graft rejection seems to be a common strategy in facing the viral infection,” he said. “In addition, the introduction of corticosteroids could help to suspend the onset of the inflammatory cascade responsible for severe forms of the disease.”

Antibiotic prophylaxis appears to be “fundamental,” he added, particularly in hospitalized patients, but “the role of specific antiviral therapies is still not fully understood in our population.”

Since July 1, they’ve seen an additional six patients with a positive test for SARS-CoV-2. Five were asymptomatic and quarantined at home without changing their immunosuppressive therapy. One patient was hospitalized for pneumonia and had immunosuppressive therapy reduced.

Dr. Bottio and the study coauthors have disclosed no relevant financial relationships.

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

Heart transplant recipients infected with SARS-CoV-2 are about twice as likely to die from COVID-19 and should be immediately referred to a transplant center for care, according to transplant experts from Northern Italy.

In a COVID Rapid Report published Dec. 9 in JACC Heart Failure, a group led by Tomaso Bottio, MD, PhD, from the University of Padua, Italy, presented findings on 47 heart transplant recipients who tested positive for SARS-Cov-2 between Feb. 21 and June 30.

The investigators found a case fatality rate of 29.7%, compared with 15.4% in the general population. Prevalence of infection was also much higher at 18 cases (vs. 7) per 1,000 population.

“In our opinion, prompt referral to a heart transplant center is crucial for immunosuppressive therapy optimization and cardiologic follow-up,” Dr. Bottio said in an interview.

Beyond the need for careful adjustment of immunosuppression, graft function should be assessed to “avoid acute rejection or decompensation,” he added.

Dr. Bottio and colleagues tracked COVID-19 cases from among the 2,676 heart transplant recipients alive before the onset of the pandemic at seven heart transplant centers in Northern Italy.

Of the 47 recipients who contracted SARS-CoV-2, 38 required hospitalization while 9 remained at home and 14 died. Mean length of stay in hospital was 17.8 days, much longer in survivors than nonsurvivors (23.2 days vs. 8.5 days; P < .001).  

Nonsurvivors were significantly older than survivors (72 vs. 58 years; P = .002). Nonsurvivors were also more likely to present with diabetes (P = .04), extra-cardiac arteriopathy (P = .04), previous percutaneous coronary intervention (P = .04), more allograft vasculopathy (P = .04), and more symptoms of heart failure (P = .02).

Although the authors said the high case fatality rate was, unfortunately, expected, they did not expect so many patients to do well at home.

“What most surprised us was the proportion of a- or pauci-symptomatic heart transplanted patients who did well being treated at home without any therapy modifications,” Dr. Bottio shared. They were also surprised to see there were no cases of graft failure caused by infection-related myocarditis.

These findings from Northern Italy are not dissimilar from the 25% case fatality rate seen in a cohort of heart transplant recipients who caught COVID-19 in New York City early in the pandemic.

In another study, this time looking at a wider group of solid organ transplant recipients with SARS-CoV-2 infection at two centers during the first 3 weeks of the outbreak in New York City, 16 of 90 patients (18%) died.
 

Treatment recommendations?

Recognizing that there is no randomized trial data informing the treatment of this vulnerable patient population, Dr. Bottio and colleagues suggested that, based on their experience, no change in immunosuppression is needed in those who are “pauci-symptomatic” (mildly symptomatic).

“On the other hand, in hospitalized patients a partial reduction in immunosuppressive therapy avoiding full discontinuation and risk of graft rejection seems to be a common strategy in facing the viral infection,” he said. “In addition, the introduction of corticosteroids could help to suspend the onset of the inflammatory cascade responsible for severe forms of the disease.”

Antibiotic prophylaxis appears to be “fundamental,” he added, particularly in hospitalized patients, but “the role of specific antiviral therapies is still not fully understood in our population.”

Since July 1, they’ve seen an additional six patients with a positive test for SARS-CoV-2. Five were asymptomatic and quarantined at home without changing their immunosuppressive therapy. One patient was hospitalized for pneumonia and had immunosuppressive therapy reduced.

Dr. Bottio and the study coauthors have disclosed no relevant financial relationships.

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

Heart transplant recipients infected with SARS-CoV-2 are about twice as likely to die from COVID-19 and should be immediately referred to a transplant center for care, according to transplant experts from Northern Italy.

In a COVID Rapid Report published Dec. 9 in JACC Heart Failure, a group led by Tomaso Bottio, MD, PhD, from the University of Padua, Italy, presented findings on 47 heart transplant recipients who tested positive for SARS-Cov-2 between Feb. 21 and June 30.

The investigators found a case fatality rate of 29.7%, compared with 15.4% in the general population. Prevalence of infection was also much higher at 18 cases (vs. 7) per 1,000 population.

“In our opinion, prompt referral to a heart transplant center is crucial for immunosuppressive therapy optimization and cardiologic follow-up,” Dr. Bottio said in an interview.

Beyond the need for careful adjustment of immunosuppression, graft function should be assessed to “avoid acute rejection or decompensation,” he added.

Dr. Bottio and colleagues tracked COVID-19 cases from among the 2,676 heart transplant recipients alive before the onset of the pandemic at seven heart transplant centers in Northern Italy.

Of the 47 recipients who contracted SARS-CoV-2, 38 required hospitalization while 9 remained at home and 14 died. Mean length of stay in hospital was 17.8 days, much longer in survivors than nonsurvivors (23.2 days vs. 8.5 days; P < .001).  

Nonsurvivors were significantly older than survivors (72 vs. 58 years; P = .002). Nonsurvivors were also more likely to present with diabetes (P = .04), extra-cardiac arteriopathy (P = .04), previous percutaneous coronary intervention (P = .04), more allograft vasculopathy (P = .04), and more symptoms of heart failure (P = .02).

Although the authors said the high case fatality rate was, unfortunately, expected, they did not expect so many patients to do well at home.

“What most surprised us was the proportion of a- or pauci-symptomatic heart transplanted patients who did well being treated at home without any therapy modifications,” Dr. Bottio shared. They were also surprised to see there were no cases of graft failure caused by infection-related myocarditis.

These findings from Northern Italy are not dissimilar from the 25% case fatality rate seen in a cohort of heart transplant recipients who caught COVID-19 in New York City early in the pandemic.

In another study, this time looking at a wider group of solid organ transplant recipients with SARS-CoV-2 infection at two centers during the first 3 weeks of the outbreak in New York City, 16 of 90 patients (18%) died.
 

Treatment recommendations?

Recognizing that there is no randomized trial data informing the treatment of this vulnerable patient population, Dr. Bottio and colleagues suggested that, based on their experience, no change in immunosuppression is needed in those who are “pauci-symptomatic” (mildly symptomatic).

“On the other hand, in hospitalized patients a partial reduction in immunosuppressive therapy avoiding full discontinuation and risk of graft rejection seems to be a common strategy in facing the viral infection,” he said. “In addition, the introduction of corticosteroids could help to suspend the onset of the inflammatory cascade responsible for severe forms of the disease.”

Antibiotic prophylaxis appears to be “fundamental,” he added, particularly in hospitalized patients, but “the role of specific antiviral therapies is still not fully understood in our population.”

Since July 1, they’ve seen an additional six patients with a positive test for SARS-CoV-2. Five were asymptomatic and quarantined at home without changing their immunosuppressive therapy. One patient was hospitalized for pneumonia and had immunosuppressive therapy reduced.

Dr. Bottio and the study coauthors have disclosed no relevant financial relationships.

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

A Food and Drug Administration advisory committee lit a long-standing fuse, recommending that evidence from the controversial TOPCAT trial can be used to support a new indication for spironolactone.

The generic aldosterone blocker is already approved for the treatment of heart failure with reduced ejection fraction (HFrEF). 

Hopes that it could be the first therapy to show improved outcomes in HF with preserved EF (HFpEF) were dashed in 2013 when TOPCAT failed to show a significant benefit over placebo for the primary endpoint of cardiovascular (CV) death, HF hospitalization, or aborted cardiac arrest.

Regional differences in the data, however, aroused concerns about the findings early on. Patients enrolled in Russia and the Republic of Georgia were younger, less likely to qualify on the basis of elevated natriuretic peptide levels, and had more evidence of ischemic heart disease than those in the Americas.

Event rates were also substantially lower in Russia/Georgia than in the Americas and in previous HFpEF trials, suggesting that many of these patients may not have had heart failure, the trialists argued.

In the Americas, results for the primary endpoint favor spironolactone over placebo (10.4 vs. 12.6 events per 100 patient-years; P = .026), whereas the rate in Russia/Georgia was much lower than in the Americas and slightly favors placebo (2.5 vs. 2.3 events/100 patient-years).

