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Medical Policy

Policy Num:       05.001.023
Policy Name:     Newer Oral Anticoagulants
Policy ID:          [5.001.023][Ac B M P ][5.01.21]

Last Review:       July 27, 2020
Next Review:      N/A
Issue:                   7:2020

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Newer Oral Anticoagulants

Summary

Since 2010, the U.S. Food and Drug Administration (FDA) has approved 4 new oral anticoagulants with unique mechanisms of action. These drugs present alternatives to oral warfarin.

These medications are:

ï‚· Dabigatran (Pradaxa®), a direct thrombin inhibitor

ï‚· Rivaroxaban (Xarelto®), a direct factor Xa inhibitor

ï‚· Apixaban (Eliquis®), a direct factor Xa inhibitor

ï‚· Edoxaban (Savaysa®), a direct factor Xa inhibitor

For stroke prevention in atrial fibrillation (AF), randomized controlled trials (RCTs) have reported that all 4 agents are noninferior to warfarin. The rates of bleeding were mixed in these trials in comparison with warfarin, but most trials have reported similar rates of overall bleeding and lower rates for intracranial hemorrhage. Some recent guidelines have favored one of the newer anticoagulants over warfarin as firstline treatment. Based on this evidence and specialty society guidelines, rivaroxaban, dabigatran, apixaban, and edoxaban may be considered medically necessary as an alternative to warfarin treatment for stroke prevention in AF.

For patients undergoing total hip replacement (THR) or total knee replacement (TKR) surgery, rivaroxaban was superior to low-molecular-weight heparin (LMWH) in clinical trials but also had a higher rate of major bleeding events. Dabigatran was noninferior to LMWH with no significant increase in major bleeding events. Apixaban was superior to LMWH on some efficacy outcomes and noninferior on others; rates of major bleeding were similar or lower than for LMWH. Based on this evidence and specialty guidelines, rivaroxaban, dabigatran, and apixaban may be considered medically necessary for prophylaxis of thromboembolism in patients undergoing THR and TKR surgery. Edoxaban was superior to LMWH in 2 of 3 trials, but generalizability of these results is limited by patient selection and comparator dosing. Additionally, clinically relevant bleeding events occurred more commonly in patients who received edoxaban, and edoxaban dosing for this indication has not been established. Whether edoxaban improves health outcomes in patients undergoing THR or TKR is therefore unclear, and edoxaban is considered investigational for this indication.

For patients with acute deep venous thrombosis (DVT) or pulmonary embolism (PE), rivaroxaban was reported to be noninferior or superior to warfarin in the EINSTEIN and EINSTEIN-PE trials in reducing rates of recurrent thromboembolism. Rates of clinically significant bleeding for rivaroxaban in these trials were similar or lower than warfarin. Dabigatran also was reported to be noninferior to warfarin and had similar bleeding risk. Patients who received dabigatran for extended prophylaxis experienced more acute coronary syndromes (ACSs). Apixaban was noninferior to warfarin for acute treatment of venous thromboembolism (VTE) and superior to placebo for extended prophylaxis without an increase in major bleeding. Acute treatment of VTE with edoxaban was noninferior to warfarin for preventing recurrent VTE at 12 months, with similar or reduced bleeding risk. Based on the results of these trials and the FDA approval of all 4 drugs for this indication, rivaroxaban, dabigatran, apixaban, and edoxaban may be considered medically necessary for treatment of acute DVT and PE.

For catheter ablation of AF, dabigatran was associated with increased risk of thromboembolic events compared with warfarin in 1 meta-analysis but not in another. Both meta-analyses showed no difference in major bleeding and reduced incidence of minor bleeding with dabigatran. Prospective, observational studies have reported comparable thromboembolic and bleeding risks with rivaroxaban, dabigatran, and vitamin K antagonists (VKAs). However, 1 study primarily used non-FDA-approved VKAs for comparison, and another study of rivaroxaban had imbalances in important clinical parameters (HAS-BLED score) at baseline. Because of uncertain risk of increased thromboembolic events with dabigatran and insufficient evidence for rivaroxaban, use of these drugs for periprocedural anticoagulation for catheter ablation of AF is considered investigational.

For cardioversion of AF, 1 exploratory RCT and 2 meta-analyses do not demonstrate improved health outcomes with newer oral anticoagulants compared with VKA because the studies were insufficiently powered to compare safety and efficacy outcomes between the 2 treatments. Use of newer oral anticoagulants in patients undergoing electrical or pharmaceutical cardioversion for AF is therefore considered investigational.

There is a lack of direct evidence on the comparative efficacy of these newer agents. Indirect comparisons based on the published trials have not consistently shown superiority of 1 agent over another. This evidence is insufficient for determining comparative efficacy of the newer agents.

Each of the new oral anticoagulants is being evaluated for other off-label uses, including secondary prevention of ACSs and thromboprophylaxis in medically ill patients. These other off-label indications are considered investigational.

Objective

Policy Statements

Nonvalvular Atrial Fibrillation

Rivaroxaban* (Xarelto®), dabigatran* (Pradaxa®), apixaban* (Eliquis®), and edoxaban* (Savaysa®) may be considered medically necessary in adult patients 18 years of age or older with documented paroxysmal, persistent, or permanent atrial fibrillation (AF) not complicated by valvular disease, as an alternative to warfarin therapy

DVT/PE Prophylaxis for Patients Undergoing THR/TKR

Rivaroxaban* (Xarelto®), dabigatran (Pradaxa®), and apixaban* (Eliquis®) may be considered medically necessary for prophylaxis of deep vein thrombosis (DVT) and pulmonary embolism in adult patients 18 years of age or older who are undergoing knee or hip replacement surgery.

Edoxaban (Savaysa®) is considered investigational for this indication.

Treatment and Secondary Prevention of Acute DVT/PE

Rivaroxaban* (Xarelto®), dabigatran* (Pradaxa®), apixaban* (Eliquis®), and edoxaban* (Savaysa®) may be considered medically necessary for treatment of acute DVT or PE, including long-term treatment and secondary prevention of thromboembolism.

Other Indications

The use of rivaroxaban, dabigatran, and apixaban, and edoxaban is considered investigational for all other indications, including but not limited to:

1. Prophylaxis of DVT and PE in hospitalized medically ill patients

2. Secondary prevention of cardiovascular events after an ACS

3. Periprocedural anticoagulation for catheter ablation of atrial fibrillation

4. Electrical or pharmaceutical cardioversion of atrial fibrillation

* FDA-approved indication.

Policy Guidelines

Active pathologic bleeding is a contraindication to dabigatran, rivaroxaban, apixaban, and edoxaban.

For dabigatran, rivaroxaban, and edoxaban, dose adjustment is required in patients with reduced creatinine clearance (CrCl):

Dabigatran

ï‚· For patients with CrCl >30 mL/min: 150 mg orally, twice daily

ï‚· For patients with CrCl 15-30 mL/min: 75 mg orally, twice daily

ï‚· Patients with CrCl ≤30 mL/min were excluded from the pivotal trial for dabigatran.

Rivaroxaban

ï‚· For patients with CrCl >50 mL/min: 20 mg orally, once daily with the evening meal

ï‚· For patients with CrCl 15-50 mL/min: 15 mg orally, once daily with the evening meal

ï‚· Patients with CrCl <30 mL/min were excluded from the pivotal trial for rivaroxaban.

Use of both drugs in patients with renal failure should be avoided. The cutoff for the definition of renal failure is not standardized; some recommendations have used a CrCl less than 15 mL/min and others have used a CrCl less than 30.

Edoxaban

ï‚· For patients with CrCl >50 mL/min: 60 mg orally, once daily

ï‚· For patients with CrCl 15-50 mL/min: 30 mg orally, once daily

ï‚· Patients with CrCl <30 mL/min were excluded from the pivotal trial for edoxaban.

