FDA: ROCKET AF Results Not Affected by Faulty INR Testing in Warfarin Arm

The US Food and Drug Administration (FDA) has concluded that inaccurate results from the point-of-care device used to measure international normalized ratio (INR) values in warfarin-treated patients as part of the ROCKET AF clinical trial did not materially affect the study’s findings.

The FDA’s Center for Drug Evaluation and Research (CDER), which today published the results of the latest review of data from the ROCKET AF clinical trial, states that while “it is quite likely” that patients treated with warfarin in the clinical trial received unintentionally higher doses of the anticoagulant, “the effects of this increased intensity of anticoagulation on clinical outcomes were likely to be quite modest.”

European regulators, conducting a similar review, reached similar conclusions last February.

First presented in 2010, ROCKET AF, a randomized clinical trial testing rivaroxaban (Xarelto, Bayer/Janssen Pharmaceuticals) in patients with nonvalvular atrial fibrillation, showed the factor Xa inhibitor was noninferior to warfarin for preventing stroke or systemic embolism without increasing the risk of major or clinically relevant bleeding.

The results of the study have come under fire, however, mainly because of concerns about what went on with INR testing in the warfarin arm of the randomized trial. As reported by TCTMD, the study investigators have performed multiple analyses of the trial, including one in February 2016 and another in July 2016, given fears the INR values might have distorted the study’s findings.

The devices in question—the INRatio and the INRatio2 PT/INR Monitor System (Alere)—were voluntarily withdrawn from the US market this summer after discussions between the FDA and Alere. Issues with INRatio were raised as early as early as 2005, according to one report, but mainly gained traction in late 2014 when Alere issued a medical device correction—through a class I FDA recall notice—warning that the devices should not be used in patients with certain conditions because of the possibility INR results would be lower than expected with laboratory testing.

This raised the possibility that patients in the warfarin arm of ROCKET AF might have been overanticoagulated and led to an excess of bleeding events in the warfarin arm, including an increase in hemorrhagic stroke, which was a component of the primary endpoint. “These distortions would tend to bias the results in favor of rivaroxaban in comparisons of bleeding rates versus warfarin, and possibly also bias the primary endpoint in favor of rivaroxaban,” according to CDER reviewers.

Running the INR Results Against Lab-Based Testing

In a review of 7,125 warfarin-treated patients who had same-day samples tested using the point-of-care INR device and a laboratory-based device at Duke University, the FDA found the INR values were, on average, 13% lower than when tested in the laboratory. Other analyses also assessed the risk of bleeding in patients with varying degrees of discordancy based on the point-of-care and laboratory INR values. The agency then performed mathematical modeling to estimate clinical outcomes that might have occurred had ROCKET AF used a more accurate INR assay to guide warfarin dosing.

The analyses predicted a small decrease in the expected rate of major bleeding in the warfarin-treated patients compared with the actual rate of 3.45 events per 100 patient-years in the trial. Using different models, the reduction ranged anywhere from 7% to 10% of the observed rate. “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 its risks if efficacy were not affected,” the CDER report says.

Based on their review, the FDA believes that if the INR devices had performed as well as the laboratory-based assessments, it is unlikely that the “benefit/risk profile of rivaroxaban compared to warfarin would have been notably different from the profile based on the observed results of ROCKET AF.” Given that, there is no need to change the label to reflect the impact of the INRatio device in the trial, and no other regulatory action is needed, says the FDA.

Two weeks ago, the controversy surrounding the INR values took yet another twist when the BMJ reported that, because of concerns about inaccurate reading, Janssen initiated a safety program shortly after the ROCKET AF trial began. The journal stated that Janssen did not reveal the results of their program—known as the Covance recheck program—to the trial’s data and safety monitoring board, Bayer, or the FDA before rivaroxaban was approved in 2011. Janssen denied the “central premise” of the journal’s report.   


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  • Center for Drug Evaluation and Research. ROCKET AF Reanalysis Reviews. http://www.fda.gov/Drugs/DrugSafety/ucm524678.htm. Published and accessed on: October 11, 2016.

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