Results of the ATLAS ACS-TIMI 46 Study Published in The Lancet
June 17, 2009:
The ATLAS ACS-TIMI 46 Study Group investigators reported today in The Lancet that among patients with acute coronary syndromes, the use of oral rivaroxaban therapy was associated with a reduction in rates of major adverse events as well as with a dose-dependent increase in rates of clinically significant bleeding.  Two candidate doses were associated with a reduction in the risk of death, MI and stroke, and these two low doses will now be studied in a large event driven phase III trial (ATLAS ACS II-TIMI 51).
While phase III studies have previously demonstrated that oral rivaroxaban use was associated with lower rates of venous thromboembolism among patients undergoing hip and knee arthroplasty than treatment with subcutaneous enoxaparin, the safety and efficacy of oral rivaroxaban among acute coronary syndrome (ACS) patients had not been investigated.  The 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 was designed to address these questions.
In this phase II, multicenter, double-blind, placebo controlled, dose-escalation study, 3491 ACS patients treated with either aspirin alone (Stratum 1 n=761) or aspirin plus clopidogrel (Stratum 2n=2730) at investigator discretion were randomized 1:1:1 to receive either placebo, rivaroxaban once daily, or rivaroxaban twice daily.  Total daily doses of oral rivaroxaban were the same whether taken once or twice daily; aspirin alone patients were administered either 5, 10 or 20 mg whereas patients treated with aspirin plus clopidogrel received either 5, 10, 15 or 20mg of the study drug. The primary safety endpoint was clinically significant bleeding (TIMI major, TIMI minor, or requiring medical attention). The primary efficacy endpoint was the composite of death, myocardial infarction, stroke or severe recurrent ischemia requiring revascularization up to 6 months post enrollment.  The secondary efficacy endpoint was the composite of death, myocardial infarction or stroke during this same 6 month period.
Compared to placebo, treatment with oral rivaroxaban was associated with a risk of clinically significant bleeding that increased in a dose-dependent fashion. Among patients receiving a total dose of 5mg daily, the hazard ratio was 2.21 (95% Confidence interval : 1.25  3.91), which increased to 3.35 (95% CI: 2.31  4.87), 3.60 (95% CI: 2.31  4.87) and 5.06 (95% CI: 3.45  7.42) among patients receiving total daily doses of 10, 15 and 20 mg respectively (p<0.0001). Treatment with the study drug was associated with a trend toward the reduction of rates of the pre-specified primary efficacy endpoint from 7.0% (79/116) for placebo to 5.6% (126/2331) for rivaroxaban, with a hazard ratio (HR) of 0.79 (95%CI: 0.60  1.05, p=0.10). The reduction of secondary efficacy endpoint reached significance (5.5%  among patients receiving placebo versus 3.9%  among patients receiving rivaroxaban, HR = 0.65, 95%CI: 0.50  0.96, p=0.027).
Given the increased risk of bleeding among patients treated at high doses, two low doses were selected for further evaluation (2.5 and 5.0 mg BID). Similar trends were observed for efficacy in both the Aspirin alone and aspirin plus clopidogrel arms as shown below:
Limitations include the fact that the 14 individual dose panels were modest in size.  The duration of treatment was only 6 months. It should be noted that Stratum 1 patients (aspirin alone patients) underwent PCI only 8.1% of the time whereas Stratum 2 patients (aspirin  plus clopidogrel) underwent PCI in 78.9% of cases.  Stratum 1 and Stratum 2 are therefore not comparable. It should be noted that these patients had been stabilized and that parenteral agents had been discontinued.
The results of this phase II study suggest oral rivaroxaban may reduce major adverse ischemic events among ACS patients with risks of clinically significant bleeding increasing in a dose-dependent manner.  Investigators are currently involved in a phase III study of low dose rivaroxaban to further determine drug efficacy.
This report was reviewed by C. Michael Gibson, M.S., M.D. who was principal investigator of the study. Dr. Gibson has received research grant support, speaking fees and consulting fees from the sponsors of the study (Johnson & Johnson, Bayer). Dr. Gibsons disclosures can be found here.

# Slides
For the set of slides presented at AHA 2008, please click here