Background:Clinical worsening (CW) is a composite end point commonly used in pulmonary arterial hypertension (PAH) trials. We aimed to assess the trial-level surrogacy of CW for mortality in PAH trials, and whether the various CW components were similar in terms of frequency of occurrence, treatment-related relative risk (RR) reduction, and importance to patients.Methods:We searched MEDLINE, Embase, and the Cochrane Library (January 1990 to December 2020) for trials evaluating the effects of PAH therapies on CW. The coefficient of determination between the RR for CW and mortality was assessed by regression analysis. The frequency of occurrence, RR reduction, and importance to patients of the CW components were assessed.Results:We included 35 independent cohorts (9450 patients). PAH therapies significantly reduced CW events (RR, 0.64 [95% CI, 0.55–0.73]), including PAH-related hospitalizations (RR, 0.61 [95% CI, 0.47–0.79]), treatment escalation (RR, 0.57 [95% CI, 0.38–0.84]) and symptomatic progression (RR, 0.58 [95% CI, 0.48–0.69]), and modestly reduced all-cause mortality when incorporating deaths occurring after a primary CW-defining event (RR, 0.860 [95% CI, 0.742–0.997]). However, the effects of PAH-specific therapies on CW only modestly correlated with their effects on mortality (R²_trial, 0.35 [95% CI, 0.10–0.59]; P<0.0001), and the gradient in the treatment effect across component end points was large in the majority of trials. The weighted proportions of CW-defining events were hospitalization (33.5%) and symptomatic progression (32.3%), whereas death (6.7%), treatment escalation (5.6%), and transplantation/atrioseptostomy (0.2%) were infrequent. CW events were driven by the occurrence of events of major (49%) and mild-to-moderate (37%) importance to patients, with 14% of the events valued as critical.Conclusions:PAH therapies significantly reduced CW events, but study-level CW is not a surrogate for mortality in PAH trials. Moreover, components of CW largely vary in frequency, response to therapy, and importance to patients and are thus not interchangeable.Registration:URL: https://www.crd.york.ac.uk/PROSPERO; Unique identifier: CRD42020178949.

中文翻译：

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评估临床恶化终点作为肺动脉高压死亡率的替代指标：随机对照试验的系统评价和荟萃分析

背景：临床恶化（CW）是肺动脉高压（PAH）试验中常用的复合终点。我们旨在评估 CW 在 PAH 试验中对死亡率的替代作用，以及各种 CW 成分在发生频率、治疗相关相对风险 (RR) 降低和对患者的重要性方面是否相似。方法：我们在 MEDLINE、Embase 和 Cochrane 图书馆（1990 年 1 月至 2020 年 12 月）中搜索评估 PAH 疗法对 CW 影响的试验。通过回归分析评估 CW 的 RR 和死亡率之间的决定系数。评估了 CW 成分的发生频率、RR 降低和对患者的重要性。结果：我们纳入了 35 个独立队列（9450 名患者）。PAH 治疗显着减少 CW 事件（RR，0.64 [95% CI，0. 55–0.73]），包括 PAH 相关住院（RR，0.61 [95% CI，0.47–0.79]）、治疗升级（RR，0.57 [95% CI，0.38–0.84]）和症状进展（RR，0.58 [ 95% CI, 0.48–0.69])，并在纳入主要 CW 定义事件后发生的死亡时适度降低全因死亡率 (RR, 0.860 [95% CI, 0.742–0.997])。然而，PAH 特异性疗法对 CW 的影响与其对死亡率的影响仅适度相关。R ²_试验，0.35 [95% CI，0.10–0.59]；磷<0.0001），并且在大多数试验中，跨组件终点的治疗效果梯度很大。CW定义事件的加权比例是住院（33.5%）和症状进展（32.3%），而死亡（6.7%）、治疗升级（5.6%）和移植/房间隔造口术（0.2%）并不常见。CW 事件是由对患者具有重大 (49%) 和轻度至中度 (37%) 重要性的事件驱动的，其中 14% 的事件被认为是关键事件。结论：PAH 治疗显着减少了 CW 事件，但研究在 PAH 试验中，CW 水平不能替代死亡率。此外，CW 的组成部分在频率、对治疗的反应和对患者的重要性方面差异很大，因此不可互换。注册：URL：https://www.crd.york.ac.uk/PROSPERO；唯一标识符：CRD42020178949。