We compared the angiotensin receptor—neprilysin inhibitor LCZ with enalapril in patients who had heart failure with a reduced ejection fraction. In previous studies, enalapril improved survival in such patients. The primary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure, but the trial was designed to detect a difference in the rates of death from cardiovascular causes. The trial was stopped early, according to prespecified rules, after a median follow-up of 27 months, because the boundary for an overwhelming benefit with LCZ had been crossed.
At the time of study closure, the primary outcome had occurred in patients A total of patients The LCZ group had higher proportions of patients with hypotension and nonserious angioedema but lower proportions with renal impairment, hyperkalemia, and cough than the enalapril group. LCZ was superior to enalapril in reducing the risks of death and of hospitalization for heart failure.
Angiotensin-converting—enzyme ACE inhibitors have been the cornerstone of the treatment for heart failure and a reduced ejection fraction for nearly 25 years, since enalapril was shown to reduce the risk of death in two trials.
Neprilysin, a neutral endopeptidase, degrades several endogenous vasoactive peptides, including natriuretic peptides, bradykinin, and adrenomedullin.
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.
The study design has been reported previously. 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 LCZ, to ensure an acceptable side-effect profile of the study drugs at target doses; and double-blind treatment in the two study groups. 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.
Exclusion criteria included symptomatic hypotension, a systolic blood pressure of less than mm Hg at screening or 95 mm Hg at randomization, an estimated glomerular filtration rate eGFR below 30 ml per minute per 1. 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 LCZ for an additional 4 to 6 weeks initially at a dose of mg twice daily, which was increased to mg twice daily. 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 LCZ, and LCZ 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 ratio to double-blind treatment with either enalapril at a dose of 10 mg twice daily or LCZ at a dose of 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.
The primary outcome was a composite of death from cardiovascular causes or a first hospitalization for heart failure.
Adjudication of these outcomes was carried out in a blinded fashion by a clinical-end-points committee according to prespecified criteria. We estimated that the annual rate of the primary end point would be Calculation of the sample size was based on mortality from cardiovascular causes.
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. On March 28, , 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, , 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. 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. The proportion of patients who withdrew from the study because of adverse events was higher during the enalapril run-in period than during the LCZ run-in period after adjustment for the longer duration of LCZ exposure.
The most common reasons for withdrawal from the study during the run-in period were hypotension, cough, hyperkalemia, and renal dysfunction. During the run-in period, 8 patients did not take enalapril and took only LCZ From December 8, , through November 23, , a total of 10, patients at centers in 47 countries entered the run-in period.
Of these patients, did not fulfill the criteria for randomization, and 43 patients underwent randomization erroneously or were enrolled at sites that were closed owing to serious Good Clinical Practice violations; these patients were prospectively omitted from all analyses before the end of the trial.
Accordingly, patients were randomly assigned to receive LCZ and to receive enalapril for the intention-to-treat analysis Figure 1.
The groups were balanced with respect to baseline characteristics. Most patients were receiving recommended pharmacologic therapy for chronic heart failure Table 1. Except for discontinuations owing to death, the study drug was discontinued in patients Eleven patients in the LCZ group and 9 patients in the enalapril group were lost to follow-up, and their data were censored at the last contact.
The median duration of follow-up was 27 months, with no significant between-group difference. Shown are estimates of the probability of the primary composite end point death from cardiovascular causes or first hospitalization for heart failure Panel A , death from cardiovascular causes Panel B , first hospitalization for heart failure Panel C , and death from any cause Panel D.
Death from cardiovascular causes or hospitalization for heart failure the primary end point occurred in patients The difference in favor of LCZ was seen early in the trial and at each interim analysis.
A total of deaths Of the patients receiving LCZ, Over the duration of the trial, the numbers of patients who would need to have been treated to prevent one primary event and one death from cardiovascular causes were 21 and 32, respectively. Shown are hazard ratios for the primary end point death from cardiovascular causes or first hospitalization for heart failure and for death from cardiovascular causes among patients in prespecified subgroups.
The size of the square corresponds to the number of patients in each subgroup. Patients who were not taking a pretrial angiotensin-converting—enzyme ACE inhibitor were taking an angiotensin-receptor blocker except for 20 patients who received neither drug before the trial.
The effect of LCZ was consistent across all prespecified subgroups. The mean change from baseline to month 8 in the KCCQ clinical summary score was a reduction of 2. When zero values were not imputed for patients who died, the score improved in the LCZ group and declined in the enalapril group, and the between-group difference 0. Four patients two in each group did not start the study medication and were excluded from the safety analyses.
