Should Rovaroxaban Be Approved by the FDA?

At the Federal Drug Administration’s Cardiovascular and Renal Drug Committee meeting this past September, rivaroxaban (Xarelto) was approved for the prevention of stroke and systemic embolism in non-valvular atrial fibrillation patients. Still, two editorialists who were not completely sold on the new drug evaluated the FDA committee’s decision in a New England Journal of Medicine editorial.

Dr. Thomas R. Fleming and Dr. Scott S. Emerson of the department of biostatistics at the University of Washington in Seattle wrote that the ROCKET-AF trial that was analyzed by the committee during the decision process, presented many strengths, along with many weaknesses.

The FDA trepidations regarding the ROCKET-AF trial included the non-constancy in terms of the higher-risk patients enrolled in the study, the five 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% of the time. This number was considerably less that the INRs seen in previous trials.

“In non-inferiority 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 non-inferiority 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.”

As the ROCKET-AF was being analyzed, the FDA found a heightened risk of systemic embolism in the rivaroxaban group among patients whose therapeutic range was exceeding the previously declared thresholds.

Fleming and Emerson suggested that per-randomized analyses should be conducted even in non-inferiority trials. They added, “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 ROCKET-AF illustrated the significance of these types of analyses.

Another drawback of the study was 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,” according to the authors.

Patients that were administered rivaroxaban saw a greater rate of events and had a higher rate of stroke or systematic embolism compared to those patients who were administered warfarin during ROCKET-AF (31 versus 12 detected events, respectively). The authors also noted a striking increase in death rates after the discontinuation of randomized treatmentthat further complicated the non-inferiority assessment in ROCKET-AF.

“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 non-constancy 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 is expected to take action on November 5^th when it will take the committee’s recommendations and findings into consideration during the approval process.

Around the Web

NEJM: Should FDA Approve Rivaroxaban Based on ROCKET-AF? [Cardiovascular Business]

Evaluating Rivaroxaban for Nonvalvular Atrial Fibrillation - Regulatory Considerations [Proceedings from The New England Journal of Medicine]