Regulatory Decision Summary for Xarelto

Review decision

The Regulatory Decision Summary explains Health Canada’s decision for the product seeking market authorization. The Regulatory Decision Summary includes the purpose of the submission and the reason for the decision.


Product type:

Drug

Medicinal ingredient(s):

Rivaroxaban

Therapeutic area:

Antithrombotic agents

Type of submission:

Supplement to a New Drug Submission (SNDS)

Control number:

233166
What was the purpose of this submission?

 

This Supplement to a New Drug Submission was filed to extend the indication of 2.5 milligrams (mg) rivaroxaban twice daily in combination with 75-100 mg acetylsalicylic acid (ASA) once daily to include the treatment of patients with peripheral artery disease (PAD) without coronary artery disease (CAD), that is (i.e.), the patients with PAD only.

 

Why was the decision issued?

 

Xarelto (rivaroxaban) is a direct acting inhibitor of Factor Xa. Xarelto (rivaroxaban) film-coated tablet (10 milligrams (mg), 15 mg, 20 mg) is currently authorized for the prevention of venous thromboembolic events (VTE) in patients who have undergone elective total hip replacement (THR) or total knee replacement (TKR) surgery; treatment of venous thromboembolic events (deep vein thrombosis [DVT], pulmonary embolism [PE]) and prevention of recurrent DVT and PE; and prevention of stroke and systemic embolism in patients with atrial fibrillation, in whom anticoagulation is appropriate. Xarelto (rivaroxaban) film-coated tablet (2.5 mg), in combination with 75 mg - 100 mg acetylsalicylic acid (ASA), is indicated for the prevention of stroke, myocardial infarction (MI) and cardiovascular (CV) death; and the prevention of acute limb ischemia and mortality in patients with coronary artery disease (CAD) with or without peripheral artery disease (PAD).

The COMPASS trial was a randomized, double-blind, active controlled superiority study in 27,395 patients with established CAD or PAD. Patients were randomized 1:1:1 to treatment with rivaroxaban 2.5 mg twice daily in combination with 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, based on a modified definition of the International Society on Thrombosis and Hemostasis (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 24% reductions 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 statistically 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, but statistically non-significant increase in fatal and critical organ bleedings.

The efficacy results were consistent in the pre-specified subpopulations of patients with CAD with or without PAD, but not in patients with PAD only. Additionally, the 2.2-fold increased risk of major bleeding in the PAD subgroup population was the highest of all subgroups. Based on the consideration of the marginal benefit (11% relative risk reduction) with over 2-fold increased risk of major bleeding, the benefit-risk balance for the patients with PAD-only was found not favorable. However, a post hoc analysis of COMPASS trial showed that symptomatic PAD patients in particular, benefit from rivaroxaban 2.5 mg with ASA antithrombotic treatment versus ASA-alone treatment, with up to 48% less amputations, major adverse limb events (MALE) or vascular interventions. Another post hoc analysis of the COMPASS study showed that rivaroxaban 2.5 mg with ASA treatment in patients with a high risk of recurrent vascular events (those with ≥2 vascular beds affected, or a history of heart failure, low renal function or diabetes) reduced the incidence of subsequent cardiovascular events (MI, stroke, acute limb ischemia, vascular amputation, CV death) by 40-50% more than that in patients treated with ASA alone. Bleeding rate was higher in the rivaroxaban 2.5 mg with ASA-treated patients, but was not statistically significant.

Overall, the observed benefits in the lower rates of stroke, MI and CV deaths as a result of this low-dose rivaroxaban in combination with ASA treatment outweigh the bleeding risks in the symptomatic PAD patients who are at increased risk of future atherothrombotic events. The use of Xarelto film-coated tablets (2.5 mg) with ASA in this patient population is considered favorable. Therefore, an indication for rivaroxaban 2.5 mg twice daily plus ASA 75-100 mg once daily in patients with symptomatic PAD was authorized.

 

Decision issued

Approved; issued a Notice of Compliance in accordance with the Food and Drug Regulations.