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Xarelto Study: Increased Risk For Internal Bleeding and Death

Xarelto internal bleedingThe blood thinning drug Xarelto has alarming side effects, the most dangerous of which is uncontrollable internal bleeding. While other anti-coagulants can also cause internal bleeding, it appears there is no available “antidote” for stopping internal bleeding in patients taking Xarelto. With warfarin, for example, vitamin K has been shown to stop bleeding. But there is no vitamin K “parallel” for people taking Xarelto. Thus, if internal bleeding starts, the patient taking Xarelto may simply have it wait it out and hope it stops on its own. Thousands of lawsuits have been filed and consolidated in New Orleans, Louisiana under MDL 2592.

In addition to Xarelto, there are three “novel anticoagulants”: dabigatran (PRADAXA), apixaban (ELIQUIS) in 2012, and edoxaban (SAVAYSA). Each has been shown to cause internal bleeding and injury.

The Institute for Safe Medication Practices (ISMP) is a nonprofit organization “devoted entirely to medication error prevention and safe medication use.” In June 2016, ISMP published a report on prescription medications causing injuries, including Xarelto. ISMP has authorized me to republish the following excerpt:

Quarter Watch: Monitoring FDA Watch Reports (June 29, 2016)

Oral Anticoagulant Use and Injuries Grow

In 2015, important changes could be seen in the utilization of oral anticoagulants, one of the highest risk outpatient drug therapies, with injury rates that can exceed 10% per person-year.[22] [23] Both use and therefore safety risks to patients increased. One of the changes with great impact on safety has been the introduction and growing use of novel oral anticoagulants as easier-to-use alternatives to warfarin. While warfarin requires bi-weekly testing and regular dose adjustments to keep inhibition of blood-clotting within the optimal range, these drugs are prescribed in only one or two dose regimens, with no therapeutic monitoring required or generally available. As outlined in several previous issues of QuarterWatch [13] [24] [25] , we believe that focusing on ease of use over the need to improve the safety profile of these high-risk drugs was a major misstep, a problem compounded by regulatory errors.[26] Five years after the first of the novel anticoagulants was approved, the picture continues to evolve. There are now four novel anticoagulants, dabigatran (PRADAXA), approved in 2010, rivaroxaban (XARELTO), in 2011, apixaban (ELIQUIS) in 2012, and this year the latest entrant, edoxaban (SAVAYSA).

Better or Worse Than Warfarin?

The clinical testing of novel oral anticoagulants was riddled with serious flaws. Comparisons between these agents and warfarin were established in four of the largest international clinical trials in recent history, together providing more than 120,000 person-years of observation. The unprecedented trial size was mandated by the need to measure very small differences with the long-established, but high-risk warfarin. Despite the large size and numerous prespecified safety endpoints, the pivotal trials for all for these drugs were characterized by flaws that raise questions about the relevance of the small differences identified. The dabigatran results were partially corrected after reanalysis disclosed unreported cases of major bleeding and acute myocardial infarction. [27] The accuracy of the rivaroxaban ROCKET-AF trial was challenged by FDA reviewers; later reviews showed the warfarin comparison group was flawed because the point-of-care devices underestimated warfarin anticoagulation effects,[28] raising questions about the entire trial.[29] The apixaban claim of a mortality benefit was not supported if the results of a clinical site in China are excluded after an FDA inspection disclosed fabricated data.[30] In the edoxaban trial (ENGAGE-AF), the FDA reviewers were concerned with weak results in patients with normal renal function,[31] resulting in a major limitation not to use the drug in this large patient group. [32] Despite the large and very expensive testing– costing billions of dollars–the best that can be concluded is that the treatments are about the same as warfarin in terms of benefits and risks in most settings. And warfarin retains the advantage of widely available laboratory tests to assess and manage the bleeding risks.

Suitable Without Dose Adjustment?

