A Review of the Efficacy and Safety Profiles of the Novel Oral Anticoagulants in the Treatment and Prevention of Venous Thromboembolism

Clinical Therapeutics/Volume ▪, Number ▪, 2018

A Review of the Efficacy and Safety Profiles of the Novel Oral Anticoagulants in the Treatment and Prevention of Venous Thromboembolism Alexis A. Coulis, MS; and William C. Mackey, MD Tufts University School of Medicine, Boston, MA, USA ABSTRACT Purpose: This study aims to review the published literature concerning the use of novel oral anticoagulants (NOACs) in the treatment and prevention of venous thromboembolism (VTE) and to identify the appropriate niche for each NOAC by comparing their behaviors in Phase III and Phase IV clinical trial settings. Methods: The ClinicalTrials.gov database was used to identify Phase III and postmarketing (Phase IV) randomized controlled trials concerning the efficacy and safety profiles of the oral NOACs (apixaban, dabigatran etexilate, exodaban, and rivaroxaban) for the treatment or prevention of VTE. Studies of special interest included those that compared the administration of a NOAC versus standard anticoagulation therapy with low-molecular-weight heparin and/or a vitamin K antagonist. Findings: Overall, the NOACs offer a simplified anticoagulation regimen that has noninferiority and similar rates of bleeding when compared with standard therapy throughout multiple studies. This finding held true across several VTE conditions that required anticoagulation, such as the treatment and prophylaxis of acute VTE, including both deep vein thrombosis and pulmonary embolism. Absence of dietary restrictions and fixed oral dosing that does not require monitoring makes NOACs ideal for the outpatient setting. Apparent niches for each individual NOAC are discussed in detail; however, the paucity of trials comparing NOAC performance in specific clinical settings makes precise definition of these niches problematic. Implications: It now seems reasonable for clinicians to consider NOACs as first-line agents for both the treatment and prophylaxis of VTE and to attempt to tailor their particular medication choices for each patient scenario. More trials comparing NOAC

performance in specific clinical settings are essential to ensure these medications are being used to their full potential. (Clin Ther. 2012;34:XXXeXXX) © 2012 Elsevier HS Journals, Inc. (Clin Ther. 2018;▪:1e28) © 2018 Published by Elsevier Inc. Keywords: NOACS, novel oral anticoagulants, venous thromboembolism, VTE.

INTRODUCTION Venous thromboembolism (VTE) is the third most prevalent vascular diagnosis after myocardial infarction and stroke. It is estimated to affect 300,000 to 600,000 persons in the United States each year.1 Deep vein thrombosis (DVT) and pulmonary embolism (PE) are the 2 acute manifestations of VTE. The mainstay of treatment and prophylaxis of VTEdanticoagulation therapydworks to inhibit blood clotting, lowering the risks of DVT or PE. An overview of the coagulation cascade and the antithrombotic therapy targets are illustrated in Figure 1. Conventional anticoagulants include heparin, a naturally occurring anticoagulant produced by basophils and mast cells that works by activating antithrombin, an inhibitor of thrombin formation. Unfractionated heparin (UFH), the pharmaceutical version of heparin, contains polysaccharide molecular chains of varying lengths. Low-molecular-weight heparin (LMWH), commonly enoxaparin sodium,* is

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* Trademark: Lovenox Bridgewater, New Jersey).

(sanofi-aventis U.S., LLC,

Accepted for publication October 9, 2018 https://doi.org/10.1016/j.clinthera.2018.10.009 0149-2918/$ - see front matter © 2018 Published by Elsevier Inc.

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Clinical Therapeutics

2 Figure 1.

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Coagulation Cascade and Antithrombotic Therapy Targets. Warfarin inhibits the synthesis of Vitamin K-dependent clotting factors including FII (Prothrombin), FVII, FIX (not pictured), and FX. Direct Thrombin Inhibitors including Dabigatran inhibit FIIa (Thrombin). Direct Factor Xa Inhibitors including Apixaban, Edoxaban, and Rivaroxaban inhibit FXa. Heparins facilitate the physiological anticoagulant Antithrombin (AT). Low Molecular Weight Heparin (LMWH) and Fondaparinux preferentially work through AT's inhibition of FXa while Unfractionated Heparin (UFH) preferentially works through AT's inhibition of FIIa (Thrombin). Working to disrupt platelet aggregation, Aspirin inhibits the generation of TxA2 while Clipidogrel inhibits the ADP receptor P2Y12.