Edoxaban should not be used in patients with CrCl greater than 95 mL/min.

For apixaban, the recommended dose is 2.5 mg twice daily in patients with any 2 of the following characteristics

ï‚· Age ≥80 years

ï‚· Body weight ≤60 kg (132 lb)

ï‚· Serum creatinine ≥1.5 mg/dL

Benefit Application

BlueCard/National Account Issues

State or federal mandates (eg, FEP) may dictate that certain FDA-approved drugs may not be considered investigational, and thus these drugs may be assessed only on the basis of their medical necessity.

Background

Before development of the new oral anticoagulants, warfarin was the only oral anticoagulant available. Its FDA-approved uses are:

1. Prophylaxis and treatment of venous thrombosis and PE

2. Prophylaxis and treatment of thromboembolic complications associated with AF and/or heart valve replacement

3. Reduction in the risk of death, recurrent myocardial infarction (MI), and thromboembolic events such as stroke or systemic embolization after MI

Warfarin is a VKA. Its safe use requires avoidance of many interacting foods and drugs and frequent international normalized ratio (INR) testing to guide dose adjustments. In contrast, because of predictable pharmacokinetic effects at FDA-approved doses, the new oral anticoagulants do not require routine laboratory monitoring and can be administered at fixed doses. They also have fewer food and drug interactions. In case of overdose or pathologic bleeding, warfarin may be reversed with the administration of oral or parenteral vitamin K1. There are no specific reversal agents (antidotes) for the new oral anticoagulants.

Stroke and Systemic Embolism in Patients With AF AF is one of the most common cardiac arrhythmias, affecting 2.66 million Americans. The Centers for Disease Control and Prevention estimates that by the year 2050, 12 million people will have AF.1 The median age of patients with AF is 66.8 years for men and 74.6 years for women.1 The disease is characterized by uncoordinated atrial activation with consequent loss of atrial mechanical function that may lead to dizziness and weakness, heart failure, ventricular tachycardia, and embolic cerebrovascular accident.2 Despite major advances in its management, AF remains a significant cause of cardiovascular morbidity and mortality, primarily due to the increased risk of ischemic stroke and heart failure. Patients with AF are 5 times more likely to have an ischemic stroke than those without AF, and up to 15% of all strokes are attributed to AF.3 The CHADS2 risk score is commonly used tool for estimating stroke risk in patients with AF.4 Five major risk factors for stroke are included

An alternate tool for the assessment of stroke risk is the CHA2DS2-VASc risk score.5 This score is similar to the CHADS2 score but adds an additional point for age 75 years or more and additional risk categories of vascular disease, age 65 to 74 years, and female sex. The CHA2DS2-VASc score has been found to better identify low-risk patients than the CHADS2 score.6 AF is classified by duration: Paroxysmal AF terminates spontaneously within 7 days, persistent AF is present continuously for more than 7 days, and permanent AF persists for more than 1 year and is refractory to cardioversion. Most AF patients are asymptomatic, and AF in itself may not be lifethreatening. Commonly, patients report nonspecific symptoms such as fatigue, dyspnea, dizziness, diaphoresis, and palpitations. Occasionally, patients present with extreme manifestations of hemodynamic compromise, such as chest pain, pulmonary edema, or syncope. AF is present in 10% to 40% of patients with a new ischemic stroke.7

The 2 main goals of AF management are to control rate and rhythm and to prevent stroke. Current evidence-based practice guidelines recommend a risk-stratified approach for the use of aspirin, clopidogrel, and oral anticoagulants for stroke prevention in patients with AF (see Practice Guidelines and Position Statements section).

VTE in Patients Undergoing Knee or Hip Replacement Surgery Following THR surgery, thromboembolism can occur in vessels in the pelvis, thigh, and calf. Without thromboprophylaxis, the incidence of objectively confirmed, hospital-acquired DVT is approximately 40% to 60% following major orthopedic surgery.8 Several factors contribute to postoperative thrombus formation and propagation of thrombi8 :

ï‚· persistent venous injury

ï‚· stasis due to continued reduced mobility

ï‚· impairment of the endogenous anticoagulant or fibrinolytic systems

ï‚· prolonged impairment of venous function

Symptomatic VTE (DVT or PE) most commonly presents after orthopedic patients are discharged from the hospital. This may result from extension of an asymptomatic DVT as thromboprophylaxis is discontinued or formation of a new thrombosis during recovery in a rehabilitation center or at home.8 Most DVTs are clinically silent and resolve spontaneously without any long-term sequelae. Symptoms may develop as a result of venous occlusion or embolization to the lungs8 and include9 :

ï‚· pain and tenderness in the calf and thigh

ï‚· positive Homan sign (pain in the calf or popliteal region elicited with abrupt flexion of the patient's ankle by the examiner while the knee is flexed to 90ï‚°)

ï‚· unilateral swelling and erythema of the leg

ï‚· low-grade fever ï‚· rapid pulse

Prevention of fatal PE is the most important goal of thromboprophylaxis.10 Proximal thrombi in the popliteal vein and above have been thought to pose a greater risk of PE than calf vein thrombi.11 Although the risk of DVT without thromboprophylaxis is greater after TKR surgery than after THR,8 proximal DVT occurs less commonly after TKR. Most PEs are asymptomatic. Symptomatic PE can present with pleuritic chest pain, diaphoresis, shortness of breath, and cough.9 In a group of 30,714 patients undergoing elective THR at Mayo Clinic, the 30-day mortality rate from PE was 0.04%.9 Following TKR, the risk of asymptomatic PE may be as high as 20%, with symptomatic PE reported in 0.5% to 3% of patients and a mortality rate of 2%.11

Venography (radiograph of the veins after injection of radiopaque dye) is considered the most sensitive and specific test for the detection of calf and thigh thrombi, but it does not reliably detect pelvic vein thrombi. In addition to being costly, uncomfortable, and invasive, venography carries the risk of anaphylactic reaction to the contrast media and a small risk of inducing DVT.9,11 Drugs currently used for DVT/PE prophylaxis in patients undergoing TKR or THR include the LMWHs, enoxaparin (Lovenox®) and dalteparin (Fragmin®), the synthetic pentasaccharide, fondaparinux (Arixtra®), unfractionated heparin, and warfarin. Each of these is administered subcutaneously except for warfarin, which is oral.

Acute VTE VTE can occur in any vein but most commonly occurs in the leg veins. The major complication of thrombosis of the deep veins of the legs (DVT) is PE. Postphlebitic syndrome due to damage of venous valves also can occur. DVT of the large proximal veins (popliteal, femoral, iliac) leads to PE or postphlebitic syndrome more commonly than small thrombi of the distal calf veins.12

  VTE occurs in both hospitalized patients and in otherwise healthy outpatients. VTE is caused by the triad of stasis (eg, immobility, increased venous pressure), vascular injury, and hypercoagulability (Virchow triad). Patients with a past history of VTE have an increased risk of future VTE. Additional risk factors include recent surgery or trauma, active malignancy, pregnancy, estrogen use, advanced age, limited mobility, severe obesity, and thrombophilic disorder. Additionally, among patients with cancer, older age, thalidomide- or lenalidomide-based chemotherapy, prechemotherapy thrombocytosis, primary cancer site (eg, gastrointestinal tract, lung, gynecologic), anemia and/or use of erythrocyte-stimulating agents, leukocytosis, obesity, and other risk factors increase VTE risk.13,14 The latter 5 factors have been incorporated into a VTE risk prediction model.15