Medication noncompliance also may have been more common in Russia/Georgia based on pharmacodynamic studies and a 2017 analysis showing undetectable levels of canrenone, an active metabolite of spironolactone, in 30% of Russian versus 3% of North American patients who reported using the drug at 1 year.

TOPCAT investigator Marc Pfeffer, MD, PhD, from Brigham and Women’s Hospital and Harvard Medical School, Boston, said no trial is without flaws but that the observations represent serious misconduct. “Really we’re talking about a cancer, a cancer that has clear margins. The margins are Russia, Georgia that warrant censoring their data.”

The FDA’s own review of the National Institutes of Health–sponsored study, however, showed no significant interaction between treatment and region (P = .12) and “insufficient evidence to conclude the two regions are different enough such that overall results should not be considered,” said FDA statistician Ququan Liu, MD, MS.

She cautioned against removing data from a whole region that constituted almost half the study population and said it would set a precedent on what is considered substantial evidence for approval.

Several advisors concurred but, ultimately, the Cardiovascular and Renal Drugs Advisory Committee voted 8 to 4, with 1 abstention, that TOPCAT provides “sufficient evidence to support any indication.”

The same committee voted yesterday in support of an expanded role for sacubitril/valsartan (Entresto, Novartis) in select patients with HFpEF. In casting a “no” vote, panelist Steven E. Nissen, MD, from the Cleveland Clinic, said that decisions made by the panel set precedent.

Catherine Hackett

“If the pharmaceutical industry came to us with a study like this and said the P value was .14 but we think a bunch of our sites weren’t very good and so we’re going to throw those data out and just look at the sites we like, the FDA would not have even brought that before us,” he said. “I cannot hold other sponsors, including our own government, to a different standard.”

Dr. Nissen argued that the primary endpoint failed by a significant margin (P = .138), the study was marginally powered, there was a troubling amount of missing data in the two regions, and spironolactone is also not without side effects. “Poor study conduct cannot be an excuse for a result we don’t like.”

Panel chair Julia B. Lewis, MD, from Vanderbilt University Medical Center in Nashville, Tenn., said she would love to support a cheap, generic drug to keep HF patients out of the hospital but was troubled by the egregious conduct of the trial and concerns about cherry-picking results. “My heart says this would be a great place for us to go but I can’t say that my head thinks this is an acceptable body of data.”

Several panelists, however, highlighted the benefits with spironolactone over placebo in the Americas including an 18% reduction in hospitalization for HF (21% vs. 25%; hazard ratio, 0.82; P = .04) and a 25% reduction in cumulative HF hospitalizations (361 vs. 438 events; incidence rate ratio, 0.75; P = .024).

There was also a reduction in CV mortality with spironolactone (11% vs. 14%; HR, 0.74; P = .027) – something, it was noted, not observed during the prior day’s proceeding on sacubitril/valsartan.

Panelist Christopher M. O’Connor, MD, from Inova Heart and Vascular Institute in Falls Church, Va., and Duke University, Durham, N.C., said he voted “yes” because of the totality of the information and that the investigators provided “compelling evidence” with or without the Russia/Georgia cohort on the efficacy on HF hospitalization reduction. “I think this is the augmented sweet spot of this data set.”

C. Michael Gibson, MD, said his decision to vote yes was not based on analyses that excluded half the patients but rather on the totality of the evidence, particularly the benefit on cumulative HF hospitalizations and in those with an EF lower than 56%.

Several panelists and members of the public cited for treatments among patients with HFpEF. Edward K. Kasper, MD, from Johns Hopkins University, Baltimore, said he found both sides of the argument persuasive but that he already uses spironolactone in this setting. “Somehow I’ve become convinced that this drug worked, so I voted yes.”

Dr. Kasper said the FDA may ultimately find there isn’t an indication for spironolactone in HFpEF but that it will likely move from a IIb to IIa recommendation in the next iteration of the American College of Cardiology guidelines.

Paul Ridker, MD, MPH, from Brigham and Women’s Hospital and Harvard Medical School, said he shared concerns about the precedent of dropping half the data, “even though, in this case, I believe half the data is wrong.”

Dr. Ridker noted that he would have been comfortable using the secondary endpoint of HF reduction as an indication in patients with mildly reduced EF but abstained because that data was not presented today, although it may be available from TOPCAT and the RALES trial.

The panel took up other nonvoting questions, including what additional data would be needed to augment support for approval. Suggestions ranged from additional analyses to a new trial, with TOPCAT serving as “pilot data,” but no recommendation was made.

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

A Food and Drug Administration advisory committee lit a long-standing fuse, recommending that evidence from the controversial TOPCAT trial can be used to support a new indication for spironolactone.

The generic aldosterone blocker is already approved for the treatment of heart failure with reduced ejection fraction (HFrEF). 

Hopes that it could be the first therapy to show improved outcomes in HF with preserved EF (HFpEF) were dashed in 2013 when TOPCAT failed to show a significant benefit over placebo for the primary endpoint of cardiovascular (CV) death, HF hospitalization, or aborted cardiac arrest.

Regional differences in the data, however, aroused concerns about the findings early on. Patients enrolled in Russia and the Republic of Georgia were younger, less likely to qualify on the basis of elevated natriuretic peptide levels, and had more evidence of ischemic heart disease than those in the Americas.

Event rates were also substantially lower in Russia/Georgia than in the Americas and in previous HFpEF trials, suggesting that many of these patients may not have had heart failure, the trialists argued.

In the Americas, results for the primary endpoint favor spironolactone over placebo (10.4 vs. 12.6 events per 100 patient-years; P = .026), whereas the rate in Russia/Georgia was much lower than in the Americas and slightly favors placebo (2.5 vs. 2.3 events/100 patient-years).

Medication noncompliance also may have been more common in Russia/Georgia based on pharmacodynamic studies and a 2017 analysis showing undetectable levels of canrenone, an active metabolite of spironolactone, in 30% of Russian versus 3% of North American patients who reported using the drug at 1 year.

TOPCAT investigator Marc Pfeffer, MD, PhD, from Brigham and Women’s Hospital and Harvard Medical School, Boston, said no trial is without flaws but that the observations represent serious misconduct. “Really we’re talking about a cancer, a cancer that has clear margins. The margins are Russia, Georgia that warrant censoring their data.”

The FDA’s own review of the National Institutes of Health–sponsored study, however, showed no significant interaction between treatment and region (P = .12) and “insufficient evidence to conclude the two regions are different enough such that overall results should not be considered,” said FDA statistician Ququan Liu, MD, MS.

She cautioned against removing data from a whole region that constituted almost half the study population and said it would set a precedent on what is considered substantial evidence for approval.

Several advisors concurred but, ultimately, the Cardiovascular and Renal Drugs Advisory Committee voted 8 to 4, with 1 abstention, that TOPCAT provides “sufficient evidence to support any indication.”

The same committee voted yesterday in support of an expanded role for sacubitril/valsartan (Entresto, Novartis) in select patients with HFpEF. In casting a “no” vote, panelist Steven E. Nissen, MD, from the Cleveland Clinic, said that decisions made by the panel set precedent.

Catherine Hackett

“If the pharmaceutical industry came to us with a study like this and said the P value was .14 but we think a bunch of our sites weren’t very good and so we’re going to throw those data out and just look at the sites we like, the FDA would not have even brought that before us,” he said. “I cannot hold other sponsors, including our own government, to a different standard.”

Dr. Nissen argued that the primary endpoint failed by a significant margin (P = .138), the study was marginally powered, there was a troubling amount of missing data in the two regions, and spironolactone is also not without side effects. “Poor study conduct cannot be an excuse for a result we don’t like.”

Panel chair Julia B. Lewis, MD, from Vanderbilt University Medical Center in Nashville, Tenn., said she would love to support a cheap, generic drug to keep HF patients out of the hospital but was troubled by the egregious conduct of the trial and concerns about cherry-picking results. “My heart says this would be a great place for us to go but I can’t say that my head thinks this is an acceptable body of data.”

Several panelists, however, highlighted the benefits with spironolactone over placebo in the Americas including an 18% reduction in hospitalization for HF (21% vs. 25%; hazard ratio, 0.82; P = .04) and a 25% reduction in cumulative HF hospitalizations (361 vs. 438 events; incidence rate ratio, 0.75; P = .024).

There was also a reduction in CV mortality with spironolactone (11% vs. 14%; HR, 0.74; P = .027) – something, it was noted, not observed during the prior day’s proceeding on sacubitril/valsartan.

Panelist Christopher M. O’Connor, MD, from Inova Heart and Vascular Institute in Falls Church, Va., and Duke University, Durham, N.C., said he voted “yes” because of the totality of the information and that the investigators provided “compelling evidence” with or without the Russia/Georgia cohort on the efficacy on HF hospitalization reduction. “I think this is the augmented sweet spot of this data set.”