A.A. Coulis and W.C. Mackey a further modified version of heparin that has undergone fractionation to sequester only short-chain polysaccharides. This helps to increase its pharmacodynamic predictability. LMWH preferentially works to activate antithrombin's inhibition of clotting factor Xa. Fondaparinux sodiumy is a synthetic pentasaccharide factor Xa inhibitor that also binds antithrombin but instead accelerates its inhibition of thrombin. UFH, LMWH, and fondaparinux must be administered by injection. The effects of UFH and LMWH can be reversed with protamine sulfate, a medication that binds to these agents and inhibits their anticoagulant activity. A second major class of conventional anticoagulants includes the vitamin K antagonists (VKAs), most notably warfarin.z By inhibiting the vitamin Kedependent synthesis of several clotting factors, VKAs effectively decrease patients' coagulation activity. Although given orally, and therefore easily administered to outpatients, VKAs have a narrow therapeutic window and require regular blood tests to monitor their therapeutic effect. Prothrombin time and the international normalized ratio (INR) are 2 values obtained to ensure correct dosing. Failure to properly monitor blood clotting parameters could result in subtherapeutic anticoagulation, risking thrombus propagation, or a supratherapeutic effect that increases the risk of major bleeding. In addition, because the effectiveness of VKAs is a direct result of their ability to inhibit a vitamin Kedependent pathway, this therapy is extremely sensitive to dietary intake of vitamin K. Patients undergoing anticoagulant treatment with VKAs must work daily to regulate their diet to ensure their medication remains in a therapeutic range. Although this often complicates patients' daily eating habits, one clinical benefit is vitamin K's ability to reverse VKA anticoagulation in the event of major bleeding or VKA overdose. Although these anticoagulation regimens have been used in clinical practice for many years, they have numerous limitations. Characteristics of an ideal anticoagulant include a simple dosing regimen with a

y Trademark: Arixtra United Kingdom).

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(GlaxoSmithKline, Brentford, ®

z Trademark: Coumadin York, New York).

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(Bristol-Myers-Squibb, New

wide therapeutic window that eliminates the need for frequent clinical monitoring, easy oral administration, minimal food and drug interactions, and the availability of an antidote that quickly and effectively reverses anticoagulation. Recently, pharmaceutical companies developed novel oral anticoagulants (NOACs) with many of these attributes. Three of the 4, apixaban,x edoxaban,jj and rivaroxaban,¶ are direct factor Xa inhibitors. Although the heparins achieve anticoagulation by increasing antithrombin's inhibition of factor Xa, these medications inhibit factor Xa directly. The fourth NOAC, dabigatran etexilate,# is the prodrug of dabigatran, which is a direct thrombin inhibitor. Taken once or twice daily at fixed oral doses, these 4 medications are approved by the US Food and Drug Administration (FDA) for a variety of anticoagulant regimens in the treatment and prophylaxis of VTE as well as in the prevention of stroke and systemic embolism in adults with nonvalvular atrial fibrillation. Figure 2 describes the current FDA dosing and administration recommendations regarding NOAC anticoagulation therapy for clinical conditions related to VTE. Benefits of anticoagulation with the NOACs include ease of their oral administration, fewer drug and dietary interactions, and predictable pharmacokinetic properties that do not require clinical monitoring (see Table I for a full comparison of anticoagulation regimens). However, because less is known about these newer medications and there is limited research to speak to their behavior in clinical practice, efficacy and complication rates in comparison with traditional VKA or heparin therapies are of major interest. Although these drugs have great promise, further investigation is needed to firmly establish their place in clinical practice and define the optimal role(s) for each of the 4 agents.

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x Trademark: Eliquis (Bristol-Myers-Squibb, New York, New York). ® jj Trademark: Savaysa (Daiichi Sankyo Co, Ltd, Tokyo, Japan). ® ¶ Trademark: Xarelto (Janssen Pharmaceuticals Inc, Raritan, New Jersey) . ® # Trademark: Pradaxa (Boehringer Ingelheim Pharmaceuticals, Inc, Ingelheim am Rhein, Germany).

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4 Figure 2. Anticoagulation Regimens in Treatment and/or Prevention of VTE. Regimens are according to the FDA prescribing recommendations in the United States. Of note, Edoxaban is not currently approved by the FDA for the extended treatment of VTE or prophylactic treatment following Total Knee or Hip Arthroplasties (TKA/THA). Additionally, Dabigatran Etexilate is not approved by the FDA for prophylactic treatment following a TKA. *Reduced 30mg dose is intended for patients with CRCL 15-50 mL/min, body weight £60kg, or those taking concomitant P-gp inhibitors. **Reduced 2.5mg dose is intended for patients with at least 2 of the following characteristics: age 80, body weight £60kg, or serum creatinine 1.5 mg/dL.

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A.A. Coulis and W.C. Mackey Table I.

Comparison of anticoagulants.

Variable Administration

Heparins

Vitamin K Antagonists

Reversal agent

Parenteral (intravenous or Oral subcutaneous) Dose adjusted to INR 2.0e3.0 Dose adjusted to INR 2.0e3.0 requiring frequent monitoring requiring frequent monitoring because of a narrow therapeutic because of a narrow therapeutic window and varied dose window and varied dose response response Fewer drug interactions Many drug interactions and directly affected by foods rich in vitamin K Protamine sulfate Vitamin K

Clinical reliability

Reliably used for years in clinical practice

Dosing

Food-drug interactions

Reliably used for years in clinical practice

Novel Oral Anticoagulants Oral Wide therapeutic window and predictable dose response allows for fixed dosing Low potential for drug interactions and unaffected by diet Andexanet alfa,* idarucizumaby Short history of clinical use

INR ¼ international normalized ratio. * Antidote for factor Xa inhibitors, approved by the US Food and Drug Administration in 2018 as a reversal agent for apixaban and rivaroxaban. y Antidote for direct thrombin inhibitors, approved by the US Food and Drug Administration in 2015 as a reversal agent for dabigatran etexilate.

