The US Food and Drug Administration (FDA) has concluded that results of the ROCKET AF trial were not significantly affected by accuracy issues with the Alere INRatio
Monitor System.
ROCKET AF was the trial used to support the 2011 approval of rivaroxaban (Xarelto) in patients with nonvalvular atrial fibrillation, and the Alere INRatio Monitor System was used to measure international normalized ratios (INRs) in the warfarin arm of the trial.
Critics have questioned the results of ROCKET AF because the INRatio system (INRatio Monitor or INRatio2 Monitor and INRatio Test Strips) has been shown to give falsely low test results.
If the system provided falsely low INR values for patients in the warfarin arm of ROCKET AF, investigators may have given those patients incorrect doses of warfarin. This could increase the risk of bleeding in those patients and give a false impression of the comparative safety of rivaroxaban.
In addition to increasing the risk of bleeding, over-anticoagulation in the warfarin arm might have reduced the rate of ischemic stroke for these patients. This might have distorted the study’s efficacy results in favor of warfarin.
Because the INRatio system was shown to be defective, it was recalled for certain patients in December 2014 and was withdrawn from the US market in July 2016.
Janssen Pharmaceuticals, Inc., the company developing rivaroxaban in cooperation with Bayer, informed the FDA of the issues with the INRatio system, and its possible impact on ROCKET AF, in September 2015.
In response, the FDA conducted a variety of analyses to assess the impact the INRatio system had on the results of ROCKET AF. Janssen also performed its own analyses.
The FDA said the results of these analyses, which are available on the FDA website, suggest the INRatio system had minimal effects on strokes and bleeding in ROCKET AF.
The FDA therefore concluded that rivaroxaban is a safe and effective alternative to warfarin for patients with nonvalvular atrial fibrillation, no changes in rivaroxaban labeling are warranted, and no other major regulatory action should be taken with respect to rivaroxaban.
This corresponds to the opinion of the European Medicine’s Agency, which released a statement earlier this year saying the defect with the INRatio system does not change the overall conclusions of ROCKET AF.
Still, the issues with rivaroxaban are not fully resolved, as a recent investigation published in The BMJ suggested that Janssen and Bayer knew about concerns regarding the accuracy of the INRatio system while ROCKET AF was underway but allowed the system to be used in the trial anyway.
The BMJ said the companies also neglected to mention these concerns to regulatory authorities prior to rivaroxaban’s approval and later failed to notify regulators about the recall of the INRatio system, and its potential impact on ROCKET AF, in a timely manner.
In addition, Janssen, which was responsible for conducting ROCKET AF, did not tell regulators about a safety program the company launched during the trial to address concerns about the INRatio system.
