Rivaroxaban (Xarelto)

Indications

Acute Coronary Syndrome (ee Coronary Artery Disease, [[Coronary Artery Disease]])

  • Investigational

Systemic Embolism Prevention in Non-Valvular Atrial Fibrillation (see Atrial Fibrillation, [[Atrial Fibrillation]])

  • FDA Approval: Nov, 2011 for non-valvular atrial fibrillation
  • Systematic Review of Novel Oral Anticoagulants, As Compared to Coumadin (Ann Intern Med, 2012) [MEDLINE]: included chronic non-valvular atrial fibrillation trials (RE-LY Trial (2009): dabigatran, ARISTOTLE Trial (2011): apixaban, ROCKET AF Trial (2011): rivaroxaban) and venous thromboembolism trials (EINSTEIN-DVT (2010): rivaroxaban, RE-COVER (2009): dabigatran, EINSTEIN-PE (2012): rivaroxaban)
    • Novel Oral Anticoagulants Decreased All-Cause Mortality, as Compared to Coumadin (risk ratio [RR], 0.88 [95% CI, 0.82 to 0.96]): novel oral anticoagulants are a viable option for patients receiving long-term anticoagulation, although the treatment benefits compared with warfarin are small and vary depending on the control achieved by coumadin treatment

Venous Thromboembolism-Deep Venous Thrombosis (DVT)/Acute Pulmonary Embolism (PE) (see Deep Venous Thrombosis, [[Deep Venous Thrombosis]] and Acute Pulmonary Embolism, [[Acute Pulmonary Embolism]])

  • FDA Approval: Nov, 2012 for venous thromboembolism
  • Systematic Review of Novel Oral Anticoagulants, As Compared to Coumadin (Ann Intern Med, 2012) [MEDLINE]: included chronic non-valvular atrial fibrillation trials (RE-LY Trial (2009): dabigatran, ARISTOTLE Trial (2011): apixaban, ROCKET AF Trial (2011): rivaroxaban) and venous thromboembolism trials (EINSTEIN-DVT (2010): rivaroxaban, RE-COVER (2009): dabigatran, EINSTEIN-PE (2012): rivaroxaban)
    • Novel Oral Anticoagulants Decreased All-Cause Mortality, as Compared to Coumadin (risk ratio [RR], 0.88 [95% CI, 0.82 to 0.96]): novel oral anticoagulants are a viable option for patients receiving long-term anticoagulation, although the treatment benefits compared with warfarin are small and vary depending on the control achieved by coumadin treatment

Deep Venous Thrombosis (DVT) Prophylaxis in Medical Patients

  • MAGELLAN Trial: Non-Inferiority Trial Comparing Rivaroxaban to Enoxaparin for DVT Prophylaxis in Medical Patients (NEJM, 2013) [MEDLINE]
    • In Acutely Ill Medical patients, Rivaroxaban was Equivalent to Enoxaparin for Standard Duration Pharmacologic DVT Prophylaxis
    • Extended-Duration Rivaroxaban Decreased the Risk of Venous Thromboembolism, as Compared to Enoxaparin
    • Rivaroxaban was Associated with an Increased Risk of Bleeding, as Compared to Enoxaparin

Venous Thromboembolism Prophylaxis Post-Knee and Hip Replacement (see Deep Venous Thrombosis, [[Deep Venous Thrombosis]])

