Heart Failure

In an ideal world, people could afford sacubitril/valsartan (Entresto), and clinicians would be allowed to prescribe it using clinical judgment as their guide. The imprimatur of an “[Food and Drug Administration]–labeled indication” would be unnecessary.

This is not our world. Guideline writers, third-party payers, and FDA regulators now play major roles in clinical decisions.

The angiotensin receptor neprilysin inhibitor is approved for use in patients with heart failure with reduced ejection fraction (HFrEF). In December 2020, an FDA advisory committee voted 12-1 in support of a vaguely worded question: Does PARAGON-HF provide sufficient evidence to support any indication for the drug in patients with heart failure with preserved ejection fraction (HFpEF)? The committee did not reach a consensus on what that indication should be.

Before I list five reasons why I hope the FDA does not approve the drug for any indication in patients with HFpEF, let’s review the seminal trial.
 

PARAGON-HF

PARAGON-HF randomly assigned slightly more than 4,800 patients with symptomatic HFpEF (left ventricular ejection fraction [LVEF] ≥45%) to sacubitril/valsartan or valsartan alone. The primary endpoint was total hospitalizations for heart failure (HHF) and death because of cardiovascular (CV) events.

Sacubitril/valsartan reduced the rate of the primary endpoint by 13% (rate ratio, 0.87; 95% confidence interval, 0.75-1.01; P = .06). There were 894 primary endpoint events in the sacubitril/valsartan arm, compared with 1,009 events in the valsartan arm.

The lower rate of events in the sacubitril/valsartan arm was driven by fewer hospitalizations for heart failure. CV death was essentially the same in both arms (204 deaths in the sacubitril/valsartan group versus 212 deaths in the valsartan group).

A note on the patients: the investigators screened more than 10,000 patients and enrolled less than half of them. The mean age was 73 years; 52% of patients were women, but only 2% were Black. The mean LVEF was 57%; 95% of patients had hypertension and were receiving diuretics at baseline.

Now to the five reasons not to approve the drug for this indication.
 

1. Uncertainty of benefit in HFpEF

A P value for the primary endpoint greater than the threshold of .05 suggests some degree of uncertainty. A nice way of describing this uncertainty is with a Bayesian analysis. Whereas a P value tells you the chance of seeing these results if the drug has no benefit, the Bayesian approach tells you the chance of drug benefit given the trial results.

By email, James Brophy, MD, a senior scientist in the Centre for Outcomes Research and Evaluation at McGill University, Montreal, showed me a Bayesian calculation of PARAGON-HF. He estimated a 38% chance that sacubitril/valsartan had a clinically meaningful 15% reduction in the primary endpoint, a 3% chance that it worsens outcomes, and a 58% chance that it is essentially no better than valsartan.

The take-home is that, in PARAGON-HF, a best-case scenario involving select high-risk patients with run-in periods and trial-level follow-up, there is substantial uncertainty as to whether the drug is any better than a generic standard.
 

2. Modest effect size in PARAGON-HF

Let’s assume the benefit seen in PARAGON-HF is not caused by chance. Was the effect clinically significant?

For context, consider the large effect size that sacubitril/valsartan had versus enalapril for patients with HFrEF.

In PARADIGM-HF, sacubitril/valsartan led to a 20% reduction in the composite primary endpoint. Importantly, this included equal reductions in both HHF and CV death. All-cause death was also significantly reduced in the active arm.

Because patients with HFpEF have a similarly poor prognosis as those with HFrEF, a truly beneficial drug should reduce not only HHF but also CV death and overall death. The lack of effect on these “harder” endpoints in PARAGON-HF points to a far more modest effect size for sacubitril/valsartan in HFpEF.

What’s more, even the signal of reduced HHF in PARAGON-HF is tenuous. The PARAGON-HF authors chose total HHF, whereas previous trials in patients with HFpEF used first HHF as their primary endpoint. Had PARAGON-HF followed the methods of prior trials, first HHF would not have made statistical significance (hazard ratio, 0.90; 95% CI, 0.79-1.04)
 

3. Subgroups not compelling

Proponents highlight the possibility that sacubitril/valsartan exerted a heterogenous effect in two subgroups.

In women, sacubitril/valsartan resulted in a 27% reduction in the primary endpoint (HR, 0.73; 95% CI, 0.59-0.90), whereas men showed no significant difference (HR, 1.03; 95% CI, 0.85-1.25). And the drug seemed to have little benefit over valsartan in patients with a median LVEF greater than 57%.

The problem with subgroups is that, if you look at enough of them, some can be positive on the basis of chance alone. For instance, patients enrolled in western Europe had an outsized benefit from sacubitril/valsartan, compared with patients from other areas.

FDA reviewers noted: “It is possible that the heterogeneity of treatment effect observed in the subgroups by gender and LVEF in PARAGON-HF is a chance finding.”

By email, clinical trial expert Sanjay Kaul, MD, from Cedars-Sinai Medical Center in Los Angeles, expressed serious concern with the subgroup analyses in PARAGON-HF because the sex interaction was confined to HHF alone. There was no interaction for other outcomes, such as CV death, all-cause mortality, renal endpoints, blood pressure, or lowering of N-terminal of the prohormone brain natriuretic peptide.

Similarly, the interaction with ejection fraction was confined to total HHF; it was not seen with New York Heart Association class improvement, all-cause mortality, quality of life, renal endpoints, or time to first event.

Dr. Kaul also emphasized something cardiologists know well, “that ejection fraction is not a static variable and is expected to change during the course of the trial.” This point makes it hard to believe that a partially subjective measurement, such as LVEF, could be a precise modifier of benefit.
 

4. Approval would stop research

If the FDA approves sacubitril/valsartan for patients with HFpEF, there is a near-zero chance we will learn whether there are subsets of patients who benefit more or less from the drug.

It will be the defibrillator problem all over again. Namely, while the average effect of a defibrillator is to reduce mortality in patients with HFrEF, in approximately 9 of 10 patients the implanted device is never used. Efforts to find subgroups that are most likely to need (or not need) an implantable defibrillator have been impossible because industry has no incentive to fund trials that may narrow the number of patients who qualify for their product.

It will be the same with sacubitril/valsartan. This is not nefarious; it is merely a limitation of industry funding of trials.
 

5. Opportunity costs

The category of HFpEF is vast.

FDA approval – even for a subset of these patients – would have huge cost implications. I understand cost issues are considered outside the purview of the FDA, but health care spending isn’t infinite. Money spent covering this costly drug is money not available for other things.

Despite this nation’s wealth, we struggle to provide even basic care to large numbers of people. Approval of an expensive drug with no or modest benefit will only exacerbate these stark disparities.
 

Conclusion

Given our current system of health care delivery, my pragmatic answer is for the FDA to say no to sacubitril/valsartan for HFpEF.

If you believe the drug has outsized benefits in women or those with mild impairment of systolic function, the way to answer these questions is not with subgroup analyses from a trial that did not reach statistical significance in its primary endpoint, but with more randomized trials. Isn’t that what “exploratory” subgroups are for?

Holding off on an indication for HFpEF will force proponents to define a subset of patients who garner a clear and substantial benefit from sacubitril/valsartan.

Dr. Mandrola practices cardiac electrophysiology in Louisville, Ky., and is a writer and podcaster for Medscape. He espouses a conservative approach to medical practice. He participates in clinical research and writes often about the state of medical evidence. MDedge is part of the Medscape Professional Network.

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

In an ideal world, people could afford sacubitril/valsartan (Entresto), and clinicians would be allowed to prescribe it using clinical judgment as their guide. The imprimatur of an “[Food and Drug Administration]–labeled indication” would be unnecessary.

This is not our world. Guideline writers, third-party payers, and FDA regulators now play major roles in clinical decisions.