METHODS The ClinicalTrials.gov database was used to identify published Phase III and postmarketing (Phase IV) randomized controlled trials concerning the efficacy and safety profiles of the oral NOACs (apixaban, dabigatran etexilate, edoxaban, and rivaroxaban). Each of these primary sources was subsequently reviewed for their results concerning the treatment or prevention of VTE. This process excluded active trials that were not yet published during or after February 2018 and Phase I or Phase II trials. Particular studies of interest included those that compared the administration of a NOAC versus standard anticoagulation therapy with LMWH and/or a VKA. Additional exclusions included trials focused on the prevention of stroke or systemic embolism in adults with atrial fibrillation because this topic was beyond the scope of the present review. In addition, although the oral direct thrombin inhibitor ximelagatran** was evaluated in Phase III clinical trials and was approved

** Trademark: Exanta United Kingdom).

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(AstraZeneca, Cambridge,

for use internationally, it was also excluded from this review because this medication did not gain approval from the FDA because of concerns regarding hepatotoxicity. Electronic searches to supplement the reported data with additional relevant articles were conducted as needed. This review aimed to speak to the practical clinical applications of each of these medications by comparing their efficacy and safety profiles in Phase III and Phase IV trial settings. As such, reported data include the individual trial designs, study outcomes, and trial authors’ commentary regarding the studied drug in clinical practice. Specifically, the measured efficacy end points included VTE progression or recurrence in treatment studies and incidence of DVT and PE in prophylaxis studies, whereas rates of major bleeding and/or clinically relevant nonmajor (CRNM) bleeding events were primary safety profile end points. The Phase III and Phase IV clinical trials, which constituted most of the reported results, were funded by the medications’ respective pharmaceutical companies; however, a formal risk of bias assessment was not performed.

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RESULTS Medication Characteristics Although the NOACs can be misinterpreted as a homogeneous group of medications with similar routes of administration and mechanisms of action, there are slight variations that could have clinical relevance. Table II provides an overview of these characteristics, which are discussed below.

Adverse Effects In Phase III clinical trials, all 4 NOAC regimens revealed a relatively low adverse effect profile2e5 Besides bleeding, the only frequently reported significant adverse effect was dyspepsia associated with dabigatran etexilate. In clinical study, this affected 3% of patients.2

Drug Interactions As substrates of the P-glycoprotein (P-gp) transporter, all 4 NOACs interact with medications, inducing or

Table II.

Medication characteristics according to the highlights of prescribing information published by the US Food and Drug Administration.

Variable Dosage forms Adverse effects

Drug interactions

Contraindicated patient populations

Antidote

inhibiting P-gp. Specifically, strong P-gp inhibitors (eg, antifungals such as ketoconazole as well as the HIV protease inhibitor ritonavir) increased medication effect and therefore elevated the risk of bleeding.6e9 For this reason, coadministration of rivaroxaban or dabigatran etexilate with the aforementioned medications or other strong P-gp inhibitors is not recommended.6,8 Conversely, P-gp inducers, such as the antibiotic rifampicin, or hypericum (commonly known as St. John's wort, an herb thought to calm feelings of anxiety or depression), decrease NOAC effect and could lead to subtherapeutic levels of anticoagulation.6e9 In addition, because apixaban, edoxaban, and rivaroxaban are all metabolized by liver oxidative pathways, including cytochrome P450 3A4 (CYP3A4), medications that induce or inhibit this enzyme will affect these anticoagulants. Including the anticonvulsants carbamazepine and phenytoin as well

Apixaban Tablets: 2.5 and 5 mg Bleeding

Dabigatran Etexilate Capsules: 75 and 150 mg Dyspepsia, bleeding

P-gp inducers Strong dual (rifampin), P-gp inhibitors or inhibitors inducers of (dronedarone, CYP34A and Psystemic gp ketoconazole) Elderly people Breastfeeding mothers, pregnancy, severe hepatic impairment Andexanet alfa Idarucizumab

Edoxaban

Rivaroxaban

Tablets: 15, 30, and Tablets: 10, 15, and 60 mg 20 mg Bleeding Rash, abnormal liver function test results, anemia, bleeding Anticoagulants, P-gp Strong dual inhibitors inducers (rifampin) or inducers of CYP34A and P-gp, anticoagulants

Breastfeeding mothers, Breastfeeding mothers, renal renal impairment, impairment, moderate-severe hepatic impairment hepatic impairment Procoagulant agents (prothrombin complex, recombinant factor VIIa)

Andexanet alfa

CYP34A ¼ cytochrome P450 3A4; P-gp ¼ P-glycoprotein.