  • FDA Approval: July, 2011 for DVT prophylaxis in hip/knee replacement
  • Regulation of Coagulation in Major Orthopedic Surgery Reducing the Risk of DVT and PE (RECORD) Trial (J Bone Joint Surg, 2009) [MEDLINE]
    • Rivaroxaban Started 6-8 hrs After Surgery was More Effective than Enoxaparin Started the Previous Evening in Preventing Symptomatic Venous Thromboembolism and All-Cause Mortality, Without Increasing Major Hemorrhage
  • Systematic Review Comparing Novel Oral and Other Anticoagulants (Fondaparinux, Dabigatran, Rivaroxaban, Apixaban) to Enoxaparin Used as Venous Thromboembolism Prophylaxis After Major Orthopedic Surgery (Ann Vasc Surg, 2013) [MEDLINE]
    • Novel Anticoagulants Can Be Considered as Alternatives to Enoxaparin, Depending on Their Individual Clinical Characteristics and Cost-Effectiveness
    • Primary Efficacy (Any DVT, Non-Fatal PE, or All-Cause Mortality) Favored Fondaparinux and Rivaroxaban Over Enoxaparin
    • Compared to Enoxaparin, the Bleeding Risk was Similar for All Agents, Except Fondaparinux (Which Manifested a Significantly Higher Any-Bleeding Risk) and Apixaban (Which Manifested a Lower Any-Bleeding Risk)

Pharmacology

  • Selective and Competitive Factor Xa Inhibitor (see Factor Xa Inhibitors, [[Factor Xa Inhibitors]]): xxx
  • Metabolism
    • Hepatic: CYP3A4 and CYP2J2 enzymes
    • Renal: 66% is excreted by kidneys (36% unchanged)
    • Feces: 28% is excreted in feces (7% unchanged)
  • Half-Life: 5-9 hrs (11-13 hrs in elderly patients)

Administration

PO Dosing

  • Non-Valvular Atrial Fibrillation: 20 mg qday
  • Deep Venous Thrombosis (DVT) Prophylaxis for Hip Replacement: 10 mg qday x 35 days (start 6-10 hrs post-op, once hemostasis has been achieved)
  • Deep Venous Thrombosis (DVT) Prophylaxis for Knee Replacement: 10 mg qday x 12 days (start 6-10 hrs post-op, once hemostasis has been achieved)
  • Venous Thromboembolism (Acute DVT or PE): 15 mg BID x 21 days, then 20 mg qday
    • Note: rivaroxaban/apixaban do not require initial parenteral (heparin, etc) anticoagulation for the treatment of venous thromboembolism (see Apixaban, [[Apixaban]])

Effect on Anticoagulation Tests

  • Prothrombin Time (PT)/International Normalized Ratio (INR) (see Prothrombin Time, [[Prothrombin Time]]): no effect-prolonged (dose-dependent)
  • Partial Thromboplastin Time (PTT) (see Partial Thromboplastin Time, [[Partial Thromboplastin Time]]): no effect-prolonged (dose-dependent, although to a lesser extent than for the INR)
  • Thrombin Time (TT) (see Thrombin Time, [[Thrombin Time]]): no effect
  • Anti-Factor Xa (see Anti-Factor Xa, [[Anti-Factor Xa]]): no effect-prolonged
    • Effect depends on whether the specific laboratory’s activity assay is calibrated for the specific anticoagulant
  • Heparin Clotting Time: prolonged
  • Bleeding Time : no effect
  • Platelet Aggregation: no effect

Hepatic Dose Adjustment

  • Child-Pugh Class B or C: avoid use
  • Coagulopathy Associated with Liver Disease: avoid use

Renal Dose Adjustment

Treatment of Venous Thromboembolism

  • CrCl ≥30 mL/min (US Package Labeing): no dose adjustment necessary
    • CrCl 30-50 mL/min (Per Beers Criteria for Patients ≥65 y/o): dose adjustment
  • CrCl <30 mL/min (US Package Labeling): avoid use
  • ESRD Requiring Hemodialysis: avoid use

Treatment of Non-Valvular Atrial Fibrillation

  • CrCl >50 mL/min mL/min: no dose adjustment necessary
  • CrCl 15-50 mL/min (US Package Labeling): 15 mg PO qday
    • CrCl 30-50 mL/min (Per Beers Criteria for Patients ≥65 y/o): dose adjustment
  • CrCl <15 mL/min (US Package Labeling): avoid use
    • CrCl <30 mL/min (Per Beers Criteria for Patients ≥65 y/o): avoid use
  • ESRD Requiring Hemodialysis: avoid use

