Utah Medicaid Pharmacy and Therapeutics Committee Drug

Utah Medicaid Pharmacy and Therapeutics Committee

Drug Class Review

Non-Vitamin K Anticoagulants for Venous Thromboembolism and Nonvalvular Atrial Fibrillation

Direct Thrombin Inhibitors Dabigatran (Pradaxa, generic) Desirudin (Iprivask)

Direct Factor Xa Inhibitors Apixaban (Eliquis) Betrixaban (Bevyxxa) Edoxaban (Savaysa) Fondaparinux (Arixtra) Rivaroxaban (Xarelto)

Low Molecular Weight Heparins Dalteparin (Fragmin, generic) Enoxaparin (Lovenox, generic)

AHFS Classification: 20:12.04.12 Direct Thrombin Inhibitors, 20:12.04.14 Direct Factor Xa Inhibitors, 20:12.04.16 Heparins

Final Report October 2018

Review prepared by: Elena Martinez Alonso, B.Pharm., MSc MTSI, Medical Writer Valerie Gonzales, Pharm.D., Clinical Pharmacist Vicki Frydrych, B.Pharm., Pharm.D., Clinical Pharmacist Lauren Heath, Pharm.D., MS, BCACP, Assistant Professor (Clinical) Michelle Fiander, MA, MLIS, Research Assistant Professor, Evidence Synthesis Librarian Joanne LaFleur, PharmD, MSPH, Associate Professor University of Utah College of Pharmacy

University of Utah College of Pharmacy, Drug Regimen Review Center Copyright © 2018 by University of Utah College of Pharmacy Salt Lake City, Utah. All rights reserved Contents Executive Summary ...... 3 Introduction ...... 7 Table 1. FDA-Approved Indications for Non-Vitamin K Anticoagulants ...... 8 Table 2. Dosage Recommendations for Non-Vitamin K Anticoagulants ...... 9 Methods...... 12 Disease Overview ...... 14 Guidelines Recommendations and Treatment Strategies ...... 15 Table 3. Clinical Guidelines for Non-vitamin K Anticoagulants ...... 16 Pharmacology ...... 19 Table 4: Pharmokinetics of Non-vitamin K Anticoagulants...... 19 Drug-drug Interactions ...... 20 Special Populations ...... 21 Table 5: Special Population Information for Non-vitamin K Anticoagulants ...... 22 Head-to Head Efficacy and Safety Comparisons ...... 25 Figure 1. PRISMA Flow Chart for Publication Screening ...... 25 Figure 2. Direct Comparative Efficacy Evidence of Direct Anticoagulants versus LMWHs for VTE Treatment and Prevention...... 26 Summary of Guideline Recommendations and Findings Reported in SR/MAs and RCTs ..... 27 Table 6. Summary of Evidence Findings and Treatment Options for NVAF and VTE patients ...... 27 Findings Reported in SR/MAs and RCTs for Venous Thromboembolism ...... 28 Findings Reported in SR/MAs and RCTs for Non-valvular Atrial Fibrillation ...... 33 Safety ...... 34 Table 7. Labeled Black Box Warnings and Most Common Adverse Events with Non- vitamin K Anticoagulants ...... 35 Summary ...... 36 References ...... 38 Appendix A: Literature Search Strategies ...... 43 Appendix B: List of Excluded Studies...... 47 Appendix C: Direct Evidence from Systematic Reviews ...... 49 Appendix D: Randomized Controlled Trials Identified in the Included Systematic Reviews ..... 60 Appendix E: Characteristics of the Main Randomized Controlled Trials Identified in the Included Systematic Reviews ...... 63

Executive Summary

Introduction: Anticoagulation is indicated for the treatment of acute venous thromboembolism (VTE), reduction in the risk of recurrent VTE, VTE prophylaxis following major surgery (eg, total hip and knee replacement), and VTE prophylaxis in patients hospitalized for an acute medical illness. Anticoagulation is also indicated for stroke and systemic embolism prevention in patients with non-valvular atrial fibrillation (NVAF). The main objective of anticoagulation is to prevent thromboembolism and further complications. Many anticoagulant therapies are currently available in the United States. This report evaluates head-to-head efficacy and safety comparisons among the following non-vitamin K anticoagulants: 2 direct thrombin inhibitors (dabigatran and desirudin), 5 direct factor Xa inhibitors (apixaban, betrixaban, edoxaban, fondaparinux, and rivaroxaban), and 2 low molecular weight heparins (LMWHs, dalteparin and enoxaparin). Each of the agents are indicated for VTE treatment or prophylaxis in various patient subgroups at once or twice daily dosing depending on the agent and indication. Apixaban, dabigatran, edoxaban, and rivaroxaban are additionally indicated for the prevention of stroke and systemic embolism in patients with NVAF. Dabigatran and the factor Xa inhibitors apixaban, betrixaban, edoxaban, and rivaroxaban are available as oral formulations. Desirudin, fondaparinux, and the 2 LMWHs are available as parenteral subcutaneous formulations. Although dabigatran and factor Xa inhibitors offer advantages over the traditional anticoagulant warfarin (ie, no need for routine laboratory monitoring, fixed oral dosing, rapid onset of action, and fewer drug interactions), individualization of therapy is important. Drug-drug interactions and renal function may limit the use of some agents. The 2014 American Heart Association/American College of Cardiology/Heart Rhythm Society (AHA/ACC/HRS) guideline for the management of atrial fibrillation recommends oral anticoagulants for patients with NVAF who have history of stroke, transient ischemic attack, or CHA2DS2- . Warfarin, dabigatran, rivaroxaban, or apixaban are recommended as first-line anticoagulant therapy options. VASc score ≥ 2 For acute treatment of VTE, the 2016 American College of Chest Physicians (CHEST) guideline recommends dabigatran or the oral factor Xa inhibitors, apixaban rivaroxaban, or edoxaban in preference to vitamin K antagonist (VKA) therapy (ie, warfarin) for at least three months following deep vein thrombosis (DVT) of the leg or pulmonary embolism (PE) in patients without cancer. In cancer patients with DVT of the leg or PE (“cancer- associated thrombosis”), LMWHs for at least 3 months are preferred over VKA therapy, dabigatran, rivaroxaban, apixaban, or edoxaban. Some patients may continue extended treatment beyond 3 months either with the initial therapy or alternative therapy according to the patient’s response or preferences. For VTE prophylaxis following THR or TKR surgery, the 2012 CHEST guideline recommends LMWH therapy for at least 10 to 14 days over other agents (ie, fondaparinux,

dabigatran, apixaban, rivaroxaban, VKA, unfractionated heparin, aspirin, and intermittent pneumatic compression device). In patients declining injectable formulations, apixaban or dabigatran are recommended. Extended-thromboprophylaxis is recommended for up to 35 days. For VTE prophylaxis in acutely ill hospitalized medical patients at high risk of thrombosis, the 2012 CHEST guideline recommends LMWH, unfractionated heparin, or fondaparinux during the hospital stay or period of immobilization.

Efficacy: After performing a systematic literature search for systematic review/meta- analysis (SR/MA) and randomized controlled trial (RCT) evidence containing head-to-head efficacy and safety comparisons among non-vitamin K anticoagulants, 16 publications were identified. Twelve additional publications were found by checking the reference lists of related articles. Non-valvular atrial fibrillation For the prevention of stroke or systemic embolism in patients with NVAF, no head-to-head RCTs comparing direct thrombin inhibitors with factor Xa inhibitors or comparing factor Xa inhibitors with one another were identified. Venous Thromboembolism For the treatment or prevention of VTE, no head-to-head RCTs comparing direct thrombin inhibitors with factor Xa inhibitors or comparing factor Xa inhibitors with one another were found. The majority of identified SR/MAs assessed the comparative efficacy and safety of dabigatran or factor Xa inhibitors (mainly apixaban or rivaroxaban) versus enoxaparin for the prevention of VTE after orthopedic surgery. This information is summarized below.

1. Prevention of VTE following total hip replacement (THR) or total knee replacement (TKR)

• Factor Xa inhibitors versus LMWHs for VTE prevention after THR or TKR - Apixaban versus enoxaparin: SR/MAs reported similar or significantly higher efficacy with apixaban versus enoxaparin for VTE prophylaxis following THR or TKR. Results for most bleeding endpoints (eg, major bleeding or clinically relevant non- major bleeding) indicated a significantly lower bleeding risk with apixaban compared to enoxaparin.

- Rivaroxaban versus enoxaparin: SR/MAs showed rivaroxaban is significantly better than enoxaparin for VTE prophylaxis following THR or TKR. Conversely, bleeding rates with rivaroxaban were either similar or significantly higher compared to enoxaparin.

- Edoxaban versus LMWHs: SR/MA evidence reported similar or significantly higher efficacy for edoxaban versus enoxaparin in the prevention of VTE following THR or TKR. In this setting, bleeding rates were similar between groups. Evidence comparing edoxaban to dalteparin found edoxaban superior in terms of VTE prophylaxis without a significant increase in bleeding.

- Fondaparinux versus enoxaparin: SR/MAs reported better efficacy for VTE prophylaxis with fondaparinux compared to enoxaparin. Fondaparinux was associated with similar or higher incidence of major bleeding.

• Direct Thrombin Inhibitors versus enoxaparin for VTE prevention after THR or TKR - Dabigatran versus enoxaparin: SR/MAs reported similar efficacy and safety between dabigatran and enoxaparin in terms of reduction in VTE events and bleeding rates.

- Desirudin versus enoxaparin: an RCT showed a significantly lower incidence of major VTE events (ie, proximal DVT, PE, or death) and similar safety profile compared to enoxaparin.

2. Prevention of VTE recurrence in patients with cancer RCT evidence comparing direct thrombin inhibitors or factor Xa inhibitors with LMWHs in cancer patients is very limited. Available data in small subgroups of cancer patients showed similar efficacy in terms of recurrent VTE events with apixaban, rivaroxaban, or fondaparinux compared to enoxaparin and with edoxaban compared to dalteparin. Bleeding rates were similar between groups or significantly higher with the factor Xa inhibitors.

3. Prevention of VTE in patients hospitalized for an acute medical illness An RCT assessing betrixaban versus enoxaparin showed no significant efficacy or safety differences between groups in terms of VTE prevention and bleeding in acutely ill, hospitalized medical patients.

4. Acute treatment of VTE Data from individual RCTs demonstrated non-inferiority of apixaban, rivaroxaban, or fondaparinux versus enoxaparin for the prevention of recurrent VTE. Bleeding rates were similar between both fondaparinux and rivaroxaban compared to enoxaparin and significantly lower with apixaban versus enoxaparin.

Adverse Drug Reactions: The most significant adverse event associated with the use of non-vitamin K anticoagulants is bleeding. In emergency situations, there are specific reversal agents for apixaban, rivaroxaban, dabigatran, and LMWHs. Labelling for each non- vitamin K anticoagulant product carries a black box warning for concomitant use with neuraxial anesthesia or spinal puncture procedures due to an increased risk for developing epidural or spinal hematomas that may cause long-lasting or permanent paralysis.

Apixaban, edoxaban, rivaroxaban, and dabigatran carry a black box warning for a potential increase in the risk of thromboembolic events upon premature discontinuation of these agents. Additionally, edoxaban has a black box warning regarding decreased efficacy in NVAF patients with creatinine clearance (CrCl) higher than 95 mL/min.

Summary: Direct comparisons have not been conducted among dabigatran, desirudin, apixaban, betrixaban, edoxaban, fondaparinux, and rivaroxaban in the setting of stroke prevention in patients with NVAF or for VTE. Therefore, there is insufficient evidence available to establish efficacy and safety differences among these agents for major clinical endpoints (eg, occurrence of stroke or systemic embolic event in NVAF patients and VTE events, all-cause mortality, recurrent VTE, major bleeding, and clinically relevant non- major bleeding in the setting of VTE disease). The majority of identified SR/MAs assessed the comparative efficacy and safety of direct thrombin inhibitors or factor Xa inhibitors versus enoxaparin for the prevention of VTE after THR or TKR surgery. In general, most identified SR/MAs suggested apixaban, edoxaban, fondaparinux, and rivaroxaban have superior efficacy for the prophylaxis of VTE after orthopedic surgery compared to enoxaparin, whereas bleeding rates are similar or increased with edoxaban, fondaparinux, or rivaroxaban, and significantly lower with apixaban, compared to enoxaparin. The direct-thrombin inhibitor, dabigatran, showed similar efficacy and safety compared to enoxaparin for VTE prevention after THR or TKR surgery. For the treatment of VTE, apixaban, rivaroxaban, and fondaparinux were non-inferior to enoxaparin/warfarin in terms of recurrent VTE. Bleeding rates were similar between both fondaparinux and rivaroxaban compared to enoxaparin and significantly lower with apixaban versus enoxaparin. Limited evidence with direct thrombin inhibitors or factor Xa inhibitors versus enoxaparin is available for the prevention of VTE recurrence in patients with cancer. Selection of anticoagulant therapy should be individualized based on the benefit of anticoagulation (ie, preventing a stroke or treating/preventing VTE events) versus the bleeding risk, patient preferences, adherence, and patient specific characteristics (eg, age, weight, comorbidities such as renal impairment, and drug-drug interactions). For the purpose of the Preferred Drug List (PDL), the following agents may be considered for inclusion in the PDL as preferred drugs: - Among the direct factor Xa inhibitors, we suggest including at least 2 oral factor Xa inhibitors - Among the direct thrombin inhibitors, we suggest including dabigatran - Among the LMWHs, we suggest including at least 1 LMWH

Introduction

Several anticoagulants are currently available in the United States (US): vitamin K antagonists (warfarin), direct thrombin inhibitors (dabigatran1 and desirudin2), factor Xa inhibitors (apixaban,3 betrixaban,4 edoxaban,5 rivaroxaban,6 and fondaparinux7), and low molecular weight heparins (LMWHs, dalteparin8 and enoxaparin9). Traditional therapies for the prevention and treatment of venous thromboembolism (VTE) include unfractionated heparin, LMWHs, fondaparinux, and vitamin K antagonists (VKAs).10 In addition, VKAs have been the cornerstone of therapy to prevent stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF) for decades.11 Until recently, VKAs (eg, warfarin) were the only oral anticoagulant agents available for clinical use.12 The need for routine laboratory monitoring of anticoagulation intensity, high risk of bleeding, and food and drug interactions are significant limitations of VKA therapy.11,13 LMWHs and fondaparinux are parenteral agents requiring daily subcutaneous injections. This may be inconvenient for certain patients resulting in reduced anticoagulant therapy adherence.14 Therefore, new oral anticoagulants have been developed and approved by the Food and Drug Administration (FDA), including 5 direct oral anticoagulants (apixaban, betrixaban, dabigatran, edoxaban, and rivaroxaban). These products offer several advantages (eg, no need for frequent laboratory monitoring, fixed oral dosing, rapid onset of action, and lower potential for drug-drug interactions) over traditional therapies.11,14 Although the newer agents offer advantages, individualization of therapy is important. Drug-drug interactions and renal function may limit the use of some agents.11,14 This report will evaluate systematic review (SR) and randomized controlled trial (RCT) evidence containing head-to-head efficacy and safety comparisons among the non-vitamin K anticoagulants listed in Table 1 for the indications of treatment and prevention of VTE and the prevention of stroke and systemic embolism in patients with NVAF. Three anticoagulant drug classes will be covered in this report, including factor Xa (FXa) inhibitors (apixaban,3 betrixaban,4 edoxaban,15 fondaparinux,7 and rivaroxaban6), direct thrombin inhibitors (dabigatran1 and desirudin2), and low molecular weight heparins (dalteparin8 and enoxaparin9). Information related to the traditional anticoagulant warfarin is not included in this report. FXa inhibitors and direct thrombin inhibitors are approved for both VTE and NVAF. LMWHs are only approved for VTE. The agents reviewed are available as oral formulations, except fondaparinux, desirudin, and the 2 LMWHs, which are available as injectable formulations. The dosing recommendations vary with respect to dosage and frequency according to the indication for use. All agents are administered either once or twice daily. Dosage adjustments may be required based on renal clearance, weight, or age. Table 1 provides specific information concerning the FDA-approved non-vitamin K anticoagulants and their labeled indications. Table 2 includes dosage recommendations for each product by indication.

