Abstrakt
Aims Although active-controlled trials with reninangiotensin 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 3450%; P < 0.0001) with similarly large effects on cardiovascular death (34%, 2144%; P < 0.0001) and heart failure hospitalization (49%, 3958%; P < 0.0001).
For all-cause mortality, the reduction compared with a putative placebo was 28% (95%CI 1539%; P < 0.0001). Putative placebo analyses based on CHARM-Alternative gave relative risk reductions of 39% (95%CI 2748%; P < 0.0001) for the composite outcome of cardiovascular death or heart failure hospitalization, 32% (95%CI 1645%; P < 0.0001) for cardiovascular death, 46% (3356%; P < 0.0001) for heart failure hospitalization, and 26% (95%CI 1139%; P < 0.0001) for all-cause mortality.