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A Medwatch review of reported events in patients who discontinued rivaroxaban (XARELTO) therapy in response to legal advertising

Open AccessPublished:February 16, 2016DOI:https://doi.org/10.1016/j.hrcr.2016.02.001

      Keywords

      Introduction

      Tabled 1KEY TEACHING POINTS
      • Novel oral anticoagulants provide a new treatment option for a variety of thrombotic conditions, including nonvalvular atrial fibrillation.
      • These drugs have rapid onsets and short half-lives and should not be prematurely discontinued.
      • Legal advertising concerning XARELTO (rivaroxaban) has resulted in some patients stopping XARELTO therapy and experiencing adverse clinical events, such as stroke.
      Rivaroxaban (XARELTO) is an oral Factor Xa inhibitor anticoagulant. Studied in over 85,000 patients,
      • Sarich T.C.
      • Peters G.
      • Berkowitz S.D.
      • et al.
      Rivaroxaban: a novel oral anticoagulant for the prevention and treatment of several thrombosis-mediated conditions.
      it was initially approved by the FDA in 2011 and is indicated to treat or prevent thrombosis in a variety of clinical settings; and when appropriately prescribed, for example in patients with atrial fibrillation, rivaroxaban has similar anticoagulant efficacy, with a lower risk of intracranial hemorrhage, as compared to the historical standard of warfarin.
      • Sarich T.C.
      • Peters G.
      • Berkowitz S.D.
      • et al.
      Rivaroxaban: a novel oral anticoagulant for the prevention and treatment of several thrombosis-mediated conditions.
      It is well established that anticoagulant therapy is associated with an increased risk of hemorrhage, regardless of the specific anticoagulant. Therefore, in the risk–benefit balance, an appropriate anticoagulation prescription occurs in the setting of increased thrombotic risk that justifies the increased bleeding risk. This is an important consideration, as the mitigation of the thrombotic risk attained by the use of an anticoagulant is terminated if the anticoagulant is stopped. Importantly, current evidence
      • Mahaffey K.W.
      • Hellkamp A.S.
      • Patel M.R.
      • et al.
      End of study transition from study drug to open-label vitamin K antagonist therapy: the ROCKET AF experience.
      does not suggest a rebound of thrombotic risk upon anticoagulation discontinuation; rather, the patient simply resumes the thrombotic risk that existed prior to anticoagulant initiation, and the lack of rebound thrombosis with rivaroxaban is supported by longitudinal studies.
      • Mahaffey K.W.
      • Hellkamp A.S.
      • Patel M.R.
      • et al.
      End of study transition from study drug to open-label vitamin K antagonist therapy: the ROCKET AF experience.
      However, in a patient at risk for a thrombotic event, premature discontinuation of any oral anticoagulant may increase the risk of thrombotic events, as outlined in The United States Prescribing Information for all of the newer non-warfarin anticoagulants (https://www.xarelto-us.com/shared/product/xarelto/prescribing-information.pdf; http://packageinserts.bms.com/pi/pi_eliquis.pdf; http://bidocs.boehringer-ingelheim.com/BIWebAccess/ViewServlet.ser?docBase=renetnt&folderPath=/Prescribing%20Information/PIs/Pradaxa/Pradaxa.pdf; http://dsi.com/prescribing-information-portlet/getPIContent?productName=Savaysa&inline=true). As a class, the novel oral anticoagulants have rapid onset of action and short half-lives; as such, it is important to avoid abrupt cessation.
      Rivaroxaban is currently the subject of a class action litigation. Beginning in 2014, advertising has appeared on television, on the radio, and in print media directed toward patients who may have experienced adverse clinical events while on rivaroxaban. Described here are a series of serious medical events reported in 28 submissions of 31 individual patients to Medwatch (The FDA Safety Information and Adverse Event Reporting System; http://www.fda.gov/Safety/MedWatch/default.htm).