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A.A. Coulis and W.C. Mackey as many of the same medications mentioned above, coadministration with apixaban, edoxaban, or rivaroxaban should be avoided.6,7,9 However, because of its limited hepatic metabolism and primarily renal elimination, dabigatran etexilate is not significantly affected by pharmaceuticals that alter CYP3A4 activity.8 Finally, concomitant use of apixaban or rivaroxaban with other medications that affect hemostasis is not recommended.6,7 Because both these medications are intended to be used as a monotherapeutic, singledrug approach to anticoagulation, overlapping administration with an additional anticoagulant increases the risk of bleeding. With regard to common antiplatelet agents, such as aspirin or clopidogrel,yy although coadministration with apixaban or rivaroxaban is not specifically contraindicated, FDA prescribing information in the United States includes a warning regarding the increased risk of bleeding and recommends that concomitant use be conducted with caution.6,7

Specific Populations Systemic anticoagulation effect increases with decreasing renal function for all 4 NOACs.6e9 For this reason, patients with severe renal insufficiency (creatinine clearance [CLCR] <30 mL/min) were excluded from study during Phase III trials and are not currently candidates for anticoagulation via a NOAC. Because of the likelihood of increased anticoagulant effect, rivaroxaban and apixaban are additionally contraindicated in patients with hepatic disease associated with coagulopathy.6,7 Although the effect of edoxaban does not appear to increase in patients with mild to moderate hepatic impairment, the FDA warns against its use in such patients because of the potential for underlying coagulation abnormalities.9 Again resulting from its renal clearance, the pharmacokinetic properties of dabigatran etexilate are not significantly affected by mild to moderate hepatic impairment.8

availability of a reversal agent or antidote in the case of medication overdose or uncontrolled bleeding. Although potential reversal strategies, including the administration of activated charcoal or nonspecific procoagulant agents (eg, prothrombin complex, recombinant factor VIIa) may be used, agents that specifically reverse NOAC anticoagulation are preferred. Developed as a reversal agent for factor Xa inhibitors and recently FDA approved, andexanet alfa is a modified human factor Xa decoy protein that was designed to sequester factor Xa inhibitors, thus restoring coagulation by permitting the activity of endogenous factor Xa. Using this mechanism, the recent Phase III Randomized, Double-Blind, Placebo-controlled Study in Older Subjects to Assess Safety and the Reversal of Apixaban Anticoagulation With Intravenously Administered Andexanet Alfa (ANNEXA) trials, ANNEXA-A and ANNEXA-R revealed that within 2 to 5 minutes, andexanet alfa reversed 94% and 92% of apixaban's and rivaroxaban's antiefactor Xa activity.10 In the subsequent ANNEX-4 study, andexanet alfa restored hemostasis in 79% of patients with acute major bleeding associated with these 2 factor Xa inhibitors.11 Although it is a factor Xa inhibitor as well, no research currently exists on andexanet alfa's effect on edoxaban anticoagulation. An additional reversal agent designed to inhibit antiefactor Xa activity, ciraparantag, is also under current investigation. As a direct thrombin inhibitor, dabigatran etexilate follows a different mechanism of action and is susceptible to a unique method of inhibition. On the recent publication of the Phase III Reversal of Dabigatran Anticoagulant Effect With Idarucizumab (RE-VERSE AD) trial, idarucizumab, a fully humanized monoclonal antibody fragment, competed with dabigatran etexilate for thrombin binding and completely reversed its anticoagulative effect. Specifically, researchers reported that idarucizumab normalized clotting times of 88%e98% of patients within minutes.12

Treatment for Acute VTE Reversal Agents Since their development and use in clinical practice, a major concern with NOAC therapy has been the

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yy Trademark: Plavix (Bristol-Myers-Squibb, New York, New York).

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In the event of acute VTE, including DVT and/or PE, standard treatment consists of a multiple-phase anticoagulant regimen. The initial component of standard therapy lasts for 5 to 10 days and calls for parenteral LMWH (enoxaparin sodium, UFH, or fondaparinux sodium). This regimen overlaps with and is followed by a long-term therapy that consists

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Clinical Therapeutics of a VKA taken for usually 3 to 6 months. Long-term therapy is not only meant to complete the treatment of acute VTE but also works to prevent recurrent thrombotic episodes.

