N Engl J Med 2012;366:9-19Background Following an acute coronary syndrome, individuals have a substantially elevated risk of recurrent events, compared to a similar individual who did not experience ACS, despite the use of appropriate risk reducing therapies. This is termed “residual risk” and the concept has been mentioned in prior reviews. The quest to lower residual risk continues to be a major driver of new products and therapeutic concepts in cardiovascular medicine.Rivaroxaban is an oral anticoagulant that directly and selectively inhibits factor Xa. Factor Xa initiates the final common pathway of the coagulation cascade resulting in the formation of thrombin. Thrombin promotes platelet aggregation. At the time the trial was undertaken, both aspirin and thienopyridines were established agents that worked via different mechanisms, downstream of thrombin formation, to stop platelets from sticking together. Could the addition of an agent that inhibits thrombin formation, upstream of platelet activation and aggregation, reduce risk further without causing a prohibitive increase in bleeding risk?A meta-analysis of small trials involving the use of warfarin, in addition to aspirin, suggested that warfarin, an indirect inhibitor of thrombin, could improve cardiovascular outcomes. And a phase 2 dose finding trial with rivaroxaban provided further support. Thus, the ATLAS ACS-TIMI 51 trial sought to test the hypothesis that adding rivaroxaban to standard therapies, at 2.5 or 5 mg twice daily, would reduce cardiovascular events compared to placebo.Cardiology Trial’s Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber.Patients Adults who had presented with an acute coronary syndrome (STEMI, NSTEMI or unstable angina). Patients under 55 years of age had to have either diabetes or a history of a previous MI. Patients were excluded if they had a platelet count <90k, hemoglobin <10g/dl, creatinine clearance <30 ml/min, clinically significant GI bleed within 12 months, previous intracranial hemorrhage or previous stroke or TIA.Baseline characteristics Patients averaged 62 years of age with 36% greater than or equal to 65 and only 9% greater than or equal to 75. The majority of patients were either white (73%) or Asian (21%). Existing medical conditions were typical for an ACS population. The index diagnosis was a STEMI in 50% with the other half split fairly evenly between NSTEMI and UA. The majority of patients enrolled were from Eastern Europe (39%) and Asia (21%). Nearly all patients were on aspirin (99%) and a thienopyridine (93%) and 83% were on a statin drug.Procedures Patients were enrolled within 7 days after hospital admission for an ACS. They had to be stable at the time of enrollment with the initial revascularization strategies completed. They were randomly assigned in a 1:1:1 fashion to twice daily rivaroxaban 2.5 mg, rivaroxaban 5 mg or placebo with a maximum follow-up of 31 months. All patients were to receive standard medical therapy. Patient follow-up occurred at 4 weeks, 12 weeks and every 12 weeks thereafter.Endpoints The primary endpoint was a composite of death from cardiovascular causes, myocardial infarction, or stroke (ischemic, hemorrhagic, or stroke of uncertain cause). The primary safety endpoint was TIMI major bleeding not related to CABG surgery.As prespecified by the investigators, the efficacy analyses were performed with the use of a modified intention-to-treat principle; however, they performed sensitivity efficacy analyses using a standard intention-to-treat approach. *Since the statistical significance of the main findings did not meaningfully change with either approach, we report the p-values based on the standard approach since using a modified approach is unconventional.The investigators determined they would need 983 primary endpoint events to provide a power of 96% to detect a 22.5% relative reduction between the comb