Rivaroxaban

Aka: Rivaroxaban, Xarelto

1. Mechanism
   1. Oral direct Xa inhibitor
   2. Factor Xa is the first step in the Common Clotting Cascade
2. Indications
   1. Atrial Fibrillation
      1. Bridging to Transesophageal Echocardiogram and early cardioversion in Atrial Fibrillation (ideal indication)
      2. Alternative to Warfarin (where Pradaxa Dyspepsia not tolerated, or twice daily dosing difficult)
      3. Poor INR control on Warfarin
      4. Barriers to INR monitoring
      5. Warfarin Drug Interactions
   2. Deep Vein Thrombosis prophylaxis post-hip or knee replacement
   3. Venous Thromboembolism (DVT or PE) management
3. Contraindications
   1. Avoid if Creatinine Clearance <30 ml/min (especially if using to treat VTE)
   2. Moderate to severe hepatic Impairment
   3. Lumbar Puncture or spinal Anesthesia (risk of Epidural Hematoma or spinal hematoma)
   4. Active bleeding
   5. Pregnancy or Lactation
4. Pharmacokinetics
   1. Oral bioavailability: 60%
   2. Half-life
      1. Young: 5-9 hours in young patients
      2. Elderly: 11-13 hours in the elderly
   3. Onset: 1-4 hours post-ingestion
      1. Maximal Factor Xa inhibition by 3 hours
   4. Mixed renal (66%) and hepatic excretion
      1. Contrast with Dabigatran which has primarily renal excretion
5. Precautions
   1. Emergent Reversal of Anticoagulation (e.g. Hemorrhage)
      1. Andexxa released in 2018
      2. Consider Prothrombin Complex Concentrate, activated PCC or recombinant Factor VIIa
   2. Increased stroke risk if stopped abruptly without other Anticoagulation in nonvalvular Atrial Fibrillation
6. Dosing
   1. Taken with evening meal increases absorption
   2. Atrial Fibrillation
      1. Creatinine Clearance >50 ml/minute: 20 mg daily
      2. Creatinine Clearance 15-50 ml/minute: 15 mg daily
         1. Do not use in patients with Creatinine Clearance <15 ml/minute
   3. Deep Vain Thrombosis prophylaxis (Hemostasis must be achieved before starting; start 6-10 hours post-op)
      1. Post hip surgery: 10 mg once daily for 35 days
      2. Post knee surgery: 10 mg once daily for 12 days
   4. Venous Thromboembolism management
      1. Initial: 15 mg orally twice daily for 21 days
      2. Maintenance: 20 mg orally daily
      3. Prevention of recurrence: 20 mg orally daily
      4. Continue for at least 3 months or as per the indicated VTE circumstances
   5. Vascular prevention (CAD or PAD)
      1. Xarelto 2.5 mg twice daily added to Aspirin 81 mg in stable chronic CAD or PAD
      2. However, NNT 71 for serious CAD related event, NNT 147 for PAD related amputation
      3. NNH 80 to cause one major bleeding event
      4. (2018) Presc Lett 25(12): 68
7. Efficacy
   1. Atrial Fibrillation
      1. Same efficacy as Warfarin in prevention against thrombotic events (e.g. CVA) in Atrial Fibrillation
   2. Venous Thromboembolism
      1. FDA approved for treatment of Venous Thromboembolism or VTE (Deep Vein Thrombosis, Pulmonary Embolism)
      2. As effective, safe as Low Molecular Weight Heparin in DVT short-term and long-term management (without bridging)
      3. Effective in PE studies using the same dosing as for Deep Vein Thrombosis (see above)
      4. (2012) N Engl J Med 366(14):1287-97 [PubMed]
      5. Bauersachs (2010) N Engl J Med 363(26): 2499-510 [PubMed]
      6. Buller (2012) N Engl J Med 366(14): 1287-97 [PubMed]
8. Disadvantages
   1. Cost: $260/month (contrast with Warfarin which is $80/month with monitoring)
      1. However, in acute management, Rivoroxaban is $14/day versus $100-200/day for Enoxaparin (Lovenox)
9. Safety
   1. Longterm data is less available than for Warfarin
   2. Fewer Intracranial Bleeding complications than with Warfarin (Coumadin)
   3. More Gastrointestinal Bleeding complications than with Coumadin
10. Contraindications
    1. Active pathologic bleeding
    2. Moderate to severe liver disease (significantly increases drug levels)
    3. Coagulopathies secondary to hepatic disease
    4. Creatinine Clearance <15 ml/min
11. Drug Interactions
    1. Strong Cytochrome P450 3A4 inducers (decreased Rivaroxaban effect)
       1. Rifampin (also induces P-Glycoprotein)
       2. Phenytoin
       3. Carbamazepine
       4. Phenobarbital
    2. P-Glycoprotein Inhibitors (increased Rivaroxaban effect)
       1. Ketoconazole
       2. Itraconazole
       3. Voriconazole
       4. Ritonavir
       5. Conivaptan
       6. Clarithromycin
       7. Dronedarone
       8. Verapamil
    3. Other Anticoagulants and antiplatelet agents (bleeding risk, esp. peptic ulcer)
       1. Aspirin and other antiplatelet agents
       2. NSAIDs
12. References
    1. (2014) Presc Lett 21(11): 61
    2. (2012) Prescr Lett 19(3):13
    3. (2011) Prescr Lett 18(12):67
    4. Lemkin (2013) Crit Dec Emerg Med 27(4): 2-9
    5. Patel (2011) N Engl J Med 365(10): 883-91 [PubMed]
    6. Wilbur (2017) Am Fam Physician 95(5): 295-302 [PubMed]
    7. Wigle (2019) Am Fam Physician 100(7): 426-34 [PubMed]