An investigation by the British Journal of Medicine (BMJ) has raised questions about the validity of the pivotal ROCKET-AF trial, the results of which formed the basis of rivaroxaban’s approval. ROCKET-AF trial results were published in The New England Journal of Medicine in 2011. The study, which included more than 14,000 patients and took place between 2006 and 2010, found the novel oral anticoagulant rivaroxaban to be non-inferior to warfarin for the prevention of stroke or embolism in patients with non-valvular atrial fibrillation. According to the BMJ report, a faulty device for testing international normalized ratio (INR) may have been used in the warfarin patient cohort.
In December 2014, the U.S. FDA issued a class I recall notice on the point-of-care devices used to measure INR, noting that the devices could deliver results that were clinically significantly lower than a laboratory method in patients with conditions such as abnormal hematocrit levels or illnesses known to increase fibrinogen levels, such as infections or inflammatory diseases. Researchers from the original ROCKET-AF trial reviewed patient-level data and reported that 37 percent of patients in the warfarin cohort had a condition that could have been affected by the INR devices, though they concluded that, despite this, rivaroxaban remained non-inferior to warfarin, without an increase in major bleeding. The European Medicines Agency also conducted an analysis and determined that the trial was not compromised by this recent development.
However, some in the medical community aren’t convinced about these findings. Deborah Cohen, MD, associate editor for BMJ, called for an independent analysis of the ROCKET-AF trial. Thomas Marciniak, MD, a former cardiovascular and renal drug reviewer at the U.S. FDA, agreed: “The care for the warfarin control arm patients appears to have been compromised.”
The U.S. FDA is involved in an investigation, which is underway, to determine if the drug’s manufacturer, Johnson & Johnson, had evidence that the device was faulty while the trial was being conducted. A spokesperson for the U.S. FDA said that the agency has not changed its recommendations for the current use of rivaroxaban, which was the most prescribed direct oral anticoagulant in 2014.
Sources: Cohen D. Rivaroxaban: can we trust the evidence? BMJ. 2016;352:i575; The New York Times, “FDA asks if faulty blood monitor tainted Xarelto approval,” February 22, 2016.