Table 1. FDA-Approved Indications for Non-Vitamin K Anticoagulants Stroke and VTE or DVT prophylaxis Reduction in Extended Prophylaxis of systemic after the risk of DVT & PE Acute treatment of ischemic Acute Generic name embolism hip/knee/abdominal recurrent DVT Treatment VTE in cancer complications in STEMI prevention in surgery or in medical & PE patients UA/NSTEMI NVAF illnessa Factor Xa Inhibitors X Apixaban3 X X X (DVT: hip/knee) X Betrixaban4 (VTE: medical illnessa) Edoxaban15 X X X (OL use) X Fondaparinux7 X (DVT: hip/knee/ abdominal) X (VTE: hip/knee) Rivaroxaban6 X X X OL use (VTE: medical illnessa) Direct Thrombin Inhibitors X Dabigatran1 X X X (VTE: hip/knee - OL use) X Desirudin2 (VTE: hip) Low Molecular Weight Heparins X Dalteparin8 X (OL use) (DVT: hip/abdominal/ X X medical illnessa) X (DVT: Enoxaparin9 X X (OL use) X X hip/knee/abdominal/ medical illnessa) Abbreviations: DVT, deep vein thrombosis; NSTEMI; non ST-segment elevation myocardial infarction or non–Q-wave myocardial infarction; NVAF, non-valvular atrial fibrillation; OL, off-label; PE, pulmonary embolism; STEMI, ST-segment elevation myocardial infarction; VTE, venous thromboembolism (includes DVT and PE); UA, unstable angina a Patients with medical illness (eg, patients with heart failure, respiratory failure, infectious disease, rheumatic disease, or ischemic stroke)16 who are hospitalized and at risk for thromboembolic complications due to moderate or severe restricted mobility and other risk factors

Table 2. Dosage Recommendations for Non-Vitamin K Anticoagulants Generic Name Brand Name Preparations Recommended Dosage by Indication (Approval date) Factor Xa Inhibitors - Reduction of risk of stroke and systemic embolism in NVAF o 5 mg BID o 2.5 mg BID in patients with at least 2 of these characteristics (age ≥ 80 years, body weight ≤ 60 kg, serum creatinine ≥ 1.5 mg/dL) - Treatment of DVT and PE: Apixaban3 Oral tablet 10 mg BID for the first 7 days of therapy, then 5 mg BID Eliquis • o 2.5 mg - Reduction in the risk of recurrent DVT and/or PE following initial therapy: (2012) • 5 mg o 2.5 mg BID after at least 6 months of treatment for DVT or PE - Prophylaxis of DVT following hip or knee replacement surgery o 2.5 mg BID; initial dose 12-24 hours after surgery o Duration of treatment: 35 days for hip replacement surgery, 12 days for knee replacement surgery - Prophylaxis of VTE in adult patients hospitalized for an acute medical illness who are at risk for thromboembolic complications due to moderate or severe restricted mobility and other risk 4 Oral capsule Betrixaban factors. Bevyxxa • 40 mg o Initial single dose: 160 mg, followed by 80 mg QD (2017) • 80 mg o Recommended duration of treatment: 35-42 days * Dose adjustment required in renal insufficiency - Reduction in the risk of stroke and systemic embolism in NVAF Oral tablet 60 mg QD (if CrCl >50 mL/min to ≤95 mL/min). Do not use if CrCl > 95 mL/min 15 o Edoxaban • 15 mg - Treatment of DVT and PE Savaysa • 30 mg 60 mg QD following 5-10 days of initial therapy with a parenteral anticoagulant (2015) o • 60 mg o 30 mg QD if CrCl 15-50 mL/min or weight ≤ 60 kg * Dose adjustment required in renal insufficiency. Avoid use if CrCl <15 mL/min or CrCl > 95 mL/min Fondaparinux7 Injection (SC): Single-dose prefilled - Prophylaxis of DVT (hip repair or replacement, knee replacement, or abdominal surgery): syringes Arixtra o 2.5 mg QD after hemostasis is established, first dose no earlier than 6-8 hours after (2001) • 2.5 mg surgery • 5 mg o Usual duration 5-9 days; extended prophylaxis course of up to 24 additional days is Generic • 7.5 mg recommended (hip surgery). available • 10 mg - Treatment of acute DVT or PE (in conjunction with warfarin):

o Weight < 50 kg: 5 mg; weight 50-100 kg: 7.5 mg; weight > 100 kg: 10 mg 9

Table 2. Dosage Recommendations for Non-Vitamin K Anticoagulants Generic Name Brand Name Preparations Recommended Dosage by Indication (Approval date) o Usual duration 5-9 days; up to 26 days treatment was used in clinical trials - Reduction of risk of stroke and systemic embolism in NVAF o CrCl > 50 mL/min: 20 mg QD with the evening meal o CrCl 15-50 mL/min: 15 mg QD with the evening meal Oral tablets - Treatment of DVT and/or PE 6 Rivaroxaban • 10 mg 15 mg BID with food for the first 21 days; then 20 mg QD with food Xarelto o • 15 mg - Reduction in the risk of recurrence of DVT and/or PE in patients at continued risk (2011) • 20 mg o 10 mg QD, after at least 6 months of standard anticoagulant treatment - Prophylaxis of DVT that may lead to PE following hip or knee replacement surgery o 10 mg QD; duration: 35 days (hip replacement), 12 days (knee replacement) * CrCl < 30 mL/min (VTE indication): not recommended Direct Thrombin Inhibitors - Reduction of risk of stroke and systemic embolism in NVAF: o CrCl > 30 mL/min: 150 mg BID Dabigatran1 o CrCl 15-30 mL/min: 75 mg BID Pradaxa Oral capsule - Treatment of DVT and PE: (2010) • 75 mg o CrCl > 30 mL/min: 150 mg BID after 5-10 days of parenteral anticoagulation • 110 mg - Reduction of risk of recurrence of DVT and PE in patients who have been previously treated: Generic • 150 mg o CrCl > 30 mL/min: 150 mg BID after previous treatment available - Prophylaxis of DVT and PE in patients who have undergone hip replacement surgery: o CrCl > 30 mL/min: 110 mg (first day), then 220 mg QD (28-35 days) * CrCl < 15 mL/min (NVAF indication), CrCl ≤ 30 mL/min (VTE indication): dosing not provided - Prophylaxis of DVT, which may lead to PE, in patients undergoing elective hip replacement Desirudin2 Injection (SC), single use vials surgery: Iprivask (15.75 mg) 15 mg SC every 12 hours, administered 5-15 min prior to surgery (2003) o * Dose adjustment required in renal insufficiency Low Molecular Weight Heparins Single-dose prefilled syringes (SC) - DVT prophylaxis in abdominal surgery, hip replacement surgery, and medical patients Dalteparin8 • 2500 IU/0.2 mL 2500 IU SC QD to 5000 IU SC QD Fragmin o • 5000 IU/0.2 mL - Extended treatment of VTE in patients with cancer to reduce the recurrence of VTE (1994) • 7500 IU/0.3 mL o Month 1: 200 IU/kg SC QD 10

Table 2. Dosage Recommendations for Non-Vitamin K Anticoagulants Generic Name Brand Name Preparations Recommended Dosage by Indication (Approval date) • 12500 IU/0.5 mL o Months 2-6: 150 IU/kg SC QD • 15000 IU/0.6 mL NOTE: Dalteparin is not indicated for the acute treatment of VTE • 18000 IU/0.72 mL - Prophylaxis of ischemic complications of UA/NSTEMI Single-dose graduated syringes (SC) o 120 IU/kg SC every 12 hours (with aspirin) • 10000 IU/1 mL Multiple dose vials: • 95000 IU/3.8 mL SC or IV injection (100 mg/mL) - Prophylaxis of DVT in abdominal surgery, hip replacement surgery, knee replacement surgery, Prefilled syringes: or medical patients with severely restricted mobility during acute illness • 30 mg/0.3 mL 30 mg SC BID or 40 mg SC QD Enoxaparin9 • 40 mg/0.4 mL o - Inpatient treatment of acute DVT with or without PE: 1 mg/kg SC every 12 hours of 1.5 mg/kg Graduated prefilled syringes: SC QD Lovenox • 60 mg/0.6 mL - Outpatient treatment of acute DVT without PE: 1 mg/kg SC every 12 hours (1993) • 80 mg/0.8 mL - Prophylaxis of ischemic complications of UA/NSTEMI: 1 mg/kg SC every 12 hours (with aspirin) • 100 mg/1 mL - Treatment of acute STEMI managed medically or with subsequent PCI: Generic Multiple-dose vials: STEMI in patients < 75 years of age: 30 mg single IV bolus plus a 1 mg/kg SC dose available • o 300 mg/3 ML followed by 1 mg/kg SC every 12 hours (with aspirin) SC or IV injection (150 mg/mL) o STEMI in patients ≥ 75 years of age: 0.75 mg/kg SC every 12 hours (NO bolus) (with Graduated prefilled syringes: aspirin) • 120 mg/0.8 mL * Dosage adjustment required in renal insufficiency • 150 mg/1 mL Abbreviations: BID, twice daily; CrCl, creatinine clearance; DVT, deep vein thrombosis; INR, international normalized ratio; IU, international units; IV, intravenous; MI, myocardial infarction; NSTEMI; non ST-segment elevation myocardial infarction or non–Q-wave MI; NVAF; non-valvular atrial fibrillation; PCI, percutaneous coronary intervention; PE, pulmonary embolism; QD, once daily; SC, subcutaneous; STEMI, ST-segment elevation myocardial infarction; UA, unstable angina; VTE, venous thromboembolism a Patients with medical illness (eg, patients with heart failure, respiratory failure, infectious disease, rheumatic disease, or ischemic stroke)16 who are hospitalized and at risk for thromboembolic complications due to moderate or severe restricted mobility and other risk factors

Methods

Systematic Literature Search Search strategies were developed by an informational scientist for OVID Medline and Embase. Strategies consisted of controlled vocabulary, such as Medical Subject Headings (MeSH), and keyword phrases. Two methodological filters were used, one for systematic reviews/meta-analyses (SR/MAs) and another for randomized controlled trials (RCT).17 Results were limited to English language. In Embase, we excluded conference abstracts. Databases were searched from 2017 to June 2018 for SR/MAs and from 2016 to June 2018 for RCTs. The complete search strategies and terms are available in Appendix A. Authors also conducted grey literature searching to identify SRs, such as publications by the Oregon Drug Effectiveness Review Project (DERP) group and the Agency for Healthcare Research and Quality (AHRQ). We also screened the reference lists of related SRs and other relevant websites for further information:

1. For guidelines addressing atrial fibrillation and VTE disease: websites of the American Heart Association/American College of Cardiology/Heart Rhythm Society (AHA/ACC/HRS) guideline, the European Society of Cardiology (ESC), and the American College of Chest Physicians (CHEST) 2. For FDA-approved prescribing information (package inserts): the FDA website (Drugs@FDA: FDA Approved Drug Products: https://www.accessdata.fda.gov/scripts/cder/daf/) and the DailyMed website (an official provider of US FDA drug-label information). 3. Evidence-based drug information databases: Micromedex and Lexicomp Screening Two review authors screened titles and abstracts. Conflicts were resolved via discussion between reviewers. The full texts for all citations receiving 2 inclusion votes were retrieved; screening and inclusion were determined by the lead author. Figure 1 on page 25 shows the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) flow chart18 for the review process.

Inclusion and Exclusion Criteria Systematic reviews/meta-analyses of RCTs and RCTs providing direct, head-to-head efficacy or safety comparisons among the non-vitamin K anticoagulant products listed in Table 1 were included. For product comparisons where a systematic review provided robust data, we examined only those trials or systematic reviews published after the search date of the robust systematic review.

Excluded references met the following exclusion criteria:

• SR/MAs reporting only class effects and not separate results for the treatment effect attributed to individual anticoagulants. Class effect results were only provided if the available information with individual agents was very limited.

• SR/MAs including observational studies, registries, and retrospective studies in the pooled analyses: only results from SR/MAs of RCTs were considered for the report

• Network meta-analyses: according to the hierarchy of evidence, the quality of network meta-analyses is downgraded because they include indirect comparisons

• Reviews not using systematic review methodology • Data comparing the anticoagulant agents included in this report versus warfarin, aspirin, or placebo

• Single studies such as observational studies, pharmacodynamic studies, studies evaluating non-FDA approved indications or doses, registries, and pilot studies.

A list containing the excluded references is provided in Appendix B.

Disease Overview Anticoagulant therapy is indicated in stroke and systemic embolism prevention in patients with nonvalvular atrial fibrillation (NVAF), and for the treatment and prevention of VTE. The incidence of NVAF and VTE is expected to rise with the aging of the population in the US.19,20 Positive outcomes depend on early diagnosis and appropriate management with medication, surgery, and healthy lifestyle.20,21 Atrial fibrillation Atrial fibrillation (AF) is the most common type of cardiac arrhythmia characterized by fast and irregular heartbeat.22,23 Patients with AF are at high risk of experiencing a stroke or a transient ischemic attack (TIA) due to a clot formation in the blood vessels of the brain.22,23 It is estimated that 2.7 to 6.1 million Americans have AF.20 The prevalence of AF is approximately 2% in people < 65 years and significantly increases as the person ages (9% in people 65 years).20 AF is associated with increases in health-care costs, hospitalizations, mortality, and reduced quality of life.20 Risk factors for AF may involve advanced age, obesity,≥ high blood pressure, diabetes, coronary heart disease, chronic kidney disease, and genetic variants.20,23,24 There are different types of AF, including paroxysmal AF, persistent AF, long-standing persistent AF, permanent AF, and nonvalvular AF.24 Nonvalvular AF (NVAF) is defined by the 2014 American Heart Association/American College of Cardiology/Heart Rhythm Society (AHA/ACC/HRS) guideline for the management of patients with AF as “atrial fibrillation in the absence of rheumatic mitral stenosis, a mechanical or bioprosthetic heart valve, or mitral valve repair”.24 Venous Thromboembolism Venous thromboembolism (VTE) is a major public health concern that is preventable and treatable if diagnosed early.21,25 VTE refers to a group of diseases characterized by abnormal coagulation. It comprises deep vein thrombosis (DVT) and its complication, pulmonary embolism (PE).21,25 DVT is caused by a blood clot development in a vein, especially in the deep veins of the legs, thigh, or pelvis.21,25 This blood clot can detach and travel to lung arteries causing PE.21 VTE is a common complication in hospitalized patients and post-surgery. It may increase medical costs, hospitalizations, duration of hospital stay, disability, and mortality.19,21,26 Estimated annual rates of VTE in the US range from 1 to 2 per 1000 individuals (ie, 900,000 Americans).27 VTE recurrences are frequent, with 33% of patients having recurrent VTE within 10 years.19,27 It is suggested that 60,000 to 100,000 deaths in the US are related to VTE; 10%-30% of Americans will die within 1 month of the event and 25% of Americans with PE will experience sudden death.27 Long-term complications such as inflammation, pain, discoloration, and ulcers in the affected limb may occur in half of patients who experience a DVT epidose.21,27

Risk factor for VTE may involve hospitalization and major surgery of the abdomen, pelvis, hips, or legs (which are attributed to 50% of VTE cases), lack of mobility, advanced age, obesity, family history of VTE, cancer, trauma, fracture, pregnancy, and hormone therapy in women.19,21,25 The risk of VTE in patients with cancer is 6 to 7 times higher than that in patient without cancer.10 Guidelines Recommendations and Treatment Strategies Anticoagulant agents such as direct thrombin inhibitors and factor Xa inhibitors are effective in reducing the risk of blood clot formation in AF patients. Direct thrombin inhibitors, factor Xa inhibitors and LMWH have demonstrated efficacy for VTE treatment and/or prophylaxis. Atrial fibrillation The most recent guidelines for the management of patients with AF (i.e., the 2014 AHA/ACC/HRS24 and the 2016 European Society of Cardiology [ESC]28 guidelines) recommend using CHA2DS2-VASc scoring system to determine the patient’s risk of stroke and their need for anticoagulation.24,28 Risk factors considered in the CHA2DS2-VASc scoring system include congestive heart failure, hypertension, age , diabetes mellitus, prior stoke or TIA, vascular disease, and sex.24,28 (65 to ≥75 years) The 2014 AHA/ACC/HRS and the 2016 ESC guidelines recommend oral anticoagulation therapy in patients with NVAF and with history of stroke, transient ischemic attack, or CHA2DS2-VASc score . The 2014 AHA/ACC/HRS guideline recommends warfarin (level of evidence [LOE]: A), dabigatran (LOE: B), rivaroxaban (LOE: B) or apixaban (LOE: B).24 The 2016 ESC guideline≥ 2 recommends a non-vitamin K oral anticoagulant (i.e., apixaban, dabigatran, edoxaban, or rivaroxaban) over a vitamin K antagonist.28 Venous Thromboembolism

a) Treatment of acute VTE An updated guideline for the treatment of VTE was last published in 2016 by the American College of Chest Physicians (CHEST).29 Regarding anticoagulation therapy, non- cancer patients with DVT of the leg or PE should be treated for at least 3 months with dabigatran or oral factor Xa inhibitors (ie, rivaroxaban, apixaban, or edoxaban) in preference to VKA therapy.29 In patients not treated with dabigatran or the oral factor Xa inhibitors, VKA therapy is preferred over LMWH.29 For cancer patients with DVT of the leg or PE, LMWH therapy for at least 3 months is preferred over VKA therapy, dabigatran, rivaroxaban, apixaban, or edoxaban.29 Some patients may continue extended treatment beyond 3 months either with the initial therapy or alternative therapy according to the patient’s response or preferences.29

b) Prevention of VTE following THR or TKR surgery For VTE prophylaxis following THR or TKR surgery, the 2012 CHEST guideline recommends LMWH therapy for at least 10 to 14 days over other agents (ie, fondaparinux, dabigatran, apixaban, rivaroxaban, VKA, unfractionated heparin, aspirin, and intermittent pneumatic compression device).30 In patients declining injectable formulations, apixaban or dabigatran are recommended. Extended-thromboprophylaxis is recommended for up to 35 days.30

c) Prevention of VTE in acutely ill hospitalized medical patients For VTE prophylaxis in acutely ill hospitalized medical patients at high risk of thrombosis, the 2012 CHEST guideline recommends LMWH, unfractionated heparin, or fondaparinux during the hospital stay or period of immobilization.31

Table 3 outlines the main guideline recommendations for AF and VTE with respect to anticoagulation therapy.

