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1 Eliquis (apixaban) Policy Number: Origination: 06/2014 Last Review: 07/2015 Next Review: 07/2016 Policy BCBSKC will provide coverage for Eliquis when it is determined to be medically necessary because the following criteria are met. When Policy Topic is covered: Coverage of Eliquis is recommendedd in those who meet thee following criteria: Food and Drug Administration (FDA)-Approved Indications 1. Nonvalvular Atrial Fibrillation (or Atrial Flutter). Approve. Eliquis is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. 1 In the ARISTOTLE trial, Eliquis was superior to warfarin for the primary endpoint of reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. 1-2 In AVERROES, Eliquis showed a significant reduction in stroke and systemic embolism compared with aspirin in a group of patients with nonvalvular atrial fibrillation who were thought not to be candidates for warfarin therapy. 1,3 The 2011 guidelines for atrial fibrillation from the American College of Cardiology Foundation (ACCF), the American Heart Association (AHA), and the Heart Rhythm Society (HRS) recommend patients with atrial flutter follow the antithrombotic therapy decisionss that are in place for atrial fibrillation. 10 The decision to adopt the criteria was based on the professional opinion of specialist physicians. 2. Prophylaxis of Deep Vein Thrombosis (DVT) in Patients Undergoing Hip or Knee Replacement Surgery. Approve for 60 days. Eliquis is indicated for the prophylaxis of DVT, which may lead to pulmonary embolism (PE), in patients who have undergone hip or knee replacement surgery. 1 In patients undergoing elective hip surgery, Eliquis 2.5 mg BID was superior to enoxaparinn 40 mg SC QD (treatment duration of 32 to 38 days) in reducing total VTE/all-cause death (P < ). 1 In patients undergoing knee replacement surgery (treatment duration 10 to 14 days), Eliquis 2. 5 mg BID had similar outcomes as enoxaparin 30 mg SC Q 12 hours and it was superior to enoxaparin 40 mg SC QD (P < ). Allowing 60 days of therapy should be a sufficient time frame to allow for an adequatee therapy duration in both scenarios. The decision to adopt the criteria was based on the professional opinion of specialist physicians. 3. Deep Vein Thrombosis (DVT) or Pulmonary Embolism (PE), Treatment. Approve. Eliquis is indicated for the treatment of DVT and for the treatment of PE. 1 After approximately 6 months of therapy, Eliquis was demonstrated to bee noninferiorr to enoxaparin/warfarin in the AMPLIFY study for the primary endpoint of recurrent symptomatic VTE (nonfatal DVT or nonfatal PE) or VTE-related death. 1,7 The decision to adopt the criteria was based on the professional opinion of specialist physicians

2 4. Deep Vein Thrombosis (DVT) or Pulmonary Embolism (PE) to Reduce the Risk of Recurrence. Approve. Eliquis is indicated to reduce the risk of recurrent DVT or PE following initial therapy. In the AMPLIFY-EXT trial, which involved patients who had previously been successfully treated with anticoagulant therapy for DVT and/or PE, Eliquis was superior to placebo in the primary endpoint of symptomatic, recurrent VTE (nonfatal DVT or nonfatal PE), or all-cause death. The decision to adopt the criteria was based on the professional opinion of specialist physicians Other Uses with Supportive Evidence 5. Treatment or Prevention of Other Thromboembolic-Related Indications not Addressed in the Conditions Not Recommended for Approval Section below (e.g., extended thromboprophylaxis in medically-ill patients, extended treatment for patients with a prior venous thromboembolism). Approve if the patient meets ONE of the following criteria (a, b or c): a) Patient has tried one of the following therapies for the condition: warfarin, Xarelto (rivaroxaban tablets), Pradaxa (dabigatran capsules), Savaysa (edoxaban tablets,) fondaparinux injection, or a low molecular weight heparin (LMWH) product (e.g., enoxaparin injection, Fragmin [dalteparin injection]); OR b) Patient is unable to take one of the medications listed above (i.e., warfarin, Xarelto, Pradaxa, Savaysa, fondaparinux injection or a LMWH) for the condition due to ONE of the following reasons: i. allergic, immunologic or inherited disorders; OR ii. adverse effects (e.g., major organ toxicities, major bleeding); OR iii. the patient has experienced ineffectiveness of anticoagulation therapy in a prior setting; OR iv. the patient has drug-drug interactions that cannot be managed (warfarin); OR v. the patient lacks access to proper monitoring (warfarin); OR vi. the patient