IMPORTANCE: In the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial, there was a significant reduction in the adjudicated primary outcome among patients with stable atherosclerotic vascular disease randomized to dual pathway inhibition (rivaroxaban 2.5 mg twice daily plus aspirin 100 mg daily) vs aspirin monotherapy, but not with rivaroxaban 5 mg twice daily vs aspirin monotherapy. Whether the results are similar without adjudication is unknown. OBJECTIVE: To examine the impact of dual pathway inhibition (with rivaroxaban plus aspirin) or rivaroxaban monotherapy compared with aspirin monotherapy on investigator-reported CV events and to understand the extent of concordance between investigator-reported and centrally adjudicated clinical events. DESIGN, SETTING, AND PARTICIPANTS: This is a secondary analysis of the COMPASS trial, an international, double-blind, double-dummy, randomized clinical trial with a 3-by-2 partial factorial design that evaluated participants with stable atherosclerotic vascular disease receiving rivaroxaban plus aspirin, rivaroxaban monotherapy, or aspirin monotherapy. End points were collected by blinded site investigators and adjudicated by a blinded clinical end point committee. Data were analyzed from March 2013 through February 2017. INTERVENTIONS: Participants received dual inhibition pathway (2.5 mg rivaroxaban twice daily plus 100 mg aspirin once daily), rivaroxaban monotherapy (5 mg twice daily), or aspirin monotherapy (100 mg once daily). MAIN OUTCOMES AND MEASURES: The primary efficacy outcome was a composite of cardiovascular (CV) death, stroke, or myocardial infarction (MI). Adjudicated and investigator-reported end points were compared. RESULTS: A total of 27 395 patients (mean [SD] age, 68.2 [7.9] years; 78.0% men) were assessed, including 9152 patients randomized to dual pathway inhibition, 9117 patients randomized to rivaroxaban monotherapy, and 9126 patients randomized to aspirin monotherapy. Adjudication reduced the number of events by 10% to 15% for most end points. Among investigator-reported end points, dual pathway inhibition significantly reduced the rate of the primary efficacy outcome compared with aspirin alone (411 patients [4.5%] vs 542 patients [5.9%]; hazard ratio [HR], 0.75 [95% CI, 0.66-0.85]; P < .001), with similar reduction in adjudicated end points, (379 patients [4.1%] vs 496 patients [5.4%]; HR, 0.76 [95% CI, 0.66-0.86]; P < .001). Likewise, effects on ischemic end points were highly concordant (κ statistic = 0.94 [95% CI, 0.93-0.95] for the primary composite end point). Unlike with adjudicated outcomes, there was a significant reduction in the primary end point with rivaroxaban monotherapy vs aspirin monotherapy using investigator-reported events (477 patients [5.2%] vs 542 patients [5.9%]; HR, 0.88 [95% CI, 0.78-0.99]; P = .04) compared with adjudicated events (448 patients [4.9%] vs 496 patients [5.4%]; HR, 0.90 [95% CI, 0.79-1.03]; P = .12). CONCLUSIONS AND RELEVANCE: This secondary analysis of the COMPASS trial found that whether assessed by blinded site investigators or adjudicators, dual pathway inhibition significantly reduced CV events among patients with stable atherosclerotic disease compared with aspirin plus placebo. These findings suggest that using investigator-reported events in blinded clinical trials may be a more efficient alternative to adjudication. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01776424.

• MeSH
• Aspirin MeSH
• Atherosclerosis * drug therapy   MeSH
• Stroke * drug therapy   MeSH
• Myocardial Infarction * epidemiology   prevention & control   chemically induced   MeSH
• Drug Therapy, Combination MeSH
• Humans MeSH
• Rivaroxaban therapeutic use   MeSH
• Aged MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Randomized Controlled Trial MeSH

BACKGROUND: Patients with established coronary artery disease or peripheral artery disease often have diabetes mellitus. These patients are at high risk of future vascular events. METHODS: In a prespecified analysis of the COMPASS trial (Cardiovascular Outcomes for People Using Anticoagulation Strategies), we compared the effects of rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg daily) versus placebo plus aspirin in patients with diabetes mellitus versus without diabetes mellitus in preventing major vascular events. The primary efficacy end point was the composite of cardiovascular death, myocardial infarction, or stroke. Secondary end points included all-cause mortality and all major vascular events (cardiovascular death, myocardial infarction, stroke, or major adverse limb events, including amputation). The primary safety end point was a modification of the International Society on Thrombosis and Haemostasis criteria for major bleeding. RESULTS: There were 10 341 patients with diabetes mellitus and 17 054 without diabetes mellitus in the overall trial. A consistent and similar relative risk reduction was seen for benefit of rivaroxaban plus aspirin (n=9152) versus placebo plus aspirin (n=9126) in patients both with (n=6922) and without (n=11 356) diabetes mellitus for the primary efficacy end point (hazard ratio, 0.74, P=0.002; and hazard ratio, 0.77, P=0.005, respectively, Pinteraction=0.77) and all-cause mortality (hazard ratio, 0.81, P=0.05; and hazard ratio, 0.84, P=0.09, respectively; Pinteraction=0.82). However, although the absolute risk reductions appeared numerically larger in patients with versus without diabetes mellitus, both subgroups derived similar benefit (2.3% versus 1.4% for the primary efficacy end point at 3 years, Gail-Simon qualitative Pinteraction<0.0001; 1.9% versus 0.6% for all-cause mortality, Pinteraction=0.02; 2.7% versus 1.7% for major vascular events, Pinteraction<0.0001). Because the bleeding hazards were similar among patients with and without diabetes mellitus, the prespecified net benefit for rivaroxaban appeared particularly favorable in the patients with diabetes mellitus (2.7% versus 1.0%; Gail-Simon qualitative Pinteraction=0.001). CONCLUSIONS: In stable atherosclerosis, the combination of aspirin plus rivaroxaban 2.5 mg twice daily provided a similar relative degree of benefit on coronary, cerebrovascular, and peripheral end points in patients with and without diabetes mellitus. Given their higher baseline risk, the absolute benefits appeared larger in those with diabetes mellitus, including a 3-fold greater reduction in all-cause mortality. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01776424.

• MeSH
• Anticoagulants administration & dosage   MeSH
• Aspirin administration & dosage   MeSH
• Diabetes Mellitus blood   drug therapy   epidemiology   MeSH
• Double-Blind Method MeSH
• Platelet Aggregation Inhibitors administration & dosage   MeSH
• Factor Xa Inhibitors MeSH
• Cardiovascular Diseases blood   drug therapy   epidemiology   MeSH
• Drug Therapy, Combination MeSH
• Middle Aged MeSH
• Humans MeSH
• Rivaroxaban administration & dosage   MeSH
• Aged MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Research Support, Non-U.S. Gov't MeSH
• Randomized Controlled Trial MeSH
• Comparative Study MeSH