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Study Summary

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The ASCEND trial tested the efficacy of aspirin for the primary prevention of cardiovascular events in patients with diabetes mellitus and no baseline cardiovascular disease. Patients aged ≥ 40 years were randomized to receive 100 mg enteric-coated aspirin or placebo daily (N=15,480). Baseline characteristics between groups were similar. Over a mean follow-up of 7.4 years, intention-to-treat analysis showed that aspirin significantly reduced the risk of the composite primary efficacy endpoint (myocardial infarction, stroke, transient ischemic attach, or death from vascular cause) by 12% compared to placebo (8.5% vs. 9.6%; rate ratio, 0.88; 95% CI 0.79 to 0.97; P = 0.01). However, aspirin significantly increased the composite bleeding endpoint (intracranial hemorrhage, sight-threatening bleeding event in the eye, gastrointestinal bleeding, or other serious bleeding) by 29% compared to placebo (4.1% vs. 3.2%, rate ratio 1.29; 95% CI 1.09 to 1.52; P = 0.003). Gastrointestinal bleeding was most common and represented 41.3% of bleeding events. In subgroup analysis stratified by risk of vascular events, none of the groups demonstrated that the benefits of aspirin clearly outweigh the risks.

Commentary

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Study Strengths: This was a large trial with a long duration of follow-up, in contrast to previously conducted smaller studies. Furthermore, compared to prior studies, a large portion of participants received cardioprotective therapies including statins and anti-hypertensives and the rate of smoking was low; therefore, the efficacy of aspirin was assessed in a contemporary context.

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Study Limitations: The majority of patients were low or moderate risk for vascular events and high risk patients were not well captured. Not all patients had type 2 diabetes (94%). Glycemic control was similar between the groups (with A1C<6% in 21%, ≥6 to 8% in 30%, and ≥8% in 12%), but a substantial proportion of patients had inadequate glycemic control (defined as A1C≤7%). Subgroup analysis by individual cardiovascular risk factors, including glycemic control, hypertension, hyperlipidemia, and chronic kidney disease, was not performed. Finally, the adherence to an antiplatelet in the aspirin group decreased over time, while use of an antiplatelet increased in the placebo group, thus potentially underestimating the efficacy and risks for bleeding of aspirin.

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Next Steps/Clinical Perspective: The ASCEND study demonstrated that the use of aspirin in patients with diabetes without known cardiovascular disease prevented serious vascular events, but also caused major bleeding events (see accompanying Hurst’s Central Illustration). These findings suggest that aspirin should not be routinely recommended for primary prevention of cardiovascular events in the setting of diabetes; further subgroup analysis is needed to clarify if there are subpopulations that may benefit.

Trial Reference

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The ASCEND Study Collaborative Group. Effects of aspirin for primary prevention in persons with diabetes mellitus. N. Engl. J. Med. doi: 10.1056/NEJMoa1804988

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