McMurray John, Packer Milton, Desai Akshay, Gong Jianjian, Greenlaw Nicola, Lefkowitz Martin, Rizkala Adel, Shi Victor, Rouleau Jean, Solomon Scott, Swedberg Karl, Zile Michael R, Andersen Karl, Arango Juan Luis, Arnold Malcolm, Bĕlohlávek Jan, Böhm Michael, Boytsov Sergey, Burgess Lesley, Cabrera Walter, Chen Chen-Huan, Erglis Andrejs, Fu Michael, Gomez Efrain, Gonzalez Angel, Hagege Albert-Alain, Katova Tzvetana, Kiatchoosakun Songsak, Kim Kee-Sik, Bayram Edmundo, Martinez Felipe, Merkely Bela, Mendoza Iván, Mosterd Arend, Negrusz-Kawecka Marta, Peuhkurinen Keijo, Ramires Felix, Refsgaard Jens, Senni Michele, Sibulo Antonio S, Silva-Cardoso José, Squire Iain, Starling Randall C, Vinereanu Dragos, Teerlink John R, Wong Raymond
Eur Heart J. 2015 Feb 14;36(7):434-9. doi: 10.1093/eurheartj/ehu455.
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.
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.
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.
尽管在射血分数降低的心力衰竭患者中，使用肾素 - 血管紧张素抑制剂的活性对照试验在伦理上是必需的，但临床医生和监管机构常常想知道与安慰剂相比，实验性治疗的效果如何。在PARADIGM - HF研究中，将血管紧张素受体 - 脑啡肽酶抑制剂LCZ696与依那普利进行了比较。我们对LCZ696与假定安慰剂的效果进行了间接比较。
我们将左心室功能障碍研究（SOLVD - T）的治疗组作为将ACE抑制剂与安慰剂进行比较的参考试验，将心力衰竭中坎地沙坦：评估死亡率和发病率降低 - 替代试验（CHARM - Alternative）作为将ARB与安慰剂进行比较的参考试验。通过LCZ696与依那普利（活性对照）以及历史活性对照（依那普利或坎地沙坦）与安慰剂的风险比之积，估算LCZ696与假定安慰剂的风险比。对于PARADIGM - HF研究中心血管死亡或心力衰竭住院的主要复合结局，与来自SOLVD - T的假定安慰剂相比，LCZ696的相对风险降低为43%（95%CI 34 - 50%；P < 0.0001），对心血管死亡（34%，21 - 44%；P < 0.0001）和心力衰竭住院（49%，39 - 58%；P < 0.0001）有同样显著的影响。对于全因死亡率，与假定安慰剂相比降低了28%（95%CI 15 - 39%；P < 0.0001）。基于CHARM - Alternative的假定安慰剂分析显示，对于心血管死亡或心力衰竭住院的复合结局，相对风险降低39%（95%CI 27 - 48%；P < 0.0001），对于心血管死亡降低32%（95%CI 16 - 45%；P < 0.0001），对于心力衰竭住院降低46%（33 - 56%；P < 0.0001），对于全因死亡率降低26%（95%CI 11 - 39%；P < 0.0001）。
这些将LCZ696与假定安慰剂进行的间接比较表明，联合血管紧张素受体阻断和脑啡肽酶抑制的策略可显著降低心血管和全因死亡率以及心力衰竭住院率。即使在综合背景β受体阻滞剂和盐皮质激素受体拮抗剂治疗基础上加用LCZ696，也能获得这些益处。
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