Fixed-dose combination therapies with and without aspirin for primary prevention of cardiovascular disease: an individual participant data meta-analysis.

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. 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. 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). 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. Population Health Research Institute.

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Declaration of interests SY reports grants from the Canadian Institutes of Health Research, Wellcome Trust, AstraZeneca, and Cadila Pharmaceuticals related to conducting the HOPE-3 or TIPS-3 studies. PJ, PG, EL, SIB, KT, and JB report institutional grants from the Wellcome Trust, Canadian Institutes of Health Research, Heart and Stroke Foundation of Ontario, Cadila Pharmaceuticals, and AstraZeneca related to the TIPS-3 or HOPE-3 studies (or both). RM and GR report institutional grant funding from Tehran University of Medical Sciences, Barakat Foundation, and Alborz Darou related to the PolyIran study. SY reports receiving honoraria and reimbursement for travel expenses from AstraZeneca, Bayer, Boehringer Ingelheim, and Ferrer. EL reports consulting fees from Amgen Canada, consulting fees and speaker honoraria from HLS Canada, institutional research grant from Boehringer Ingelheim, and consulting fees from NovoNordisk. MDH reports grants from the World Heart Federation via unrestricted educational grants from Boehringer Ingelheim and Novartis, grants from the American Heart Association, Verily, and AstraZeneca, and personal fees from the American Medical Association outside the submitted work. In addition, MDH has a patent pending for heart failure polypills. PP reports funding from St John's Research Institute, Bangalore, India, during the conduct of the study. AR reports that George Health Enterprises, the social enterprise arm of The George Institute for Global Health, has received investment to develop fixed-dose combination products containing aspirin, statin, and blood pressure lowering drugs. George Health Enterprises has submitted patents for low-dose blood pressure combinations, on which AR is listed as one of the inventors. AR is seconded part-time to George Medicines. All staff employed by The George Institute have an institutional interest to declare with respect to George Health Enterprises, although none of the staff have a direct financial interest in these investments. DX reports grants from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Coca-Cola India, Eli Lilly, the Indian Council of Medical Research, Pfizer, Sanofi, UK Medical Research Council, and Wellcome Trust, outside the submitted work. JB reports personal fees from Bayer, outside the submitted work. RD reports grants from Amarin, DalCor, and the Population Health Research Institute, outside the submitted work. VF and JMC report grants from H2020 related to the ongoing SECURE trial. JMC reports receiving honoraria and reimbursement for travel expenses from Ferrer, Pfizer, and Bayer. AA reports grants from Bayer, EMS Pharma, and the Population Health Research Institute; and consulting fees from Bayer, Eli Lilly, NovoNordisk, and EMS Pharma outside the submitted work. All other authors declare no competing interests.