The angiotensin receptor neprilysin inhibitor is approved for use in patients with heart failure with reduced ejection fraction (HFrEF). In December 2020, an FDA advisory committee voted 12-1 in support of a vaguely worded question: Does PARAGON-HF provide sufficient evidence to support any indication for the drug in patients with heart failure with preserved ejection fraction (HFpEF)? The committee did not reach a consensus on what that indication should be.

Before I list five reasons why I hope the FDA does not approve the drug for any indication in patients with HFpEF, let’s review the seminal trial.
 

PARAGON-HF

PARAGON-HF randomly assigned slightly more than 4,800 patients with symptomatic HFpEF (left ventricular ejection fraction [LVEF] ≥45%) to sacubitril/valsartan or valsartan alone. The primary endpoint was total hospitalizations for heart failure (HHF) and death because of cardiovascular (CV) events.

Sacubitril/valsartan reduced the rate of the primary endpoint by 13% (rate ratio, 0.87; 95% confidence interval, 0.75-1.01; P = .06). There were 894 primary endpoint events in the sacubitril/valsartan arm, compared with 1,009 events in the valsartan arm.

The lower rate of events in the sacubitril/valsartan arm was driven by fewer hospitalizations for heart failure. CV death was essentially the same in both arms (204 deaths in the sacubitril/valsartan group versus 212 deaths in the valsartan group).

A note on the patients: the investigators screened more than 10,000 patients and enrolled less than half of them. The mean age was 73 years; 52% of patients were women, but only 2% were Black. The mean LVEF was 57%; 95% of patients had hypertension and were receiving diuretics at baseline.

Now to the five reasons not to approve the drug for this indication.
 

1. Uncertainty of benefit in HFpEF

A P value for the primary endpoint greater than the threshold of .05 suggests some degree of uncertainty. A nice way of describing this uncertainty is with a Bayesian analysis. Whereas a P value tells you the chance of seeing these results if the drug has no benefit, the Bayesian approach tells you the chance of drug benefit given the trial results.

By email, James Brophy, MD, a senior scientist in the Centre for Outcomes Research and Evaluation at McGill University, Montreal, showed me a Bayesian calculation of PARAGON-HF. He estimated a 38% chance that sacubitril/valsartan had a clinically meaningful 15% reduction in the primary endpoint, a 3% chance that it worsens outcomes, and a 58% chance that it is essentially no better than valsartan.

The take-home is that, in PARAGON-HF, a best-case scenario involving select high-risk patients with run-in periods and trial-level follow-up, there is substantial uncertainty as to whether the drug is any better than a generic standard.
 

2. Modest effect size in PARAGON-HF

Let’s assume the benefit seen in PARAGON-HF is not caused by chance. Was the effect clinically significant?

For context, consider the large effect size that sacubitril/valsartan had versus enalapril for patients with HFrEF.

In PARADIGM-HF, sacubitril/valsartan led to a 20% reduction in the composite primary endpoint. Importantly, this included equal reductions in both HHF and CV death. All-cause death was also significantly reduced in the active arm.

Because patients with HFpEF have a similarly poor prognosis as those with HFrEF, a truly beneficial drug should reduce not only HHF but also CV death and overall death. The lack of effect on these “harder” endpoints in PARAGON-HF points to a far more modest effect size for sacubitril/valsartan in HFpEF.

What’s more, even the signal of reduced HHF in PARAGON-HF is tenuous. The PARAGON-HF authors chose total HHF, whereas previous trials in patients with HFpEF used first HHF as their primary endpoint. Had PARAGON-HF followed the methods of prior trials, first HHF would not have made statistical significance (hazard ratio, 0.90; 95% CI, 0.79-1.04)
 

3. Subgroups not compelling

Proponents highlight the possibility that sacubitril/valsartan exerted a heterogenous effect in two subgroups.

In women, sacubitril/valsartan resulted in a 27% reduction in the primary endpoint (HR, 0.73; 95% CI, 0.59-0.90), whereas men showed no significant difference (HR, 1.03; 95% CI, 0.85-1.25). And the drug seemed to have little benefit over valsartan in patients with a median LVEF greater than 57%.

The problem with subgroups is that, if you look at enough of them, some can be positive on the basis of chance alone. For instance, patients enrolled in western Europe had an outsized benefit from sacubitril/valsartan, compared with patients from other areas.

FDA reviewers noted: “It is possible that the heterogeneity of treatment effect observed in the subgroups by gender and LVEF in PARAGON-HF is a chance finding.”

By email, clinical trial expert Sanjay Kaul, MD, from Cedars-Sinai Medical Center in Los Angeles, expressed serious concern with the subgroup analyses in PARAGON-HF because the sex interaction was confined to HHF alone. There was no interaction for other outcomes, such as CV death, all-cause mortality, renal endpoints, blood pressure, or lowering of N-terminal of the prohormone brain natriuretic peptide.

Similarly, the interaction with ejection fraction was confined to total HHF; it was not seen with New York Heart Association class improvement, all-cause mortality, quality of life, renal endpoints, or time to first event.

Dr. Kaul also emphasized something cardiologists know well, “that ejection fraction is not a static variable and is expected to change during the course of the trial.” This point makes it hard to believe that a partially subjective measurement, such as LVEF, could be a precise modifier of benefit.
 

4. Approval would stop research

If the FDA approves sacubitril/valsartan for patients with HFpEF, there is a near-zero chance we will learn whether there are subsets of patients who benefit more or less from the drug.

It will be the defibrillator problem all over again. Namely, while the average effect of a defibrillator is to reduce mortality in patients with HFrEF, in approximately 9 of 10 patients the implanted device is never used. Efforts to find subgroups that are most likely to need (or not need) an implantable defibrillator have been impossible because industry has no incentive to fund trials that may narrow the number of patients who qualify for their product.

It will be the same with sacubitril/valsartan. This is not nefarious; it is merely a limitation of industry funding of trials.
 

5. Opportunity costs

The category of HFpEF is vast.

FDA approval – even for a subset of these patients – would have huge cost implications. I understand cost issues are considered outside the purview of the FDA, but health care spending isn’t infinite. Money spent covering this costly drug is money not available for other things.

Despite this nation’s wealth, we struggle to provide even basic care to large numbers of people. Approval of an expensive drug with no or modest benefit will only exacerbate these stark disparities.
 

Conclusion

Given our current system of health care delivery, my pragmatic answer is for the FDA to say no to sacubitril/valsartan for HFpEF.

If you believe the drug has outsized benefits in women or those with mild impairment of systolic function, the way to answer these questions is not with subgroup analyses from a trial that did not reach statistical significance in its primary endpoint, but with more randomized trials. Isn’t that what “exploratory” subgroups are for?

Holding off on an indication for HFpEF will force proponents to define a subset of patients who garner a clear and substantial benefit from sacubitril/valsartan.

Dr. Mandrola practices cardiac electrophysiology in Louisville, Ky., and is a writer and podcaster for Medscape. He espouses a conservative approach to medical practice. He participates in clinical research and writes often about the state of medical evidence. MDedge is part of the Medscape Professional Network.

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

In an ideal world, people could afford sacubitril/valsartan (Entresto), and clinicians would be allowed to prescribe it using clinical judgment as their guide. The imprimatur of an “[Food and Drug Administration]–labeled indication” would be unnecessary.

This is not our world. Guideline writers, third-party payers, and FDA regulators now play major roles in clinical decisions.

The angiotensin receptor neprilysin inhibitor is approved for use in patients with heart failure with reduced ejection fraction (HFrEF). In December 2020, an FDA advisory committee voted 12-1 in support of a vaguely worded question: Does PARAGON-HF provide sufficient evidence to support any indication for the drug in patients with heart failure with preserved ejection fraction (HFpEF)? The committee did not reach a consensus on what that indication should be.

Before I list five reasons why I hope the FDA does not approve the drug for any indication in patients with HFpEF, let’s review the seminal trial.
 

PARAGON-HF

PARAGON-HF randomly assigned slightly more than 4,800 patients with symptomatic HFpEF (left ventricular ejection fraction [LVEF] ≥45%) to sacubitril/valsartan or valsartan alone. The primary endpoint was total hospitalizations for heart failure (HHF) and death because of cardiovascular (CV) events.

