FDA Finds Faulty INR Monitor Did Not Affect ROCKET AF Results

Deborah Brauser

October 13, 2016

The faulty device used in the ROCKET AF trial to monitor anticoagulation in patients randomly assigned to receive warfarin compared with the group receiving rivaroxaban (Xarelto, Bayer/Johnson & Johnson) did not significantly affect the trial's overall results, the US Food and Drug Administration (FDA) concludes in a statement posted on its website.

"The FDA concludes that Xarelto is a safe and effective alternative to warfarin in patients with atrial fibrillation," the agency noted in the report.

The original ROCKET AF findings that rivaroxaban was noninferior to warfarin for stroke prevention in these patients were published in 2011 and formed the basis for the FDA's approval of the drug 3 months later.

However, controversy has surrounded the international normalized ratio (INR) measuring device used in the trial to monitor warfarin administration. The Alere INRatio Monitor System was part of a class I recall by the FDA last year because of its "potential to generate inaccurate results," said the agency.

Others have suggested that the device could have made the warfarin results in the trial appear worse than they really were and that falsely low readings could have caused warfarin doses to be unnecessarily increased, which could in turn increase risk for bleeding.

Because of these concerns, the FDA conducted their own series of analyses to evaluate whether the device really did affect the ROCKET AF findings. Their investigators found that "the effects on strokes or bleeding, including bleeding in the head, were minimal."

In addition, they write in the summary of their 74-page report that "no changes in rivaroxaban labeling to reflect the impact of use of the INRatio device in ROCKET are warranted" and "no other major regulatory action should be taken with respect to rivaroxaban."

In a joint statement sent to Medscape Medical News, Bayer and Janssen, the pharmaceutical arm of Johnson & Johnson, note that the companies are "pleased to see that the FDA's reanalysis of the ROCKET-AF trial data confirms that the benefit-risk profile of Xarelto remains positive."

They add that the conclusion comes after and is line with a re-evaluation by the European Medicines Agency in September and a reanalysis of trial data published in Research Letters in The New England Journal of Medicine in February and July by ROCKET AF investigators and committee members, including Keith A.A. Fox, University of Edinburgh, Scotland.

When asked for comment, Dr Fox reiterated these points, telling Medscape Medical News via email that "the FDA findings are entirely consistent with what the Steering Committee found and published in the letters to the NEJM."

"Modest" Effects

The FDA's analyses included examining data for 7125 patients treated with warfarin in ROCKET. They found that readings from the INRatio device at a patient's point of care were almost 13% less than INR readings from a lab-based device at Duke University, Durham, North Carolina.

After use of "mathematical modelling approaches to estimate the clinical outcomes results that might have occurred in ROCKET if a more accurate INR assay has be used to guide warfarin dosing," three of the models predicted 7% to 10% lower expected rates of major bleeding in the warfarin group vs the 3.45 events per 100 patient-years that were observed in ROCKET.

"Overall, these estimated reductions in the rates of bleeding events in the warfarin arm were small enough so that the benefits of rivaroxaban would still outweigh the risks if efficacy were not affected," note the FDA's investigators.

They add that "it is quite likely that patients in the warfarin arm of ROCKET unintentionally received higher doses of warfarin than they would have received if the INRatio device had provided results similar" to those by the Duke lab–based device.

"However, the effects of this increased intensity of anticoagulation on clinical outcomes were likely to have been quite modest."

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