has experienced prior heparin-induced thrombocytopenia (HIT) or heparininduced thrombocytopenia and thrombosis (HITT) [fondaparinux injection and LMWH]; OR vii. the patient is unable to perform injections or have injections administered to them (fondaparinux injection and LMWH); OR c) The patient has been started on Eliquis for the treatment of an acute thromboembolic condition. Note: If the patient has a history of an ACS or coronary artery disease (CAD) (excluded indications), but is requesting Eliquis for a non-acs or non-cad condition, approval can be considered if criteria are met. Eliquis has been studied in other conditions that require anticoagulant therapy (e.g., as an extended treatment for patients who have completed therapy for DVT or PE, and for thromboprophylaxis in medically-ill patients). 4,8 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 The criteria will allow for continuation of therapy for patients who have been started on Eliquis for an acute thromboembolic condition. In the professional opinion of specialist physicians reviewing the data, we have adopted these criteria. 6. Patients Currently Receiving Eliquis Therapy. For patients started on Eliquis, if there is insufficient information available to make a determination regarding approval OR if the prescribing physician or a representative of the physician cannot be contacted OR if the patient requires time to initiate another therapy (e.g., warfarin, LMWH), a short-term supply of Eliquis for up to 14 days can be approved. (In the professional opinion of specialist physicians we have adopted this criterion).

3 When Policy Topic is not covered: Eliquis 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). The APPRAISE-2 trial was terminated after it was found that the addition of Eliquis to antiplatelet therapy in high-risk patients after an ACS event increased the number of major bleeding events without a significant reduction in recurrent ischemic events. 10 Other alternative, proven, effective, established therapies that are detailed in nationallyrecognized guidelines are available for those who have experienced an ACS (e.g., heparin, aspirin, clopidogrel, Effient [prasugrel tablets], Brilinta [ticagrelor tablets], and LMWHs) In the professional opinion of specialist physicians reviewing the data, we have adopted these criteria. 2. Primary or Secondary Prevention of Coronary Artery Disease (CAD). Eliquis is not indicated for this condition and data are limited. Many other proven, established medications are used for patients with CAD. In the professional opinion of specialist physicians reviewing the data, we have adopted these criteria. 3. Coverage is not recommended for circumstances not listed in the Recommended Authorization Criteria. Criteria will be updated as new published data are available. Considerations Eliquis 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: Hayes Medical Technology Directory, 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 Eliquis is a factor Xa inhibitor anticoagulant indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. 1 For this indication, the recommended dose for most patients is 5 mg twice daily (BID). The recommended dose of Eliquis is 2.5 mg BID in nonvalvular atrial fibrillation for patients with any two of the following characteristics: age 80 years; body weight 60 kg; and serum creatinine 1.5 mg/dl. Eliquis is also indicated for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE), in patients who have undergone hip or knee replacement surgery. For this indication, the recommended dose of Eliquis is 2.5 mg taken orally BID. The initial dose should be taken 12 to 24 hours after surgery. In patients undergoing hip replacement surgery, the recommendation duration of treatment is 35 days and in patients undergoing knee replacement surgery the recommended duration of treatment is 12 days. Eliquis is also indicated for the treatment of DVT and PE, and for the reduction in the risk of recurrent DVT and PE following initial therapy. For the treatment of DVT and PE, the recommended dose is 10 mg BID for 7 days, followed by 5 mg BID. For the reduction in the risk of recurrent DVT and PE following initial therapy, the initial dose is 2.5 mg BID. Also, when Eliquis is given with medications that are strong dual inhibitors of cytochrome P450 (CYP) and P-glycoprotein (P-gp) [e.g., ketoconazole, itraconazole], the Eliquis recommended dose is 2.5 mg BID. The most common adverse events (AEs) with Eliquis are related to bleeding. 1