Sacubitril/valsartan reduced the rate of the primary endpoint by 13% (rate ratio, 0.87; 95% confidence interval, 0.75-1.01; P = .06). There were 894 primary endpoint events in the sacubitril/valsartan arm, compared with 1,009 events in the valsartan arm.

The lower rate of events in the sacubitril/valsartan arm was driven by fewer hospitalizations for heart failure. CV death was essentially the same in both arms (204 deaths in the sacubitril/valsartan group versus 212 deaths in the valsartan group).

A note on the patients: the investigators screened more than 10,000 patients and enrolled less than half of them. The mean age was 73 years; 52% of patients were women, but only 2% were Black. The mean LVEF was 57%; 95% of patients had hypertension and were receiving diuretics at baseline.

Now to the five reasons not to approve the drug for this indication.
 

1. Uncertainty of benefit in HFpEF

A P value for the primary endpoint greater than the threshold of .05 suggests some degree of uncertainty. A nice way of describing this uncertainty is with a Bayesian analysis. Whereas a P value tells you the chance of seeing these results if the drug has no benefit, the Bayesian approach tells you the chance of drug benefit given the trial results.

By email, James Brophy, MD, a senior scientist in the Centre for Outcomes Research and Evaluation at McGill University, Montreal, showed me a Bayesian calculation of PARAGON-HF. He estimated a 38% chance that sacubitril/valsartan had a clinically meaningful 15% reduction in the primary endpoint, a 3% chance that it worsens outcomes, and a 58% chance that it is essentially no better than valsartan.

The take-home is that, in PARAGON-HF, a best-case scenario involving select high-risk patients with run-in periods and trial-level follow-up, there is substantial uncertainty as to whether the drug is any better than a generic standard.
 

2. Modest effect size in PARAGON-HF

Let’s assume the benefit seen in PARAGON-HF is not caused by chance. Was the effect clinically significant?

For context, consider the large effect size that sacubitril/valsartan had versus enalapril for patients with HFrEF.

In PARADIGM-HF, sacubitril/valsartan led to a 20% reduction in the composite primary endpoint. Importantly, this included equal reductions in both HHF and CV death. All-cause death was also significantly reduced in the active arm.

Because patients with HFpEF have a similarly poor prognosis as those with HFrEF, a truly beneficial drug should reduce not only HHF but also CV death and overall death. The lack of effect on these “harder” endpoints in PARAGON-HF points to a far more modest effect size for sacubitril/valsartan in HFpEF.

What’s more, even the signal of reduced HHF in PARAGON-HF is tenuous. The PARAGON-HF authors chose total HHF, whereas previous trials in patients with HFpEF used first HHF as their primary endpoint. Had PARAGON-HF followed the methods of prior trials, first HHF would not have made statistical significance (hazard ratio, 0.90; 95% CI, 0.79-1.04)
 

3. Subgroups not compelling

Proponents highlight the possibility that sacubitril/valsartan exerted a heterogenous effect in two subgroups.

In women, sacubitril/valsartan resulted in a 27% reduction in the primary endpoint (HR, 0.73; 95% CI, 0.59-0.90), whereas men showed no significant difference (HR, 1.03; 95% CI, 0.85-1.25). And the drug seemed to have little benefit over valsartan in patients with a median LVEF greater than 57%.

The problem with subgroups is that, if you look at enough of them, some can be positive on the basis of chance alone. For instance, patients enrolled in western Europe had an outsized benefit from sacubitril/valsartan, compared with patients from other areas.

FDA reviewers noted: “It is possible that the heterogeneity of treatment effect observed in the subgroups by gender and LVEF in PARAGON-HF is a chance finding.”

By email, clinical trial expert Sanjay Kaul, MD, from Cedars-Sinai Medical Center in Los Angeles, expressed serious concern with the subgroup analyses in PARAGON-HF because the sex interaction was confined to HHF alone. There was no interaction for other outcomes, such as CV death, all-cause mortality, renal endpoints, blood pressure, or lowering of N-terminal of the prohormone brain natriuretic peptide.

Similarly, the interaction with ejection fraction was confined to total HHF; it was not seen with New York Heart Association class improvement, all-cause mortality, quality of life, renal endpoints, or time to first event.

Dr. Kaul also emphasized something cardiologists know well, “that ejection fraction is not a static variable and is expected to change during the course of the trial.” This point makes it hard to believe that a partially subjective measurement, such as LVEF, could be a precise modifier of benefit.
 

4. Approval would stop research

If the FDA approves sacubitril/valsartan for patients with HFpEF, there is a near-zero chance we will learn whether there are subsets of patients who benefit more or less from the drug.

It will be the defibrillator problem all over again. Namely, while the average effect of a defibrillator is to reduce mortality in patients with HFrEF, in approximately 9 of 10 patients the implanted device is never used. Efforts to find subgroups that are most likely to need (or not need) an implantable defibrillator have been impossible because industry has no incentive to fund trials that may narrow the number of patients who qualify for their product.

It will be the same with sacubitril/valsartan. This is not nefarious; it is merely a limitation of industry funding of trials.
 

5. Opportunity costs

The category of HFpEF is vast.

FDA approval – even for a subset of these patients – would have huge cost implications. I understand cost issues are considered outside the purview of the FDA, but health care spending isn’t infinite. Money spent covering this costly drug is money not available for other things.

Despite this nation’s wealth, we struggle to provide even basic care to large numbers of people. Approval of an expensive drug with no or modest benefit will only exacerbate these stark disparities.
 

Conclusion

Given our current system of health care delivery, my pragmatic answer is for the FDA to say no to sacubitril/valsartan for HFpEF.

If you believe the drug has outsized benefits in women or those with mild impairment of systolic function, the way to answer these questions is not with subgroup analyses from a trial that did not reach statistical significance in its primary endpoint, but with more randomized trials. Isn’t that what “exploratory” subgroups are for?

Holding off on an indication for HFpEF will force proponents to define a subset of patients who garner a clear and substantial benefit from sacubitril/valsartan.

Dr. Mandrola practices cardiac electrophysiology in Louisville, Ky., and is a writer and podcaster for Medscape. He espouses a conservative approach to medical practice. He participates in clinical research and writes often about the state of medical evidence. MDedge is part of the Medscape Professional Network.

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

Although not correlated with each other, increased levels of circulating neprilysin and corin concentrations correlate with increased risk of cardiovascular death and heart failure hospitalizations in chronic heart failure (CHF) patients, according to prospective analysis involving 1,009 HF patients.

This implies that these enzymes might have value for individualizing care, including treatment of patients in heart failure with preserved ejection fraction (HFpEF), reported a team of investigators led by D.H. Frank Gommans, MD, PhD, department of cardiology, Radboud University Medical Center, Nijmegen, the Netherlands.

When followed for up to 7 years and after adjustment for differences in sex and age, the highest risk for the primary composite endpoint of cardiovascular (CV) death and heart failure hospitalization was observed in those with both high soluble neprilysin (sNEP) and high soluble corin (sCOR). The lowest risk was observed in the group with low levels of both enzymes.

The data suggest that monitoring these enzymes might provide “a step toward individualized CHF patient management,” Dr. Gommans reported in JACC Heart Failure, the adjusted hazard ratio for elevated sNEP and sCOR translated into a greater than 50% increase in the composite primary endpoint relative to low levels of both (HR, 1.56; P = .003). After a “comprehensive multivariable analysis,” the increased risk remained substantial and significant (HR, 1.41; P = .03).

In the natriuretic peptide pathway, which has long been recognized as a mediator of vasodilation, venous compliance, diuresis, and other processes dysregulated in heart failure, NEP and COR are “key mediators,” according to the investigators, who cited previously published studies. More attention has turned to these enzymes as potential biomarkers in the context of the PARADIGM trial, which associated an angiotensin-receptor neprilysin inhibitor (ARNI) with a survival benefit in CHF.

