Overview of the Blood Thinner Rivaroxaban (XARELTO): An Update

Rivaroxaban (XARELTO) is one of a few so-called “novel” oral anticoagulants (blood thinners). It was initially approved by the Food and Drug Administration (FDA) in July 2011 to prevent deep vein thrombosis (blood clots in large veins in the legs) and pulmonary embolism (blood clot in the lungs) after hip or knee replacement surgery.[1]

Subsequently, the agency expanded its approved uses to include, among other things, reducing the risk of stroke and blood clots in patients with nonvalvular atrial fibrillation (a heart rhythm disorder that is not caused by a defective heart valve) as well as treating and preventing the risk of recurrence of deep vein thrombosis or pulmonary embolism in general.[2]

In 2016, Public Citizen’s Health Research Group designated rivaroxaban as Do Not Use for Seven Years (until at least July 2018) because it did not represent a clear breakthrough over standard well-studied anticoagulants that have been used for decades — mainly oral anticoagulants that work against vitamin K (such as warfarin [JANTOVEN]) and injectable low-molecular-weight heparins (such as enoxaparin [LOVENOX]).[3]

We now have designated rivaroxaban as Do Not Use because its benefit-risk profile remains no better than those of standard anticoagulants. Also, unlike standard anticoagulants, rivaroxaban still lacks a routinely available monitoring test[4] and its reversal agent, andexanet (ANDEXXA), is questionable.[5] Therefore, these disadvantages tip the scale against rivaroxaban.

No benefit-harm advantage over standard therapies

Most of the clinical trials that supported FDA approval of rivaroxaban were noninferiority trials: They showed that rivaroxaban was statistically no worse than warfarin alone or enoxaparin followed by warfarin for preventing or treating clots.[6]

ROCKET, the principal trial that compared rivaroxaban with warfarin for preventing stroke in the setting of nonvalvular atrial fibrillation,[7] which accounts for one of the largest patient populations using these drugs,[8] suffered from major methodological issues that disadvantaged warfarin-treated subjects. As emphasized by FDA reviewers, warfarin users received adequate doses of the drug only 55% of the time according to blood test data for international normalized ratio (INR), a standard test for monitoring warfarin’s effects. Therefore, these reviewers concluded that it is unclear that rivaroxaban is “as good as” warfarin when warfarin users receive properly adjusted doses most of the time based on INR monitoring. Those reviewers recommended rivaroxaban as a second-line oral anticoagulant.

ROCKET was questioned again after a 2016 BMJ investigation discovered that the INR tests in this trial used a device that had been recalled in 2014 because it was delivering erroneous results.[9] This meant that warfarin users had likely received higher doses of the drug and were therefore put at high risk of bleeding.

The repercussions of the BMJ investigation led the FDA to reanalyze the trial data, but it concluded that the effect of INR device malfunctioning was likely modest and did not impact its findings.[10] However, several experts, including a former FDA reviewer of rivaroxaban, questioned the FDA backing of the trial’s validity. For example, a renowned cardiologist who served on the FDA advisory committee for rivaroxaban and voted against its approval in 2011 asserted, “[g]iven the fact that the device was inaccurate, there is no way anybody can tell you what would have happened in the trial.”[11]

Forsaking safety for convenience

Standard anticoagulants (such as warfarin) are available in multiple strengths, and their doses can be adjusted based on readily available monitoring tests to maintain a balance between their blood-thinning benefits and adverse bleeding effects.

In contrast, rivaroxaban is approved for only one or two, mostly once-a-day, doses for each of its uses and does not have any routinely available monitoring test.[12] In fact, this simple, unmonitored dosing was selected by its makers as a marketing strategy, presenting the drug as a more convenient alternative to standard anticoagulants which require monitoring and dosage adjustment.

In 2011, FDA reviewers asserted that the pharmacological properties of rivaroxaban suggested that the drug should be administered twice daily.[13] In 2016, a separate group of FDA and other federal researchers came to the same conclusion.[14] Those researchers analyzed data for approximately 119,000 Medicare enrollees with nonvalvular atrial fibrillation who started either rivaroxaban or dabigatran (PRADAXA), a novel oral anticoagulant with the same half-life (a measure of how quickly a drug is eliminated from the body) as rivaroxaban that is approved for a twice-a-day dosage. They found that rivaroxaban was associated with a statistically significant increase in bleeding events inside the brain and major bleeding events outside the brain (including gastrointestinal bleeding) compared with dabigatran. The researchers concluded that rivaroxaban’s net increase in bleeding inside the brain exceeded its net reduction in clot-related stroke.

Similarly, an independent analysis of domestic adverse-event reports received by the FDA in 2016 showed that rivaroxaban accounted for 68% of nearly 22,000 bleeding-related reports pertaining to all oral anticoagulants. In contrast, generic warfarin accounted for only 8% of these reports.[15]

Importantly, although warfarin and other standard anticoagulants have well-validated and affordable reversal agents for bleeding adverse effects, rivaroxaban was approved without such an agent.

