Low-Dose Aspirin for Primary Prevention of Cardiovascular Events in Patients with Type 2 Diabetes: 10-year Follow-up of a Randomized Controlled Trial
Background—The long-term efficacy and safety of low-dose aspirin for primary prevention of cardiovascular events in patients with type 2 diabetes are still inconclusive.
Methods—The Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes (JPAD) trial was a randomized, open-label, standard-care controlled trial examining whether low-dose aspirin affected cardiovascular events in 2539 Japanese patients with type 2 diabetes and without pre-existing cardiovascular disease. Patients were randomly allocated to receive aspirin (81 mg or 100 mg daily, aspirin group) or no aspirin (no-aspirin group) in the JPAD trial. After that the trial ended in 2008, we followed the patients until 2015, with no attempt to change the previously assigned therapy. Primary end points were cardiovascular events, including sudden death, fatal or nonfatal coronary artery disease, fatal or nonfatal stroke, and peripheral vascular disease. For the safety analysis, hemorrhagic events, consisting of gastrointestinal bleeding, hemorrhagic stroke, and bleeding from any other sites, were also analyzed. The primary analysis was conducted for cardiovascular events among patients who retained their original allocation (a per-protocol cohort). Analyses on an intention-to-treat cohort were conducted for hemorrhagic events and statistical sensitivity.
Results—The median follow-up period was 10.3 years, 1621 (64%) patients were followed throughout the study, and 2160 (85%) patients retained their original allocation. Low-dose aspirin did not reduce cardiovascular events in the per-protocol cohort (hazard ratio, 1.14; 95% confidence interval, 0.91 to 1.42). Multivariable Cox proportional hazard model adjusted for age, sex, glycemic control, kidney function, smoking status, hypertension, and dyslipidemia showed similar results (hazard ratio, 1.04; 95% confidence interval, 0.83 to 1.30), with no heterogeneity of efficacy in subgroup analyses stratified by each of these factors (interaction P-values all > 0.05). Sensitivity analyses on the intention-to-treat cohort yielded consistent results (hazard ratio, 1.01; 95% confidence interval, 0.82 to 1.25). Gastrointestinal bleeding occurred in 25 (2%) patients in the aspirin group and 12 (0.9%) in the no-aspirin group (P = 0.03), though the incidence of hemorrhagic stroke was not different between the groups.
Conclusions—Low-dose aspirin did not affect the risk for cardiovascular events, but increased risk for gastrointestinal bleeding in patients with type 2 diabetes in a primary prevention setting.
Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00110448.
- Received October 3, 2016.
- Revision received November 2, 2016.
- Accepted November 4, 2016.