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Study Summary

The RIVER trial was designed to assess the efficacy of direct oral anticoagulation (DOAC), specifically rivaroxaban, for stroke thromboprophylaxis in patients with atrial fibrillation and a bioprosthetic mitral valve (See accompanying Hurst’s Central Illustration). A total of 1005 patients in Brazil underwent randomization with 500 patients assigned to rivaroxaban and 505 patients assigned to warfarin. Mean CHADS2-VASC score was 2.6, indicating the population was at low risk for stroke. The trial was designed to test for noninferiority of rivaroxaban with respect to warfarin using restricted mean survival time analysis. The primary outcome was composite of death, major cardiovascular events, or major bleeding at 12 months. At 1-year follow up, patients in the rivaroxaban and warfarin arms had a mean time of 347.5 and 340.1 days until a primary outcome event, respectively. This met the criteria for non-inferiority (P<0.001 and P=0.10 for superiority). Furthermore, rivaroxaban was non-inferior to warfarin with regards to cardiovascular death, thromboembolic events, major bleeding events, and valve thrombosis.

Commentary

Study Strengths: The RIVER trial is the first large randomized controlled trial to assess the efficacy of DOACs in patients with atrial fibrillation and a bioprosthetic mitral valve. Utilizing restricted mean survival time analysis, the investigators were able to show that rivaroxaban was non-inferior to warfarin, and may be a consideration for patients with atrial fibrillation and bioprosthetic mitral valves.

Study Limitations: Significant limitations of the RIVER trial include its open-label design which could have introduced bias in the ascertainment or reporting of events. However, event adjudication was blinded. Additionally, the reason for mitral valve replacement is not reported, which may affect outcomes for these patients. The majority of patients were women and of an age younger than most patients typically undergoing mitral valve replacement, perhaps implying rheumatic heart disease as the predominant mechanism of valvular disease in the study population . Finally, the findings of this trial cannot be extrapolated to patients with bioprosthetic aortic valves or mechanical prostheses in any position.

Next Steps/Clinical Perspective: In the ARISTOTLE and ENGAGE AF-TIMI 48 trials, only 31 and 131 patients had bioprosthetic mitral valves, respectively. There was no significant difference with respect to cardiovascular events between apixaban and warfarin or between edoxaban and warfarin. The lower dose of edoxaban (30 mg) was associated with fewer bleeding events. In a recent trial of 218 patients comparing edoxaban to warfarin presented at ACC in March 2020, the incidence of thromboembolic events was 0% in the edoxaban group and 3.7% in the warfarin group with similar incidence of bleeding events in both groups. The RIVER trial builds on these previous findings, and furthermore provides information regarding the use of DOAC within 3 months of mitral valve replacement. The use of DOAC in this patient population is expected to grow.

Trial Reference

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Guimaraes  HP, Lopes  RD, de Barros  e Silva PGM, et al. Rivaroxaban in patients with atrial fibrillation and bioprosthetic mitral valve. N Engl J Med. DOI: 10.1056/NEJMoa2029603

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