C. Michael Gibson, MD, said his decision to vote yes was not based on analyses that excluded half the patients but rather on the totality of the evidence, particularly the benefit on cumulative HF hospitalizations and in those with an EF lower than 56%.

Several panelists and members of the public cited for treatments among patients with HFpEF. Edward K. Kasper, MD, from Johns Hopkins University, Baltimore, said he found both sides of the argument persuasive but that he already uses spironolactone in this setting. “Somehow I’ve become convinced that this drug worked, so I voted yes.”

Dr. Kasper said the FDA may ultimately find there isn’t an indication for spironolactone in HFpEF but that it will likely move from a IIb to IIa recommendation in the next iteration of the American College of Cardiology guidelines.

Paul Ridker, MD, MPH, from Brigham and Women’s Hospital and Harvard Medical School, said he shared concerns about the precedent of dropping half the data, “even though, in this case, I believe half the data is wrong.”

Dr. Ridker noted that he would have been comfortable using the secondary endpoint of HF reduction as an indication in patients with mildly reduced EF but abstained because that data was not presented today, although it may be available from TOPCAT and the RALES trial.

The panel took up other nonvoting questions, including what additional data would be needed to augment support for approval. Suggestions ranged from additional analyses to a new trial, with TOPCAT serving as “pilot data,” but no recommendation was made.

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

A Food and Drug Administration advisory committee lit a long-standing fuse, recommending that evidence from the controversial TOPCAT trial can be used to support a new indication for spironolactone.

The generic aldosterone blocker is already approved for the treatment of heart failure with reduced ejection fraction (HFrEF). 

Hopes that it could be the first therapy to show improved outcomes in HF with preserved EF (HFpEF) were dashed in 2013 when TOPCAT failed to show a significant benefit over placebo for the primary endpoint of cardiovascular (CV) death, HF hospitalization, or aborted cardiac arrest.

Regional differences in the data, however, aroused concerns about the findings early on. Patients enrolled in Russia and the Republic of Georgia were younger, less likely to qualify on the basis of elevated natriuretic peptide levels, and had more evidence of ischemic heart disease than those in the Americas.

Event rates were also substantially lower in Russia/Georgia than in the Americas and in previous HFpEF trials, suggesting that many of these patients may not have had heart failure, the trialists argued.

In the Americas, results for the primary endpoint favor spironolactone over placebo (10.4 vs. 12.6 events per 100 patient-years; P = .026), whereas the rate in Russia/Georgia was much lower than in the Americas and slightly favors placebo (2.5 vs. 2.3 events/100 patient-years).

Medication noncompliance also may have been more common in Russia/Georgia based on pharmacodynamic studies and a 2017 analysis showing undetectable levels of canrenone, an active metabolite of spironolactone, in 30% of Russian versus 3% of North American patients who reported using the drug at 1 year.

TOPCAT investigator Marc Pfeffer, MD, PhD, from Brigham and Women’s Hospital and Harvard Medical School, Boston, said no trial is without flaws but that the observations represent serious misconduct. “Really we’re talking about a cancer, a cancer that has clear margins. The margins are Russia, Georgia that warrant censoring their data.”

The FDA’s own review of the National Institutes of Health–sponsored study, however, showed no significant interaction between treatment and region (P = .12) and “insufficient evidence to conclude the two regions are different enough such that overall results should not be considered,” said FDA statistician Ququan Liu, MD, MS.

She cautioned against removing data from a whole region that constituted almost half the study population and said it would set a precedent on what is considered substantial evidence for approval.

Several advisors concurred but, ultimately, the Cardiovascular and Renal Drugs Advisory Committee voted 8 to 4, with 1 abstention, that TOPCAT provides “sufficient evidence to support any indication.”

The same committee voted yesterday in support of an expanded role for sacubitril/valsartan (Entresto, Novartis) in select patients with HFpEF. In casting a “no” vote, panelist Steven E. Nissen, MD, from the Cleveland Clinic, said that decisions made by the panel set precedent.

Catherine Hackett

“If the pharmaceutical industry came to us with a study like this and said the P value was .14 but we think a bunch of our sites weren’t very good and so we’re going to throw those data out and just look at the sites we like, the FDA would not have even brought that before us,” he said. “I cannot hold other sponsors, including our own government, to a different standard.”

Dr. Nissen argued that the primary endpoint failed by a significant margin (P = .138), the study was marginally powered, there was a troubling amount of missing data in the two regions, and spironolactone is also not without side effects. “Poor study conduct cannot be an excuse for a result we don’t like.”

Panel chair Julia B. Lewis, MD, from Vanderbilt University Medical Center in Nashville, Tenn., said she would love to support a cheap, generic drug to keep HF patients out of the hospital but was troubled by the egregious conduct of the trial and concerns about cherry-picking results. “My heart says this would be a great place for us to go but I can’t say that my head thinks this is an acceptable body of data.”

Several panelists, however, highlighted the benefits with spironolactone over placebo in the Americas including an 18% reduction in hospitalization for HF (21% vs. 25%; hazard ratio, 0.82; P = .04) and a 25% reduction in cumulative HF hospitalizations (361 vs. 438 events; incidence rate ratio, 0.75; P = .024).

There was also a reduction in CV mortality with spironolactone (11% vs. 14%; HR, 0.74; P = .027) – something, it was noted, not observed during the prior day’s proceeding on sacubitril/valsartan.

Panelist Christopher M. O’Connor, MD, from Inova Heart and Vascular Institute in Falls Church, Va., and Duke University, Durham, N.C., said he voted “yes” because of the totality of the information and that the investigators provided “compelling evidence” with or without the Russia/Georgia cohort on the efficacy on HF hospitalization reduction. “I think this is the augmented sweet spot of this data set.”

C. Michael Gibson, MD, said his decision to vote yes was not based on analyses that excluded half the patients but rather on the totality of the evidence, particularly the benefit on cumulative HF hospitalizations and in those with an EF lower than 56%.

Several panelists and members of the public cited for treatments among patients with HFpEF. Edward K. Kasper, MD, from Johns Hopkins University, Baltimore, said he found both sides of the argument persuasive but that he already uses spironolactone in this setting. “Somehow I’ve become convinced that this drug worked, so I voted yes.”

Dr. Kasper said the FDA may ultimately find there isn’t an indication for spironolactone in HFpEF but that it will likely move from a IIb to IIa recommendation in the next iteration of the American College of Cardiology guidelines.

Paul Ridker, MD, MPH, from Brigham and Women’s Hospital and Harvard Medical School, said he shared concerns about the precedent of dropping half the data, “even though, in this case, I believe half the data is wrong.”

Dr. Ridker noted that he would have been comfortable using the secondary endpoint of HF reduction as an indication in patients with mildly reduced EF but abstained because that data was not presented today, although it may be available from TOPCAT and the RALES trial.

The panel took up other nonvoting questions, including what additional data would be needed to augment support for approval. Suggestions ranged from additional analyses to a new trial, with TOPCAT serving as “pilot data,” but no recommendation was made.

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

UPDATED DECEMBER 17

A panel of federal advisers on Tuesday effectively backed a bid to expand approval of sacubitril/valsartan for use in a form of heart failure for which there is not yet an approved medication.

Wikimedia Commons/FitzColinGerald/ Creative Commons License

The U.S. Food and Drug Administration asked its Cardiovascular and Renal Drugs Advisory Committee to broadly consider whether new analyses of data from the PARAGON-HF trial, combined with other information, could support use of sacubitril/valsartan (Entresto, Novartis) in heart failure with preserved ejection fraction (HFpEF).

The advisory committee voted 12-1 on this question, which can be seen as a marker for an expanded approval: “Does PARAGON-HF, perhaps supported by previous studies, provide sufficient evidence to support any indication?”

The dissenting vote was cast by the panel’s chairperson, Julia B. Lewis, MD, a professor of medicine from Vanderbilt University. In explaining her vote, Dr. Lewis cited concerns about expanding use of the drug, which has a potential for hypotension. But she noted that the rest of the panelists were “impressed by the totality of the evidence” presented, including a willingness to take a new look at the PARAGON-HF trial. This study was perceived at first pass as having failed to prove a benefit for people with HFpEF.

The 2019 initial unveiling of the PARAGON-HF results had dampened hopes for an evidence-based drug therapy for HFpEF. Patients treated with the first-of-its-kind renin-angiotensin system (RAS) inhibitor, compared with those who received standard valsartan, had 13% fewer heart failure hospitalizations or cardiovascular (CV) deaths over an average of about 3 years, but the difference missed significance at a P value of .059.

