In September, rivaroxaban (Xarelto, Bayer/Johnson & Johnson) received a thumbs up at the FDA’s Cardiovascular and Renal Drug Committee meeting, recommending the drug's approval for the prevention of stroke and systemic embolism in non-valvular atrial fibrillation (AF) patients. In a New England Journal of Medicine perspective Oct. 5, two editorialists evaluated the FDA committee’s decision.

Thomas R. Fleming, PhD, and Scott S. Emerson, MD, PhD, from the department of biostatistics at the University of Washington, Seattle, wrote that while data from the ROCKET-AF trial, which the committee analyzed during its decision process, had many strengths, it also had many drawbacks.

“In noninferiority trials, the 'constancy assumption' must be satisfied: the control treatment, as administered in the new trial, must have the same magnitude of benefit relative to placebo as it had in the reference trials used to estimate its effect,” Fleming and Emerson wrote. “The noninferiority margin might need to be modified if the results in the control group are for a different patient population, intensity of treatment, or measure of outcome than was used in the reference trials.”

The FDA had concerns with ROCKET-AF that stemmed from the nonconstancy in terms of the higher-risk patients enrolled in the study, the 5 percent of patients who discontinued follow-up and the fact that the international normalized ratio (INR) for patients in the warfarin group was between two and three only 55 percent of the time—considerably less than the INRs seen in previous trials.

As the FDA analyzed ROCKET-AF, the agency reported a heightened risk of systemic embolism in the rivaroxaban group in patients whose therapeutic range was above the aforementioned thresholds.

“Even in noninferiority trials, per-randomization analyses should be conducted,” Fleming and Emerson offered. “These analyses avoid the bias that occurs with per-protocol on-treatment analyses when patients discontinue their randomized treatment for reasons related to the treatment itself and the patients who do so have a different risk profile from those who don't.”

The authors wrote that the importance of these types of analyses became evident in ROCKET-AF. Another drawback of the study was the fact that on-treatment analysis was based on observations that “were truncated at two days after discontinuation of randomized treatment—a time frame likely to miss events related to inadequate coagulation during the transition to alternative treatment,” the authors added.

During ROCKET-AF, patients administered rivaroxaban saw a greater rate of events and had a higher rate of stroke or systemic embolism compared to those patients who were administered warfarin: 31 vs. 12 detected events, respectively.

“A striking increase in death rates after the discontinuation of randomized treatment further complicates the noninferiority assessment in ROCKET-AF,” the authors noted.

FDA policy notes that a new therapy must be as effective as the alternatives already approved on the market. “Does rivaroxaban satisfy this criterion?” Fleming and Emerson asked. The authors noted that additional data may be necessary that compares rivaroxaban to the already approved dabigatran (Pradaxa).

“The RE-LY results and uncertainty about the validity of the constancy assumption in ROCKET-AF raise concerns that rivaroxaban could be inferior to either dabigatran or warfarin, particularly when the latter is 'used skillfully,'” the authors noted. “The apparent nonconstancy of warfarin treatment between the two trials is problematic, although it's unclear whether the lower average time in therapeutic range in ROCKET-AF reflects greater difficulty in caring for higher-risk patients or is an artifact of the protocol design and trial conduct, including the mandated blinding of INR monitoring.”

The FDA will take the committee’s recommendations and findings into consideration during the approval process. FDA is expected to take action Nov. 5.