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 - ATLAS ACS-TIMI 46

Jun 23, 2009
Font Size
A
A
A
Trial Sponsor:
Johnson & Johnson Pharmaceutical Research & Development, and Bayer Healthcare AG.
Date Presented:
01/01/2008
Date Published:
01/01/2009
Date Updated:
06/23/2009
Original Posted Date:
06/23/2009
References

Description:

Despite percutaneous coronary intervention (PCI) and dual antiplatelet therapy, death or myocardial infarction (MI) at 1 year remain high in patients presenting with acute coronary syndromes (ACS). Oral anticoagulant therapy remains an unmet need in these patients. This was a phase II trial designed to identify tolerable doses of rivaroxaban, an oral direct factor Xa inhibitor, in the treatment of patients with ACS.

Hypothesis:

Rivaroxaban would be safe and efficacious compared with placebo in the treatment of patients with ACS.

Study Design

Study Design:

Patients Screened: 3,576
Patients Enrolled: 3,491
Mean Follow Up: 6 months
Mean Patient Age: 58 years

Patient Populations:

  • ACS symptoms >10 minutes at rest within 7 days of randomization
  • ST-elevation MI or non–ST-elevation MI/unstable angina with at least one of the following: elevated cardiac biomarkers, ≥1 mm ST-segment deviation, and TIMI risk score ≥3

Exclusions:

  • Patients at increased bleeding risk
  • Gastrointestinal bleed within the past 6 months
  • Indication for warfarin
  • History of any intracranial hemorrhage
  • Ischemic stroke or transient ischemic attack within 30 days
  • Abciximab treatment within 8 hours, eptifibatide, or tirofiban within 2 hours
  • Hemoglobin <10 g/dl
  • Platelet count <90,000/µl
  • Planned PCI within 30 days
  • Severe concomitant disease such as cardiogenic shock, severe renal dysfunction, known significant liver disease, and life expectancy <6 months

Primary Endpoints:

  • Efficacy: Death, MI, stroke, severe ischemia requiring revascularization
  • Safety: Clinically significant bleeding (TIMI major, TIMI minor, or bleeding requiring medical attention)

Secondary Endpoints:

  • Efficacy: Death, MI, or stroke
  • Safety: TIMI major bleeding, TIMI minor bleeding, and bleeding requiring medical attention

Drug/Procedures Used:

This study was stratified by use of aspirin alone or aspirin and clopidogrel. Patients were randomized in a 1:1:1 fashion to either placebo, rivaroxaban daily, or rivaroxaban twice daily. The investigators followed a dose escalation pattern, with rivaroxaban 5 mg, followed by 10 mg, and then 20 mg, in either single or divided doses.

Concomitant Medications:

Aspirin 75-100 mg (100%), clopidogrel (78.2%), beta-blockers (89.8%), angiotensin-converting enzyme inhibitor/angiotensin-receptor blocker (81%), statin (88.5%)

Principal Findings:

A total of 3,491 patients were randomized, 761 to aspirin alone, and 2,730 to aspirin and clopidogrel. Of these, 1,160 patients received placebo, 1,166 received rivaroxaban daily, and 1,156 received rivaroxaban twice daily. Baseline characteristics were fairly similar between the groups. About 19% had diabetes, and 23% had a history of prior MI. Renal dysfunction (creatinine clearance <60 ml/min) was noted in 7.8% of the patients. About one-half of the patients presented with ST-elevation MI.

Efficacy: The primary efficacy endpoint of death, MI, stroke, or severe ischemia requiring revascularization occurred less frequently in the rivaroxaban arm compared with placebo, although this was not statistically significant (5.6% vs. 7.0%, hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.60-1.05, p = 0.10). There was significant heterogeneity based on stratum (p = 0.03), and in the aspirin only arm, rivaroxaban was associated with a significant reduction in the primary endpoint (HR 0.53, 95% CI 0.33-0.84). There was also a statistically significant reduction in the secondary endpoint of death, MI, or stroke in the rivaroxaban arm compared with placebo (3.9% vs. 5.5%, HR 0.69, 95% CI 0.50-0.96, p = 0.028).

Safety: There was a dose-response curve with respect to the primary safety endpoint of clinically significant bleeding (combination of TIMI major, TIMI minor, and bleeding requiring medical attention). Bleeding rates were 15.3%, 12.7%, 10.9%, 6.1%, and 3.3% (p < 0.001) for rivaroxaban 20 mg, 15 mg, 10 mg, 5 mg, and placebo, respectively. Bleeding was higher in the dual antiplatelet therapy arm, compared with aspirin alone, for all doses studied. Liver test abnormalities, as defined by an alanine aminotransferase >3 x upper limit of normal, was noted equally between the rivaroxaban and placebo arms (3.7% vs. 4.5%, p = 0.30).

Interpretation:

The results of the ATLAS ACS-TIMI 46 trial indicate that rivaroxaban, an oral factor Xa inhibitor, is associated with reasonable efficacy compared with placebo for triple therapy in patients presenting with ACS, with a higher risk of clinically significant bleeding. This was a phase II trial, and based on safety and efficacy analyses, doses of rivaroxaban 2.5 and 5 mg twice daily were selected for further study in a large phase III trial (13,500-16,000 patients, expected median follow-up: 33 months).

Rivaroxaban has already been studied for venous thromboembolic disorders in the RECORD I-IV trials, and this represents one of the first studies in arterial thrombosis with this medication.

References:

Mega JL, Braunwald E, Mohanavelu S, et al., on behalf of the 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;Jun 17:[Epub ahead of print].

Presented by Dr. C. Michael Gibson at the American Heart Association Annual Scientific Sessions, New Orleans, November 2008.

Keywords: Myocardial Infarction, Acute Coronary Syndrome, Stroke, Follow-Up Studies, Morpholines, Thiophenes, Coronary Disease, Ticlopidine, Creatinine, Percutaneous Coronary Intervention, Biomarkers, Thrombosis, Confidence Intervals, Factor Xa, Diabetes Mellitus


< Back to Listings