Xarelto Clinical Trial Data Questioned Due to Use of Faulty Device

Serious questions have been raised about the validity of the clinical trials that led to approval of the controversial anticoagulant Xarelto, which is the subject of thousands of lawsuits filed on behalf of individuals who have suffered severe and uncontrollable bleeds. 

In a report published in The BMJ (subscription required) on December 3, researchers warns that a defective device used during the clinical trials may have led to an underestimation of the rate of Xarelto bleeding complications.

The device, the INRatio, by Alere, was used in the ROCKET-AF clinical trials, which compared the rate of bleeding events between Xarelto (rivaroxaban) and Coumadin (warfarin). The device measured the levels of warfarin in patients’ blood and was used to adjust their dosage. However, in December 2014 there was an INRatio recall after it was discovered that some of the devices could return results that were falsely low. The recall came after Alere received nearly 19,000 reports of malfunctions, 14 of which resulted in serious injuries.

The recall could affect the ROCKET-AF results, because falsely low readings could have resulted in warfarin patients being given too high a dose, increasing their risk of bleeding. If the device caused excessive bleeding among warfarin patients, it could have given the false impression that Xarelto had a lower rate of bleeding events.

The BMJ noted that the ROCKET-AF clinical trials, used to convince the FDA to grant Xarelto approval, was already the subject of serious concerns, long before the INRatio recall was linked to the study. Many of those criticisms were focused on patients’ use of warfarin.

“Even before the recall, the ROCKET-AF trial had been criticized for the relatively short time that participants taking warfarin were in the correct therapeutic range of the drug,” The BMJ noted. “The implication of the criticism was that patients’ use of warfarin was not adequately controlled, which, if correct, would have the effect of making rivaroxaban seem safer and more effective.”

The BMJ noted that it contacted Johnson & Johnson and Bayer Healthcare, the manufacturers of Xarelto, in September, about the INRatio recall. However, Johnson & Johnson officials indicated that they were unaware of it.

Xarelto Bleeding Problems

Xarelto (rivaroxaban) is part of a new class of blood thinners introduced in recent years as a replacement for warfarin. It is most commonly prescribed to reduce the risk of blood clots and strokes among patients with atrial fibrillation or following hip or knee replacement surgery.

Known as a factor xa drug, Xarelto was designed to compete with Boehringer Ingelheim’s Pradaxa, which is another member of the same new class of medications, which are promoted as easier to use than warfarin, since they do not require consistent monitoring to maintain appropriate dosage. A third member of this new class is Eliquis, and all three medications have been aggressively promoted in direct-to-consumer advertisements in recent years.

Problems with Xarelto, Pradaxa and Eliquis have been reported due to the lack of an antidote for any of the medications at the times they were released, often leaving doctors helpless to stop bleeds that may develop among users of the blood thinners.

While users of warfarin can be given a dose of vitamin K to reduce the blood thinning effects of the medication, there were no similar reversal agents available for Pradaxa, Xarelto or Eliquis until recently.

In October, the FDA approved the use of Praxbind, a reversal agent for Pradaxa. This has been seen by many observers as a clear market advantage for Pradaxa in this lucrative treatment field, increasing the pressure on the makers of Xarelto to finalize their own reversal agent.

Portola Pharmaceuticals has said it expects to present a Xarelto reversal agent for approval this month.

Xarelto Lawsuits

Bayer and Johnson & Johnson are currently facing a growing number of Xarelto lawsuits filed on behalf of individuals and families throughout the U.S., alleging that the drug makers failed to adequately research the medication, warn about the bleeding risk or the lack of an effective reversal agent.

Several thousand similar Pradaxa lawsuits were filed against Boehringer Ingelheim following it’s approval, and that drug maker ultimately agreed to pay about $650 million in settlements for Pradaxa users in May 2014, with an average of about $150,000 per claim. However, additional cases continue to be filed by individuals who have suffered injuries since the date of the settlement.

There are currently about 3,000 lawsuits over Xarelto bleeding problems pending throughout the federal court system, which are currently centralized for pretrial proceedings as part of an MDL, or multidistrict litigation.

Unless Xarelto settlements are reached to resolve the litigation, the first trials are expected to begin by August 2016.