论文一
论文二
论文标题：Fixed-dose combination therapies with and without aspirin for primary prevention of cardiovascular disease: an individual participant data meta-analysis
作者：Philip Joseph, Gholamreza Roshandel, Peggy Gao, Prem Pais, Eva Lonn, Denis Xavier, Alvaro Avezum, Jun Zhu, Lisheng Liu, Jackie Bosch, Gilles R Dagenais, Reza Malekzadeh, Salim Yusuf
期刊：The Lancet
发表时间：2021/08/29
数字识别码：10.1016/S0140-6736(21)01827-4
摘要：BackgroundIn 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.MethodsWe 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.FindingsThree 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).InterpretationFixed-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.FundingPopulation Health Research Institute.
四合一药物总体来说也保持了安全耐受性，但与对照组相比没有提高。所有用药12周的患者中，四合一药物组发生了7例（3%，位置性眩晕、气短、非心源性胸痛、强直性阵挛发作、踝关节骨折、胆囊炎和偏头痛）严重不良事件，对照组发生了3例（1%，非心源性胸痛、肺炎和心梗）。两组因不良事件相关的治疗退出率没有显著差异（4.0% vs 2.4%）。
在安全性方面，消化道出血并不常见，服用含阿司匹林多合一药物的患者中，发生率略高于对照组（0.4% vs 0.2%），但统计学差异不显著。出血性中风（0.2% vs 0.3%）、致命性出血（<0.1% vs 0.1%）和消化性溃疡（0.7% vs 0.8%）的发生率较低，在多合一药物组和对照组之间没有显著差异。多合一药物组的头晕更常见（11.7% vs 9.2%）。
在《柳叶刀》同期刊发的评论文章中，剑桥大学（University of Cambridge）Jonathan Mant教授和牛津大学（University of Oxford）Richard McManus教授指出，在不少地区，许多有用药指征甚至已经出现心血管疾病的人都没有好好吃药，这表明用药策略要尽可能的简单。而在另一些地区，根据风险因素来调整药物，在实际临床环境中也可能会导致治疗不足，多合一药物与精确调准用药相比具有成本效益。
[1] Clara K Chow, et al., (2021). Initial treatment with a single pill containing quadruple combination of quarter doses of blood pressure medicines versus standard dose monotherapy in patients with hypertension (QUARTET): a phase 3, randomised, double-blind, active-controlled trial. The Lancet, DOI: 10.1016/S0140-6736(21)01922-X
[2] Philip Joseph, et al., (2021). Fixed-dose combination therapies with and without aspirin for primary prevention of cardiovascular disease: an individual participant data meta-analysis. The Lancet, DOI: 10.1016/S0140-6736(21)01827-4
[3] Jonathan Mant, Richard McManus. Polypills with or without aspirin for primary prevention of cardiovascular disease. The Lancet, DOI: https://doi.org/10.1016/S0140-6736(21)01913-9
