Among diabetic patients with multiple risk factors for cardiovascular events, aspirin increases major bleeding events while possibly providing a small and likely clinically insignificant reduction in serious vascular events.
Aspirin has a long-established role for secondary prevention of cardiovascular events but questions remain about aspirin as a primary prevention measure ASCEND trial (A Study of Cardiovascular Events iN Diabetes) addressed the question of aspirin as primary prevention for serious vascular events among patients with diabetes. In this study, researchers conducted a multicenter, double-blinded, placebo controlled trial comparing aspirin to placebo for prevention of serious vascular events in patients with diabetes without known occlusive vascular disease. The investigators randomized over 15,000 patients with type I or type II diabetes in a factorial design to either aspirin 100 mg daily or placebo and an n-3 fatty acid supplement or placebo. Participants with known vascular disease or indication for aspirin use were excluded as were those at high risk of major bleeding event, including those on anticoagulant therapy. The initial composite outcome was time to first serious vascular event, which included non-fatal myocardial infarction, non-fatal stroke, transient ischemic attack or death from any vascular cause. Trial results of the n-3 fatty acid arm were published simultaneously with the aspirin arm results.
Diabetic patients had similar baseline characteristics in each group, with 75% on statin therapy, 61% with diagnosed hypertension, and over half with a hemoglobin A1C of < 9%. In an intention to treat analysis after 7.4 years of follow-up, the rate of serious vascular event was 8.5% in the aspirin arm and 9.6% in the placebo arm (p = 0.01, NNT 91). None of the individual components of composite outcome were statistically significant. Additionally, without inclusion of transient ischemic attacks (which was added to the composite outcome four years after the trial began), there was no difference in serious vascular events between the groups. Rates of major bleeding were higher in the aspirin arm as compared to placebo (4.1% versus, 3.25%, NNH 112). In analysis of secondary outcomes, all-cause mortality and gastrointestinal cancer rates did not differ between the two groups. In a separate study, the authors reported no evidence of proportional effects with n-3 fatty acid use among patient taking aspirin versus placebo.
The change in the definition of the primary outcome after the trial was underway is a major threat to the validity of the trial.
Current standard of care for diabetic patients in this age group includes statin therapy and ACE inhibitor for those with hypertension which may minimize the benefit of aspirin as primary prevention for diabetic patients. The change in the definition of the primary outcome after the trial was underway is a major threat to the validity of the trial. In addition, it is unclear whether preventing a TIA, by definition a completely reversible event, is worth the bleeding risk. Finally, those at the highest risk of serious vascular events also had the highest risk of major bleeding events with aspirin use, further questioning the benefit of another prescription for our diabetic patients.
Reference: ASCEND Study (N Engl J Med. 2018 Aug 26 early online) (level 2 [mid-level] evidence)