During the run-in period, After randomization, patients in the LCZ group were more likely than those in the enalapril group to have symptomatic hypotension, but these events rarely required the discontinuation of treatment Table 3.
In contrast, cough, a serum creatinine level of 2. Overall, fewer patients in the LCZ group than in the enalapril group stopped their study medication because of an adverse event The most frequent serious adverse events and adverse events leading to discontinuation of the study drug are summarized in Sections 6 and 7 in the Supplementary Appendix. As compared with the value at randomization, the mean systolic blood pressure at 8 months was 3.
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However, when the between-group difference in blood pressure was modeled as a time-dependent covariate, it was not a determinant of the incremental benefit of LCZ At 8 months, there were no significant changes from baseline in heart rate or serum creatinine level between the two groups.
No patient had airway compromise or required mechanical airway protection.
In our study involving patients with chronic heart failure and a reduced ejection fraction, the inhibition of both the angiotensin II receptor and neprilysin with LCZ was more effective in reducing the risk of death from cardiovascular causes or hospitalization for heart failure than was ACE inhibition with enalapril.
LCZ was also superior to enalapril in reducing the risk of death from any cause and reducing symptoms and physical limitations of heart failure. The magnitude of these advantages of LCZ over ACE inhibition was highly significant and clinically important, particularly since the drug was compared with a dose of enalapril that has been shown to reduce mortality, as compared with placebo.
The benefit with respect to cardiovascular mortality was consistent in all relevant subgroups. The trial was devised to show an advantage with respect to cardiovascular mortality alone, which was the primary determinant of the sample size and for which a statistically compelling effect was required to stop the trial early because of a benefit.
Although in clinical practice, many patients with heart failure receive low and potentially subtherapeutic doses of ACE inhibitors and ARBs, 26 we included a run-in period to ensure that LCZ would be compared with doses of enalapril that have been shown to reduce mortality.
The mean dose of enalapril that was used in our study The favorable results of our study contrast with the disappointing findings in an earlier large-scale trial involving patients with heart failure, 18 which showed no significant difference in clinical outcomes between enalapril and omapatrilat a drug that inhibits ACE, neprilysin, and aminopeptidase P.
However, in that trial, omapatrilat was given once daily to reflect its use in patients with hypertension , even though its pharmacologic advantages over enalapril in patients with heart failure were not maintained throughout the hour dosing interval. The superiority of LCZ over enalapril was not accompanied by important safety concerns; fewer patients stopped their study medication overall or because of an adverse event in the LCZ group than in the enalapril group.
Because of its greater vasodilator effects, treatment with LCZ was associated with a higher rate of symptomatic hypotension, but there was no increase in the rate of discontinuation because of possible hypotension-related adverse effects. Although the greater hypotensive effect of LCZ might impair renal perfusion, clinically important increases in the serum creatinine level and discontinuation of the study drug because of renal impairment were less frequent in the LCZ group than in the enalapril group.
These effects of LCZ on renal function are consistent with the effects observed in experimental studies 15 and with the findings in earlier trials of omapatrilat. Although we recruited patients with at least mildly increased levels of natriuretic peptides in order to achieve our projected event rate, the characteristics of our patients with heart failure were similar to those of study populations in other relevant trials and patients in the community.
Doses of the study drugs were increased to target levels during the run-in phase, primarily to ensure that patients in the enalapril group received doses that have been shown to reduce mortality. Hence, our results are applicable to a broad spectrum of patients with heart failure, including those who are currently taking an ACE inhibitor or ARB or who are likely to be able to take such an agent without having unacceptable side effects.
In conclusion, angiotensin receptor—neprilysin inhibition with LCZ was superior to ACE inhibition alone in reducing the risks of death and of hospitalization for heart failure. The magnitude of the beneficial effect of LCZ, as compared with enalapril, on cardiovascular mortality was at least as large as that of long-term treatment with enalapril, as compared with placebo. Disclosure forms provided by the authors are available with the full text of this article at NEJM.
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Address reprint requests to Dr. N Engl J Med ; - Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. Mortality and morbidity reduction with candesartan in patients with chronic heart failure and left ventricular systolic dysfunction: results of the CHARM low-left ventricular ejection fraction trials. Circulation ; - Cohn JN, Tognoni G. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure.