Five Reasons Sacubitril/Valsartan Should NOT Be Approved for HFpEF

John Mandrola, MD


January 15, 2021

In an ideal world, people could afford sacubitril/valsartan (Entresto, Novartis) and clinicians would be allowed to prescribe it using clinical judgment as their guide.

The imprimatur of an "FDA-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 randomly assigned slightly more than 4800 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 due to cardiovascular (CV) causes.

Sacubitril/valsartan reduced the rate of the primary endpoint by 13% (rate ratio, 0.87; 95% CI, 0.75 - 1.01; P = .06). There were 894 primary endpoint events in the sacubitril/valsartan arm compared with 1009 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 vs 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 female, 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, 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 due to chance. Was the effect clinically significant?

For context, consider the large effect size that sacubitril/valsartan had vs 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 [HR], 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 pro B-type 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.

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 FDA, but healthcare 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.


Given our current system of healthcare 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.

Editor’s Note: An earlier version of this column incorrectly stated that James Brophy, MD is at McMaster University. Brophy is a Professor of Medicine & Epidemiology at McGill University.

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

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