Low doses of rivaroxaban effectively lower the risk of cardiac events

Comparison of the Efficacy and Safety of Two Rivaroxaban Doses in Acute Coronary Syndrome (from ATLAS ACS 2-TIMI 51)

Literature - Mega JL, Braunwald E, Wiviott SD et al. - Am J Cardiol. 2013 May 24

Mega JL, Braunwald E, Wiviott SD et al.
Am J Cardiol. 2013 May 24. pii: S0002-9149(13)00984-3. doi: 10.1016/j.amjcard.2013.04.011


Disease state and background antiplatelet therapies appear important to determine the dosing of antithrombotic medication. The Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Aspirin With/Without Thienopyridine Therapy in Subjects With Acute Coronary  Syndrome -Thrombolysis In Myocardial Infarction 46 (ATLAS ACS-TIMI 46) trial tested a broad range of rivaroxaban (a factor Xa inhibitor) doses in patients with recent acute coronary syndromes (ACS) treated with antiplatelet therapies [1]. The numerically largest reductions in cardiovascular (CV) events were observed with the lowest rivaroxaban doses, when administered twice daily [1].
In the phase 3 ATLAS ACS 2-TIMI 51 trial, 15526 post-ACS patients received either 2.5 mg or 5 mg rivaroxaban twice daily, as adjunctive therapy [2, 3]. Both doses significantly reduced the primary efficacy endpoint of CV death, myocardial infarction (MI) or stroke [2,3].
This analysis of the randomised, double-blind, placebo-controlled event-driven  ATLAS ACS 2-TIMI 51 trial directly compares rivaroxaban 2.5 mg and 5 mg twice daily.

Main results

  • 26.9% of patients receiving 2.5 mg twice daily and 29.4% of those administered 5 mg twice daily prematurely discontinued rivaroxaban treatment (P=0.004), while 26.4% of patients receiving placebo stopped prematurely.
  • There was no significant difference between rivaroxaban 2.5 mg and 5 mg twice daily with regard to the composite primary endpoint of CV death, MI or stroke (HR: 0.99. 95%CI: 0.85-1.16, P=0.89), nor in the rates of MI (HR: 1.13, 95%CI: 0.93-1.38) or stent thrombosis (P=0.59). No significant difference was seen in the rate of cardiac events in a broad sense (268 events in 2.5 mg group, 256 events in 5 mg group, P=0.68, each significantly lower than in the placebo group (P=0.017 and P=0.005).
  • More fatal new MIs were seen in the 5 mg group (30/174: 17.2%) as compared to the 2.5 mg group (18/204: 8.8%, P=0.074). Overall fatal cardiac events were more common in the 5 mg group (112/256: 43.8%) than in the 2.5 mg group (82/268: 30.6%, P=0.025). Incidence of overall CV death was higher in patients receiving 5 vs 2.5 mg (HR: 0.70, 95%CI: 0.54-0.92, P=0.009).
  • Rate of fatal bleeding were lower in the 2.5 mg-arm than in the 5 mg-arm (HR: 0.39 (95%CI: 0.15-1.01, P=0.044), with the hazard reaching a plateau over time.
  • Fewer TIMI bleeding requiring medical attention was seen in the 2.5 mg-arm than in the 5 mg-arm (12.9% vs. 16.2%, P<0.001).
  • No significant interactions for subgroups of patients receiving different doses of anticoagulant were found. The reduction in bleeding rate seen with the 2.5 mg dose in comparison to the 5 mg dose of rivaroxaban was consistent across the subgroups.


Both low doses of rivaroxaban showed to be effective in reducing cardiac events. 5 mg twice daily showed a relative increase in clinically evident bleeding in patients receiving dual-antiplatelet therapy, as compared to 2.5 mg twice daily. Addition of very low dose anticoagulation with rivaroxaban 2.5 mg twice daily appears to be a more favourable option in patients with recent ACS.


1. Mega JL, Braunwald E, Mohanavelu S, et al. Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial. Lancet 2009;374:29e38.
2. Mega JL, Braunwald E, Wiviott SD, et al. Rivaroxaban in patients with a recent acute coronary syndrome. N EnglJ Med 2012;366:9e19.
3. Gibson CM, Mega JL, Burton P, et al. Rationale and design of the Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects With Acute Coronary Syndrome-Thrombolysis In Myocardial Infarction 51 (ATLAS-ACS 2 TIMI 51) trial: a randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of rivaroxaban in subjects with acute coronary syndrome. Am Heart J 2011;161:815e821.

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