Dosing and Administration Both apixaban and rivaroxaban were approved as a single-drug approach for the treatment of acute VTE and do not require initial parenteral treatment with LMWH or UFH.4,5 Specifically, apixaban is dosed at 10 mg twice daily for 7 days followed by 5 mg twice daily for 6 months. Rivaroxaban is administered at 15 mg twice daily for 3 weeks and is followed by 20 mg once daily for 3 to 12 months. Dabigatran etexilate and edoxaban were both approved for the treatment of acute VTE after initial parenteral anticoagulation with heparin.2,3 On the completion of the initial heparin regimen, dabigatran etexilate is dosed as 150 mg twice daily for 6 months, and edoxaban can be prescribed at 60 or 30 mg/d for 3 to 12 months. The 30-mg reduced dose of edoxaban is intended for medically fragile patients who were defined in the study conditions as those with a CLCR of 30 50 mL/min, those with a weight of 60 kg, or those receiving concomitant treatment with a strong P-gp inhibitor.3

Study Findings Through Phase III clinical trials investigating the tolerability and efficacy of the NOACs versus enoxaparin and warfarin standard therapy, each of the 4 NOACs were approved by the FDA for shortterm treatment of VTE, including DVT and PE.2e5 Although Hokusai VTE Cancer trial was the only Phase III trial to speak to the efficacy of edoxaban, the use of the other 3 NOACs was supported by secondary studies designed to confirm the initial results. Specifically, after Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy (AMPLIFY), a smaller but similarly structured trial in Japanese patients (AMPLIFY-J) was conducted in Japanese patients and restated apixaban's noninferiority to conventional treatment.13 In the case of dabigatran etexilate, an identical Randomized Trial of Dabigatran Versus Warfarin in the Treatment of Acute Venous Thromboembolism (RE-COVER) II trial was run and confirmed the results of the original RE-COVER investigation.14 Finally, the EINSTEIN

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researchers published 2 separate clinical studies individually revealing rivaroxaban's noninferiority to enoxaparin and warfarin for the short-term treatments of DVT and PE.5,15 In each Phase III clinical trial, apixaban, dabigatran etexilate, edoxaban, and rivaroxaban were noninferior to conventional therapy for the short-term treatment of VTE. Further investigating rivaroxaban's efficacy in the clinical setting, the noninterventional, prospective XA Inhibition With Rivaroxaban for Long-term and Initial Anticoagulation in Venous Thromboembolism (XALIA) study supported the results of the EINSTEIN trials, which revealed rates of recurrent VTE (for rivaroxaban vs LMWH/VKA: 1.4% vs 2.3%; propensity score-adjusted hazard ratio [HR] ¼ 0.91; 95% CI, 0.54e1.54; P ¼ 0.72) and major bleeding (for rivaroxaban vs LMWH/VKA: 0.8% vs 2.1%; HR ¼ 0.77; 95% CI, 0.40e1.50; P ¼ 0.44) that were consistent with the Phase III findings.16 However, subgroup analysis of the XALIA study, which investigated the outcomes of early switchers (patients who received LMWH or fondaparinux and/ or a VKA for >2 to 14 days before switching to rivaroxaban) revealed that this patient population experienced higher rates of major bleeding (1.4% vs 0.7%) and recurrent VTE (2.2% vs 1.4%) than the original rivaroxaban cohort.17 In addition, all 4 NOACs depicted similar or lowered bleeding profiles.2e5 Apixaban, however, was the only NOAC to reveal a clinically relevant reduction in major bleeding events. Specifically, only 0.6% of patients taking apixaban compared with 1.8% of those receiving conventional therapy experienced major bleeding (relative risk ¼ 0.31; 95% CI, 0.17e0.55; P < 0.001 for superiority).4 The numerical results from each trial are given in Table III. In their investigations of NOACs versus standard anticoagulation therapy, 2 separate Cochrane reviews spoke to the effectiveness and tolerability of these oral medications for the treatment of acute DVT and PE. In the review concerning DVT, 11 randomized controlled trials in which participants had confirmed DVT were evaluated. Meta-analysis of the 3 studies (n ¼ 7596) concerning the oral direct thrombin inhibitors dabigatran etexilate and ximelagatran found no difference in the rates of recurrent VTE (odds ratio [OR] ¼ 1.12; 95% CI 0.80e1.49) and associated these 2 medications with reduced rates of

