Aspirin and Primary Prevention in Patients with Diabetes—A Critical Evaluation of Available Randomized Trials and Meta-Analyses

Abstract

Primary prevention of cardiovascular events with aspirin in patients with elevated cardiovascular risk, including diabetics, is currently under intense discussion. Data from meta-analyses suggests that the efficacy of aspirin in these patients is low, whereas there is a significantly increased bleeding tendency. However, meta-analyses are based on trials that differ in many important aspects, including study selection. Fresh insights were expected from the ASCEND trial, by far the largest primary, randomized, placebo-controlled prevention trial in diabetics without known cardiovascular disease. There was a small but significant reduction in serious cardiovascular events by aspirin (8.6% vs. 9.6%) but also a significant increase in major bleeding: 4.1% versus 3.2%. Unfortunately, this trial did not meet the desired annual rate of elevated vascular risk of ≥ 2%. It was only 1.2 to 1.3%, and thus in the range of other primary prevention trials in low-risk patients. Apart from potential compliance problems, possible explanations for the small cardioprotective effect of antiplatelet treatment include a healthy lifestyle as well as improved vascular protection by comedication with vasoactive and anti-inflammatory drugs, such as statins or antihypertensive agents, as well as proton-pump inhibitors that might modify bleeding, specifically in the upper gastrointestinal tract—the most frequently affected site. Also, the introduction of new antidiabetic drugs with more favorable cardiovascular effects may in part explain the low event rate. ASCEND, similar to ARRIVE, did not study patients at elevated (as planned) but only at low vascular risk and, therefore, was largely confirmatory of earlier primary prevention trials.

Aspirin for Primary and Secondary Prevention of Cardiovascular Disease: Time to Stop?

“…2 This will cause much dismay to those with a dogmatic belief in aspirin's benefits but, perhaps, much rejoicing amongst patients who have one less pill thrust upon them. 3 4 5 The failure of aspirin for primary prevention should now lead to a re-examination of the evidence for aspirin for secondary prevention. 1 6 7 8 9 10 11…”

“…2 This will cause much dismay to those with a dogmatic belief in aspirin's benefits but, perhaps, much rejoicing amongst patients who have one less pill thrust upon them. [3][4][5] The failure of aspirin for primary prevention should now lead to a re-examination of the evidence for aspirin for secondary prevention. 1,[6][7][8][9][10][11] Calderone et al 12 provide an updated meta-analysis of 21 randomized trials of aspirin for the primary prevention of cardiovascular events, including 173,810 patients and almost one million patient-years of follow-up.…”

Platelets: The Balance between Aggregation and Bleeding

“…First, the role of antiplatelet therapy in primary prevention of cardiovascular disease in a healthy but high-risk growing population: the diabetics. 7 Combining antiplatelet and anticoagulant therapy is the next topic, when dual or single antiplatelet therapy is combined in high-risk patients with stable coronary artery disease. 8 Implantation of devices is now current practice in cardiology.…”

Contemporary Clinical Use of Aspirin: Mechanisms of Action, Current Concepts, Unresolved Questions, and Future Perspectives

“…[40][41][42] Meta-analyses including all four trials did not support routine use of aspirin as primary prophylaxis in patients with diabetes. 7,43 As the pendulum moves away from aspirin for primary prophylaxis, the debate continues. It has been emphasized that the 2018 trials summarized earlier had relatively short follow-up time of approximately 5 to 8 years and high degree of crossover between treatment groups, thus resulting in only 60 to 70% compliance.…”