Table 3. Clinical Guidelines for Non-vitamin K Anticoagulants Guideline Recommendations Prevention of stroke in Non-valvular Atrial Fibrillation Patients 2014 AHA/ACC/HRS guideline - CHA2DS2-VASc score is recommended to evaluate stroke risk for the management of patients - If prior stroke, TIA, or CHA2DS2-VASc score ≥ 2  oral anticoagulants (OACs) with atrial fibrillation: a report are recommended: of the American College of o Warfarin (LOE: A – data from multiple RCTs or MAs), OR Cardiology/ American Heart o Dabigatran, rivaroxaban or apixaban (LOE: B – Data from single Association Task Force on RCTs or nonrandomized studies) practice guidelines and the - If NVAF and CHA2DS2-VASc score=0  No antithrombotic therapy Heart Rhythm Society (January, - If NVAF and CHA2DS2-VASc score=1  No antithrombotic therapy. OACs or 201424) aspirin may be considered 2016 ESC guidelines - If CHA2DS2-VASc score=0  No therapy for the management of atrial - If CHA2DS2-VASc score=1  consider oral anticoagulation therapy fibrillation (Kirchhof, 201628) - If CHA2DS2-VASc score ≥ 2  oral anticoagulation therapy recommended: a non-vitamin K oral anticoagulant (apixaban, dabigatran, edoxaban, and rivaroxaban) is preferred over VKA Atrial fibrillation: management. - If CHADS2 score ≥ 2  offer oral anticoagulation (options include: apixaban, NICE guideline, 2014 [CG180]32 rivaroxaban, dabigatran or vitamin K antagonist) - Technology appraisal guidance [TA355]5: “Edoxaban is recommended, within its marketing authorisation, as an option for preventing stroke and systemic embolism in adults with non‑valvular atrial fibrillation with one or more risk factors” Treatment/Prevention of DVT/PE Antithrombotic Therapy for VTE Acute VTE and no cancer: Disease. CHEST Guideline and - 1st option: Dabigatran, rivaroxaban, apixaban, or edoxaban are preferred over Expert Panel Report (2016) VKA therapy for the first 3 months (all Grade 2B – weak recommendation (Kearon, 201629) based on moderate quality evidence) - 2nd option: VKA therapy is preferred over LMWH for the first 3 months (Grade 2C - weak recommendation based on low quality evidence) - 3rd option: Switch to LMWH in patients with recurrent VTE on treatment with non-LMWH anticoagulant (1st or 2nd option) (Grade 2C). For recurrent VTE on LMWH, we suggest increasing the LMWH dose (Grade 2C) 16

Table 3. Clinical Guidelines for Non-vitamin K Anticoagulants Guideline Recommendations Acute VTE and cancer: - LMWH is preferred as long-term anticoagulant therapy over VKA (Grade 2B), dabigatran (Grade 2C), rivaroxaban (Grade 2C), apixaban (Grade 2C), or edoxaban (Grade 2C) Duration of therapy for proximal DVT or PE (ie, VTE): long-term (3 months) anticoagulant therapy is preferred over less than 3-month therapy, over treatment of a longer time-period (6, 12, or 24 months), or over extended therapy (no planned stop date) (all Grade 1B – Strong recommendation based on moderate quality evidence) Extended therapy (> 3 months and no planned stop date): - Extended treatment (longer than 3 months) is recommended in some patients - In patients receiving extended therapy, the choice of anticoagulant is not needed to be changed after the first 3 months (Grade 2C) Venous Thromboembolism VTE prophylaxis Prophylaxis and Treatment in - “Routine thromboprophylaxis is not recommended for patients with cancer in Patients With Cancer: American the outpatient setting” Society of Clinical - Patients with myeloma receiving chemotherapy and/or dexamethasone: Oncology Clinical Practice LMWH or low-dose aspirin Guideline Update 2014 (Lyman, - Treatment for DVT and PE and long-term secondary prophylaxis (at least 6 201533) months): LMWH - Novel oral anticoagulants are not recommended due to limited evidence in cancer patients NICE guideline [NG89] VTE prophylaxis Venous thromboembolism in - Acutely ill medical patients: use LMWH. If LMWH contraindicated, use over 16s: reducing the risk of fondaparinux hospital-acquired deep vein - Renal impairment: LMWH thrombosis or pulmonary - Cancer patients: 34 embolism, March 2018 o Mieloma patients receiving chemotherapy: aspirin or LMWH o Pancreatic cancer patients receiving chemotherapy: LMWH - Interventions for people having orthopaedic surgery: o Lower limb immobilisation: LMWH or fondaparinux o Fragility fractures of the pelvis, hip and proximal femur: LMWH or fondaparinux o Elective hip replacement: LMWH or rivaroxaban. Alternatives: apixaban, dabigatran o Elective knee replacement: aspirin, LMWH, rivaroxaban. Alternatives: apixaban, dabigatran - Abdominal surgery: LMWH or fondaparinux Diagnosis and treatment of Definition of incidental VTE: “DVT or PE that is clinically unsuspected at the time incidental venous of the diagnosis. thromboembolism in cancer - Recommended treatment: LMWH patients: guidance from the SSC - Alternative treatment: VKA of the ISTH. (Di Nisio, 201535) - Newer oral anticoagulants are not recommended due to limited evidence available

Venous thromboembolic Treatment of VTE diseases: diagnosis, - Patients with confirmed VTE: offer LMWH or fondaparinux management and thrombophilia - Patients with active cancer: LMWH testing; NICE guideline, 2012 - Patients with unprovoked DVT/PE: VKA [CG144] (Updated: 2015)36

Table 3. Clinical Guidelines for Non-vitamin K Anticoagulants Guideline Recommendations Prevention of VTE in Orthopedic VTE prevention in patients undergoing major orthopedic surgery: Surgery Patients; CHEST, 2012 - LMWH, fondaparinux, dabigatran, apixaban, rivaroxaban, (total hip (Falck-Ytter 201230) arthroplasty or total knee arthroplasty but not hip fracture surgery), low-dose unfractionated heparin (LDUH), adjusted-dose vitamin K antagonist, aspirin (all Grade 1B), or an intermittent pneumatic compression device (IPCD) (Grade 1C) are recommended for at least 10 to 14 days - LMWH is suggested as preferred over the other agents for THR or TKR - Extended-thromboprophylaxis for up to 35 days is recommended Patients undergoing hip fracture surgery - LMWH, fondaparinux, LDUH, adjusted-dose VKA, aspirin, or IPCD are recommended for 10 to 14 days - LMWH is suggested as preferred over the other agents - Extended-thromboprophylaxis for up to 35 days is recommended Prevention of VTE in Nonsurgical Acutely ill hospitalized medical patients at increased risk of thrombosis: LMWH, Patients; CHEST, 2012 (Kahn low-dose unfractionated heparin BID, low-dose unfractionated heparin TID, or 201231) fondaparinux are recommended. Treatment extension beyond hospital stay or period of immobilization is not recommended Abbreviations: AHA/ACC/HRS, American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society; CHEST, American College of Chest Physicians; DVT, deep vein thrombosis, ISTH, International Society on Thrombosis and Haemostasis; LMWH, low molecular weight heparins; LOE, level of evidence; MA, meta-analysis; OAC, oral anticoagulant; PE, pulmonary embolism; RCT, randomized controlled trials; SSC, Scientific and Standardization Committee; VKA, vitamin K antagonist; VTE, venous thromboembolism

Pharmacology Factor Xa Inhibitors Apixaban, betrixaban, edoxaban, and rivaroxaban directly inhibit free and clot-bound factor Xa, which results in inhibition of the conversion of prothrombin to thrombin and inhibition of platelet activation and fibrin clot formation.37 Fondaparinux is a synthetic pentasaccharide that inhibits factor Xa via antithrombin III. This causes inhibition of platelet activation and fibrin clot formation.37 Direct Thrombin Inhibitors Dabigatran and desirudin (recombinant hirudin)38 are direct thrombin inhibitors.37 Both agents inhibit free and fibrin-bound thrombin preventing the cleavage of fibrinogen to fibrin monomers, activation of several clotting factors (eg, V and XIII), and aggregation of platelets.37 Dabigatran etexilate is a prodrug rapidly hydrolyzed by esterases to the active dabigatran upon oral administration.14 Low Molecular Weight Heparins Dalteparin and enoxaparin have antithrombin properties. They bind to antithrombin III, potentiating the inactivation of factor Xa and, to a lesser extent, factor IIa.

Table 4 includes pharmacokinetic characteristics for the non-vitamin K anticoagulants.

Table 4: Pharmokinetics of Non-vitamin K Anticoagulants37,39 Generic Absorption/ Name Distribution/ Metabolism Excretion Half-life Brand Name Tmax Factor Xa Inhibitors • Metabolized mainly via CYP3A4 with minor contributions from BA: 50% Renal: 27% CYP1A2, 2C8, 2C9, 2C19, and 2J2. (unchanged) Apixaban Tmax: 3-4 hours • O-demethylation and 12 hours Biliary/intestinal: hydroxylation at the 3- PB: 87% remainder oxopiperidinyl moiety are the major sites of biotransformation • Minimal via hydrolysis to inactive BA: 34% metabolites Renal: 11% Betrixaban Tmax: 3-4 hours • Less than 1% metabolism via CYP 19-27 hours Fecal: 85% PB: 60% 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 3A4

BA: 62% • Minimal metabolism via Renal: 50% hydrolysis (mediated by (unchanged) Edoxaban Tmax: 1-2 hours 10-14 hours carboxylesterase 1), conjugation, Biliary/intestinal: PB: 55% and oxidation by CYP3A4 remainder

Table 4: Pharmokinetics of Non-vitamin K Anticoagulants37,39 Generic Absorption/ Name Distribution/ Metabolism Excretion Half-life Brand Name Tmax BA: 100% Renal: 77% Fondaparinux Tmax: 2-3 hours Not investigated 17-21 hours (unchanged) PB: 94% to ATIII BA: Renal: 66% (36% 10 mg dose: 80- unchanged, 30% inactive 100% • Oxidative degradation catalyzed metabolites) Rivaroxaban 20 mg dose: 66% by CYP3A4/5 and CYP2J2 and 5-9 hours hydrolysis Feces: 28% (7% Tmax: 2-4 hours unchanged, 21% PB: 92-95% to inactive albumin metabolites) Direct Thrombin Inhibitors

BA: 3%-7% • Hepatic metabolism via plasma Dabigatran Tmax: 1 hour and hepatic esterases and hepatic Renal: 80% 12-17 hours PB: 35% glucuronidation • Primarily metabolized by the Renal: 40% to kidney (stepwise degradation Desirudin Tmax: 1-3 hours 50% (unchanged 2 hours from the C-terminus catalyzed by drug) carboxypeptidase) Low Molecular Weight Heparins BA (anti-Xa activity): 87% SC dosing: 3- Dalteparin Primarily renal sodium Tmax for anti-Xa Not specified 5 hours activity: 4 hours BA (anti-Xa activity): 100% Based on anti- • Hepatic via desulfation and/or Tmax for anti-Xa Factor Xa Enoxaparin depolymerization Renal: 40%, and ATIIa activity: 4.5 to sodium • Metabolites are much less potent 10% unchanged activity: 3- 7 hours 5 hours after SC injection Abbreviations: Anti-Xa, anti-Factor Xa; ATIII, antithrombin III; ATIIa, antithrombin IIa; BA, bioavailability; IU; international units; IV, intravenous; SC, subcutaneous; Tmax, time of maximum concentration

Drug-drug Interactions

Direct oral anticoagulants are associated with less drug-drug interactions compared to warfarin.11 These agents are substrates for P-glycoprotein (P-gp) and are mainly metabolized through cytochrome P450 3A4 (CYP3A4) pathways (except dabigatran and betrixaban).14,40 Dose adjustment or avoidance of concomitant use with P-gp and strong

CYP3A4 inhibitors and inducers is required.3,6,11,14,15 In addition, dabigatran is mainly eliminated by the kidneys and dose reduction in patients with renal dysfunction taking P-gp inhibitors is required.1,14 Co-administration of other anticoagulants (eg, aspirin, non- steroidal anti-inflammatories, antiplatelet agents) should be avoided or used with caution due to an increased risk of hemorrhage.1,3,4,6-9,15

Special Populations

Potential issues that should be considered in clinical practice with direct thrombin inhibitors, factor Xa inhibitors, and LMWHs include renal impairment, hepatic impairment, elderly population, and neuraxial anesthesia (see safety section).1,3,4,6-9,15 Table 5 summarizes special population information for non-vitamin K anticoagulants. Patients with renal insufficiency are at higher risk for bleeding episodes due to reduced renal clearance of anticoagulant drug.11 Non-vitamin K anticoagulants display variable renal excretion rates ranging from 27% for apixaban to 80% for dabigatran.1,3 Renal function should be assessed before administering anticoagulants and during treatment to adjust the dose accordingly. Dose adjustment varies by labeled indication and severity of renal insufficiency. Some anticoagulants are not recommended in patients with severe renal impairment. See Table 5 for further information. Renal function is especially important in the elderly population because they have a reduced renal function. Dabigatran is mainly excreted by the kidneys and cases of major bleeding have been reported in this older patients with severe renal impairment.13 Beers criteria for potentially inappropriate medication use in older adults states the need for avoiding the use or reducing the dose of non-vitamin K anticoagulants (eg, apixaban, dabigatran, edoxaban, enoxaparin, fondaparinux, and rivaroxaban) in older adults with renal insufficiency due to an increased risk of bleeding.41 Non-vitamin K anticoagulants should be used with caution in patients with hepatic impairment due to a potential increase of bleeding risk. Some products such as apixaban are not recommended in patients with severe hepatic impairment.3 Apixaban, edoxaban, and fondaparinux require dose adjustment based on body weight, especially those patients with low body weight.3,7,15 Safety and efficacy of non-vitamin K anticoagulants have not been established in pediatric patients. Pediatric dosing is available in tertiary sources (eg, Micromedex) for dalteparin and enoxaparin.39

Table 5: Special Population Information for Non-vitamin K Anticoagulants37,39 Generic Name Pediatrics Geriatrics Renal & Hepatic Impairment Pregnancy & Lactation

Factor Xa Inhibitors Renal: Pregnancy: Safety and No differences noted NVAF patients with ESRD: Evidence is lacking Not recommended effectiveness between older and Treatment and prophylaxis of DVT: No dose Apixaban have not been younger patients for adjustment is recommended Lactation: established safety or effectiveness Hepatic: Consider discontinuing Severe Hepatic Impairment: Not recommended medication or breast feeding Renal: Pregnancy: Severe renal dysfunction (CrCl ≥ 15 mL/min to ≤ Consider the risk/benefit of Safety and No differences noted 30 mL/min): reduce dose due to increased risk of therapy effectiveness between older and Betrixaban bleeding events have not been younger patients for Lactation: established safety or effectiveness Hepatic: Consider discontinuing Not recommended (not studied) medication or breast feeding Renal: Pregnancy: CrCl 15-50 mL/min: reduce dose Consider the risk/benefit of Safety and No differences noted CrCl < 15 mL/min or CrCl > 95 mL/min (NVAF therapy effectiveness between older and Edoxaban patients): not recommended have not been younger patients for Lactation: established safety or effectiveness Hepatic: Consider discontinuing Child-Pugh class B and C: not recommended medication or breast feeding Renal: Severe renal impairment (CrCl <30 mL/min): not recommended Pregnancy: Safety and Risk of bleeding increases Renal impairment is associated with reduced Consider the risk/benefit of effectiveness with age and reduced clearance and increased risk of bleeding therapy Fondaparinux have not been renal function: Use with Assess renal function periodically established caution Lactation Hepatic: Use with caution Mild to moderate dysfunction: no adjustment Hepatic impairment may increase the risk for bleeding

Table 5: Special Population Information for Non-vitamin K Anticoagulants37,39 Generic Name Pediatrics Geriatrics Renal & Hepatic Impairment Pregnancy & Lactation Renal: Pregnancy: DVT/PE indications: CrCl < 30 mL/min: Avoid use Consider the risk/benefit of Safety and No differences noted NVAF: CrCl 15-50 mL/min: reduce dose therapy effectiveness between older and Rivaroxaban have not been younger patients for Hepatic: Lactation: established safety of effectiveness Child-Pugh class B or C: Avoid use Consider the risk/benefit of Any hepatic disease associated with coagulopathy: discontinuing medication or Avoid use breast feeding Direct Thrombin Inhibitors Pregnancy: Renal: Safety and Consider the risk/benefit of Risk of bleeding increases NVAF: CrCl 15-30 mL/min: reduce dose effectiveness therapy Dabigatran with age and reduced have not been renal function Hepatic: Lactation: established No dose adjustments Discontinue breast feeding Pregnancy: Renal: Consider the risk/benefit of Safety and No differences noted Moderate and severe impairment: Reduce the dose therapy Desirudin effectiveness between older and have not been younger patients for Hepatic: Lactation: established safety of effectiveness No dose adjustments Consider discontinuing medication or breast feeding Low Molecular Weight Heparins Pregnancy: Renal: Consider the risk/benefit of Safety and No differences noted Severe renal impairment: use with caution therapy effectiveness between older and Dalteparin sodium have not been younger patients for Hepatic: Lactation: established safety of effectiveness Severe hepatic impairment: use with caution Consider discontinuing medication or breast feeding

Table 5: Special Population Information for Non-vitamin K Anticoagulants37,39 Generic Name Pediatrics Geriatrics Renal & Hepatic Impairment Pregnancy & Lactation Renal: Pregnancy: Consider the risk/benefit of Safety and Mild and moderate renal impairment: observe therapy effectiveness patients for bleeding symptoms Monitor for increased risk Enoxaparin sodium have not been Severe renal impairment (CrCl <30 mL/min): adjust of bleeding Lactation: established the dose Consider discontinuing Hepatic: use with caution medication or breast feeding Abbreviations: CrCl, creatinine clearance; ESRD, end-stage renal disease; NVAF, non-valvular atrial fibrillation

Head-to Head Efficacy and Safety Comparisons

The literature search identified 1,342 articles, of which 16 publications (13 SR/MAs and 3 RCTs) evaluating the comparative efficacy and safety of the anticoagulant agents listed in Table 1 met inclusion criteria. Twelve additional relevant SR/MAs and RCTs identified from the reference lists of related articles were included for evaluation. Figure 1 shows the PRISMA flow chart18 for the review process of SR/MAs and RCTs.