Symptoms and signs of VTE result from obstruction to venous outflow, inflammation of the vessel wall, or embolization of thrombus into the pulmonary circulation. However, most thrombi are asymptomatic. Asymptomatic PE is detected by perfusion lung scanning in approximately 50% of patients with documented proximal vein thrombosis and asymptomatic VTE. Conversely, proximal DVT is found in approximately 70% of patients with confirmed PE. Proximal vein thrombosis has a recurrence rate over 3 months of 47% if inadequately treated but 2% to 4% when treated with oral anticoagulants or subcutaneous heparin. After 3 months of anticoagulant therapy, the recurrence rate is 5% to 10% during the following year.12 Preferred treatments include immediate short-term LMWH or fondaparinux with VKA and long-term VKA therapy (target INR, 2.5; range, 2.0-3.0) for 3 months in most patients.16,17

Acute Coronary Syndromes ACS are caused by acute myocardial ischemia (ie, lack of oxygen to cardiac muscle cells). ACS includes 3 clinical presentations: unstable angina, non-ST segment elevation myocardial infarction (NSTEMI), and ST segment elevation myocardial infarction (STEMI). In the United States, approximately 900,000 people suffer an MI annually, 20% of whom die before reaching the hospital, and 30% die within 30 days.18

Unstable angina is defined as angina (chest pain or pressure) occurring at rest or with minimal exertion, new-onset angina, or worsening symptoms in a previously stable patient, such as increased frequency or duration of attacks, resistance to previously effective medications, or provocation with decreasing levels of exertion.

A universal definition of MI was published by the European Society of Cardiology in 2012.6 Acute MI describes myocardial necrosis in a clinical setting suggesting acute myocardial ischemia. Additional criteria for making the diagnosis include: a typical rise and fall of a serum cardiac biochemical marker (either troponin or the muscle-brain fraction of creatine kinase [CK-MB]), clinical symptoms, electrocardiogram (ECG) changes, imaging or angiographic findings, and coronary artery intervention (ie, percutaneous coronary intervention or coronary artery bypass graft surgery)

Acute MI is classified at presentation by findings on the ECG, as either STEMI or NSTEMI. Depression or no change of the ST segment is associated with subendocardial ischemia, affecting the inner layers of the ventricular wall. ST elevation suggests transmural injury. The differentiation between STEMI and NSTEMI has important implications in terms of management, therapeutic intervention, outcome, and prognosis.1

The twin goals of treatment of ACS are the immediate relief of ischemia and the prevention of serious adverse outcomes (ie, death, MI, reinfarction). Treatments include anti-ischemic therapy (eg, oxygen, nitroglycerin, -blockers), antithrombotic therapy, and reperfusion.

Regulatory Status

Rivaroxaban was FDA approved for prophylaxis of DVT and PE in patients undergoing knee or hip replacement surgery in July 2011; for prevention of stroke and systemic embolism in patients with nonvalvular AF in November 2011; and for acute treatment of DVT and/or PE and long-term prophylaxis of thromboembolism in November 2012.

In June 2012, a new drug application for rivaroxaban in secondary prevention of ACS [acute coronary syndrome] received Complete Response Letters from FDA.19 An FDA Advisory Committee cited concerns about missing data in the pivotal ATLAS-ACS 2 TIMI 51 trial20 and increased bleeding risk with rivaroxaban.21 In January 2014, an FDA Advisory Committee considered a revised application for rivaroxaban within the first 90 days after ACS; ATLAS-ACS 2 TIMI 51 results, regarding study of the drug for chronic use, was resubmitted to support this application. The committee voted unanimously (with 1 abstention) against recommending approval for the revised indication

Dabigatran received FDA approval to reduce the risk of stroke and systemic embolism in patients with nonvalvular AF in October 2010 and for treatment of acute DVT and PE and reduction of recurrence risk in April 2014. Dabigatran is not approved in the United States for thromboprophylaxis after TKR and THR but is approved for this indication in Europe and Canada. The manufacturer of dabigatran (BoehringerIngelheim) has not applied to FDA for this indication after dabigatran failed to demonstrate noninferiority to the FDA-approved dose of enoxaparin in the RE-MOBILIZE TKR trial.22

Apixaban received FDA approval to reduce the risk of stroke and systemic embolism in patients with nonvalvular AF in December 2012; for prophylaxis of DVT which may lead to PE in adult patients who have undergone hip or knee replacement surgery in March 2014; and for treatment of DVT and PE and reduction in the risk of recurrent DVT and PE after initial therapy in August 2014.

In January 2015, edoxaban received FDA approval to reduce the risk of stroke and systemic embolism in patients with nonvalvular AF, and for treatment of DVT and PE after 5 to 10 days of initial therapy with a parenteral anticoagulant.

Current FDA-approved indications of the 4 drugs are listed in Table 3.

A-Fib: atrial fibrillation; DVT: deep venous thrombosis; FDA: U.S. Food and Drug Administration; PE: pulmonary embolism; THR: total hip replacement; TKR: total knee replacement. a To reduce the risk of stroke and systemic embolism in patients with nonvalvular AF. b For prophylaxis of DVT, which may lead to PE in adult patients who have undergone hip or knee replacement surgery. c For treatment of acute DVT and PE and reduction of recurrence risk

Rationale

This policy was created in September 2012 based on TEC Specialty Pharmacy Reports 14-2010 “Dabigatran/Pradaxa®”23 and 15-2011 “Rivaroxaban/Xarelto®.” 24 The policy was updated in February 2013 based on TEC Specialty Pharmacy Report 2-2013 “Apixaban/Eliquis®”25 and again in May 2015 incorporating TEC Specialty Pharmacy Report 19-2014 “Edoxaban/Savaysa™.”26 This policy will review randomized controlled trials (RCTs) in 4 disease categories that have used one of the newer oral anticoagulant medications and have evaluated at least one of the following clinical outcomes:

Prevention of stroke and systemic embolism in patients with atrial fibrillation (AF)

ï‚· Prophylaxis of venous thromboembolism (VTE) in patients undergoing knee or hip replacement surgery

ï‚· Extended prophylaxis of deep venous thrombosis (DVT) and pulmonary embolism (PE) in medically ill patients requiring hospitalization

ï‚· Treatment of acute DVT and/or PE

ï‚· Secondary prevention in acute coronary syndromes (ACS) The most recent literature search was conducted through April 13, 2015

Prevention of Stroke and Systemic Embolism in Patients With AF Results of the trials discussed below are summarized in Table 4.

Rivaroxaban Rocket AF Trial The efficacy of rivaroxaban to reduce the risk of stroke and systemic embolism in patients with nonvalvular AF was assessed in the pivotal Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonist for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF; N=14,264).27 ROCKET AF was a 4-year, double-blind, double-dummy, noninferiority RCT. Enrolled patients were adults with nonvalvular AF who were at moderate to high risk of future stoke or systemic embolism, as evidenced by a history of prior stroke, transient ischemic attack (TIA), or systemic embolism, or by a CHADS2 risk score of 2 or more. Patients scheduled for electrical or pharmacologic cardioversion and those with creatinine clearance (CrCl) less than 30 mL/min were excluded. Patients were randomized to receive rivaroxaban 20 mg orally daily (15 mg in those with CrCl, 30-49 mL/min) or dose-adjusted warfarin. The primary efficacy end point was the incidence of stroke or systemic embolism. Median patient age was 73 years, and mean CHADS2 score was 3.5. Patients randomized to warfarin were in the therapeutic range 55% of the time

In the per protocol population, rivaroxaban was not inferior to warfarin based on a noninferiority margin of 1.38. Primary end point event rates per 100 patient-years were 1.7 in rivaroxaban-treated patients and 2.2 in warfarin-treated patients (hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.66 to 0.96; p<0.001). Subsequent prespecified testing failed to demonstrate superiority. In the intention-to-treat population, rivaroxaban was inferior to warfarin. Primary efficacy end point event rates per 100 patientyears were 2.1 in rivaroxaban-treated patients and 2.4 in warfarin-treated patients (HR=0.88; 95% CI, 0.75 to 1.03; p=0.117). Rates per 100 patient-years of myocardial infarction (MI) (0.9 rivaroxaban vs 1.1 warfarin, HR=0.81; 95% CI, 0.63 to 1.06; p=0.121) and all-cause mortality (1.9 rivaroxaban vs 2.2 warfarin, HR=0.85; 95% CI, 0.70 to 1.02; p=0.073) did not differ statistically between treatment groups.

