Rivaroxaban non inferior to warfarin in patients with AF, bioprotetic mitral valve: RIVER

Among patients with atrial fibrillation and bioprotetic mitral valve, rivaroxaban was non-inferior to warfarin for the primary outcome of median survival time to death, major cardiovascular event, or major bleeding at 1 year, the researchers reported.

Patients who received rivaroxaban (Xarelto, Janssen / Bayer) experienced fewer strokes at 1 year, but the researchers urged caution in interpreting this finding, according to results presented at the American Heart Association’s virtual science sessions.

For the randomized RIVER study, published concurrently in The New England of Medicine, the researchers enrolled 1,005 patients with AF and a bioprosthetic mitral valve. Patients were randomly assigned to rivaroxaban 20 mg once daily or dose-adjusted warfarin (target INR, 2-3). The primary outcome was a compound of death, major bleeding, or major cardiovascular events, defined as stroke, transient ischemic attack, systemic embolism, valve thrombosis, or hospitalization for HF at 1 year.

One primary outcome event occurred at a mean of 347.5 days among patients assigned rivaroxaban versus 340.1 days among those assigned warfarin.

The difference between the groups was calculated as a limited mean survival time. Patients assigned warfarin experienced 7.4 days longer event-free survival than assigned rivaroxaban, but the non-inferiority margin was reached (95% CI, 1.4 to 16.3; P. for non-inferiority <.001), based on the results.

Secondary efficacy endpoints did not differ significantly between the rivaroxaban and warfarin groups, including:

• CV mortality or thromboembolic events (HR = 0.65; 95% CI, 0.35-1.2);
• CV death (HR = 0.85; 95% CI, 0.38-1.9);
• death from all causes (HR = 1.01; 95% CI, 0.54-1.87); is
• valve thrombosis (HR = 1.68; 95% CI, 0.4-7.01).

Otavio Berwanger

Before RIVER, “we didn’t have specific proof [evaluated rivaroxaban] in this population ” Otavio Berwanger, MD, PhD, cardiologist, clinical epidemiologist and director of the HCor Research Institute and Heart Hospital in São Paulo, said during a press conference. “These findings have the potential to inform practice and rivaroxaban may represent an attractive alternative for this patient population.”

For the secondary endpoint of stroke, patients assigned rivaroxaban reported fewer events than those assigned warfarin (HR = 0.25; 95% CI, 0.07-0.88).

“This result must be interpreted with caution as we have a low number of events, a large confidence interval and this difference has not been adjusted for multiplicity,” Berwanger said at the press conference.

The risk of major bleeding was lower in the rivaroxaban group; however, the results were not significant (HR = 0.54; 95% CI, 0.21-1.35). There were no episodes of intracranial or fatal bleeding in the rivaroxaban group.

Additionally, clinically relevant risk of non-major bleeding (HR = 1.05; 95% CI, 0.6-1.87), minor bleeding (HR = 0.75; 9% CI, 0.49-1.15) and total bleeding (HR = 0.83; 95% CI, 0.59-1.15) did not differ significantly between treatment groups.

In a subgroup analysis of patients randomized up to 3 months after bioprosthetic mitral valve implantation, the mean time to event was 348.6 days among patients in the rivaroxaban group vs 313.5 days in the warfarin group (difference, 35.1 days; 95% CI, 8.6-61.7). Additionally, the risk of a primary outcome event among patients in this subgroup was lower in the rivaroxaban group than in the warfarin group (HR = 0.31; 95% CI, 0.12-0.79).

“Event-free survival time was 35 days longer with rivaroxaban than with warfarin,” Berwanger said during the presentation. “This is a subgroup analysis and, at best, it generates hypotheses.”

Discussant Elaine M. Hylek, MD, MPH, professor of medicine at Boston University School of Medicine, said during the press conference that “if we look at the key components of the primary composite endpoint, there are some numbers that actually raise the question in an open-label study of whether or not we might. to have been some kind of misclassification.But the blinded judgment here was a real selling point.

“The RIVER experimentation adds in an important way to the field. Is the biggest [randomized controlled trial] to date, “Hylek said.” There were too few patients enrolled in the 48 hours after the interruption until 30 days after[bioprosthetic valve] period of surgical intervention. There were only 95 patients in that critical period enrolled, and the results would have been strengthened with systematic mitral valve assessment with some type of exit echocardiogram. Overall, it was a well-conducted study. “

Reference:

Perspective

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Julia Grapsa, MD, PhD, FACC

The results of the RIVER study are consistent with previous research, including ROCKET AF, ARISTOTLE, and ENGAGE AF-TIMI 48, and is important for patients with bioprosthetic mitral valves. As rivaroxaban does not require monitoring of INR and has a more consistent and less influenced anticoagulant effect from food or concomitant medications than warfarin, it represents an attractive alternative for this patient population. In clinical practice, we have few patients who compromise their quality of life when they need to take warfarin, and until now we didn’t have many options to feel reassured they were safe. The RIVER study is the largest to date to confirm the safety of rivaroxaban.

However, the authors point out some limitations: the results cannot be extrapolated to patients with a bioprothetic aortic valve in the aortic position, or to patients with mitral stenosis or with mechanical valves, because there is ongoing evidence. In addition, open label design could have introduced bias in ascertaining or reporting events.

Despite the limitations, no one can doubt that these findings are important for clinical practice and give us more options in the therapeutic spectrum.

Julia Grapsa, MD, PhD, FACC

Associate Professor of Cardiology, University College London

Attending Cardiologist, Guys and St. Thomas NHS Hospitals Trust, London

Editor-in-Chief, JACC: Case Reports

Disclosures: Grapsa does not report any relevant financial information.

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