Separating the Rumors from the Science: Rivaroxaban

CoMeta™ Life Science adds pharmaceutical Litagion® agent profiles to CoMeta focusing on evaluating the liability that could arise from a manufacturer’s failure to warn physicians regarding the risk of specific bodily injuries. One pharmaceutical Litagion agent in CoMeta is rivaroxaban, widely known by its trade name Xarelto®. Rivaroxaban belongs to the new oral anticoagulants (NOACs) class of drugs which seek to replace warfarin as the primary blood thinner in the market. The advantage of NOACs over warfarin is their administration. Warfarin requires the establishment of a 2-4 week dosing regimen for every patient while NOACs have straightforward dosage directions. Rivaroxaban is currently the top seller among NOACs. However, it has been negatively portrayed in the news due to a faulty blood testing device, cover up accusations, and existing multi-district litigation (MDL) due to enter court trials this year.

The controversy surrounding rivaroxaban began in 2014 when a blood testing device by Alere was recalled for giving out inaccurate data. This device had been used in a Duke University study sponsored by Janssen, the pharmaceutical arm of Johnson and Johnson, along with their partner Bayer in order to compare rivaroxaban’s safety and effectiveness to warfarin’s. The study was called The Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF). The results were published in the New England Journal of Medicine (NEJM) in 2011[1]. The U.S. Food and Drug Administration (FDA) used these results to approve rivaroxaban for the U.S. market later that year; followed by the European Medicines Agency (EMA) in 2013. When it became known the Alere device was used in the ROCKET AF study, scientists were concerned the warfarin study participants may have received a higher than necessary dosage.  Since a higher warfarin dosage can lead to dangerous bleeding events, the device’s malfunction would have given an advantage to rivaroxaban in the study.

In response to the scrutiny regarding rivaroxaban’s effectiveness, the same Duke research team published another NEJM article in February 2016 to revalidate the results[2], but the second article was also criticized. Critics claimed the researchers had simply re-analyzed their previous data to confirm their results. Other observers suggested a different and superior validation method would have been able to compare the device readings against a second set of results from the same patients analyzed by another procedure; however, since these results were not presented, scrutinizers assumed they could not be accomplished.

This assumption turned out to be false.

Shortly after the publication of the second NEJM article, an intrepid New York Times reporter found a footnote in a federal legal briefing stating that blood samples from the warfarin patients were tested at a central lab twice during the original Duke study. These blood samples were still available for testing when the second rivaroxaban article was published. The withholding of this information by Janssen and Bayer resulted in accusations that they were trying to deceive the NEJM[3]. Yet, at the same time, the EMA concluded their investigation into the potential role of the Alere device and concluded the device did not alter the ROCKET AF’s key findings. In 2016, the FDA released a statement also concluding that the Alere device did not distort the ROCKET AF’s results.

Stepping back from the news and accusations, what does CoMeta Life Science convey about rivaroxaban and failure to warn physicians for bodily injuries? Two bodily injury hypotheses are profiled: blood injury and cardiovascular disease. The general causation (GC) risk scores are analyzed as a comparison of rivaroxaban to warfarin and other NOACs. Presently, the rivaroxaban hypothesis for blood injury has a low general causation (GC) risk score of -0.65. This indicates that scientists generally reject the hypothesis that rivaroxaban confers greater risk than warfarin or other NOACs for blood injuries. The rivaroxaban hypothesis for cardiovascular disease has a GC of -0.68, which also indicates rejection of the exposure-harm hypothesis.

Lawsuits regarding rivaroxaban causing serious harm or death were consolidated into MDL 2592 in 2014. The first bellwether trial is scheduled for September 2017. Praedicat is closely monitoring these proceedings. While it can be hard to establish the truth regarding rivaroxaban with the media and lawsuits, the EMA and the FDA have stood by the data from the rivaroxaban ROCKET AF clinical trial. Additionally, CoMeta Life Science does not support an association between rivaroxaban and blood injury or cardiovascular disease.