Is XARELTO Really the 'Right Move' for Patients With Blood Clots or Risk for Stroke?

If you watch TV, you likely have seen two types of sharply conflicting ads involving the new oral anticoagulant (blood thinner) rivaroxaban (XARELTO).

On the one hand, there are the ads featuring comedian Kevin Nealon, NASCAR driver Brian Vickers and professional golfer Arnold Palmer, who all praise the drug as “the right move” for them because it does not require dietary restrictions or regular blood tests. On the other hand, there are the ads that promote lawsuits on behalf of patients who have suffered major internal bleeding after taking the drug, and that promise financial compensation from the drugmakers.

Rivaroxaban is less cumbersome to use than conventional blood thinners such as warfarin (COUMADIN, JANTOVEN). Patients taking warfarin — which has been around for decades — must restrict their intake of green leafy vegetables and other high-vitamin-K foods, and they also must undergo periodic drug level monitoring.

Rivaroxaban has no such restrictions or requirements, but it has its own share of disadvantages: It is not an exceptional breakthrough drug, and — unlike warfarin — there is no antidote to counteract its effect if bleeding occurs.

That is why Public Citizen’s Health Research Group has classified rivaroxaban as Do Not Use for Seven Years. We recommend that patients wait until at least July 2018 (seven years after the drug was first approved) to take this drug.

Evaluating the evidence

The Food and Drug Administration (FDA) approved rivaroxaban for three orgindications over the past few years:[1]

1. Reducing the risk of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients undergoing knee or hip replacement surgery. A DVT involves formation of a blood clot in a deep vein in the body, most often in the legs. A PE, which can be life-threatening, occurs when a clot that formed in a deep vein in another part of the body breaks off and blocks one of the arteries in the lungs.
2. Treatment of DVT and PE, and reduction of their recurrence risk.
3. Reducing the risk of stroke and embolism (blockage of an artery due to a blood clot that initially formed in the heart) in patients with atrial fibrillation (a common heart rhythm disorder) that is not due to heart valve problems.

The FDA based its approval decisions on results from clinical trials funded by the drug’s makers.[2],[3],[4] These trials showed that rivaroxaban’s effect is similar to (but not better than) that of older blood thinners such as warfarin. However, the studies suffered from limitations that likely resulted in data that overstated rivaroxaban’s effect.

For example, FDA inspectors found significant deficiencies in the conduct of the trials used to support the drug’s approval for patients undergoing knee or hip replacement surgery, including incomplete reporting of adverse events.[5]

Likewise, the FDA medical reviewers raised concerns about inadequate dosing of warfarin given to the comparison group in the trial used to support rivaroxaban’s approval for treating patients with atrial fibrillation, known as the ROCKET trial.[6] A recent analysis led by a former FDA medical reviewer also showed that there was inadequate follow-up for 22 percent of subjects in the ROCKET trial, which was much higher than the dropout rate reported by the drugmakers.[7]

News broke in late 2015 that the European Medicines Agency had begun an investigation of the ROCKET trial results because a defective device was used to monitor and adjust the warfarin doses in control group patients.[8]

Any one of these problems could have undermined the validity of the trials and biased the results in favor of the rivaroxaban-treated subjects.

Adverse reactions[9]

Rivaroxaban’s most common adverse reaction, as with all blood thinners, is bleeding. Bleeding can come from the skin (symptoms include bruising), nose, mouth or vagina. Rivaroxaban also can cause major and life-threatening bleeding in internal organs, including the brain, urinary tract (causing red or brown urine) and gastrointestinal tract (causing dark, tarry or bloody stool).

One particularly dangerous and avoidable bleeding complication associated with the use of rivaroxaban is described in a black-box warning in the drug’s label: Patients using the drug who undergo spinal injections (for diagnostic reasons or for the administration of drugs for anesthesia or pain relief) can develop significant bleeding within the spine at the injection site. The accumulation of blood can compress the spinal cord, causing paralysis.

A special concern regarding rivaroxaban’s bleeding complications is that — unlike warfarin, whose blood-thinning effect can be reversed quickly with high-dose vitamin K — rivaroxaban has no specific antidote. Making things even worse is the lack of data assessing the best way to manage bleeding among rivaroxaban patients.[10] Therefore, rivaroxaban patients are at much greater risk for fatal uncontrollable bleeding than warfarin patients.