At least two of the four novel oral anticoagulants have pharmacological properties that render them a poor choice as a warfarin substitute without anticoagulation monitoring, or better individualized dosing. Dabigatran, because of low bioavailability (3-7%) and a single renal route of elimination, was revealed to have a five-fold variability in patients receiving the same dose.[33] One simulation model showed that at the standard therapeutic dose 18% would receive a sub-therapeutic dose and more than 40% would receive a higher dose than needed, increasing bleeding risk.[26] In a previous analysis of rivaroxaban, we raised questions about its suitability for use under the current dosing regimen. [34] The problem is that a drug with a 5-9 hour terminal half-life was tested and marketed for once-a-day dosing (unlike the other novel agents, with twice-a-day regimens and longer half-lives). For rivaroxaban, this mean higher initial maximum concentrations soon after dosing to get enough drug on board in a single dose, but low trough concentrations for 12 hours of the 24-hour treatment cycle because of its rapid elimination.

Changes in Utilization

We identified four important changes in anticoagulant prescribing in 2015 using dispensed outpatient prescription data from IMS Health. 1) Novel oral anticoagulant dispensed prescriptions rose 73.6% from ©Institute for Safe Medication Practices 2015 Q4 QuarterWatch – Page 12 of 19 2014 Q1 through 2015 Q4. 2) The growth was roughly divided between an expanded patient population and use as a substitute for warfarin, for which prescription volume declined 10.9% over the same period. 3) The market share for apixaban, the third entrant into the market, grew more than four-fold, and looked poised to overtake rivaroxaban. 4) Prescriptions for dabigatran, first to win approval, continued to decline (-18.4%) because of safety concerns and possibly as a result of marketing competition. The newest novel anticoagulant, edoxaban, was approved only in January 2015, had a restrictive indication, and as yet had little market impact. Warfarin continued to dominate the oral anticoagulant market, but was reduced to about 66% of dispensed outpatient prescriptions. See Table 4.

Adverse Events Summary

In 2015 the five anticoagulant drugs accounted for 34,765 adverse drug event reports, including 2,997 patient deaths, 9,523 cases requiring hospitalization, and 10,815 cases classified as not having a serious outcome. The report total included 8,796 (26%) cases that were of foreign origin. The reports were, as expected from the anticoagulant mechanism of action, dominated by 16,222 (46.7%) reports of hemorrhage. The most frequently reported bleeding sites were gastrointestinal (n = 4,828), followed by cerebral hemorrhages and other bleeding in the central nervous system (n = 3,711). The anticoagulant adverse events were occurring primarily in older patients: the median age was 73 years, and one-quarter were 81 years or older. Rivaroxaban also accounted for the largest number of domestic, serious adverse event reports that the FDA received in 2015, and is further discussed in the report section on leading drugs in four monitoring categories.


Although previous QuarterWatch reports have compared the anticoagulant drugs, this analysis does not distinguish among the five drugs in this class. Marketing competition between the four novel oral anticoagulants seeking to replace warfarin could increase the reporting of bleeding and other serious adverse drug events. The newly approved edoxaban accounted for only 402 reports, or 1.2% of the total.

Domestic, Serious Adverse Drug Events: Rivaroxaban (XARELTO)

The anticoagulant rivaroxaban (XARELTO) accounted for 10,674 reports of fatal, disabling, and serious injury in the U.S., more than any other of the 1,395 identifiable drugs we regularly monitor in this category. For comparison, the median number of reports per drug was 7 cases, with 25% of drugs accounting for 4 or fewer serious cases in 2015, and 25% accounting for 103 cases or more. The rivaroxaban total also included 1,121 reported patient deaths. Rivaroxaban is one of the novel oral anticoagulants examined in a separate section of this report. The primary hazards of oral anticoagulants are twofold: with too much inhibition of the body’s ability to form blood clots the result is hemorrhage. Not enough anticoagulation foils the drug’s intended purpose of preventing thrombotic strokes and pulmonary and venous embolism. The adverse event reports mirror these risks, with 8,643 (80.9%) indicating a hemorrhage, and 1,611 (10.9%) an embolic-thrombotic or clot-related event. We identified other factors that contributed to the large report total for rivaroxaban. In 2015 an intense marketing competition was underway among four novel anticoagulants to replace warfarin, an off-patent generic available since 1957. Marketing and promotion increase manufacturer contact with health professionals and consumers, which causes companies to learn about more adverse events. In addition, while these reports of serious injury were first received by the FDA in 2015, we found 36% had occurred in previous years and were being reported for the first time in 2015, also increasing the total. It is also possible that some of these reports were included among the group of 354,000 reports the FDA transferred into FAERS in 2015. On the other hand, it means that in prior years, injury reports were understated. Thus, several factors combined to create the exceptionally large total of reported serious injuries for rivaroxaban. However, it remains a strong signal that improving the safety of oral anticoagulant treatments should be a major priority in drug safety.