The primary safety outcome in ROCKET AF was the composite of major bleeding (defined as fatal bleeding, bleeding in a critical area or organ, bleeding leading to permanent disability, a decrease in hemoglobin of at least 2 g/dL, or transfusion of at least 2 units of blood) and nonmajor clinically relevant bleeding (defined as overt bleeding associated with medical intervention, temporary interruption of study drug, or patient discomfort). The event rate per 100 person-years for this outcome was 14.9 in rivaroxaban-treated patients and 14.5 in warfarin-treated patients (HR=1.03; 95% CI, 0.96 to 1.11; p=0.442). Compared with warfarin-treated patients, rivaroxaban-treated patients had:

ï‚· Fewer intracranial hemorrhages (0.5 vs 0.7 per 100 patient-years, HR=0.67; 95% CI, 0.47 to 0.93; p=0.019)

ï‚· Fewer critical organ bleeds (0.8 vs 1.2 per 100 patient-years, HR=0.69; 95% CI, 0.53 to 0.91; p=0.007)

ï‚· Fewer bleeding-related deaths (0.2 vs 0.5 per 100 patient-years, HR=0.50; 95% CI, 0.31 to 0.79; p=0.003)

ï‚· More frequent decreased hemoglobin (2.8 vs 2.3 per 100 patient-years, HR=1.22; 95% CI, 1.03 to 1.44; p=0.019)

ï‚· More frequent transfusions (1.6 vs 1.3 per 100 patient-years, HR=1.25; 95% CI, 1.01 to 1.55; p=0.044

A 2014 meta-analysis of ROCKET-AF plus 9 other trials showed no increased risk of drug-induced liver injury (defined as transaminase elevation >3 times the upper limit of normal [ULN] concomitant with total bilirubin elevation >2 times the ULN) with rivaroxaban compared with warfarin.28 Pooled relative risk (RR) was 0.96 (95% CI, 0.69 to 1.35). There was no statistical heterogeneity (I 2 =0%).

Dabigatran RE-LY Trial29 Evidence for the efficacy of dabigatran for the prevention of stroke and systemic embolism in patients with nonvalvular AF comes from the international phase 3 “Randomized Evaluation of Long Term Anticoagulant Therapy” (RE-LY) trial. RE-LY was a 3-year trial that enrolled 18,113 patients with nonvalvular AF and at least 1 risk factor for stroke. Patients with CrCl less than 30 mL/min were excluded. Thirty-six percent of patients were recruited from North America. A prospective, randomized, open-label, blinded-end point (PROBE) trial design was used. There were 3 treatment arms: (1) dabigatran 110 mg twice daily; (2) dabigatran 150 mg twice daily; and (3) dose-adjusted warfarin with target international normalized ratio (INR) of 2.0 to 3.0. The primary efficacy end point was the incidence of stroke or systemic embolism. Secondary end points included the incidence of hemorrhagic stroke and MI. The primary objective of the trial was to test each dose of dabigatran for noninferiority to dose-adjusted warfarin for the primary efficacy outcome. Mean patient age was 71.5, and mean CHADS2 score was 2.1. For patients randomized to warfarin, mean proportion of time in the therapeutic range was 64%.

For the primary efficacy end point, both doses of dabigatran were noninferior to warfarin based on a noninferiority margin of 1.46. Only the 150-mg dose was superior to warfarin (RR=0.65; 95% CI, 0.52 to 0.81; p<0.001; absolute risk ratio [ARR], 1.1 percentage points; number needed to treat [NNT], 87). Both doses of dabigatran significantly decreased the risk of hemorrhagic stroke compared with warfarin (150 mg dabigatran: RR=0.26; 95% CI, 0.14 to 0.49; p<0.001; ARR=0.6 percentage points, NNT=182; 110 mg dabigatran: RR=0.31; 95% CI, 0.17 to 0.56; p<0.001; ARR=0.5 percentage points, NNT=194). Both doses of dabigatran were associated with statistically nonsignificant increases in the risk of MI (150 mg dabigatran: RR=1.27; 95% CI, 0.94 to 1.71; p=0.12; 110 mg dabigatran: RR=1.29; 95% CI, 0.96 to 1.75; p=0.09).

The primary safety end point was major bleeding, which was defined as life-threatening or fatal bleeding, a decrease in hemoglobin of at least 2 g/dL, transfusion of at least 2 units of blood, or symptomatic bleeding in a critical area or organ. Although there was no significant difference in the risk of major bleeding with 150 mg of dabigatran relative to warfarin (RR=0.93, p=0.32), the risk of intracranial hemorrhage was reduced (0.3% vs 0.8%; RR=0.41, p<0.001). The lower dabigatran dose (110 mg twice daily) was associated with a 20% reduction in the risk of major bleeding compared with warfarin (p=0.003, ARR=1.3%). Patients in the higher dose dabigatran group had a 48% greater risk of major gastrointestinal bleeding compared with patients taking warfarin (p<0.001, absolute risk increase [ARI], 1.0%; NNH=100). The risk of major gastrointestinal bleeding in the lower dose dabigatran group was not statistically different from that in the warfarin group (p=0.52).

Elevated Liver Enzymes In the RE-LY trial, elevations in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than 3 times the ULN concurrent with bilirubin elevations greater than 2 times ULN (drug-induced liver injury) occurred in 0.2% of patients in both dabigatran groups and in 0.3% of patients in the warfarin group. In a meta-analysis of RE-LY and 5 other trials (RE-COVER, RE-MEDY, RE-SONATE, REMOBILIZE, RE-NOVATE, reviewed next), Caldeira et al (2014) found no increased risk of drug-induced liver injury (pooled RR=0.67; 95% CI, 0.40 to 1.11).28 No statistical heterogeneity was observed (I 2 =0%).

Bleeding Risk: Subsequent Evaluation After FDA approval of dabigatran in October 2010, reports to FDA’s Adverse Event Reporting System (FAERS) of dabigatran-associated serious and fatal bleeding events exceeded those of warfarinassociated events. In response, FDA reviewed its safety surveillance database of insurance claim and administrative data, Mini-Sentinel, through December 31, 2011. FDA examined inpatient diagnosis codes for intracranial and gastrointestinal hemorrhages associated with new use of dabigatran or warfarin. No increase in bleeding rates with dabigatran in patients with or without AF was identified (incidence per 100,000 days at risk, 1.6 with dabigatran vs 3.5 with warfarin in patients with AF). The relative increase in reports of dabigatran-associated bleeding was attributed to “stimulated reporting” because of novelty of dabigatran and increased media coverage.30 McConeghy et al queried the FAERS database through 2011 and reported that the proportion of dabigatran-associated bleeding events that were fatal was higher than that observed in the RE-LY trial (15% in FAERS vs 9% in RE-LY).31 Given inherent biases in a voluntary reporting system, this result is considered suggestive.

