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ATLAS TIMI 46: Rivaroxaban did not lower endpoint of death, MI, stroke, severe ischemia requiring revascularization
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Patients taking rivaroxaban, an oral direct factor Xa inhibitor, did not experience a significantly reduced risk for death, MI, stroke or severe ischemia requiring revascularization, according to the results of the phase-2 ATLAS TIMI 46 trial.
Researchers for ATLAS TIMI 46 enrolled 3,491 patients and assigned them to either an aspirin alone group (n=761) or a group receiving aspirin plus clopidogrel (n=2,730). Patients in both strata were then assigned to receive rivaroxaban either once daily at 5 mg, 10 mg, 15 mg and 20 mg twice daily at the same dosing levels or placebo. The primary efficacy endpoint of the study was the combination of all-cause death, MI, stroke or severe ischemia requiring revascularization.
There was no difference in the primary efficacy endpoint between patients taking placebo and patients taking rivaroxaban (7.0% vs. 5.6%; HR=0.79; 95% CI, 0.60-1.05). For the secondary efficacy endpoint of the incidence of all-cause death, MI and stroke, patients assigned rivaroxaban had lower risk than those assigned placebo, with an absolute risk reduction of 1.6% (5.5% vs. 3.9%; HR=0.69; 95% CI, 0.50-0.96).
The researchers reported that patients assigned 2.5 mg and 5.0 mg twice daily rivaroxaban in both the aspirin alone and aspirin plus clopidogrel groups had the most efficacious results vs placebo. There was an 11.9% rate of CV death, MI and stroke with placebo vs. a rate of 6.6% with the 2.5 mg and 5.0 mg rivaroxaban doses combined in the aspirin alone group (P=.08). There was a 3.8% rate of CV death, MI and stroke with placebo vs. a 2.0% rate with the 2.5 mg and 5.0 mg rivaroxaban doses combined in the aspirin plus clopidogrel group (P=.09). This will be further tested in the phase-3 trial of rivaroxaban set to begin in December 2008.
The increased risk for bleeding was one aspect of the study results that warranted more attention in future trials.
“The addition of rivaroxaban to antiplatelet therapy did indeed result in dose-dependent increase in bleeding, and as we move forward in larger trials these nuances will become more apparent in lower doses,” Elaine M. Hylek, MD, associate professor of medicine at Boston University School of Medicine, said in the discussant portion of the presentation. “I also make a plea for uniform reporting of bleeding across trials and indications worldwide so that we can facilitate a more informed assessment of benefit and risk for our patients and their providers.”