1. FDA Adverse Events Reporting System (FAERS) : Latest Quarterly Data Files. (2015) Food and Drug Administration web site. URL: s/ucm082193.htm. Accessed 17 March 2016. 2. Code of Federal Regulations Title 21 314.80 Postmarketing reporting of adverse drug experiences. (2011) Food and Drug Administration. URL: Accessed 7 April 2014. 3. MedDRA MSSO. (2015). Introductory Guide MedDRA Version 18.1. Chantilly, VA: MedDRA Maintenance and Support Services Organization. 4. MedDRA MSSO. (2015). Introductory Guide for Standardised MedDRA Queries (SMQs) Version 18.1. Chantilly, VA: MedDRA Maintenance and Support Services Organization. 5. Unified Medical Language System: RxNorm. (2014) National Library of Medicine. URL: Accessed 23 April 2014. 6. Moore TJ, Furberg CD, Mattison DR, Cohen MR. (2015). QuarterWatch 2014 Quarter 2: New Safety Perspectives Institute for Safe Medication Practices. URL: 7. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, et al. (2015). Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med 373: 2117–2128. 8. CANVAS – CANagliflozin cardioVascular Assessment Study (2016) URL: Accessed 23 May 2016. 9. Watts NB, Bilezikian JP, Usiskin K, Edwards R, Desai M, et al. (2016). Effects of Canagliflozin on Fracture Risk in Patients With Type 2 Diabetes Mellitus. J Clin Endocrinol Metab 101: 157–166. 10. Bilezikian JP, Watts NB, Usiskin K, Polidori D, Fung A, et al. (2016). Evaluation of Bone Mineral Density and Bone Biomarkers in Patients With Type 2 Diabetes Treated With Canagliflozin. J Clin Endocrinol Metab 101: 44–51. 11. European Medicines Agency – Human medicines – Canagliflozin. (2016) European Medicines Agency web site. URL: referral_prac_000059.jsp&mid=WC0b01ac05805c516f. Accessed 19 May 2016. 12. FDA Drug Safety Communication: Interim clinical trial results find increased risk of leg and foot amputations, mostly affecting the toes, with the diabetes medicine canagliflozin (Invokana, Invokamet); FDA to investigate. (2016) Food and Drug Administration web site. URL: Accessed 19 May 2016. 13. Moore TJ, Cohen MR, Furberg CD. (2013). QuarterWatch 2012 Quarter 2: Perspectives on finasteride (PROPECIA), the methylphenidate patch (DAYTRANA), and update on anticoagulants. Institute for Safe Medication Practices. URL: 14. Moore TJ, Furberg CD, Mattison DR, Cohen MR. (2016). QuarterWatch 2015 Quarters 1-2: Signals for suvorexant, changes in opioid use, and update on new diabetes drugs Institute for Safe Medication Practices. URL: 15. FDA Drug Safety Communication: FDA strengthens kidney warnings for diabetes medicines canagliflozin (Invokana, Invokamet) and dapagliflozin (Farxiga, Xigduo XR). (2016) Food and Drug Administration web site. URL: Accessed 15 June 2016. 16. FDA Drug Safety Communication: FDA revises label of diabetes drug canagliflozin (Invokana, Invokamet) to include updates on bone fracture risk and new information on decreased bone mineral density. (2015) Food and Drug Administration web site. URL: Accessed 24 May 2016. 17. FDA Drug Safety Communication: FDA revises labels of SGLT2 inhibitors for diabetes to include warnings about too much acid in the blood and serious urinary tract infections. (2015) Food and Drug Administration web site. URL: Accessed 15 June 2016. 18. FDA Drug Safety Communication: FDA warns that SGLT2 inhibitors for diabetes may result in a serious condition of too much acid in the blood. (2015) Food and Drug Administration web site. URL: Accessed 24 May 2016. 