“Everybody agreed that the P value of .05 was not written in stone,” Dr. Lewis said in summarizing the panelists’ views on the voting question.

At the FDA’s request, the panel also addressed several other questions without voting on them. The agency asked the panel to describe the patient population for whom an expanded approval would be appropriate. The FDA initially approved sacubitril/valsartan in 2015 to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction.

Novartis in April submitted an application to the FDA, seeking to expand the use of sacubitril/valsartan from the currently approved indication for the treatment of chronic heart failure (CHF) patients with reduced ejection fraction (HFrEF) to include what the company terms “the adjacent population of patients with preserved ejection fraction (HFpEF) who have a left ventricular ejection fraction (LVEF) below normal.” The American Society of Echocardiography and European Association of Cardiovascular Imaging define normal LVEF and normal range (±2 standard deviations) as 62% (range, 52%-72%) in men and 64% (range, 54%-74%) in women, Novartis said in its briefing materials for the meeting.

FDA panelist Christopher M. O’Connor, MD, for example, suggested that an expanded approval could allow for use of sacubitril/valsartan for the reduction of heart failure or hospitalization in patients with mildly reduced ejection fraction as defined by greater than 45% through 55%. FDA panelist C. Noel Bairey Merz, MD, director of the Barbra Streisand Women’s Heart Center at Cedars-Sinai Medical Center in Los Angeles, suggested extending this to 57% to acknowledge the higher threshold for women.

Another FDA panelist, Steven E. Nissen, MD, of the Cleveland Clinic, argued against use of imprecise terms in defining an expanded patient population for sacubitril/valsartan. If used in the right patient population, the drug could provide a benefit for people who have active heart failure with symptoms, including preventing hospitalizations and renal disease, he said.

“If you are symptomatic with a syndrome that’s consistent with heart failure and you have an ejection fraction below the lower limits of normal, I believe it’s in the public interest for you to get sacubitril/valsartan,” Dr. Nissen said.

The FDA usually follows the advice of its panels, but is not obligated to. But in this case, the agency staff were clearly seeking a path for an expanded approval of sacubitril/valsartan.


 

Challenging a standard

The FDA had encouraged Novartis to submit the supplementary application for the HFpEF indication and even suggested some of the post-hoc analyses, the agency staff said in a briefing document for the meeting.

PARAGON-HF illustrated some of the agency’s concerns about missed opportunities in general in large research trials. Some events of interest in studies may be miscounted due to a lack of information such as a requirement for the presence of physical examination findings that are not documented in the patient’s dossier, the FDA staff said.

“We would like to consider giving ‘partial credit’ to events based on the level of evidence provided, e.g., use of an ordinal variable rather than a dichotomous ‘yes’ or ‘no,’ ” the staff said in the briefing document.

At the panel meeting, Norman Stockbridge, MD, PhD, director of the Division of Cardiology and Nephrology in the FDA’s Center for Drug Evaluation and Research, told the panelists there is no basis in law for setting a P value of .05 as the benchmark on whether to declare a trial a success or failure.

“I wanted to take a few minutes and make sure that you on the committee understands what flexibility you have in addressing the case study in question,” Dr. Stockbridge said at the start of the meeting.

He then reviewed cases where the FDA had approved claims for cardiac medicines that had not shown desired results in key tests. These include approval of enalapril for use in asymptomatic left ventricular dysfunction on the basis of the SOLVD-Prevention trial, approval of digoxin for heart failure on the basis of the DIG study, and approval of carvedilol for reduced ejection fraction following myocardial infarction on

the basis of the CAPRICORN study, Dr. Stockbridge said.

In reviewing the data for sacubitril/valsartan, FDA staff noted a similarity between investigator-reported and adjudicated results, Stockbridge said.

“This suggested that there were events that did not need all evidentiary criteria as qualified events, but likely were nonetheless,” he said. “This is an example of dichotomization of events being wasteful of information.”

Post-hoc exploratory analyses in PARAGON-HF were able to meet the commonly used standard, according to the FDA briefing document. Among the key findings of these analyses were:

• An analysis of investigator-reported events for the primary composite endpoint of total hospitalizations for heart failure (HHF) and cardiovascular (CV) death demonstrated a rate ratio (RR) of 0.84 (95% confidence interval 0.74- 0.97; P = .01).
• Investigator-reported events added 226 and 290 HHF events but decreased CV death by 56 and 58 events in the sacubitril/valsartan and valsartan arms, respectively. Hence, a net 170 and 232 events were added to the clinical endpoint committee–reported primary composite endpoint leading to a P value of .01, without a significant change in RR.
• Analysis of investigator-reported expanded primary composite endpoint events including total HHF, urgent HF visits, and CV death demonstrated a RR of 0.83 (95% CI, 0.73-0.95; P = .006. There were 136 and 173 investigator-reported urgent HF events in sacubitril/valsartan and valsartan arms, respectively.

Opening a floodgate?

Cynthia L. Chauhan, MSW, of Wichita, Kansas, who served as the consumer representative on the panel, questioned whether a decision to revisit the data on PARAGON-HF might lead drugmakers to seek to repurpose other failed trials.

“Are we opening any kind of floodgate for other researchers to go back and see this is an invitation to try to, for want of a better term, back-door their way into some approvals?” Ms. Chauhan asked.

Dr. Nissen assured her that this concern was valid and would be considered. The goal would be to allow some flexibility in cases that merit further consideration, while preventing companies from data mining until they find some evidence to support an FDA application, he said.

Re-analyzing trials “should be done carefully, conservatively, and only when it really is compelling that the public interest supports it,” Dr. Nissen stressed.

Panelists reported no conflicts of interest related to the topic of the meeting.
 

UPDATED DECEMBER 17

A panel of federal advisers on Tuesday effectively backed a bid to expand approval of sacubitril/valsartan for use in a form of heart failure for which there is not yet an approved medication.

Wikimedia Commons/FitzColinGerald/ Creative Commons License

The U.S. Food and Drug Administration asked its Cardiovascular and Renal Drugs Advisory Committee to broadly consider whether new analyses of data from the PARAGON-HF trial, combined with other information, could support use of sacubitril/valsartan (Entresto, Novartis) in heart failure with preserved ejection fraction (HFpEF).

The advisory committee voted 12-1 on this question, which can be seen as a marker for an expanded approval: “Does PARAGON-HF, perhaps supported by previous studies, provide sufficient evidence to support any indication?”

The dissenting vote was cast by the panel’s chairperson, Julia B. Lewis, MD, a professor of medicine from Vanderbilt University. In explaining her vote, Dr. Lewis cited concerns about expanding use of the drug, which has a potential for hypotension. But she noted that the rest of the panelists were “impressed by the totality of the evidence” presented, including a willingness to take a new look at the PARAGON-HF trial. This study was perceived at first pass as having failed to prove a benefit for people with HFpEF.

The 2019 initial unveiling of the PARAGON-HF results had dampened hopes for an evidence-based drug therapy for HFpEF. Patients treated with the first-of-its-kind renin-angiotensin system (RAS) inhibitor, compared with those who received standard valsartan, had 13% fewer heart failure hospitalizations or cardiovascular (CV) deaths over an average of about 3 years, but the difference missed significance at a P value of .059.

“Everybody agreed that the P value of .05 was not written in stone,” Dr. Lewis said in summarizing the panelists’ views on the voting question.

At the FDA’s request, the panel also addressed several other questions without voting on them. The agency asked the panel to describe the patient population for whom an expanded approval would be appropriate. The FDA initially approved sacubitril/valsartan in 2015 to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction.

Novartis in April submitted an application to the FDA, seeking to expand the use of sacubitril/valsartan from the currently approved indication for the treatment of chronic heart failure (CHF) patients with reduced ejection fraction (HFrEF) to include what the company terms “the adjacent population of patients with preserved ejection fraction (HFpEF) who have a left ventricular ejection fraction (LVEF) below normal.” The American Society of Echocardiography and European Association of Cardiovascular Imaging define normal LVEF and normal range (±2 standard deviations) as 62% (range, 52%-72%) in men and 64% (range, 54%-74%) in women, Novartis said in its briefing materials for the meeting.

FDA panelist Christopher M. O’Connor, MD, for example, suggested that an expanded approval could allow for use of sacubitril/valsartan for the reduction of heart failure or hospitalization in patients with mildly reduced ejection fraction as defined by greater than 45% through 55%. FDA panelist C. Noel Bairey Merz, MD, director of the Barbra Streisand Women’s Heart Center at Cedars-Sinai Medical Center in Los Angeles, suggested extending this to 57% to acknowledge the higher threshold for women.

