Effects of LCZ696 on Clinical Outcomes in Heart Failure
Effects of LCZ696 on Clinical Outcomes in Heart Failure
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.
Ethically, new antagonists of the renin–angiotensin system such as angiotensin-receptor blockers (ARBs) and direct renin inhibitors have to be tested in heart failure with reduced ejection fraction (HF-REF) in active-controlled comparisons with an angiotensin converting enzyme (ACE) inhibitor. Recently, LCZ696 which both blocks the angiotensin II type 1 receptor as well as inhibits neprilysin, the enzyme responsible for degradation of natriuretic and other vasoactive peptides, was also compared with enalapril in patients with HF-REF. LCZ696 was superior to enalapril, reducing the primary composite outcome of cardiovascular death or heart failure hospitalization (and both components of this composite), as well as all-cause mortality. Although active-controlled trials such as this may be ethically mandated, clinicians and regulators often want to know how the experimental therapy would have performed had it been compared directly with placebo. Well-developed statistical approaches allow such indirect comparisons to be made, assuming that a comparison of the active-control (standard therapy) and placebo is available, which is the case in HF-REF. We describe putative placebo analyses for LCZ696 using both a placebo-controlled ACE inhibitor and a similar ARB trial in HF-REF.
Abstract and Introduction
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.
Introduction
Ethically, new antagonists of the renin–angiotensin system such as angiotensin-receptor blockers (ARBs) and direct renin inhibitors have to be tested in heart failure with reduced ejection fraction (HF-REF) in active-controlled comparisons with an angiotensin converting enzyme (ACE) inhibitor. Recently, LCZ696 which both blocks the angiotensin II type 1 receptor as well as inhibits neprilysin, the enzyme responsible for degradation of natriuretic and other vasoactive peptides, was also compared with enalapril in patients with HF-REF. LCZ696 was superior to enalapril, reducing the primary composite outcome of cardiovascular death or heart failure hospitalization (and both components of this composite), as well as all-cause mortality. Although active-controlled trials such as this may be ethically mandated, clinicians and regulators often want to know how the experimental therapy would have performed had it been compared directly with placebo. Well-developed statistical approaches allow such indirect comparisons to be made, assuming that a comparison of the active-control (standard therapy) and placebo is available, which is the case in HF-REF. We describe putative placebo analyses for LCZ696 using both a placebo-controlled ACE inhibitor and a similar ARB trial in HF-REF.
