RIVER: Rivaroxaban Opponents Warfarin in AF, Mitral Bioprosthesis

The insist oral anticoagulants (DOACs) took cardiology by storm a decade ago when trials showed they had been at the least as protected and efficient as warfarin for several indications, particularly lowering stroke threat in atrial fibrillation (AF). But the trials that established the medication in AF largely excluded sufferers with valve illness, leaving them with no correct proof scandalous in reinforce of the medication.

Now that proof scandalous is a miniature firmer. In the RIVER trial, medicine with the element Xa inhibitor rivaroxaban (Xarelto, Bayer/Janssen) used to be noninferior to warfarin for a predominant endpoint that included loss of life, cardiovascular events, stroke, and bleeding over 1 year in more than 1000 sufferers with AF and bioprosthetic mitral valves.

Unlike warfarin, rivaroxaban would no longer require anticoagulation monitoring for dosage titration, has more constant outcomes, and so “represents an attractive alternative for this population,” talked about Otavio Berwanger, MD, PhD, when presenting the RIVER outcomes November 14 within the middle of the  American Coronary heart Association (AHA) Scientific Sessions 2020 virtual meeting.

Patients with AF and bioprosthetic mitral valves had been largely absent from the main nonvalvular AF DOAC trials, and “most of our ideas in sufferers with valve illness are in accordance to expert blueprint,” Berwanger talked about. As an illustration, ARISTOTLE with apixaban (Eliquis, Pfizer/Bristol-Myers Squibb) and ENGAGE-TIMI 48 with edoxaban (Lixiana, Daiichi-Sankyo) between them included only about 160 sufferers with bioprosthetic mitral valves. There had been none within the main rivaroxaban trial, ROCKET-AF.

RIVER “objects the stage to higher survey this population,” talked about Berwanger, from Study Institute HCor and Albert Einstein Sanatorium, Sao Paulo, Brazil, who may be senior creator on the trial’s identical-day newsletter within the Fresh England Journal of Medication.

Of reveal, females made up about 60% of the population in RIVER, which used to be conducted at 49 centers in Brazil; the total population’s median age used to be 59 years.

Consequently, they had been presumably at worthy decrease threat for stroke in comparison with the older sufferers within the three nonvalvular AF trials, observed Elaine M. Hylek, MD, MPH, invited discussant following the Berwanger presentation. As an illustration, she talked about, the imply age in ROCKET-AF used to be 73 years.

That method “we may presumably perchance well simply no longer be in a space to extrapolate the efficacy and safety from this explicit survey to older sufferers in whom a bioprosthetic valve would seemingly be most accepted,” talked about Hylek, from Boston College School of Medication in Massachusetts.

The RIVER population used to be indeed “superb young for sufferers getting bioprosthetic valves,” agreed Athena Poppas, MD, Brown College School of Medication, Windfall, Rhode Island, in an interview. That cautions in opposition to applying their expertise to, to illustrate, North American or European populations with AF and prosthetic mitral valves. The on the total older age of the latter sufferers may presumably perchance well simply attach them at greater bleeding threat than the sufferers in RIVER.

Also, or no longer it is that it is doubtless you’ll presumably perchance well presumably mediate of that many sufferers within the Brazilian trial obtained their bioprosthesis attributable to rheumatic valvular illness. Such an inflammatory coronary heart course of would seemingly elevate their threat for stroke, observed Poppas, who used to be no longer part of RIVER. “Their atria may presumably perchance well simply furthermore be bizarre and at greater threat of thrombosis.” That will presumably perchance well also complicate comparisons with other populations.    

Rheumatic coronary heart illness drove the necessity for a prosthetic mitral valve in about 20% of sufferers in RIVER, Berlanger instructed theheart.org | Medscape Cardiology, “so we factor in most of its sufferers are equivalent to sufferers in North American and Europe.”

RIVER randomly assigned 1005 adults with AF and bioprosthetic mitral valves to receive rivaroxaban, 20 mg/day (or 15 mg/day in sufferers with renal dysfunction), or warfarin titrated to a map global  normalized ratio of two.0 to some.0 on an originate-label basis.  Randomization occurred at the least 48 hours after the implantation surgical treatment; it used to be within 3 months of surgical treatment in 18.8% of the cohort and at the least 1 year afterward in about 63%.

Patients assigned to rivaroxaban or to warfarin fared equally over 12 months for the main endpoint of all-home off mortality, stroke, transient ischemic assault, predominant bleeding, valve thrombosis, non-neurologic systemic embolism, or hospitalization for coronary heart failure.

The protocol called for the main final result to be interpreted with admire to restricted imply survival time (RMST)—that is, common time free from a predominant final result match, which reflects the discover online page below the survival curve— RIVER documentation explains. The time to such an match on warfarin used to be subtracted from that for rivaroxaban, yielding an RMST that, when sure, indicated a rivaroxaban profit.

The imply time till a predominant match by map-to-contend with prognosis used to be 347.5 days for the 500 sufferers assigned to rivaroxaban and 340.1 days for the 505 receiving warfarin, for a rivaroxaban RMST of seven.4 days at 1 year (P < .001 for noninferiority; P = .10 for superiority).

In two sensitivity analyses, the rivaroxaban RMST for outcomes used to be 9.6 days on a per-protocol basis and 10.5 days on an as-treated basis. Both had been major for noninferiority at P < .001 and likewise for superiority at P = .01, Berlanger reported.

These analyses therefore “counsel that rivaroxaban used to be no longer only noninferior, but also superior to warfarin for the main endpoint,” he proposed.

Table. Chosen Secondary Outcomes at 1 Year in RIVER, Rivaroxaban vs Warfarin

In a subgroup prognosis of the 189 sufferers randomly assigned within 3 months of bioprosthetic valve surgical treatment (18.8% of the population), the 94 within the rivaroxaban neighborhood showed a prime profit over the 95 warfarin recipients for the main endpoint, at a hazard ratio of 0.31 (95% CI, 0.12 – 0.79; P = .01) and an RMST of 35.2 days.

“Positively there may be a provocative imprint there that deserves to be additional tested,” Berwanger talked about. “No trials within the past have included one of these population,” he instructed theheart.org | Medscape Cardiology.

The rivaroxaban noninferiority finding in RIVER’s sufferers may presumably perchance well simply effectively be a DOAC class stop, Poppas speculated, worthy as the medication collectively showed at the least identical efficacy and safety in nonvalvular AF. That particularly applies to the other element Xa inhibitors, apixaban and edoxaban, she talked about, but potentially also the insist thrombin inhibitor dabigatran (Pradaxa, Boehringer-Ingelheim).

RIVER used to be funded by Bayer and the Brazilian Ministry of Health. Berwanger discloses receiving be taught grants from AstraZeneca, Bayer, Amgen, Novartis, Pfizer, Boehringer-Ingelheim, and Servier. Hylek discloses receiving be taught reinforce from Abbott, Bristol-Myers Squibb, Janssen, Boehringer-Ingelheim, Squibb, Medtronic, and CryoLife; consulting for Bayer, Boehringer-Ingelheim, BMS/Pfizer, and Janssen; and receiving honoraria from Boehringer-Ingelheim and BMS/Pfizer. Poppas had no relevant disclosures.

American Coronary heart Association (AHA) Scientific Sessions 2020. LBS.03. Offered November 14, 2020.

N Engl J Med. November 14, 2020. Summary

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