Trial Oversight

ASCEND was designed and conducted by independent investigators in the Clinical Trial Service Unit at the University of Oxford (the regulatory trial sponsor). The trial methods, characteristics of the participants, and data analysis plan (including outcome definitions) have been reported previously.15,16 The protocol (available with the full text of this article at NEJM.org) was approved by the North West Multicenter Research Ethics Committee. The trial was funded by the British Heart Foundation. The aspirin and matching placebo (along with funding for packaging) were provided by Bayer (Germany), and Solvay, Abbott, and Mylan provided the n−3 fatty acid and placebo capsules and some funding for packaging. Bayer (Germany) commented on the design of the trial, and both Bayer and Mylan commented on the draft of the manuscript but had no part in the collection, handling, analysis, or interpretation of the data or in the decision to submit the manuscript for publication. The manuscript was prepared by the writing committee and reviewed and approved for submission for publication by the steering committee. The first and last members of the writing committee vouch for the accuracy and completeness of the data and analyses and for the fidelity of the trial to the protocol and the data analysis plan.

Data Sharing

Deidentified data about the individual participants are to be shared with the Antithrombotic Trialists’ Collaboration for meta-analysis. Requests for data sharing will be handled in line with the data access and sharing policy of the Nuffield Department of Population Health, University of Oxford (www.ndph.ox.ac.uk/about/data-access-policy).

Participants

Men and women at least 40 years of age were considered to be eligible if they had received a diagnosis of diabetes mellitus (any type) and did not have known cardiovascular disease and if there was substantial uncertainty about whether antiplatelet therapy would confer worthwhile benefit. Key exclusion criteria were a clear indication for aspirin or a contraindication to aspirin or the presence of other clinically significant conditions that might limit adherence to the trial regimen for at least 5 years. All the participants provided written informed consent.

Procedures

Potential participants were identified from regional diabetes registers or general practices from around the United Kingdom and were sent a screening questionnaire. Those who returned the questionnaire indicating that they were willing and eligible to participate entered a prerandomization run-in phase, during which placebo aspirin (and placebo n−3 fatty acids) was supplied. Their family doctor was informed of their potential participation, and they were sent a kit to obtain blood and urine samples and to record blood pressure, height, and weight. After this run-in period of 8 to 10 weeks, participants remained eligible if they returned a randomization questionnaire confirming their willingness to continue, they still met the eligibility criteria, and they had adhered to the trial regimen.

Using minimized randomization, we then assigned eligible participants to receive 100 mg of aspirin once daily or a matching placebo tablet16; participants were also assigned to receive 1-g capsules containing n−3 fatty acid once daily or a matching placebo capsule. The participants were then mailed a 6-month supply of aspirin or placebo tablets and n−3 fatty acids or placebo capsules, as appropriate.

After randomization, we sent follow-up questionnaires and appropriate tablets and capsules to participants every 6 months until the end of the trial. In these questionnaires, we sought information regarding all serious adverse events (including potential trial outcomes), adherence to the trial regimen, use of nontrial antiplatelet or anticoagulant therapy, nonserious adverse events resulting in discontinuation of the trial regimen, and any symptomatic bleeding episodes for which patients saw a doctor. After a mean follow-up of 2.5 years, we requested blood and urine samples, along with measures of blood pressure and weight, from 1800 randomly selected participants. (Details are provided in the Methods section in Supplementary Appendix 1, available at NEJM.org.)

Outcomes

While recruitment was still ongoing, we modified the original primary outcome to include transient ischemic attack in the definition of serious vascular event, a change that was made to increase the statistical power of the trial. Thus, the prespecified primary efficacy outcome was the first serious vascular event, which was defined as a 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). The primary safety outcome was the first occurrence of any major bleeding event, which was defined as a composite of any confirmed intracranial hemorrhage, sight-threatening bleeding event in the eye, gastrointestinal bleeding, or any other serious bleeding (i.e., a bleeding event that resulted in hospitalization or transfusion or that was fatal). Secondary outcomes were gastrointestinal tract cancer (overall and excluding those occurring during the first 3 years of follow-up) and the composite of any serious vascular event or any arterial revascularization procedure.

All the reports of possible primary or secondary outcomes were adjudicated centrally by clinicians who were unaware of the trial-group assignments in accordance with prespecified definitions. The data analysis plan prespecified that analyses would be based on all the confirmed events plus unrefuted events (see the Methods section in Supplementary Appendix 1).

Statistical Analysis

The data analysis plan was finalized by the steering committee and was published16 while all the members were still unaware of the trial results according to group assignment (except for the statistician, who was aware of these assignments and who was not involved in development of the data analysis plan). In addition to revising the definition of serious vascular events to include transient ischemic attack, the sample was increased to at least 15,000 participants and the duration of follow-up was increased to at least 7 years to increase the power of the trial. (Details are provided in the Methods section in Supplementary Appendix 1.)

On the basis of an event rate of 1.2 to 1.3% per year, as observed in both groups combined when recruitment was complete, we determined that 7.5 years of the scheduled trial regimen would provide the trial with 90% power, at a P value of less than 0.05, to detect a 15% difference between the treatment groups in the risk of a serious vascular event. The expected number of gastrointestinal tract cancers was estimated to provide the trial with 60% power to detect a 30% lower risk in the aspirin group than in the placebo group during this period, but the prespecified focus for assessing the effects on cancer is 5 and 10 years after the end of the scheduled intervention phase.

We used log-rank methods to conduct intention-to-treat comparisons in time-to-event analyses of the first occurrence of each type of event of interest among participants in the aspirin group as compared with those in the placebo group.17,18 A two-tailed P value of less than 0.05 was considered to indicate statistical significance for the primary efficacy and safety outcomes. It was prespecified that the combined secondary outcome of serious vascular event or revascularization would be used for any subgroup analyses. We made allowance for multiple hypothesis testing in the interpretation of secondary and exploratory outcomes, with no formal adjustment to the P values. Consequently, the results are reported as point estimates and 95% confidence intervals that have not been adjusted for multiple comparisons, so the confidence intervals should not be used to infer definitive treatment effects within subgroups or with regard to secondary outcomes.

The baseline 5-year risk of vascular events among participants was categorized into three groups — less than 5%, 5% to less than 10%, and 10% or more — with the use of a risk score that had been developed with the use of Poisson regression. Details regarding this and other secondary and exploratory assessments are provided in the data analysis plan16 and in Supplementary Appendix 1. The Clinical Trial Service Unit at the University of Oxford holds the full database and performed all the analyses.