SHORT DESCRIPTION OF THE ARTICLE
In this open-label, multicentre trial (RIVER trial1), 1005 patients (≥18 years of age) from 49 Brazil sites with permanent, paroxysmal, or persistent atrial fibrillation (AF) and a bioprosthetic mitral valve were randomized (1:1 ratio) to receive either rivaroxaban (20 mg once daily or 15mg once daily if calculated creatinine clearance was 30 to 49 ml per minute per 1.73 m2 of body-surface area) or dose adjusted warfarin [target international normalized ratio (INR 2-3]. The primary outcome was a composite of death, major cardiovascular events [transient ischemic attack (TIA), stroke, valve thrombosis, systemic embolism, or hospitalization for heart failure], or major bleeding at twelve months. Follow-up visits were scheduled at 30 days and then at 3, 6, 9, and 12 months. The mean time to primary outcome was 347.5 days in the rivaroxaban group and 340.1 days in the warfarin group [95% confidence interval (CI), −1.4 to 16.3; P<0.001 for noninferiority]. Death from thromboembolic events or cardiovascular causes occurred in seventeen patients (3.4%) in the rivaroxaban group, while in warfarin group in twenty-six patients (5.1%) [hazard ratio (HR), 0.65; 95% CI, 0.35 to 1.20]. The incidence of stroke was 0.6% in the rivaroxaban group and 2.4% in the warfarin group (HR, 0.25; 95% CI, 0.07 to 0.88). Major bleeding recorded in seven patients (1.4%) in the rivaroxaban group and in thirteen patients (2.6%) in the warfarin group (HR, 0.54; 95% CI, 0.21 to 1.35). The authors conclude that in AF patients with a bioprosthetic mitral valve, rivaroxaban was noninferior to warfarin with respect to the mean time until the primary outcome of death, major cardiovascular events, or major bleeding at twelve months. This was an investigator-initiated trial, which was supported by the Brazilian Ministry of Health (PROADI-SUS) and Bayer. (RIVER Trial; ClinicalTrials.gov identifier, NCT02303795)
COMMENT BY Panteleimon E. Papakonstantinou, MD, MSc, PhD
The safety and efficacy of Non-Vitamin K antagonist oral anticoagulants (NOACs) in patients with atrial fibrillation (AF) and bioprosthetic heart valves have not been formally tested by the major NOAC trials. The data concerning the use of NOACs in patients with bioprosthetic heart valves are sparse in the literature. Current ESC guidelines for the diagnosis and management of AF2 recommend that NOACs should not be used in patients with prosthetic mechanical heart valves, while there is no clear recommendation for patients with AF and bioprosthetic heart valves. In particular, the data for the use of NOACs in AF patients with a bioprosthetic mitral valve comes from subgroup analyses of pivotal trials of edoxaban (131 patients) and apixaban (31 patients) and a pilot trial of dabigatran (27 patients)1. Therefore, the effects of NOACs in patients with atrial fibrillation and a bioprosthetic mitral valve remain uncertain.
ROCKET AF3 study showed that rivaroxaban was non-inferior to Vitamin K antagonists (VKAs) for the prevention of systemic embolism or stroke in AF patients, but patients with bioprosthetic heart valves were excluded from this study3. The RIVER study1 was the first large investigator-initiated randomized trial (funded by the Brazilian Ministry of Health and Bayer), with an open-label, non-inferiority design which aimed to assess the efficacy and safety of a NOAC (rivaroxaban) as compared with warfarin in AF patients with a bioprosthetic mitral valve. The study showed in AF patients with a bioprosthetic mitral valve, that a direct oral anticoagulant (rivaroxaban) was non-inferior to VKAs (warfarin) for the mean time until the primary outcome of death, major cardiovascular events, or major bleeding at 12 months.
The RIVER trial1 confirms and extends the non-inferiority of rivaroxaban to warfarin for the prevention of stroke or systemic embolism, as established by the ROCKET AF3 study. The study enrolled primarily younger individuals (mean age 59 years) with a mean CHA2DS2-VASc score of 2.5. Fourteen percent (14%) of the patients had a history of prior stroke or transient ischemic attack, and 35% had their bioprosthetic mitral valve implantation within one year prior to randomization. RIVER trial’s results1 came during the difficult times of COVID-19 pandemic, in which the use of NOACs seems an attractive anticoagulation treatment option as they have predictable anticoagulation effect (rapid onset and offset) and they do not require regular monitoring of anticoagulant effect (avoid frequent visits of patients to healthcare centres and/or hospitals)4.
The RIVER study1 finding cannot be extrapolated to AF patients with a bioprosthetic aortic valve or those with mitral stenosis or with mechanical valves. Moreover, the authors do not specify the original indications for mitral valve replacement in these patients, especially for patients with previous rheumatic mitral valve disease. Further larger multi-centre international trials are required to confirm the results and prove the efficacy and safety of NOACs in populations with a specific thrombotic risk profile such as patients with bioprosthetic heart valves. Although RIVER study1 seems to be a revolution in the anticoagulation management of AF patients with bioprosthetic valves, till further data become available, its results should be interpreted with caution.
COMMENT BY Christina Christersson MD, PhD, FESC
There are still evidence gaps of the optimal oral anticoagulant treatment in patients with AF and biological valve prosthesis, both regarding the early time-period after valve intervention, and how to treat patients with AF and biological mitral valve prosthesis due to rheumatic valvular disease5. The RIVER trial is the first randomized trial were NOAC and warfarin is compared in patients with AF and biological mitral valve prosthesis1. This study contributes to our knowledge regarding rivaroxaban in AF patients with surgical biological valve prosthesis, since this patient category have been limited in the large AF trials comparing NOAC and warfarin. Patients with rheumatic mitral stenosis and AF have a high risk for thromboembolic events, the mechanism are not fully explored but the low-flow with formation of thrombi outside the left atrial appendage seems to contribute. The alteration of hemodynamics upon mitral valve intervention reduce parameters reflecting coagulation and fibrinolytic activities together with inflammatory markers. However, even though improved flow the large atria persists which have led to cautions in recommendation of NOAC in these patients5,6. In the RIVER trial rivaroxaban was non-inferior to warfarin for the primary outcome. The total number of thromboembolic events during 12 months was low. Only three stroke events occurred in the rivaroxaban group and all were ischemic stroke. In the warfarin group seven out of twelve stroke were ischemic. Valve thrombosis was found in five and three patients randomized to rivaroxaban and warfarin, respectively. The paper lacks a description of the underlying disease mechanism of the mitral valve, which would have been valuable, based on our current knowledge. Experimental and clinical studies have shown that the coagulation system is triggered by artificial surfaces and the risk of valvular thrombosis is highest in the early phase after a surgical intervention7. The ARISTOTLE and ENGAGE AF trials including selected categories of patients with valvular diseases but surgery within three months was an exclusion criterion so the knowledge of NOAC in this early phase after surgery is lacking8,9. In the study by Guimaraes et al, inclusion were allowed within 48 hours from intervention and 189 patients were included in the first three month period after valve intervention1. Even though this sub-group is a large cohort of AF patients with early mitral valve intervention, with promising results, additional studies are needed where patients are randomized to oral anticoagulant treatment at discharge from valvular surgery. The results from the ongoing trials of oral anticoagulant treatment in AF patients undergoing transcatheter valvular interventions cannot be translated to valvular surgery and open-heart surgery will still be the treatment option for a proportion of AF patients with valvular disease.
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