Sipahi et al (2014) conducted a subsequent meta-analysis of the RE-LY trial and 3 other trials in patients with acute DVT or PE (RE-COVER, RE-MEDY, RE-COVER II, reviewed next). In contrast to FDA’s MiniSentinel analysis, the authors found a statistically significant 41% increase in the incidence of gastrointestinal tract bleeding with dabigatran compared with warfarin (pooled RR=1.41; 95% CI, 1.28 to 1.55).32 Similarly, Bloom et al (2014) reported a 51% increase in the risk of gastrointestinal bleeding with dabigatran compared with warfarin (pooled RR=1.51; 95% CI, 1.23 to 1.84) based on a meta-analysis of 2 trials (RE-LY, RE-COVER).33 This result was largely driven by the RE-LY trial. There was no statistical heterogeneity (I 2 =0%). FDA is conducting a protocol-based assessment using Mini-Sentinel claims data adjusted for confounding factors (see Ongoing and Unpublished Clinical Trials section).

Population Reference No. 1 Policy Statement

For stroke prevention in atrial fibrillation (AF), randomized controlled trials (RCTs) have reported that all 4 agents are noninferior to warfarin. The rates of bleeding were mixed in these trials in comparison with warfarin, but most trials have reported similar rates of overall bleeding and lower rates for intracranial hemorrhage. Some recent guidelines have favored one of the newer anticoagulants over warfarin as firstline treatment. Based on this evidence and specialty society guidelines, rivaroxaban, dabigatran, apixaban, and edoxaban may be considered medically necessary as an alternative to warfarin treatment for stroke prevention in AF.

Population Reference No. 2 Policy Statement

For patients undergoing total hip replacement (THR) or total knee replacement (TKR) surgery, rivaroxaban was superior to low-molecular-weight heparin (LMWH) in clinical trials but also had a higher rate of major bleeding events. Dabigatran was noninferior to LMWH with no significant increase in major bleeding events. Apixaban was superior to LMWH on some efficacy outcomes and noninferior on others; rates of major bleeding were similar or lower than for LMWH. Based on this evidence and specialty guidelines, rivaroxaban, dabigatran, and apixaban may be considered medically necessary for prophylaxis of thromboembolism in patients undergoing THR and TKR surgery. Edoxaban was superior to LMWH in 2 of 3 trials, but generalizability of these results is limited by patient selection and comparator dosing. Additionally, clinically relevant bleeding events occurred more commonly in patients who received edoxaban, and edoxaban dosing for this indication has not been established. Whether edoxaban improves health outcomes in patients undergoing THR or TKR is therefore unclear, and edoxaban is considered investigational for this indication.

Population Reference No. 3 Policy Statement

For patients with acute deep venous thrombosis (DVT) or pulmonary embolism (PE), rivaroxaban was reported to be noninferior or superior to warfarin in the EINSTEIN and EINSTEIN-PE trials in reducing rates of recurrent thromboembolism. Rates of clinically significant bleeding for rivaroxaban in these trials were similar or lower than warfarin. Dabigatran also was reported to be noninferior to warfarin and had similar bleeding risk. Patients who received dabigatran for extended prophylaxis experienced more acute coronary syndromes (ACSs). Apixaban was noninferior to warfarin for acute treatment of venous thromboembolism (VTE) and superior to placebo for extended prophylaxis without an increase in major bleeding. Acute treatment of VTE with edoxaban was noninferior to warfarin for preventing recurrent VTE at 12 months, with similar or reduced bleeding risk. Based on the results of these trials and the U.S. Food and Drug Administration (FDA)--approval of all 4 drugs for this indication, rivaroxaban, dabigatran, apixaban, and edoxaban may be considered medically necessary for treatment of acute DVT and PE.

Population Reference No. 4 Policy Statement

For catheter ablation of AF, dabigatran was associated with increased risk of thromboembolic events compared with warfarin in 1 meta-analysis but not in another. Both meta-analyses showed no difference in major bleeding and reduced incidence of minor bleeding with dabigatran. Prospective, observational studies have reported comparable thromboembolic and bleeding risks with rivaroxaban, dabigatran, and vitamin K antagonists (VKAs). However, 1 study primarily used non-FDA-approved VKAs for comparison, and another study of rivaroxaban had imbalances in important clinical parameters (HAS-BLED score) at baseline. Because of uncertain risk of increased thromboembolic events with dabigatran and insufficient evidence for rivaroxaban, use of these drugs for periprocedural anticoagulation for catheter ablation of AF is considered investigational.

Population Reference No. 1 Policy Statement

For cardioversion of AF, 1 exploratory RCT and 2 meta-analyses do not demonstrate improved health outcomes with newer oral anticoagulants compared with VKA because the studies were insufficiently powered to compare safety and efficacy outcomes between the 2 treatments. Use of newer oral anticoagulants in patients undergoing electrical or pharmaceutical cardioversion for AF is therefore considered investigational. There is a lack of direct evidence on the comparative efficacy of these newer agents. Indirect comparisons based on the published trials have not consistently shown superiority of 1 agent over another. This evidence is insufficient for determining comparative efficacy of the newer agents. 

Population Reference No. 1 Policy Statement

Text

Supplemental Information

Practice Guidelines and Position Statements Prevention of Stroke and Systemic Embolism in Patients With AF Recent evidence-based guidelines published by the American College of Chest Physicians (ACCP), the American Heart Association (AHA) jointly with the American Stroke Association (ASA) and the Heart Rhythm Society (HRS), the Canadian Cardiovascular Society, and the European Society of Cardiology (ESC) recommend a risk-stratified approach to the use of anticoagulant therapy in AF patients. For patients at intermediate or high risk of stroke, ACCP guidelines (2012) include a weak recommendation based on moderate-quality evidence (grade 2B) for the use of dabigatran 150 mg twice daily over adjusted-dose warfarin therapy based on greater net clinical benefit shown with dabigatran in the pivotal RE-LY trial.98 However, caution is advised due to the lack of an antidote for dabigatran and performance in clinical practice that may differ from that in the trial setting because of “less-restricted patient selection” and reduced adherence to “unmonitored drug.” Continuation of warfarin in patients whose INR is maintained in the therapeutic range and who are satisfied with treatment is supported.98 Recommendations about rivaroxaban and apixaban were not included in the ACCP guidelines because neither drug was FDA-approved at the time the guidelines were written. Current AHA/ASA/HRS guidelines (2014) recommend rivaroxaban, dabigatran, and apixaban as alternatives to warfarin for the prevention of first and recurrent stroke in patients with nonvalvular AF, particularly for patients unable to maintain warfarin in a therapeutic range (class I recommendations based on level B evidence [a single RCT or nonrandomized studies]). 99 Edoxaban was not reviewed in these guidelines.

Guideline developers also noted: 1. Because of the short half-lives (approximately 12 hours) of the newer oral anticoagulants, patients who miss even 1 dose may be at increased risk for thromboembolism. 2. Patients with mechanical or bioprosthetic heart valves or hemodynamically significant mitral stenosis were excluded from all 3 pivotal trials; therefore, these patients should be managed with warfarin. Based on level B evidence, dabigatran is contraindicated in patients with mechanical heart valves. 3. Each of the 3 pivotal trials excluded: pregnant or lactating women; children; patients with reversible causes of AF; patients with severe hypertension (systolic blood pressure >180 mm Hg or diastolic blood pressure >100 mm Hg); patients with recent stroke (within 7 to 14 days); patients with significant liver disease; and complex patients with multiple chronic comorbid diseases. 4. Dose modifications of the newer oral anticoagulants may be made for patients with chronic kidney disease (CKD). However, for those with severe or end-stage CKD, warfarin remains the anticoagulant of choice.

