The U.S. Food and Drug Administration (FDA) approved the blood thinner Xarelto (Rivaroxaban) in 2011. However, the highly-controversial anticoagulant caused thousands of lethal bleeding events and injuried many patients who took it, in less than four years. Other Novel Oral Anticoagulants (NOACs) such as Pradaxa (dabigatran) and Eliquis (apixaban) also caused many adverse reactions, leading to an impressive number of litigations filed in court. Xarelto lawsuits are, to date, well over 2,000, with at least 1,600 mass tort cases centralized in the Multidistrict Litigation in the Eastern District of Louisiana. Another 300 plaintiffs who complained about the Xarelto adverse events joined a class-action suit in Pennsylvania.
Janssen and Bayer are accused, according to the various disputes, of not providing sufficient warnings to patients and doctors about the drug’s risks and dangers. The Big Pharma allegedly hide crucial information about Xarelto bleeding events, and since no antidote is available, patients’ lives are always at risk if any accident happens. Since a new reversal agent has been approved for its competitor dabigatran, drugmakers that manufacture rivaroxaban lost a significant profit margin. According to FiercePharma, the market for blood thinners is one of the largest among all drug categories. Experts projected an estimated increase for the blood thinner’s market of more than $15 billion by the next two years. Xarelto is one of the leading medications in this category, with sales that may grab up to 20% of total market shares.
The FDA’s difficult approval of Xarelto
When the FDA evaluated the approval of rivaroxaban back in 2011, several members of the advisory board expressed some concerns about the clinical trial that Bayer used to prove the drug’s superiority over its competitor Warfarin, the ROCKET-AF trial. FDA recommendation was against Xarelto’s approval because of “a lack of substantial evidence that Xarelto will have its desired effect when used as recommended in labeling” . Comparing Warfarin’s effectiveness in preventing stroke and embolism to rivaroxaban, patients were not properly evaluated. Many of them spent more than half of the time above the adequate international normalized ratio (INR). This parameter is a measurement of the effectiveness of an anticoagulant and defines the time needed for blood clots to form. Since the INR was skewed, the entire results of the study have been contested.
Regardless, the regulatory agency granted approval to Xarelto in July 2011. The drug was indicated to treat Deep Vein Thrombosis (DVT) and to reduce the risk of clotting in patients undergoing knee or hip replacement surgery. Later, the FDA also approved Bayer’s NOAC for many additional indications, including preventing stroke risk in subjects suffering from acute coronary syndrome and atrial fibrillation.
Xarelto bleeding events and side effects
Over the course of the subsequent years, many studies provided new evidence on Xarelto dangerousness [2, 3]. Subjects who took any NOAC, including Eliquis (apixaban) or dabigatran, suffered from a heightened risk of lethal gastrointestinal hemorrhages as well as several other potentially fatal bleeding accidents. Compard to patients treated with older anticoagulants, the risk of bleeding was two-fold higher. An additional risk of liver damage and injury was also found in patients treated with Xarelto, posing further concerns about its alleged safety .
In 2014, the regulators required Janssen and Bayer to update the drug’s label with a new warning, the “black box.”. This warning is the most urgent one used by the FDA to alert patients about life-threatening adverse reactions that may cause their death if the drug is not used properly .
Xarelto manufacturers later announced in a press release, that they published two new clinical trials that allegedly supported the medicine’s safety. Janssen Pharmaceuticals, a subsidiary of Johnson and Johnson, performed a large study in a real-world setting that should demonstrate that rivaroxaban can be used safely in daily care. The aim of the pharmaceutical companies is to provide consistent evidence that confirms those found in their pivotal Phase 3 clinical trial ROCKET-AF. This study is a Post-Market Safety Surveillance that includes additional information on Xarelto’s effectiveness in reducing the risk of stroke in people suffering from atrial fibrillation. The second study is, instead, an observational one named XANTUS and aims at showing the world rivaroxaban’s superiority over all its counterparts. However, there’s no comparator arm in either study, so there’s no way to determine if Xarelto is actually better than Warfarin, for example. Also, both clinical trials have been paid by Bayer, the other drugmaker that markets the new blood thinner as a partner of Janssen.
Article by Dr. Claudio Butticè, PharmD.
- Food and Drug Administration. FDA draft briefing document for the cardiovascular and renal drugs advisory committee. September 8, 2011. http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/ucm270795.htm
- Chang, Hsien-Yen; Zhou, Meijia; Tang, Wenze; Alexander, G. Caleb; Singh, Sonal (2015-04-24). “Risk of gastrointestinal bleeding associated with oral anticoagulants: population based retrospective cohort study”. The BMJ 350: h1585. doi:10.1136/bmj.h1585. ISSN 1756-1833. PMC 4413867. PMID 25911526.
- Holster, I. Lisanne; Valkhoff, Vera E.; Kuipers, Ernst J.; Tjwa, Eric T. T. L. (2013-07-01). “New oral anticoagulants increase risk for gastrointestinal bleeding: a systematic review and meta-analysis”. Gastroenterology 145 (1): 105–112.e15. doi:10.1053/j.gastro.2013.02.041. ISSN 1528-0012. PMID 23470618.
- Russmann, Stefan; Niedrig, David F.; Budmiger, Mathias; Schmidt, Caroline; Stieger, Bruno; Hürlimann, Sandra; Kullak-Ublick, Gerd A. (2014-08-01). “Rivaroxaban postmarketing risk of liver injury”. Journal of Hepatology 61 (2): 293–300. doi:10.1016/j.jhep.2014.03.026. ISSN 1600-0641. PMID 24681117.
- S. Food & Drug Administration. “Xarelto (Rivaroxaban) Tablets. Boxed warning.” (March 2014.) FDA.gov. Accessed Oct. 27, 2014
- “New Global Real-World Data from Atrial Fibrillation Studies Confirm the Safety Profile of XARELTO®| Johnson & Johnson”. jnj.com. Retrieved 2015-10-28.