The observational study consisted of CHF patients attending a heart failure clinic and who were ARNI naive at inclusion. On the basis of circulating enzyme measurements undertaken from blood samples employing standard techniques, they were stratified into four groups. Those with low levels of both enzymes served as the reference. They were compared with those with low sNEP and high sCOR, those with high sNEP and low sCOR, and those with high levels of both enzymes.

Over the course of a median 4.5 years of follow-up, there were 511 deaths, of which 54% were from a CV cause. There were also 331 heart failure hospitalizations. In all, 449 patients reached the primary composite endpoint.

When compared with the group with low sNEP and low sCOR, an elevation in either enzyme was associated with a numerically but not significantly greater hazard ratio for the primary composite endpoint. The lack of correlation in the elevation of these two enzymes suggests each provides different prognostic information, although it appears that both must be considered together to predict outcomes.

Clinically, stratification of these enzymes might be most useful in HFpEF patients. Relative to the separation of event curves in the CHF patients with reduced ejection fraction (HFrEF), the divergence in the event curves for HFpEF were greater. In addition, event curves separated from the reference in HFpEF patients but not the HFrEF patients if either enzyme was elevated.

Asked if these data hold particular promise for monitoring and individualizing therapy in HFpEF patients, Dr. Gommans said yes. Although he cautioned that this was an observational study and that the differences between the HFpEF and HFrEF should be considered exploratory, he agreed that components of the natriuretic peptide pathway have particular potential to provide new prognostic information and individualize care in HFpEF, where therapeutic options remain limited.

Stratification of natriuretic peptide enzymes in this group might “present as an interesting alternative to ejection fraction” for prognosis and the consideration of treatment choices, he suggested.

Although further validation of the prognostic importance of sNEP and sCOR is needed, according to Dr. Gommans, he foresees the potential of therapeutic trials based on elevated levels of these enzymes. For example, he speculated that these levels might distinguish HFpEF patients who could benefit from a first-line ARNI.

In an accompanying editorial, significant doubts were expressed about simple measurements of sNEP and sCOR concentrations to predict clinical course or guide treatment decisions. The authors of the editorial agreed this is an important area of study but warned of its complexity.

“Concentrations of circulating neprilysin have been shown to correlate poorly with neprilysin activity. Thus the rate of natriuretic peptide degradation by neprilysin cannot be determined solely by measuring circulating levels,” cautioned Peder L. Myhre, MD, PhD, who is a cardiology fellow at Akershus University Hospital in Nordbyhagen, Norway, and postdoc researcher at the University of Oslo.

“Accordingly, concentrations of neprilysin and corin cannot alone be used to predict response to therapies interacting with these peptides,” he added. He agreed that neprilysin and corin might be appropriate biomarkers in CHF, but he thinks the focus must be on their enzymatic activity, not their circulating levels.

“Measuring the enzymatic activity may be a feasible strategy, but this remains to be seen,” he said.

Dr. Gommans reported a financial relationship with Novartis. Dr. Myhre reported financial relationships with Amgen, Novartis, and Novo Nordisk.

Although not correlated with each other, increased levels of circulating neprilysin and corin concentrations correlate with increased risk of cardiovascular death and heart failure hospitalizations in chronic heart failure (CHF) patients, according to prospective analysis involving 1,009 HF patients.

This implies that these enzymes might have value for individualizing care, including treatment of patients in heart failure with preserved ejection fraction (HFpEF), reported a team of investigators led by D.H. Frank Gommans, MD, PhD, department of cardiology, Radboud University Medical Center, Nijmegen, the Netherlands.

When followed for up to 7 years and after adjustment for differences in sex and age, the highest risk for the primary composite endpoint of cardiovascular (CV) death and heart failure hospitalization was observed in those with both high soluble neprilysin (sNEP) and high soluble corin (sCOR). The lowest risk was observed in the group with low levels of both enzymes.

The data suggest that monitoring these enzymes might provide “a step toward individualized CHF patient management,” Dr. Gommans reported in JACC Heart Failure, the adjusted hazard ratio for elevated sNEP and sCOR translated into a greater than 50% increase in the composite primary endpoint relative to low levels of both (HR, 1.56; P = .003). After a “comprehensive multivariable analysis,” the increased risk remained substantial and significant (HR, 1.41; P = .03).

In the natriuretic peptide pathway, which has long been recognized as a mediator of vasodilation, venous compliance, diuresis, and other processes dysregulated in heart failure, NEP and COR are “key mediators,” according to the investigators, who cited previously published studies. More attention has turned to these enzymes as potential biomarkers in the context of the PARADIGM trial, which associated an angiotensin-receptor neprilysin inhibitor (ARNI) with a survival benefit in CHF.

The observational study consisted of CHF patients attending a heart failure clinic and who were ARNI naive at inclusion. On the basis of circulating enzyme measurements undertaken from blood samples employing standard techniques, they were stratified into four groups. Those with low levels of both enzymes served as the reference. They were compared with those with low sNEP and high sCOR, those with high sNEP and low sCOR, and those with high levels of both enzymes.

Over the course of a median 4.5 years of follow-up, there were 511 deaths, of which 54% were from a CV cause. There were also 331 heart failure hospitalizations. In all, 449 patients reached the primary composite endpoint.

When compared with the group with low sNEP and low sCOR, an elevation in either enzyme was associated with a numerically but not significantly greater hazard ratio for the primary composite endpoint. The lack of correlation in the elevation of these two enzymes suggests each provides different prognostic information, although it appears that both must be considered together to predict outcomes.

Clinically, stratification of these enzymes might be most useful in HFpEF patients. Relative to the separation of event curves in the CHF patients with reduced ejection fraction (HFrEF), the divergence in the event curves for HFpEF were greater. In addition, event curves separated from the reference in HFpEF patients but not the HFrEF patients if either enzyme was elevated.

Asked if these data hold particular promise for monitoring and individualizing therapy in HFpEF patients, Dr. Gommans said yes. Although he cautioned that this was an observational study and that the differences between the HFpEF and HFrEF should be considered exploratory, he agreed that components of the natriuretic peptide pathway have particular potential to provide new prognostic information and individualize care in HFpEF, where therapeutic options remain limited.

Stratification of natriuretic peptide enzymes in this group might “present as an interesting alternative to ejection fraction” for prognosis and the consideration of treatment choices, he suggested.

Although further validation of the prognostic importance of sNEP and sCOR is needed, according to Dr. Gommans, he foresees the potential of therapeutic trials based on elevated levels of these enzymes. For example, he speculated that these levels might distinguish HFpEF patients who could benefit from a first-line ARNI.

In an accompanying editorial, significant doubts were expressed about simple measurements of sNEP and sCOR concentrations to predict clinical course or guide treatment decisions. The authors of the editorial agreed this is an important area of study but warned of its complexity.

“Concentrations of circulating neprilysin have been shown to correlate poorly with neprilysin activity. Thus the rate of natriuretic peptide degradation by neprilysin cannot be determined solely by measuring circulating levels,” cautioned Peder L. Myhre, MD, PhD, who is a cardiology fellow at Akershus University Hospital in Nordbyhagen, Norway, and postdoc researcher at the University of Oslo.

“Accordingly, concentrations of neprilysin and corin cannot alone be used to predict response to therapies interacting with these peptides,” he added. He agreed that neprilysin and corin might be appropriate biomarkers in CHF, but he thinks the focus must be on their enzymatic activity, not their circulating levels.

“Measuring the enzymatic activity may be a feasible strategy, but this remains to be seen,” he said.

Dr. Gommans reported a financial relationship with Novartis. Dr. Myhre reported financial relationships with Amgen, Novartis, and Novo Nordisk.

Although not correlated with each other, increased levels of circulating neprilysin and corin concentrations correlate with increased risk of cardiovascular death and heart failure hospitalizations in chronic heart failure (CHF) patients, according to prospective analysis involving 1,009 HF patients.