19. Fact Sheet: Obama Administration Announces Additional Actions to Address the Prescription Opioid Abuse and Heroin Epidemic. (2016) URL: Accessed 2 June 2016. 20. CDC Guideline for Prescribing Opioids for Chronic Pain | Drug Overdose | CDC Injury Center. (2016) Centers for Disease Control and Prevention web site. URL: Accessed 2 June 2016. 21. Press Announcements – Califf, FDA top officials call for sweeping review of agency opioids policies. (2016) Food and Drug Administration web site. URL: Accessed 2 June 2016. 22. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, et al. (2009). Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 361: 1139–1151. 23. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, et al. (2011). Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 365: 883–891. 24. Moore TJ, Cohen MR, Furberg CD. (2013). QuarterWatch 2012 Quarter 4: Leading Drug Safety Issues of 2012 Institute for Safe Medication Practices. URL: 25. Moore TJ, Cohen MR, Mattison DR, Furberg CD. (2014). QuarterWatch 2013 Quarter 1: Perspective on Drug Hypersensitivity Institute for Safe Medication Practices. 26. Moore TJ, Cohen MR, Mattison DR. (2014). Dabigatran, bleeding, and the regulators. BMJ 349: g4517. 27. Connolly SJ, Wallentin L, Yusuf S. (2014). Additional events in the RE-LY trial. N Engl J Med 371: 1464–1465. 28. Patel MR, Hellkamp AS, Fox KAA. (2016). Point-of-Care Warfarin Monitoring in the ROCKET AF Trial. N Engl J Med 374: 785–788. 29. Cohen D. (2015). Data on trial of anticoagulant is to be reanalyzed after discovery that investigators used faulty device. BMJ 351: h6431. 30. Seife C. (2015). Research misconduct identified by the US Food and Drug Administration: out of sight, out of mind, out of the peer-reviewed literature. JAMA Intern Med 175: 567–577. 31. Blank MJ, McDowell T-Y. (2014). Clinical Review: Edoxaban Savaysa Oral Anticoagulant. Silver Spring, MD: Food and Drug Administration, Center for Drug Evaluation and Research. 32. Prescribing information for SAVAYSA – edoxaban tosylate tablet, film coated [package insert]. (2015). Tokyo, Japan: Daiichi Sankyo Co.,LTD. 33. Reilly PA, Lehr T, Haertter S, Connolly SJ, Yusuf S, et al. (2014). The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy). J Am Coll Cardiol 63: 321–328. 34. Moore TJ, Furberg CD, Mattison DR, Cohen MR. (2015). QuarterWatch 2014 Quarters 3-4: Annual Report Issue Institute for Safe Medication Practices. 35. Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem. (2006). Washington, D.C.: National Academies Press. 36. Moore TJ, Cohen MR, Furberg CD. (2007). Serious adverse drug events reported to the Food and Drug Administration, 1998-2005. Arch Intern Med 167: 1752–1759. 37. Lewis JD, Ferrara A, Peng T, Hedderson M, Bilker WB, et al. (2011). Risk of bladder cancer among diabetic patients treated with pioglitazone: interim report of a longitudinal cohort study. Diabetes Care 34: 916–922. 38. Pollack A. (2015). Takeda Agrees to Pay $2.4 Billion to Settle Suits Over Cancer Risk of Actos. N Y Times. 39. Lewis JD, Habel LA, Quesenberry CP, Strom BL, Peng T, et al. (2015). Pioglitazone Use and Risk of Bladder Cancer and Other Common Cancers in Persons With Diabetes. JAMA 314: 265–277.


Check the Institute for Safe Medication Practices for more useful information on Xarelto and other prescription drugs. You can also check out the full report on Xarelto and other medications from ISMP’s Quarter Watch: Monitoring FDA Watch Reports (June 29, 2016) here.

This excerpt is copyrighted by ISMP, and ISMP is solely responsible for its content. Reprinted by permission.