Among patients on hemodialysis, warfarin has been used with acceptable bleeding risk. 5. Although the short half-lives of the newer oral anticoagulants may reduce the need for a reversal agent, antidotes for these drugs are currently unavailable. In 2014, the Canadian Cardiovascular Society published a focused update of its guidelines for stroke prevention and rate/rhythm control in AF.100 The update incorporated findings from the ROCKET AF, RELY, AVERROES, ARITSTOTLE, and ENGAGE AF-TIMI 48 trials. These trials were considered highquality evidence. The guidelines include strong recommendations for oral anticoagulant therapy in patients at high risk of stroke (CHADS2 score, ≥2) and most patients at intermediate risk of stroke Section: Prescription Drug Subsection: Original Policy Date: December 2012 Page: 41 © 2015 Blue Cross Blue Shield Association. Reproduction without prior authorization is prohibited. MPRM 5.01.21 Newer Oral Anticoagulants ARCHIVED (CHADS2 score, 1). A strong recommendation based on high-quality evidence is made for use of dabigatran, rivaroxaban, apixaban, or edoxaban in preference to warfarin when oral anticoagulation therapy is indicated in patients with nonvalvular AF. In patients with a mechanical prosthetic valve, rheumatic mitral stenosis, or creatinine clearance of 15 to 30 mL/min, warfarin is preferred (strong recommendation based on moderate-quality evidence). Based on a systematic review and meta-analyses of antithrombotic treatments, current Canadian Agency for Drugs and Technology in Health (CADTH) guidelines (2013) recommend the new oral anticoagulants, dabigatran, rivaroxaban, and apixaban for stroke prevention in patients with nonvalvular AF in whom warfarin is indicated who have a CHADS2 score 1 or higher but cannot maintain adequate anticoagulation with warfarin.101 An explicit definition of “adequate anticoagulation with warfarin” was not provided due to variation across jurisdictions in access to INR testing and other variables. CADTH authors noted that evidence was insufficient “to identify a preferred anticoagulation treatment strategy for patients with AF who have a lower risk of stroke (CHADS2 score <1).” Further, “evidence-based differentiation” of the newer anticoagulants is limited by the lack of head-to-head trials. Edoxaban was not reviewed in these guidelines. ESC published a focused update of its AF guidelines in 2012.6 Based on the 3 trials that directly compared the new oral anticoagulants to warfarin (ROCKET AF, RE-LY, ARISTOTLE), rivaroxaban, dabigatran, or apixaban (pending approval) is recommended over adjusted-dose warfarin for most patients who require oral anticoagulation (CHA2DS2-VASc ≥2 [class I recommendation based on multiple RCTs and general agreement] or CHAD2S2-VASc=1 [class IIa recommendation based on multiple RCTs without general agreement]).

Women younger than 65 years with a CHAD2S2-VASc score of 1 for sex category should not be treated (class IIa recommendation based on large nonrandomized studies without general agreement). No recommendation is made for 1 newer oral anticoagulant over another. Edoxaban was not reviewed in these guidelines. The American Academy of Neurology published a 2014 update to its practice parameter on stroke prevention in nonvalvular atrial fibrillation. 102 Evidence-based consensus recommendations for oral anticoagulants to reduce stroke risk included warfarin; dabigatran if creatinine clearance is greater than 30 mL/min; and rivaroxaban or apixaban with dose adjustments for renal insufficiency (and for apixaban, body weight and age) (level B recommendation). Guideline developers concluded, “In patients with NVAF, dabigatran, rivaroxaban, and apixaban are probably at least as effective as warfarin in preventing stroke and have a lower risk of intracranial hemorrhage.” Edoxaban was not reviewed in these guidelines. Prophylaxis of Venous Thromboembolism in Patients Undergoing Knee or Hip Replacement Surgery Evidence-based guidelines published by the American Academy of Orthopedic Surgeons (AAOS) in 2011103 and by ACCP in 201260,104 support VTE prophylaxis using pharmacologic treatments and/or mechanical compressive devices in patients undergoing THR and TKR. In developing its guidelines, AAOS did not accept DVT as a surrogate for PE, thus limiting the evidence for specific prophylactic treatments. As summarized by Eikelboom et al: “Both guideline panels accepted prevention of fatal PE as the most important goal of thromboprophylaxis. However, the ACCP included asymptomatic (and symptomatic) DVT detected by venography as a measure of the efficacy of thromboprophylaxis, whereas the AAOS rejected DVT (both asymptomatic and symptomatic) as a valid outcome because the panelists considered the link between DVT and PE in patients undergoing hip or knee surgery to be unproven.

Thus the AAOS only accepted symptomatic PE and fatal PE as valid outcomes and limited their analysis to studies reporting this outcome.”10 Current AAOS guidelines103 suggest the use of pharmacologic agents and/or mechanical compressive devices for VTE prophylaxis in patients undergoing elective THR or TKR whose risk of VTE or bleeding is not elevated above that of the surgery itself (grade of recommendation: moderate). ï‚· However, due to inconclusive evidence, no specific recommendations for the choice or duration of prophylactic regimen are made. Section: Prescription Drug Subsection: Original Policy Date: December 2012 Page: 42 © 2015 Blue Cross Blue Shield Association. Reproduction without prior authorization is prohibited. MPRM 5.01.21 Newer Oral Anticoagulants ARCHIVED ï‚· Consensus recommendations (based on expert opinion) include the use of pharmacologic prophylaxis and mechanical compressive devices in patients who have had a prior VTE, and use of mechanical compressive devices in patients with a known bleeding disorder (eg, hemophilia) and/or active liver disease. Current ACCP guidelines include strong recommendations based on moderate quality evidence (grade 1B) for a minimum of 10 to 14 days prophylaxis with LMWH, fondaparinux, apixaban, dabigatran, rivaroxaban, low-dose unfractionated heparin, adjusted-dose VKA, or aspirin in patients with no increased bleeding risk. For patients who decline or are uncooperative with injections or an intermittent pneumatic compression device, apixaban or dabigatran (alternatively rivaroxaban or adjusted-dose VKA if apixaban or dabigatran are unavailable) rather than alternative forms of prophylaxis is recommended. Treatment of Acute DVT and/or PE ACCP guidelines published in 2012 strongly recommend initial parenteral anticoagulant therapy (with LMWH or fondaparinux) in combination with VKA therapy for the treatment of acute DVT or PE. Parenteral anticoagulation should be continued for a minimum of 5 days and until the INR is 2.0 or more for at least 24 hours (grade 1B recommendations based on moderate quality evidence). Generally, anticoagulation for 3 months is recommended over shorter and longer (eg, 6 or 12 months) periods (grade 1B). Exceptions include first unprovoked VTE (proximal DVT or PE) or second unprovoked VTE in patients with a low or moderate bleeding risk, and any VTE in patients with active cancer. In these instances, extended duration anticoagulation therapy (ie, not time-limited) is recommended. In patients with cancer,

LMWH is recommended for long-term therapy, and in patients without cancer, VKA therapy (target INR, 2.5; range 2.0-3.0) is recommended. Both treatments are recommended over dabigatran or rivaroxaban for long-term therapy. (Weak recommendation based on low quality evidence [ie, indirect comparisons].)16 In 2014, ESC updated its evidence-based guidelines for the diagnosis and management of acute PE.105 The guidelines state: “[R]esults of the trials using NOACs [new oral anticoagulants] in the treatment of VTE indicate that these agents are noninferior (in terms of efficacy) and possibly safer (particularly in terms of major bleeding) than the standard heparin/VKA regimen…. At present, NOACs can be viewed as an alternative to standard treatment…. Experience with NOACs is still limited but continues to accumulate.” In 2015, the American Society of Clinical Oncology updated its evidence-based clinical practice guideline for venous thromboembolism prophylaxis and treatment in patients with cancer.106 The guideline states, “Use of novel oral anticoagulants is not currently recommended for patients with malignancy and VTE because of limited data in patients with cancer.” Catheter Ablation of AF 2014 AHA/ASA/HRS evidence-based guidelines do not include specific recommendations for periprocedural anticoagulation for catheter ablation of AF. Cardioversion of AF 2014 AHA/ASA/HRS evidence-based guidelines include class I recommendations for: 1. Anticoagulation with warfarin in patients with AF or atrial flutter of at least 48 hours or unknown duration regardless of CHA2DS2-VASc score and method of cardioversion (electrical or pharmacological) used (level B evidence [a single RCT or nonrandomized studies]) 2. Anticoagulation with intravenous heparin or LMWH, or administration of a factor Xa or direct thrombin inhibitor, as soon as possible before or immediately after cardioversion in patients with AF or atrial flutter of less than 48 hours duration and with high risk of stroke (level C evidence [expert consensus, case studies]) U.S. Preventive Services Task Force Recommendations Not applicable.

