Trial Conduct

The COMPASS trial, conducted at 602 centers in 33 countries, is a double-blind, double-dummy, randomized trial using a 3-by-2 partial factorial design and involving patients with a history of stable atherosclerotic vascular disease.9 In one randomized comparison (now completed and reported here), rivaroxaban with or without aspirin was compared with aspirin alone. In the other randomized comparison (still ongoing), pantoprazole is being compared with placebo in patients participating in the trial who are not receiving a proton-pump inhibitor. For an overview of the study design, see Table S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org.

The trial sponsor is Bayer. The steering committee, comprising Population Health Research Institute (PHRI) investigators, study leaders in each country, and Bayer representatives, was responsible for the development of the protocol, which is available at NEJM.org, and for the conduct and oversight of the study. The protocol was approved by the relevant health authorities and institutional review boards. A list of participating investigators and committee members is provided in the Supplementary Appendix. All the data analyses were independently performed at PHRI. The first author vouches for the completeness and accuracy of the data and analyses and for the fidelity of the trial to the protocol.

Eligibility

Patients were eligible if they provided written informed consent and met the criteria for coronary artery disease, peripheral arterial disease, or both (see the Supplementary Appendix). Patients with coronary artery disease who were younger than 65 years of age were also required to have documentation of atherosclerosis involving at least two vascular beds or to have at least two additional risk factors (current smoking, diabetes mellitus, an estimated glomerular filtration rate [GFR] <60 ml per minute, heart failure, or nonlacunar ischemic stroke ≥1 month earlier). Exclusion criteria were a high bleeding risk; a recent stroke or previous hemorrhagic or lacunar stroke; severe heart failure; advanced stable kidney disease (estimated GFR <15 ml per minute); the use of dual antiplatelet therapy, anticoagulation, or other antithrombotic therapy; and noncardiovascular conditions deemed by the investigator to be associated with a poor prognosis. In addition, patients receiving a proton-pump inhibitor were not eligible for the pantoprazole randomization. Written informed consent was obtained from all the participants.

Randomization and Follow-up

Eligible participants (except those who underwent randomization 4 to 14 days after coronary-artery bypass graft [CABG] surgery) entered a run-in phase during which they received a rivaroxaban-matched placebo twice daily and aspirin at a dose of 100 mg once daily. The purpose of the run-in phase was to identify participants who were unwilling or unable to adhere to the trial regimen, who had adverse events, or who were otherwise not suitable for randomization. Patients who underwent randomization 4 to 14 days after CABG surgery were not required to participate in the run-in phase because thrombotic graft occlusion is most common during the first few weeks after surgery and we sought to enroll such patients promptly.

Participants who adhered to the assigned regimen and who did not have adverse events, as well as those enrolled 4 to 14 days after CABG surgery, were randomly assigned in a 1:1:1 ratio to receive rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg once daily), rivaroxaban (5 mg twice daily) with an aspirin-matched placebo once daily, or aspirin (100 mg once daily) with a rivaroxaban-matched placebo twice daily, stratified according to center and the use of proton-pump inhibitor therapy at the time of randomization. Study aspirin was enteric-coated. Patients who were eligible for the proton-pump inhibitor randomization were also randomly assigned in a 1:1 ratio to receive pantoprazole (40 mg once daily) or matched placebo. After randomization, participants were seen at 1 and 6 months and then at 6-month intervals.

Outcomes

The primary efficacy outcome for the randomized comparison of rivaroxaban with or without aspirin versus aspirin alone was the composite of cardiovascular death, stroke, or myocardial infarction. The main safety outcome was a modification of the International Society on Thrombosis and Haemostasis (ISTH) criteria for major bleeding and included fatal bleeding, symptomatic bleeding into a critical organ, bleeding into a surgical site requiring reoperation, and bleeding that led to hospitalization (including presentation to an acute care facility without an overnight stay). Unlike the ISTH criteria,10 we considered all bleeding that led to presentation to an acute care facility or hospitalization as major.

Three secondary efficacy outcomes were specified: the composite of ischemic stroke, myocardial infarction, acute limb ischemia, or death from coronary heart disease; the composite of ischemic stroke, myocardial infarction, acute limb ischemia, or cardiovascular death; and death from any cause. Tertiary efficacy outcomes included individual components of the primary and secondary outcomes, as well as hospitalization for cardiovascular causes, revascularization, limb amputation, stent thrombosis, angina, heart failure, venous thromboembolism, resuscitated cardiac arrest, and a new diagnosis of cancer. The net-clinical-benefit outcome was the composite of cardiovascular death, stroke, myocardial infarction, fatal bleeding, or symptomatic bleeding into a critical organ. The main outcome for the pantoprazole versus placebo randomization was upper gastrointestinal complications.9 Event definitions and a full list of prespecified events included in this report are provided in the Supplementary Appendix.

Statistical Analysis

We planned on enrolling 27,400 participants. As an event-driven trial, with an expected control-group event rate of 3.3 per 100 person-years, it was designed to continue until at least 2200 participants had a confirmed primary efficacy outcome, thereby providing 90% power to detect a 20% lower risk in each of the two comparisons of rivaroxaban versus aspirin.

An independent data and safety monitoring board monitored the study, with formal stopping guidelines for efficacy and nonformal guidelines for safety. Two formal interim analyses of efficacy were planned, when 50% and 75% of primary efficacy events had occurred. A modified Haybittle–Peto rule was used, which required a difference of 4 SD at the first interim analysis that was consistent over a period of 3 months, and a consistent difference of 3 SD at the second interim analysis (see the Supplementary Appendix).

All the outcome events in all randomly assigned patients that occurred between randomization and the date of stopping the trial were included in the analysis, according to the intention-to-treat principle. Comparisons between each of the rivaroxaban-based groups and the common aspirin control group were performed with the use of two separate log-rank tests stratified according to treatment with a proton-pump inhibitor (not randomly assigned to a proton-pump inhibitor, pantoprazole at a dose of 40 mg once daily, or a pantoprazole-matched placebo once daily). To address multiplicity related to testing two primary and six secondary hypotheses, we planned to use a mixture gatekeeping procedure based on the Hochberg test to control the familywise error rate of 5%11 (see the Supplementary Appendix). However, an early stop of both antithrombotic treatment groups for efficacy had not been anticipated, and therefore a strategy for formal testing of secondary outcomes at the interim analysis was not prespecified.

Kaplan–Meier estimates of the cumulative risk were used to evaluate the timing of event occurrences in the three antithrombotic treatment groups. Hazard ratios and corresponding 95% confidence intervals were obtained from stratified Cox proportional-hazards models. The assumptions of the Cox models were verified with plots of log of negative log of the survival function against the log of time. All reported P values are two-sided.