Pradaxa (dabigatran) Policy Number: 5.01.574 Last Review: 7/2018 Origination: 6/2014 Next Review: 7/2019 LoB: ACA Policy Blue Cross and Blue Shield of Kansas City (Blue KC) will provide coverage for Pradaxa when it is determined to be medically necessary because the following criteria are met. When Policy Topic is covered Prior authorization is recommended for prescription benefit coverage of Pradaxa. All approvals are provided for 1 year in duration unless otherwise noted below. Food and Drug Administration (FDA)-Approved Indications 1. Atrial Fibrillation (or Atrial Flutter). Approve for 1 year if the patient has tried Eliquis or Xarelto. Pradaxa is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. 1 In the RE-LY trial, Pradaxa 150 mg BID significantly reduced the primary composite endpoint of stroke and systemic embolism relative to warfarin in patients with nonvalvular, persistent, paroxysmal or permanent atrial fibrillation with one or more risk factors. 1-2 The 2014 guidelines for nonvalvular atrial fibrillation recommend patients with atrial flutter follow the antithrombotic therapy decisions that are in place for atrial fibrillation. 3 Although not FDA-approved, some evidence suggests that Pradaxa may be useful in patients with atrial fibrillation and valvular heart disease. 18-19 In 2017, the American Heart Association (AHA)/American College of Cardiology (ACC) published a focused update of the 2014 AHA/ACC guideline for the management of patients with valvular heart disease. 19 It states that it is reasonable to use direct oral anticoagulants (DOACs) as an alternative to vitamin K antagonist in patients with atrial fibrillation and native aortic valve disease, tricuspid valve disease, or mitral regurgitation and a CHA 2 DS 2 -VASc score of 2 or greater. Patients with native valvular heart disease has been assessed comparing these agents to warfarin. Subgroup analyses have demonstrated that direct oral anticoagulants appear as effective and safe in patients with valvular heart disease as in those without valvular heart disease. Also, the rate of intracranial hemorrhage among patients with DOACs was lower compared with warfarin, regardless of the presence of valvular heart disease. 18 Another review concurred with this recommendation. 19 2. Deep Vein Thrombosis (DVT) or Pulmonary Embolism (PE), Treatment. Approve for 1 year if the patient meets one of the following (A or B): A) The patient has tried Eliquis or Xarelto; OR B) The patient is currently receiving Pradaxa for this condition. Pradaxa is indicated for the treatment of DVT and PE in patients who have been treated with a parenteral anticoagulant for 5 to 10 days. In two trials regarding these clinical scenarios (RE- COVER and RE-COVER II), Pradaxa was non-inferior to warfarin based on the primary composite endpoint of fatal PE or symptomatic non-fatal PE and/or DVT. 1,4
3. Deep Vein Thrombosis (DVT) or Pulmonary Embolism (PE), To Reduce the Risk of Recurrence. Approve for 1 year if the patient has tried Eliquis or Xarelto. Pradaxa is indicated to reduce the risk of recurrence of DVT and PE in patients who have been previously treated. Based on trials regarding these scenarios (RE-MEDY and RE-SONATE), Pradaxa was noted to be non-inferior to warfarin and superior to placebo. 1,5 4. Deep Vein Thrombosis (DVT) or Pulmonary Embolism (PE), Prophylaxis Following Hip Replacement Surgery. Approve for 60 days if the patient meets one of the following (A or B): A) The patient has tried Eliquis or Xarelto; OR B) The patient is currently receiving Pradaxa for this condition. Pradaxa is indicated for the prophylaxis of DVT and PE in patients who have undergone hip replacement surgery. 1 Based on trials involving patients who had undergone hip replacement surgery (RE-NOVATE and RE-NOVATE II) 6-7 for the prophylaxis of DVT and PE, use of Pradaxa at a dose of 110 mg 1 to 4 hours after surgery followed by 220 mg QD was non-inferior to enoxaparin 40 mg QD. 1 The median duration of use for both medications was 33 days. Allowing 60 days of therapy should be a sufficient time frame to allow for an adequate therapy duration in this scenario. Other Uses with Supportive Evidence 5. Treatment or Prevention of Other Thromboembolic-Related Conditions (e.g., prevention of venous thromboembolism after knee replacement surgery, cancer-associated venous thromboembolic disease). Approve for 6 months if the patient meets ONE of the following criteria (A or B): A) The patient meets one of the following for the condition (i or ii): a. The patient has tried warfarin, fondaparinux, or a low molecular weight heparin (LMWH) product (e.g., enoxaparin, Fragmin [dalteparin injection]); OR b. The patient has tried Eliquis (apixaban tablets) or Xarelto (rivaroxaban tablets); OR B) The patient has been started on Pradaxa for the treatment of an acute thromboembolic condition. Pradaxa has been used in other clinical scenarios (e.g., prophylaxis of DVT and PE after knee replacement surgery). 