After nine hours of debate, the FDA’s Cardiovascular and Renal Drug committee, who deliberated whether rivaroxaban (Xarelto, Bayer/Johnson & Johnson) would join warfarin and dabigatran (Pradaxa, Boehringer Ingelheim) on the U.S. anticoagulant market, recommend that FDA approve the oral Xa Inhibitor for the prevention of stroke and systemic embolism in non-valvular atrial fibrillation patients. The vote was nine to two with one abstention. The majority, however, said that it merits a claim for patients failing other anticoagulant therapy, rather than a superiority claim or alternative to warfarin.

Panelists discussed dosing regiments, time to therapeutic range (TTR) and whether or not the drug was superior or inferior to warfarin or placebo. Prior to the meeting FDA reviewers argued that data from ROCKET AF were not robust enough, particularly for the current indication. Throughout the day, the panelists agreed that while rivaroxaban may be better than placebo, it does not hold superiority to warfarin when used adequately.

“If you look at the results of the ROCKET AF trial in the way it was designed there would be little to talk about,” Robert M. Califf, MD, vice chancellor clinical research at Duke University Medical Center in Durham, N.C., and director of the Duke Translational Medicine Institute and senior author of the ROCKET AF trial, said during a presentation. “We have been wrestling with these issues because of the global implications.”

“Rivaroxaban is noninferior for stroke or systemic embolism prevention by all analyses, and there were also lower rates of intracranial and fatal bleeding, categories that are valued as most important,” Califf added.

Califf addressed key questions raised by the FDA regarding dose and regiment selections and TTR. In previously released briefing documents, FDA argued that a twice daily dose of rivaroxaban may have had better outcomes; however, Califf argued that Phase II data supported either once or twice daily dosing and said that it would not have been “irrational” to have studied a twice-daily dose of the drug.

Steven Nissen, MD, chair of the department of cardiovascular medicine at the Cleveland Clinic Foundation Heart and Vascular Institute in Cleveland, argued that the fact that rivaroxaban has nearly half the half-life when compared with dabigatran, a twice-daily drug, speculated that the once a day decision was a marketing decision, rather than a scientific one.

"ROCKET AF's primary objective was met," Califf argued. “We designed a trial in good faith that set out to find an alternative to warfarin.” Additionally, he said that comparing ROCKET AF to RE-LY is “hazardous,” due to the fact that these studies included different drugs, different study designs, different patient population and different regions.”

Califf said that rivaroxaban is an important alternative to warfarin and additionally for patients who cannot tolerate dabigatran due to the increased risk of GI bleeds.

An additional issue that FDA brought up with ROCKET was the fact that the researchers did not stipulate an algorithm for the management of INR, Martin Rose, MD, JD, efficacy data clinical reviewer of the FDA’s Division of Cardiovascular and Renal Products, said. “RE-LY and ARISTOLE used an algorithm, it wasn’t mandated but at least they had paper in front of them at the site when they were performing this,” Rose offered. Additionally, he said concerns stemmed from the fact that site level data for TTR varied within study sites, and the fact that enrolled sites did not manage warfarin well. “INR control in ROCKET was worse than in other recent trials, potentially biasing the overall results in favor of rivaroxaban,” Rose offered.

“The current landscape of anticoagulant therapy is important. Now there is an alternative to warfarin. RE-LY demonstrated that dabigatran was robustly noninferior and that it is reasonable to ask the same of rivaroxaban. Rivaroxaban does not meet this test,” Rose concluded.

Nissen offered that because the percentage that INR was in the therapeutic range was lower in ROCKET AF; this hindered the effectiveness of INR management during the trial. “Knowing that we needed to see robust evidence of non inferiority, it would have been prudent to take precautions,” to ensure that this occurred.

"Rivaroxaban is superior to placebo; however, in terms of superiority clearly it [rivaroxaban] is not superior to warfarin," Panelist Sanjay Kaul, MD, director of the cardiovascular diseases fellowship training program at Cedars-Sinai Heart Institute in Los Angeles, said.

Nissen and others said that an additional post-marketing study would be beneficial to understand the benefits in AF patients. Nissen offered that if this type of trial takes place, “please get a TTR in the mid 60s.”