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

Azole Anti-Fungals (see Azole Anti-Fungals, [[Azole Anti-Fungals]])
HIV Protease Inhibitors (see Anti-Retrovirals, [[Anti-Retrovirals]])

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

Adrenal Hemorrhage (see Adrenal Insufficiency, [[Adrenal Insufficiency]])
Diffuse Alveolar Hemorrhage (DAH) (see Diffuse Alveolar Hemorrhage, [[Diffuse Alveolar Hemorrhage]]
Epistaxis (see Epistaxis, [[Epistaxis]])
Gastrointestinal Hemorrhage (see Gastrointestinal Hemorrhage, [[Gastrointestinal Hemorrhage]])
Hematuria (see Hematuria, [[Hematuria]])
Intracerebral Hemorrhage (Hemorrhagic Cerebrovascular Accident) (see Intracerebral Hemorrhage, [[Intracerebral Hemorrhage]])
Intracranial Epidural Hematoma (see Intracranial Epidural Hematoma, [[Intracranial Epidural Hematoma]])
Retroperitoneal Hemorrhage (see Retroperitoneal Hemorrhage, [[Retroperitoneal Hemorrhage]])
Spinal Epidural Hematoma (see Spinal Epidural Hematoma, [[Spinal Epidural Hematoma]])
Subarachnoid Hemorrhage (SAH) (see Subarachnoid Hemorrhage, [[Subarachnoid Hemorrhage]])
Subdural Hematoma (SDH) (see Subdural Hematoma, [[Subdural Hematoma]])

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]