8-10 Also, Pradaxa has been used for cancer-associated VTE; however, the National Comprehensive Cancer Network guidelines for cancer-associated VTE (version 1.2017) prefer LMWH in these clinical scenarios. 20 Many other medications have been determined to be effective in the treatment of various thromboembolic conditions, as noted in the 2012 American College of Chest Physicians (ACCP) evidence-based clinical practice guidelines for antithrombotic therapy and the prevention of thrombosis 11 as well as in the CHEST Guideline and Expert Panel Report of antithrombotic therapy for VTE disease. 12 The criteria will allow for continuation of therapy for patients who have been started on Pradaxa for an acute thromboembolic condition. In the professional opinion of specialist physicians reviewing the data, we have adopted these criteria. When Policy Topic is not covered Pradaxa has not been shown to be effective, or there are limited or preliminary data or potential safety concerns that are not supportive of general approval for the following conditions. Rationale for noncoverage for these specific conditions is provided below. (Note: This is not an exhaustive list of Conditions Not Recommended for Approval.) 1. Mechanical Prosthetic Heart Valves (To Prevent Thromboembolic Complications). Pradaxa is contraindicated in patients with mechanical prosthetic heart valves. 1 The safety and efficacy of Pradaxa in patients with a bileaflet mechanical prosthetic heart valve was evaluated in the RE- ALIGN (Randomized, Phase II study to Evaluate the safety and pharmacokinetics of oral dabigatran etexilate in patients after heart valve replacement) study. 1,13-14 RE-ALIGN was terminated early because there were significantly more thromboembolic events (valve thrombosis,
stroke, transient ischemic attack, and myocardial infarction) and an excess of major bleeding in patients randomized to Pradaxa compared to those randomized to warfarin. The FDA recommends that health care professionals should promptly transition any patient with a mechanical heart valve who is receiving Pradaxa to take another medication. 13 Note: If the patient has a mechanical prosthetic heart valve, a history of an acute coronary syndrome (ACS) or coronary artery disease (CAD) [conditions not recommended for approval] but is requesting Pradaxa for another use, approval can be considered if criteria are met. 2. Use After an Acute Coronary Syndrome (ACS) [e.g., unstable angina, non-st elevation myocardial infarction {MI}, or ST elevation MI] to Reduce the Potential for Thrombotic Events (e.g., cardiovascular [CV] death, MI, or stroke). Limited data support the role of Pradaxa at this time. 15 Other alternative, proven, effective, established therapies that are detailed in nationally-recognized guidelines are available for those who have experienced an ACS (e.g., warfarin, heparin, aspirin, clopidogrel, Effient [prasugrel tablets], Brilinta [ticagrelor tablets], and LMWHs). 16-17 Note: If the patient has a mechanical prosthetic heart valve, a history of an ACS or CAD (conditions not recommended for approval) but is requesting Pradaxa for another use, approval can be considered if criteria are met. Considerations Pradaxa requires prior authorization through the pharmacy services department. This Blue Cross and Blue Shield of Kansas City policy Statement was developed using available resources such as, but not limited to: Food and Drug Administration (FDA) approvals, Facts and Comparisons, National specialty guidelines, Local medical policies of other health plans, Medicare (CMS), Local providers. Description of Procedure or Service Pradaxa is a direct thrombin inhibitor. It has the following indications: to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation; for the treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE) in patients who have been treated with a parenteral anticoagulant for 5 to 10 days; to reduce the risk of recurrence of DVT and PE in patients who have been previously treated; and for the prophylaxis of DVT and PE in patients who have undergone hip replacement surgery. 1 Dosing for prophylaxis of DVT and PE after hip replacement surgery is once daily (QD); the recommended dose is twice daily (BID) for all other indications. The most common adverse reactions (> 15%) with Pradaxa are gastritis-like symptoms and bleeding. 1 References 1. Pradaxa capsules [prescribing information]. Ridgefield, CT: Boehringer Ingelheim; November 2015. 2. Connolly SJ, Ezekowitz MD, Yusuf S, et al, for the RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139-1151. 3. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the heart rhythm society. Circulation. 2014;130(23):2171-2104. Available at: http://circ.ahajournals.org/content/early/2014/04/10/cir.0000000000000041. Accessed on November 30, 2015. 4. Schulman S, Kearon C, Kakkar AK, et al, for the RE-COVER Study Group. Dabigatran versus warfarin for the treatment of acute venous thromboembolism. N Engl J Med. 2009;361(24):2342-2352. 5. Schulman S, Kearon C, Kakkar AK, et al, for the RE-MEDY and the RE-SONATE Trials Investigators. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med. 2013;368(8):709-718.
