Public Citizen slams rivaroxaban, ROCKET-AF to FDA

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Despite receiving praise from the FDA’s Cardiovascular and Renal Drug Advisory Committee, the anticoagulant rivaroxaban (Xarelto, Bayer/Johnson & Johnson) is now getting scrutiny from Public Citizen. In a letter dated Oct. 20 and sent to the FDA, Public Citizen questioned the safety and efficacy of the drug and urged that it not be approved to prevent strokes and systemic embolism in patients with atrial fibrillation (AF).

While the FDA committee recommended last month that the FDA approve the oral Xa inhibitor for the aforementioned indication, Public Citizen said that the drug may cause “a rebound occurrence of strokes when the medication is discontinued, and the uncertainty surrounding the clinical trial testing the drug prompted three FDA reviewers to explicitly recommend against approving the drug for this additional use,” according to a statement.

According to Public Citizen, there were problems with the ROCKET-AF trial, which compared rivaroxaban to warfarin. “Problems with this trial centered on the inadequate use of warfarin, the standard treatment to prevent such strokes, in the control population, thereby falsely making rivaroxaban appear superior,” according to advocacy group. Additionally, Public Citizen Health Research Group representatives said that other concerns include the trial researcher’s decision to test a single, once-daily dose of rivaroxaban, despite previous claims that a twice-daily regimen was safer.

“With so much uncertainty as to whether rivaroxaban is truly as safe and effective as existing therapy to prevent such strokes, and with two drugs already available to treat this condition, the FDA must not rush to approve rivaroxaban for such a broad use,” wrote Sammy Almashat, MD, a researcher with Public Citizen’s Health Research Group and co-author of the letter.

Earlier this month, Thomas R. Fleming, PhD, and Scott S. Emerson, MD, PhD, from the University of Washington, Seattle, also questioned whether the FDA should approve rivaroxaban based on the ROCKET-AF trial. In the New England Journal of Medicine perspective, Fleming and Emerson noted that the ROCKET-AF trial had nonconstancy in terms of the higher-risk patients enrolled in the study and in 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—less than what was seen in previous trials.

Rivaroxaban was approved in July 2011 for the prevention of blood clots following orthopedic surgery. Currently, the companies are asking the FDA to expand the drug’s indication for stroke and systemic embolism in AF patients. If approved, rivaroxaban would join warfarin and dabigatran (Pradaxa, Boehringer Ingelheim) on the anticoagulant market.

During the Sept. 8 FDA committee meeting, some members argued that rivaroxaban was superior to placebo and that it was nonsuperior to warfarin, while others said that they were concerned with the fact that the researchers did not use an algorithm for the management of INR during ROCKET-AF. Committee member’s agreed that the drug should be restricted for use as a third-line treatment only to be used when warfarin and dabigatran fail.

“The FDA should follow the recommendations of its expert reviewers and reject the new request to approve rivaroxaban to prevent strokes until the drug’s manufacturers conduct another, better-performed clinical trial,” Public Citizen wrote. Lastly, it called on the FDA to further investigate the design of the ROCKET-AF clinical trial.