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Table III. Variable

Trial results for the treatment of acute VTE.* Apixaban AMPLIFY4

Dabigatran Etexilate AMPLIFY-J13

RE-COVER2

RE-COVER II14

Edoxaban Hokusai VTE Cancer Trial3

Rivaroxaban EINSTEIN-DVT5

EINSTEIN-PE15

Rivaroxaban 15 mg LMWH or UFH LMWH or UFH for Enoxaparin or UFH Rivaroxaban 15 Apixaban 10 mg Apixaban twice daily for 7 mg twice daily 5e11 days, then for up to 5 days, 10 mg twice for 5e11 days, twice daily for 7 for 7 weeks, then weeks, then then edoxaban then dabigatran dabigatran daily for 7 days, then 5 mg 20 mg/d for 3, 6, 20 mg/d for 3, 6, etexilate 150 mg 60 mg/d (or etexilate days, then twice daily for 6 30 mg/d) for 3e12 or 12 months vs or 12 months vs twice daily for 6 150 mg twice 5 mg twice months vs enoxaparin and months vs warfarin enoxaparin and months vs daily for 6 daily for 6 enoxaparin and VKA VKA warfarin months vs months vs warfarin warfarin UFH and warfarin Edoxaban (n ¼ Dabigatran Dabigatran Apixaban Patients Apixaban Rivaroxaban Rivaroxaban etexilate (n ¼ 40; 22 etexilate (n ¼ 2691; (n ¼ 2419 with (n ¼ 1731 with 4118; 2468 with (n ¼ 1273; 880 (n ¼ 1280; 877 with DVT, 1749 with DVT, PE), enoxaparin DVT), DVT, 1650 with with DVT, 298 18 with PE), with DVT, 270 678 with PE), or VKA enoxaparin or PE), warfarin with PE), with PE), UFH and enoxaparin and (n ¼ 2413 with VKA (n ¼ 1718 (n ¼ 4122; 2453 warfarin warfarin warfarin warfarin PE) with DVT) with DVT, 1669 (n ¼ 2704; 1783 (n ¼ 40; 23 (n ¼ 1266; 869 (n ¼ 1288; 873 with PE) with DVT, 297 with DVT, 271 with DVT, with DVT, 681 with PE) 17 with PE) with PE) with PE) Recurrent VTE Recurrent VTE Recurrent VTE or Recurrent VTE or Recurrent VTE Results Recurrent VTE Recurrent VTE occurred in 2.1% occurred in 2.1% occurred in 3.2% death occurred death occurred occurred in 2.3% occurred in of patients taking in 2.3% of in 2.4% of 0 patients of patients of patients of patients edoxaban and 3.5% taking patients taking patients taking taking taking apixaban taking of those receiving dabigatran dabigatran apixaban and 2.7% of rivaroxaban and rivaroxaban and warfarin etexilate and subjects and etexilate and those taking 1.8% of those 3.0% of those (HR ¼ 0.89; 95% 2.2% of those 2.1% receiving 1 patient enoxaparin and raking taking CI, 0.70e1.13; receiving warfarin taking UFH warfarin (−0.4% enoxaparin or enoxaparin or P < 0.001) warfarin (HR ¼ 1.10; difference in risk; or warfarin VKA (HR ¼ 0.68; VKA (HR ¼ 1.12; (HR ¼ 1.08; 95% 95%, CI 0.65 95% CI, −1.3 to 95% CI, 0.75 95% CI, 0.44 CI, 0.64e1.80; e1.84) 0.4; P < 0.001) e1.68; e1.04; P < 0.001) P ¼ 0.003) P < 0.001)

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Table III.

Apixaban AMPLIFY

4

Dabigatran Etexilate AMPLIFY-J

13

RE-COVER

2

RE-COVER II

Edoxaban 14

Hokusai VTE Cancer Trial3

Rivaroxaban EINSTEIN-DVT5

EINSTEIN-PE15

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Major or CRNM Major bleeding ¼Major bleeding Major or CRNM Major bleeding Major or Major bleeding or CRNM bleeding occurred in 1.2% bleeding occurred occurred in occurred in 0.6% CRNM occurred in 8.1% bleeding in 8.5% of patients 1.6% of patients of patients bleeding of patients occurred in of patients taking edoxaban taking taking occurred in taking apixaban 10.3% of and 10.3% of those taking dabigatran dabigatran 7.5% of and 1.8% of patients rivaroxaban and receiving warfarin etexilate and etexilate and patients those taking 8.1% of those (HR ¼ 0.81; 95% 1.7% of those 1.9% of those taking undergoing rivaroxaban taking CI, 0.71e0.94; receiving receiving apixaban enoxaparin and and 11.4% of enoxaparin or P ¼ 0.004) warfarin warfarin warfarin therapy and 28.2% those taking VKA (HR ¼ 0.69; 95% (HR ¼ 0.82; (RR ¼ 0.31; 95% of those enoxaparin or CI, 0.36e1.32) 95% CI, 0.45 taking UFH CI, 0.17e0.55; VKA e1.48) or warfarin P < 0.001) (HR ¼ 0.90; 95% CI, 0.76 e1.07; P ¼ 0.23) Pooled analysis revealed HRs of 1.09 Pooled analysis revealed HRs of 0.89 for recurrent VTE (95% CI, 0.66 (95% CI, 0.76e1.57) for recurrent e1.19; P < 0.001) and 0.54 for VTE and 0.73 for major bleeding major bleeding (95% CI, 0.37e0.79; (95% CI, 0.48e1.11) P ¼ 0.002) Noninferior Noninferior efficacy Noninferior Noninferior No clinically Noninferior Outcome Noninferior efficacy with a efficacy with a with significantly efficacy with a efficacy with a important efficacy with a potentially potentially less bleeding lowered risk of clinically relevant difference in similar safety improved improved bleeding efficacy with profile reduction in benefit-risk benefit-risk a favorable major bleeding profile profile safety profile AMPLIFY ¼ Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy; AMPLIFY-J ¼ Japanese AMPLIFY; CRNM ¼ clinical relevant nonmajor; DVT ¼ deep vein thrombosis; EINSTEIN-DVT ¼ Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Deep Vein Thrombosis; EINSTEIN-PE ¼ Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Acute Symptomatic Pulmonary Embolism; HR ¼ hazard ratio; LMWH ¼ low-molecular-weight heparin; PE ¼ pulmonary embolism; RE-COVER ¼ Randomized Trial of Dabigatran Versus Warfarin in the Treatment of Acute Venous Thromboembolism; RR ¼ relative risk; UFH ¼ unfractionated heparin; VKA ¼ vitamin K agonist; VTE ¼ venous thromboembolism. * Major bleeding and clinically relevant nonmajor bleeding were defined according to the International Society on Thrombosis Haemostasis and bleeding scale. LMWH and VKA were dose adjusted to INR of 2.0e3.0.

