A putative placebo analysis of the effects of LCZ696 on clinical outcomes in heart failure

Abstract

Aims: Although active-controlled trials with renin–angiotensin inhibitors are ethically mandated in heart failure with reduced ejection fraction, clinicians and regulators often want to know how the experimental therapy would perform compared with placebo. The angiotensin receptor-neprilysin inhibitor LCZ696 was compared with enalapril in PARADIGM-HF. We made indirect comparisons of the effects of LCZ696 with putative placebos.

Methods and results: We used the treatment-arm of the Studies Of Left Ventricular Dysfunction (SOLVD-T) as the reference trial for comparison of an ACE inhibitor to placebo and the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity-Alternative trial (CHARM-Alternative) as the reference trial for comparison of an ARB to placebo. The hazard ratio of LCZ696 vs. a putative placebo was estimated through the product of the hazard ratio of LCZ696 vs. enalapril (active-control) and that of the historical active-control (enalapril or candesartan) vs. placebo. For the primary composite outcome of cardiovascular death or heart failure hospitalization in PARADIGM-HF, the relative risk reduction with LCZ696 vs. a putative placebo from SOLVD-T was 43% (95%CI 34–50%; P < 0.0001) with similarly large effects on cardiovascular death (34%, 21–44%; P < 0.0001) and heart failure hospitalization (49%, 39–58%; P < 0.0001). For all-cause mortality, the reduction compared with a putative placebo was 28% (95%CI 15–39%; P < 0.0001). Putative placebo analyses based on CHARM-Alternative gave relative risk reductions of 39% (95%CI 27–48%; P < 0.0001) for the composite outcome of cardiovascular death or heart failure hospitalization, 32% (95%CI 16–45%; P < 0.0001) for cardiovascular death, 46% (33–56%; P < 0.0001) for heart failure hospitalization, and 26% (95%CI 11–39%; P < 0.0001) for all-cause mortality.

Conclusion: These indirect comparisons of LCZ696 with a putative placebo show that the strategy of combined angiotensin receptor blockade and neprilysin inhibition led to striking reductions in cardiovascular and all-cause mortality, as well as heart failure hospitalization. These benefits were obtained even though LCZ696 was added to comprehensive background beta-blocker and mineralocorticoid receptor antagonist therapy.

Trial registration: ClinicalTrials.gov NCT01035255.

Figure 1

Schematic of the trials and comparisons used in the putative placebo analysis. SOLVD-T = treatment arm of the Studies Of Left Ventricular Dysfunction (comparing enalapril with placebo). CHARM-Alternative = Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity-Alternative trial (comparing candesartan with placebo). PARADIGM-HF = Prospective comparison of Angiotensin Receptor Neprilysin inhibitor (ARNI) with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure (comparing LCZ696 with enalapril). For enalapril, solid arrows indicate directly performed comparison in the trials specified (direction of arrow indicates comparison of experimental treatment to the reference treatment); the interrupted arrow indicates the indirect, putative, placebo comparison (direction of arrow indicates comparison of experimental treatment to the putative placebo). For candesartan, the figure structure is the same except that it is assumed that the comparison in PARADIGM-HF was LCZ696 vs. candesartan (as opposed to enalapril in reality). The hazard ratios shown are those measured in the trials specified; the indirectly calculated hazard ratios for LCZ696 against placebo are shown in Table 3. (a) Cardiovascular death or heart failure hospitalization, (b) cardiovascular death, (c) heart failure hospitalization, and (d) all-cause mortality.

Figure 2

Putative placebo analysis based upon the Studies Of Left Ventricular Dysfunction (SOLVD-T) as the reference trial for comparison of an angiotensin converting enzyme inhibitor to placebo and the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity-Alternative trial (CHARM-Alt.) as the reference trial for comparison of an angiotensin receptor blocker to placebo. (A) Composite of death from cardiovascular causes or heart failure hospitalization, (B) cardiovascular death, (C) heart failure hospitalization, and (D) all-cause mortality.