This implies that these enzymes might have value for individualizing care, including treatment of patients in heart failure with preserved ejection fraction (HFpEF), reported a team of investigators led by D.H. Frank Gommans, MD, PhD, department of cardiology, Radboud University Medical Center, Nijmegen, the Netherlands.

When followed for up to 7 years and after adjustment for differences in sex and age, the highest risk for the primary composite endpoint of cardiovascular (CV) death and heart failure hospitalization was observed in those with both high soluble neprilysin (sNEP) and high soluble corin (sCOR). The lowest risk was observed in the group with low levels of both enzymes.

The data suggest that monitoring these enzymes might provide “a step toward individualized CHF patient management,” Dr. Gommans reported in JACC Heart Failure, the adjusted hazard ratio for elevated sNEP and sCOR translated into a greater than 50% increase in the composite primary endpoint relative to low levels of both (HR, 1.56; P = .003). After a “comprehensive multivariable analysis,” the increased risk remained substantial and significant (HR, 1.41; P = .03).

In the natriuretic peptide pathway, which has long been recognized as a mediator of vasodilation, venous compliance, diuresis, and other processes dysregulated in heart failure, NEP and COR are “key mediators,” according to the investigators, who cited previously published studies. More attention has turned to these enzymes as potential biomarkers in the context of the PARADIGM trial, which associated an angiotensin-receptor neprilysin inhibitor (ARNI) with a survival benefit in CHF.

The observational study consisted of CHF patients attending a heart failure clinic and who were ARNI naive at inclusion. On the basis of circulating enzyme measurements undertaken from blood samples employing standard techniques, they were stratified into four groups. Those with low levels of both enzymes served as the reference. They were compared with those with low sNEP and high sCOR, those with high sNEP and low sCOR, and those with high levels of both enzymes.

Over the course of a median 4.5 years of follow-up, there were 511 deaths, of which 54% were from a CV cause. There were also 331 heart failure hospitalizations. In all, 449 patients reached the primary composite endpoint.

When compared with the group with low sNEP and low sCOR, an elevation in either enzyme was associated with a numerically but not significantly greater hazard ratio for the primary composite endpoint. The lack of correlation in the elevation of these two enzymes suggests each provides different prognostic information, although it appears that both must be considered together to predict outcomes.

Clinically, stratification of these enzymes might be most useful in HFpEF patients. Relative to the separation of event curves in the CHF patients with reduced ejection fraction (HFrEF), the divergence in the event curves for HFpEF were greater. In addition, event curves separated from the reference in HFpEF patients but not the HFrEF patients if either enzyme was elevated.

Asked if these data hold particular promise for monitoring and individualizing therapy in HFpEF patients, Dr. Gommans said yes. Although he cautioned that this was an observational study and that the differences between the HFpEF and HFrEF should be considered exploratory, he agreed that components of the natriuretic peptide pathway have particular potential to provide new prognostic information and individualize care in HFpEF, where therapeutic options remain limited.

Stratification of natriuretic peptide enzymes in this group might “present as an interesting alternative to ejection fraction” for prognosis and the consideration of treatment choices, he suggested.

Although further validation of the prognostic importance of sNEP and sCOR is needed, according to Dr. Gommans, he foresees the potential of therapeutic trials based on elevated levels of these enzymes. For example, he speculated that these levels might distinguish HFpEF patients who could benefit from a first-line ARNI.

In an accompanying editorial, significant doubts were expressed about simple measurements of sNEP and sCOR concentrations to predict clinical course or guide treatment decisions. The authors of the editorial agreed this is an important area of study but warned of its complexity.

“Concentrations of circulating neprilysin have been shown to correlate poorly with neprilysin activity. Thus the rate of natriuretic peptide degradation by neprilysin cannot be determined solely by measuring circulating levels,” cautioned Peder L. Myhre, MD, PhD, who is a cardiology fellow at Akershus University Hospital in Nordbyhagen, Norway, and postdoc researcher at the University of Oslo.

“Accordingly, concentrations of neprilysin and corin cannot alone be used to predict response to therapies interacting with these peptides,” he added. He agreed that neprilysin and corin might be appropriate biomarkers in CHF, but he thinks the focus must be on their enzymatic activity, not their circulating levels.

“Measuring the enzymatic activity may be a feasible strategy, but this remains to be seen,” he said.

Dr. Gommans reported a financial relationship with Novartis. Dr. Myhre reported financial relationships with Amgen, Novartis, and Novo Nordisk.

Two recent observational studies suggest that myocarditis, at least on cardiac magnetic resonance (CMR) imaging, might be far less common in elite-level athletes recovering from COVID-19 than suggested in influential earlier reports.

AlexLMX/Getty Images

Both new studies documented a rate less than one-quarter as high as those previously reported from smaller cohorts, raising questions about the diagnostic yield of CMR in highly conditioned athletes with recent COVID-19 absent other evidence, such as from biomarker assays or electrocardiography (ECG).

That could have implications for some top-tier university athletics programs that mandate CMR imaging, biomarker assays, and other evaluations for myocarditis on all their players who test positive for SARS-CoV-2 before they can return to play.

The findings collectively point to CMR imaging features that might be a hallmark of an athlete’s heart, characterized by normal myocardial remodeling brought on by elite-level exercise training, which in athletes with recent COVID-19 could be misinterpreted as evidence of myocarditis. That may have thrown off prevalence estimates in the literature, the studies’ investigators speculated.

The two studies were retrospective takes on university athletes who underwent CMR imaging while recovering from COVID-19, who were either asymptomatic or with only mild to moderate symptoms and were generally without ECG or troponin evidence of myocarditis.

One of them showed a less than 2% incidence of myocarditis by CMR among 145 such cases, a low yield for imaging that is “raising doubt regarding its utility to evaluate athletes without a clinical presentation or abnormal ancillary tests to support the diagnosis of myocarditis,” argues a report published Jan. 14 in JAMA Cardiology, with lead author Jitka Starekova, MD, University of Wisconsin – Madison.

“Part of the problem is that occult myocarditis is, at least with other viruses, a risk factor for sudden death in competitive athletes. So you don’t want to let one slip through the cracks,” senior author Scott B. Reeder, MD, PhD, from the same institution, said in an interview.

Whether a policy of routine CMR imaging in elite athletes who test positive for the new coronavirus is better than more selective use driven by symptoms or other screening tests is unknown. But the more pressing issue, Dr. Reeder said, “is if they have a normal electrocardiogram and troponins, do they still need cardiac magnetic resonance imaging?”

The current study, he said, “certainly provides helpful evidence that maybe we don’t need as many.”

The other study, which featured two control groups, saw a similarly low incidence of myocarditis by CMR in athletes with recent COVID-19. One of the control groups included university athletes imaged prior to the advent of SARS-CoV-2 in the university’s region of the country. The other consisted of apparently healthy adult nonathletes.

Armed with two non-COVID-19 cohorts and two athlete cohorts, the researchers found comparable rates of myocarditis by CMR in both the COVID-19 athletes and the healthy athletes. And only 3% of the COVID-19 athletes had the tell-tale CMR signs, notes the report, published Dec. 17 in Circulation, with lead author Daniel E. Clark, MD, MPH, Vanderbilt University Medical Center, Nashville, Tenn.
 

Reassurance and concern

“The incidence is much lower than we feared, and so that’s reassuring,” Clark said in an interview. Still, the athletes with myocarditis by CMR “would have been completely missed by a protocol that did not include cardiac MR, and that’s concerning,” he said. “Both had active myocarditis.”

The study’s two non-COVID-19 control groups – elite athletes in one and nonathletes in the other – allowed them to tease out the potential contribution of athletic myocardial remodeling to CMR features that could be interpreted as scar tissue, which are characterized by late gadolinium enhancement (LGE).

As it turned out, focal regions of LGE located in the right ventricular (RV) septum on the scans were often seen in both athlete cohorts. “This kind of trivial nonischemic fibrosis in the mid RV septal insertion site was common among athletic control subjects. It was seen in 24% of them, which is almost identical to the percentage that we saw in the COVID-19 athletes, 22%,” Dr. Clark said.

The LGE finding, wrote Dr. Clark and coauthors, “may represent remodeling from athletic training, and should not be conflated with myocarditis.”

Of note, the other study saw a comparable incidence of the same or a very similar CMR feature in its athletes; 26% of the Wisconsin COVID-19 athlete cohort showed limited focal LGE in the inferior RV insertion site.

“And you get a little bit in the mid-septum, as well,” Dr. Reeder said. But the sign, in the absence of any corresponding T2 abnormalities, was not judged to represent myocarditis. “We interpreted all of these studies with this potential confounder in mind.”

Conceivably, Dr. Reeder proposed, the earlier studies may have “over-called” the prevalence of myocarditis in their cohorts. “I haven’t seen their images, but it’s possible there could be false-positives.”

It’s noteworthy that the Vanderbilt and Wisconsin reports saw closely similar incidences of the tell-tale CMR sign in all the athlete cohorts whether or not COVID-19 was involved, Aaron L. Baggish, MD, Massachusetts General Hospital, Boston, said in an interview.

“It looks very much like just an unrecognized part of athletic remodeling and isn’t in any way, shape, or form implicated as being a COVID-related issue,” said Dr. Baggish, who directs the cardiovascular performance program at his center and is unaffiliated with either study.

Still, that connection remains unproven given how little is yet known about the prevalence of clinically important myocarditis in milder cases of COVID-19, according to an accompanying editorial from Jonathan H. Kim, MD, MSc.

Although isolated LGE at the interventricular RV insertion site is “more commonly described among masters-level endurance athletes, the clinical significance and prevalence of this finding in youthful athletes is uncertain and should not be assumed to be a normal consequence of intense athletic training in young competitive athletes,” argued Dr. Kim, of Emory University, Atlanta.

There’s probably little about being a young competitive athlete that would render a person any more or less prone to COVID-19 cardiac involvement, Dr. Baggish said. Rather, “I think what we’re seeing, as the studies continue to come out, is that prevalence estimates are getting into the low single digits.”

The estimates are similar to those associated with influenza before the COVID-19 age; about 2% of patients showed cardiac involvement, Dr. Baggish said. “So the degree to which COVID is a special virus from this perspective, I think, is still a topic of some debate.”

The two current studies have limitations and neither is positioned to change practice, he said. “I would say that they are both kind of important, reassuring pieces of an unfinished jigsaw puzzle. But we still don’t know what the picture on the puzzle is.”
 

Routine CMR for positive cases

The University of Wisconsin group looked at all of the institution’s competitive athletes who underwent gadolinium-enhanced CMR imaging and other tests during recovery from COVID-19 from the beginning of the pandemic to the end of November 2020.

The imaging was performed on average about 2 weeks after a first positive SARS-CoV-2 assay result. About one-half and one-fourth of the cohort had experienced mild and moderate symptoms, respectively, and about 17% were asymptomatic; none had been hospitalized.

All CMR scans were reviewed by two experienced radiologists for, among other things, evidence of myocarditis according to modified Lake Louise criteria, the group wrote. Those criteria are based on CMR markers of fibrosis and other characteristics of scarring from myocarditis.

Such evidence was seen in only two members of the cohort, or 1.4%, one with elevated troponins but normal with respect to other biomarkers, and the other negative for all assays. Both were asymptomatic at the time of imaging, the report noted.

The Vanderbilt analysis from Dr. Clark and associates centered on 59 university athletes recently with COVID-19 who underwent CMR imaging along with other tests about 3 weeks after confirmation of SARS-CoV-2 infection. Symptoms had been mild in 78% of the group, and the remainder were asymptomatic.

They were compared with 60 retrospectively identified college athletes and elite-conditioned military personnel who had undergone CMR imaging prior to the advent of COVID-19, and to 27 apparently healthy nonathlete adults in whom CMR had been previously performed to define normal CMR imaging criteria at that center.

The only two post-COVID-19 athletes who met modified Lake Louise criteria for myocarditis showed no abnormalities on ECG or myocardial strain echocardiography, and had normal troponins, the group reported.

The COVID-19 athletes showed increased cardiac chamber volumes and myocardial mass “consistent with athletic remodeling,” compared with the healthy control subjects, the group wrote. But “most standard CMR parameters were similar” between the COVID-19 athletes and the control athletes, consistent with the 22% and 24% rates, respectively, for the finding of focal late LGE isolated to the inferoseptal RV insertion site.

At the end of the day, all published experiences on athletes with recent COVID-19 “are descriptive studies, without any hint of follow-up,” Dr. Baggish noted, so their clinical implications are unknown.

“We need time to sit and watch to see what happens to these individuals,” he said. “And if the answer is nothing, then that’s a very reassuring story. If the answer is that we start to see events, then that’s really important for us to take stock of.”

Dr. Starekova had no disclosures. Dr. Reeder reports that the University of Wisconsin receives research support from GE Healthcare and Bracco Diagnostics; and that he has ownership interests in Calimetrix, Reveal Pharmaceuticals, Cellectar Biosciences, Elucent Medical, and HeartVista; and has received grant support from Bayer Healthcare. Disclosures for the other coauthors are in the report. Dr. Clark and coauthors had no disclosures. Dr. Baggish reported no conflicts. Kim discloses receiving funding from the National Heart, Lung, and Blood Institute; compensation as team cardiologist for the Atlanta Falcons; and research stipends from the Atlanta Track Club.

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

Two recent observational studies suggest that myocarditis, at least on cardiac magnetic resonance (CMR) imaging, might be far less common in elite-level athletes recovering from COVID-19 than suggested in influential earlier reports.

AlexLMX/Getty Images

Both new studies documented a rate less than one-quarter as high as those previously reported from smaller cohorts, raising questions about the diagnostic yield of CMR in highly conditioned athletes with recent COVID-19 absent other evidence, such as from biomarker assays or electrocardiography (ECG).

That could have implications for some top-tier university athletics programs that mandate CMR imaging, biomarker assays, and other evaluations for myocarditis on all their players who test positive for SARS-CoV-2 before they can return to play.

The findings collectively point to CMR imaging features that might be a hallmark of an athlete’s heart, characterized by normal myocardial remodeling brought on by elite-level exercise training, which in athletes with recent COVID-19 could be misinterpreted as evidence of myocarditis. That may have thrown off prevalence estimates in the literature, the studies’ investigators speculated.

The two studies were retrospective takes on university athletes who underwent CMR imaging while recovering from COVID-19, who were either asymptomatic or with only mild to moderate symptoms and were generally without ECG or troponin evidence of myocarditis.

One of them showed a less than 2% incidence of myocarditis by CMR among 145 such cases, a low yield for imaging that is “raising doubt regarding its utility to evaluate athletes without a clinical presentation or abnormal ancillary tests to support the diagnosis of myocarditis,” argues a report published Jan. 14 in JAMA Cardiology, with lead author Jitka Starekova, MD, University of Wisconsin – Madison.

“Part of the problem is that occult myocarditis is, at least with other viruses, a risk factor for sudden death in competitive athletes. So you don’t want to let one slip through the cracks,” senior author Scott B. Reeder, MD, PhD, from the same institution, said in an interview.

Whether a policy of routine CMR imaging in elite athletes who test positive for the new coronavirus is better than more selective use driven by symptoms or other screening tests is unknown. But the more pressing issue, Dr. Reeder said, “is if they have a normal electrocardiogram and troponins, do they still need cardiac magnetic resonance imaging?”

The current study, he said, “certainly provides helpful evidence that maybe we don’t need as many.”

The other study, which featured two control groups, saw a similarly low incidence of myocarditis by CMR in athletes with recent COVID-19. One of the control groups included university athletes imaged prior to the advent of SARS-CoV-2 in the university’s region of the country. The other consisted of apparently healthy adult nonathletes.

Armed with two non-COVID-19 cohorts and two athlete cohorts, the researchers found comparable rates of myocarditis by CMR in both the COVID-19 athletes and the healthy athletes. And only 3% of the COVID-19 athletes had the tell-tale CMR signs, notes the report, published Dec. 17 in Circulation, with lead author Daniel E. Clark, MD, MPH, Vanderbilt University Medical Center, Nashville, Tenn.
 

Reassurance and concern

“The incidence is much lower than we feared, and so that’s reassuring,” Clark said in an interview. Still, the athletes with myocarditis by CMR “would have been completely missed by a protocol that did not include cardiac MR, and that’s concerning,” he said. “Both had active myocarditis.”

The study’s two non-COVID-19 control groups – elite athletes in one and nonathletes in the other – allowed them to tease out the potential contribution of athletic myocardial remodeling to CMR features that could be interpreted as scar tissue, which are characterized by late gadolinium enhancement (LGE).

As it turned out, focal regions of LGE located in the right ventricular (RV) septum on the scans were often seen in both athlete cohorts. “This kind of trivial nonischemic fibrosis in the mid RV septal insertion site was common among athletic control subjects. It was seen in 24% of them, which is almost identical to the percentage that we saw in the COVID-19 athletes, 22%,” Dr. Clark said.

The LGE finding, wrote Dr. Clark and coauthors, “may represent remodeling from athletic training, and should not be conflated with myocarditis.”

Of note, the other study saw a comparable incidence of the same or a very similar CMR feature in its athletes; 26% of the Wisconsin COVID-19 athlete cohort showed limited focal LGE in the inferior RV insertion site.

“And you get a little bit in the mid-septum, as well,” Dr. Reeder said. But the sign, in the absence of any corresponding T2 abnormalities, was not judged to represent myocarditis. “We interpreted all of these studies with this potential confounder in mind.”

Conceivably, Dr. Reeder proposed, the earlier studies may have “over-called” the prevalence of myocarditis in their cohorts. “I haven’t seen their images, but it’s possible there could be false-positives.”

It’s noteworthy that the Vanderbilt and Wisconsin reports saw closely similar incidences of the tell-tale CMR sign in all the athlete cohorts whether or not COVID-19 was involved, Aaron L. Baggish, MD, Massachusetts General Hospital, Boston, said in an interview.

“It looks very much like just an unrecognized part of athletic remodeling and isn’t in any way, shape, or form implicated as being a COVID-related issue,” said Dr. Baggish, who directs the cardiovascular performance program at his center and is unaffiliated with either study.

Still, that connection remains unproven given how little is yet known about the prevalence of clinically important myocarditis in milder cases of COVID-19, according to an accompanying editorial from Jonathan H. Kim, MD, MSc.

Although isolated LGE at the interventricular RV insertion site is “more commonly described among masters-level endurance athletes, the clinical significance and prevalence of this finding in youthful athletes is uncertain and should not be assumed to be a normal consequence of intense athletic training in young competitive athletes,” argued Dr. Kim, of Emory University, Atlanta.

There’s probably little about being a young competitive athlete that would render a person any more or less prone to COVID-19 cardiac involvement, Dr. Baggish said. Rather, “I think what we’re seeing, as the studies continue to come out, is that prevalence estimates are getting into the low single digits.”

The estimates are similar to those associated with influenza before the COVID-19 age; about 2% of patients showed cardiac involvement, Dr. Baggish said. “So the degree to which COVID is a special virus from this perspective, I think, is still a topic of some debate.”

The two current studies have limitations and neither is positioned to change practice, he said. “I would say that they are both kind of important, reassuring pieces of an unfinished jigsaw puzzle. But we still don’t know what the picture on the puzzle is.”
 

Routine CMR for positive cases

The University of Wisconsin group looked at all of the institution’s competitive athletes who underwent gadolinium-enhanced CMR imaging and other tests during recovery from COVID-19 from the beginning of the pandemic to the end of November 2020.

The imaging was performed on average about 2 weeks after a first positive SARS-CoV-2 assay result. About one-half and one-fourth of the cohort had experienced mild and moderate symptoms, respectively, and about 17% were asymptomatic; none had been hospitalized.

All CMR scans were reviewed by two experienced radiologists for, among other things, evidence of myocarditis according to modified Lake Louise criteria, the group wrote. Those criteria are based on CMR markers of fibrosis and other characteristics of scarring from myocarditis.

Such evidence was seen in only two members of the cohort, or 1.4%, one with elevated troponins but normal with respect to other biomarkers, and the other negative for all assays. Both were asymptomatic at the time of imaging, the report noted.

The Vanderbilt analysis from Dr. Clark and associates centered on 59 university athletes recently with COVID-19 who underwent CMR imaging along with other tests about 3 weeks after confirmation of SARS-CoV-2 infection. Symptoms had been mild in 78% of the group, and the remainder were asymptomatic.

They were compared with 60 retrospectively identified college athletes and elite-conditioned military personnel who had undergone CMR imaging prior to the advent of COVID-19, and to 27 apparently healthy nonathlete adults in whom CMR had been previously performed to define normal CMR imaging criteria at that center.

The only two post-COVID-19 athletes who met modified Lake Louise criteria for myocarditis showed no abnormalities on ECG or myocardial strain echocardiography, and had normal troponins, the group reported.

The COVID-19 athletes showed increased cardiac chamber volumes and myocardial mass “consistent with athletic remodeling,” compared with the healthy control subjects, the group wrote. But “most standard CMR parameters were similar” between the COVID-19 athletes and the control athletes, consistent with the 22% and 24% rates, respectively, for the finding of focal late LGE isolated to the inferoseptal RV insertion site.

At the end of the day, all published experiences on athletes with recent COVID-19 “are descriptive studies, without any hint of follow-up,” Dr. Baggish noted, so their clinical implications are unknown.

“We need time to sit and watch to see what happens to these individuals,” he said. “And if the answer is nothing, then that’s a very reassuring story. If the answer is that we start to see events, then that’s really important for us to take stock of.”

Dr. Starekova had no disclosures. Dr. Reeder reports that the University of Wisconsin receives research support from GE Healthcare and Bracco Diagnostics; and that he has ownership interests in Calimetrix, Reveal Pharmaceuticals, Cellectar Biosciences, Elucent Medical, and HeartVista; and has received grant support from Bayer Healthcare. Disclosures for the other coauthors are in the report. Dr. Clark and coauthors had no disclosures. Dr. Baggish reported no conflicts. Kim discloses receiving funding from the National Heart, Lung, and Blood Institute; compensation as team cardiologist for the Atlanta Falcons; and research stipends from the Atlanta Track Club.

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

Two recent observational studies suggest that myocarditis, at least on cardiac magnetic resonance (CMR) imaging, might be far less common in elite-level athletes recovering from COVID-19 than suggested in influential earlier reports.

AlexLMX/Getty Images

Both new studies documented a rate less than one-quarter as high as those previously reported from smaller cohorts, raising questions about the diagnostic yield of CMR in highly conditioned athletes with recent COVID-19 absent other evidence, such as from biomarker assays or electrocardiography (ECG).

That could have implications for some top-tier university athletics programs that mandate CMR imaging, biomarker assays, and other evaluations for myocarditis on all their players who test positive for SARS-CoV-2 before they can return to play.

The findings collectively point to CMR imaging features that might be a hallmark of an athlete’s heart, characterized by normal myocardial remodeling brought on by elite-level exercise training, which in athletes with recent COVID-19 could be misinterpreted as evidence of myocarditis. That may have thrown off prevalence estimates in the literature, the studies’ investigators speculated.

The two studies were retrospective takes on university athletes who underwent CMR imaging while recovering from COVID-19, who were either asymptomatic or with only mild to moderate symptoms and were generally without ECG or troponin evidence of myocarditis.