4 Rationale Clinical Efficacy Atrial Fibrillation Two multinational, double-blind, double-dummy, randomized, published trials assessed the efficacy and safety of Eliquis in patients with nonvalvular atrial fibrillation. The ARISTOTLE (Apixaban for Reduction In STroke and Other ThromboemboLic Events) trial compared Eliquis with warfarin (n = 18,201). 1-2 Eliquis 5 mg BID was superior to warfarin for the primary endpoint of reducing the risk of stroke and systemic embolism (1.27% per year for Eliquis vs. 1.60% per year for warfarin; P = 0.01). Eliquis also led to a significantly lower rate of all-cause death compared with warfarin (P = 0.046). The AVERROES trial compared Eliquis with aspirin in patients who were not candidates for warfarin therapy (n = 5,599). 1,3 Patients were randomized to Eliquis 5 mg BID (or 2.5 mg BID) or aspirin 81 to 324 mg once daily (QD). The trial was stopped early on the basis of a prespecified interim analysis demonstrating a significant reduction in stroke and systemic embolism for patients randomized to Eliquis compared with aspirin (1.62% per year with Eliquis vs. 3.63% per year with aspirin; P < ). 1,3 The mean follow-up was 1.1 years. 3 Prophylaxis of DVT Following Hip or Knee Replacement Surgery The effectiveness of Eliquis was derived from the ADVANCE 1,4-6 (Apixiban Dose orally Vs. ANtiCoagulant with Enoxaparin)-1, ADVANCE-2, and ADVANCE-3 trials involving adults undergoing elective hip (ADVANCE-3) 6 or knee (ADVANCE-2 and ADVANCE-1) 4-5 replacement surgery. In total, 11,659 patients were randomized in three double-blind, multinational studies. 1,4-6 In ADVANCE-3, 5,407 patients undergoing hip replacement surgery were randomized to receive either Eliquis 2.5 mg BID or enoxaparin 40 mg subcutaneously (SC) QD; treatment duration was 32 to 38 days. 1,6 In ADVANCE-3 involving patients who underwent elective hip replacement surgery, the percentage of patients with events (total venous thromboembolism [VTE]/all-cause death) was 3.86% for patients (n = 74/1,917) receiving enoxaparin 40 mg SC QD vs. 1.39% for patients (n = 27/1,949) in the Eliquis 2.5 mg BID group (P < ). 1,7 In patients undergoing elective knee replacement surgery, Eliquis 2.5 mg BID was compared with enoxaparin 40 mg SC QD (ADVANCE-2, n = 3,057) 1,5 or enoxaparin 30 mg SC every 12 hours (ADVANCE-1, n = 3,195). 1,4 Treatment duration in both ADVANCE-2 and ADVANCE-1 was 10 to 14 days. In the ADVANCE-1 group, the percentage of patients undergoing elective knee surgery with events during the 12-day treatment period (total VTE/all-cause death) was 8.85% for patients given enoxaparin 30 mg QD every 12 hours (n = 100/1,130) compared with 8.99% of patients given Eliquis 2.5 mg BID (n = 104/1,157). 1,4 In the ADVANCE-2 group, the percentage of patients undergoing elective knee surgery with events during the 12-day treatment period (total VTE/allcause death) was 24.37% for patients given enoxaparin 40 mg QD (n = 243/997) compared with 15.06% of patients given Eliquis 2.5 mg BID (n = 147/976) [P < ]. 1,5 Treatment of DVT and PE and Reduction in the Risk of Recurrence of DVT and PE The effectiveness of Eliquis for the treatment of DVT and PE, and for the reduction in the risk of recurrent DVT and PE following 6 to 12 months of anticoagulant treatment was assessed in the AMPLIFY (Apixaban after the initial Management of PuLmonary embolism and deep vein thrombosis with First-line therapy and AMPLIFY-EXT trial (EXtended Treatment) trials. 1,7-8 Both studies were randomized, parallel-group, double-blind trials involving patients with symptomatic proximal DVT and/or symptomatic PE. In AMPLIFY (n = 5,244) patients were given Eliquis 10 mg BID for 7 days, followed by Eliquis 5 mg BID for 6 months, or enoxaparin 1 mg/kg BID SC for at least 5 days, followed by warfarin for 6 months. After a mean of approximately 153 days, Eliquis was noninferior to enoxparin/warfarin in the primary endpoint of recurrent symptomatic VTE or VTE-related deaths over 6 months (2.3% with Eliquis vs. 2.7% with enoxaparin/warfarin). 1,7 The AMPLIFY-EXT trial involved patients (n = 2,482) who had been treated for DVT and/or PE for 6 to 12 months with anticoagulant therapy without experiencing a recurrent event and were randomized to Eliquis 2.5 mg BID, Eliquis 5 mg BID, or placebo for 12 months. 1,8 Approximately one-third of patients had been in the AMPLIFY trial before enrollment in AMPLIFY-EXT. 1 After almost 1 year of follow-up, Eliquis was superior to placebo as the primary endpoint of recurrent VTE or all-cause death occurred in 3.8%, 4.2% and 11.6% of patients assigned to Eliquis 2.5 mg BID, Eliquis 5 mg BID, or placebo, respectively.

