Regulatory Decision Summary for Xarelto

The pivotal COMPASS trial was a randomized, double-blind, active controlled superiority study in 27,395 patients with established coronary arterial disease (CAD) or peripheral arterial disease (PAD). Patients were randomized 1:1:1 to treatment with rivaroxaban 2.5 mg twice daily. + ASA 100 mg once daily, rivaroxaban 5 mg twice daily alone, or ASA 100 mg once daily alone. The primary efficacy outcome was a composite of stroke, MI or CV death. The primary safety outcome was major bleeding events, i.e., modified definition of the International Society on Thrombosis and Haemostasis (ISTH).

The efficacy results showed that, relative to ASA 100 mg once daily, rivaroxaban 2.5 mg twice daily in combination with ASA 100 mg once daily caused statistically and clinically significant reductions (24%) of the primary composite outcome of stroke, MI or CV death. This beneficial effect was seen throughout the treatment period (median ~1.7 years). Stroke and CV death were significantly reduced (by 42% and 22%, respectively) while the incidence of MI was also slightly reduced (by 14%). There was a 1.2- to 1.5-fold increase in fatal and critical organ bleedings, but it was statistically non-significant.

The efficacy results were consistent in the pre-specified subpopulations of patients with CAD, with or without PAD. This was not the case however with the PAD sub-population as efficacy results did not reach statistical significance. Additionally, in patients with PAD-only, the risk of major bleeding (2.2-fold increase) was the highest of all subgroup populations. Based on the consideration of the marginal benefit (11% relative risk reduction) with a 2.2-fold increase in the risk of major bleeding, the benefit risk ratio for the patients with PAD-only was not considered to be favorable.

Relative to ASA 100 mg once daily, rivaroxaban 5 mg twice daily alone did not significantly reduce the primary efficacy outcome, while the incidence rates for the primary safety outcome were significantly increased.

The subgroup analysis also showed that anti-thrombotic efficacy decreases and bleeding risk increases with age, so that treatment in patients >75 years of age should be started with caution, and the benefit, in light of the risks, should be assessed at frequent, regular intervals. The primary reason for premature, permanent study drug discontinuation during the COMPASS trial were gastrointestinal disorders that occurred 1.5-fold more frequently in patients on Rivaroxaban 2.5 mg + ASA 100 mg than in patients on ASA-alone. The information was included in the Product Monograph.

Overall, the lower rates of stroke, MI and CV deaths observed outweighed the bleeding risks reported in the pre-specified subpopulations of patients with coronary artery disease (CAD) alone or in combination with peripheral artery disease (PAD). Therefore, the use of Xarelto film-coated tablets (2.5 mg) with ASA in patients with CAD with or without PAD was authorized.