      Case report

      Overall, based on the available data, the mean age of the patients was 72 (range, 45–90), and 13 patients were male. All were prescribed rivaroxaban and subsequently discontinued their anticoagulant without consulting their physician after viewing negative rivaroxaban legal advertising.
      In the majority of these cases (23/31, 75%), patients experienced a stroke or a transient ischemic neurologic event; 2 patients had persistent residual paralysis. One patient, a 45-year-old man receiving rivaroxaban for treatment of a deep vein thrombosis, stopped the drug and died of a subsequent pulmonary embolism, and 1 female patient, receiving rivaroxaban for stroke prevention, stopped the drug and died of a massive stroke (Table). All these cases were considered to be serious medical events by the health care professionals that submitted the reports.
      TableSummary of clinical outcomes following abrupt rivaroxaban termination as reported to Medwatch
      CaseAgeSexAnticoagulant indicationConsequence of stopping anticoagulantEvent reported
      1NRFNVAFTIA/possible strokeSeptember 2014
      280FNVAFDVT of armNovember 2014
      380MNRStrokeDecember 2014
      4NRMNVAFStrokeJanuary 2015
      5NRNRNRStrokeJanuary 2015
      680FNVAFStrokeMarch 2015
      7NRMNRStrokeMarch 2015
      855MNVAFCardiac thrombosisApril 2015
      9NRNRNRStrokeApril 2015
      10NRMVTECerebral and lower limb thrombosisApril 2015
      1160MNVAFStrokeApril 2015
      12NRNRNRStroke in 2 patientsMay 2015
      13NRFNVAFDVTJune 2015
      14NRFVTEPulmonary embolismJune 2015
      1545MVTEDeath due to pulmonary embolismJune 2015
      1690MNVAFStrokeJune 2015
      17NRNRNRStroke in 3 patientsJune 2015
      18NRNRNRThrombosisJune 2015
      1969FNVAFTIAJuly 2015
      20NRFNVAFStrokeAugust 2015
      21NRNRNVAFStrokeSeptember 2015
      22NRFNVAFDeath following strokeSeptember 2015
      23NRMVTEThrombosisSeptember 2015
      24NRNRNRStrokeOctober 2015
      25NRMAFStrokeNovember 2015
      2670MNRStrokeNovember 2015
      2790MAFCardiomyopathy/TIADecember 2015
      28NRMAFStrokeDecember 2015
      AF = atrial fibrillation; DVT = deep vein thrombosis; NR = not reported; NVAF = nonvalvular atrial fibrillation; TIA = transient ischemic attack; VTE = venous thromboembolism.

      Discussion

      There are obvious numerous and significant limitations to this report. These include the limited description of clinical characteristics of the individual cases within the Medwatch submissions, such as prior medical history, clinical risk (eg, CHADS2 score), the lack of ability to follow up on an individual case basis, the potential for bias in the reporting mechanism that cannot be controlled, and an unknown denominator of the “at-risk” population. Further, it is not known how many patients abruptly ceased rivaroxaban and did not experience a clinical event, nor is it known how many patients ceased their anticoagulant and suffered an adverse event that was not reported. Finally, while the language in these forms clearly states that patients viewed legal advertising and stopped their rivaroxaban, this cannot be definitively known. However, it is clear that some patients are intimidated enough by the ongoing legal campaign to stop their anticoagulant, and thus suffer an adverse event.
      These cases serve to highlight the importance of following anticoagulant prescribing information, and that physicians should emphasize that patients should not stop anticoagulants without medical consultation. Continued partnership between drug manufacturers, physicians, regulators, and patients is necessary to provide sufficient education to ensure that these important medical events do not occur.

      Have Atrial Fibrillation? Blood Thinners Can Prevent Strokes, Save Lives. Available at 〈http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm467201.htm〉. Accessed December 20 2015.

      References

        • Sarich T.C.
        • Peters G.
        • Berkowitz S.D.
        • et al.
        Rivaroxaban: a novel oral anticoagulant for the prevention and treatment of several thrombosis-mediated conditions.
        Ann N Y Acad Sci. 2013; 1291: 42-55
        • Mahaffey K.W.
        • Hellkamp A.S.
        • Patel M.R.
        • et al.
        End of study transition from study drug to open-label vitamin K antagonist therapy: the ROCKET AF experience.
        Circ Cardiovasc Qual Outcomes. 2013; 6: 470-478
      1. Have Atrial Fibrillation? Blood Thinners Can Prevent Strokes, Save Lives. Available at 〈http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm467201.htm〉. Accessed December 20 2015.