Drug Class Monograph Class: Oral Anticoagulants Drug: Coumadin (warfarin), Eliquis (apixaban), Pradaxa (dabigatran), Savaysa (edoxaban), arelto (rivaroxaban) Formulary Medications: Eliquis (apixaban), Coumadin (warfarin), arelto (rivaroxaban) Line of Business: Medi-Cal Effective Date: February 15, 2017 Revision Date: February 15, 2017 This policy has been developed through review of medical literature, consideration of medical necessity, generally accepted medical practice standards, and approved by the IEHP Pharmacy and Therapeutics Subcommittee. Policy/Criteria: Code 1 Criteria: 1. Eliquis (apixaban), arelto (rivaroxaban) a. Confirmed diagnosis of deep venous thrombosis (DVT) and/or pulmonary embolism (PE); OR DVT thromboprophylaxis following hip or knee replacement surgery. Prior Authorization Criteria: 1. Eliquis (apixaban), arelto (rivaroxaban) systemic embolism); Failure or clinically significant adverse effects to warfarin. 2. Pradaxa (dabigatran) systemic embolism) or treatment of DVT, PE; Failure or clinically significant adverse effects to Eliquis and arelto. b. Confirmed diagnosis of DVT thromboprophylaxis following hip replacement surgery.
3. Savaysa (edoxaban) systemic embolism) or treatment of DVT, PE; Failure or clinically significant adverse effects to warfarin. Clinical Justification: Comparison of FDA Approved Indications Coumadin (warfarin) Eliquis (apixaban) Pradaxa (dabigatran) Savaysa (edoxaban) arelto (rivaroxaban) Stroke prevention in nonvalvular atrial fibrillation (AF) Venous thromboembolism (VTE) prophylaxis following hip or knee replacement VTE treatment Reduction in the risk of recurrence of DVT/PE Thromboembolism prevention in heart valve replacement Post myocardial infarction (Hip surgery) Usual Dosage Routine Lab Anticoagulant Monitoring Reversal Agent Dabigatran Rivaroxaban Apixaban Edoxaban Warfarin AF: 150mg AF: once VTE tx: 150mg titrate to INR 2 3 AF: 20mg VTE tx: 15mg x21 days, then 20mg VTE ppx: 10mg AF: 5 mg VTE tx: 10mg x 7 days, then 5mg VTE ppx: 2.5mg AF: 60mg VTE tx: 60mg No No No No Yes Yes No No No Yes Dietary Consideratio n Time to maximum concentration No 1 2 hours (no Yes, take with evening meal for doses > 10mg 2 4 hours (no No No Yes; consistency with vitamin K food 3 4 hours (no 1 2 hours (no Peak effect delayed 72 96 hours Required
(e.g. LMWH) Half Life 12 17 hours 5 9 hours 12 hours 10 14 hours ~40 hours Renal Dosing Adjustment AF: CrCl 15 30 ml/min: 75mg RELY: CrCl <30ml/min: excluded VTE tx: CrCl 30 ml/min: avoid use AF: CrCl 15 50 ml/min: 15mg once ROCKET AF: CrCl<30ml/min excluded VTE tx: CrCl<30ml/min: VTE ppx: CrCl<30ml/min: AF: SCr 1.5 mg/dl and one of the following: Age 80, wt 60kg: 2.5mg VTE tx: no adjustment VTE ppx: no adjustment AF: Should not used in patients with CrCl>95 ml/min AF/VTE tx: CrCl 15 50mL/min: 30mg once. CrCl <15mL/min: Titrate to INR 2 3 Atrial Fibrillation 2016 American College of Chest Physicians (ACCP) CHEST Guidelines: Studies show that patients with non-valvular atrial fibrillation may have a higher risk of GI bleed with dabigatran, rivaroxaban and edoxaban over warfarin. 2014 American Heart Association (AHA), American Stroke Association (ASA) and Heart Rhythm Society (HRS) Guideline for the Management of Patients with Atrial Fibrillation: Executive Summary: In patients with nonvalvular AF, the CHADS2-VASc score is recommended for assessment of stroke risk. For patients with nonvalvular AF with prior stroke, transient ischemic attack (TIA), or a CHADS 2-VASc score of 2 or greater, oral anticoagulants are recommended. Options include warfarin (INR 2.0 to 3.0) (Level of Evidence: A), dabigatran (Level of Evidence: B), rivaroxaban (Level of Evidence: B), or apixaban (Level of Evidence: B)
