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rivaroxaban (Xarelto)

Indications: - DVT prophylaxis after arthroplasty - superior to enoxaparin for DVT prophylaxis after total knee arthroplasty or total hip arthroplasty [2,6] - prevention of stroke in patients with atrial fibrillation [4,8,10] - lower annual rates of ischemic stroke or systemic embolism than warfarin (3.0% vs 3.3%) [23] - annual risk of death not different from warfarin (7.7% vs 8.5%) [23] - superior to warfarin in Asians [25]; - reduced risks for ischemic stroke/systemic embolism, intracranial hemorrhage, & all-cause mortality at 1 year [25] - safe for patients with bioprosthetic mitral valves [36] - acute deep vein thrombosis (DVT) [5,15,28] - pulmonary embolism [15] - secondary prevention of myocardial infarction in conjunction with dual anti-platelet therapy [11] (NICE) - FDA-approved to reduce risk for major cardiovascular events in patients with oronary artery disease or peripheral artery disease [34] * safe & effective in the elderly [18] Contraindications: - hypersensitivity - active bleeding - ESRD [20]; not recommended if creatinine clearance < 30 mL/min - severe liver disease - valvular heart disease [5] - morbid obesity (BMI >40 mg/kg) [39] - high-risk antiphospholipid antibody syndrome * questionable - pregnancy - osteoporosis (GRS11: due to increased fracture risk relative to warfarin) [39] - ref [38] concludes decreased fracture risk relative to warfarin Pregnancy category: C Dosage: - prophylaxis for venous thromboembolism (VTE) - 10 mg PO QD (start 6-8 hours after surgery) - continue for 30-35 days after surgery - stroke prevention for atrial fibrillation: 20 mg PO QD [4] - DVT or pulmonary embolism: - 15 mg PO BID for 3 weeks, then 20 mg PO QD [5] - no need for bridging LMW heparin [29] - 2.5 mg PO BID (secondary prevention of MI) [11] - stop 24-48 hours prior to surgery (see perioperative anticoagulation) Tabs: 10 mg Dosage adjustment in renal failure: - 15 mg QD for creatinine clearance 15-50 ml/min (AF) - do not use for VTE with creatinine clearance < 30 ml/min [20] - no dosage adjustment treating VTE for creatinine clearance > 30 ml/min Pharmacokinetics: - renal elmination: - 66%, 33% as active metabolite; 30% [32] - substrate of both CYP3A4 & P-glycoprotein - time to maximum concentration: 3 hours - 1/2life: 7-11 hours - protein binding: 95% Adverse effects: - bleeding most common adverse effect - clinically significant bleeding more common with rivaroxaban than LMW heparin in acutely ill hospitalized patients (4.1 vs 1.7%) [17] - major bleeding* < 1% of patients - similar risk of GI bleed compared with warfarin [19,28] - risk of GI bleeding highest among direct oral anticoagulants [37] - less major bleeding than LMW heparin/warfarin when used to treat DVT [21] - higher risk of hospitalization for GI bleed & for intracranial hemorrhage than with dabigatran [25,26] - increased mortality (20-50%) relative to warfarin [33] - similar risks for ischemic stroke & bleeding as warfarin but lower risk for death in nursing home residents (RR=0.7-0.8) [35] * treatment of major bleeding - stop rivaroxaban - administer fresh frozen plasma until bleeding stops [13] - prothombin complex concentrate reverses anticoagulant effect of rivaroxaban [12]; 70% effective [30] - neither prothrombin complex concentrate nor tranexamic acid limits bleeding [31] - andexanet reverses factor Xa inhibition - a specific reversal agent is not yet licensed [31] Drug interactions: - inhibitors of CYP3A4 may increase levels of rivaroxaban - inducers of CYP3A4 may decrease levels of rivaroxaban - rivaroxaban itself neither induces or inhibits CYP3A4 Laboratory: - rivaroxaban in serum/plasma Mechanism of action: - small molecule inhibitor of factor Xa Clinical trials: - ROCKET AF trial - point-of-care device used to measure INR after dosing with warfarin in ROCKET AF trial later recalled by FDA because the device was prone to giving falsely low INR readings [8,22]* - falsely low INR readings may have prompted higher doses of warfarin resulting in higher risks for bleeding making rivaroxaban seem comparatively safer [22] - authors of ROCKET AF trial reanalyzed their data & concluded that use of the device had not significant clinical effect on the primary efficacy or safety outcomes in the trial - data not publically available * Janssen, the pharmaceutical branch of Johnson & Johnson, knew that a point-of-care device used for measuring INR was giving falsely low readings during the ROCKET AF trial [24] * FDA concludes results of ROCKET AF trial not effected by faulty monitoring device [27]

