BACKGROUND: The role of aspirin in primary prevention of cardiovascular disease (CVD) remains unclear. We aimed to investigate the benefit-risk ratio of aspirin for primary prevention of CVD with a particular focus on subgroups. METHODS: Randomized controlled trials comparing the effects of aspirin for primary prevention of CVD versus control and including at least 1000 patients were eligible for this meta-analysis. The primary efficacy outcome was all-cause mortality. Secondary outcomes included cardiovascular mortality, major adverse cardiovascular events (MACE), myocardial infarction, ischemic stroke, and net clinical benefit. The primary safety outcome was major bleeding. Subgroup analyses involving sex, concomitant statin treatment, diabetes, and smoking were performed. RESULTS: Thirteen randomized controlled trials comprising 164,225 patients were included. The risk of all-cause and cardiovascular mortality was similar for aspirin and control groups (RR 0.98; 95% CI, 0.93-1.02; RR 0.99; 95% CI, 0.90-1.08; respectively). Aspirin reduced the relative risk (RRR) of major adverse cardiovascular events (MACE) by 9% (RR 0.91; 95% CI, 0.86-0.95), myocardial infarction by 14% (RR 0.86; 95% CI, 0.77-0.95), and ischemic stroke by 10% (RR 0.90; 95% CI, 0.82-0.99), but was associated with a 46% relative risk increase of major bleeding events (RR 1.46; 95% CI, 1.30-1.64) compared with controls. Aspirin use did not translate into a net clinical benefit adjusted for event-associated mortality risk (mean 0.034%; 95% CI, - 0.18 to 0.25%). There was an interaction for aspirin effect in three patient subgroups: (i) in patients under statin treatment, aspirin was associated with a 12% RRR of MACE (RR 0.88; 95% CI, 0.80-0.96), and this effect was lacking in the no-statin group; (ii) in non-smokers, aspirin was associated with a 10% RRR of MACE (RR 0.90; 95% CI, 0.82-0.99), and this effect was not present in smokers; and (iii) in males, aspirin use resulted in a 11% RRR of MACE (RR 0.89; 95% CI, 0.83-0.95), with a non-significant effect in females. CONCLUSIONS: Aspirin use does not reduce all-cause or cardiovascular mortality and results in an insufficient benefit-risk ratio for CVD primary prevention. Non-smokers, patients treated with statins, and males had the greatest risk reduction of MACE across subgroups. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019118474.

• Keywords
• Aspirin, Cancer, Cardiovascular disease, Major adverse cardiovascular event, Major bleeding, Meta-analysis, Myocardial infarction, Primary prevention, Stroke,
• MeSH
• Aspirin therapeutic use   MeSH
• Stroke mortality   MeSH
• Risk Assessment MeSH
• Myocardial Infarction mortality   MeSH
• Cardiovascular Diseases complications   mortality   prevention & control   MeSH
• Diabetes Complications MeSH
• Humans MeSH
• Primary Prevention MeSH
• Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use   MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Meta-Analysis MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Aspirin MeSH
• Hydroxymethylglutaryl-CoA Reductase Inhibitors MeSH