Xarelto (rivaroxaban)

Transcription

1 Xarelto (rivaroxaban) Policy Number: 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 Xarelto 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 Xarelto in the 15 mg and 20 mg tablet strengths. The 10-mg strength of Xarelto is not included in this policy. All approvals are provided for 1 year in duration unless otherwise noted below. Coverage of Xarelto (in 15 mg and 20 mg tablet strengths) is recommended in those who meet the following criteria: Food and Drug Administration (FDA)-Approved Indications 1. Atrial Fibrillation (or Atrial Flutter). Approve for 1 year. Xarelto is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. 1 In the ROCKET AF trial, Xarelto doses of 15 mg or 20 mg QD were shown to be non-inferior to warfarin when the primary composite endpoint, the time to first occurrence of stroke or non-cns systemic embolism, was examined in patients with nonvalvular atrial fibrillation. 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 Xarelto may be useful in patients with atrial fibrillation and valvular heart disease 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. 13 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 have been assessed comparing these agents to warfarin. Subgroup analyses have demonstrated that direct oral anticoagulants appear as effective and safety in patients with valvular heart disease as in those without valvular heart disease. Also, the rate of intracranial hemorrhage was lower among patients given DOACs compared with warfarin, regardless of the presence of valvular heart disease. 13 Another review concurred with this recommendation Deep Vein Thrombosis (DVT) in Patients Undergoing Knee or Hip Replacement Surgery, Prophylaxis. Approve for 60 days. Xarelto is indicated for this condition. 1 The Xarelto dose is 10 mg QD, taken at least 6 to 10 hours after surgery once hemostasis has been achieved. For patients undergoing hip replacement surgery, a 35-day treatment period is recommended. For those undergoing knee replacement surgery, a 12-day treatment duration is recommended. Allowing 60 days of therapy should be a sufficient time frame to allow for an adequate therapy duration in both scenarios.

2 3. Deep Vein Thrombosis (DVT), Treatment. Approve for 1 year. Xarelto is indicated for the treatment of DVT. 1,4 The recommended dose is 15 mg BID with food for the first 21 days, followed by 20 mg QD with food for the remaining treatment. 4. Deep Vein Thrombosis (DVT) or Pulmonary Embolism (PE), to Reduce the Risk of Recurrence. Approve for 1 year. Xarelto is indicated for the reduction in the risk of recurrence of DVT and or PE following initial 6 months treatment for DVT and/or PE. 1 The recommended dose is 20 mg QD with food. 5. Pulmonary Embolism (PE), Treatment. Approve for 1 year. Xarelto is indicated for the treatment of PE. 1,5 The recommended dose is 15 mg BID with food for the first 21 days, followed by 20 mg QD with food for the remaining treatment. Other Uses with Supportive Evidence 6. Treatment or Prevention of Other Thromboembolic-Related Conditions (e.g., long-term use for thromboprophylaxis in medically-ill patients, 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), Pradaxa (dabigatran capsules), or Savaysa (edoxaban tablets); OR B) The patient has been started on Xarelto for the treatment of an acute thromboembolic condition. Xarelto has been used for other thromboembolic conditions. 6 For example, a trial investigated the use of Xarelto for thromboprophylaxis in medically-ill patients. Although Xarelto had adequate efficacy, use was associated with an increased risk of bleeding when used for an extended duration compared with enoxaparin. 6 Also, Xarelto has been used for cancer-associated VTE; however, the National Comprehensive Cancer Network guidelines for cancer-associated VTE (version ) prefer LMWH in these clinical scenarios. 15 Many other medications have been determined to be effective in the treatment of various thromboembolic conditions, as noted in the 2012 ACCP evidence-based clinical practice guidelines for antithrombotic therapy and the prevention of thrombosis, 7 as well as in the CHEST Guideline and Expert Panel Report of antithrombotic therapy for VTE disease. 8 The criteria will allow for continuation of therapy for patients who have been started on Xarelto 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 Xarelto 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. 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). Xarelto has been studied in ACS 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) Note: If the patient has a history of an ACS or coronary artery disease (CAD) [conditions not recommended for