Interactions

drug interactions drug adverse effects of direct oral anticoagulants

Related

apixaban (Eliquis)

General

coagulation factor Xa inhibitor direct oral anticoagulant; novel oral anticoagulant (DOAC, NOAC)

Database Correlations

PUBCHEM correlations

References

  1. Eriksson BI et al, Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthriplasty. N Engl J Med 2008, 358:2765 PMID: 18579811 - Lassen MR et al, Rivaroxaban for thromboprophylaxis after total knee arthroplasty. N Engl J Med 2008, 358:2776 PMID: 18579812
  2. Lassen MR et al Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty N Engl J Med 2008 Jun 26; 358:2776 PMID: 18579812 - Kakkar AK 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 Jul 5; 372:31. PMID: 18582928 - Eriksson BI et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med 2008 Jun 26; 358:2765. PMID: 18579811
  3. Prescriber's Letter 15(8): 2008 New Drugs on the Horizon: Pradaxa (Dabigatran) and Xarelto (Rivaroxaban) Detail-Document#: 240805 (subscription needed) http://www.prescribersletter.com
  4. American Heart Association News Release Rivaroxaban comparable to warfarin in preventing stroke and other complications of irregular heartbeat American Heart Association Annual Meeting. Abstract 21839 Chicago, IL Nov. 15, 2010 http://www.newsroom.heart.org/index.php?s=43&item=1191
  5. The EINSTEIN Investigators Oral Rivaroxaban for Symptomatic Venous Thromboembolism N Engl J Med December 3, 2010 PMID: 21128814 http://www.nejm.org/doi/full/10.1056/NEJMoa1007903
  6. FDA NEWS RELEASE July 5, 2011 http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm261839.htm
  7. Prescriber's Letter 18(8): 2011 New Drug: Xarelto (Rivaroxaban) Detail-Document#: 270806 (subscription needed) http://www.prescribersletter.com
  8. Patel MR, Mahaffey KW, Garg J et al. for the ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011 Aug 10 PMID: 21830957
  9. Prescriber's Letter 18(9): 2011 Reversing Dabigatran and Rivaroxaban Detail-Document#: 270912 (subscription needed) http://www.prescribersletter.com
  10. FDA NEWS RELEASE: Nov. 4, 2011 FDA approves Xarelto to prevent stroke in people with common type of abnormal heart rhythm http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm278646.htm
  11. Mega JL et al. for the ATLAS ACS 2-TIMI 51 Investigators. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med 2011 Nov 13 PMID: 22077192 http://www.nejm.org/doi/full/10.1056/NEJMoa1112277 - Roe MT and Ohman EM. A new era in secondary prevention after acute coronary syndrome. N Engl J Med 2011 Nov 13 PMID: 22077849 http://www.nejm.org/doi/full/10.1056/NEJMe1112770
  12. Eerenberg ES et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: A randomized, placebo-controlled, crossover study in healthy subjects. Circulation 2011 Oct 4; 124:1573. PMID: 21900088 - Battinelli EM. Reversal of new oral anticoagulants. Circulation 2011 Oct 4; 124:1508. PMID: 21969317
  13. Prescriber's Letter 19(1): 2012 Reversing Dabigatran and Rivaroxaban Detail-Document#: 280102 (subscription needed) http://www.prescribersletter.com
  14. Buller HR et al. for the EINSTEIN-PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012 Mar 26 PMID: 22449293 http://www.nejm.org/doi/full/10.1056/NEJMoa1113572
  15. FDA News Release: Nov. 2, 2012 FDA expands use of Xarelto to treat, reduce recurrence of blood clots. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm326654.htm
  16. Prescriber's Letter 19(12): 2012 Comparison of Oral Antithrombotics Detail-Document#: 281222 (subscription needed) http://www.prescribersletter.com
