Background

In randomised controlled trials, fixed-dose combination treatments (or polypills) have been shown to reduce a composite of cardiovascular disease outcomes in primary prevention. However, whether or not aspirin should be included, effects on specific outcomes, and effects in key subgroups are unknown.

Methods

We did an individual participant data meta-analysis of large randomised controlled trials (each with ≥1000 participants and ≥2 years of follow-up) of a fixed-dose combination treatment strategy versus control in a primary cardiovascular disease prevention population. We included trials that evaluated a fixed-dose combination strategy of at least two blood pressure lowering agents plus a statin (with or without aspirin), compared with a control strategy (either placebo or usual care). The primary outcome was time to first occurrence of a composite of cardiovascular death, myocardial infarction, stroke, or arterial revascularisation. Additional outcomes included individual cardiovascular outcomes and death from any cause. Outcomes were also evaluated in groups stratified by the inclusion of aspirin in the fixed-dose treatment strategy, and effect sizes were estimated in prespecified subgroups based on risk factors. Kaplan-Meier survival curves and Cox proportional hazard regression models were used to compare strategies.

Findings

Three large randomised trials were included in the analysis (TIPS-3, HOPE-3, and PolyIran), with a total of 18 162 participants. Mean age was 63·0 years (SD 7·1), and 9038 (49·8%) participants were female. Estimated 10-year cardiovascular disease risk for the population was 17·7% (8·7). During a median follow-up of 5 years, the primary outcome occurred in 276 (3·0%) participants in the fixed-dose combination strategy group compared with 445 (4·9%) in the control group (hazard ratio 0·62, 95% CI 0·53–0·73, p<0·0001). Reductions were also observed for the separate components of the primary outcome: myocardial infarction (0·52, 0·38–0·70), revascularisation (0·54, 0·36–0·80), stroke (0·59, 0·45–0·78), and cardiovascular death (0·65, 0·52–0·81). Significant reductions in the primary outcome and its components were observed in the analyses of fixed-dose combination strategies with and without aspirin, with greater reductions for strategies including aspirin. Treatment effects were similar at different lipid and blood pressure levels, and in the presence or absence of diabetes, smoking, or obesity. Gastrointestinal bleeding was uncommon but slightly more frequent in the fixed-dose combination strategy with aspirin group versus control (19 [0·4%] vs 11 [0·2%], p=0·15). The frequencies of haemorrhagic stroke (10 [0·2%] vs 15 [0·3%]), fatal bleeding (two [<0·1%] vs four [0·1%]), and peptic ulcer disease (32 [0·7%] vs 34 [0·8%]) were low and did not differ significantly between groups. Dizziness was more common with fixed-dose combination treatment (1060 [11·7%] vs 834 [9·2%], p<0·0001).

Interpretation

Fixed-dose combination treatment strategies substantially reduce cardiovascular disease, myocardial infarction, stroke, revascularisation, and cardiovascular death in primary cardiovascular disease prevention. These benefits are consistent irrespective of cardiometabolic risk factors.

Funding

Population Health Research Institute.

中文翻译：

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固定剂量联合疗法联合和不联合阿司匹林用于心血管疾病一级预防：个体参与者数据荟萃分析

背景

在随机对照试验中，固定剂量联合治疗（或复方药丸）已被证明可以减少初级预防中心血管疾病的复合结局。然而，是否应包括阿司匹林、对特定结果的影响以及对关键亚组的影响尚不清楚。

方法

我们对主要心血管疾病预防人群中固定剂量联合治疗策略与对照的大型随机对照试验（每个试验有≥1000名受试者和≥2年的随访）进行了个体受试者数据荟萃分析。我们纳入的试验评估了至少两种降压药加一种他汀类药物（加或不加阿司匹林）的固定剂量联合策略与对照策略（安慰剂或常规治疗）的比较。主要结果是首次发生心血管死亡、心肌梗死、卒中或动脉血运重建的复合事件的时间。其他结局包括个体心血管结局和全因死亡。还通过将阿司匹林纳入固定剂量治疗策略分层的组中评估结果，根据风险因素在预先指定的亚组中估计效应量。Kaplan-Meier 生存曲线和 Cox 比例风险回归模型用于比较策略。

发现

分析中包括三项大型随机试验（TIPS-3、HOPE-3 和 PolyIran），共有 18162 名参与者。平均年龄为 63·0 岁 (SD 7·1)，9038 (49·8%) 名参与者为女性。估计人群的 10 年心血管疾病风险为 17·7% (8·7)。在 5 年的中位随访期间，固定剂量联合策略组的 276 名 (3·0%) 参与者发生了主要结果，而对照组为 445 名 (4·9%) 参与者（风险比 0·62 , 95% CI 0·53–0·73, p<0·0001)。主要结局的各个组成部分也出现了减少：心肌梗死（0·52、0·38-0·70）、血运重建（0·54、0·36-0·80）、中风（0·59、 0·45–0·78) 和心血管死亡 (0·65, 0·52–0·81)。在使用和不使用阿司匹林的固定剂量联合策略的分析中观察到主要结果及其组成部分显着降低，包括阿司匹林在内的策略降低幅度更大。在不同的血脂和血压水平，以及存在或不存在糖尿病、吸烟或肥胖的情况下，治疗效果相似。与对照组相比，阿司匹林组的固定剂量联合策略中胃肠道出血并不常见，但发生率略高（19 [0·4%]与11 [0·2%]，p=0·15)。出血性中风（10 [0·2%] vs 15 [0·3%]）、致命性出血（2 [<0·1%] vs 4 [0·1%]）和消化性溃疡病（32 [0·7%]与34 [0·8%]) 的比例较低，组间差异不显着。头晕在固定剂量联合治疗组中更为常见（1060 [11·7%] vs 834 [9·2%]，p<0·0001）。

解释

固定剂量联合治疗策略可显着减少初级心血管疾病预防中的心血管疾病、心肌梗死、中风、血运重建和心血管死亡。无论心脏代谢危险因素如何，这些益处都是一致的。

资金

人口健康研究所。