MD Nexus

Rivaroxaban (Xarelto)

Indications

Acute Coronary Syndrome (ee Coronary Artery Disease)

Clinical Efficacy

  • Investigational

Peripheral Artery Disease (PAD) After Revascularization (see Peripheral Artery Disease)

FDA approved 2021 expanded peripheral artery disease (PAD) Indication for Xarelto® (rivaroxaban) plus aspirin to include patients after lower-extremity revascularization (LER) due to symptomatic PAD. News release. Janssen Pharmaceuticals, Inc. Accessed August 24, 2021. https://www.prnewswire.com/news-releases/fda-approves-expanded-peripheral-artery-disease-pad-indication-for-xarelto-rivaroxaban-plus-aspirin-to-include-patients-after-lower-extremity-revascularization-ler-due-to-symptomatic-pad-301361537.html.

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

Clinical Efficacy-General

  • FDA Approved in November, 2011 for Stroke Prevention in 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 Requiring Long-Term Anticoagulation, Although the Treatment Benefits Compared with Coumadin are Small and Vary Depending on the Control Achieved by Coumadin Treatment
  • Systematic Review and Meta-Analysis of Bleeding Complications with DOAC’s in Atrial Fibrillation and Venous Thromboembolism (Blood. 2014) [MEDLINE]
    • DOAC’s were Associated with Less Major Bleeding Less Fatal Bleeding, Less Intracranial Bleeding, Less Clinically Relevant Bleeding, and Less Total Bleeding, as Compared to Coumadin
  • Systematic Review and Meta-Analysis of Mortality Outcomes of DOAC’s in Patients with Atrial Fibrillation and Venous Thromboembolism (J Thromb Haemost, 2015) [MEDLINE]
    • DOAC’s were Associated with a Lower Rate of Fatal Bleeding, Lower Case-Fatality Rate of Major Bleeding, Decreased Cardiovascular Mortality, and Decreased All-Cause Mortality, as Compared to Coumadin

Clinical Efficacy-Cost Effectiveness

  • Systematic Review of Cost-Effectiveness of Novel Oral Anticoagulants for Stroke Prevention in Non-Valvular Atrial Fibrillation (Rev Port Cardiol, 2015) [MEDLINE]
    • Novel Oral Anticoagulants are Cost-Effective for Stroke Prevention in Atrial Fibrillation, as Compared to Coumadin
  • Review of Cost-Effectiveness of Novel Oral Anticoagulants for Stroke Prevention in Non-Valvular Atrial Fibrillation (Curr Cardiol Rep, 2015) [MEDLINE]
    • Novel Oral Anticoagulants are Cost-Effective for Stroke Prevention in Atrial Fibrillation, as Compared to Coumadin

Venous Thromboembolism (see Deep Venous Thrombosis and Acute Pulmonary Embolism)

Clinical Efficacy

  • FDA Approved in November, 2012 for the Treatment of 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 Requiring Long-Term Anticoagulation, Although the Treatment Benefits Compared with Coumadin are Small and Vary Depending on the Control Achieved by Coumadin Treatment
  • Cochrane Systematic Review and Meta-Analysis of DOAC’s (Dabigatran, Rivaroxaban, Apixaban, and Edoxaban) in the Treatment of Acute Symptomatic Venous Thromboembolism (J Thromb Haemost, 2014) [MEDLINE]
    • DOAC’s Have Comparable Efficacy to Coumadin and are Associated with a Significantly Lower Risk of Hemorrhagic Complications (Although the Number Needed to Treatment to Prevent One Major Bleed was Notably High at 149)
  • Systematic Review and Meta-Analysis of Bleeding Complications with DOAC’s in Atrial Fibrillation and Venous Thromboembolism (Blood. 2014) [MEDLINE]
    • DOAC’s were Associated with Less Major Bleeding Less Fatal Bleeding, Less Intracranial Bleeding, Less Clinically Relevant Bleeding, and Less Total Bleeding, as Compared to Coumadin
  • Systematic Review and Meta-Analysis of Mortality Outcomes of DOAC’s in Patients with Atrial Fibrillation and Venous Thromboembolism (J Thromb Haemost, 2015) [MEDLINE]
    • DOAC’s were Associated with a Lower Rate of Fatal Bleeding, Lower Case-Fatality Rate of Major Bleeding, Decreased Cardiovascular Mortality, and Decreased All-Cause Mortality, as Compared to Coumadin