One of them showed a less than 2% incidence of myocarditis by CMR among 145 such cases, a low yield for imaging that is “raising doubt regarding its utility to evaluate athletes without a clinical presentation or abnormal ancillary tests to support the diagnosis of myocarditis,” argues a report published Jan. 14 in JAMA Cardiology, with lead author Jitka Starekova, MD, University of Wisconsin – Madison.

“Part of the problem is that occult myocarditis is, at least with other viruses, a risk factor for sudden death in competitive athletes. So you don’t want to let one slip through the cracks,” senior author Scott B. Reeder, MD, PhD, from the same institution, said in an interview.

Whether a policy of routine CMR imaging in elite athletes who test positive for the new coronavirus is better than more selective use driven by symptoms or other screening tests is unknown. But the more pressing issue, Dr. Reeder said, “is if they have a normal electrocardiogram and troponins, do they still need cardiac magnetic resonance imaging?”

The current study, he said, “certainly provides helpful evidence that maybe we don’t need as many.”

The other study, which featured two control groups, saw a similarly low incidence of myocarditis by CMR in athletes with recent COVID-19. One of the control groups included university athletes imaged prior to the advent of SARS-CoV-2 in the university’s region of the country. The other consisted of apparently healthy adult nonathletes.

Armed with two non-COVID-19 cohorts and two athlete cohorts, the researchers found comparable rates of myocarditis by CMR in both the COVID-19 athletes and the healthy athletes. And only 3% of the COVID-19 athletes had the tell-tale CMR signs, notes the report, published Dec. 17 in Circulation, with lead author Daniel E. Clark, MD, MPH, Vanderbilt University Medical Center, Nashville, Tenn.
 

Reassurance and concern

“The incidence is much lower than we feared, and so that’s reassuring,” Clark said in an interview. Still, the athletes with myocarditis by CMR “would have been completely missed by a protocol that did not include cardiac MR, and that’s concerning,” he said. “Both had active myocarditis.”

The study’s two non-COVID-19 control groups – elite athletes in one and nonathletes in the other – allowed them to tease out the potential contribution of athletic myocardial remodeling to CMR features that could be interpreted as scar tissue, which are characterized by late gadolinium enhancement (LGE).

As it turned out, focal regions of LGE located in the right ventricular (RV) septum on the scans were often seen in both athlete cohorts. “This kind of trivial nonischemic fibrosis in the mid RV septal insertion site was common among athletic control subjects. It was seen in 24% of them, which is almost identical to the percentage that we saw in the COVID-19 athletes, 22%,” Dr. Clark said.

The LGE finding, wrote Dr. Clark and coauthors, “may represent remodeling from athletic training, and should not be conflated with myocarditis.”

Of note, the other study saw a comparable incidence of the same or a very similar CMR feature in its athletes; 26% of the Wisconsin COVID-19 athlete cohort showed limited focal LGE in the inferior RV insertion site.

“And you get a little bit in the mid-septum, as well,” Dr. Reeder said. But the sign, in the absence of any corresponding T2 abnormalities, was not judged to represent myocarditis. “We interpreted all of these studies with this potential confounder in mind.”

Conceivably, Dr. Reeder proposed, the earlier studies may have “over-called” the prevalence of myocarditis in their cohorts. “I haven’t seen their images, but it’s possible there could be false-positives.”

It’s noteworthy that the Vanderbilt and Wisconsin reports saw closely similar incidences of the tell-tale CMR sign in all the athlete cohorts whether or not COVID-19 was involved, Aaron L. Baggish, MD, Massachusetts General Hospital, Boston, said in an interview.

“It looks very much like just an unrecognized part of athletic remodeling and isn’t in any way, shape, or form implicated as being a COVID-related issue,” said Dr. Baggish, who directs the cardiovascular performance program at his center and is unaffiliated with either study.

Still, that connection remains unproven given how little is yet known about the prevalence of clinically important myocarditis in milder cases of COVID-19, according to an accompanying editorial from Jonathan H. Kim, MD, MSc.

Although isolated LGE at the interventricular RV insertion site is “more commonly described among masters-level endurance athletes, the clinical significance and prevalence of this finding in youthful athletes is uncertain and should not be assumed to be a normal consequence of intense athletic training in young competitive athletes,” argued Dr. Kim, of Emory University, Atlanta.

There’s probably little about being a young competitive athlete that would render a person any more or less prone to COVID-19 cardiac involvement, Dr. Baggish said. Rather, “I think what we’re seeing, as the studies continue to come out, is that prevalence estimates are getting into the low single digits.”

The estimates are similar to those associated with influenza before the COVID-19 age; about 2% of patients showed cardiac involvement, Dr. Baggish said. “So the degree to which COVID is a special virus from this perspective, I think, is still a topic of some debate.”

The two current studies have limitations and neither is positioned to change practice, he said. “I would say that they are both kind of important, reassuring pieces of an unfinished jigsaw puzzle. But we still don’t know what the picture on the puzzle is.”
 

Routine CMR for positive cases

The University of Wisconsin group looked at all of the institution’s competitive athletes who underwent gadolinium-enhanced CMR imaging and other tests during recovery from COVID-19 from the beginning of the pandemic to the end of November 2020.

The imaging was performed on average about 2 weeks after a first positive SARS-CoV-2 assay result. About one-half and one-fourth of the cohort had experienced mild and moderate symptoms, respectively, and about 17% were asymptomatic; none had been hospitalized.

All CMR scans were reviewed by two experienced radiologists for, among other things, evidence of myocarditis according to modified Lake Louise criteria, the group wrote. Those criteria are based on CMR markers of fibrosis and other characteristics of scarring from myocarditis.

Such evidence was seen in only two members of the cohort, or 1.4%, one with elevated troponins but normal with respect to other biomarkers, and the other negative for all assays. Both were asymptomatic at the time of imaging, the report noted.

The Vanderbilt analysis from Dr. Clark and associates centered on 59 university athletes recently with COVID-19 who underwent CMR imaging along with other tests about 3 weeks after confirmation of SARS-CoV-2 infection. Symptoms had been mild in 78% of the group, and the remainder were asymptomatic.

They were compared with 60 retrospectively identified college athletes and elite-conditioned military personnel who had undergone CMR imaging prior to the advent of COVID-19, and to 27 apparently healthy nonathlete adults in whom CMR had been previously performed to define normal CMR imaging criteria at that center.

The only two post-COVID-19 athletes who met modified Lake Louise criteria for myocarditis showed no abnormalities on ECG or myocardial strain echocardiography, and had normal troponins, the group reported.

The COVID-19 athletes showed increased cardiac chamber volumes and myocardial mass “consistent with athletic remodeling,” compared with the healthy control subjects, the group wrote. But “most standard CMR parameters were similar” between the COVID-19 athletes and the control athletes, consistent with the 22% and 24% rates, respectively, for the finding of focal late LGE isolated to the inferoseptal RV insertion site.

At the end of the day, all published experiences on athletes with recent COVID-19 “are descriptive studies, without any hint of follow-up,” Dr. Baggish noted, so their clinical implications are unknown.

“We need time to sit and watch to see what happens to these individuals,” he said. “And if the answer is nothing, then that’s a very reassuring story. If the answer is that we start to see events, then that’s really important for us to take stock of.”

Dr. Starekova had no disclosures. Dr. Reeder reports that the University of Wisconsin receives research support from GE Healthcare and Bracco Diagnostics; and that he has ownership interests in Calimetrix, Reveal Pharmaceuticals, Cellectar Biosciences, Elucent Medical, and HeartVista; and has received grant support from Bayer Healthcare. Disclosures for the other coauthors are in the report. Dr. Clark and coauthors had no disclosures. Dr. Baggish reported no conflicts. Kim discloses receiving funding from the National Heart, Lung, and Blood Institute; compensation as team cardiologist for the Atlanta Falcons; and research stipends from the Atlanta Track Club.

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.

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.

[email protected]

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.

[email protected]

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.

[email protected]

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.