ROCKET AF Controversy: New INR Analysis Backs Primary Results

Deborah Brauser

July 18, 2016

CHAPEL HILL, NC — In response to a letter to the editor of the New England Journal of Medicine stating that ROCKET AF's validity could be diminished because of unanswered questions surrounding the faulty international normalized ratio (INR) monitoring device that was used, the trial's investigators presented results from additional analyses―which they say are consistent with their original findings.

Both the letter[1] and response[2] were published online July 6, 2016.

As reported by heartwire from Medscape, there has been ongoing controversy about the way ROCKET AF obtained INR readings on its way to concluding that rivaroxaban (Xarelto, Bayer/Johnson) was noninferior to warfarin for preventing major embolism or stroke in those with nonvalvular atrial fibrillation.

The US Food and Drug Administration (FDA) issued a class 1 recall at the end of 2014 after Alere sent out an alert about its INRatio monitor system, saying the device could give clinically lower INR values vs those found in lab readings in certain patients. Although this device was used to measure INR levels in the ROCKET AF participants, investigators have said that they didn't know about the alert until the fall of 2015.

The European Medicines Agency (EMA) issued their own report this past February, noting that "Xarelto can continue to be used as before, in line with the current prescribing information."

"Although the EMA found insufficient evidence to alter the benefit/risk conclusion of the original rivaroxaban study, the agency did not address several important questions," writes Dr J Robert Powell (University of North Carolina, Chapel Hill) in the new letter.

This includes the number of patients in the warfarin-treated group who had major bleeding because of errors in the Alere device and whether this resulted in "a change in the percentage of time that patients receiving warfarin were in the therapeutic range."

Stored Blood Samples

In the authors' reply, Dr Manesh R Patel and Anne S Hellkamp (Duke Clinical Research Institute, Durham, NC) and Dr Keith AA Fox (University of Edinburgh, Scotland) report that they're releasing data on central-lab INR measurements on stored blood samples from ROCKET AF to try to answer these questions and "provide further insight."

The blood sample draws occurred at 12- and 24-week follow-ups and represented 22,250 of the 356,654 point-of-care tests performed (6%).

Although 13% of the samples obtained at 12 or 24 weeks from the warfarin group had discrepancies between point-of-care and lab testing, only 4% of samples from both follow-ups had discrepancies. "These discrepancies were unrelated to the presence of conditions (eg, inflammatory disorders, infections, and anemia) that are listed in the FDA recall notice," write the investigators.

The warfarin-treated participants with value discrepancies had higher rates of bleeding and stroke vs those without discrepancies. In rivaroxaban-treated participants, those with discrepant INR values also had higher rates of bleeding but lower rates of stroke vs those without discrepant values.

When researchers reexamined ROCKET AF outcomes after removing those with discrepant values, there were 1.46 strokes or systemic embolisms per 100 patient-years (the primary efficacy end point) in those receiving rivaroxaban vs 1.37 per 100 patient-years in those receiving warfarin (P=0.03 for noninferiority).

And the combined primary safety end point of major and nonmajor bleeding showed 11.36 and 12.42 events per 100 patient-years, respectively.

"These results are consistent with the originally reported overall trial results," write the researchers, although they admit that the new analyses had some limitations.

"To be fully informative, we would need to provide paired central-laboratory and point-of-care INR values throughout the trial, and these values are not available."

As for the devices at the center of the controversy, Alere announced last week that it is initiating a voluntary withdrawal of all INRatio and INRatio2 monitoring systems from the US market.

Neither Powell nor the investigators report any conflicts of interest in their letters. The ROCKET AF study was sponsored by Johnson & Johnson and Bayer.

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