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Xarelto Recall

The FDA has taken steps to address risks of Xarelto bleeding events and drug manufacturers are conducting research to develop an antidote for the drug. Johnson & Johnson has conducted trials examining how this blood thinner compares to other blood thinners currently on the market.

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Xarelto, an anticoagulant, has been linked to an increase in the risk of uncontrollable bleeding, but the FDA hasn’t issued a recall.

What FDA Actions/Events Have Been Taken Regarding Xarelto?

In multiple attempts to mitigate bleeding problems, the FDA initiated several actions regarding Xarelto:

  • In January 2011, the FDA voiced concerns regarding the series of ROCKET clinical trials that had been conducted. The potential for liver toxicity was insufficiently characterized; moreover, problems with data integrity were cited. 1
  • In July 2011, the FDA imposed 3 postmarketing requirements on Xarelto’s maker: 2
    • To develop a 5-mg tablet or scored 10-mg tablet as a lower dosing option
    • To conduct a clinical trial to determine the serious risks associated with renal impairment
    • To track and generate quarterly pharmacovigilance reports for 3 years (2011 – 2014), then annually thereafter, on risk factors, clinical management and outcomes of all major bleeding episodes.
  • The FDA’s November 2011 approval of Xarelto for use with nonvalvular atrial fibrillation (NVAF) was accomplished only after much discussion and debate. The panel’s concerns, detailed in the CDER Summary Review, cited the following: Xarelto did not appear to be superior to warfarin, although it met the criteria for being an effective alternative if other anticoagulant therapy had failed. Other concerns surrounded the low rate of people whose anticoagulation was adequately controlled in the warfarin study group during the ROCKET-AF clinical trial, the higher rate of strokes in people on Xarelto after the study ended, the lack of a “rational basis” for Janssen’s dosing in ROCKET-AF, and the inability to determine if Xarelto was “as good as warfarin when the INR can be maintained in the therapeutic INR range most of the time.”
  • In June 6, 2013, the FDA deemed that patient-directed advertising (print ads) were misleading and thus, that Xarelto was misbranded. 3 Among the major points cited in the FDA’s notice regarding this advertising were the manufacturer’s claims that no dosage adjustment was needed and no routine testing was needed. Both are indicated, especially if renal function (CrCl) is < 50 mL/min.
  • In March 2014, the FDA issued additional language be added to Xarelto’s black box warning (the FDA’s most urgent and strongest warning), informing users of the serious side effects of using the drug, specifically the risks of thrombotic events with premature discontinuation. 4

The Quest for an Antidote

Xarelto overrides the body’s system of checks and balances for blood clotting: too much clotting can lead to strokes or other thrombotic events, but too little clotting can lead to serious bleeding events. Tipping the scales too far in one direction can cause uncontrolled bleeding in the presence of any anticoagulant, even though all manufacturers of Factor Xa inhibitors claim that this type of anticoagulant is safer than warfarin.

Who’s Who:

Because no Factor Xa inhibitor has an antidote yet to stop uncontrolled bleeding, it is important to understand the therapies that are being developed to counteract this class of drug.

  • Bayer teamed with Janssen, a subsidiary of Johnson & Johnson, to make Xarelto.

  • Boehringer Ingelheim makes Pradaxa (dabigatran).

  • Pfizer and Bristol-Myers Squibb joined forces in making Eliquis (apixaban).

  • Daiichi Sankyo makes Lixiana (edoxaban).

How does one stop bleeding if it runs amok? Doctors must attempt to reverse it, with an antidote that counteracts the effects of the anticoagulant. Two drug manufacturers are attempting to develop an antidote for Factor Xa inhibition, namely Boehringer Ingelheim (the manufacturer of Pradaxa) and Portola Pharmaceuticals.

Because no Factor Xa inhibitor has an antidote [yet] to stop uncontrolled bleeding, it is important to understand the therapies that are being developed to counteract this class of drug. All four drugs are direct Factor Xa inhibitors.

While Boehringer Ingelheim is working on its own proprietary antidote, 5 a small company called Portola Pharmaceuticals has been developing a compound whose purpose is to block the actions of any direct thrombin (FXa) inhibitor.