Venous Thromboembolism Prophylaxis

  • CrCl >50 mL/min: no dose adjustment necessary
  • CrCl 30-50 mL/min: no dose adjustment specified, but use with caution
    • CrCl 30-50 mL/min (Per Beers Criteria for Patients ≥65 y/o): dose adjustment
  • CrCl <30 mL/min: avoid use
  • ESRD Requiring Hemodialysis: avoid use

Drug Interactions

Pregnancy

  • Not Approved for Use in Pregnancy: due to possible teratogenicity and secretion in breast milk

Conversion from/to Other Anticoagulants

Conversion From Rivaroxaban

  • Conversion From Rivaroxaban -> Unfractionated Heparin/Low Molecular Weight Heparin: discontinue rivaroxaban and start unfractionated heparin drip/low molecular weight heparin at the time the next dose of rivaroxaban would have been taken

Conversion to Rivaroxaban

  • Conversion From Coumadin -> Rivaroxaban: start rivaroxaban when INR <3
  • Conversion From Low Molecular Weight Heparin -> Rivaroxaban: start rivaroxaban 0-2 hrs prior to the next scheduled evening administration of low molecular weight heparin
  • Conversion From Unfractionated Heparin -> Rivaroxaban: stop the heparin drip and start rivaroxaban at the same time

Management of Rivaroxaban Anticoagulation for Procedures

  • Consider Discontinuation at Least 24 hrs Prior to Surgery or Invasive Procedures

Reversal of Anticoagulation

  • Activated Charcoal (see Activated Charcoal, [[Activated Charcoal]])
    • Clinical Efficacy: indicated to decrease rivaroxaban absorption
  • Andexanet (see Andexanet, [[Andexanet]])
    • Clinical Efficacy: investigational
  • Hemodialysis (see Hemodialysis, [[Hemodialysis]])
    • Clinical Efficacy: unlikely to be effective (due to high degree of rivaroxaban protein binding)
  • Prothrombin Complex Concentrate-4 Factor (Kcentra, Beriplex, Confidex) (see Prothrombin Complex Concentrate-4 Factor, [[Prothrombin Complex Concentrate-4 Factor]])
    • Clinical Efficacy: suggested for apixaban-associated hemorrhage (Biomed Res Int, 2014) [MEDLINE]
      • Abstract from Rat Study Suggests Efficacy
    • Administration: 50 units/kg IV
  • Recombinant Factor VIIa (see Factor VIIa, [[Factor VIIa]])
    • Clinical Efficacy: pre-clinical trials suggest that this may be effective
  • Recombinant Factor Xa
    • Clinical Efficacy: investigational

Adverse Effects

Hemorrhagic Adverse Effects

Comparative Rates of Hemorrhage Between Coumadin and Novel Oral Anticoagulants

  • Systematic Review of Novel Oral Anticoagulants, As Compared to Coumadin (Ann Intern Med, 2012) [MEDLINE]: included chronic non-valvular atrial fibrillation trials (RE-LY Trial (2009): dabigatran, ARISTOTLE Trial (2011): apixaban, ROCKET AF Trial (2011): rivaroxaban) and venous thromboembolism trials (EINSTEIN-DVT (2010): rivaroxaban, RE-COVER (2009): dabigatran, EINSTEIN-PE (2012): rivaroxaban)
    • Decreased Risk of Fatal Bleeding, as Compared to Coumadin (RR, 0.60 [CI, 0.46 to 0.77])
    • Decreased Risk of Major Bleeding, as Compared to Coumadin (RR, 0.80 [CI, 0.63 to 1.01])
    • Increased Risk of Gastrointestinal Bleeding, as Compared to Coumadin (RR, 1.30 [CI, 0.97 to 1.73])
    • Increased Risk of Discontinuation Due to Adverse Events, as Compared to Coumadin (RR, 1.23 [CI, 1.05 to 1.44])
    • Bleeding Risk for New Oral Anticoagulants May Be Higher in Patients >75 y/o or Those Receiving Coumadin Who Have Good Control
  • Systematic Review/Meta-Analysis Comparing Rates of Hemorrhage of Novel Oral Anticoagulants vs Coumadin When Used in the Setting of Renal Insufficiency (Chest, 2016) [MEDLINE]
    • CrCl 50-80 mL/min: novel oral anticoagulants had a significantly decreased risk of major bleeding, as compared to coumadin
    • CrCl <50 mL/min: novel oral anticoagulants had a non-significantly decreased risk of major bleeding, as compared to coumadin
      • Apixaban had the lowest rate of major bleeding in this subgroup