Practice Guidelines and Position Statements

Practice Guidelines and Position Statements Prevention of Stroke and Systemic Embolism in Patients With AF Recent evidence-based guidelines published by the American College of Chest Physicians (ACCP), the American Heart Association (AHA) jointly with the American Stroke Association (ASA) and the Heart Rhythm Society (HRS), the Canadian Cardiovascular Society, and the European Society of Cardiology (ESC) recommend a risk-stratified approach to the use of anticoagulant therapy in AF patients. For patients at intermediate or high risk of stroke, ACCP guidelines (2012) include a weak recommendation based on moderate-quality evidence (grade 2B) for the use of dabigatran 150 mg twice daily over adjusted-dose warfarin therapy based on greater net clinical benefit shown with dabigatran in the pivotal RE-LY trial.98 However, caution is advised due to the lack of an antidote for dabigatran and performance in clinical practice that may differ from that in the trial setting because of “less-restricted patient selection” and reduced adherence to “unmonitored drug.” Continuation of warfarin in patients whose INR is maintained in the therapeutic range and who are satisfied with treatment is supported.98 Recommendations about rivaroxaban and apixaban were not included in the ACCP guidelines because neither drug was FDA-approved at the time the guidelines were written. Current AHA/ASA/HRS guidelines (2014) recommend rivaroxaban, dabigatran, and apixaban as alternatives to warfarin for the prevention of first and recurrent stroke in patients with nonvalvular AF, particularly for patients unable to maintain warfarin in a therapeutic range (class I recommendations based on level B evidence [a single RCT or nonrandomized studies]). 99 Edoxaban was not reviewed in these guidelines. Guideline developers also noted: 1. Because of the short half-lives (approximately 12 hours) of the newer oral anticoagulants, patients who miss even 1 dose may be at increased risk for thromboembolism. 2. Patients with mechanical or bioprosthetic heart valves or hemodynamically significant mitral stenosis were excluded from all 3 pivotal trials; therefore, these patients should be managed with warfarin. Based on level B evidence, dabigatran is contraindicated in patients with mechanical heart valves. 3. Each of the 3 pivotal trials excluded: pregnant or lactating women; children; patients with reversible causes of AF; patients with severe hypertension (systolic blood pressure >180 mm Hg or diastolic blood pressure >100 mm Hg); patients with recent stroke (within 7 to 14 days); patients with significant liver disease; and complex patients with multiple chronic comorbid diseases. 4. Dose modifications of the newer oral anticoagulants may be made for patients with chronic kidney disease (CKD). However, for those with severe or end-stage CKD, warfarin remains the anticoagulant of choice. Among patients on hemodialysis, warfarin has been used with acceptable bleeding risk. 5. Although the short half-lives of the newer oral anticoagulants may reduce the need for a reversal agent, antidotes for these drugs are currently unavailable. In 2014, the Canadian Cardiovascular Society published a focused update of its guidelines for stroke prevention and rate/rhythm control in AF.100

The update incorporated findings from the ROCKET AF, RELY, AVERROES, ARITSTOTLE, and ENGAGE AF-TIMI 48 trials. These trials were considered highquality evidence. The guidelines include strong recommendations for oral anticoagulant therapy in patients at high risk of stroke (CHADS2 score, ≥2) and most patients at intermediate risk of stroke Section: Prescription Drug Subsection: Original Policy Date: December 2012 Page: 41 © 2015 Blue Cross Blue Shield Association. Reproduction without prior authorization is prohibited. MPRM 5.01.21 Newer Oral Anticoagulants ARCHIVED (CHADS2 score, 1). A strong recommendation based on high-quality evidence is made for use of dabigatran, rivaroxaban, apixaban, or edoxaban in preference to warfarin when oral anticoagulation therapy is indicated in patients with nonvalvular AF. In patients with a mechanical prosthetic valve, rheumatic mitral stenosis, or creatinine clearance of 15 to 30 mL/min, warfarin is preferred (strong recommendation based on moderate-quality evidence). Based on a systematic review and meta-analyses of antithrombotic treatments, current Canadian Agency for Drugs and Technology in Health (CADTH) guidelines (2013) recommend the new oral anticoagulants, dabigatran, rivaroxaban, and apixaban for stroke prevention in patients with nonvalvular AF in whom warfarin is indicated who have a CHADS2 score 1 or higher but cannot maintain adequate anticoagulation with warfarin.101 An explicit definition of “adequate anticoagulation with warfarin” was not provided due to variation across jurisdictions in access to INR testing and other variables. CADTH authors noted that evidence was insufficient “to identify a preferred anticoagulation treatment strategy for patients with AF who have a lower risk of stroke (CHADS2 score <1).” Further, “evidence-based differentiation” of the newer anticoagulants is limited by the lack of head-to-head trials. Edoxaban was not reviewed in these guidelines. ESC published a focused update of its AF guidelines in 2012.6 Based on the 3 trials that directly compared the new oral anticoagulants to warfarin (ROCKET AF, RE-LY, ARISTOTLE), rivaroxaban, dabigatran, or apixaban (pending approval) is recommended over adjusted-dose warfarin for most patients who require oral anticoagulation (CHA2DS2-VASc ≥2 [class I recommendation based on multiple RCTs and general agreement] or CHAD2S2-VASc=1 [class IIa recommendation based on multiple RCTs without general agreement]). Women younger than 65 years with a CHAD2S2-VASc score of 1 for sex category should not be treated (class IIa recommendation based on large nonrandomized studies without general agreement). No recommendation is made for 1 newer oral anticoagulant over another. Edoxaban was not reviewed in these guidelines. The American Academy of Neurology published a 2014 update to its practice parameter on stroke prevention in nonvalvular atrial fibrillation. 102 Evidence-based consensus recommendations for oral anticoagulants to reduce stroke risk included warfarin; dabigatran if creatinine clearance is greater than 30 mL/min; and rivaroxaban or apixaban with dose adjustments for renal insufficiency (and for apixaban, body weight and age) (level B recommendation).