In 2019, rivaroxaban’s makers paid $775 million to settle approximately 25,000 lawsuits because they failed to warn the public that the drug can cause uncontrollable massive bleeding.[16]

Andexanet was approved by the FDA in 2018 for rivaroxaban-treated patients with life-threatening bleeding. However, we classified this drug as Do Not Use because of its questionable clinical efficacy and safety.[17]

What You Can Do

If you are at a risk of blood clots or stroke and your doctor recommends anticoagulant therapy, consult him or her about taking warfarin or another standard anticoagulant.

If you are currently taking rivaroxaban or another novel oral anticoagulant, consider talking to your doctor about transitioning to a standard anticoagulant. If you switch to warfarin, you may need to also take an injectable anticoagulant initially, because warfarin’s full effect is not achieved until several days after its initiation. Failing to take an injectable anticoagulant alongside warfarin initially after switching from rivaroxaban can increase your risk of stroke.

Unless you experience sudden severe bleeding, never discontinue rivaroxaban or any other anticoagulant without talking with your doctor because doing so can increase your risk of developing blood clots or stroke.

Seek immediate medical help if you fall or injure yourself, particularly if you hit your head, or if you experience any signs of bleeding, a blot clot or a stroke while taking any anticoagulant.
 

References

[1] Food and Drug Administration. Approval package for application number: 022406Orig1s000. Xarelto 10 mg immediate release tablets. July 1, 2011. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022406Orig1s000Approv.pdf. Accessed March 10, 2021.

[2] Janssen Pharmaceuticals, Inc. Label: rivaroxaban (XARELTO). January 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/022406s036,202439s036lbl.pdf. Accessed March 10, 2021.

[3] Is XARELTO really the 'right move' for patients with blood clots or risk for stroke? Worst Pills, Best Pills News. April 2016. https://www.worstpills.org/newsletters/view/1026. Accessed March 10, 2021.

[4] Janssen Pharmaceuticals, Inc. Label: Rivaroxaban (XARELTO). January 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/022406s036,202439s036lbl.pdf. Accessed March 10, 2021.

[5] Overview of the questionable drug andexanet (ANDEXXA). Worst Pills, Best Pills News. February 2021. https://www.worstpills.org/newsletters/view/1379. Accessed March 10, 2021.

[6] Janssen Pharmaceuticals, Inc. Label: Rivaroxaban (XARELTO). January 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/022406s036,202439s036lbl.pdf. Accessed March 10, 2021.

[7] Food and Drug Administration. Summary review. Deputy division director decisional memo for application number: 202439Orig1s000SumR. XARELTO/rivaroxaban. November 4, 2011. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202439Orig1s000SumR.pdf. Accessed March 10, 2021.

[8] Fletcher J. Making anticoagulation easier and safer in DVT. Cochrane Database Syst Rev. 2015;6(June 30):ED000100.

[9] Cohen D. Manufacturer failed to disclose faulty device in rivaroxaban trial. BMJ. 2016;354(September 28):i5131.

[10] Food and Drug Administration. ROCKET AF reanalysis reviews. Application number: 202439Orig1s000. September 26, 2016. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202439Orig1s000RocketAFReanalysis.pdf. Accessed March 10, 2021.

[11] Cohen D. Manufacturer failed to disclose faulty device in rivaroxaban trial. BMJ. 2016;354(September 28):i5131.

[12] Janssen Pharmaceuticals, Inc. Rivaroxaban (XARELTO). January 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/022406s036,202439s036lbl.pdf. Accessed March 10, 2021.

[13] Food and Drug Administration. Summary review. Deputy division director decisional memo for application number: 202439Orig1s000SumR. XARELTO/rivaroxaban. November 4, 2011. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202439Orig1s000SumR.pdf. Accessed March 10, 2021.

[14] Graham DJ, Reichman ME, Wernecke M, et al. Stroke, bleeding, and mortality risks in elderly Medicare beneficiaries treated with dabigatran or rivaroxaban for nonvalvular atrial fibrillation. JAMA Intern Med. 2016;176(11):1662-1671.

[15] Institute for Safe Medication Practices. Quarter Watch. Annual report issue. July 12, 2017. https://www.ismp.org/quarterwatch/annual-report-2016. Accessed March 10, 2021.

[16] Thomas K. Bayer and Johnson & Johnson settle lawsuits over xarelto, a blood thinner, for $775 million. NYT. March 25, 2019. https://www.nytimes.com/2019/03/25/health/xarelto-blood-thinner-lawsuit-settlement.html. Accessed March 10, 2021.

[17] Overview of the questionable drug andexanet (ANDEXXA). Worst Pills, Best Pills News. February 2021. https://www.worstpills.org/newsletters/view/1379. Accessed March 10, 2021.