Figure 1. PRISMA Flow Chart for Publication Screening

Records identified from Medline and Embase Records identified from

searches through June 2018, duplicates removed reference list of related • Systematic reviews (n = 353) articles (n = 12) • Randomized controlled trials (n = 983)

Identification

Records screened Records excluded (n = 1,348) (n = 1292) Screening

Full-text articles assessed for Full-text articles excluded, eligibility with reasonsa Eligibility (n = 56) (n = 28) Wrong study design (21) Wrong comparator (7)

Publications included in qualitative synthesis

Included (n = 28 publications) a See Appendix B for descriptions

Figure 2 summarizes head-to-head evidence identified from the literature search comparing the efficacy of direct thrombin inhibitors or factor Xa inhibitors versus LMWHs for VTE prophylaxis. Table 1 of Appendix C includes key findings reported in the SR/MAs identified from the literature search. Table 2 of Appendix C includes key findings reported in relevant SR/MAs identified in the reference list of included SR/MAs.

Figure 2. Direct Comparative Efficacy Evidence of Direct Anticoagulantsa versus LMWHs for VTE Treatment and Prevention

Al Hajri, 2017 Boyd 2017 Caldeira, 2017 Cimminiello, 2017 Gao, 2017 Suen, 2017 Venker, 2017 SR/MAs and RCTs for VTE Wang, 2017 prophylaxis after THR and Ning, 2016 TKR surgery Feng 2015 Yoshida, 2013 Gomez-Outes, 2012 Huang, 2011 Turun, 2011 Cao, 2010 Direct comparative Kim, 2016 evidence with direct anticoagulantsa versus Raskob, 2010 LMWHs for treatment Eriksson, 1997 or prevention of VTE

SR/MAs and RCTs for acute Agnelli, 2013 treatment of VTE Buller, 2012 Bauersachs, 2010 Buller, 2004

SR/MAs and RCTs for the Hakoum, 2018 prevention of VTE Yan, 2018 recurrence in patients with cancer Raskob, 2018 Brunetti, 2017

SR/MAs and RCTs in Al Yami, 2017 hospitalized, medically ill patients Cohen, 2016

Abbreviations: LMWH, low molecular weight heparins; RCT, randomized controlled trials; SR/MA, systematic review/meta-analysis; THR, total hip replacement; TKR, total knee replacement; VTE, venous thromboembolism a Direct anticoagulants include dabigatran and desirudin (direct thrombin inhibitors) and apixaban, betrixaban, edoxaban, fondaparinux, and rivaroxaban (direct factor Xa inhibitors)

Summary of Guideline Recommendations and Findings Reported in SR/MAs and RCTs

Table 6. Summary of Evidence Findings and Treatment Options for NVAF and VTE patients Guideline SR/MA and RCT Evidence for Non-vitamin K Population Recommendations24,29-31 Anticoagulants

VTE VTE prophylaxis after THR or No head-to-head RCTs comparing DTIs with FXa TKR30 inhibitors or comparing FXa inhibitors with one another are available for VTE treatment or First-line therapy: LMWH prevention Alternatives: eg, Head-to-head comparisons among DTI or FXa fondaparinux, dabigatran, inhibitors versus LMWHs: apixaban, rivaroxaban, and Prevention of VTE VKA VTE prophylaxis after THR or TKR

VTE prophylaxis in medically - Apixaban has similar or better efficacy and lower ill patients31 bleeding rates compared to enoxaparin - Dabigatran has similar efficacy and similar or higher First-line therapy: LMWH, bleeding rates compared to enoxaparin unfractionated heparin, or - Edoxaban has similar or better efficacy and similar fondaparinux safety profile compared to enoxaparin Treatment of acute VTE29 - Edoxaban has better efficacy and similar bleeding profile compared to dalteparin First-line therapy: - Fondaparinux has better efficacy and similar or higher bleeding rates compared to enoxaparin Oral anticoagulants (ie, - Rivaroxaban has better efficacy and similar or apixaban, edoxaban, higher bleeding rates compared to enoxaparin rivaroxaban, or dabigatran). Treatment of VTE in There is no preference for VTE prophylaxis in medically ill patients patients without severe one oral anticoagulant over renal impairment or another - Betrixaban vs. enoxaparin: no significant efficacy cancer29 and safety differences between groups Alternatives: Treatment of acute VTE 1. Warfarin 2. LMWH - Apixaban has similar efficacy and better bleeding profile compared to enoxaparin - Fondaparinux and rivaroxaban have similar efficacy and safety profile compared to enoxaparin

Treatment of cancer No head-to-head RCTs comparing DTIs with FXa patients with acute VTE inhibitors or comparing FXa inhibitors with one Treatment of VTE in another are available. There is no preference for one First-line therapy: LMWH patients with cancer non-vitamin K anticoagulants over another and VTE (“cancer- Alternatives: VKAs, Head-to-head comparisons among DTI or FXa related thrombosis”)29 dabigatran, rivaroxaban, inhibitors versus LMWHs: Limited evidence in small apixaban, or edoxaban subgroups of cancer patients is available

Table 6. Summary of Evidence Findings and Treatment Options for NVAF and VTE patients Guideline SR/MA and RCT Evidence for Non-vitamin K Population Recommendations24,29-31 Anticoagulants

NVAF First-line therapy: oral No head-to-head RCTs comparing DTIs with FXa Patients with NVAF and anticoagulants (ie, warfarin, inhibitors or comparing FXa inhibitors with one with history of stroke, apixaban, rivaroxaban, or another are available transient ischemic dabigatran). There is no attack, or CHA2DS2- preference for one oral VASc score ≥ 2 anticoagulant over another

CHA2DS2-VASc score ≥ 2 Warfarin is more reasonable N/A and end-stage CKD DTI and FXa inhibitors are (CrCl <15 mL/min) or not recommended on hemodialysis

Moderate-to-severe Reduced doses of DTI or FXa N/A CKD and CHA2DS2-VASc inhibitors may be considered scores ≥2

Abbreviations: CHA2DS2-VASc, Congestive heart failure, Hypertension, Age ≥75 years (doubled), Diabetes mellitus, Prior Stroke or TIA or thromboembolism (doubled), Vascular disease, Age 65 to 74 years, Sex category; CKD, chronic kidney disease; CrCl, creatinine clearance; DTI, direct thrombin inhibitor; FXa, factor Xa; N/A, not applicable; NVAF, non-valvular atrial fibrillation; VTE, venous thromboembolism

Findings Reported in SR/MAs and RCTs for Venous Thromboembolism Head-to-head comparisons among dabigatran, desirudin, apixaban, betrixaban, edoxaban, rivaroxaban, and fondaparinux Our systematic literature search found no direct evidence comparing dabigatran, apixaban, betrixaban, edoxaban, rivaroxaban, and fondaparinux with each other for the prevention of VTE after major orthopedic surgery, acute treatment of VTE, reduction in the risk of recurrent VTE, and VTE prophylaxis in medically ill adult patients. Head-to-head comparisons for dabigatran, desirudin, apixaban, betrixaban, edoxaban, rivaroxaban, or fondaparinux versus LMWHs Direct evidence comparing direct thrombin inhibitors (dabigatran and desirudin) or factor Xa inhibitors (apixaban, betrixaban, edoxaban, rivaroxaban, and fondaparinux) versus LMWHs (dalteparin and enoxaparin) was identified for the prevention of VTE after major orthopedic surgery,42 acute treatment of VTE, reduction in the risk of recurrent VTE, and VTE prophylaxis in medically ill adult patients. Most identified publications focus on rivaroxaban or apixaban compared to LMWHs for the prevention of VTE, especially following total hip replacement (THR) or total knee replacement (TKR). The majority of RCTs included in SR/MAs evaluated the incidence of VTE (DVT and non-fatal PE) and all-cause mortality as the primary composite efficacy

endpoint, and major bleeding rate and clinically relevant non-major bleeding rate as the primary composite safety endpoint. Secondary endpoints were primarily comprised of the individual components of the primary endpoint, total VTE (proximal or distal DVT and non- fatal PE), and major VTE (proximal DVE or non-fatal PE), among others. Publications including head-to-head comparisons of direct thrombin inhibitors or FXa inhibitors versus LMWH for acute treatment of VTE or reduction in the risk of recurrent VTE following initial therapy is very limited. One RCT comparing VTE events with betrixaban versus enoxaparin in patients hospitalized for an acute medical illness was identified. See Appendix C for a summary of SR/MA and RCT results. 1. Prevention of VTE following total hip or knee replacement surgery Apixaban versus enoxaparin SR/MAs assessing apixaban versus LMWHs in the prevention of VTE following orthopedic surgery (THR or TKR) were identified. Evidence was mainly driven by 1 phase IIb RCT (APROPOS [Lassen 2007]) and 3 phase III RCTs (ADVANCE-1 [Lassen 2009], ADVANCE-2 [Lassen 2010], and ADVANCE-3 [Lassen 2010]) that compared apixaban 2.5 mg twice daily versus enoxaparin (30 mg twice daily or 40 mg daily) for 10 to 38 days (mean follow-up: 72 to 95 days) in the prevention of VTE after orthopedic surgery. Data from 6 relevant SR/MAs12,42-46 including these RCTs are reported as follows: - Compared to enoxaparin (all regimens combined: 30 mg twice daily or 40 mg once daily), apixaban significantly reduced the risk of VTE and overall mortality (primary composite efficacy endpoint) in 2 SR/MAs (Caldeira 201743 and Feng 201512) including the main 4 RCTs. However, another SR/MA excluding the phase 2 RCT showed no significant differences for the same primary composite efficacy endpoint (Yoshida 201342). Three SR/MAs reported a significant benefit with apixaban for the incidence of DVT (asymptomatic or symptomatic) compared to enoxaparin.42,44,47 Results for the composite endpoint of symptomatic VTE or VTE-related death43 and other individual efficacy endpoints such as symptomatic VTE43,45 and major VTE42,43 indicated no significant differences between apixaban and enoxaparin. Incidence of PE was numerically higher with apixaban compared to enoxaparin in 3 SR/MAs; however, results were not statistically significant.44,45,47 - Regarding safety, apixaban seems to have lower bleeding rates compared to enoxaparin, with statistically significant results in favor of apixaban for the safety endpoints of major bleeding or clinically relevant non-major bleeding (primary composite endpoint) (2 SR/MAs: Venker 201746 and Gomez-Outes 201245), clinically relevant non-major bleeding (1 SR/MA: Gao 201744), and any bleeding (1 SR/MA: Yoshida 201342). However, these SR/MAs reported no significant differences between groups for the individual endpoints of the primary safety endpoint42,45 and other bleeding endpoints such as minor bleeding.42,44

- Subgroup analysis by enoxaparin regimen showed better results in VTE prevention or overall mortality when apixaban was compared to enoxaparin 40 mg once daily and no significant differences for all efficacy and safety endpoints when apixaban was compared with enoxaparin 30 mg twice daily.43,47 Edoxaban versus enoxaparin or dalteparin SR/MAs assessing edoxaban versus LMWHs in the prevention of VTE following an orthopedic surgery (THR or TKR) were identified. Evidence was mainly driven by 2 RCTs that compared edoxaban 15 or 30 mg once daily versus enoxaparin 2000 IU twice daily for 11 to 14 days postoperatively (STARS E-3 [Fuji, 2014] and STARS J-V [Fuji, 2015]) and 1 RCT comparing edoxaban (multiple doses) versus dalteparin (Raskob 201048) for 7 to 10 days. Data from 4 relevant SR/MAs12,44,46,49 and 1 RCT48 are reported as follows:

• Edoxaban versus enoxaparin Compared to enoxaparin, results from 4 SR/MAs (Boyd 2017, Gao 2017,44 Venker 2017,46 and Feng 201512) indicated a significantly greater efficacy regarding total VTE events, major VTE, asymptomatic DVT, and VTE or all-cause mortality (composite endpoint) with edoxaban compared to enoxaparin. However, some efficacy endpoints such as symptomatic DVT and PE showed no significant differences between groups (1 SR/MA: Gao 2017). SR/MAs reported numerically higher bleeding rates with edoxaban compared to enoxaparin, but differences between groups for the composite endpoint of major bleeding and clinically relevant bleeding were not statistically significant.12,44,46,49

• Edoxaban versus dalteparin Raskob et al48 (2010) reported that edoxaban is superior to dalteparin for VTE prophylaxis following orthopedic surgery. Differences in bleeding rates were not statistically significant between treatment groups. Fondaparinux versus enoxaparin SR/MAs identified mainly included 4 RCTs comparing fondaparinux 2.5 mg once daily versus enoxaparin (30 mg twice daily or 40 mg once daily): Bauer 2001 (PENTAMAKS), Eriksson 2001 (PENTHIFRA), Turpie 2002 (PENTATHLON 2000), and Lassen 2002 (EPHESUS). Data from 2 relevant SR/MAs42,46 are reported as follows: - Two SR/MAs42,46 reported better efficacy in terms of VTE prophylaxis with fondaparinux compared to enoxaparin; however, similar or significantly higher incidence of major bleeding was reported with fondaparinux compared to enoxaparin.42,46 Rivaroxaban versus enoxaparin Direct evidence comparing rivaroxaban 10 mg once daily vs. enoxaparin 30 mg twice daily or 40 mg once daily for 13 to 42 days was mainly driven by 4 RCTs (Eriksson 2008

[RECORD-1], Kakkar 2008 [RECORD-2], Lassen 2008 [RECORD-3], and Turpie 2009 [RECORD-4]). Data from 7 relevant SR/MAs42,44-46,49-51 are reported as follows: - SR/MAs showed significantly better results in VTE prophylaxis with rivaroxaban compared to enoxaparin in patients undergoing total hip or knee replacement. Key efficacy endpoints assessed in SR/MAs included total VTE (Venker 2017,46 Boyd 201749), major VTE (Boyd 201749), asymptomatic DVT (Gao 201744), symptomatic VTE (Gomez-Outes 201245 and Ning 201650), and the composite endpoint of VTE or all-cause mortality (Cao 2010,51 Yoshida 201342). Bleeding rates were similar (Cao 2010,51 Yoshida 2013,42 Gao 2017,44 Boyd 201749) or significantly higher (Gomez-Outes 2012,45 Yoshida 2013,42 Venker 2017,46 Ning 201650) with rivaroxaban compared to enoxaparin. An additional RCT (Kim, 201652) on surgical complications after total hip replacement indicated no significant differences between rivaroxaban 10 mg once daily and enoxaparin 40 mg once daily in the incidence of major surgical wound complications (primary outcome) and VTE events (secondary outcome). Dabigatran versus enoxaparin Direct evidence comparing dabigatran 150 mg or 220 mg once daily vs. enoxaparin 30 mg twice daily or 40 mg once daily for 6 to 35 days was mainly driven by 4 RCTs, including Eriksson 2007 (RE-MODEL), Eriksson 2007 (RE-NOVATE), Ginsberg 2009 (RE-MOBILIZE), and Eriksson 2011 (RE-NOVATE II). Data from 4 relevant SR/MAs42,45,46,49 are reported as follows: - SR/MAs demonstrated that dabigatran is similarly efficacious in the prevention of VTE (Boyd 2017,49 Venker 2017,46 Yoshida 2013,42 Gomez-Outes 201245) to enoxaparin in patients undergoing total hip or knee replacement. Bleeding rates were similar (Boyd 2017,49 Venker 2017,46 Yoshida 2013,42 Gomez-Outes 201245) or significantly higher (Yoshida 201342) with dabigatran compared to enoxaparin. Desirudin versus enoxaparin An RCT conducted by Eriksson et al38 (1997) compared desirudin 15 mg twice daily versus enoxaparin 40 mg once daily for 8 to 12 days in the prevention of VTE after total hip replacement.38 Desirudin showed a significantly lower incidence of major VTE events (ie, proximal DVT, PE, or death) and similar safety profile compared to enoxaparin. Authors stated that the superior efficacy of desirudin may be associated with the differences in the timing of drug administration.38 2. Prevention of VTE recurrence in patients with cancer Cancer patients with VTE are at higher risk of experiencing a recurrent event of VTE than patients without cancer.53 The 2016 CHEST guideline states that LMWHs are preferred over VKA, dabigatran, rivaroxaban, apixaban, or edoxaban for the prevention of VTE recurrence in cancer patients with confirmed VTE, mainly due to the limited direct