Guideline developers concluded, “In patients with NVAF, dabigatran, rivaroxaban, and apixaban are probably at least as effective as warfarin in preventing stroke and have a lower risk of intracranial hemorrhage.” Edoxaban was not reviewed in these guidelines. Prophylaxis of Venous Thromboembolism in Patients Undergoing Knee or Hip Replacement Surgery Evidence-based guidelines published by the American Academy of Orthopedic Surgeons (AAOS) in 2011103 and by ACCP in 201260,104 support VTE prophylaxis using pharmacologic treatments and/or mechanical compressive devices in patients undergoing THR and TKR. In developing its guidelines, AAOS did not accept DVT as a surrogate for PE, thus limiting the evidence for specific prophylactic treatments. As summarized by Eikelboom et al: “Both guideline panels accepted prevention of fatal PE as the most important goal of thromboprophylaxis. However, the ACCP included asymptomatic (and symptomatic) DVT detected by venography as a measure of the efficacy of thromboprophylaxis, whereas the AAOS rejected DVT (both asymptomatic and symptomatic) as a valid outcome because the panelists considered the link between DVT and PE in patients undergoing hip or knee surgery to be unproven. Thus the AAOS only accepted symptomatic PE and fatal PE as valid outcomes and limited their analysis to studies reporting this outcome.”10 Current AAOS guidelines103 suggest the use of pharmacologic agents and/or mechanical compressive devices for VTE prophylaxis in patients undergoing elective THR or TKR whose risk of VTE or bleeding is not elevated above that of the surgery itself (grade of recommendation: moderate). ï‚· However, due to inconclusive evidence, no specific recommendations for the choice or duration of prophylactic regimen are made. Section: Prescription Drug Subsection: Original Policy Date: December 2012 Page: 42 © 2015 Blue Cross Blue Shield Association. Reproduction without prior authorization is prohibited. MPRM 5.01.21 Newer Oral Anticoagulants ARCHIVED ï‚· Consensus recommendations (based on expert opinion) include the use of pharmacologic prophylaxis and mechanical compressive devices in patients who have had a prior VTE, and use of mechanical compressive devices in patients with a known bleeding disorder (eg, hemophilia) and/or active liver disease. Current ACCP guidelines include strong recommendations based on moderate quality evidence (grade 1B) for a minimum of 10 to 14 days prophylaxis with LMWH, fondaparinux, apixaban, dabigatran, rivaroxaban, low-dose unfractionated heparin, adjusted-dose VKA, or aspirin in patients with no increased bleeding risk. For patients who decline or are uncooperative with injections or an intermittent pneumatic compression device, apixaban or dabigatran (alternatively rivaroxaban or adjusted-dose VKA if apixaban or dabigatran are unavailable) rather than alternative forms of prophylaxis is recommended. Treatment of Acute DVT and/or PE ACCP guidelines published in 2012 strongly recommend initial parenteral anticoagulant therapy (with LMWH or fondaparinux) in combination with VKA therapy for the treatment of acute DVT or PE. Parenteral anticoagulation should be continued for a minimum of 5 days and until the INR is 2.0 or more for at least 24 hours (grade 1B recommendations based on moderate quality evidence).

Generally, anticoagulation for 3 months is recommended over shorter and longer (eg, 6 or 12 months) periods (grade 1B). Exceptions include first unprovoked VTE (proximal DVT or PE) or second unprovoked VTE in patients with a low or moderate bleeding risk, and any VTE in patients with active cancer. In these instances, extended duration anticoagulation therapy (ie, not time-limited) is recommended. In patients with cancer, LMWH is recommended for long-term therapy, and in patients without cancer, VKA therapy (target INR, 2.5; range 2.0-3.0) is recommended. Both treatments are recommended over dabigatran or rivaroxaban for long-term therapy. (Weak recommendation based on low quality evidence [ie, indirect comparisons].)16 In 2014, ESC updated its evidence-based guidelines for the diagnosis and management of acute PE.105 The guidelines state: “[R]esults of the trials using NOACs [new oral anticoagulants] in the treatment of VTE indicate that these agents are noninferior (in terms of efficacy) and possibly safer (particularly in terms of major bleeding) than the standard heparin/VKA regimen…. At present, NOACs can be viewed as an alternative to standard treatment….

Experience with NOACs is still limited but continues to accumulate.” In 2015, the American Society of Clinical Oncology updated its evidence-based clinical practice guideline for venous thromboembolism prophylaxis and treatment in patients with cancer.106 The guideline states, “Use of novel oral anticoagulants is not currently recommended for patients with malignancy and VTE because of limited data in patients with cancer.” Catheter Ablation of AF 2014 AHA/ASA/HRS evidence-based guidelines do not include specific recommendations for periprocedural anticoagulation for catheter ablation of AF. Cardioversion of AF 2014 AHA/ASA/HRS evidence-based guidelines include class I recommendations for: 1. Anticoagulation with warfarin in patients with AF or atrial flutter of at least 48 hours or unknown duration regardless of CHA2DS2-VASc score and method of cardioversion (electrical or pharmacological) used (level B evidence [a single RCT or nonrandomized studies]) 2. Anticoagulation with intravenous heparin or LMWH, or administration of a factor Xa or direct thrombin inhibitor, as soon as possible before or immediately after cardioversion in patients with AF or atrial flutter of less than 48 hours duration and with high risk of stroke (level C evidence [expert consensus, case studies]) U.S. Preventive Services Task Force Recommendations Not applicable.

Medicare National Coverage

Medicare National Coverage There is no national coverage determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of local Medicare carriers

References

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2. Wyndham CR. Atrial fibrillation: the most common arrhythmia. Tex Heart Inst J. 2000;27(3):257-267. PMID 11093410 3. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke. Aug 1991;22(8):983-988. PMID 1866765

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6. Camm AJ, Lip GY, De Caterina R, et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur Heart J. Nov 2012;33(21):2719-2747. PMID 22922413

7. Dresing T, Schweikert R. Atrial Fibrillation In: Abelson A, Gordon S, Hobbs R, et al., eds. Cleveland Clinic: Current Clinical Medicine. 2nd ed. Philadelphia: Saunders Elsevier; 2009. 8. Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. Jun 2008;133(6 Suppl):381S-453S. PMID 18574271

9. Harkess J, Crockarell J. Arthroplasty of the hip. In: Canale S, Beaty J, eds. Campbell's Operative Orthopaedics, 11th edition. Philadelphia: Mosby Elsevier; 2008. 10. Eikelboom JW, Karthikeyan G, Fagel N, et al. American association of orthopedic surgeons and american college of chest physicians guidelines for venous thromboembolism prevention in hip and knee arthroplasty differ. Chest. 2009;135(2):513-520. 11. Crockarell J, Guyton J. Arthroplasty of the knee. In: Canale S, Beaty J, eds. Campbell's Operative Orthopaedics, 11th edition. Philadelphia: Mosby Elsevier; 2008.

12. Lim W, Crowther M, Ginsberg J. Venous thromboembolism. In: Hoffman R, EJ Benz J, Shattil S, et al., eds. Hematology: Basic Principles and Practice, 5th edition. Philadelphia: Churchill Livingstone Elsevier; 2009.

13. Lyman GH, Khorana AA, Falanga A, et al. American Society of Clinical Oncology guideline: recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer. J Clin Oncol. Dec 1 2007;25(34):5490-5505. PMID 17968019

14. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Cancer-associated venous thromboembolic disease, version 2.2014. http://www.nccn.org/professionals/physician_gls/pdf/vte.pdf. Accessed April 21, 2015.

15. Khorana AA. Risk assessment and prophylaxis for VTE in cancer patients. J Natl Compr Canc Netw. Jul 1 2011;9(7):789-797. PMID 21715725 16. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. Feb 2012;141(2 Suppl):e419S-494S. PMID 22315268 17. Torbicki A, Perrier A, Konstantinides S, et al. Guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J. 2008;29(18):2276-2315. PMID 18. Brady W, Harrigan R, Chan T. Acute coronary syndrome. In: Mars J, Hockberger R, Walls R, eds. Rosen's Emergency Medicine, 7th edition: Mosby Elsevier; 2009.

19. FDA. Draft Questions for the January 16, 2014 Meeting of the Cardiovascular and Renal Drugs Advisory Committee. http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvi soryCommittee/ucm378911.htm. Accessed April 21, 2015. 20. Mega JL, Braunwald E, Wiviott SD, et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med. Jan 5 2012;366(1):9-19. PMID 22077192 21. FDA. Minutes for the May 23, 2012 meeting of the Cardiovascular and Renal Drugs Advisory Committee. tp://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvi soryCommittee/ucm285415.htm. Accessed April 21, 2015. Section: Prescription Drug Subsection: Original Policy Date: December 2012 Page: 44 © 2015 Blue Cross Blue Shield Association. Reproduction without prior authorization is prohibited. MPRM 5.01.21 Newer Oral Anticoagulants ARCHIVED

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