Angiotensin–Neprilysin Inhibition in Acute Decompensated Heart Failure

Trial Design

Details of the trial design have been published previously.9 We conducted a multicenter, randomized, double-blind, active-controlled trial of the in-hospital initiation of sacubitril–valsartan therapy, as compared with enalapril therapy, among patients who had been admitted for acute decompensated heart failure with reduced ejection fraction. The trial protocol (available with the full text of this article at was approved by ethics committees at participating centers. Novartis was the sole sponsor and conducted the trial in collaboration with the Duke Clinical Research Institute (DCRI) and the Thrombolysis in Myocardial Infarction (TIMI) Study Group.

The academic leadership committee (see the Supplementary Appendix, available at designed the protocol, identified the participating centers, and oversaw implementation of the protocol in conjunction with the trial sponsor. United BioSource Corporation (UBC), a contract research organization, was involved in trial operations. All statistical analyses were completed by UBC and were verified independently by the DCRI and the sponsor. An independent data and safety monitoring board (see the Supplementary Appendix) monitored safety data during the trial. The first draft of the manuscript was written by the first author, and all the authors critically reviewed and revised the manuscript at every stage before acceptance. All the authors had full access to the data and vouch for the completeness and accuracy of the data and for the fidelity of the trial to the protocol.

Trial Patients

Patients 18 years of age or older were eligible for inclusion in the trial if they had a left ventricular ejection fraction of 40% or less and an N-terminal pro–B-type natriuretic peptide (NT-proBNP) concentration of 1600 pg per milliliter or more or a B-type natriuretic peptide (BNP) concentration of 400 pg per milliliter or more and had received a primary diagnosis of acute decompensated heart failure, including signs and symptoms of fluid overload. Patients were enrolled no less than 24 hours and up to 10 days after initial presentation to the hospital, while they were still hospitalized. Before randomization, patients were required to be hemodynamically stable, which was defined by maintenance of a systolic blood pressure of at least 100 mm Hg for the preceding 6 hours, with no increase in the dose of intravenous diuretics and no use of intravenous vasodilators during the preceding 6 hours and no use of intravenous inotropes during the preceding 24 hours. A complete list of the inclusion and exclusion criteria is provided in Table S1 in the Supplementary Appendix. All the patients provided written informed consent.

Trial Procedures

Patients were randomly assigned to receive either sacubitril–valsartan or enalapril. Randomization was performed with the use of an interactive Web-based response system. The initial dose of sacubitril–valsartan (either 24 mg of sacubitril with 26 mg of valsartan or 49 mg of sacubitril with 51 mg of valsartan as a fixed-dose combination) or enalapril (either 2.5 mg or 5 mg) was administered orally twice daily, with dosing selected on the basis of the systolic blood pressure at randomization, according to a prespecified algorithm (Fig. S1 in the Supplementary Appendix). To ensure blinding, with each dose patients also received a placebo that resembled the other trial drug. Patients in the enalapril group received the assigned trial drug and placebo starting with the first dose. Patients in the sacubitril–valsartan group received two doses of placebo alone (with tablets that resembled both trial drugs), to ensure a washout period of a minimum of 36 hours before the initiation of sacubitril–valsartan, and then received the assigned trial drug and placebo starting with the third dose. All the patients were monitored for a minimum of 6 hours after the third dose was administered before they were discharged from the hospital.

During the 8-week trial period, the dose of sacubitril–valsartan was adjusted with a target of 97 mg of sacubitril with 103 mg of valsartan twice daily, and the dose of enalapril was adjusted with a target of 10 mg twice daily. Dose adjustment was guided by an algorithm that was based on the systolic blood pressure and by the investigator’s assessment of side effects (Fig. S1 in the Supplementary Appendix). Follow-up visits were to be scheduled for weeks 1 and 2 and every 2 weeks thereafter. Hematologic, chemical, and biomarker analyses of blood and urine samples were performed at a central laboratory. The last dose of the assigned trial drug was administered on the morning of the week 8 visit.

Trial Outcomes

The primary efficacy outcome was the time-averaged proportional change in the NT-proBNP concentration from baseline through weeks 4 and 8. Key safety outcomes were the incidences of worsening renal function (an increase in the serum creatinine concentration of ≥0.5 mg per deciliter [≥44 μmol per liter] and a decrease in the estimated glomerular filtration rate of ≥25%), hyperkalemia (a serum potassium concentration of ≥5.5 mmol per liter), symptomatic hypotension, and angioedema. Any angioedema-like event that was reported by a site investigator was reviewed by an angioedema adjudication committee whose members were unaware of the treatment assignments (see the Supplementary Appendix). Secondary biomarker outcomes included time-averaged proportional changes in the high-sensitivity troponin T concentration, BNP concentration, and ratio of BNP to NT-proBNP. We also conducted analyses of exploratory clinical outcomes, including the incidence of a composite of death, rehospitalization for heart failure, implantation of a left ventricular assist device, inclusion on the list of patients eligible for heart transplantation, an unplanned visit for acute heart failure that led to the use of intravenous diuretics, an increase in the dose of diuretics of more than 50%, or the use of an additional drug for heart failure.

Statistical Analysis

We calculated that a sample of 882 patients would provide the trial with 85% power to detect an 18 percentage-point greater time-averaged proportional reduction in the NT-proBNP concentration, from the baseline value to the geometric mean of values obtained at weeks 4 and 8, in the sacubitril–valsartan group than in the enalapril group, at a two-sided significance level of 0.05. This calculation was based on the assumption of a ratio of the NT-proBNP concentration at week 8 as compared with baseline of 0.95 in the enalapril group, a geometric standard deviation of the log normal distribution of 0.85, and a rate at which samples are missing or cannot be evaluated of 25%.

All efficacy analyses were performed according to the intention-to-treat principle, with the use of all available data through the 8-week trial period. The analyses were based on the likelihood method, with the assumption that data were missing at random. The analyses included all enrolled patients except those who underwent randomization inappropriately.

The primary analysis of the proportional change in the NT-proBNP concentration from baseline on a logarithmic scale was performed with the use of an analysis of covariance model, with adjustment for the baseline value. A similar method was used to analyze the secondary biomarker outcomes. The incidences of worsening renal function, hyperkalemia, symptomatic hypotension, and angioedema were calculated along with relative risks and associated 95% confidence intervals. Cumulative clinical-event rates were calculated according to the Kaplan–Meier method; the differences in clinical outcomes between the two treatment groups were assessed with the log-rank test, and hazard ratios and associated 95% confidence intervals were calculated with a Cox proportional-hazards model. Confidence intervals for all outcomes except the primary efficacy outcome have not been adjusted for multiple comparisons, and therefore, inferences drawn from these intervals may not be reproducible. The consistency of treatment effect was examined across six prespecified subgroups and six additional exploratory subgroups. All analyses were performed with the use of SAS software, version 9.3 or higher (SAS Institute).

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