evidence available with LMWHs compared to direct oral anticoagulants in patients with cancer.29 Evidence directly comparing factor Xa inhibitors versus LMWHs in patients with cancer and VTE is described as follows: - An SR/MA conducted by Brunetti et al (2017)54 in a small subgroup of cancer patients with VTE showed rivaroxaban and apixaban have comparable efficacy profiles (ie, VTE recurrence) to enoxaparin, but significantly worse safety profile in terms of bleeding rate. Separate results for the treatment effect attributed to each oral anticoagulant agent versus enoxaparin was not provided. - An SR (Hakoum et al [2018]53) including a subgroup analysis in cancer patients (van Doormaal et al55 [2009]) revealed fondaparinux is similarly efficacious to enoxaparin in terms of all-cause mortality at 3 months, recurrent VTE, or bleeding. The 2 aforementioned SRs evaluated data from the subgroup of patients with cancer who were included in phase III clinical trials for VTE. Authors expressed the need for further well-conducted RCTs exclusively including cancer patients.53,54 - An RCT performed by Raskob et al56 (2018) (Hokusai-Cancer trial) in patients with cancer and VTE showed edoxaban is noninferior to dalteparin in terms of recurrent VTE or major bleeding. 3. Prevention of VTE in patients hospitalized for an acute medical illness Betrixaban versus enoxaparin (1 RCTs: Cohen, 2016) Patients hospitalized with acute medical illness (eg, cancer, respiratory disease, heart failure, and acute coronary syndromes) are at increased risk of experiencing VTE events due to a rise in pro-inflammatory molecules (eg, cytokines).40 Betrixaban is the first direct oral anticoagulant approved for VTE prophylaxis in adult patients hospitalized for an acute medical illness.40 Recommended duration of treatment is 35 to 42 days; therefore, patients can be on treatment in the post-discharge period to prevent VTE events.40 Other direct oral anticoagulants (apixaban and rivaroxaban) have been studied for extended-duration thromboprophylaxis in medically ill patients in comparison to short-duration thromboprophylaxis with enoxaparin (ADOPT and MAGELLAN trials);57 however, both apixaban and rivaroxaban are not currently approved for this indication.3,6 The APEX trial (Cohen, 201658) evaluated extended-duration thromboprophylaxis with betrixaban (80 mg once daily, 35 to 42 days) compared to short-duration thromboprophylaxis with enoxaparin (40 mg once daily, 6 to 14 days) in medically ill patients. Outcomes were assessed in 3 pre-specified cohorts. In the first cohort (ie, patients with an increased D-dimer level), no significant differences for the primary composite endpoint (ie, asymptomatic proximal DVT and symptomatic VTE) were reported between groups. According to the statistical analysis plan, if one of the 3 analyses resulted in non- significant differences between groups, the remaining analyses were exploratory. Thus,

32 results from cohort 2 (patients with an increased D-dimer level or an age 75 years) and cohort 3 (overall population), although showed a significant benefit of betrixaban for the primary endpoint, were considered exploratory. Major bleeding rates were≥ similar between groups. 4. Acute treatment of VTE Apixaban versus enoxaparin/warfarin Agnelli et al59 2013 (AMPLIFY) evaluated the efficacy and safety with apixaban (10 mg twice daily for 7 days, then 5 mg for 6 months) compared to enoxaparin 5 days, followed by warfarin in patients with acute VTE. Results indicated apixaban is not inferior to enoxaparin for the primary efficacy endpoint (ie, recurrent symptomatic VTE or VTE- related death) at month 6. Apixaban was superior to enoxaparin in relation to major bleeding rates. The composite endpoint of major bleeding and clinically relevant bleeding was significantly lower with apixaban versus enoxaparin. Fondaparinux vs. enoxaparin/warfarin Buller et al60 2004 (MATISSE-DVT) showed fondaparinux is non-inferior to enoxaparin regarding the incidence of symptomatic recurrent VTE events in patients with DVT. Major bleeding was similar between treatment groups. Rivaroxaban versus enoxaparin/warfarin - Bauersachs et al61 2010 (EINSTEIN-DVT) assessed rivaroxaban 15 mg twice daily (3 weeks), followed by 20 mg once daily vs. enoxaparin, followed by VKA therapy for 3 to 12 months in patients with acute DVT. Rivaroxaban was non-inferior to enoxaparin/VKA in terms of recurrent nonfatal or fatal VTE (primary efficacy endpoint) and major plus clinically relevant bleeding. - Buller et al62 2012 (EINSTEIN-PE) assessed rivaroxaban 15 mg twice daily (3 weeks), followed by 20 mg once daily vs. enoxaparin, followed by VKA therapy for 3 to 12 months in patients with confirmed PE with or without DVT. Non-inferiority of rivaroxaban vs. enoxaparin was demonstrated for the primary efficacy endpoint (symptomatic recurrent VTE). No significant differences were reported between groups for the primary safety endpoint (major or clinically non-major bleeding). Findings Reported in SR/MAs and RCTs for Non-valvular Atrial Fibrillation Our systematic literature search found no head-to-head comparisons among dabigatran, apixaban, edoxaban, and rivaroxaban for the prevention of stroke and systemic embolism in patients with NVAF, which is consistent with 2014 AHA/ACC/HRS guideline for AF24 and multiple, recent systematic reviews identified in our literature search (Lopez- Lopez 2017,63 Sommerauer 2017,13 and Align 201664).

Safety

The most common adverse events reported with anticoagulant agents are bleeding, gastrointestinal symptoms, and injection site-related reactions with the parenteral formulations.1-4,6-9,15 The most relevant adverse event associated with the use of non-vitamin K anticoagulants is bleeding. Some SR/MAs showed higher risk of bleeding with rivaroxaban compared to enoxaparin42,45,46,50 or lower risk of bleeding with apixaban compared to enoxaparin42,44-46 for VTE prevention after THR or TKR. Other SR/MAs found similar rates of bleeding with edoxaban versus enoxaparin for VTE prevention after THR or TKR.12,44,46,49 In emergency situations with excessive bleeding, reversal of anticoagulant effects may be managed with specific antidotes. The lack of antidotes for the reversal of new anticoagulant effects has been a major concern in the past. Most recently, 2 antidotes have been approved, idarucizumab (Praxbind) for dabigatran reversal and coagulation factor Xa (recombinant), inactivated-zhzo (Andexxa) for apixaban and rivaroxaban reversal.65 Protamine is recommended for the reversal of LMWH effects.66 Guidelines for reversal recommend management of bleeding with an antidote for “life-threatening bleeding, bleeding into a critical organ or closed space, persistent bleeding despite local hemostatic measures, high risk for recurrent bleeding because of delayed DOAC clearance or DOAC overdose, and urgent intervention associated with high bleeding risk”.67 For the population with NVAF, comparisons of direct thrombin inhibitor-, direct FXa inhibitor- or LMWH-related bleeding rates have only been evaluated against warfarin. Results showed a decrease in the incidence of intracranial hemorrhage with direct oral anticoagulants but a higher incidence in gastrointestinal bleeding.24,67 Apixaban, dabigatran, edoxaban, and rivaroxaban are not recommended in patients with mechanical heart valve or moderate-to-severe mitral stenosis.1,3,6,15 Unlike warfarin, new anticoagulants do not require careful coagulation monitoring to maintain the target international normalized ratio (INR). Each anticoagulant product has a black box warning for concomitant use with neuraxial anesthesia or spinal puncture procedures due to the increased risk for developing epidural or spinal hematomas that may cause long-lasting or permanent paralysis.1-4,6-9,15 Oral direct anticoagulants, except betrixaban, carry a black box warning for a potential increase in the risk of thromboembolic events (eg, stroke) upon premature discontinuation of therapy.1,3,6,15 Edoxaban has an additional black box warning regarding the decreased efficacy in NVAF patients with CrCL > 95 mL/min.15

Table 6 lists the labeled black box warnings and most common adverse events associated with the use of anticoagulant agents.

Table 7. Labeled Black Box Warnings and Most Common Adverse Events with Non-vitamin K Anticoagulants Generic Name Black Box Warnings Most Common Adverse Events

- An increased risk of thromboembolic events may occur upon premature discontinuation of apixaban Apixaban3 - Spinal/epidural hematoma may occur with concurrent Bleeding (>1%) neuraxial or spinal puncture, resulting in long-term or permanent paralysis

- Spinal/epidural hematoma with concurrent neuraxial or spinal Betrixaban4 Bleeding (>5%) puncture

- Decreased efficacy in NVAF patients with CrCL > 95 mL/min NVAF: bleeding and anemia (≥ - An increased risk of thromboembolic events may occur upon 5%) Edoxaban15 premature discontinuation of edoxaban VTE: bleeding, rash, abnormal - Spinal/epidural hematoma with concurrent neuraxial or spinal liver function tests and anemia (≥ puncture 1%)

- Spinal/epidural hematoma with concurrent neuraxial or spinal Fondaparinux7 Bleeding complications puncture

- An increased risk of thromboembolic events may occur upon premature discontinuation of rivaroxaban Rivaroxaban6 Bleeding (>5%) - Spinal/epidural hematoma with concurrent neuraxial or spinal puncture

- An increased risk of thromboembolic events may occur upon premature discontinuation of dabigatran Gastritis-like symptoms and Dabigatran1 - Spinal/epidural hematoma with concurrent neuraxial or spinal bleeding (>15%) puncture Hemorrhage (33%) Injection site mass, wound 2 - Spinal/epidural hematoma with concurrent neuraxial or spinal Desirudin secretion, anemia, deep puncture thrombophlebitis and nausea (≥2%)

Hemorrhage, thrombocytopenia (Type I), hematoma at the Dalteparin - Spinal/epidural hematoma with concurrent neuraxial or spinal injection site, pain at the injection sodium8 puncture site, transient elevation of transaminases (>1%)

Bleeding, anemia, Enoxaparin - Spinal/epidural hematoma with concurrent neuraxial or spinal thrombocytopenia, elevation of

sodium9 puncture serum aminotransferase, diarrhea, and nausea (>1%) Abbreviations: CrCl, creatinine clearance; NVAF, non-valvular atrial fibrillation

Summary After performing a systematic literature search, 16 publication containing head-to- head comparisons among the anticoagulants listed in table 1 were identified. Twelve additional publications were identified from the reference lists of related articles. Direct comparisons have not been conducted between direct thrombin inhibitors and factor Xa inhibitors in the setting of stroke prevention in patients with NVAF or for VTE. Therefore, there is insufficient evidence available to establish efficacy and safety differences among these agents for major clinical endpoints (eg, occurrence of stroke or systemic embolic event in NVAF patients and VTE events, all-cause mortality, recurrent VTE, major bleeding, and clinically relevant bleeding in the setting of VTE disease). The majority of identified SR/MAs assessed the comparative efficacy and safety of apixaban and rivaroxaban versus enoxaparin for the prevention of VTE after orthopedic surgery (THR or TKR). In general, apixaban, edoxaban, fondaparinux, and rivaroxaban were significantly better for the prophylaxis of VTE after orthopedic surgery compared to enoxaparin, whereas bleeding rates were slightly increased with edoxaban, fondaparinux, and rivaroxaban, and lower with apixaban compared to enoxaparin. The direct-thrombin inhibitor, dabigatran, performed similarly in comparison to enoxaparin for VTE prevention after total hip or knee replacement. For the treatment of VTE, apixaban, rivaroxaban, and fondaparinux were non-inferior to enoxaparin/warfarin in terms of recurrent VTE. Bleeding rates were similar between both fondaparinux and rivaroxaban compared to enoxaparin and significantly lower with apixaban versus enoxaparin. Limited evidence with direct thrombin inhibitors or factor Xa inhibitors versus enoxaparin is available for the prevention of VTE recurrence in patients with cancer. The 2014 AHA/ACC/HRS guideline for the management of atrial fibrillation recommends oral anticoagulant therapy with warfarin, dabigatran, rivaroxaban, or apixaban in patients with NVAF who have CHA2DS2- e, or transient ischemic attack. VASc score ≥ 2, history of strok The 2016 CHEST guideline of antithrombotic therapy for the treatment of VTE recommends the use of dabigatran or the oral factor Xa inhibitors rivaroxaban, apixaban, or edoxaban in preference to VKA therapy for the treatment of VTE patients without cancer. In patients with VTE and cancer, LMWHs are preferred over VKA, dabigatran, rivaroxaban, apixaban, or edoxaban. Anticoagulant therapy for at least 3 months is recommended. For VTE prophylaxis following THR or TKR surgery, the 2012 CHEST guideline recommends LMWH therapy for at least 10 to 14 days over other agents (ie, fondaparinux, dabigatran, apixaban, rivaroxaban, VKA, unfractionated heparin, aspirin, and intermittent pneumatic compression device). In patients declining injectable formulations, apixaban or dabigatran are recommended. Extended-thromboprophylaxis is recommended for up to 35 days. For VTE prophylaxis in acutely ill hospitalized medical patients at high risk of thrombosis, the 2012 CHEST guideline recommends LMWH, unfractionated heparin, or fondaparinux during the hospital stay or period of immobilization.

The most important adverse event associated with the use of oral anticoagulants is bleeding. There are specific reversal agents for apixaban, rivaroxaban, dabigatran, and LMWHs. Each anticoagulant product has a black box warning for concomitant use with neuraxial anesthesia or spinal puncture procedures due to the increased risk for developing epidural or spinal hematomas that may cause long-lasting or permanent paralysis. Oral anticoagulants, except betrixaban, carry a black box warning for a potential increase in the risk of thromboembolic events upon premature discontinuation of therapy. Edoxaban has an additional black box warning regarding the decreased efficacy in NVAF patients with CrCL > 95 mL/min. Selection of anticoagulant therapy should be individualized based on the benefit of preventing a stroke or treating/preventing VTE events versus the bleeding risk, patient preferences, adherence, and patient specific characteristics (eg, age, weight, comorbidities such as renal impairment, and drug-drug interactions).

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53. Hakoum MB, Kahale LA, Tsolakian IG, et al. Anticoagulation for the initial treatment of venous thromboembolism in people with cancer. The Cochrane database of systematic reviews. 2018;1:CD006649. 54. Brunetti ND, Gesuete E, De Gennaro L, et al. Direct oral anti-coagulants compared with vitamin-K inhibitors and low-molecular-weight-heparin for the prevention of venous thromboembolism in patients with cancer: A meta-analysis study. Int J Cardiol. 2017;230:214-221. 55. van Doormaal FF, Raskob GE, Davidson BL, et al. Treatment of venous thromboembolism in patients with cancer: subgroup analysis of the Matisse clinical trials. Thromb Haemost. 2009;101(4):762-769. 56. Raskob GE, van Es N, Verhamme P, et al. Edoxaban for the Treatment of Cancer-Associated Venous Thromboembolism. N Engl J Med. 2018;378(7):615-624. 57. Al Yami MS, Alfayez OM, Kurdi SM, Alsheikh R. Direct oral anticoagulants for extended- duration thromboprophylaxis in hospitalized medically ill patients: are we there yet? Journal of thrombosis and thrombolysis. 2017;44(1):1-8. 58. Cohen AT, Harrington RA, Goldhaber SZ, et al. Extended Thromboprophylaxis with Betrixaban in Acutely Ill Medical Patients. N Engl J Med. 2016;375(6):534-544. 59. Agnelli G, Buller HR, Cohen A, et al. Apixaban for extended treatment of venous thromboembolism. N Engl J Med. 2013;368(8):699-708. 60. Buller HR, Davidson BL, Decousus H, et al. Fondaparinux or enoxaparin for the initial treatment of symptomatic deep venous thrombosis: a randomized trial. Annals of internal medicine. 2004;140(11):867-873. 61. Bauersachs R, Berkowitz SD, Brenner B, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363(26):2499-2510. 62. Buller HR, Prins MH, Lensin AW, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366(14):1287-1297. 63. Lopez-Lopez JA, Sterne JAC, Thom HHZ, et al. Oral anticoagulants for prevention of stroke in atrial fibrillation: systematic review, network meta-analysis, and cost effectiveness analysis. Bmj. 2017;359:j5058. 64. Alings M. Individualising Anticoagulant Therapy in Atrial Fibrillation Patients. Arrhythmia & electrophysiology review. 2016;5(2):102-109. 65. Tornkvist M, Smith JG, Labaf A. Current evidence of oral anticoagulant reversal: A systematic review. Thrombosis research. 2018;162:22-31. 66. Frontera JA, Lewin JJ, 3rd, Rabinstein AA, et al. Guideline for Reversal of Antithrombotics in Intracranial Hemorrhage: Executive Summary. A Statement for Healthcare Professionals From the Neurocritical Care Society and the Society of Critical Care Medicine. Critical care medicine. 2016;44(12):2251-2257. 67. Levy JH, Ageno W, Chan NC, Crowther M, Verhamme P, Weitz JI. When and how to use antidotes for the reversal of direct oral anticoagulants: guidance from the SSC of the ISTH. J Thromb Haemost. 2016;14(3):623-627. 68. Yan YD, Zhang C, Shen L, et al. Net Clinical Benefit of Non-vitamin K Antagonist Oral Anticoagulants for Venous Thromboembolism Prophylaxis in Patients With Cancer: A Systematic Review and Trade-Off Analysis From 9 Randomized Controlled Trials. Front Pharmacol. 2018;9:575. 69. AlHajri L, Jabbari S, AlEmad H, AlMahri K, AlMahri M, AlKitbi N. The Efficacy and Safety of Edoxaban for VTE Prophylaxis Post-Orthopedic Surgery: A Systematic Review. J Cardiovasc Pharmacol Ther. 2017;22(3):230-238. 70. Cimminiello C, Prandoni P, Agnelli G, et al. Thromboprophylaxis with enoxaparin and direct oral anticoagulants in major orthopedic surgery and acutely ill medical patients: a meta- analysis. Intern. 2017;12(8):1291-1305.

