4.2.0.0 Risk Reduction
Aspirin has been shown to be effective in reducing cardiovascular morbidity and mortality in high-risk patients with previous MI or stroke (secondary prevention) and is strongly recommended. In primary prevention, however, among patients with no previous cardiovascular events, its net benefit is more controversial (116,117).
Previous randomized controlled trials of aspirin specifically in patients with diabetes failed to consistently show a significant reduction in overall ASCVD end points, raising questions about the efficacy of aspirin for primary prevention in people with diabetes, although some sex differences were suggested (118-120).
The Antithrombotic Trialists’ Collaboration published an individual patient– level meta-analysis (116) of the six large trials of aspirin for primary prevention in the general population. These trials collectively enrolled over 95,000 participants, including almost 4,000 with diabetes. Overall, they found that aspirin reduced the risk of serious vascular events by 12% (RR 0.88 [95% CI 0.82–0.94]). The largest reduction was for nonfatal MI, with little effect on CHD death (RR 0.95 [95% CI 0.78–1.15]) or total stroke.
Most recently, the ASCEND (A Study of Cardiovascular Events iN Diabetes) trial randomized 15,480 patients with diabetes but no evident cardiovascular disease to aspirin 100 mg daily or placebo (121). The primary efficacy end point was vascular death, MI, or stroke or transient ischemic attack. The primary safety outcome was major bleeding (i.e., intracranial hemorrhage, sight-threatening bleeding in the eye, gastrointestinal bleeding, or other serious bleeding). During a mean follow-up of 7.4 years, there was a significant 12% reduction in the primary efficacy end point (8.5% vs. 9.6%; P = 0.01). In contrast, major bleeding was significantly increased from 3.2% to 4.1% in the aspirin group (rate ratio 1.29; P = 0.003), with most of the excess being gastrointestinal bleeding and other extra-cranial bleeding. There were no significant differences by sex, weight, or duration of diabetes or other baseline factors including ASCVD risk score.
Two other large randomized trials of aspirin for primary prevention, in patients without diabetes (ARRIVE [Aspirin to Reduce Risk of Initial Vascular Events]) (122) and in the elderly (ASPREE [Aspirin in Reducing Events in the Elderly]) (123), including 11% with diabetes, found no benefit of aspirin on the primary efficacy end point and an increased risk of bleeding. In ARRIVE, with 12,546 patients over a period of 60 months follow-up, the primary end point occurred in 4.29% vs. 4.48% of patients in the aspirin versus placebo groups (HR 0.96; 95% CI 0.81–1.13; P = 0.60). Gastrointestinal bleeding events (characterized as mild) occurred in 0.97% of patients in the aspirin group vs. 0.46% in the placebo group (HR 2.11; 95% CI 1.36–3.28; P = 0.0007). In ASPREE, including 19,114 persons, for the rate of cardiovascular disease (fatal CHD, MI, stroke, or hospitalization for heart failure) after a median of 4.7 years of follow-up, the rates per 1,000 person-years were 10.7 vs. 11.3 events in aspirin vs. placebo groups (HR 0.95; 95% CI 0.83–1.08). The rate of major hemorrhage per 1,000 person-years was 8.6 events vs. 6.2 events, respectively (HR 1.38; 95% CI 1.18–1.62; P < 0.001).
Thus, aspirin appears to have a modest effect on ischemic vascular events, with the absolute decrease in events depending on the underlying ASCVD risk. The main adverse effect is an increased risk of gastrointestinal bleeding. The excess risk may be as high as 5 per 1,000 per year in real-world settings. However, for adults with ASCVD risk >1% per year, the number of ASCVD events prevented will be similar to the number of episodes of bleeding induced, although these complications do not have equal effects on long-term health (124).