Another FDA panelist, Steven E. Nissen, MD, of the Cleveland Clinic, argued against use of imprecise terms in defining an expanded patient population for sacubitril/valsartan. If used in the right patient population, the drug could provide a benefit for people who have active heart failure with symptoms, including preventing hospitalizations and renal disease, he said.

“If you are symptomatic with a syndrome that’s consistent with heart failure and you have an ejection fraction below the lower limits of normal, I believe it’s in the public interest for you to get sacubitril/valsartan,” Dr. Nissen said.

The FDA usually follows the advice of its panels, but is not obligated to. But in this case, the agency staff were clearly seeking a path for an expanded approval of sacubitril/valsartan.


 

Challenging a standard

The FDA had encouraged Novartis to submit the supplementary application for the HFpEF indication and even suggested some of the post-hoc analyses, the agency staff said in a briefing document for the meeting.

PARAGON-HF illustrated some of the agency’s concerns about missed opportunities in general in large research trials. Some events of interest in studies may be miscounted due to a lack of information such as a requirement for the presence of physical examination findings that are not documented in the patient’s dossier, the FDA staff said.

“We would like to consider giving ‘partial credit’ to events based on the level of evidence provided, e.g., use of an ordinal variable rather than a dichotomous ‘yes’ or ‘no,’ ” the staff said in the briefing document.

At the panel meeting, Norman Stockbridge, MD, PhD, director of the Division of Cardiology and Nephrology in the FDA’s Center for Drug Evaluation and Research, told the panelists there is no basis in law for setting a P value of .05 as the benchmark on whether to declare a trial a success or failure.

“I wanted to take a few minutes and make sure that you on the committee understands what flexibility you have in addressing the case study in question,” Dr. Stockbridge said at the start of the meeting.

He then reviewed cases where the FDA had approved claims for cardiac medicines that had not shown desired results in key tests. These include approval of enalapril for use in asymptomatic left ventricular dysfunction on the basis of the SOLVD-Prevention trial, approval of digoxin for heart failure on the basis of the DIG study, and approval of carvedilol for reduced ejection fraction following myocardial infarction on

the basis of the CAPRICORN study, Dr. Stockbridge said.

In reviewing the data for sacubitril/valsartan, FDA staff noted a similarity between investigator-reported and adjudicated results, Stockbridge said.

“This suggested that there were events that did not need all evidentiary criteria as qualified events, but likely were nonetheless,” he said. “This is an example of dichotomization of events being wasteful of information.”

Post-hoc exploratory analyses in PARAGON-HF were able to meet the commonly used standard, according to the FDA briefing document. Among the key findings of these analyses were:

• An analysis of investigator-reported events for the primary composite endpoint of total hospitalizations for heart failure (HHF) and cardiovascular (CV) death demonstrated a rate ratio (RR) of 0.84 (95% confidence interval 0.74- 0.97; P = .01).
• Investigator-reported events added 226 and 290 HHF events but decreased CV death by 56 and 58 events in the sacubitril/valsartan and valsartan arms, respectively. Hence, a net 170 and 232 events were added to the clinical endpoint committee–reported primary composite endpoint leading to a P value of .01, without a significant change in RR.
• Analysis of investigator-reported expanded primary composite endpoint events including total HHF, urgent HF visits, and CV death demonstrated a RR of 0.83 (95% CI, 0.73-0.95; P = .006. There were 136 and 173 investigator-reported urgent HF events in sacubitril/valsartan and valsartan arms, respectively.

Opening a floodgate?

Cynthia L. Chauhan, MSW, of Wichita, Kansas, who served as the consumer representative on the panel, questioned whether a decision to revisit the data on PARAGON-HF might lead drugmakers to seek to repurpose other failed trials.

“Are we opening any kind of floodgate for other researchers to go back and see this is an invitation to try to, for want of a better term, back-door their way into some approvals?” Ms. Chauhan asked.

Dr. Nissen assured her that this concern was valid and would be considered. The goal would be to allow some flexibility in cases that merit further consideration, while preventing companies from data mining until they find some evidence to support an FDA application, he said.

Re-analyzing trials “should be done carefully, conservatively, and only when it really is compelling that the public interest supports it,” Dr. Nissen stressed.

Panelists reported no conflicts of interest related to the topic of the meeting.
 

UPDATED DECEMBER 17

A panel of federal advisers on Tuesday effectively backed a bid to expand approval of sacubitril/valsartan for use in a form of heart failure for which there is not yet an approved medication.

Wikimedia Commons/FitzColinGerald/ Creative Commons License

The U.S. Food and Drug Administration asked its Cardiovascular and Renal Drugs Advisory Committee to broadly consider whether new analyses of data from the PARAGON-HF trial, combined with other information, could support use of sacubitril/valsartan (Entresto, Novartis) in heart failure with preserved ejection fraction (HFpEF).

The advisory committee voted 12-1 on this question, which can be seen as a marker for an expanded approval: “Does PARAGON-HF, perhaps supported by previous studies, provide sufficient evidence to support any indication?”

The dissenting vote was cast by the panel’s chairperson, Julia B. Lewis, MD, a professor of medicine from Vanderbilt University. In explaining her vote, Dr. Lewis cited concerns about expanding use of the drug, which has a potential for hypotension. But she noted that the rest of the panelists were “impressed by the totality of the evidence” presented, including a willingness to take a new look at the PARAGON-HF trial. This study was perceived at first pass as having failed to prove a benefit for people with HFpEF.

The 2019 initial unveiling of the PARAGON-HF results had dampened hopes for an evidence-based drug therapy for HFpEF. Patients treated with the first-of-its-kind renin-angiotensin system (RAS) inhibitor, compared with those who received standard valsartan, had 13% fewer heart failure hospitalizations or cardiovascular (CV) deaths over an average of about 3 years, but the difference missed significance at a P value of .059.

“Everybody agreed that the P value of .05 was not written in stone,” Dr. Lewis said in summarizing the panelists’ views on the voting question.

At the FDA’s request, the panel also addressed several other questions without voting on them. The agency asked the panel to describe the patient population for whom an expanded approval would be appropriate. The FDA initially approved sacubitril/valsartan in 2015 to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction.

Novartis in April submitted an application to the FDA, seeking to expand the use of sacubitril/valsartan from the currently approved indication for the treatment of chronic heart failure (CHF) patients with reduced ejection fraction (HFrEF) to include what the company terms “the adjacent population of patients with preserved ejection fraction (HFpEF) who have a left ventricular ejection fraction (LVEF) below normal.” The American Society of Echocardiography and European Association of Cardiovascular Imaging define normal LVEF and normal range (±2 standard deviations) as 62% (range, 52%-72%) in men and 64% (range, 54%-74%) in women, Novartis said in its briefing materials for the meeting.

FDA panelist Christopher M. O’Connor, MD, for example, suggested that an expanded approval could allow for use of sacubitril/valsartan for the reduction of heart failure or hospitalization in patients with mildly reduced ejection fraction as defined by greater than 45% through 55%. FDA panelist C. Noel Bairey Merz, MD, director of the Barbra Streisand Women’s Heart Center at Cedars-Sinai Medical Center in Los Angeles, suggested extending this to 57% to acknowledge the higher threshold for women.

Another FDA panelist, Steven E. Nissen, MD, of the Cleveland Clinic, argued against use of imprecise terms in defining an expanded patient population for sacubitril/valsartan. If used in the right patient population, the drug could provide a benefit for people who have active heart failure with symptoms, including preventing hospitalizations and renal disease, he said.

“If you are symptomatic with a syndrome that’s consistent with heart failure and you have an ejection fraction below the lower limits of normal, I believe it’s in the public interest for you to get sacubitril/valsartan,” Dr. Nissen said.

The FDA usually follows the advice of its panels, but is not obligated to. But in this case, the agency staff were clearly seeking a path for an expanded approval of sacubitril/valsartan.


 

Challenging a standard

The FDA had encouraged Novartis to submit the supplementary application for the HFpEF indication and even suggested some of the post-hoc analyses, the agency staff said in a briefing document for the meeting.

PARAGON-HF illustrated some of the agency’s concerns about missed opportunities in general in large research trials. Some events of interest in studies may be miscounted due to a lack of information such as a requirement for the presence of physical examination findings that are not documented in the patient’s dossier, the FDA staff said.

“We would like to consider giving ‘partial credit’ to events based on the level of evidence provided, e.g., use of an ordinal variable rather than a dichotomous ‘yes’ or ‘no,’ ” the staff said in the briefing document.

At the panel meeting, Norman Stockbridge, MD, PhD, director of the Division of Cardiology and Nephrology in the FDA’s Center for Drug Evaluation and Research, told the panelists there is no basis in law for setting a P value of .05 as the benchmark on whether to declare a trial a success or failure.

