Despite the advent of dual antiplatelet therapy with aspirin and clopidogrel, rates of in-hospital and 1-year mortality and reinfarction after acute coronary syndrome (ACS) are approximately 10%. The results of the ATLAS ACS-TIMI 46 (NCT00402597) trial represent an important step toward meeting a need for more effective antithrombotic therapy after ACS.

ATLAS ACS-TIMI 46 was a phase 2 dose-finding trial of rivaroxaban that was added to standard antiplatelet therapy with either aspirin alone or aspirin plus clopidogrel. C. Michael Gibson, MD, the TIMI Study Group, Boston, MA, lead author of the trial, explained that rivaroxaban is a potent oral direct inhibitor of Factor Xa that works at the intersection of the intrinsic and extrinsic pathways of the coagulation cascade, thus blocking initiation of the final common pathway of coagulation.

This multicenter trial enrolled 3491 patients who were in stable condition 1–7 days after an ACS event. The study population was categorized into 2 strata according to the treating physician's decision on antiplatelet therapy: Stratum 1 included 761 patients who were treated with aspirin (75–100 mg) alone, and Stratum 2 included 2730 patients who were treated with aspirin and clopidogrel. Dr. Gibson noted that these 2 study populations differed substantially from each other in terms of age, comorbidities, and, especially, with regard to ACS treatment. PCI was performed in only 8% of patients in Stratum 1 but was performed in 79% of patients in Stratum 2.

The patients in each stratum were randomly assigned to receive 6 months of placebo or once-daily or twice-daily rivaroxaban, wherein 3 total daily doses (5, 10, and 20 mg) were evaluated in Stratum 1 and 4 total daily doses (5, 10, 15, and 20 mg) were evaluated in Stratum 2.

The primary safety endpoint of the study was clinically significant bleeding, defined as a composite of thrombolysis in myocardial infarction (TIMI) major and minor bleeding and any bleeding that required medical attention. The study also explored the efficacy of rivaroxaban to reduce ischemic complications (primary composite=death from cardiovascular casuses, myocardial infarction (MI), stroke, and revascularization; secondary composite=risk of death, MI, or stroke).

Dr. Gibson reported that the incidence of bleeding followed a dose-response pattern, with higher bleeding rates as the dose of rivaroxaban increased (3.3% for placebo, 6.1% for 5 mg rivaroxaban, 10.9% for 10 mg, and 15.3% for 20 mg). The majority of bleeding events was categorized as bleeding that required medical attention (Table 1).

Rivaroxaban did not significantly reduce the risk of the primary composite endpoint (7.0% for placebo compared with 5.6% for the combined rivaroxaban groups (HR, 0.79; 95% CI, 0.60 to 1.05; p=0.1) in an analysis that combined the data across both strata among patients who received placebo compared with all doses of rivaroxaban combined. There was, however, a decrease in the secondary composite of death, MI, or stroke (5.5% vs 3.9%; HR, 0.69; 95% CI, 0.50 to 0.96; p=0.028), yielding a number that was needed to treat to prevent 1 event of 63.

Dr. Gibson announced that doses of 2.5 mg and 5 mg twice daily will be evaluated next in a phase 3 trial.

In ATLAS ACS-TIMI 46, those doses led to a rate of the secondary efficacy endpoint of 6.6% in Stratum 1 (compared with 11.9% for placebo; HR, 054; p=0.08) and of 2.0% in Stratum 2 (compared with 3.8% for placebo; HR, 0.55; p=0.09), with a tradeoff of increased bleeding rates of 1.2% (p=0.17) and 1.0% (p=0.03), respectively. The phase 3 trial (ATLAS II – TIMI 51) is expected to enroll 13,500–16,000 patients and will begin in December 2008.