Boehringer Ingelheim’s antidote is a monoclonal antibody called idarucizumab. Operating like a lock and key, the antibody selectively binds to Pradaxa, neutralizing the FXa inhibitor so it can’t hinder the clotting cascade. If the body can clot, it can arrest an uncontrolled bleeding event. Idarucizumab passed Phase 1 and 2 trials, and enrollment has started in a Phase 3 trial. 6

In contrast, Portola’s antidote is a Factor Xa decoy: it attracts the FXa inhibitor more strongly than the drug’s target protein in the cascade sequence. This makes the inhibitor bind more readily to the antidote, enabling the clotting cascade to proceed. Portola’s decoy (PRT4445, or andexanet alfa) is in Phase 3 trials. Johnson & Johnson and Pfizer have already signed an agreement with Portola to utilize its new antidote (providing it attains FDA approval). If PRT4445 gains FDA approval, J&J will license the decoy as Xarelto’s antidote. 7

Of note, Portola is also in late-stage trials for its own FXa inhibitor, purported to be safer for people with diminished renal function and less likely to cause drug interactions because it, unlike the other Factor Xa inhibitors, is not metabolized in the liver. 8

Xarelto Controversy

Specifically, some FDA committee members expressed concern about the exclusion of certain drugs (like warfarin) and procedures (such as cardioversion) from the trials, which potentially skewed the results of the data presented by Johnson & Johnson.

The FDA’s 2011 approval of Xarelto for reducing the risk of stroke in people with NVAF 9 was accompanied by a number of concerns, related both to side effects of the drug and the methods used during the ROCKET-AF trials.

Specifically, some FDA committee members expressed concern about the exclusion of certain drugs (like warfarin) and procedures (such as cardioversion) from the trials, which potentially skewed the results of the data presented by Johnson & Johnson. Other concerns were expressed with regard to the difference in dosing levels and frequency during the trial versus non-trial conditions. 10

Notably, an FDA advisory committee rejected Bayer’s latest application to approve Xarelto for preventing recurrent cardiovascular events after Acute Coronary Syndrome (ACS, a term describing any sudden interruption to the heart muscle’s blood supply). This was the second denial for an indication that used ATLAS ACS TIMI 51 trial data, and no additional trials had been conducted since the first rejection of this data. 11

Product liability attorneys are reviewing potential lawsuits, alleging a link between Xarelto and wrongful deaths from brain hemorrhage, hemorrhagic stroke, and other types of bleeding.

Continuing Push for Expanded Use, Despite Controversy

Despite public concerns regarding Pradaxa and Xarelto, neither Xarelto nor its competitors have curbed their push to expand the uses for their anticoagulants. Collectively, 435 clinical trials were registered for Xarelto and its top two competitors when this article was written. 12

Johnson & Johnson is conducting clinical trials to investigate additional uses for Xarelto in broader patient populations: 13

  • Children (0 – 17 years of age)
  • People with severely impaired renal function (CrCl 15 – 30 mL/min)
  • People with nonvalvular afibrillation who undergo stent placement after acute coronary syndrome (ACS)
  • Patients with peripheral artery disease
  • Hemodialysis patients
  • Patients with heart valve prostheses
  • Patients with cancer and certain autoimmune diseases, where the condition itself or one of its treatments may predispose patients to developing blood clots

Pivotal Clinical Trials for Xarelto

How does Xarelto compare to other anticoagulants? Clinical trials must prove that a new drug is safe, works better than giving a placebo (a sham with no drug activity, equivalent to no intervention), and is not inferior to an existing drug. A chart summarizing key Xarelto clinical trials follows. Interestingly, all the current FDA-approved indications for Xarelto use doses of 10, 15 or 20 mg. Janssen’s push for expanded uses focuses on conditions that might benefit from lower doses (2.5 or 5 mg) but potentially longer-term usage. How the FDA may view that as it considers Xarelto’s applications for additional indications is yet unknown.

