ATLAS ACS-TIMI 46

Anti-Xa Therapy to Lower cardiovascular events in addition to Aspirin with or without thienopyridine therapy in Subjects with Acute Coronary Syndrome – Thrombolysis in Myocardial Infarction 46 Trial (2009)

Condition

Antithrombotic therapy in patients with recent ACS 

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Objective

Primary goal: to assess the safety and efficacy of rivaroxaban in patients after an ACS and to select the most favorable dose and dosing regimen for a phase III trial
Secondary goal: to explore efficacy of rivaroxaban at tolerable doses 

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Trial design

Phase II dose ranging study
Active treatment: 

  • Stratum 1 (patients receiving ASA alone; n=761): rivaroxaban in doses of 5, 10 and 20 mg p.o. once daily (n=254), or 2.5, 5 and 10 mg twice daily (n=254) for 6 months
  • Stratum 2 (patients receiving ASA plus clopidogrel; n=2730): rivaroxaban in doses of 5, 10, 15 and 20 mg p.o. once daily (n=912), or 2.5, 5, 7.5 and 10 mg twice daily (n=911) for 6 months

Control treatment: placebo for 6 months (stratum 1: n=253, stratum 2: n=907)

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Endpoints

Primary safety endpoint: clinically significant bleeding (major, minor bleeding and bleeding requiring medical attention)
Secondary safety endpoints: adverse events, abnormal laboratory para­meters
Primary efficacy endpoint: composite of death, myocardial infarction, stroke or severe recurring ischemia requiring revascularisation
Secondary efficacy endpoint: composite of death, myocardial infarction, stroke

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Trial participants

3491 patients with recent ACS in stabilized condition, 1–7 days post index event 

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Results

Safety outcome: Clinically significant bleeding up to 6 months occurred in 6.1% of the patients receiving a total daily dose of 5 mg rivaroxaban, 10.9% receiving 10 mg, 12.7% receiving 15 mg and 15.3% receiving 20 mg, compared to 3.3% in the placebo group. Bleeding events were more frequent in stratum 2. There were no significant differences in liver function abnormalities
Efficacy outcome: The primary efficacy endpoint occurred in 5.6% of all patients given rivaroxaban (n=2331) and in 7.0% of all patients given placebo (n=1160). The secondary efficacy endpoint occurred in 3.9% of the rivaroxaban and in 5.5% of the placebo patients

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Summary

Safety: 

  • Most bleeding was bleeding requiring medical attention
  • Increased bleeding rates were observed with higher doses of rivaroxaban
  • Twice daily dosing appeared slightly safer 
  • No evidence of drug induced liver injury

Efficacy: 

  • Rivaroxaban numerically reduced the risk of death, myocardial infarction, stroke or severe recurrent ischemia (primary endpoint)
  • Rivaroxaban significantly reduced the risk of death, myocardial infarction or stroke (secondary endpoint)
  • Twice daily dosing appeared slightly more efficacious

Dosage: Two low doses, 2.5 mg twice daily and 5 mg once daily, have been selected for the phase III trial

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Reference

Mega JL, Braunwald E, Mohanavelu S Burton P, Poulter R, Misselwitz F, Hricak V, Barnathan ES, Bordes P, Witkowski A, Markov V, Oppenheimer L, Gibson CM; ATLAS ACS-TIMI 46 Study Group. Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial. Lancet 2009;374:29-38

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Corresponding author

TIMI Study Group, Boston, MA, USA. jmega@partners.org

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