Rivaroxaban an Option for Patients with Bioprosthetic Mitral Valves and A-fib

Rivaroxaban (Xarelto; Bayer/Janssen) is a reasonable alternative to warfarin for patients with atrial fibrillation/flutter and a bioprosthetic mitral valve, the randomized RIVER trial indicates.

During the first year of follow-up, the average time between randomization and the occurrence of a primary composite outcome event—death, a major CV event, or major bleeding—was 7.4 days longer in rivaroxaban-treated patients, which met criteria for noninferiority but not superiority, according to Otavio Berwanger, MD, PhD (HCor Research Institute and Hospital Israelita Albert Einstein, São Paulo, Brazil).

In general, clinical and bleeding events were numerically—but mostly not significantly—lower in the rivaroxaban arm. There were five cases of valve thrombosis in the rivaroxaban group and three in the warfarin group, Berwanger reported during the virtual American Heart Association 2020 Scientific Sessions.

“Most patients today are treated with warfarin and we had no data before with rivaroxaban. We have [had] no dedicated trial in this population,” he said during a press briefing. “And these results can potentially inform practice, and rivaroxaban may represent an attractive alternative for this patient population.”

The trial, published simultaneously online in the New England Journal of Medicine, with lead author Hélio Penna Guimarães, MD, PhD (HCor Research Institute), also “sets the stage for further research in the field,” Berwanger said.

The RIVER Trial

Berwanger noted that patients with A-fib and a bioprosthetic mitral valve typically require long-term anticoagulation and usually receive warfarin. But the optimal regimen is not clear, and there is only limited evidence regarding use of direct oral anticoagulants (DOACs) in this setting coming from small subgroups of the large pivotal A-fib trials. ROCKET-AF, however, excluded patients with bioprosthetic valves.

RIVER, an open-label, noninferiority study conducted at 49 Brazilian centers, is the first trial designed to address this issue. Investigators enrolled 1,005 patients (mean age 59.3 years; 60.4% women) with atrial fibrillation or flutter (96% A-fib) who had undergone mitral valve surgery with a bioprosthesis at least 48 hours prior to randomization. Mean CHA2DS2-VASc and HAS-BLED scores were 2.6 and 1.6, respectively.

The patients were randomized to rivaroxaban 20 mg (15 mg for patients with renal dysfunction) or warfarin adjusted to an INR of 2.0 to 3.0. The median time in therapeutic range in the warfarin arm was 65.5%.

The primary outcome was a composite of all-cause death, major CV events (stroke, TIA, systemic embolism, valve thrombosis, or hospitalization for heart failure), or major bleeding, assessed as the difference in event-free survival through the first year. A primary outcome event occurred an average of 347.5 days after randomization in the rivaroxaban group and 340.1 days in the warfarin group, resulting in a difference in restricted mean survival time of 7.4 days favoring rivaroxaban (P < 0.001 for noninferiority). Rates of the composite outcome through 1 year were 9.4% and 10.3% in the rivaroxaban and warfarin arms, respectively.

Among secondary outcomes, the rate of CV death or thromboembolic events was numerically but not significantly lower in the rivaroxaban-treated patients (3.4% vs 5.1%; HR 0.65; 95% CI 0.35-1.20). The stroke rate was significantly lower with rivaroxaban (0.6% vs 2.4%; HR 0.25; 95% CI 0.07-0.88), but the finding should be interpreted with caution, Berwanger said, because of the small number of events, the wide confidence interval, and the lack of adjustment for multiplicity.

The major bleeding rate was 1.4% with rivaroxaban and 2.6% with warfarin (HR 0.54; 95% CI 0.21-1.35). There were no intracranial or fatal bleeds in the rivaroxaban group, and five and two cases of each, respectively, in the warfarin arm.

Other serious adverse events occurred at similar frequencies in the rivaroxaban and warfarin groups (5.8% and 6.9%).

Rivaroxaban appeared to have an enhanced benefit in the subgroup of patients who were less than 3 months out from their mitral valve surgery, representing 18.8% of the trial population, with a primary outcome rate of 6.4% versus 18.9% (HR 0.31; 95% CI 0.12-0.79). There were previously no data in these types of patients, Berwanger said. He added, however, that these findings are “hypothesis-generating at best” and need to be confirmed in large-scale trials.

Reassuring, With Caveats

Commenting on the findings for TCTMD, American College of Cardiology President Athena Poppas, MD (Lifespan Cardiovascular Institute and Brown University, Providence, RI), said RIVER is an important trial because it fills a void in the literature when it comes to anticoagulation in patients with bioprosthetic valves, who were largely excluded from the large A-fib trials.

Rivaroxaban had a favorable efficacy and safety profile in the trial, but there are concerns about generalizability, Poppas said, pointing to the younger, lower-risk patient population compared with a typical US cohort, for instance. That raises questions about whether many of these patients had rheumatic heart disease, which carries a higher stroke risk but is not as common in the United States as it is in Brazil, Poppas said.

US physicians do not often use DOACs in patients with A-fib and bioprosthetic valves because of the lack of data, she noted. RIVER now provides some “reassuring” evidence, particularly in patients starting treatment early after their mitral valve surgery. “I think in younger patients with low HAS-BLED scores you could consider using this, whereas before you wouldn’t have felt comfortable using that. You would have been without any data to base that on—just a few patients that had been included in other trials,” Poppas said.

Elaine Hylek, MD (Boston University School of Medicine, MA), a discussant for the study, also highlighted the lower-risk patient population included in RIVER. “With that being said, it’s important to realize that you’re trying to isolate the thrombotic risk of the bioprosthetic valve, so I actually think that that was a strength of the study design,” she observed. “However, [it’s] important to also appreciate that we can’t necessarily extrapolate these results to an older population in whom a bioprosthetic valve might actually be the choice.”

Overall, Hylek said, “I think the RIVER trial importantly adds to the field.”