FDA-approved indications (listed chronologically)


ACS: acute coronary syndrome;
AF: afibrillation;
CABG: coronary artery bypass graft;
coag: coagulation;
CV: cardiovascular;
DVT: deep vein thrombosis;
LMWH: low molecular weight heparin;
NEJM: New England Journal of Medicine;
PE: pulmonary embolism;
TIMI: thrombolysis in myocardial infarction;
NVAF: nonvalvular afibrillation;
VKA: vitamin K antagonist;

Treat DVT and PE and reduce risk of recurrence
Non-inferior to enoxaparin (a low-molecular-weight heparin, or LMWH) for treating DVT and PE; also, risk reduction for recurrence DVT = NEJM 2010;363:2499-2510PE = NEJM 2012;366:1287-1297
EINSTEIN Extension study 16
Reduce the risk of VTE recurrence in people who need additional anticoagulant therapy after standard treatment
A subanalysis of the other EINSTEIN studies comparing Xarelto to placebo. After 6 to 12 months of additional treatment with Xarelto, the study found that it “significantly” reduced the risk of recurrent VTE at the cost of a “moderate” increase in bleeding complications. Study limitations included lack of diversity of patient types represented. Expert Rev Cardiovasc Ther. 2011(7):841-844
Reduce stroke risk in nonvalvular atrial fibrillation (NVAF)
Demonstrated non-inferiority to warfarin but could not claim superiority in patients whose anticoagulation was well controlled with warfarin FDA approved this indication, but not without reservations NEJM 2011; 365:883-891
RECORD 1, 2, and 3 18 19 20
Prevent deep vein thrombosis (DVT) after hip or knee replacement surgery
10 – 50% fewer occurrences of DVT when 10 mg Xarelto used before and after surgery, compared to treatment with enoxaparin RECORD 1: NEJM 2008;358:2776-2786 RECORD 2: The Lancet, 2008;372(9632):, 31-39 RECORD 3: NEJM 2008; 358:2776-2786

Studies that Evaluated Uses NOT Approved by the FDA

Determine the effect of giving Xarelto to patients who are taking various drugs that strongly induce CYP3A4 (a liver enzyme that oxidizes toxins and drugs so the body can remove them)
25 patients studied; only 14 finished the study 20-mg dosing appeared to be safe enough to be acceptable in patients that must take a CYP3A4 inducer at the same time Results not published, except in a Bayer brief 2012 Bayer synopsis
To lower the risk of recurrent CV events after ACS [Indication REJECTED twice by FDA]
Twice-daily dosing at low levels (2.5 and 5 mg) ↓ death from MI or stroke by 8.9 and 10.7%, respectively, so overall reduction in CV mortality; but ↑ risk of non-fatal bleeding with higher dose Rates of TIMI bleeding not related to CABG were lower in the 2.5 mg arm Statistical analyses were labeled as “descriptive” NEJM 2012;366:9-19
X-VeRT 23
Phase 3b study of people with NVAF who will undergo electrical or pharmacological cardioversion Compared Xarelto to warfarin/similar vit K antagonists (VKA)
Did not have the statistical power to establish Xarelto as non-inferior to VKA, so statistical analyses were “exploratory” Sept. 2, 2014 e-pub in advance of print: Eur Heart Journal
To prevent major CV events in coronary or peripheral artery disease
Twice-daily dosing at low levels (2.5 and 5 mg) Comparator arm: aspirin Study in progress through 2018: NCT NCT01776424

