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

Abstract

AimsAlthough 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 resultsWe 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.ConclusionThese 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.

Sacubitril/valsartan: An important piece in the therapeutic puzzle of heart failure

“…40 The reduction in mortality obtained in this study was similar to that compared to placebo in the treatment arm of the Studies of Left Ventricular Dysfunction (SOLVD-T), which established ACEIs as a first-line treatment for HD. 41 It should be noted that the dose of enalapril (10 mg twice daily) was higher than in SOLVD-T.…”

Τhe role of sacubitril/valsartan therapy on renal function and glucose metabolism in chronic heart failure patients

“…These active drugs augment neprilysin substrates such as natriuretic peptides while inhibiting AT1-receptormediated responses with reduced ejection fraction [24]. Additionally, natriuretic peptide (NP) system which is released represents a group of structurally related but genetically different hormones or paracrine factors, having actions focusing at protecting the cardiovascular system from volume overload.…”

Angiotensin Receptor Neprilysin Inhibition in Heart Failure: Mechanistic Action and Clinical Impact

“…75 With the use of the putative placebo from the enalapril trial, the relative risk reduction (RRR) with LCZ696 on the primary composite of cardiovascular death or HF hospitalization was 43%, with RRRs of 34% for cardiovascular death, 49% for HF hospitalization, and 28% for all-cause mortality. All the effects seen were statistically significant.…”

“…This analysis adds further evidence to support beneficial effects of LCZ696 on important clinical outcomes in HF patients, including reductions in mortality and HF hospitalizations. 75 …”