2014 American College of Cardiology and American Heart Association Task Force on Practice Guidelines for the Management of Patients with Atrial Fibrillation: Oral anticoagulant options include warfarin (Level of Evidence A), dabigatran (Level of Evidence B), rivaroxaban (Level of Evidence B), or apixaban (Level of Evidence B) for patients with nonvalvular atrial fibrillation with prior stroke or CHADS-VAS score of 2 or greater. For patients with moderate to severe CKD, safety and efficacy for reduced doses of dabigatran, rivaroxaban or apixaban have not been established. 1. According to the three pivotal large clinical trials, RELY, ROCKET AF and ARISTOTLE, dabigatran, rivaroxaban and apixaban, respectively, demonstrated noninferior efficacy in the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Furthermore, dabigatran and apixaban were shown to be superior to warfarin for their primary composite endpoint of stroke or systemic embolism. Favorable mortality benefits were noted with all three newer agents than warfarin. 2. There is no head-to-head comparison study among the newer oral anticoagulant agents. 3. Dabigatran is associated with increased gastrointestinal bleeding, particularly in patients of age 75 years and older. 4. Despite concerns of post-marketing reports of bleeding, dabigatran did not appear to associate with higher bleeding rates than warfarin according to the FDA statement issued in November 2012. Venous Thromboembolism (VTE) Treatment 2016 ACCP CHEST Guidelines: Dabigatran, rivaroxaban, apixaban or edoxaban are preferred over warfarin in the treatment of VTE in patients with no cancer (Grade 2B). Rivaroxaban, apixaban and dabigatran have established noninferior efficacy and comparable major bleeding rates in comparison to warfarin in the prevention of recurrent VTE in patients with acute VTE. VTE Prophylaxis in Total Knee Replacement and Total Hip Replacement 2012 ACCP CHEST Guidelines: LMWH is preferred over rivaroxaban or dabigatran in the prevention of VTE in patients undergoing total knee replacement or total hip replacement (Grade 2B), given the lack of long term safety data with the newer agents.
2011 American Academy of Orthopedia Surgeons Guidelines: Do not have preference for one agent over another for VTE prophylaxis for total knee replacement or total hip replacement. Rivaroxaban, apixaban and dabigatran have demonstrated noninferior efficacy as enoxaparin 40mg once for VTE prophylaxis in patients undergoing total hip replacement with comparable major bleeding rates. References: 1. Guyatt GH, Akl EA, Crowther M, et al. Executive Summary: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines Chest. Feb 2012;141(2 Suppl):7S-47S. 2. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-51. 3. Furie KL, Goldstein LB, Albers GW, et al. Oral antithrombotic agents for the prevention of stroke in nonvalvular atrial fibrillation: a science advisory for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2012;43:3442-53. 4. Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 2013. 5. arelto [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2013. 6. Eliquis [package insert]. New York, NY: Bristol-Myers Squibb, Princeton NJ and Pfizer Inc.; 2012. 7. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation (RE-LY). N Engl J Med. 2009;361:1139-51. 8. Connolly SJ, Wallentin L, Ezekowitz MD, et al. The long-term multicenter observational study of dabigatran treatment in patients with atrial fibrillation (RELY-ABLE) Study. Circulation. 2013;128:237-43. 9. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation (ROCKET AF). N Engl J Med. 2011; Sep 8;365(10):883-91. 10. FDA. Medical Review for dabigatran. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/022512orig1s000medr.pdf. Accessed May 28, 2013. 11. Falck-Ytter Y, Francis CW, Johanson NA, et al. Prevention of VTE in orthopedic surgery patients. CHEST 2012;141(2)(Suppl):e278S-325S. 12. American Academy of Orthopedic Surgeons (AAOS). Preventing venous thromboembolic disease in patients undergoing elective hip and knee arthroplasty. Summary of Recommendations. September 24, 2011. Available at: http://www.aaos.org/research/guidelines/vte/vte_summary_of_recs.pdf. Accessed May 21, 2013. 13. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation, Journal of the American College of Cardiology (2014), doi: 10.1016/j.jacc.2014.03.022.