Study Oversight

The executive committee designed and oversaw the conduct of the trial and data analysis in collaboration with the sponsor, Novartis. The trial was reviewed by an independent data and safety monitoring committee. Data were collected, managed, and analyzed by the sponsor according to a predefined statistical analysis plan, and the analyses were replicated by an independent academic statistician. The first draft of the manuscript was prepared by the first two authors, who had unrestricted access to the data, and was reviewed and edited by all the authors. All the authors made the decision to submit the manuscript for publication and assume responsibility for the accuracy and completeness of the analyses.

Study Design

The study design has been reported previously.23,24 The trial protocol and the statistical analysis plan (included in the Supplementary Appendix) are available with the full text of this article at NEJM.org. The trial was approved by the ethics committee at each study center. All the patients provided written informed consent.

The study consisted of three phases: the screening period; a single-blind run-in period during which all patients received enalapril, which was followed by a single-blind run-in period during which all patients received LCZ696, to ensure an acceptable side-effect profile of the study drugs at target doses; and double-blind treatment in the two study groups.

Study Patients

Eligibility requirements at screening included an age of at least 18 years, New York Heart Association (NYHA) class II, III, or IV symptoms, and an ejection fraction of 40% or less (which was changed to 35% or less by an amendment to the protocol on December 15, 2010). Patients were required to have a plasma B-type natriuretic peptide (BNP) level of at least 150 pg per milliliter (or an N-terminal pro-BNP [NT-proBNP] level ≥600 pg per milliliter) or, if they had been hospitalized for heart failure within the previous 12 months, a BNP of at least 100 pg per milliliter (or an NT-proBNP ≥400 pg per milliliter). Patients taking any dose of an ACE inhibitor or ARB were considered for participation, but for at least 4 weeks before screening, patients were required to take a stable dose of a beta-blocker and an ACE inhibitor (or ARB) equivalent to at least 10 mg of enalapril daily.23

Exclusion criteria included symptomatic hypotension, a systolic blood pressure of less than 100 mm Hg at screening or 95 mm Hg at randomization, an estimated glomerular filtration rate (eGFR) below 30 ml per minute per 1.73 m2 of body-surface area at screening or at randomization or a decrease in the eGFR of more than 25% (which was amended to 35%) between screening and randomization, a serum potassium level of more than 5.2 mmol per liter at screening (or above 5.4 mmol per liter at randomization), or a history of angioedema or unacceptable side effects during receipt of ACE inhibitors or ARBs.

Study Procedures

Eligible patients were switched from the ACE inhibitor or ARB that they had been receiving to single-blind treatment with enalapril (at a dose of 10 mg twice daily) for 2 weeks. If no unacceptable side effects occurred, this regimen was followed by single-blind treatment with LCZ696 for an additional 4 to 6 weeks (initially at a dose of 100 mg twice daily, which was increased to 200 mg twice daily). (The ARB component of the 200-mg dose of LCZ696 is equivalent to 160 mg of valsartan.) During this run-in period, to minimize the risk of angioedema caused by overlapping ACE and neprilysin inhibition, enalapril was withheld a day before the initiation of treatment with LCZ696, and LCZ696 was withheld a day before randomization.

Patients who had no unacceptable side effects of the target doses of the two study medications were randomly assigned in a 1:1 ratio to double-blind treatment with either enalapril (at a dose of 10 mg twice daily) or LCZ696 (at a dose of 200 mg twice daily) with the use of a computerized randomization system involving concealed study-group assignments. Patients were evaluated every 2 to 8 weeks during the first 4 months of double-blind therapy and every 4 months thereafter. The dose of the study drug could be reduced in patients who had unacceptable side effects at target doses.

Study Outcomes

The primary outcome was a composite of death from cardiovascular causes or a first hospitalization for heart failure. The secondary outcomes were the time to death from any cause, the change from baseline to 8 months in the clinical summary score on the Kansas City Cardiomyopathy Questionnaire (KCCQ)25 (on a scale from 0 to 100, with higher scores indicating fewer symptoms and physical limitations associated with heart failure), the time to a new onset of atrial fibrillation, and the time to the first occurrence of a decline in renal function (which was defined as end-stage renal disease or as a decrease in the eGFR of at least 50% or a decrease of more than 30 ml per minute per 1.73 m2 from randomization to less than 60 ml per minute per 1.73 m2). Adjudication of these outcomes was carried out in a blinded fashion by a clinical-end-points committee according to prespecified criteria.

Statistical Analysis

We estimated that the annual rate of the primary end point would be 14.5% and the rate of death from cardiovascular causes would be 7.0% in the enalapril group. Calculation of the sample size was based on mortality from cardiovascular causes. We estimated that we would need to follow approximately 8000 patients for 34 months, with 1229 deaths from cardiovascular causes, to provide the study with a power of 80% to detect a relative reduction of 15% in the risk of death from cardiovascular causes in the LCZ696 group, at an overall two-sided alpha level of 0.05. On the basis of these calculations, we estimated that the primary end point would occur in 2410 patients, which would provide a power of 97% to detect a 15% reduction in the risk of this outcome.

The data and safety monitoring committee specified that three interim efficacy analyses should be conducted after the accrual of one third, one half, and two thirds of the events, and the statistical stopping guideline for a compelling benefit required a one-sided nominal P value of less than 0.0001 at the first analysis and less than 0.001 at the second and third analyses in favor of LCZ696 for both death from cardiovascular causes and the primary end point. On March 28, 2014, at the third interim analysis (after enrollment had been completed), the committee informed the two coprincipal investigators that the prespecified stopping boundary for an overwhelming benefit had been crossed. The executive committee voted to stop the trial and selected March 31, 2014, as the cutoff date for all efficacy analyses; the sponsor accepted this decision.

We included data from all patients who had undergone a valid randomization in the analyses of the primary and secondary outcomes, according to the intention-to-treat principle. A sequentially rejective procedure was used for analysis of the secondary efficacy end points, with the first two secondary end points at the highest level of the testing sequence. (For details, see the statistical analysis plan in the Supplementary Appendix.) Time-to-event data were evaluated with the use of Kaplan–Meier estimates and Cox proportional-hazards models, with treatment and region as fixed-effect factors; hazard ratios, 95% confidence intervals, and two-sided P values were calculated with the use of the Cox models. We assessed the consistency of the treatment effect among 18 prespecified subgroups and used a repeated-measures covariance model to evaluate the KCCQ score, with baseline values, study group, region, study visit, and the interaction between study visit and study group as covariates; a score of zero was used for patients who had died. We used Fisher's exact test to compare rates of adverse events. Data on symptomatic hypotension, worsening renal function, hyperkalemia, cough, and angioedema were collected prospectively as events of interest.