Types of Hemorrhage

Other Adverse Effects

  • xxx
  • xxx
  • xxx

References

  • Prothrombin complex concentrate reverses the effects of high-dose rivaroxaban in rats [abstract]. J Thromb Haemost. 2009;7(suppl 2):183
  • Comparative pharmacodynamics and pharmacokinetics of oral direct thrombin and factor Xa inhibitors in development. Clin Pharmacokin 2009;48(1):1-22 [MEDLINE]
  • Bayer Schering Pharma. Xarelto. Summary of Product Characteristics. May 2009. www.xarelto.com/html/downloads/ XareltoSummaryofProductCharacteristics_May2009.pdf
  • RECORD trial: Oral rivaroxaban for the prevention of symptomatic venous thromboembolism after elective hip and knee replacement. J Bone Joint Surg Br. 2009 May;91(5):636-44. doi: 10.1302/0301-620X.91B5.21691 [MEDLINE]
  • Assessment of laboratory assays to measure rivaroxaban — an oral, direct factor Xa inhibitor. Thromb Haemost. 2010;103:815-825
  • Effects of the oral, direct factor Xa inhibitor rivaroxaban on commonly used coagulation assays. J Thromb Haemost. 2011;9:133-139
  • Comparative effectiveness of warfarin and new oral anticoagulants for the management of atrial fibrillation and venous thromboembolism: a systematic review. Ann Intern Med. 2012 Dec 4;157(11):796-807 [MEDLINE]
  • The new oral anticoagulants and the future of haemostasis laboratory testing. Biochem Med (Zagreb). 2012;22:329-341
  • Systematic review of randomized controlled trials of new anticoagulants for venous thromboembolism prophylaxis in major orthopedic surgeries, compared with enoxaparin. Ann Vasc Surg. 2013 Apr;27(3):355-69. doi: 10.1016/j.avsg.2012.06.010. Epub 2013 Jan 23 [MEDLINE]
  • MAGELLAN Trial: Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med. 2013 Feb 7;368(6):513-23. doi: 10.1056/NEJMoa1111096 [MEDLINE]
  • New oral anticoagulants in the treatment of pulmonary embolism: efficacy, bleeding risk, and monitoring. Thrombosis 2013;2013:973710. doi: 10.1155/2013/973710 [MEDLINE]
  • Management of the bleeding patient receiving new oral anticoagulants: a role for prothrombin complex concentrates. BioMed Res Int. 2014; Article ID 583794 [MEDLINE]
  • Treatment of intracerebral hemorrhage associated with new oral anticoagulant use: the neurologist’s view. Clin Lab Med. 2014;34:587–594 [MEDLINE]
  • Reversal of anticoagulants: an overview of current developments. Thromb Haemost. 2015;113(5):931–942 [MEDLINE]
  • Major Bleeding and Hemorrhagic Stroke with Direct Oral Anticoagulants in Patients with Renal Failure: Systematic Review and Meta-Analysis of Randomized Trials. Chest. 2016,(): doi:10.1016/j.chest.2015.12.029 [MEDLINE]