“I wanted to take a few minutes and make sure that you on the committee understands what flexibility you have in addressing the case study in question,” Dr. Stockbridge said at the start of the meeting.

He then reviewed cases where the FDA had approved claims for cardiac medicines that had not shown desired results in key tests. These include approval of enalapril for use in asymptomatic left ventricular dysfunction on the basis of the SOLVD-Prevention trial, approval of digoxin for heart failure on the basis of the DIG study, and approval of carvedilol for reduced ejection fraction following myocardial infarction on

the basis of the CAPRICORN study, Dr. Stockbridge said.

In reviewing the data for sacubitril/valsartan, FDA staff noted a similarity between investigator-reported and adjudicated results, Stockbridge said.

“This suggested that there were events that did not need all evidentiary criteria as qualified events, but likely were nonetheless,” he said. “This is an example of dichotomization of events being wasteful of information.”

Post-hoc exploratory analyses in PARAGON-HF were able to meet the commonly used standard, according to the FDA briefing document. Among the key findings of these analyses were:

• An analysis of investigator-reported events for the primary composite endpoint of total hospitalizations for heart failure (HHF) and cardiovascular (CV) death demonstrated a rate ratio (RR) of 0.84 (95% confidence interval 0.74- 0.97; P = .01).
• Investigator-reported events added 226 and 290 HHF events but decreased CV death by 56 and 58 events in the sacubitril/valsartan and valsartan arms, respectively. Hence, a net 170 and 232 events were added to the clinical endpoint committee–reported primary composite endpoint leading to a P value of .01, without a significant change in RR.
• Analysis of investigator-reported expanded primary composite endpoint events including total HHF, urgent HF visits, and CV death demonstrated a RR of 0.83 (95% CI, 0.73-0.95; P = .006. There were 136 and 173 investigator-reported urgent HF events in sacubitril/valsartan and valsartan arms, respectively.

Opening a floodgate?

Cynthia L. Chauhan, MSW, of Wichita, Kansas, who served as the consumer representative on the panel, questioned whether a decision to revisit the data on PARAGON-HF might lead drugmakers to seek to repurpose other failed trials.

“Are we opening any kind of floodgate for other researchers to go back and see this is an invitation to try to, for want of a better term, back-door their way into some approvals?” Ms. Chauhan asked.

Dr. Nissen assured her that this concern was valid and would be considered. The goal would be to allow some flexibility in cases that merit further consideration, while preventing companies from data mining until they find some evidence to support an FDA application, he said.

Re-analyzing trials “should be done carefully, conservatively, and only when it really is compelling that the public interest supports it,” Dr. Nissen stressed.

Panelists reported no conflicts of interest related to the topic of the meeting.
 

For 2021, the American Diabetes Association offers new guidance on assessing patients’ financial and social barriers to care, especially given the COVID-19 pandemic, individualizing treatment of patients with type 2 diabetes, and use of diabetes technology.

As it does every year, the annual update incorporates new clinical information that has become available since the last guideline, with occasional revisions during the year as needed. “Standards of Medical Care in Diabetes – 2021,” was published online as a supplement to Diabetes Care.

The new standards advise that patients be assessed for food and housing insecurity, social support, and “cost-related medication nonadherence,” and those found to have difficulty referred to appropriate community resources.

“Clinicians need to be sensitive to the fact that patients may have very good reasons for not taking their medication, [as in] if they can’t afford it,” ADA chief science & medical officer Robert A. Gabbay, MD, PhD, said in an interview.

Dr. Gabbay noted that “a heightened awareness” of social determinants of health is weaved throughout the 2021 standards because of the pandemic, with information on the topic derived from a July 2020 joint consensus statement in Diabetes Care, endorsed by a number of other societies, as well as a November publication also in Diabetes Care.

“We made several recommendations that speak to social determinants of health, placing an emphasis on engaging in conversations around this subject and screening for related issues such as food insecurity that weren’t there previously,” he said.

“Screening tools are suggested. It helped us to have an in-depth scientific review of the literature to know the prevalence of this in people with diabetes. ... Having the science to put it in was a key step,” Dr. Gabbay noted.
 

Consider kidney, heart disease in type 2 treatment individualization

Recent data from trials such as CREDENCE and DAPA-HF, among others, have been added to inform the choice of pharmacologic treatment in patients with type 2 diabetes with comorbid diabetic kidney disease and chronic heart failure.

“ADA has been advocating individualization of treatment based on comorbidities for a while, but we’ve taken more steps in that direction. Beyond lifestyle for all individuals with type 2 diabetes, clinicians want to think early on about which comorbidities patients have and then think about the appropriate treatment based on that,” Dr. Gabbay said.

And for the third year in a row, the section on cardiovascular disease and risk management has been endorsed by the American College of Cardiology.

“All the things in that section are very much aligned with ACC and that’s been a great partnership,” Dr. Gabbay said.

Now, ADA is in discussions with other professional societies representing relevant specialties to create further such unified messages.

“What we all want to avoid is having multiple different guidelines. We want to speak with one voice and find common ground as much as possible. … It makes it much easier for clinicians to know what to do. That’s the goal of all this,” he noted.
 

Diabetes technology: The rise of CGM during pandemic and beyond

New information about continuous glucose monitoring (CGM) has been added to the diabetes technology section. Use of CGM is now recommended for anyone with diabetes who takes multiple daily injections or uses an insulin pump, regardless of age or diabetes type. The document provides expanded advice on use of time in range data for glycemic monitoring, particularly during the COVID-19 pandemic when remote monitoring is preferable.

Insurers are increasingly covering CGM for patients on insulin, but it’s far from universal. While the ultimate goal is to ensure access to CGM for everyone with diabetes, those treated with multiple daily insulin doses are the priority for now.

“Our hope is that as there’s greater evidence there will be more movement towards coverage. There are still so many people for whom it’s quite clear they would benefit because they’re on insulin but don’t have access to it. That’s an important area that ADA is advocating for, and it’s reflected in the standards of care,” Dr. Gabbay said.

In another technology-related revision, the term “blinded” CGM has been replaced with “professional CGM,” because clinic-based use of the devices can be “blinded” to the patient or monitored in real-time by both the patient and clinician. Also, a new recommendation has been added to address skin reactions associated with diabetes technology use.

Information about use of CGM in hospital settings during the COVID-19 pandemic has also been added in the technology section.

The COVID-19 pandemic comes up again in the section on vaccines.

“We mention that people with diabetes should be considered high priority [for COVID-19 vaccines], and that’s something that ADA is strongly advocating for because 40% of COVID-19 deaths have been in people with diabetes,” Dr. Gabbay said.

Dr. Gabbay reported being on the advisory boards of Onduo, Health Reveal, Vida Health, Lark, and Form Health.

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

For 2021, the American Diabetes Association offers new guidance on assessing patients’ financial and social barriers to care, especially given the COVID-19 pandemic, individualizing treatment of patients with type 2 diabetes, and use of diabetes technology.

As it does every year, the annual update incorporates new clinical information that has become available since the last guideline, with occasional revisions during the year as needed. “Standards of Medical Care in Diabetes – 2021,” was published online as a supplement to Diabetes Care.

The new standards advise that patients be assessed for food and housing insecurity, social support, and “cost-related medication nonadherence,” and those found to have difficulty referred to appropriate community resources.

“Clinicians need to be sensitive to the fact that patients may have very good reasons for not taking their medication, [as in] if they can’t afford it,” ADA chief science & medical officer Robert A. Gabbay, MD, PhD, said in an interview.

Dr. Gabbay noted that “a heightened awareness” of social determinants of health is weaved throughout the 2021 standards because of the pandemic, with information on the topic derived from a July 2020 joint consensus statement in Diabetes Care, endorsed by a number of other societies, as well as a November publication also in Diabetes Care.

“We made several recommendations that speak to social determinants of health, placing an emphasis on engaging in conversations around this subject and screening for related issues such as food insecurity that weren’t there previously,” he said.

“Screening tools are suggested. It helped us to have an in-depth scientific review of the literature to know the prevalence of this in people with diabetes. ... Having the science to put it in was a key step,” Dr. Gabbay noted.
 

Consider kidney, heart disease in type 2 treatment individualization

Recent data from trials such as CREDENCE and DAPA-HF, among others, have been added to inform the choice of pharmacologic treatment in patients with type 2 diabetes with comorbid diabetic kidney disease and chronic heart failure.

“ADA has been advocating individualization of treatment based on comorbidities for a while, but we’ve taken more steps in that direction. Beyond lifestyle for all individuals with type 2 diabetes, clinicians want to think early on about which comorbidities patients have and then think about the appropriate treatment based on that,” Dr. Gabbay said.

And for the third year in a row, the section on cardiovascular disease and risk management has been endorsed by the American College of Cardiology.