Venous Thromboembolism Prophylaxis in Medical Patients (see Deep Venous Thrombosis and Acute Pulmonary Embolism)

Clinical Efficacy

  • MAGELLAN Non-Inferiority Trial Comparing Rivaroxaban (x 35 +/- 4 Days) to Enoxaparin (x 10 +/- 4 Days) for DVT Prophylaxis in Acutely Ill Medical Patients (NEJM, 2013) [MEDLINE]: multi-center, randomized ( n = 8101)
    • At Day 10: Rivaroxaban was Equivalent (2.7%) to Enoxaparin (2.7%), in Terms of Venous Thromboembolism
    • At Day 35: Rivaroxaban was Superior (4.4%) to Enoxaparin (5.7%), in Terms of Venous Thromboembolism
    • At Day 10: Rivaroxaban Had Significantly Higher Bleeding Risk (2.8%) vs Enoxaparin (1.2%)
    • At Day 35: Rivaroxaban Had Significantly Higher Bleeding Risk (4.1%) vs Enoxaparin (1.7%)
  • MARINER Trial of Prophylactic Rivaroxaban Begun and Continuing After Hospital Discharge (x 45 Days) in High-Risk Medical Patients (Thromb Haemost, 2016) [MEDLINE]: randomized, double-blind, placebo-controlled
    • In Process: endpoints of symptomatic VTE and VTE-related death

Venous Thromboembolism Prophylaxis Post-Knee and Hip Replacement (see Deep Venous Thrombosis and Acute Pulmonary Embolism)

Clinical Efficacy

  • 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

Mechanism of Action

Metabolism

  • Hepatic: CYP3A4 and CYP2J2 enzymes
  • Renal: 66% is excreted by kidneys (36% unchanged)
  • Feces: 28% is excreted in feces (7% unchanged)

Pharmacokinetics

  • Time to Peak Level in Plasma: 2-4 hrs
  • 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)

Effect on Anticoagulation Tests

  • Prothrombin Time (PT)/International Normalized Ratio (INR) (see Prothrombin Time): no effect-prolonged (dose-dependent)
  • Partial Thromboplastin Time (PTT) (see Partial Thromboplastin Time): no effect-prolonged (dose-dependent, although to a lesser extent than for the INR)
  • Thrombin Time (TT) (see Thrombin Time): no effect
  • Anti-Factor Xa Activity (see Anti-Factor Xa Activity): 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

Dose Adjustment for Obesity (2016 International Society of Thrombosis and Hemostasis Recommendations) (J Thromb Haemost, 2016) [MEDLINE]

  • BMI ≤40 kg/m2 and Weight <120 kg: standard dosing is recommended for both venous thromboembolism and atrial fibrillation
  • BMI >40 kg/m2 or Weight >120 kg: direct oral anticoagulants are not recommended (due to limited clinical data and possibility that patient may be underdosed)
    • If Direct Oral Anticoagulants are Used in this Patient Group, Drug-Specific Peak and Trough Levels (Anti-Factor Xa for Apixaban/Edoxaban/Rivaroxaban, Ecarin Time or Dilute Thrombin Time with Appropriate Calibrators for Dabigatran, or Mass Spectrometry for Any of the Agents) Should Be Measured: if levels fall below the expected range, change to coumadin is recommended (rather than dose adjustment of the direct oral anticoagulant)

Drug Interactions

Pregnancy (see 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

Periprocedural/Perioperative Management of Rivaroxaban Anticoagulation

Recommendations for Periprocedural/Perioperative Management of Rivaroxaban (American College of Chest Physicians Clinical Practice Guideline for the Perioperative Management of Antithrombotic Therapy) (Chest, 2022) [MEDLINE]

Reversal of Rivaroxaban Anticoagulation

Activated Charcoal (see Activated Charcoal)

Andexanet Alfa (see Andexanet)

Hemodialysis (see Hemodialysis)

Prothrombin Complex Concentrate-4 Factor (Kcentra, Beriplex, Confidex) (see Prothrombin Complex Concentrate-4 Factor)

Recombinant Factor VIIa (see Factor VIIa)

Adverse Effects

Hemorrhagic Adverse Effects

Comparative Rates of Hemorrhage Between Coumadin and Novel Oral Anticoagulants

Types of Hemorrhage

Other Adverse Effects

References

General

Indications

Atrial Fibrillation

Venous Thromboembolism

Administration

Administration in Specific Clinical Subsets of Patients

Reversal of Anticoagulation

Adverse Effects