5 Other Data Eliquis has been used off-label for other conditions requiring antithrombotic therapy. The ADOPT (Apixaban Dosing to Optimize Protection from Thrombosis) trial investigated the use of Eliquis vs. enoxaparin in medically-ill patients in an extended thromboprophylaxis setting. 9 The APPRAISE (APixaban for PRevention of Acute ISchemic Events)-2 trial was terminated prematurely after it was found that the addition of Eliquis to antiplatelet therapy in high-risk patients after an acute coronary syndrome (ACS) increased the number of major bleeding events without a significant reduction in recurrent ischemic events. 10 References: 1. Eliquis tablets [prescribing information]. Princeton, NJ: Bristol-Myers Squibb and New York, NY: Pfizer Inc; August Granger CB, Alexander JH, McMurray JJV, et al, for the ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11): [Supplementary appendix]. 3. Connolly SJ, Eikelboom J, Joyner C, et al, for the AVERROES Steering Committee and Investigators. Apixaban in patients with atrial fibrillation. N Engl J Med. 2011;364(9): [Supplementary appendix]. 4. Lassen MR, Raskob GE, Gallus A, et al. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med. 2009;361: Lassen MR, Raskob GE, Gallus A, et al, and the ADVANCE-2 investigators. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomized, doubleblind trial. Lancet. 2010;375: Lassen MR, Gallus A, Raskob GE, et al, for the ADVANCE-3 investigators. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med. 2010;363(26): Agnelli G, Buller HR, Cohen A, et al, for the AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369(9): Agnelli G, Buller HR, Cohen A, et al, for the AMPLIFY-EXT Investigators. Apixaban for extended treatment of venous thromboembolism. N Engl J Med. 2013;368(8): Goldhaber SZ, Leizorovicz A, Kakkar AK, et al, for the ADOPT Trial Investigators. Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients. N Engl J Med. 2011;365: Alexander JH, Lopes RD, James S, et al, for the APPRAISE-2 investigators. Apixaban with antiplatelet therapy after acute coronary syndrome. N Engl J Med. 2011;365(8): 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. 13. 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 Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;127(4):e Available at Accessed on September 19, 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

6 Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2012;126: Available at Access on September 19, Billing Coding/Physician Documentation Information NA Additional Policy Key Words Policy Number: Related Topics N/A Policy Implementation/Update Information 06/2014 New Policy titled Eliquis (apixaban) 07/2015 Annual review- Added new indications regarding treatment of deep vein thrombosis or pulmonary embolism and for the reduction in the risk of recurrent deep vein thrombosis or pulmonary embolism; 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. This Medical Policy is designed for informational purposes only and is not an authorization, an explanation of benefits, or a contract. Each benefit plan defines which services are covered, which are excluded, and which are subject to dollar caps or other limits. Members and their providers will need to consult the member's benefit plan to determine if there is any exclusion or other benefit limitations applicable to this service or supply. Medical technology is constantly changing and Blue Cross and Blue Shield of Kansas City reserves the right to review and revise medical policy. This information is proprietary and confidential and cannot be shared without the written permission of Blue Cross and Blue Shield of Kansas City.