“All the things in that section are very much aligned with ACC and that’s been a great partnership,” Dr. Gabbay said.

Now, ADA is in discussions with other professional societies representing relevant specialties to create further such unified messages.

“What we all want to avoid is having multiple different guidelines. We want to speak with one voice and find common ground as much as possible. … It makes it much easier for clinicians to know what to do. That’s the goal of all this,” he noted.
 

Diabetes technology: The rise of CGM during pandemic and beyond

New information about continuous glucose monitoring (CGM) has been added to the diabetes technology section. Use of CGM is now recommended for anyone with diabetes who takes multiple daily injections or uses an insulin pump, regardless of age or diabetes type. The document provides expanded advice on use of time in range data for glycemic monitoring, particularly during the COVID-19 pandemic when remote monitoring is preferable.

Insurers are increasingly covering CGM for patients on insulin, but it’s far from universal. While the ultimate goal is to ensure access to CGM for everyone with diabetes, those treated with multiple daily insulin doses are the priority for now.

“Our hope is that as there’s greater evidence there will be more movement towards coverage. There are still so many people for whom it’s quite clear they would benefit because they’re on insulin but don’t have access to it. That’s an important area that ADA is advocating for, and it’s reflected in the standards of care,” Dr. Gabbay said.

In another technology-related revision, the term “blinded” CGM has been replaced with “professional CGM,” because clinic-based use of the devices can be “blinded” to the patient or monitored in real-time by both the patient and clinician. Also, a new recommendation has been added to address skin reactions associated with diabetes technology use.

Information about use of CGM in hospital settings during the COVID-19 pandemic has also been added in the technology section.

The COVID-19 pandemic comes up again in the section on vaccines.

“We mention that people with diabetes should be considered high priority [for COVID-19 vaccines], and that’s something that ADA is strongly advocating for because 40% of COVID-19 deaths have been in people with diabetes,” Dr. Gabbay said.

Dr. Gabbay reported being on the advisory boards of Onduo, Health Reveal, Vida Health, Lark, and Form Health.

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

For 2021, the American Diabetes Association offers new guidance on assessing patients’ financial and social barriers to care, especially given the COVID-19 pandemic, individualizing treatment of patients with type 2 diabetes, and use of diabetes technology.

As it does every year, the annual update incorporates new clinical information that has become available since the last guideline, with occasional revisions during the year as needed. “Standards of Medical Care in Diabetes – 2021,” was published online as a supplement to Diabetes Care.

The new standards advise that patients be assessed for food and housing insecurity, social support, and “cost-related medication nonadherence,” and those found to have difficulty referred to appropriate community resources.

“Clinicians need to be sensitive to the fact that patients may have very good reasons for not taking their medication, [as in] if they can’t afford it,” ADA chief science & medical officer Robert A. Gabbay, MD, PhD, said in an interview.

Dr. Gabbay noted that “a heightened awareness” of social determinants of health is weaved throughout the 2021 standards because of the pandemic, with information on the topic derived from a July 2020 joint consensus statement in Diabetes Care, endorsed by a number of other societies, as well as a November publication also in Diabetes Care.

“We made several recommendations that speak to social determinants of health, placing an emphasis on engaging in conversations around this subject and screening for related issues such as food insecurity that weren’t there previously,” he said.

“Screening tools are suggested. It helped us to have an in-depth scientific review of the literature to know the prevalence of this in people with diabetes. ... Having the science to put it in was a key step,” Dr. Gabbay noted.
 

Consider kidney, heart disease in type 2 treatment individualization

Recent data from trials such as CREDENCE and DAPA-HF, among others, have been added to inform the choice of pharmacologic treatment in patients with type 2 diabetes with comorbid diabetic kidney disease and chronic heart failure.

“ADA has been advocating individualization of treatment based on comorbidities for a while, but we’ve taken more steps in that direction. Beyond lifestyle for all individuals with type 2 diabetes, clinicians want to think early on about which comorbidities patients have and then think about the appropriate treatment based on that,” Dr. Gabbay said.

And for the third year in a row, the section on cardiovascular disease and risk management has been endorsed by the American College of Cardiology.

“All the things in that section are very much aligned with ACC and that’s been a great partnership,” Dr. Gabbay said.

Now, ADA is in discussions with other professional societies representing relevant specialties to create further such unified messages.

“What we all want to avoid is having multiple different guidelines. We want to speak with one voice and find common ground as much as possible. … It makes it much easier for clinicians to know what to do. That’s the goal of all this,” he noted.
 

Diabetes technology: The rise of CGM during pandemic and beyond

New information about continuous glucose monitoring (CGM) has been added to the diabetes technology section. Use of CGM is now recommended for anyone with diabetes who takes multiple daily injections or uses an insulin pump, regardless of age or diabetes type. The document provides expanded advice on use of time in range data for glycemic monitoring, particularly during the COVID-19 pandemic when remote monitoring is preferable.

Insurers are increasingly covering CGM for patients on insulin, but it’s far from universal. While the ultimate goal is to ensure access to CGM for everyone with diabetes, those treated with multiple daily insulin doses are the priority for now.

“Our hope is that as there’s greater evidence there will be more movement towards coverage. There are still so many people for whom it’s quite clear they would benefit because they’re on insulin but don’t have access to it. That’s an important area that ADA is advocating for, and it’s reflected in the standards of care,” Dr. Gabbay said.

In another technology-related revision, the term “blinded” CGM has been replaced with “professional CGM,” because clinic-based use of the devices can be “blinded” to the patient or monitored in real-time by both the patient and clinician. Also, a new recommendation has been added to address skin reactions associated with diabetes technology use.

Information about use of CGM in hospital settings during the COVID-19 pandemic has also been added in the technology section.

The COVID-19 pandemic comes up again in the section on vaccines.

“We mention that people with diabetes should be considered high priority [for COVID-19 vaccines], and that’s something that ADA is strongly advocating for because 40% of COVID-19 deaths have been in people with diabetes,” Dr. Gabbay said.

Dr. Gabbay reported being on the advisory boards of Onduo, Health Reveal, Vida Health, Lark, and Form Health.

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

The beneficial effects of sacubitril/valsartan on reverse cardiac remodeling in patients with heart failure and reduced ejection fraction have been well established, but those benefits haven’t been as clearly demonstrated to carry over to HFrEF patients who also have type 2 diabetes mellitus (T2DM).

Now, a post-hoc analysis of a pivotal clinical trial reports that those benefits do extend to patients with HFrEF and T2DM.

“It’s really not about a Sophie’s choice of whether you give this or that drug in these patients,” said corresponding author Javed Butler, MD, MPH, MBA. “We really ought to be giving all of these drugs – the angiotensin receptor neprilysin inhibitors (ARNIs) and sodium-glucose transporter 2 (SGLT-2) inhibitors – to our patients for the best outcomes.”

The post-hoc analysis, published in JACC: Heart Failure, evaluated 361 patients with T2DM who were enrolled in the PROVE-HF trial of sac/val therapy for HF, published in JAMA.

PROVE-HF evaluated biomarkers, myocardial remodeling, and outcomes through a year of treatment with sac/val. The primary endpoint was the level of changes in natriuretic peptide (NT-proBNP) concentrations, left-ventricle ejection fraction (LVEF) and overall Kansas City Cardiomyopathy Questionnaire (KCCQ)-23 scores through 12 months of treatment.

The post hoc study reported that baseline NT-proBNP concentrations were higher in the DM patients (854 pg/mL vs. 706 pg/mL), but at 12 months those levels were 513 and 441 pg/mL, respectively.

LVEF changed similarly from baseline to 12 months in both groups: from 28.3% to 37% in the DM patients and from 28.1% to 38.34% in non-DM patients. Overall KCCQ-23 scores improved similarly in both groups, but longitudinal analyses found modestly higher gains in the T2DM group, 9.3 vs. 8.6 points (P = .07).

“The real reason I wanted to do this study is that I’m a huge fan of all the SGLT-2 inhibitors, and I’m very involved in those trials, and there is right now so much momentum behind SGLT-2 inhibitors that I don’t want people to forget that ARNI is still the base therapy for HF,” said Dr. Butler, chair of cardiovascular research and the department of medicine at the University of Mississippi in Jackson.

He noted that the size of the diabetes cohort in PROVE-HF “is a nonissue” for evaluating power of the post hoc analysis because it tracked key measures in the study population continuously at eight intervals over the 12 months.

The analysis further demonstrates the synergistic effects of ARNI and SGLT-2 inhibitors in patients with T2DM and HF that were also reported in the PARADIGM-HF study, Dr. Butler said.

