Low-Dose Aspirin for Primary Prevention of Cardiovascular Events in Patients With Type 2 Diabetes Mellitus

Abstract

Background: The long-term efficacy and safety of low-dose aspirin for primary prevention of cardiovascular events in patients with type 2 diabetes mellitus are still inconclusive. Methods: The JPAD trial (Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes) 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 mellitus and without preexisting cardiovascular disease. Patients were randomly allocated to receive aspirin (81 or 100 mg daily; aspirin group) or no aspirin (no-aspirin group) in the JPAD trial. After that trial ended in 2008, we followed up with 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 patients (64%) were followed up throughout the study; and 2160 patients (85%) retained their original allocation. Low-dose aspirin did not reduce cardiovascular events in the per-protocol cohort (hazard ratio, 1.14; 95% confidence interval, 0.91–1.42). 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, 0.83–1.30), with no heterogeneity of efficacy in subgroup analyses stratified by each of these factors (all interaction P >0.05). Sensitivity analyses on the intention-to-treat cohort yielded consistent results (hazard ratio, 1.01; 95% confidence interval, 0.82–1.25). Gastrointestinal bleeding occurred in 25 patients (2%) in the aspirin group and 12 (0.9%) in the no-aspirin group ( P =0.03), and the incidence of hemorrhagic stroke was not different between 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 mellitus in a primary prevention setting. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT00110448.

Pros and Cons of Aspirin for the Primary Prevention of Cardiovascular Events: A Secondary Study of Trial Sequential Analysis

“…Among 1 441 searched articles, we identi ed 26 studies for full-text review, of which 14 studies were eligible for qualitative and quantitative analyses (Appendix Figure S1). The 14 included studies [12][13][14][15][16][17][18][19][20][21][22][23][24][25] encompassed a total of 163 840 patients and used intention-to-treat principles. The detailed study characteristics are summarized in Table 1.…”

“…The detailed study characteristics are summarized in Table 1. Two studies 13,17 were conducted in America, 6 studies were conducted in Europe (5 12,14,18,20,23 in the UK and 1 16 in Italy), 3 studies 19,21,22 were performed in Japan, and 3 studies 15,24,25 were performed in multiple nations. The comparator treatment was a placebo group in 9 studies 13-15, 17, 18, 20, 23-25 and was a no aspirin group in 5 studies.…”

“…Across the included studies, 78 696 (48%) patients were males. Four studies 18,19,22,23 exclusively enrolled diabetic patients (including type I and type II diabetes). The mean BMI of eligible participants was 28.5, and the mean 10-y MACE% was 7.24.…”

“…Deferring the start of long-term aspirin use for primary prevention is a noted alternative that has the main advantage of avoiding an increased risk of slight or major bleeding events but has the disadvantage that the initial manifestation may be a disabling or fatal event. In previous primary prevention trials [12][13][14][15][16][17][18][19][20][21][22][23][24][25] , control populations with non-fatal CVD (non-fatal CHD or non-fatal occlusive stroke) would probably be prescribed long-term aspirin use to avoid recurrence, hence helping to compare the e cacy of immediate versus deferred aspirin use.…”

Ticagrelor Monotherapy in Patients with Concomitant Diabetes Mellitus and Chronic Kidney Disease: A post Hoc Analysis of The GLOBAL LEADERS Trial

“…Platelets can also undoubtedly trigger the onset of arterial thrombosis in response to atherosclerotic plaque rupture [28]. Moreover, although an in vitro study reported that platelet response to aspirin did not differ by diabetes status [29], there are data suggesting a reduction in the cardioprotective bene ts of aspirin in patients with diabetes [30], raising concerns about "aspirin resistance". These observations can be attributed to a number of factors, including increased platelet turnover rates in DM patients, suggesting that alternative aspirin dosing regimens (i.e., twice daily, the ANDAMAN trial, NCT02520921) or formulations be used [31][32][33].…”