71. Suen K, Westh RN, Churilov L, Hardidge AJ. Low-Molecular-Weight Heparin and the Relative Risk of Surgical Site Bleeding Complications: Results of a Systematic Review and Meta- Analysis of Randomized Controlled Trials of Venous Thromboprophylaxis in Patients After Total Joint Arthroplasty. J Arthroplasty. 2017;32(9):2911-2919.e2916. 72. Wang Z, Zheng J, Zhao Y, Xiang Y, Chen X, Jin Y. Effectiveness and Tolerability of Anticoagulants for Thromboprophylaxis after Major Joint Surgery: a Network Meta- Analysis. Cell Physiol Biochem. 2017;42(5):1999-2020. 73. Turun S, Banghua L, Yuan Y, Zhenhui L, Ying N, Jin C. A systematic review of rivaroxaban versus enoxaparin in the prevention of venous thromboembolism after hip or knee replacement. Thrombosis research. 2011;127(6):525-534. 74. Cohen AT, Spiro TE, Buller HR, et al. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med. 2013;368(6):513-523. 75. Goldhaber SZ, Leizorovicz A, Kakkar AK, et al. Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients. N Engl J Med. 2011;365(23):2167-2177. 76. Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Portman RJ. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med. 2009;361(6):594-604. 77. Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Hornick P. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet (London, England). 2010;375(9717):807-815. 78. Lassen MR, Gallus A, Raskob GE, Pineo G, Chen D, Ramirez LM. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med. 2010;363(26):2487-2498. 79. Eriksson BI, Dahl OE, Rosencher N, et al. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double- blind, non-inferiority trial. Lancet (London, England). 2007;370(9591):949-956. 80. Eriksson BI, Dahl OE, Rosencher N, et al. Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. J Thromb Haemost. 2007;5(11):2178-2185. 81. Ginsberg JS, Davidson BL, Comp PC, et al. Oral thrombin inhibitor dabigatran etexilate vs North American enoxaparin regimen for prevention of venous thromboembolism after knee arthroplasty surgery. J Arthroplasty. 2009;24(1):1-9. 82. Eriksson BI, Dahl OE, Huo MH, et al. Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II*). A randomised, double-blind, non-inferiority trial. Thromb Haemost. 2011;105(4):721-729. 83. Fuji T, Wang CJ, Fujita S, et al. Safety and efficacy of edoxaban, an oral factor Xa inhibitor, versus enoxaparin for thromboprophylaxis after total knee arthroplasty: the STARS E-3 trial. Thrombosis research. 2014;134(6):1198-1204. 84. Fuji T, Fujita S, Kawai Y, et al. Efficacy and safety of edoxaban versus enoxaparin for the prevention of venous thromboembolism following total hip arthroplasty: STARS J-V. Thrombosis journal. 2015;13:27. 85. Eriksson BI, Borris LC, Friedman RJ, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008;358(26):2765-2775. 86. Kakkar AK, Brenner B, Dahl OE, et al. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet (London, England). 2008;372(9632):31- 39. 87. Lassen MR, Ageno W, Borris LC, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008;358(26):2776-2786. 88. Turpie AG, Lassen MR, Davidson BL, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet (London, England). 2009;373(9676):1673-1680.

Appendix A: Literature Search Strategies

Literature Search for Systematic Reviews and Randomized Controlled Trials

1. Database(s): Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations and Ovid MEDLINE(R) 1996 to June 27, 2018, Ovid MEDLINE(R) Epub Ahead of Print June 27, 2018, Ovid MEDLINE(R) Daily Update June 27, 2018 Search Strategy:

# Searches ANTICOAGULANTS Results

1 dalteparin/ or enoxaparin/ 3700

(dalteparin? or fragmin? or tedelparin? or "fr 860" or "fr-860" or "kabi 2165" or "kabi-2165" or 2 1086 kabi2165).ti,ab,kw,kf.

3 (enoxaparin? or clexan or clexane or inhixa or klexane$ or lovenox or neoparin? or thorinan?).ti,ab,kw,kf. 3932

4 (apixaban? or eliquis?).ti,ab,kw,kf. 2338

5 (betrixaban? or bevyxxa$ or "prt 054021" or "prt054021").ti,ab,kw,kf. 110

6 (edoxaban$ or endoxaban$ or lixiana$ or roteas$ or savaysa$).ti,ab,kw,kf. 958

(rivaroxaban$ or "bay 59 7939" or "bay 59-7939" or "bay 597939" or "bay59 7939" or "bay59-7939" or 7 3696 "bay597939" or xarelto$).ti,ab,kw,kf.

8 (arixtra$ or fondaparin$).ti,ab,kw,kf. 1606

9 Dabigatran/ 2398

10 (dabigatran$ or "bibr 1048" or pradaxa?).ti,ab,kw,kf. 3894

(desirudin$ or "cgp 39393" or "cgp-39393" or "cgp39393" or desulfatohirudin$ or desulphatohirudin$ or "ik- 11 107 hir02" or iprivask$ or "recombinant hv1 hirudin$" or revasc).ti,ab,kw,kf.

12 or/1-11 [Agents] 13315

13 Heparin, Low-Molecular-Weight/ 6789

14 (heparin? adj2 low).ti,ab,kw,kf. 2072

15 or/13-14 [LMWH] 8249

16 Factor Xa Inhibitors/ 3300

17 factor xa inhibitor?.ti,ab,kw,kf. 2001

18 or/16-17 [Factor Xa Inhibitors--in MeSH rivaroxaban maps here] 4280

19 *Anticoagulants/ 31799

20 anticoagulant?.ti. 10262

21 or/19-20 [Anticoagulants] 35122

22 Meta-Analysis/ 87514

23 (metaanaly$ or meta-analy$).ti,ab,kw,kf. 128524

24 ((systematic adj3 review?) or (overview? adj4 review?)).ti,kw,kf. 91809

25 (cochrane$ or systematic review?).jw. 15574

26 (or/22-25) and English.la. [SR Filter] 195448

(randomized controlled trial or controlled clinical trial).pt. or randomized.ab. or placebo.ab. or clinical trials as 27 936940 topic.sh. or randomly.ab. or trial.ti.

28 exp animals/ not humans.sh. 2410725

(animal? or beaver? or beef or bovine or breeding or bull or canine or castoris or cat or cattle or cats or chicken? or chimp$ or cow or dog or dogs or equine or feline? or foal or foals or fish or insect? horse or horses 29 1264178 or livestock or mice or monkey? or mouse or murine or plant or plants or pork or porcine or protozoa? or purebred or rat or rats or rodent? or sheep or simian? or thoroughbred).ti. or veterinar$.ti,ab,kw,kf,hw.

30 (27 not (or/28-29)) and English.la. [Cochrane RCT Filter 6.4.d SP-Max & additional Animal exclusions] 792842

31 12 or 15 or 18 or 21 46789

32 (and/26,31) not (or/28-29) [SRs] 1634

33 32 and (2017$ or 2018$).yr. 291

34 remove duplicates from 33 289

35 21 and 30 [RCTs 1996-2018] 5061

36 remove duplicates from 35 5024

37 36 and 2018$.yr. 70

38 36 and 2017$.yr. 252

39 36 and 2016$.yr. 313

40 36 and 2015$.yr. 307

41 36 and (2010$ or 2011$ or 2012$ or 2013$ or 2014$).yr. 1374

42 36 and (2005$ or 2006$ or 2007$ or 2008$ or 2009$).yr. 1075

43 36 and (2000$ or 2001$ or 2002$ or 2003$ or 2004$).yr. 986

44 32 and (2015$ or 2016$).yr. [SR-2015-2016] 368

45 36 not (or/37-43) [Remaining RCTs 1996-1999] 647

46 32 and (2013$ or 2014$).yr. [SR-2013-2014] 292

47 32 and (2011$ or 2012$).yr. [SR-2011-2012] 157

48 32 and (2009$ or 2010$).yr. [SR-2009-2010] 95

49 32 and (2005$ or 2006$ or 2007$ or 2008$).yr. [SR-2005-2008] 193

50 32 and (2000$ or 2001$ or 2002$ or 2003$ or 2004$).yr. [SR-2000-2004] 180

51 32 and (1996$ or 1997$ or 1998$ or 1999$).yr. [SR 1996-1999] 56

2. Embase Search Strategy

No. Query Results Date 1 'dalteparin'/mj OR dalteparin*:ti,ab,kw,tn OR fragmin$:ti,ab,kw,tn OR 3628 28-Jun-18 tedelparin$:ti,ab,kw 2 'enoxaparin'/mj OR clexan:ti,ab,kw OR clexane:ti,ab,kw OR enoxaparin*:ti,ab,kw OR 8866 28-Jun-18 inhixa:ti,ab,kw OR klexane*:ti,ab,kw OR lovenox:ti,ab,kw OR neoparin*:ti,ab,kw OR thorinane*:ti,ab,kw

3 'apixaban'/mj OR apixaban*:ti,ab,kw OR eliquis:ti,ab,kw 5000 28-Jun-18 4 'betrixaban'/de OR betrixaban*:ti,ab,kw,tn OR bevyxxa*:ti,ab,kw,tn OR 'prt 460 28-Jun-18 054021':ti,ab,kw,rn,tn OR 'prt054021':ti,ab,kw,rn,tn

5 'edoxaban'/de OR edoxaban*:ti,ab,tn,kw OR endoxaban*:ti,ab,tn,kw OR 3089 28-Jun-18 lixiana*:ti,ab,tn,kw OR roteas*:ti,ab,tn,kw OR savaysa*:ti,ab,tn,kw

6 'rivaroxaban'/mj OR rivaroxaban*:ti,ab,kw OR 'bay 59 7939':ti,ab,kw OR 'bay 59- 7973 28-Jun-18 7939':ti,ab,kw OR 'bay 597939':ti,ab,kw OR 'bay59 7939':ti,ab,kw OR 'bay59- 7939':ti,ab,kw OR 'bay597939':ti,ab,kw OR xarelto*:ti,ab,kw

7 'fondaparinux'/mj OR arixtra*:ti,ab,kw OR fondaparin*:ti,ab,kw 2943 28-Jun-18 8 'dabigatran'/mj OR dabigatran*:ti,ab,kw 8024 28-Jun-18 9 desirudin*:ti,ab,kw,tn OR 'cgp 39393':ti,ab,kw,tn OR 'cgp-39393':ti,ab,kw,tn OR 517 28-Jun-18 'cgp39393':ti,ab,kw,tn OR desulfatohirudin*:ti,ab,kw,tn OR desulphatohirudin*:ti,ab,kw,tn OR 'ik-hir02':ti,ab,kw,tn OR iprivask*:ti,ab,kw,tn OR 'recombinant hv1 hirudin*':ti,ab,kw,tn OR revasc:ti,ab,kw,tn

10 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 27372 28-Jun-18 11 'thrombin inhibitor'/mj OR 'thrombin inhibitor*':ti,ab,kw 6933 28-Jun-18 12 'blood clotting factor 10a inhibitor'/mj OR ((('blood clotting factor' OR 'direct factor xa') 1913 28-Jun-18 NEAR/2 inhibitor*):ti,ab,kw)

13 'low molecular weight heparin'/mj OR ((heparin* NEAR/2 low):ti,ab,kw) 12397 28-Jun-18 14 #11 OR #12 OR #13 20380 28-Jun-18 15 'anticoagulant agent'/mj OR anticoagulant*:ti OR 'anti-coagulant*':ti 48310 28-Jun-18 16 1996:py OR 1997:py OR 1998:py OR 1999:py OR 2000:py OR 2001:py OR 2002:py OR 21261277 28-Jun-18 2003:py OR 2004:py OR 2005:py OR 2006:py OR 2007:py OR 2008:py OR 2009:py OR 2010:py OR 2011:py OR 2012:py OR 2013:py OR 2014:py OR 2015:py OR 2016:py OR 2017:py OR 2018:py 17 'conference abstract'/it OR 'conference review'/it 3068743 28-Jun-18 18 ('animal'/exp OR 'invertebrate'/exp OR 'animal experiment'/exp OR 'animal model'/exp 6502857 28-Jun-18 OR 'animal tissue'/exp OR 'animal cell'/exp OR 'nonhuman'/de) NOT (('animal'/exp OR 'invertebrate'/exp OR 'animal experiment'/exp OR 'animal model'/exp OR 'animal tissue'/exp OR 'animal cell'/exp OR 'nonhuman'/de) AND ('human'/exp OR 'human cell'/de))

19 animal*:ti OR beaver*:ti OR beef:ti OR bovine:ti OR breeding:ti OR canine:ti OR 2636670 28-Jun-18 castoris:ti OR cat:ti OR cattle:ti OR cats:ti OR chicken*:ti OR cow:ti OR dog:ti OR dogs:ti OR equine:ti OR foal:ti OR foals:ti OR fish:ti OR insect*:ti OR livestock:ti OR mice:ti OR mouse:ti OR murine:ti OR plant:ti OR plants:ti OR pork:ti OR porcine:ti OR protozoa*:ti OR purebred:ti OR rabbit*:ti OR rat:ti OR rats:ti OR rodent*:ti OR sheep:ti OR thoroughbred:ti OR veterinar*:ti,ab,de

20 ('clinical study'/mj OR 'clinical trial'/mj OR 'controlled clinical trial'/mj OR 'controlled 889419 28-Jun-18 study'/mj OR 'major clinical study'/mj OR 'randomized controlled trial'/mj OR 'control group'/mj OR (((clinical OR randomi* OR controlled OR multicentre OR multicenter OR 'multi centre' OR 'multi center') NEAR/3 (study OR trial)):ti,ab) OR placebo:ab,ti OR 'head to head':ti,ab) AND [english]/lim

21 #10 AND #20 AND #16 NOT #17 NOT (#18 OR #19) 1798 28-Jun-18 22 #14 AND #20 AND #16 NOT #17 NOT (#18 OR #19 OR #21) 596 28-Jun-18 23 #15 AND #20 AND #16 NOT #17 NOT (#18 OR #19 OR #21 OR #22) 730 28-Jun-18 24 (cochrane*:jt OR 'systematic review*':jt OR 'meta analysis'/mj OR 'systematic 187536 28-Jun-18 review'/mj OR ((systematic NEAR/3 review):ti) OR 'meta analys*':ti,ab,kw OR metaanalys*:ti,ab,kw OR ((overview NEAR/4 (review OR reviews)):ti)) NOT ('conference abstract'/it OR 'conference review'/it) AND [english]/lim

25 (#10 OR #14 OR #15) AND #24 NOT (#17 OR #18 OR #19) 1420 28-Jun-18 26 (#10 OR #14 OR #15) AND #24 NOT (#17 OR #18 OR #19) AND (2017:py OR 2018:py) 257 28-Jun-18 27 (#10 OR #14 OR #15) AND #24 NOT (#17 OR #18 OR #19) AND (2015:py OR 2016:py) 300 28-Jun-18 28 (#10 OR #14 OR #15) AND #24 NOT (#17 OR #18 OR #19) AND (2013:py OR 2014:py) 250 28-Jun-18 29 (#10 OR #14 OR #15) AND #24 NOT (#17 OR #18 OR #19) AND #16 NOT (#26 OR #27 OR 575 28-Jun-18 #28) 30 #21 OR #22 OR #23 3124 28-Jun-18 31 #30 AND 2018:py 142 28-Jun-18 32 #30 AND (2017:py OR 2016:py) 480 28-Jun-18 33 #30 AND (2014:py OR 2015:py) 448 28-Jun-18 34 #30 AND (2012:py OR 2013:py) 370 28-Jun-18 35 #30 AND (2010:py OR 2011:py) 251 28-Jun-18 36 #30 AND (2008:py OR 2009:py) 214 28-Jun-18 37 #30 NOT (#36 OR #35 OR #34 OR #33 OR #32 OR #31) 1219 28-Jun-18