Clinical Therapeutics

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Variable

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A.A. Coulis and W.C. Mackey bleeding (OR ¼ 0.68; 95% CI 0.47e0.98).18 Concerning the oral factor Xa inhibitors apixaban, edoxaban, and rivaroxaban, meta-analysis of 8 studies (n ¼ 16356) found similar rates of recurrent VTE (OR ¼ 0.89; 95% CI, 0.73e1.07) and reduced rates bleeding (OR ¼ 0.84; 95% CI, 0.43e0.76).18 In the review concerning PE, 5 randomized controlled trials in which participants had confirmed PE were evaluated. For direct thrombin inhibitors, analysis of 2 studies (n ¼ 1602) indicated no difference in the effectiveness of dabigatran etexilate or ximelagatran versus standard anticoagulation in the prevention of recurrent VTE (OR ¼ 0.93; 95% CI, 0.52e1.66) or in the number of major bleeding events (OR ¼ 0.50; 95% CI, 0.15e1.68).19 In the analysis of direct factor Xa inhibitors, 3 studies (n ¼ 6295) also indicated no significant difference in the rates of recurrent VTE (OR ¼ 0.85; 95% CI, 0.63e1.15) or major bleeding (OR ¼ 0.97; 95% CI, 0.59e1.62).19 Summarizing their results, the Cochrane review authors concluded that both oral direct thrombin inhibitors and oral factor Xa inhibitors may be tolerable and effective alternatives to conventional anticoagulation for the treatment of both acute DVT and PE.18,19

Subgroup Analysis Subgroup analysis of the Phase III trials investigated whether the results reported above could be generalized to vulnerable populations, specifically patients with active cancer, impaired renal function, or advanced age.

Active Cancer Although patients with cancer are at risk for developing VTE, anticoagulant treatment with VKAs in this population is associated with an elevated risk of recurrent VTE and higher rates of bleeding. As such, current guidelines recommend that patients with cancer and VTE be treated with a monotherapy of LMWH for 6 months. However, because a long-term regimen of this subcutaneous injection is extremely inconvenient, many patients with cancer and VTE continue to be treated with VKAs. If NOACs had noninferiority with respect to VKAs in the prevention of recurrent VTE while additionally exhibiting fewer rates of bleeding, these medications could be convenient options for patients with active cancer and VTE who decide against LMWH monotherapy as per

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current recommendations. On subgroup analysis for each NOAC regarding its performance in patients with active cancer, these 4 medications remained noninferior to warfarin in the prevention of recurrent VTE and continued to be associated with a lower risk of bleeding (Table IV).20e23 Edoxaban was the only medication to undergo further research to investigate its performance against the recommended long-term LMWH monotherapy. Evaluating the efficacy and tolerability of edoxaban 60 mg/d after a 5-day regimen of LMWH, the Hokusai VTE Cancer trial established edoxaban's noninferiority to LMWH monotherapy in the prevention of recurrent VTE in patients with cancer (12.8% in the edoxaban group compared with 13.5% in the dalteparin group; HR ¼ 0.97; 95% CI, 0.70e1.35; P ¼ 0.006 for noninferiority and P ¼ 0.87 for superiority).24 However, the rate of major bleeding was significantly higher with edoxaban (6.9% in the edoxaban group compared with 4.0% in the dalteparin group; 2.9% difference in risk; 95% CI, 0.1e5.6).24

Impaired Renal Function Because renal function directly affects the rate at which a medication is eliminated from the body, renal impairment could increase NOAC exposure and potentially result in more adverse bleeding events. Acknowledging this, subgroup analyses of renally impaired patients in the RE-COVER II and the Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Deep Vein Thrombosis (EINSTEIN-DVT) and in Patients With Acute Symptomatic Pulmonary Embolism (EINSTEIN-PE) studies examined the effect of decreased renal function on dabigatran etexilate's (primarily renal clearance) and rivaroxaban's (both hepatic and renal clearance) efficacy and tolerability compared with the warfarin standard (primarily hepatic clearance). On subgroup analysis of patients taking dabigatran etexilate with mild (CRCL 50e80 mL/min) to moderate (CRCL 30e50 mL/min) renal impairment, decreasing renal function was associated with lowered rates of recurrent VTE. This trend was not reflected in the warfarin group. In both the dabigatran etexilate and warfarin groups, however, the rates of bleeding increased with decreased renal function.25 Similar subgroup analysis of patients taking rivaroxaban revealed slightly different results because decreased renal function was associated with increased rates of recurrent VTE and bleeding for both rivaroxaban and