3 approval], but is requesting Xarelto for a non-acs or non-cad condition, approval can be considered if criteria are met. Considerations Xarelto 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 Xarelto, an oral factor Xa inhibitor, is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. 1 For this indication, there are limited data on the relative effectiveness of Xarelto and warfarin in reducing the risk of stroke and systemic embolism when patients receiving warfarin therapy are well-controlled. Xarelto is also indicated for the treatment of deep vein thrombosis (DVT) and for the treatment of pulmonary embolism (PE). Xarelto is indicated for the reduction in the risk of recurrence of DVT and/or PE following an initial 6 months of treatment for DVT and PE. Xarelto is also indicated for the prophylaxis of DVT, which may lead to PE, in those undergoing knee or hip replacement surgery. The Xarelto dose for nonvalvular atrial fibrillation for patients with an estimated creatinine clearance (CrCL) is > 50 ml/min is 20 mg once daily (QD) with the evening meal. In patients with nonvalvular atrial fibrillation with an estimated CrCL of 15 to 50 ml/min, the recommended dose is 15 mg QD with the evening meal. For patients receiving therapy for the prophylaxis of DVT, the recommended Xarelto dose is 10 mg QD with or without food; initiate therapy at least 6 to 10 hours after surgery once hemostasis has been established. Use is short-term (12 days for knee replacement surgery and 35 days for hip replacement surgery). For the treatment of DVT, PE, and the reduction of the risk of recurrence of DVT and of PE the recommended dose is 15 mg twice daily (BID) with food for the first 21 days for the initial treatment of acute DVT or PE. After the initial treatment period, 20 mg orally QD with food for the remaining treatment and the long-term reduction in the risk of recurrence of DVT and/or PE is recommended. Xarelto is available in the following tablet strengths: 10 mg, 15 mg and 20 mg. The 10 mg strength is not targeted in this policy because this dosage strength is generally used for the prophylaxis of DVT in patients undergoing knee or hip replacement surgery. In the pivotal trials that led to the approval for this indication, Xarelto was generally more efficacious than comparator agents (e.g., enoxaparin) and use was short-term (the mean duration of therapy was less than 33 days). 1 Rationale Clinical Efficacy The efficacy and safety of Xarelto were assessed in the ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) trial (n = 14,264). 1-2 ROCKET AF was a multinational, randomized, double-blind, double-dummy, event-driven trial that compared Xarelto (20 mg QD with the evening meal in those with an estimated CrCL > 50 ml/min and 15 mg QD with the evening meal in those with an estimated CrCL 30 to < 50 ml/min) to warfarin (titrated to achieve an International Normalized Ratio [INR] of 2.0 to 3.0) to reduce the risk of stroke and non-central nervous system (CNS) systemic embolism in patients with nonvalvular atrial fibrillation. Patients in the trial had to have additional risk factors for stroke (e.g., prior stroke). The trial was designed to determine if Xarelto was noninferior to warfarin regarding the primary endpoint of stroke or non-cns systemic embolism. Regarding the primary composite endpoint involving the intent-to-treat (ITT) population, the time to the first occurrence of stroke or non-cns systemic embolism demonstrated that Xarelto was non-inferior to warfarin (hazard ratio [HR] 0.88; 95% confidence interval [CI]: 0.74, 1.03; P < for noninferiority). In the ITT analysis, the primary endpoint occurred in 269 patients given Xarelto (3.8%; 2.1 event rate [per 100 patient-years]) and in 306 patients given warfarin (4.3%; 2.4 event rate [per 100 patients-years]). Xarelto was not noted to be superior to warfarin. 1-2