Another serious problem with rivaroxaban, described in a black-box warning, is that stopping it prematurely can cause blood clots — the very condition the drug is supposed to prevent.

Some data suggest there are variations among patients in terms of how they respond to rivaroxaban.[11] Specifically, the drug’s safety and effectiveness have not been sufficiently studied in the elderly or in patients with liver disease, artificial heart valves or moderate to severe kidney failure.[12]

Drug interactions

Use of rivaroxaban along with nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, antiplatelet agents such as clopidogrel (PLAVIX) or any medicine that contains heparin increases the risk for bleeding.

Other drugs that may cause adverse interactions when taken with rivaroxaban include antibiotics (for example, erythromycin [E.E.S, E.E.S 400, ERYC, ERYPED, ERY-TAB, ERYTHROCIN, PCE], clarithromycin [BIAXIN, PREVPAC] and rifampin [RIFADIN, RIFAMATE, RIFATER, RIMACTANE]), antifungal medications (such as ketoconazole and fluconazole [DIFLUCAN]), and HIV drugs (such as ritonavir [KALETRA, NORVIR, TECHNIVIE, VIEKIRA PAK]).

What You Can Do

If you are at risk for blood clots or stroke, you should discuss with your health care provider the proper blood thinner to use. Given the established effectiveness, safety and availability of a blood-thinning antidote for warfarin, you should not start using rivaroxaban or any other new blood thinner (dabigatran [PRADAXA], apixaban [ELIQUIS] or edoxaban [SAVAYSA]). These drugs do not represent a clear breakthrough over the existing treatment, and it is still too early to adequately understand whether their benefits outweigh their risks in the long run.

If you are already on one of these new blood thinners, be aware that discontinuing rivaroxaban, dabigatran, apixaban or edoxaban increases your risk of blood clots. Transitioning onto another anticoagulant when you stop taking any of these drugs may help reduce, but not necessarily eliminate, these risks. We advise that if you are already on rivaroxaban, you should talk to your doctor about transitioning to warfarin, in which case you may need to take an injectable blood thinner in addition to warfarin, because it will take a few days for warfarin to start working.

You can report serious adverse reactions to drugs or product quality problems to the FDA’s MedWatch Adverse Event Reporting System online by visiting www.fda.gov/MedWatch or by calling 800-332-1088.

References

[1] Food and Drug Administration. FDA expands use of Xarelto to treat, reduce recurrence of blood clots. November 2012. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm326654.htm. Accessed January 14, 2016.

[2] Eriksson BI, Kakkar AK, Turpie AG, et al. Oral rivaroxaban for the prevention of symptomatic venous thromboembolism after elective hip and knee replacement. J Bone Joint Surg Br. 2009;91(5):636-644.

[3] The EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010; 363(26):2499-2510.

[4] Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883-891.

[5] Food and Drug Administration. Medical reviews for application number: 022406Orig1s000. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022406Orig1s000MedR.pdf. Accessed February 11, 2016.

[6] Food and Drug Administration. FDA draft briefing document for the Cardiovascular and Renal Drugs Advisory Committee (CRDAC). September 8, 2011, meeting. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/UCM270796.pdf. Accessed February 11, 2016.

[7] Marciniak TA, Cherepanov V, Golukhova E, et al. Drug discontinuation and follow-up rates in oral antithrombotic trials. JAMA Intern Med. 2016:175(2):257-259.

[8] Project on Government Oversight. Drug problems: European regulator investigating trial led by FDA nominee. November 30, 2015. http://www.pogo.org/blog/2015/11/regulator-investigating-clinical-trial-led-by-fda-nominee.html. Accessed February 11, 2016.

[9] Janssen Pharmaceuticals, Inc. XARELTO drug label. Revised January 2015. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/022406s012lbl.pdf. Accessed February 11, 2016.2015.

[10] Levy JH. Pharmacology and safety of new oral anticoagulants: The challenge of bleeding persists. Clin Lab Med. 2014;34(3):443-452.

[11] Ramos-Esquivel A. Monitoring anticoagulant therapy with new oral agents. World J Methodol. 2015;5(4):212-215.

[12] Mavrakanas T, Samer C, Fontana P, Perrier A. Direct oral anticoagulants: Efficacy and safety in patient subgroups. Swiss Med Wkly. 2015 Feb 6;145:w14081. doi:10.4414/smw.2015.14081.