Aspirin With or Without Statin in Individuals Without Atherosclerotic Cardiovascular Disease Across Risk Categories
Abstract
Background
The effects of aspirin in adults without atherosclerotic cardiovascular disease (ASCVD), stratified by statin use across different ASCVD risks, remain uncertain.
Objective
To examine the effects of aspirin in adults without ASCVD, stratified by statin use across different ASCVD risks.
Methods
We searched databases through March 2022 and selected randomized controlled trials of aspirin without ASCVD and follow-up of ≥1 year. We used random-effects models and estimated relative and absolute risks for cardiovascular outcomes, major bleeding, and mortality over 5 years. We calculated absolute risk differences assuming constant relative risks (RRs) across statin use and ASCVD risks. The Cholesterol Treatment Trialists Collaboration, and the ASCEND (A Study of Cardiovascular Events in Diabetes) trial were used to estimate baseline risks.
Results
In 16 trials [171,215 individuals; median age, 64 (Q1-Q3: 60-65) years], aspirin vs control reduced myocardial infarction (MI) [RR: 0.85 (95% CI: 0.77-0.95)] but increased major bleeding [RR: 1.48 (1.32-1.66)]. Aspirin did not reduce mortality. Statin vs no statin was associated with lower bleeding and MI risk; the bleeding and MI risk were proportional to ASCVD risk. For every 10,000 adults, aspirin reduced MI (very low risk: 3 events as monotherapy or 1 event with statin; very high risk: 49 events as monotherapy or 37 events with statin) and increased major bleeding (very low risk: 21 events as monotherapy or 20 events with statin; very high risk: 98 events as monotherapy or 94 events with statin) proportional to baseline ASCVD risk.
Conclusions
In adults without ASCVD, concomitant statin appeared to significantly reduce absolute risk reduction for MI associated with aspirin without influencing bleeding risk. The anticipated absolute risk of major bleeding with aspirin exceeds absolute MI benefits for every level of ASCVD risk.
Central Illustration
The role of aspirin in the primary prevention of atherosclerotic cardiovascular disease (ASCVD) remains controversial. In 2019, the American College of Cardiology/American Heart Association recommended considering prophylactic low-dose aspirin only among asymptomatic individuals at high risk of ASCVD events, low bleeding risk, and age <70 years (IIb).1 In 2021, the European Society of Cardiology primary prevention guidelines endorsed a similar recommendation.2 More recently, the updated United States Preventive Services Task Force (USPSTF) 2022 guidelines recommended individualizing low-dose aspirin only among adults aged 40 to 59 years, if their 10-year ASCVD risk is ≥10% and they have low bleeding risk (Class C). In contrast, the guidelines recommend against the use of aspirin among adults ≥60 years (Class D). These recommendations stem from a USPSTF meta-analysis of 11 randomized controlled trials demonstrating a significant reduction in major ASCVD events with aspirin at the cost of higher rates of major bleeding.
Statin is used as first-line therapy for the primary prevention of ASCVD due to cardiovascular benefits.3 Most randomized evidence favoring aspirin in primary prevention was conducted in the pre-statin era,4 whereas statin therapy use was more frequent at baseline in recent trials. For instance, the proportion of participants on a statin in ASPREE (Aspirin in Reducing Events in the Elderly),5, 6, 7 ARRIVE (Aspirin to Reduce Risk of Initial Vascular Events),8 and ASCEND (A Study of Cardiovascular Events in Diabetes)9 trials were 65%, 43%, and 75%, respectively. Since statin therapy would mitigate baseline ASCVD risk,10 lower cardiovascular effects of aspirin in post-statin era trials might be attributable to the higher use of statin therapy.11 Furthermore, given a much more favorable risk-benefit profile, most patients considered for ASCVD risk reduction in current clinical practice would be expected to be on baseline statin therapy before entertaining a decision on possible aspirin initiation.
Prior studies4,11,12 did not explore the potential impact of statin therapy on the net risk/benefit ratio of aspirin therapy. Therefore, this meta-analysis investigated the relative and absolute effects of aspirin in adults without ASCVD, stratified by statin use across different ASCVD risks.
Figure 2. Forest Plots Comparing Aspirin vs Control for Myocardial Infarction and Any Major Bleeding
Forest plot comparing aspirin vs control for (A) myocardial infarction and (B) any major bleeding.