  17. Cohen AT et al. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med 2013 Feb 7; 368:513. PMID: 23388003 http://www.nejm.org/doi/full/10.1056/NEJMoa1111096
  18. Sardar P et al. New oral anticoagulants in elderly adults: Evidence from a meta-analysis of randomized trials. J Am Geriatr Soc 2014 May; 62:857 PMID: 24786913 http://onlinelibrary.wiley.com/doi/10.1111/jgs.12799/abstract
  19. Chang H-Y et al. Risk of gastrointestinal bleeding associated with oral anticoagulants: Population based retrospective cohort study. BMJ 2015;350:h1585 PMID: 25911526 http://www.bmj.com/content/350/bmj.h1585 - Abraham NS et al. Comparative risk of gastrointestinal bleeding with dabigatran, rivaroxaban, and warfarin: Population based cohort study. BMJ 2015;350:h1857 PMID: 25910928 http://www.bmj.com/content/350/bmj.h1857 - Vaughan Sarrazin MS and Rose A. Safety of new oral anticoagulants. BMJ 2015;350:h1679 PMID: 25911527 http://www.bmj.com/content/350/bmj.h1679
  20. Medical Knowledge Self Assessment Program (MKSAP) 17, American College of Physicians, Philadelphia 2015
  21. Eerenberg ES et al. Clinical impact and course of major bleeding with rivaroxaban and vitamin K antagonists. J Thromb Haemost 2015 Sep; 13:1590 PMID: 26179293
  22. Cohen D Rivaroxaban: can we trust the evidence? BMJ 2016;352:i575 PMID: 26843102 http://www.bmj.com/content/352/bmj.i575
  23. Larsen TB et al Comparative effectiveness and safety of non-vitamin K antagonist oral anticoagulants and warfarin in patients with atrial fibrillation: propensity weighted nationwide cohort study. BMJ 2016;353:i3189 PMID: 27312796 Free full text http://www.bmj.com/content/353/bmj.i3189
  24. Cohen D Manufacturer failed to disclose faulty device in rivaroxaban trial. BMJ 2016;354:i5131 PMID: 27681119 http://www.bmj.com/content/354/bmj.i5131 - Mahtani KR, Heneghan C Novel oral anticoagulants for atrial fibrillation BMJ 2016;354:i5187 PMID: 27681833 http://www.bmj.com/content/354/bmj.i5187 - Rathi VK, Krumholz HM, Ross JS Commentary: Diagnostic devices in clinical trials have high stakes for patient care. BMJ 2016;354:i5197 PMID: 27681285 http://www.bmj.com/content/354/bmj.i5197
  25. Chan YH, Kuo CT, Yeh YH et al. Thromboembolic, bleeding, and mortality risks of rivaroxaban and dabigatran in Asians with nonvalvular atrial fibrillation. J Am Coll Cardiol 2016 Sep 27; 68:1389. PMID: 27659460 Free Article - Ruff C. The reality of "real-world" data: More questions than answers. J Am Coll Cardiol 2016 Sep 27; 68:1402 PMID: 27659461
  26. 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. Published online October 03, 2016 PMID: 27695821 http://archinte.jamanetwork.com/article.aspx?articleid=2560376 - Parks AL, Redberg RF Comparing Non-Vitamin K Oral Anticoagulants. Where We Are Now. JAMA Intern Med. Published online October 03, 2016 PMID: 27695820 archinte.jamanetwork.com/article.aspx?articleid=2560371
  27. FDA News Release. Oct 11, 2016 FDA analyses conclude that Xarelto clinical trial results were not affected by faulty monitoring device. http://www.fda.gov/Drugs/DrugSafety/ucm524678.htm
  28. Larsen TB, Skjoth F, Kjaeldgaard JN et al Effectiveness and safety of rivaroxaban and warfarin in patients with unprovoked venous thromboembolism: a propensity- matched nationwide cohort study. The Lancet Haematology. April 11, 2017 PMID: 28411120 http://thelancet.com/journals/lanhae/article/PIIS2352-3026(17)30054-6/fulltext - Johnsen SP The lure and pitfalls of administrative health registers. The Lancet Haematology. April 11, 2017 PMID: 28411122 http://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(17)30056-X/fulltext
