Findings From a Randomized Controlled Trial May Usher the Adoption of Angiotensin–Neprilysin Inhibition to the Heart-Failure Armamentarium Presented At the American College of Cardiology Annual Scientific Session (ACC 2019), New Orleans, LA.

The results of a trial presented by Dr. Adam DeVore at the American College of Cardiology Annual Scientific Session (ACC 2019), New Orleans, LA, reflected that among patients with heart failure with reduced ejection fraction who were hospitalized for acute decompensated heart failure, the initiation of sacubitril–valsartan therapy led to a greater reduction in the NT-proBNP concentration as compared with enalapril therapy. In addition to this, the rates of worsening renal function, hyperkalemia, symptomatic hypotension, and angioedema did not differ significantly between the two arms.

In the United States, the rates of short-term unplanned rehospitalization and death associated with acute decompensated heart failure are high (21% and 12%, respectively).  Despite multiple trials of promising therapies, the standard of care, which consists of decongestion with intravenous diuretics and hemodynamic support with vasodilators and inotropes, has remained largely unchanged during the past 45 years. The PIONEER-HF trial was performed to evaluate the use of a neprilysin inhibitor added to a renin-angiotensin system inhibitor, as compared with a renin-angiotensin system inhibitor alone, in the treatment of patients who were hospitalized for acute heart failure. Whether the initiation of sacubitril–valsartan therapy was safe and effective among patients who were hospitalized for acute decompensated heart failure was largely unknown.

According to the article that was published in NEJM, Eric J. Velazquez and his colleagues enrolled a total of 881 patients with heart failure with reduced ejection fraction who were hospitalized for acute decompensated heart failure at 129 sites in the United States. After hemodynamic stabilization, patients were randomly assigned to receive sacubitril–valsartan (target dose, 97 mg of sacubitril with 103 mg of valsartan twice daily) or enalapril (target dose, 10 mg twice daily). The primary efficacy outcome was the time-averaged proportional change in the N-terminal pro–B-type natriuretic peptide (NT-proBNP) concentration from baseline through weeks 4 and 8. Key safety outcomes were the rates of worsening renal function, hyperkalemia, symptomatic hypotension, and angioedema.

The investigators found that of the 881 patients who underwent randomization, 440 were assigned to receive sacubitril–valsartan and 441 to receive enalapril. The time-averaged reduction in the NT-proBNP concentration was significantly greater in the sacubitril–valsartan group than in the enalapril group; the ratio of the geometric mean of values obtained at weeks 4 and 8 to the baseline value was 0.53 in the sacubitril–valsartan group as compared with 0.75 in the enalapril group (percent change, −46.7% vs. −25.3%; ratio of change with sacubitril–valsartan vs. enalapril, 0.71; 95% confidence interval [CI], 0.63 to 0.81; P<0.001). The greater reduction in the NT-proBNP concentration with sacubitril–valsartan than with enalapril was evident as early as week 1 (ratio of change, 0.76; 95% CI, 0.69 to 0.85). The rates of worsening renal function, hyperkalemia, symptomatic hypotension, and angioedema did not differ significantly between the two groups. Hence, the results of the trial portrayed how the initiation of sacubitril–valsartan therapy after hemodynamic stabilization led to a greater reduction in the NT-proBNP concentration than enalapril therapy, a difference that was evident by the first week.

Scrutinizing the results of this trial in an accompanying editorial, Dr. John Jarcho wrote, “The more important and novel observation from the PIONEER-HF trial is the safety profile of sacubitril–valsartan in the context of acute decompensated heart failure. The trial protocol defined four principal safety measures: worsening renal function, hyperkalemia, symptomatic hypotension, and angioedema. There was no significant difference between the two trial groups in the incidence of any of these four adverse events. This information is of fundamental importance to clinicians who are deciding whether and how to initiate the use of sacubitril–valsartan in their patients with heart failure with reduced ejection fraction.” However, he did mention there were certain limitations to the strength of the safety evidence in the trial. The confidence intervals for the relative risk of each safety outcome were quite wide and were consistent with increases of as much as 28% in worsening renal function, 84% in hyperkalemia, 64% in symptomatic hypotension, and 38% in angioedema with the use of sacubitril–valsartan. In addition, achievement of a safety profile similar to that seen in the PIONEER-HF trial would require reproduction of specific features of the PIONEER-HF trial design, including patient selection, the timing of treatment, and drug dosing. Nonetheless, he stated, “The PIONEER-HF trial provides the best evidence available to guide the initiation of sacubitril–valsartan in patients with acute decompensated heart failure. One would anticipate that, if this treatment is initiated in-hospital as described in this report, and if the patient remains adherent to the treatment after hospital discharge, the long-term benefits on clinical outcomes that were seen in the PARADIGM-HF trial should be attainable. These findings may help to increase the adoption of this important addition to the heart-failure armamentarium.”