ASCEND
Effects of Aspirin for Primary Prevention in Persons with Diabetes Mellitus
Clinical Question
Does low-dose aspirin prevent first cardiovascular events in patients with diabetes without established cardiovascular disease, and does the benefit outweigh the bleeding risk?
Bottom Line
In persons with diabetes and no evident cardiovascular disease, aspirin 100 mg daily significantly reduced serious vascular events (RR 0.88) but caused an offsetting increase in major bleeding (RR 1.29), such that the absolute vascular benefits were largely counterbalanced by the bleeding hazard — routine aspirin for primary prevention in diabetes is not clearly justified.
Major Points
- Aspirin 100 mg daily reduced serious vascular events by 12% (RR 0.88; 95% CI 0.79-0.97; P=0.01) in 15,480 patients with diabetes without cardiovascular disease.
- Aspirin increased major bleeding by 29% (RR 1.29; 95% CI 1.09-1.52; P=0.003), driven mainly by gastrointestinal and other extracranial bleeding.
- Absolute vascular benefits (~1.1 percentage points) were largely counterbalanced by the absolute increase in major bleeding (~0.9 percentage points).
- No significant effect on gastrointestinal tract cancer (2.0% vs 2.0%) or all cancers (11.6% vs 11.5%) at mean 7.4-year follow-up; long-term cancer follow-up planned.
- Findings do not support routine use of aspirin for primary prevention in patients with diabetes.
Design
Study Type: Randomized, double-blind, placebo-controlled trial with 2x2 factorial design (aspirin vs placebo and n-3 fatty acids vs placebo)
Randomization: 1
Blinding: Double-blind (participants and outcome adjudicators unaware of trial-group assignments)
Allocation: Minimized randomization, 1:1 to aspirin 100 mg daily vs matching placebo
Enrollment Period: June 2005 through July 2011
Follow-up Duration: Mean 7.4 years
Centers: 0
Countries: United Kingdom
Sample Size: 15480
Analyzed: 15341
Analysis: Intention-to-treat; log-rank methods for time-to-event analyses; two-tailed P<0.05 considered significant for primary outcomes
Power Calculation: With an event rate of 1.2-1.3% per year, 7.5 years of treatment provided 90% power at P<0.05 to detect a 15% difference in serious vascular events; 60% power to detect a 30% lower risk of GI tract cancer
Registration: ISRCTN60635500; ClinicalTrials.gov NCT00135226
Inclusion Criteria
- Men and women aged ≥40 years
- Diagnosis of diabetes mellitus (any type)
- No known cardiovascular disease
- Substantial uncertainty about whether antiplatelet therapy would confer worthwhile benefit
- Completion of pre-randomization run-in phase with adequate adherence
- Written informed consent
Exclusion Criteria
- Clear indication for aspirin
- Contraindication to aspirin
- Other clinically significant conditions that might limit adherence to trial regimen for at least 5 years
Arms
| Field | Aspirin | Control |
|---|---|---|
| N | 7740 | 7740 |
| Intervention | Enteric-coated aspirin 100 mg once daily | Matching placebo tablet once daily |
| Duration | Mean 7.4 years | Mean 7.4 years |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| First serious vascular event — composite of nonfatal myocardial infarction, nonfatal stroke (excluding confirmed intracranial hemorrhage) or transient ischemic attack, or death from any vascular cause (excluding confirmed intracranial hemorrhage) | Primary | 743 (9.6%) | 658 (8.5%) | 0.88 | 0.01 |
| Gastrointestinal tract cancer | Secondary | 158 (2.0%) | 157 (2.0%) | Not significant | |
| All cancers | Secondary | 887 (11.5%) | 897 (11.6%) | Not significant | |
| First major bleeding event — composite of intracranial hemorrhage, sight-threatening bleeding in the eye, gastrointestinal bleeding, or other serious bleeding (requiring hospitalization/transfusion or fatal) | Safety | 245 (3.2%) | 314 (4.1%) | 1.29 | 0.003 |
Subgroup Analysis
Prespecified subgroup analyses based on baseline 5-year vascular risk categories (<5%, 5-<10%, ≥10%); combined secondary outcome of serious vascular event or revascularization used for subgroup analyses. Detailed subgroup results not provided in the extracted text.
Criticisms
- Adherence to assigned regimen was only ~70% in both groups, with a between-group difference in aspirin/antiplatelet use of only 69 percentage points — potentially diluting the observed treatment effect
- Predominantly white (96.5%) UK population limits generalizability to other ethnic groups and healthcare settings
- High baseline statin use (~75%) reflects contemporary background therapy but may reduce aspirin's relative benefit compared with earlier primary prevention trials
- Modification of the primary outcome during recruitment to include TIA (to increase statistical power) may raise concerns about outcome definition changes
- Cancer outcomes require longer follow-up (5-10 years post-intervention) to assess reliably
Funding
British Heart Foundation (primary funder); aspirin and matching placebo (plus packaging funding) provided by Bayer (Germany); Solvay, Abbott, and Mylan provided n-3 fatty acid and placebo capsules and some packaging funding. Bayer commented on trial design; Bayer and Mylan commented on manuscript draft but had no role in data collection, analysis, interpretation, or the decision to submit.
Based on: ASCEND (New England Journal of Medicine, 2018)
Authors: ASCEND Study Collaborative Group (Bowman L, Mafham M, Wallendszus K, ..., Armitage J)
Citation: N Engl J Med 2018;379:1529-39
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