“We have sort of moved on, saying that SGLT-2 inhibitors have a benefit on the heart, but the reverse is also true: ARNIs are still heart failure drugs, and we don’t think of them as diabetes drugs, but the PARADIGM-HF data showed that there was a substantial reduction in hemoglobin A1c in those who had diabetes,” he said.

The researchers noted that an absence of a control group may contribute to an overestimation of reverse cardiac remodeling in the T2DM patients, and that the PROVE-HF study wasn’t prospectively powered to delineate differences in how sac/val therapy affected patients with or without diabetes. “Future investigations seeking to evaluate differences by T2DM status after sacubitril/valsartan initiation may use our findings to plan prospective sample sizes,” the researchers wrote.

Dr. Butler disclosed financial relationships with Abbott, Amgen, Array, AstraZeneca, Bayer, Boehringer Ingelheim, CVRx, Eli Lilly, G3 Pharmaceutical, Impulse Dynamics, Innolife, Janssen, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Sequana, StealthPeptide and Vifor. Lead author Muhammad Shahzeb Khan, MD, MSc, a professor at the University of Mississippi, has no relevant financial relationships to disclose.

SOURCE: Kahn MS et al. JACC: HF. 2020 Dec 9. doi: 10.1016/j.jchf.2020.09.014.
 

The beneficial effects of sacubitril/valsartan on reverse cardiac remodeling in patients with heart failure and reduced ejection fraction have been well established, but those benefits haven’t been as clearly demonstrated to carry over to HFrEF patients who also have type 2 diabetes mellitus (T2DM).

Now, a post-hoc analysis of a pivotal clinical trial reports that those benefits do extend to patients with HFrEF and T2DM.

“It’s really not about a Sophie’s choice of whether you give this or that drug in these patients,” said corresponding author Javed Butler, MD, MPH, MBA. “We really ought to be giving all of these drugs – the angiotensin receptor neprilysin inhibitors (ARNIs) and sodium-glucose transporter 2 (SGLT-2) inhibitors – to our patients for the best outcomes.”

The post-hoc analysis, published in JACC: Heart Failure, evaluated 361 patients with T2DM who were enrolled in the PROVE-HF trial of sac/val therapy for HF, published in JAMA.

PROVE-HF evaluated biomarkers, myocardial remodeling, and outcomes through a year of treatment with sac/val. The primary endpoint was the level of changes in natriuretic peptide (NT-proBNP) concentrations, left-ventricle ejection fraction (LVEF) and overall Kansas City Cardiomyopathy Questionnaire (KCCQ)-23 scores through 12 months of treatment.

The post hoc study reported that baseline NT-proBNP concentrations were higher in the DM patients (854 pg/mL vs. 706 pg/mL), but at 12 months those levels were 513 and 441 pg/mL, respectively.

LVEF changed similarly from baseline to 12 months in both groups: from 28.3% to 37% in the DM patients and from 28.1% to 38.34% in non-DM patients. Overall KCCQ-23 scores improved similarly in both groups, but longitudinal analyses found modestly higher gains in the T2DM group, 9.3 vs. 8.6 points (P = .07).

“The real reason I wanted to do this study is that I’m a huge fan of all the SGLT-2 inhibitors, and I’m very involved in those trials, and there is right now so much momentum behind SGLT-2 inhibitors that I don’t want people to forget that ARNI is still the base therapy for HF,” said Dr. Butler, chair of cardiovascular research and the department of medicine at the University of Mississippi in Jackson.

He noted that the size of the diabetes cohort in PROVE-HF “is a nonissue” for evaluating power of the post hoc analysis because it tracked key measures in the study population continuously at eight intervals over the 12 months.

The analysis further demonstrates the synergistic effects of ARNI and SGLT-2 inhibitors in patients with T2DM and HF that were also reported in the PARADIGM-HF study, Dr. Butler said.

“We have sort of moved on, saying that SGLT-2 inhibitors have a benefit on the heart, but the reverse is also true: ARNIs are still heart failure drugs, and we don’t think of them as diabetes drugs, but the PARADIGM-HF data showed that there was a substantial reduction in hemoglobin A1c in those who had diabetes,” he said.

The researchers noted that an absence of a control group may contribute to an overestimation of reverse cardiac remodeling in the T2DM patients, and that the PROVE-HF study wasn’t prospectively powered to delineate differences in how sac/val therapy affected patients with or without diabetes. “Future investigations seeking to evaluate differences by T2DM status after sacubitril/valsartan initiation may use our findings to plan prospective sample sizes,” the researchers wrote.

Dr. Butler disclosed financial relationships with Abbott, Amgen, Array, AstraZeneca, Bayer, Boehringer Ingelheim, CVRx, Eli Lilly, G3 Pharmaceutical, Impulse Dynamics, Innolife, Janssen, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Sequana, StealthPeptide and Vifor. Lead author Muhammad Shahzeb Khan, MD, MSc, a professor at the University of Mississippi, has no relevant financial relationships to disclose.

SOURCE: Kahn MS et al. JACC: HF. 2020 Dec 9. doi: 10.1016/j.jchf.2020.09.014.
 

The beneficial effects of sacubitril/valsartan on reverse cardiac remodeling in patients with heart failure and reduced ejection fraction have been well established, but those benefits haven’t been as clearly demonstrated to carry over to HFrEF patients who also have type 2 diabetes mellitus (T2DM).

Now, a post-hoc analysis of a pivotal clinical trial reports that those benefits do extend to patients with HFrEF and T2DM.

“It’s really not about a Sophie’s choice of whether you give this or that drug in these patients,” said corresponding author Javed Butler, MD, MPH, MBA. “We really ought to be giving all of these drugs – the angiotensin receptor neprilysin inhibitors (ARNIs) and sodium-glucose transporter 2 (SGLT-2) inhibitors – to our patients for the best outcomes.”

The post-hoc analysis, published in JACC: Heart Failure, evaluated 361 patients with T2DM who were enrolled in the PROVE-HF trial of sac/val therapy for HF, published in JAMA.

PROVE-HF evaluated biomarkers, myocardial remodeling, and outcomes through a year of treatment with sac/val. The primary endpoint was the level of changes in natriuretic peptide (NT-proBNP) concentrations, left-ventricle ejection fraction (LVEF) and overall Kansas City Cardiomyopathy Questionnaire (KCCQ)-23 scores through 12 months of treatment.

The post hoc study reported that baseline NT-proBNP concentrations were higher in the DM patients (854 pg/mL vs. 706 pg/mL), but at 12 months those levels were 513 and 441 pg/mL, respectively.

LVEF changed similarly from baseline to 12 months in both groups: from 28.3% to 37% in the DM patients and from 28.1% to 38.34% in non-DM patients. Overall KCCQ-23 scores improved similarly in both groups, but longitudinal analyses found modestly higher gains in the T2DM group, 9.3 vs. 8.6 points (P = .07).

“The real reason I wanted to do this study is that I’m a huge fan of all the SGLT-2 inhibitors, and I’m very involved in those trials, and there is right now so much momentum behind SGLT-2 inhibitors that I don’t want people to forget that ARNI is still the base therapy for HF,” said Dr. Butler, chair of cardiovascular research and the department of medicine at the University of Mississippi in Jackson.

He noted that the size of the diabetes cohort in PROVE-HF “is a nonissue” for evaluating power of the post hoc analysis because it tracked key measures in the study population continuously at eight intervals over the 12 months.

The analysis further demonstrates the synergistic effects of ARNI and SGLT-2 inhibitors in patients with T2DM and HF that were also reported in the PARADIGM-HF study, Dr. Butler said.

“We have sort of moved on, saying that SGLT-2 inhibitors have a benefit on the heart, but the reverse is also true: ARNIs are still heart failure drugs, and we don’t think of them as diabetes drugs, but the PARADIGM-HF data showed that there was a substantial reduction in hemoglobin A1c in those who had diabetes,” he said.

The researchers noted that an absence of a control group may contribute to an overestimation of reverse cardiac remodeling in the T2DM patients, and that the PROVE-HF study wasn’t prospectively powered to delineate differences in how sac/val therapy affected patients with or without diabetes. “Future investigations seeking to evaluate differences by T2DM status after sacubitril/valsartan initiation may use our findings to plan prospective sample sizes,” the researchers wrote.

Dr. Butler disclosed financial relationships with Abbott, Amgen, Array, AstraZeneca, Bayer, Boehringer Ingelheim, CVRx, Eli Lilly, G3 Pharmaceutical, Impulse Dynamics, Innolife, Janssen, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Sequana, StealthPeptide and Vifor. Lead author Muhammad Shahzeb Khan, MD, MSc, a professor at the University of Mississippi, has no relevant financial relationships to disclose.

SOURCE: Kahn MS et al. JACC: HF. 2020 Dec 9. doi: 10.1016/j.jchf.2020.09.014.