Heart of the Matter

Entresto, inpatient therapy, and surrogate markers


The recently published PIONEER-HF study attempts to move sacubitril/valsartan (Entresto) therapy to the inpatient environment to improve patient and physician acceptance of this therapy for patients with heart failure (N Engl J Med. 2019 Feb 7;380;539-48).

Dr. Sidney Goldstein is professor of medicine at Wayne State University and the division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit.

Dr. Sidney Goldstein

When given to outpatients in the PARADIGM-HF trial, the combination was superior to enalapril for reducing the risks of death and hospitalization for heart failure (N Engl J Med 2014;371:993-1004.) Specifically, sacubitril/valsartan decreased mortality by 15% and hospitalization by 21% as an outpatient therapy for patients with systolic heart failure. Nevertheless, there has not been widespread adoption of this approach. It is well known that physicians can be slow to adopt new therapies, but one overriding factor may be the cost of the drug compared to enalapril, one of the first drugs shown to be effective in heart failure therapy (Entresto costs more than $4,000 per year; enalapril costs about $120 per year).

The investigators in the PIONEER-HF study compared Entresto to enalapril over a 2-month period in patients hospitalized with systolic heart failure. To accelerate the trial, the investigators used the proportional change in patients’ N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels as the primary endpoint rather than the traditional outcome of morbidity and mortality. In the short term, no significant clinical benefits were observed, but there was a significant decrease in NT-proBNP of about 30% (P less than .001).

The investigators suggested that this finding extended the previous benefit observed with Entresto during outpatient initiation and could be used as a rationale for initiating Entresto therapy in the hospital. This earlier application of the therapy could make the drug more widely acceptable.

Considerable investigation in BNP measurement has occurred over the last few years, and although it is clear that BNP is elevated in heart failure patients, there is no evidence to confirm that the decrease in BNP is associated with improved outcome. BNP will fall with decrease in ventricular volume, which may have significant physiologic mechanisms but ventricular volume could decrease with fall in blood pressure that may have occurred in this population since hypotension tended to be more frequent with Entresto than with enalapril. The traditional measure of heart failure benefit with beta-blockers, ACE inhibitors, and aldosterone antagonists in the inpatient and early postdischarge period has depended on clinical outcomes.

Regardless of the physiologic explanation of this fall in BNP, we must pause in our assumptions when a surrogate measure is used to assess clinical benefit as inpatient therapy. The Food and Drug Administration has long given up using surrogate measures as proof of efficacy, and rightly so. Clinical medicine is replete with dubious drug benefits based on surrogate measures. Let’s not forget that only a few years ago suppression of premature ventricular contractions was considered to be a measure of the pharmacologic prevention of sudden death. We have come a long way from that and other clinical missteps to use BNP, an uncertain marker at best of clinical improvement, as a surrogate for the improvement in heart failure.

There is a substantial amount of data supporting the benefit of Entresto in the clinical management of outpatients with heart failure without using the PIONEER-HF trial results as a pretense to initiate therapy when patients are hospitalized. One might suggest that if Novartis is concerned about introducing the drug in the clinical management of heart failure, the company might consider the possibility of decreasing its price.

Dr. Goldstein is professor of medicine at Wayne State University and the division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit.

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