Appendix B: List of Excluded Studies

Wrong study design 1. Al Yami MS, Badreldin HA, Mohammed AH, Elmubark AM, Alzahrani MY, Alshehri AM. Direct oral anticoagulants for the treatment of venous thromboembolism in patients with active malignancy: a systematic review and meta-analysis. Journal of thrombosis and thrombolysis. 2018:12. 2. Al Yami MS, Silva MA, Donovan JL, Kanaan AO. Venous thromboembolism prophylaxis in medically ill patients: a mixed treatment comparison meta-analysis. Journal of thrombosis and thrombolysis. 2018;45(1):36-47. 3. Bai Y, Shi XB, Ma CS, Lip GYH. Meta-Analysis of Effectiveness and Safety of Oral Anticoagulants in Atrial Fibrillation With Focus on Apixaban. Am J Cardiol. 2017;120(9):1689-1695. 4. Brandao GM, Junqueira DR, Rollo HA, Sobreira ML. Pentasaccharides for the treatment of deep vein thrombosis. The Cochrane database of systematic reviews. 2017;12:CD011782. 5. Bundhun PK, Soogund MZ, Teeluck AR, Pursun M, Bhurtu A, Huang WQ. Bleeding outcomes associated with rivaroxaban and dabigatran in patients treated for atrial fibrillation: a systematic review and meta-analysis. BMC Cardiovasc Disord. 2017;17(1):15. 6. Deitelzweig S, Farmer C, Luo X, et al. Comparison of major bleeding risk in patients with non- valvular atrial fibrillation receiving direct oral anticoagulants in the real-world setting: a network meta-analysis. Curr Med Res Opin. 2018;34(3):487-498. 7. Di Nisio M, Porreca E, Candeloro M, De Tursi M, Russi I, Rutjes AW. Primary prophylaxis for venous thromboembolism in ambulatory cancer patients receiving chemotherapy. Cochrane Database of Systematic Reviews. 2016;2016(12). 8. Dong K, Song Y, Li X, et al. Pentasaccharides for the prevention of venous thromboembolism. The Cochrane database of systematic reviews. 2016;10((Song Y.; Li X.; Ding J.; Gao Z.; Lu D.; Zhu Y.)):CD005134. 9. Guo L, Li S, Wang P, Zhong X, Hong Y. Comparative Efficacy of Clinical Events Prevention of Five Anticoagulants in Patients With Atrial Fibrillation (A Network Meta-Analysis). Am J Cardiol. 2017;119(4):585-593. 10. Hisatake S, Kabuki T, Kiuchi S, et al. Short-term subcutaneous fondaparinux and oral edoxaban for acute venous thromboembolism. Circulation Journal. 2017;81(6):855-861. 11. Hur M, Park SK, Koo CH, et al. Comparative efficacy and safety of anticoagulants for prevention of venous thromboembolism after hip and knee arthroplasty. Acta Orthop. 2017;88(6):634-641. 12. Kapoor A, Ellis A, Shaffer N, et al. Comparative effectiveness of venous thromboembolism prophylaxis options for the patient undergoing total hip and knee replacement: a network meta- analysis. J Thromb Haemost. 2017;15(2):284-294. 13. Kheiri BHTAAOMASOKBGHMBDL, Author A, Department of Internal Medicine HMCMS, et al. Non- vitamin K antagonist oral anticoagulants in cardioversion of atrial fibrillation: a network meta- analysis. Journal of thrombosis and thrombolysis. 2018;(1-5). 14. Maraveyas A, Muazzam I, Noble S, Bozas G. Advances in managing and preventing thromboembolic disease in cancer patients. Curr. 2017;11(4):347-354. 15. Mayer A, Schuster P, Fink B. A comparison of apixaban and dabigatran etexilate for thromboprophylaxis following hip and knee replacement surgery. Archives of Orthopaedic and Trauma Surgery. 2017;137(6):797-803. 16. Robertson L, Yeoh SE, Ramli A. Secondary prevention of recurrent venous thromboembolism after initial oral anticoagulation therapy in patients with unprovoked venous thromboembolism. The Cochrane database of systematic reviews. 2017;12:CD011088. 17. Siontis KC, Yao X, Gersh BJ, Noseworthy PA. Direct Oral Anticoagulants in Patients With Atrial Fibrillation and Valvular Heart Disease Other Than Significant Mitral Stenosis and Mechanical Valves: A Meta-Analysis. Circulation. 2017;135(7):714-716.

18. Sommerauer C, Schlender L, Krause M, et al. Effectiveness and safety of vitamin K antagonists and new anticoagulants in the prevention of thromboembolism in atrial fibrillation in older adults - a systematic review of reviews and the development of recommendations to reduce inappropriate prescribing. BMC geriatr. 2017;17(Suppl 1):223. 19. Sterne JA, Bodalia PN, Bryden PA, et al. Oral anticoagulants for primary prevention, treatment and secondary prevention of venous thromboembolic disease, and for prevention of stroke in atrial fibrillation: systematic review, network meta-analysis and cost-effectiveness analysis. Health Technol Assess. 2017;21(9):1-386. 20. Torjesen I. Bleeding risk higher with rivaroxaban than dabigatran for stroke prevention, head-to- head trial shows. BMJ (Clinical research ed). 2016;355((Torjesen I.) London):i5362. 21. Trikha R, Kowey PR. Practical Considerations for the Nonvitamin K Antagonist Oral Anticoagulants. Cardiology. 2017;136(2):115-124. Wrong comparison 22. Di Nisio M, Porreca E, Candeloro M, De Tursi M, Russi I, Rutjes AW. Primary prophylaxis for venous thromboembolism in ambulatory cancer patients receiving chemotherapy. Cochrane Database of Systematic Reviews. 2016;2016(12). 23. Riva N, Dentali F, Permunian ET, Ageno W. Major Bleeding and Case Fatality Rate with the Direct Oral Anticoagulants in Orthopedic Surgery: A Systematic Review and Meta-Analysis. Semin Thromb Hemost. 2016;42(1):42-54. 24. Robertson L, Yeoh SE, Ramli A. Secondary prevention of recurrent venous thromboembolism after initial oral anticoagulation therapy in patients with unprovoked venous thromboembolism. The Cochrane database of systematic reviews. 2017;12:CD011088. 25. Siontis KC, Yao X, Gersh BJ, Noseworthy PA. Direct Oral Anticoagulants in Patients With Atrial Fibrillation and Valvular Heart Disease Other Than Significant Mitral Stenosis and Mechanical Valves: A Meta-Analysis. Circulation. 2017;135(7):714-716. 26. Sun Q, Chang S, Lu S, Zhang Y, Chang Y. The Efficacy and Safety of 3 Types of Interventions for Stroke Prevention in Patients With Cardiovascular and Cerebrovascular Diseases: A Network Meta-analysis. Clin Ther. 2017;39(7):1291-1312.e1298. 27. Tao DL, Bien JY, DeLoughery TG, Shatzel JJ. Extended thromboprophylaxis with direct oral anticoagulants for medical patients: a systematic review and meta-analysis. Blood. 2017;129(5):653-655. 28. Xia ZN, Zhou Q, Zhu W, Weng XS. Low molecular weight heparin for the prevention of deep venous thrombosis after total knee arthroplasty: A systematic review and meta-analysis. Int J Surg. 2018;54(Pt A):265-275.

Appendix C: Direct Evidence from Systematic Reviews

LMWHs compared to direct anticoagulants (ie, direct thrombin inhibitors or direct factor Xa inhibitors) for Venous Thromboembolism

Table 1. Characteristics and Results of Included Systematic Reviews (from the Literature Search) Number of Literature First author, head-to- search year, study Population Intervention head RCTs Efficacy and safety results databases design included in (search date) the SR/MA Hakoum, Patients 3 types of 15 RCTs - CENTRAL, Fondaparinux was similar to heparins (enoxaparin or UFH) in terms of 201853 with cancer parenteral only 1 Medline, Embase all-cause mortality, recurrent VTE, or bleeding and anticoagulants: subgroup SR of RCTs confirmed (1) LMWH analysis of (Jan 2018) in reduction VTE (2) Fondaparin MATISSE of VTE ux RCT was of recurrence (3) UFH interest: fondaparinu x vs. enoxaparin or UFH Yan, 201868 Patients (1) NOACs 9 RCTs (5 Medline, The majority of RCTs compared NOACs vs. warfarin. Only results from with or (Apixaban, RCTs Embase, NOACs vs. LMWHs are reported here SR of RCTs without dabigatran, compared Cochrane Library NOACs vs. LMWHs: in reduction cancer edoxaban, NOACs vs. - NOACs revealed non-inferior net clinical benefit (VTE events and of VTE rivaroxaba LMWHs) (Feb 2018) bleeding events) vs. LMWHs in cancer patients recurrence n, - Results were mainly driven by 1 RCT (Raskob, 201856 – edoxaban betrixaban) vs. dalteparin up to 12 months). Raskob et al (Hokusai-Cancer trial) (2) Warfarin showed edoxaban is noninferior to dalteparin in terms of recurrent (3) LMWHs VTE or major bleeding (numerically, edoxaban may decrease VTE risk but increase bleeding risk compared to dalteparin) - Further studies are required. RCTs included in this SR were not designed to evaluate VTE and bleeding risk of NOACs in cancer patients

Table 1. Characteristics and Results of Included Systematic Reviews (from the Literature Search) Number of Literature First author, head-to- search year, study Population Intervention head RCTs Efficacy and safety results databases design included in (search date) the SR/MA Al Hajri, Patients Edoxaban vs. 6 RCTs (5 Google Scholar, VTE events: 201769 with lower dalteparin or RCTs of PubMed, - 3 studies: Significant reduction in VTE events with edoxaban vs. limb enoxaparin interest) Medline, dalteparin or enoxaparin (p<0.05) SR of RCTs orthopedic ScienceDirect - 2 studies showed edoxaban is similar to enoxaparin in VTE surgery (hip, Bleeding events: prophylaxis knee) (2015) - Bleeding rates higher with edoxaban compared to dalteparin or enoxaparin, but differences are not statistically significant Al Yami, Hospitalized Apixaban, 3 RCTs (only ClinicalTrials.gov APEX trial (Cohen, 2016) 201757 medically ill betrixaban 1 RCT of registry, Embase, Betrixaban (extended-duration) vs. enoxaparin (short-duration) patients rivaroxaban interest) MEDLINE - Prevention of VTE in patients with elevated D-dimer: RR 0.81; 95% vs.enoxaparin databases, and CI 0.65–1.00; P=0.054 CENTRAL - Major bleeding events in all patients: RR 1.19; 95% CI 0.67–2.12; P=0.55 Boyd, Patients Apixaban, 89 RCTs Medline - Total VTE: Apixaban, edoxaban, rivaroxaban and dabigatran have 201749 undergoing dabigatran, significantly greater efficacy than enoxaparin (both doses) THR and TKR edoxaban, (April 2014) - Major VTE: Apixaban, edoxaban, rivaroxaban and dabigatran have Dose- fondaparinux, significantly greater efficacy than enoxaparin 40 mg QD. Apixaban response or rivaroxaban and dabigatran were similarly efficacious to enoxaparin 30 mg BID model- vs. - Major bleeding and clinically relevant bleeding: based MA of enoxaparin o Similar bleeding rates for apixaban, edoxaban, and RCTs in VTE rivaroxaban compared to enoxaparin 40 mg QD. prophylaxis Dabigatran showed significantly higher bleeding than enoxaparin 40 mg QD. o Similar bleeding rates for edoxaban, rivaroxaban, and dabigatran compared to enoxaparin 30 mg BID. Apixaban showed significantly lower bleeding than enoxaparin 30 mg BID - Enoxaparin 30 mg BID has significantly better results in total VTE with significantly more bleeding compared to enoxaparin 40 mg QD

Table 1. Characteristics and Results of Included Systematic Reviews (from the Literature Search) Number of Literature First author, head-to- search year, study Population Intervention head RCTs Efficacy and safety results databases design included in (search date) the SR/MA Brunetti Patients Rivaroxaban or 9 – only 2 Medline DOACs (rivaroxaban or apixaban) vs. LMWHs (separate results by 201754 with VTE apixaban vs. studies of DOAC were not provided) and cancer enoxaparin interest (Dec 2015) - Incidence of recurrent VTE: no significant differences MA of RCTs (DOACs vs. - Incidence of bleeding: significantly higher with DOACs vs. LMWH in the LMWH) (OR 2.72, 95% CI, 1.05–7.01) prevention - The 2 RCTs included medically ill patients (only 3% to 7% were of VTE cancer patients). Authors considered studies including exclusively recurrence patients with cancer are necessary (cancer) Caldeira, Patients Apixaban 2.5 4 RCTs Medline, Apixaban vs. LMWH (all regimens) 201743 undergoing mg BID vs. Embase, - Primary efficacy endpoint: All VTE events and overall mortality THR and TKR LMWH (30 mg CENTRAL combined: RR: 0.63, 95% CI: 0.42-0.95, favors apixaban MA of RCTs BID or 40 mg - Major VTE events: no significant differences in VTE QD) (Sept 2016) - Symptomatic VTE events and VTE-related mortality combined: no prophylaxis significant differences - Major bleeding (primary safety endpoint) and surgery site bleeding: no significant differences (However, results were underpowered) - Subgroup analyses: o Apixaban vs. LMWH 40 mg QD: . the risk of all VTE events and overall mortality, and major VTE events was significantly lower with apixaban . No significant differences for symptomatic VTE or VTE- related death, major bleeding, and surgery site bleeding o Apixaban vs. LMWH 30 mg BID: . No significant differences for all endpoints (all VTE events or overall mortality, major VTE, symptomatic VTE or VTE- related death, major bleeding, and surgery site bleeding)

Table 1. Characteristics and Results of Included Systematic Reviews (from the Literature Search) Number of Literature First author, head-to- search year, study Population Intervention head RCTs Efficacy and safety results databases design included in (search date) the SR/MA Cimminiello Patients DOACs 14 Medline, DOACs vs. LMWH: 201770 undergoing (thrombin Embase, SCOPUS - No significant differences for overall mortality, symptomatic DVT, THR, TKR inhibitors and Cochrane non-fatal PE, major and non-major clinical relevant bleeding events MA of RCTs and acutely (dabigatran) Library - Significantly lower risk with enoxaparin compared to DOACs for the in VTE ill and factor Xa composite endpoint of fatal PE plus VTE-related death prophylaxis hospitalized inhibitors (Dec 2016) - The incidence of major and clinically relevant non-major bleeding is patients (apixaban, significantly lower with enoxaparin 40 mg but clinical relevance is betrixaban, limited edoxaban and Subgroup analysis: rivaroxaban) vs. Mortality: LMWH - Apixaban vs. enoxaparin: less mortality cases with enoxaparin; p = 0.0350 - No differences for enoxaparin vs. the remaining DOACs Symptomatic DVT: - Apixaban or rivaroxaban vs. enoxaparin: lower symptomatic DVT with apixaban (p = 0.0192) and rivaroxaban (p = 0.0122) Major bleeding: - No significant differences with apixaban, rivaroxaban, or dabigatran vs. enoxaparin Gao, 201744 Patients (1) Edoxaban 19 PubMed, Traditional pair-wise MA results undergoing (2) Dabigatan Embase, Incidence of asymptomatic DVT: NMA with orthopedic (3) Apixaban Cochrane Library - Edoxaban vs. enoxaparin: OR 0.38, 95% CI 0.23–0.63, favors pair-wise surgery (4) Rivaroxaba edoxaban MAs in VTE n (Nov 2016) - Apixaban vs. enoxaparin: OR 0.34, 95% CI 0.16–0.74, favors prophylaxis (5) Warfarin apixaban (6) Heparin - Rivaroxaban vs. enoxaparin: OR 0.41, 95% CI 0.22–0.76, favors (7) Bemiparin rivaroxaban (8) Ximelagatr CRNM bleeding: an

Table 1. Characteristics and Results of Included Systematic Reviews (from the Literature Search) Number of Literature First author, head-to- search year, study Population Intervention head RCTs Efficacy and safety results databases design included in (search date) the SR/MA (9) enoxaparin - Apixaban vs. enoxaparin: OR 0.66, 95% CI 0.45–0.97, favors apixaban Symptomatic DVT, PE, and major and minor bleeding: no significant differences between groups Suen, 201771 Patients LMWH, 45 RCTs (18 Medline, Embase Primary outcome: surgical site - especific bleeding complications undergoing warfarin, RCTs of - LMWH vs. apixaban: RR 1.27; 1.00-1.63; P=0.05; trend toward MA of RCTs TKR or THR rivaroxaban, interest) (Dec 2015) increased risk of surgical site bleeding with LMWH in VTE surgery apixaban, - LMWH vs. rivaroxaban: no differences prophylaxis dabigatran, - LMWH vs. dabigatran: RR 4.38; 1.53-12.57; P =0.03; increased risk aspirin, or no of surgical site bleeding episodes with LMWH pharmacologic Secondary outcomes: efficacy and bleeding outcomes treatment - Apixaban was more effective than LMWH in VTE prevention and there was a trend toward a decrease in major and clinically relevant bleeding with apixaban - Dabigatran was similar to LMWH in terms of VTE prevention and major and clinically relevant bleeding - Rivaroxaban was more effective in VTE prevention than LMWH but with higher incidence of major and clinically relevant bleeding Venker, Patients Apixaban, 18 RCTs Medline, Embase Primary efficacy outcome: VTE events compared to enoxaparin (most 201746 undergoing dabigatran, commonly 40 mg QD): TKR or THR fondaparinux, (January 2016) - Apixaban vs. enoxaparin: RR (95% CI) 0.71 (0.52–0.96), favors MA of RCTs surgery edoxaban apixaban in VTE - Dabigatran vs. enoxaparin: no significant differences prophylaxis Vs. - Fondaparinux vs. enoxaparin: RR (95% CI) 0.53 (0.45–0.63), favors fondaparinux Enoxaparin - Rivaroxaban vs. enoxaparin: RR (95% CI) 0.55 (0.46–0.66), favors (several doses) rivaroxaban - Edoxaban vs. enoxaparin: RR (95% CI) 0.49 (0.32–0.75), favors edoxaban