4 Xarelto for the treatment of DVT and/or PE, and for the reduction in the risk of recurrence of DVT and of PE was evaluated in EINSTEIN DVT and EINSTEIN PE. 1,3-4 These trials were multinational, openlabel, non-inferiority studies that compared Xarelto (15 mg BID for 3 weeks, followed by 20 mg QD with food) to enoxaparin by subcutaneous (SC) injection (1.0 mg/kg of body weight BID for at least 5 days), followed by a vitamin K antagonist (either warfarin or acenocoumarol dose adjusted to maintain an INR of 2.0 to 3.0) 1,3 for 3, 6, or 12 months. In total, 8,281 patients (3,449 in EINSTEIN DVT and 4,832 in EINSTEIN PE) were randomized and followed on therapy for a mean of 208 days for patients given Xarelto and 204 days in patients given enoxaparin followed by a vitamin K antagonist. In the EINSTEIN DVT and EINSTEIN PE studies, Xarelto was found to be non-inferior to enoxaparin followed by a vitamin K antagonist for the primary composite endpoint of time to first occurrence of recurrent DVT or non-fatal or fatal PE. In the EINSTEIN DVT study 36 events occurred with Xarelto (2.1%) vs. 51 events with enoxaparin followed by a vitamin K antagonist (3.0%) [HR 0.68, 95% CI: 0.44, 1.04]. In the EINSTEIN PE study events occurred in 50 patients (2.1%) given Xarelto vs. 44 patients (1.8%) in the enoxaparin followed by a vitamin K antagonist group (HR 1.12, 95% CI: 0.75, 1.68). The EINSTEIN Extension was a multinational, double-blind, superiority study that assessed 602 patients in the group given Xarelto 20 mg QD with food and 594 patients in the placebo group for the reduction in the risk of recurrence of DVT and PE in those who had completed 6 to 14 months of treatment after an acute event. Patient follow-up was 190 days. Xarelto had superior efficacy compared with placebo (8 events with Xarelto [1.3%] vs. 42 events with placebo [7.1%]; P < ). Xarelto has been used off-label for other conditions requiring antithrombotic therapy. Xarelto has been used for extended prophylaxis in acutely ill medical patients. 5 Xarelto has also been studied in patients who have experienced an acute coronary syndrome (ACS). 6-7 A double-blind, placebo-controlled trial randomized patients with a recent ACS (e.g., myocardial infarction [MI], unstable angina) [n = 15,526] to Xarelto 2.5 mg BID, Xarelto 5 mg BID, or placebo; patients also received standard medical therapy according to guidelines. 7 The mean duration of therapy was approximately 13 months; however, some patients received medications for up to 31 months. 7 The primary efficacy endpoint, a composite of death from cardiovascular (CV) causes, MI, or stroke, was reduced by a statistically significant extent with Xarelto (9.1% for those given Xarelto 2.5 mg BID and 8.8% for those given Xarelto 5 mg BID) compared with placebo (10.7%). Of note, Xarelto therapy reduced the risk of stent thrombosis compared with placebo (2.3% vs. 2.9%; P = 0.02). However, patients given Xarelto had an increased risk of intracranial hemorrhage and major bleeding not related to coronary-artery bypass grafting. 7 Many other medications are utilized for patients with an ACS and nationally-recognized guidelines provide recommendations. 8-9 References 1. Xarelto tablets [prescribing information]. Titusville, NJ: Janssen; Eli Lilly and Company; September Patel MR, Mahaffey KW, Garg J, et al, and the ROCKET AF Steering Committee, for the ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10): The EINSTEIN Investigators, Bauersachs R, Berkowitz SD, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363: The EINSTEIN-PE Investigator, Buller HR, Prins MH, Lensing AWA, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366: Cohen AT, Spiro TE, Buller HR, et al. Rivaroxaban for thromboprophylaxis in acute ill medical patients. N Engl J Med. 2013;368: Mega JL, Braunwald E, Mohanavelu S, et al, on behalf of the ATLAS ACS-TIMI 46 Study Group. Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomized, double-blind, phase II trial. Lancet. 2009;374: Mega JL, Braunwald E, Wiviott SD, et al, for the ATLAS ACS 2-TIMI 51 Investigators. Rivaroxaban in patients with recent acute coronary syndrome. N Engl J Med. 2012;366(1): O Gara PT, Kushner FG, Ascheim DD, et al, American College of Cardiology Foundation/American Heart Association Task Force on Practice guidelines ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology

5 Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;127(4):e Available at Accessed on September 25, Jneid H, Anderson JL, Wright S, et al 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: Available at Access on September 25, January CT, Wann LS, Alpert JS, et al 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 April 10 [Epub ahead of print]. Available at Accessed on September 19, 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 Accessed on September 25, Billing Coding/Physician Documentation Information NA Pharmacy benefit Additional Policy Key Words Policy Number: Policy Implementation/Update Information 06/2014 New Policy titled Xarelto (rivaroxaban) 07/2015 Annual Review- For the treatment or prevention of other thromboembolic-related indications, Savaysa was added to the list of multiple other agents (e.g., oral anticoagulants and heparin-type products) for which the patient is recommended to have tried one of prior to approval 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 statement 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.