Abstract Aims The PARADIGM-HF and PARAGON-HF trials tested sacubitril/valsartan against active controls given renin–angiotensin system inhibitors (RASi) are ethically mandated in heart failure (HF) with reduced ejection fraction and are used in the vast majority of patients with HF with preserved ejection fraction. To estimate the effects of sacubitril/valsartan had it been tested against a placebo control, we made indirect comparisons of the effects of sacubitril/valsartan with putative placebos in HF across the full range of left ventricular ejection fraction (LVEF). Methods and results We analysed patient-level data from the PARADIGM-HF and PARAGON-HF trials (n = 13 194) and the CHARM-Alternative and CHARM-Preserved trials (n = 5050, candesartan vs. placebo). The rate ratio (RR) of sacubitril/valsartan vs. putative placebo was estimated by the product of the RR for sacubitril/valsartan vs. RASi and the RR for RASi vs. placebo. Total HF hospitalizations and cardiovascular death were analysed using the negative binomial method. Treatment effects were estimated using cubic spline methods by ejection fraction as a continuous measure. Across the range of LVEF, sacubitril/valsartan was associated with a RR 0.54 [95% confidence interval (CI) 0.45–0.65] for the recurrent primary endpoint compared with putative placebo (P < 0.001). Treatment benefits of sacubitril/valsartan vs. putative placebo varied non-linearly with LVEF with attenuation of effects observed at LVEF above 60%. When analyzing data from PARADIGM-HF and CHARM-Alternative, the estimated risk reduction of sacubitril/valsartan vs. putative placebo was 48% (95% CI 35–58%); P < 0.001. When analyzing data from PARAGON-HF and CHARM-Preserved (with LVEF ≥ 45%), the estimated risk reduction of sacubitril/valsartan vs. putative placebo was 29% (95% CI 7–46%); P = 0.013. Across the full range of LVEF, consistent effects were observed for time-to-first endpoints: first primary endpoint (RR 0.72, 95% CI 0.64–0.82), first HF hospitalization (RR 0.67, 95% CI 0.58–0.78), cardiovascular death (RR 0.76, 95% CI 0.64–0.89), and all-cause death (RR 0.83, 95% CI 0.71–0.96); all P < 0.02. Conclusion This putative placebo analysis reinforces the treatment benefits of sacubitril/valsartan on risk of adverse cardiovascular events across the full range of LVEF, with most pronounced effects observed at a LVEF up to 60%.

中文翻译：

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对沙库巴曲/缬沙坦在射血分数全范围内对心力衰竭影响的假定安慰剂分析

摘要目的 PARADIGM-HF 和 PARAGON-HF 试验测试了沙库巴曲/缬沙坦与活性对照的对比，因为肾素-血管紧张素系统抑制剂 (RASi) 在射血分数降低的心力衰竭 (HF) 中是伦理上强制要求的，并且用于绝大多数患有以下疾病的患者。射血分数保留的 HF。为了评估沙库巴曲/缬沙坦对安慰剂对照的影响，我们间接比较了沙库巴曲/缬沙坦与推定安慰剂在整个左心室射血分数 (LVEF) 范围内对 HF 的影响。方法和结果 我们分析了来自 PARADIGM-HF 和 PARAGON-HF 试验（n = 13194）以及 CHARM-Alternative 和 CHARM-Preserved 试验（n = 5050，坎地沙坦与安慰剂）的患者水平数据。沙库巴曲/缬沙坦的比率 (RR) 与 推定的安慰剂是通过沙库巴曲/缬沙坦与 RASi 的 RR 和 RASi 与安慰剂的 RR 的乘积来估计的。使用负二项式方法分析总 HF 住院和心血管死亡。使用三次样条方法通过射血分数作为连续测量来估计治疗效果。在整个 LVEF 范围内，与推定的安慰剂相比，沙库巴曲/缬沙坦与复发性主要终点的 RR 0.54 [95% 置信区间 (CI) 0.45–0.65] 相关（P < 0.001）。沙库巴曲/缬沙坦与推定安慰剂的治疗益处随 LVEF 呈非线性变化，在 LVEF 超过 60% 时观察到的效果减弱。在分析来自 PARADIGM-HF 和 CHARM-Alternative 的数据时，与推定的安慰剂相比，沙库巴曲/缬沙坦的估计风险降低了 48% (95% CI 35–58%)；P < 0.001。在分析来自 PARAGON-HF 和 CHARM-Preserved（LVEF ≥ 45%）的数据时，与推定的安慰剂相比，沙库巴曲/缬沙坦的估计风险降低了 29%（95% CI 7–46%）；P = 0.013。在整个 LVEF 范围内，观察到首次终点时间的一致影响：第一个主要终点（RR 0.72，95% CI 0.64–0.82），首次 HF 住院（RR 0.67，95% CI 0.58–0.78），心血管死亡（RR 0.76, 95% CI 0.64–0.89）和全因死亡（RR 0.83, 95% CI 0.71–0.96）；所有 P < 0.02。结论这项假定的安慰剂分析强化了沙库巴曲/缬沙坦对整个 LVEF 范围内不良心血管事件风险的治疗益处，在 LVEF 高达 60% 时观察到最明显的效果。推定的安慰剂为 29%（95% CI 7–46%）；P = 0.013。在整个 LVEF 范围内，观察到首次终点时间的一致影响：第一个主要终点（RR 0.72，95% CI 0.64–0.82），首次 HF 住院（RR 0.67，95% CI 0.58–0.78），心血管死亡（RR 0.76, 95% CI 0.64–0.89）和全因死亡（RR 0.83, 95% CI 0.71–0.96）；所有 P < 0.02。结论这项假定的安慰剂分析强化了沙库巴曲/缬沙坦对整个 LVEF 范围内不良心血管事件风险的治疗益处，在 LVEF 高达 60% 时观察到最明显的效果。推定的安慰剂为 29%（95% CI 7–46%）；P = 0.013。在整个 LVEF 范围内，观察到首次终点时间的一致影响：第一个主要终点（RR 0.72，95% CI 0.64–0.82），首次 HF 住院（RR 0.67，95% CI 0.58–0.78），心血管死亡（RR 0.76, 95% CI 0.64–0.89）和全因死亡（RR 0.83, 95% CI 0.71–0.96）；所有 P < 0.02。结论这项假定的安慰剂分析强化了沙库巴曲/缬沙坦对整个 LVEF 范围内不良心血管事件风险的治疗益处，在 LVEF 高达 60% 时观察到最明显的效果。心血管死亡（RR 0.76, 95% CI 0.64–0.89）和全因死亡（RR 0.83, 95% CI 0.71–0.96）；所有 P < 0.02。结论这项假定的安慰剂分析强化了沙库巴曲/缬沙坦对整个 LVEF 范围内不良心血管事件风险的治疗益处，在 LVEF 高达 60% 时观察到最明显的效果。心血管死亡（RR 0.76, 95% CI 0.64–0.89）和全因死亡（RR 0.83, 95% CI 0.71–0.96）；所有 P < 0.02。结论这项假定的安慰剂分析强化了沙库巴曲/缬沙坦对整个 LVEF 范围内不良心血管事件风险的治疗益处，在 LVEF 高达 60% 时观察到最明显的效果。