  29. Bauersachs R, Berkowitz SD, Brenner B, et al Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363(26):2499-2510 PMID: 21128814 Free full text
  30. Majeed A, Agren A, Holmstrom M et al. Management of rivaroxaban or apixaban associated major bleeding with prothrombin complex concentrates: A cohort study. Blood 2017 Aug 23 PMID: 28835439
  31. Levy JH, Moore KT, Neal MD et al. Rivaroxaban reversal with prothrombin complex concentrate or tranexamic acid in healthy volunteers. J Thromb Haemost 2018 Jan; 16:54 PMID: 29106076 http://onlinelibrary.wiley.com/doi/10.1111/jth.13894/abstract
  32. Ashley J, Sood MM Novel oral anticoagulants in chronic kidney disease: ready for prime time? Curr Opin Nephrol Hypertens. 2018;27(3):201-208 PMID: 29570468 https://www.medscape.com/viewarticle/895572
  33. Vinogradova Y, Coupland C, Hill T, Hippisley-Cox J Risks and benefits of direct oral anticoagulants versus warfarin in a real world setting: cohort study in primary care. BMJ 2018;362:k2505 PMID: 29973392 https://www.bmj.com/content/362/bmj.k2505
  34. Eikelboom JW, Connolly SJ, Bosch J, et al. Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med 2017 Aug 27; [e-pub]. PMID: 28844192 http://www.nejm.org/doi/10.1056/NEJMoa1709118 - Braunwald E. An important step for thrombocardiology. N Engl J Med 2017 Aug 27; PMID: 28844176 http://www.nejm.org/doi/10.1056/NEJMe1710241 - Connolly SJ, Eikelboom JW, Bosch J et al. Rivaroxaban with or without aspirin in patients with stable coronary artery disease: An international, randomised, double- blind, placebo-controlled trial. Lancet 2017 Nov 10; PMID: 29132879 - Ohman EM. Secondary prevention shifts into second gear. Lancet 2017 Nov 10 PMID: 29132878 - Janssen. Johnson & Johnson U.S. FDA Approves XARELTO (rivaroxaban) to Reduce the Risk of Major Cardiovascular Events in Patients with Chronic Coronary Artery Disease (CAD) or Peripheral Artery Disease (PAD). News Release. Oct 11, 2018 https://www.janssen.com/us-fda-approves-xareltor-rivaroxaban-reduce-risk-major-cardiovascular-events-patients-chronic - HIGHLIGHTS OF PRESCRIBING INFORMATION XARELTO (rivaroxaban) http://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/XARELTO-pi.pdf
  35. Alcusky M et al. Comparative safety and effectiveness of direct-acting oral anticoagulants versus warfarin: A national cohort study of nursing home residents. J Gen Intern Med 2020 Aug; 35:2329. PMID: 32291717 PMCID: PMC7403286 https://link.springer.com/article/10.1007/s11606-020-05777-3
  36. Guimaraes HP et al. Rivaroxaban in patients with atrial fibrillation and a bioprosthetic mitral valve. N Engl J Med 2020 Nov 14; [e-pub]. PMID: 33196155 https://www.nejm.org/doi/10.1056/NEJMoa2029603
  37. Ingason AB, Hreinsson JP, Agustsson AS et al. Rivaroxaban is associated with higher rates of gastrointestinal bleeding than other direct oral anticoagulants: A nationwide propensity score-weighted study. Ann Intern Med 2021 Oct 12; [e-pub]. PMID: 34633836 https://www.acpjournals.org/doi/10.7326/M21-1474
  38. Sugiyama T An update on hip fracture risk associated with anticoagulant therapy: warfarin versus direct oral anticoagulants. Expert Opinion on Drug Safety. 2020 19(10):1219-1220 PMID: 32795203
  39. Geriatric Review Syllabus, 11th edition (GRS11) Harper GM, Lyons WL, Potter JF (eds) American Geriatrics Society, 2022