6. Eriksson BI, Dahl OE, Rosencher N, et al, for the RE-NOVATE Study Group. Dabigatran etexilate versus enoxparin for prevention of venous thromboembolism after total hip replacement: a randomized, double-blind, non-inferiority trial. Lancet. 2007;370:949-956. 7. Eriksson BI, Dahl OE, Huo MH, et al, for the RE-NOVATE II Study Group. Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II). A randomized, double-blind, non-inferiority trial. Thromb Haemost. 2011;105(4):721-729. 8. Eriksson BI, Dahl OE, Rosencher N, et al, for the RE-MODEL Study Group. Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. J Thromb Haemost. 2007;5:2178-2185. 9. RE-MOBILIZE Writing Committee, Ginsberg JS, Davidson BL, Comp PC, et al. Oral thrombin inhibitor dabigatran etexilate vs. North American Enoxaparin regimen for prevention of venous thromboembolism after knee arthroplasty surgery. J Arthroplasty. 2009;24(1):1-9. 10. Burness CD, McKeage K. Dabigatran Etexilate. A review of its use for the prevention of venous thromboembolism after total hip or knee replacement surgery. Drugs. 2012;72(7):963-986. 11. Guyatt GH, Akl EA, Crowther M, et al., for the American College of Chest Physicians Antithrombotic Therapy and Prevention of Thrombosis Panel. Executive summary: antithrombotic therapy and prevention of thrombosis, 9 th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141:7S-47S. Available at: http://journal.publications.chestnet.org/data/journals/chest/23443/112304.pdf. Accessed on November 30, 2015. 12. U.S. Food and Drug Administration. FDA Drug Safety Communication: Pradaxa (dabigatran etexilate mesylate) should not be used in patients with mechanical prosthetic heart valves. Posted 12/19/2012. Available at http://www.fda.gov/safety/medwatch/safetyinformation/safetyalertsforhumanmedicalproducts/ucm 332949.htm. Accessed on November 30, 2015. 13. Van de Werf F, Brueckmann M, Connolly SJ, et al. A comparison of dabigatran etexilate with warfarin in patients with mechanical heart valves: the Randomized, phase II study to Evaluate the safety and pharmacokinetics of oral dabigatran etexilate in patients after heart valve replacement (RE-ALIGN). Am Heart J. 2012;163(6):931-937. 14. Oldgren J, Budaj A, Granger DB, et al, for the RE-DEEM Investigators. Dabigatran vs. placebo in patients with acute coronary syndromes on dual antiplatelet therapy: a randomized, double-blind, phase II trial. Eur Heart J. 2011;32:2781-2789. 15. O Gara PT, Kushner FG, Ascheim DD, et al, for the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;127(4):E362-425. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23247304. Accessed on November 30, 2015. 16. Jneid H, Anderson JL, Wright S, et al. 2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non-st elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update): A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2012;126:875-910. Available at: http://circ.ahajournals.org/content/126/7/875.full.pdf+html. Access on November 30, 2015.
Billing Coding/Physician Documentation Information NA Pharmacy benefit Additional Policy Key Words Policy Number: 5.01.574 Policy Implementation/Update Information 06/2014 New Policy titled Pradaxa (dabigatran) 07/2015 Annual review- no changes made 07/2016 Annual review-no changes to policy statement 07/2017 Annual review-no changes to policy statement 07/2018 Annual review no changes to policy State and Federal mandates and health plan contract language, including specific provisions/exclusions, take precedence over Medical Policy and must be considered first in determining eligibility for coverage. The medical policies contained herein are for informational purposes. The medical policies do not constitute medical advice or medical care. Treating health care providers are independent contractors and are neither employees nor agents Blue KC and are solely responsible for diagnosis, treatment and medical advice. No part of this publication may be reproduced, stored in a retrieval system or transmitted, in any form or by any means, electronic, photocopying, or otherwise, without permission from Blue KC.