  1. Center for Drug and Evaluation Research. Application number: 022406Orig1s000. Reference ID: 2968673. January 4, 2011.
  2. Center for Drug Evaluation and Research. Approval package for: Application # 022406Orig1s000. July 1, 2011.
  3. Haverkamp D, Hutten BA, Büller HR, et al. The use of specific antidotes as a response to bleeding complications during anticoagulant therapy for venous thromboembolism. J Thromb Haemost. 2003;1:69-73.
  4. U.S. Food and Drug Administration. Xarelto (Rivaroxaban) Tablets. Boxed warning. March 2014. http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm367392.htm. Accessed October 12, 2014.
  5. Antidote for rapid reversal of Pradaxa (dabigatran etexilate) progresses into next stage of clinical investigation with study in patients. [press release] May 22, 2014. http://www.boehringer-ingelheim.com/news/news_releases/press_releases/2014/22_may_2014_dabigatranetexilate.html. Accessed October 13, 2014.
  6. Garde D. Boehringer bags a ‘breakthrough’ tag for its Pradaxa antidote. Fierce Biotech. June 26, 2014. http://www.fiercebiotech.com/story/boehringer-bags-breakthrough-tag-its-pradaxa-antidote/2014-06-26. Accessed October 10, 2014.
  7. Portola, Bristol-Myers Squibb and Pfizer Sign Clinical Collaboration Agreement to Study ELIQUIS and Portola’s Universal Factor Xa Inhibitor Antidote PRT4445 [press release]. November 1, 2012. http://news.bms.com/press-release/partnering-news/portola-bristol-myers-squibb-and-pfizer-sign-clinical-collaboration-ag. Accessed October 13, 2014.
  8. Portola Pharmaceuticals website. Betrixaban: FXa Inhibitor. http://www.portola.com/clinical-development/betrixaban-fxa-inhibitor/. Accessed October 12, 2014.
  9. U.S. Food & Drug Administration. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm326654.htm FDA expands use of Xarelto to treat, reduce recurrence of blood clots (Nov. 2, 2012) Accessed Dec. 16, 2014.
  10. U.S. Food & Drug Administration. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/UCM278480.pdfSummary Minutes of the Cardiovascular and Renal Drug Advisory Committee (Sept. 8, 2011) Accessed Dec. 16, 2014.
  11. Wood, S. http://www.medscape.com/viewarticle/819318 Again, FDA Advisors Deliver Solid ‘No’ to Rivaroxaban in ACS Medscape. (Jan 16, 2014) Accessed Dec. 16, 2014.
  12. U.S. National Institutes of Health. http://www.clinicaltrials.gov. Accessed October 10, 2014.
  13. U.S. National Institutes of Health. Xarelto clinical trials. http://www.clinicaltrials.gov/ct2/results?term=Xarelto&Search=Search. Accessed October 10, 2014.
  14. Bauersachs R, Berkowitz SD, Brenner B, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363(26):2499-510.
  15. Büller HR, Prins MH, Lensin AW, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366(14):1287-97.
  16. Romualdi E, Donadini MP, Ageno W. Oral rivaroxaban after symptomatic venous thromboembolism: the continued treatment study (EINSTEIN-extension study). Expert Rev Cardiovasc Ther. 2011(7):841-844. 
  17. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. NEJM 2011;365(10):883-891
  18. Eriksson BI, Borris LC, Friedman RJ, et al. Rivaroxaban versus Enoxaparin for Thromboprophylaxis after Hip Arthroplasty. N Engl J Med. 2008;358(26):2765-2775.
  19. Kakkar AK, Brenner B, Dahl OE, et al. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet. 2008;372(9632):31-9.
  20. Lassen MR1, Ageno W, Borris LC, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008; 358:2776-2786. 
  21. Bayer Health Care. Clinical Study Synopsis (NCT00786422; The EINSTEIN CYP cohort study). http://trialfinder.bayerscheringpharma.de/html/pdf/13238_Study_Synopsis_CTP_2012-07-02.pdf. Accessed October 14, 2014.
  22. Mega JL,Braunwald E, Wiviott SD. Rivaroxaban in Patients with a Recent Acute Coronary Syndrome. 2012;366(1):9-19.
  23. Cappato R, Ezekowitz MD, Klein AL, et al. Rivaroxaban vs. vitamin K antagonists for cardioversion in atrial fibrillation. Eur Heart J. Advance access September 2, 2014. doi:10.1093/eurheartj/ehu367.
  24. U.S. National Institutes of Health. Rivaroxaban for the Prevention of Major Cardiovascular Events in Coronary or Peripheral Artery Disease (COMPASS). http://clltrials.gov/show/NCT01776424. Accessed October 13, 2014.