ATLAS ACS 2-TIMI 51

Anti-Xa Therapy to Lower cardiovascular events in addition to Aspirin with or without thienopyridine therapy in Subjects with Acute Coronary Syndrome 2 – Thrombolysis in Myocardial Infarction 51 Trial (2011)

Condition

Prevention of ACS in patients who are treated with ASA and a thienopyridine, given at their physician’s discretion

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Objective

To investigate, if rivaroxaban, when added to standard care, is safe and reduces the risk of the composite of cardiovascular death, myocardial infarction, or stroke in patients with ACS compared to placebo

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Trial design

Randomized placebo-controlled event-driven phase III study, comparing two doses of rivaroxaban with placebo in a 1:1:1 fashion
Active treatment:

  • Stratum 1 (patients receiving ASA alone): rivaroxaban 2.5 or 5 mg p.o. twice daily for at least 6 months
  • Stratum 2 (patients receiving ASA plus clopidogrel): rivaroxaban 2.5 or 5 mg p.o. twice daily for at least 6 months

Control treatment: stratum 1 and stratum 2: placebo for at least 6 months

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Endpoints

Primary efficacy endpoint: composite of death from cardiovascular causes, myocardial infarction, or stroke (ischemic, hemorrhagic, or stroke of uncertain cause)
Secondary efficacy endpoint: death from any cause, myocardial infarction, or stroke
Primary safety endpoint: TIMI major bleeding events not associated with CABG surgery
Secondary safety endpoints: other bleeding events, serious adverse events

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Trial participants

15,526 patients ≥18 years of age with recent ACS in stabilized condition were included 1–7 days post index event. 5174 of the patients were randomly assigned to receive the 2.5-mg dose of rivaroxaban, 5176 to receive the 5-mg dose of rivaroxaban, and 5176 to receive placebo

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Results

Efficacy outcome: The primary efficacy endpoint occured in 8.9% of all patients treated with rivaroxaban (n=10,229) and in 10.7% of all patients assigned to receive placebo (n=5113) (RRR 16% for the combined rivaroxaban groups; p=0.008). Each of the doses reduced the risk of cardiovascular death, myocardial infarction, or stroke, as compared with placebo, with rates in patients receiving the 2.5-mg dose of 9.1% vs. 10.7% (RRR 16%; p=0.02) and rates in patients receiving the 5-mg dose of 8.8% vs. 10.7% (RRR 15%; p=0.03). The twice-daily 2.5-mg dose of rivaroxaban reduced the rates of death from cardiovascular causes (2.7% vs. 4.1%, p=0.002) and from any cause (2.9% vs. 4.5%, p=0.002). This survival benefit was not seen with the twice-daily 5-mg dose
Safety outcome: Rivaroxaban increased the rates of major bleeding not related to CABG (2.1% vs. 0.6%; p<0.001) and intracranial hemorrhage (0.6% vs. 0.2%, p=0.009), without a significant increase in fatal bleeding (0.3% vs. 0.2%, p=0.66), a finding that was also significant for the 2.5-mg and 5-mg doses of rivaroxaban (p<0.001 for both comparisons). The twice-daily 2.5-mg dose resulted in fewer fatal bleeding events than the twice-daily 5-mg dose (0.1% vs. 0.4%, p=0.04). The rates of adverse events that were not related to bleeding were similar in the rivaroxaban and placebo groups

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Summary

Efficacy outcome: Added to standard medical treatment, both doses of the oral factor Xa inhibitor rivaroxaban reduced the risk of the composite end point of death from cardiovascular causes, myocardial infarction, or stroke in patients with a recent acute coronary syndrome, as compared with placebo
Safety outcome: The overall results showed a threefold increase in major bleeding and intracranial hemorrhage but no significant increase in fatal bleeding with rivaroxaban. The 2.5-mg twice-daily dose had the better benefit/risk balance, due to a lower bleeding risk than the 5-mg twice-daily dose

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Reference

(1) Gibson CM, Mega JL, Burton P, Goto, S, Verheugt F, Bode C, Plotnikov A, Sun X, Cook-Bruns N, Braunwald E. 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;161:815-821
(2) Mega JL, Braunwald E, Wiviott SD, Bassand JP, Bhatt DL, Bode C, Burton P, Cohen M, Cook-Bruns N, Fox KA, Goto S, Murphy SA, Plotnikov AN, Schneider D, Sun X, Verheugt FW, Gibson CM, for the ATLAS ACS 2-TIMI 51 Investigators. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med 2012;366:9-19

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Corresponding author

Jessica L. Mega, MD, MPH, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, 75 Francis St., Boston, MA 02115, e-mail: jmega@partners.org.

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