Table 1. Characteristics and Results of Included Systematic Reviews (from the Literature Search) Number of Literature First author, head-to- search year, study Population Intervention head RCTs Efficacy and safety results databases design included in (search date) the SR/MA Primary safety outcome: Major/clinically relevant bleeding (RR [95% CI]): - Apixaban vs. enoxaparin: RR (95% CI) 0.84 (0.70–0.99), favors apixaban - Dabigatran vs. enoxaparin: no significant differences - Fondaparinux vs. enoxaparin (major bleeding): no significant differences - Rivaroxaban vs. enoxaparin: RR (95% CI) 1.27 (1.01–1.59), favors enoxaparin - Edoxaban vs. enoxaparin: no significant differences Wang, Patients Apixaban 104 RCTs (8 PubMed, All-cause VTE: 201772 undergoing Betrixaban RCTs of Embase, Apixaban vs. enoxaparin: LogOR (95% CI) -0.6 (-0.96, -0.23) major joint Edoxaban interest) Cochrane Library Major VTE: NMA with surgery LMWHs Betrixaban vs. enoxaparin: LogOR (95% CI) -0.13 (-0.88, 1.63) pair-wise Other agents (July 2016) All bleeding events: MAs in VTE Apixaban vs. enoxaparin: LogOR (95% CI) 0.13 (-0.01, 0.28) prophylaxis Major bleeding: Betrixaban vs. enoxaparin: LogOR (95% CI) -1.49 (-3.10, 0.10) Dalteparin vs. edoxaban: LogOR (95% CI) -1.95 (-4.79, 0.88) Ning, 201650 Patients Rivaroxaban vs. 9 RCTs PubMed, Rivaroxaban vs. enoxaparin undergoing enoxaparin Embase, Primary efficacy endpoint: Symptomatic VTE: RR 0.44, 95% CI 0.29 to SR/MA of TKR or THR CENTRAL 0.67, P = 0.0001; favors rivaroxaban RCTs surgery Secondary efficacy endpoints: (Sept 2015) - Symptomatic DVT (P = 0.0001), favors rivaroxaban - Symptomatic pulmonary embolism: no significant differences between groups Primary safety endpoint: Major bleeding: RR 1.37, 95% CI 1.05 to 1.78, P = 0.02; increased risk with rivaroxaban

Table 2. Characteristics and Results of Relevant Systematic Reviews Identified in the Reference List of Included Systematic Reviews Number of First author, head-to- Literature search year, study Population Intervention head RCTs databases (search Efficacy and safety results design included in date) the SR/MA Feng, 201512 Patients Oral direct 20 RCTs PubMed, EMBASE and Primary efficacy outcome (total VTE: DVT, non-fatal PE, and all- undergoing factor Xa Cochrane Library cause mortality): SR/MA of TKR or THR inhibitor - Rivaroxaban vs. enoxaparin: RR 0.70, 0.60 to 0.81, favors RCTs (rivaroxaban, (Search date nor rivaroxaban apixaban, specified) - Apixaban vs. enoxaparin: RR 0.62, 0.47 to 0.81, favors betrixaban, apixaban darexaban - Edoxaban vs. enoxaparin: RR 0.62, 0.39 to 0.97, favors and edoxaban edoxaban) vs. Primary bleeding outcomes (major bleeding or clinically relevant enoxaparin non-major bleeding) - Rivaroxaban vs. enoxaparin: RR 1.52, 1.14 to 2.02, increased risk with rivaroxaban - Apixaban vs. enoxaparin: no significant differences - Edoxaban vs. enoxaparin: no significant differences Yoshida, Patients New 15 RCTs Cochrane Primary efficacy endpoint (DVT, nonfatal PE, or all-cause 201342 undergoing anticoagulants Peripheral Vascular mortality): major (fondaparinux, Diseases Group - Fondaparinux vs. enoxaparin (mixed doses): RR 0.50; 95% CI, SR/MA of orthopedic rivaroxaban, records, CENTRAL, 0.39, 0.63, favors fondaparinux RCTs surgery dabigatran, Medline, Embase, - Rivaroxaban vs. enoxaparin (mixed doses): RR 0.50; 95% CI, (THR, TKR, and apixaban) Literatura 0.34, 0.73, favors rivaroxaban hip fracture vs. enoxaparin Latino-Americana e do - Dabigatran 220 mg or apixaban vs. enoxaparin: no repair) Caribe em Ciencias da differences Saude - Dabigatran 150 mg vs. enoxaparin (mixed doses): dabigatran is inferior (January 2000 – March Incidence of proximal DVT: 2011) - Apixaban vs. enoxaparin: RR 0.45; 95% CI, 0.27, 0.75, favors apixaban - Remaining NACs vs. enoxaparin: no differences Symptomatic DVT - Apixaban vs. enoxaparin: RR 0.38; 95% CI, 0.16, 0.90 - Rivaroxaban vs. enoxaparin: RR 0.45; 95% CI, 0.27, 0.77 - Remaining NACs vs. enoxaparin: no differences 56

Major VTE: - Rivaroxaban vs. enoxaparin: RR 0.44; 95% CI, 0.25, 0.81, favors rivaroxaban - Remaining NACs vs. enoxaparin: no differences Any bleeding: - Fondaparinux vs. enoxaparin: RR 1.27; 95% CI, 1.04, 1.55), favors enoxaparin - Apixaban vs. enoxaparin: RR 0.88; 95% CI, 0.79, 0.99, favors apixaban - Remaining NACs vs. enoxaparin: no differences Major bleeding/minor bleeding/clinically relevant non-major bleeding: - Similar results between NACs and enoxaparin, except for dabigatran 150 mg, which showed significantly higher bleeding rates than enoxaparin - Death: no differences - Liver enzymes elevation: better results with dabigatran 220 mg compared to enoxaparin Gomez- Patients New 16 RCTs (4 Medline, CENTRAL Primary efficacy outcome (reduction in symptomatic VTE: Outes, undergoing anticoagulants RCTs of symptomatic DVT or PE): 201245 TKR or THR (rivaroxaban, dabigatran (April 2011) - Rivaroxaban vs. enoxaparin: RR 0.48, 95% CI 0.31 to 0.75; dabigatran, vs. P=0.001, favors rivaroxaban SR/MA of and apixaban) enoxaparin, - Dabigatran (220 mg or 150 mg) or apixaban vs. enoxaparin: RCTs vs. enoxaparin 8 RCTs of no significant differences rivaroxaban Secondary efficacy outcomes (each component of the primary vs. efficacy endpoint and all cause death): enoxaparin, - Rivaroxaban vs. enoxaparin: and 4 RCTs o Significantly lower risk of symptomatic DVT, total VTE or of apixaban all cause death, and major VTE or VTE-related death vs. with rivaroxaban enoxaparin) o No significant differences for symptomatic PE - Dabigatran vs. enoxaparin: o No significant differences between groups for symptomatic DVT or PE, total VTE or all cause death, and major VTE or VTE-related death - Apixaban vs. enoxaparin: o Significantly lower risk of symptomatic DVT, total VTE or all cause death with apixaban, but more PE events (non-

significant results in the MA but significant results in the 2 individual RCTs on TKR). No significant differences between groups in total VTE or all cause death Primary safety outcome (clinically relevant bleeding: major bleeding or clinically relevant non-major bleeding): - Rivaroxaban vs. enoxaparin: RR 1.25, 95% CI 1.05 to 1.49; P=0.01, increased risk with rivaroxaban - Dabigatran (both doses) vs. enoxaparin: no differences - Apixaban vs. enoxaparin: RR 0.82, 95% CI 0.69 to 0.98; P=0.03, reduced risk with apixaban Secondary safety outcomes: - No significant differences between groups for each component of the primary safety endpoint (major bleeding or clinically relevant non-major bleeding) Net clinical endpoint (composite of symptomatic venous thromboembolism, major bleeding, and death): No significant differences between apixaban, dabigatran, or rivaroxaban vs. enoxaparin for efficacy and safety Huang, Patients Apixaban 2.5 3 RCTs Medline, Embase, Apixaban vs. enoxaparin (all doses) 201147 undergoing mg vs. CENTRAL Primary efficacy endpoint (ie, composite of major VTE TKR or THR enoxaparin [asymptomatic or symptomatic proximal DVT and objectively SR/MA of (30 mg BID or (1996 - July 2010) confirmed PE]): RCTs 40 mg QD) - Proximal DVT (3 RCTs including 2 RCTs with enoxaparin 30 mg BID and 1 RCT with enoxaparin 40 mg QD): OR 0.47, 95%CI: 0.27 to 0.82, p=0.007; favors apixaban • Subgroup analysis: Apixaban vs. enoxaparin 30 mg BID (2 RCTs): No differences for proximal DVT - PE (3 RCTs): no differences between groups, although there was a numerical increase of PE events with apixaban Secondary efficacy outcome (all-cause mortality) (3 RCTs): no differences between groups Primary safety endpoint (ie, major bleeding events): OR 0.55 (95% CI 0.32 to 0.96, p=0.034); favors apixaban Secondary safety outcomes (clinically relevant non-major bleeding events, raised hepatic transaminase enzyme or bilirubin concentrations, MI, and stroke): no significant differences between groups

Turun, Patients Rivaroxaban 8 RCTs Cochrane Rivaroxaban vs. enoxaparin 201173 undergoing vs. enoxaparin library, Embase, Primary efficacy outcome (incidence of VTE: any DVT [proximal TKR or THR (30 mg BID or Pubmed, and Chinese and/or distal]; nonfatal, symptomatic, SR/MA of 40 mg QD) databases objectively confirmed PE, and all-cause death): RCTs - Rivaroxaban vs. enoxaparin 40 mg QD: RR= 0.38, 95%CI [0.25–0.59]; P<0.0001, favors rivaroxaban - Rivaroxaban vs. enoxaparin 30 mg BID: RR= 0.77 95%CI [0.59, 1.00]; p=0.05, rivaroxaban is not inferior Primary safety endpoint (Preoperative major bleeding): no significant differences Other endpoints: Incidence of major VTE: - Rivaroxaban vs. enoxaparin 40 mg QD: favors rivaroxaban - Rivaroxaban vs. enoxaparin 30 mg BID: no significant differences Clinical relevant non-major bleeding: - Rivaroxaban vs. enoxaparin 40 mg QD: increased risk with rivaroxaban - Rivaroxaban vs. enoxaparin 30 mg BID: no significant differences Cao, 201051 Patients Rivaroxaban 8 RCTs PubMed, Embase, Rivaroxaban vs. enoxaparin undergoing vs. enoxaparin CENTRAL Primary efficacy outcome (ie, total VTE and all-cause mortality): SR of RCTs TKR or THR (30 mg BID or RR 0.56, 95% CI 0.39-0.80, favors rivaroxaban 40 mg QD) (March 2010) Subgroup analysis: - Major VTE: RR 0.42, 95% CI 0.20–0.84; favors rivaroxaban - DVT: RR 0.54, 95% CI 0.37–0.79; favors rivaroxaban - Symptomatic VTE: RR 0.49, 95% CI 0.34–0.72; favors rivaroxaban Safety outcomes: - Major bleeding, clinically relevant non-major bleeding, total bleeding events: no significant differences, although rivaroxaban group showed numerically higher bleeding events compared to enoxaparin - Drug-related AEs: no significant differences Abbreviations: AE, adverse event; CENTRAL, Cochrane central register of Controlled Trials; BID, twice daily; CI, confidence interval; DVT, deep vein thrombosis; MA, meta-analysis; MI, myocardial infarction; NAC, new anticoagulants; OR, odds ratio; PE, pulmonary embolism; QD, once daily; RR, relative risk; SR, systematic review; THR, total hip replacement; TKR, total knee replacement; VTE, venous thromboembolism

Appendix D: Randomized Controlled Trials Identified in the Included Systematic Reviews

Table 1. Randomized Controlled Trials Included in the Selected Systematic Reviews for VTE Treatment and Prevention SYSTEMATIC REVIEWS

44 51 68 O Randomized

53 43 54 70 69 46 42 45 47 71 72 12 73 50 Controlled Trials , Caldeira 2017 Hajri,Al 2017 Hakoum Hakoum 2018 Yoshida, 2013 Gomez 2012 Huang 2011 Suen, 2017 Wang, 2017 Gao 2017 Brunetti 2017 Cimminiello 2017 Boyd 2017 Venker, 2017 Yan 2018 Cao 2010 Feng, 2015 Turun 2011 Ning 20 16 FONDAPARINUX vs. ENOXAPARIN Lassen 2002 X X X X (EPHESUS) Turpie 2002 X X X X (PENTATHLON 2000) Bauer 2001 X X X X (PENTAMARKS) Eriksson 2001 X X X (PENTHIFRA) van Doormaal 200955 (subgroup analysis of X an RCT - Büller 2004) DABIGATRAN vs. ENOXAPARIN Eriksson 2005 X X (BISTRO II) Eriksson 2007 (RE- X X X X X X X MODEL) Eriksson 2007 (RE- X X X X X X X X NOVATE) Eriksson 2011 (RE- X X X X X X X X NOVATE II) Ginsberg 2009 (RE- X X X X X X X X MOBILIZE) Mirdamadi 2014 X Friedman 2010 X RIVAROXABAN vs. ENOXAPARIN Eriksson 2006 X X X X X X X X X (ODIXa-HIP)

Table 1. Randomized Controlled Trials Included in the Selected Systematic Reviews for VTE Treatment and Prevention SYSTEMATIC REVIEWS

44 51 68 O Randomized

53 43 54 70 69 46 42 45 47 71 72 12 73 50 Controlled Trials , Caldeira 2017 Al Hajri,Al 2017 Hakoum Hakoum 2018 Yoshida, 2013 Gomez 2012 Huang 2011 Suen, 2017 Wang, 2017 Gao 2017 Brunetti 2017 Cimminiello 2017 Boyd 2017 Venker, 2017 Yan 2018 Cao 2010 Feng, 2015 Turun 2011 Ning 20 16 Eriksson 2006 X X X X X X X X X (ODIXa-OD HIP Eriksson 2007 (dose- escalation)- PROOF X X X X X X X OF CONCEPT Eriksson 2008 X X X X X X X X X X X X (RECORD-1) Kakkar 2008 X X X X X X X X (RECORD-2) Lassen 2008 X X X X X X X X X X X X (RECORD-3) Turpie 2005 (ODIXA X X X X X X X KNEE) Turpie 2009 X X X X X X X X X X X X (RECORD-4) Cai Wei, 2008 X Cohen 201374 (MAGELLAN) – Medically ill patients, X X X including cancer patients Zou, 2014 X EDOXABAN vs. ENOXAPARIN Fuji 2014 (STARS E-3) X X X X X X Fuji 2015 (STARS J-V) X X X X X Fuji 2014 (STARS J-2) X X X Fuji 2014 X X X APIXABAN vs. ENOXAPARIN Lassen 2007 X X X X X X X X X (Apropos) Lassen 2009 X X X X X X X X X X X (ADVANCE-1)

Table 1. Randomized Controlled Trials Included in the Selected Systematic Reviews for VTE Treatment and Prevention SYSTEMATIC REVIEWS

44 51 68 O Randomized

Appendix E: Characteristics of the Main Randomized Controlled Trials Identified in the Included Systematic Reviews

Table 1. Characteristics of the Main Phase III Trials comparing Direct Anticoagulants vs. LMWHs in VTE Treatment and Prevention Author, year (Trial N Patient population Intervention acronym) Apixaban Prevention of VTE in major orthopedic surgery Lassen, 200976 3,195 Patients undergoing Apixaban 2.5 mg BID vs. enoxaparin 30 mg BID, 10-14 days (ADVANCE-1) TKR Lassen, 201077 3,057 Patients undergoing Apixaban 2.5 mg BID vs. enoxaparin 40 mg daily, 10-14 days (ADVANCE-2) TKR Lassen, 201078 5,407 Patients undergoing Apixaban 2.5 mg BID vs. enoxaparin 40 mg daily, 32-38 days (ADVANCE-3) THR Acute Treatment of VTE Agnelli, 201359 5,400 Patients with Apixaban 10 mg BID (7 days), then 5 mg BID (6 months) vs. (AMPLIFY) confirmed VTE enoxaparin 1 mg/kg BID (5 days), then warfarin (INR 2-3) Betrixaban Cohen, 201658 7513 Patients Extended-duration thromboprophylaxis with betrixaban for 35-42 (APEX trial) hospitalized with days vs. short-duration thromboprophylaxis with enoxaparin for 6- acute medically ill 14 days patients Dabigatran Prevention of VTE in major orthopedic surgery Eriksson, 3,493 Patients undergoing Dabigatran 150 mg or 220 mg QD vs. enoxaparin 40 mg QD, 28 – 35 200779 THR days (RE-NOVATE) Eriksson, 2,101 Patients undergoing Dabigatran 150 mg or 220 mg QD vs. enoxaparin 40 mg QD, 6 – 10 200780 TKR days (RE-MODEL) Ginsberg, 2,615 Patients undergoing Dabigatran 150 mg or 220 mg QD vs. enoxaparin 30 mg BID, 12 – 15 200981 TKR days (RE-MOBILIZE) Eriksson, 2,055 Patients undergoing Dabigatran 220 mg QD vs. enoxaparin 40 mg QD 201182 THR (RE-NOVATE II) Edoxaban Fuji, 201483 716 Patients undergoing Edoxaban 30 mg QD vs. enoxaparin 2000 IU (20 mg) BID, 11 to 14 (STARS E-3) TKR days Fuji, 201584 610 Patients undergoing Edoxaban 30 mg QD vs. enoxaparin 2000 IU (20 mg) BID, 11 to 14 (STARS J-V) THR days Fondaparinux Acute Treatment of VTE Buller 200460 2,205 Patients with DVT Fondaparinux 7.5 mg QD vs. enoxaparin mg/kg BID (MATISSE DVT) and cancer