Guimarães HP, Lopes RD, de Barros E, Silva PGM, et al. Rivaroxaban in patients with atrial fibrillation and bioprosthetic mitral valve. N Engl J Med. 2020;383:21172126.

Patients with atrial fibrillation (AF) require long-term anticoagulation therapy for stroke prevention. The pivotal randomized trials in AF comparing the direct oral anticoagulants (DOACs) to vitamin K antagonists (VKAs) demonstrated a significant reduction in stroke and systemic embolism, with a reduction in major bleeding with DOACs.1  However, these trials mostly excluded patients with moderate-to-severe mitral stenosis and prosthetic heart valves. For this reason, current guidelines from the American Heart Association recommend using VKAs over DOACs for patients with moderate-to-severe mitral stenosis or mechanical heart valves.2 

There remains uncertainty about the efficacy and safety of DOACs in patients with AF with bioprosthetic mitral valves. These patients were not included in the ROCKET-AF study (rivaroxaban); however, 162 such patients were included in the Aristotle (apixaban) and ENGAGE AF-TIMI 48 (edoxaban) trials.3,4  A recent meta-analysis of patients with AF and valvular heart disease aside from significant mitral stenosis and mechanical heart valves demonstrated a reduction in stroke and systemic embolism with DOACs compared with VKA. However, there is a paucity of randomized comparisons of DOACs compared with warfarin in patients with bioprosthetic valves.5  The RIVER trial provided this comparison specifically in those with AF and bioprosthetic mitral valves.

This was a randomized, open-label, noninferiority study completed at 49 sites in Brazil. Patients with AF or flutter and bioprosthetic mitral valve were randomly assigned to receive rivaroxaban 20 mg daily (or 15 mg daily if creatinine clearance is 30-49 mL/min) or warfarin (international normalized ratio target, 2.0-3.0). The primary outcome was a composite of major cardiovascular events (including transient ischemic attack [TIA], stroke, valve thrombosis, systemic embolism, or hospitalization for heart failure), death, or major bleeding at 12 months. The study included primarily younger individuals (mean age 59 years) with a mean CHA2DS2-VASc score of 2.5. Fourteen percent had prior stroke or TIA, and 35 percent had their mitral valve prosthesis implantation within one year prior to randomization.

The mean time to primary outcome was similar in the rivaroxaban and warfarin groups (347.5 days vs. 340.1 days; 95% CI, –1.4 to 16.3; p<0.001 for noninferiority). Death from cardiovascular causes or thromboembolic events was numerically lower in the rivaroxaban group (3.4%) compared with warfarin (5.1%), and incidence of stroke was 0.6 percent and 2.4 percent, respectively. The incidence of valve thrombosis was similar between the two groups (1.0% vs. 0.6%). Major bleeding occurred less frequently with rivaroxaban (1.4%) compared with warfarin (2.6%). In the subgroup of patients who had undergone randomization within three months of valve implantation (n = 189), the incidence of the primary outcome appeared to be numerically lower with rivaroxaban (6.4%) compared with warfarin (18.9%).

Weaknesses of this study include its open-label design, and it is unclear whether the mitral valve surgery in this younger population was done for mitral stenosis related to rheumatic heart diseases (where warfarin continues to be the recommended anticoagulant). However, this study finally provides good, randomized data supporting the use of DOACs for patients with bioprosthetic mitral valves and AF, with no differences in ischemic stroke or valve thrombosis.

Notably, these results cannot be applied to patients with other bioprosthetic valves (including aortic), or to those with mitral stenosis and mechanical valves. Indeed, other studies have demonstrated more thromboembolic complications and major bleeding when DOACs have been used in patients with mechanical valves (RE-ALIGN study).6  Overall, the noninferiority of the primary outcome coupled with rivaroxaban’s superior safety profile and ease of administration suggest that this study will be practice-changing for these patients and will provide evidence for another indication for the DOACs. The RIVER and RE-ALIGN studies contrast and provide an important reminder that before novel therapies are used for new indications, robust randomized studies are needed to ensure both efficacy and safety.

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Competing Interests

Dr. Tseng indicated no relevant conflicts of interest.