Failure or significant adverse effects to all of the alternatives: Eliquis and Xarelto

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1 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. Drug: apixaban (Eliquis), dabigatran (Pradaxa), edoxaban (Savaysa), rivaroxaban (Xarelto), warfarin (Coumadin) Class: Oral Anticoagulant Formulary Medication: warfarin (Coumadin) Code 1 Medications: apixaban (Eliquis), rivaroxaban (Xarelto) LOB: Non-Medicare Effective Date: August 19, 2015 Revision Date: August 19, 2015 Policy/Criteria: Code 1 Criteria: 1. Apixaban (Eliquis), Rivaroxaban (Xarelto) 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. Apixaban (Eliquis) Failure or significant adverse effects to the alternative: warfarin 2. Dabigatran (Pradaxa) Failure or significant adverse effects to all of the alternatives: Eliquis and Xarelto b. Treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE) Failure or significant adverse effects to all of the alternatives: Eliquis and Xarelto 3. Rivaroxaban (Xarelto) Failure or significant adverse effects to the alternative: warfarin

2 4. Edoxaban (Savaysa) Failure or significant adverse effects to the alternative: warfarin b. Treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE) Failure or significant adverse effects to the alternative: warfarin Clinical Justification: Comparison of Indications Dabigatran Rivaroxaban Apixaban Edoxaban Warfarin Stroke prevention in non-valvular X X X X X atrial fibrillation (AF) Venous thromboembolism (VTE) X X X prophylaxis following hip or knee replacement VTE treatment X X X X X Reduction in the risk of X X X X recurrence of DVT/PE Thromboembolism prevention in X heart valve replacement Post myocardial infarction X Usual Dosage Routine Lab Anticoagulant Monitoring Reversal Agent Dabigatran Rivaroxaban Apixaban Edoxaban Warfarin AF: 150mg AF: 60mg daily AF: once VTE tx: 150mg VTE tx: 60mg daily titrate daily to INR 2-3 AF: 20mg daily VTE tx: 15mg x21 days, then 20mg daily VTE ppx: 10mg daily AF: 5 mg VTE tx: 10mg x 7 days, then 5mg VTE ppx: 2.5mg No No No No Yes No No No No Yes Dietary Consideration No Yes, take with evening meal for doses > 10mg No No Yes; consistency with vitamin K food Time to maximum 1-2 hours (no 2-4 hours (no 3-4 hours (no 1-2 hours (no Peak effect delayed 72- concentration required) required) required) required) 96 hours Required (e.g. LMWH) Half-Life hours 5-9 hours 12 hours hours ~40 hours

3 Renal Dosing Adjustment AF: CrCl ml/min: 75mg RELY: CrCl <30ml/min: excluded VTE tx: CrCl 30 ml/min: avoid use AF: CrCl ml/min: 15mg once daily 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 daily. CrCl <15mL/min: Titrate to INR 2-3 Atrial Fibrillation 2012 American College of Chest Physicians (ACCP) CHEST Guidelines: A weak preference (Grade 2B) for dabigatran over warfarin is recommended for patients with non-valvular atrial fibrillation at intermediate to high risk of stroke. Only dabigatran is FDA-approved for atrial fibrillation at the time guideline was published. In other clinical conditions including rheumatic mitral valve disease, mitral valve stenosis, stable coronary artery disease status post intracoronary stent placement or acute coronary syndrome, stroke prevention with dabigatran in atrial fibrillation is not preferred over warfarin American Heart Association (AHA) and American Stroke Association (ASA) Science Advisory on Oral Antithrombotic Agents in Nonvalvular Atrial Fibrillation: Dabigatran and apixaban are recommended as an efficacious alternative to warfarin in patients with nonvalvular atrial fibrillation with risk factor for stroke (Class I; Level of Evidence B). On the other hand, rivaroxaban is a reasonable alternative to warfarin (Grade IIb; Level of Evidence C) 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 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 Venous Thromboembolism (VTE) Treatment 2012 ACCP CHEST Guidelines: Warfarin is preferred over rivaroxaban or dabigatran in the treatment of acute and long term treatment of VTE in patients with no cancer (Grade 2C), contributed by the lack of long term safety data for the newer agents. Guidelines were published before the AMPLIFY study with apixaban. 1. 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 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 1. Rivaroxaban, apixaban and dabigatran have demonstrated noninferior efficacy as enoxaparin 40mg once daily 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: 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: Dabigatran (Pradaxa) Prescribing Information. Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT. April Rivaroxaban (Xarelto) Prescribing Information. Janssen Pharmaceuticals, Inc. Titusville, NJ. August Apixaban (Eliquis) Prescribing Information. Bristol-Myers Squibb, Princeton NJ and Pfizer Inc. New York, NY. December Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation (RE-LY). N Engl J Med. 2009;361:

5 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: 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): FDA Medical Review for dabigatran. Accessed at: (Accessed on 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, Accessed at: (Accessed on May 21, 2013). 13. A Report of the American College of Cardiology/American heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. Guidelines for the management of patients with atrial fibrillation. Journal of the American College of Cardiology, S (14)