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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, P interaction =0.77) and all-cause mortality (hazard ratio, 0.81, P =0.05; and hazard ratio, 0.84, P =0.09, respectively; P interaction =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 P interaction P interaction =0.02; 2.7% versus 1.7% for major vascular events, P interaction P interaction =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.

OBJECTIVESWe sought to evaluate whether oral anticoagulant (AC) therapy given for five months was superior to standard (control) therapy in patients with unstable angina receiving aspirin.BACKGROUNDThe long-term risk of myocardial infarction (MI) or death remains high in patients with unstable angina, despite the use of aspirin. Therefore, additional treatments are necessary.METHODSOf the 10,141 patients entering the main trial, 3,712 were randomized 12 to 48 h later to receive oral AC therapy (n = 1,848) or standard therapy (n = 1,864).RESULTSOne-hundred forty patients (7.6%) suffered from cardiovascular death, MI or stroke while receiving oral AC, compared with 155 patients (8.3%) on standard therapy (relative risk [RR] 0.90, 95% confidence interval [CI] 0.72 to 1.14; p = 0.40). The rates of the primary outcomes plus refractory angina were 16.7% (n = 308) versus 17.5% (n = 327) (RR 0.95, 95% CI 0.81 to 1.11; p = 0.53). Countries were divided into good or poor compliers (based on the use of oral AC above or below 70% at 35 days), without knowledge of results by country. In good-complier countries, oral AC was discontinued in only 10.4% of patients at seven days and in 23.6% by five months, compared with 27.6% and 44.9%, respectively, in poor complier countries. There were significant reductions in the risks of both the primary (6.1% vs. 8.9%; RR 0.68, 95% CI 0.48 to 0.95; p = 0.02) and secondary outcomes (11.9% vs. 16.5%; RR 0.70, 95% CI 0.55 to 0.90; p = 0.005) with oral AC in the good-complier countries. There was little difference in the poor-complier countries (9.0% vs. 7.8% for the primary and 21.3% vs. 18.5% for the secondary outcomes, tests for interactions comparing the RRs for the primary and secondary outcomes were p < 0.02 and p = 0.002, respectively, between the two sets of countries). In the overall study, there was an excess of major bleeding (2.7% vs. 1.3%; p = 0.004), which was larger in the good-complier countries (RR 2.71) compared with the poor-complier countries (RR 1.58). There were also reductions in cardiac catheterization (RR 0.80; p = 0.004) and coronary revascularization procedures (RR 0.82; p = 0.06) in the good-complier countries, but not in the poor-complier countries (RR 0.98 and 1.06, respectively, p for interaction of 0.06 and 0.04, respectively).CONCLUSIONSOverall, oral AC led to a small, nonsignificant reduction in the risk of the primary and secondary outcomes. Stratifying the countries or centers by their rates of compliance to oral AC suggested that good compliance to oral AC could potentially lead to clinically important reductions in major ischemic cardiovascular events.

Background Other than aspirin, there are few oral antithrombotic treatments with proven efficacy in patients with acute coronary syndrome. In this report, we present the rationale, design and baseline characteristics of the Clopidogrel in Unstable angina to prevent Recurrent ischaemic Events (CURE) trial, which includes a meta-analysis of the effects of thienopyridines in patients with vascular disease. Methods and Results Combined data from randomized trials of thienopyrindines in patients with atherosclerotic disease demonstrated a 29% reduction in vascular events when compared with placebo/control (n=2392) (OR 0.71, 95% CI 0.58-0.86, P=0.0006) and a 10% reduction in vascular events when compared with aspirin (n=22 254) (OR 0.91, 95% Cl 0.84-0.99, P=0.039). Similarly, randomized trials of aspirin plus thienopyridines in patients undergoing intracoronary stenting, demonstrated marked benefit of aspirin plus ticlopidine in reducing death or myocardial infarction compared with aspirin alone (OR 0.23, 95% CI 0.11-0.49, P=0.0001) or aspirin plus warfarin (OR 0.51, 95% CI 0.33-0.78, P=0.002). Whether these benefits extend to the much larger population of patients with acute coronary syndrome is unknown. CURE is an international, randomized, double-blind trial, in which patients with acute coronary syndrome will be randomized to receive either a bolus dose of clopidogrel (300 mg) followed by 75 mg per day for 3-12 months, or matching placebo. Both groups will receive aspirin. The co-primary efficacy end-points of CURE are: (1) the composite of cardiovascular death, myocardial infarction or stroke; and (2) the composite of cardiovascular death, myocardial infarction, stroke or refractory ischaemia. CURE will recruit approximately 12 500 patients with acute coronary syndrome (from 28 countries) and its power to detect moderate treatment benefits will be in the region of 80-90%, while maintaining an overall type I error (a) of 0.05. The baseline characteristics of the study population are consistent with at least a moderate risk group of patients with acute coronary syndrome. Conclusions Randomized trials of thienopyridines in patients with vascular disease demonstrate that thienopyridines are effective in reducing vascular events when compared with placebo/control or aspirin, as well as when used in combination with aspirin in patients undergoing intracoronary stent implantation. The CURE trial is a large international study to determine if acute and longterm treatment with the combination of clopidogrel and aspirin is superior to aspirin alone in patients with acute coronary syndrome. (C) 2000 The European Society of Cardiology.