11

Clinical Therapeutics

Table IV. Results of subgroup analysis for patients with active cancer.* Variable

Apixaban (AMPLIFY4)

Dabigatran Etexilate (RE-COVER II2,14)

Edoxaban (Hokusai VTE Cancer Trial3)

Rivaroxaban (EINSTEINDVT and EINSTEINPE5,15)

Edoxaban (n ¼ 378), Rivaroxaban (n ¼ 354), Dabigatran etexilate Patients Apixaban (n ¼ 88), warfarin (n ¼ 393) enoxaparin or VKA (n ¼ 114), warfarin enoxaparin and (n ¼ 301) (n ¼ 107) warfarin (n ¼ 81) Recurrent VTE occurred Recurrent VTE occurred in Results Recurrent VTE occurred in Recurrent VTE or 5% of patients taking in 4% of patients 3.7% of patients taking related death rivaroxaban and 7% of taking edoxaban and occurred in 5.8% of apixaban and 6.4% of those receiving 7% of those taking those taking enoxaparin patients taking enoxaparin or VKA warfarin (HR ¼ 0.53; or warfarin (RR ¼ 0.56; dabigatran etexilate (HR ¼ 0.67; 95% CI, and 7.4% of patients 95% CI, 0.28e1.00; 95% CI, 0.13e2.37) 0.35e1.30) P ¼ 0.0007) taking warfarin Major and CRNM Major bleeding Major bleeding Major bleeding occurred bleeding occurred in occurred in 3.8% of occurred in 2.3% of in 2% of patients taking 12% of patients taking patients taking patients taking rivaroxaban and 5% of edoxaban and 19% of dabigatran etexilate apixaban patients and those receiving those taking warfarin and 4.6% of those 5.0% of those taking enoxaparin or VKA (HR ¼ 0.64; 95% CI, taking warfarin enoxaparin and (HR ¼ 0.42; 95% CI, 0.45e0.92; P ¼ 0.017) 0.19e0.99) warfarin (RR ¼ 0.45; 95% CI, 0.08e2.46) AMPLIFY ¼ Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy; CRNM ¼ clinically relevant nonmajor; EINSTEIN-DVT ¼ Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Deep Vein Thrombosis; EINSTEIN-PE ¼ Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Acute Symptomatic Pulmonary Embolism; HR ¼ hazard ratio; RE-COVER ¼ Randomized Trial of Dabigatran Versus Warfarin in the Treatment of Acute Venous Thromboembolism; RR ¼ relative risk; VKA ¼ vitamin K agonist; VTE ¼ venous thromboembolism. * Major bleeding and CRNM bleeding were defined according to the International Society on Thrombosis Haemostasis bleeding scale. VKA was dose adjusted to international normalized ratio of 2.0e3.0.

warfarin.26 In both subgroup analyses, however, the rates of recurrent VTE and bleeding were lower in the NOAC groups than in their warfarin counterparts, maintaining their noninferiority to standard anticoagulation treatment in patients with mild-to-moderate renal impairment (Table V).25,26

Advanced Age In conjunction with the investigations on the effect of renal impairment, subgroup analyses regarding elderly patients (75 years old) were additionally performed for dabigatran etexilate and rivaroxaban. Analysis of the RE-COVER II subgroups revealed no increase in VTE recurrence or bleeding in older (75 years old) versus younger (<75 years old) patients taking

12

dabigatran etexilate within equivalent ranges of CRCL.25 Although the EINSTEIN investigators speak to the efficacy and safety profile of rivaroxaban in elderly patients by establishing its noninferiority in the broader subgroup of medically fragile patients (age >75 years, CLCR <50 mL/min, or weight 50 kg),27 an independent trial was able to confirm that the maximum plasma concentration of rivaroxaban is not increased in elderly people.28 Meanwhile, although the AMPLIFY investigators state that the efficacy and tolerability of apixaban remain consistent across a broad range of subgroups, including those older than 75 years, no in-depth subgroup analysis has been published on apixaban's efficacy and safety profile this population.

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Table V. Variable

Results of subgroup analysis for patients with decreased renal function.* Dabigatran Etexilate (RE-COVER II2,14)

Rivaroxaban (EINSTEIN-DVT and EINSTEIN-PE5,15)

In patients taking rivaroxaban and warfarin Results In patients taking dabigatran etexilate, VTE and combined, VTE occurred in 1.8% of those with associated deaths occurred in 3.1% of those normal renal function, 2.8% of those with mild with normal renal function, 1.9% of those with renal impairment, 3.3% of those with moderate mild renal impairment, and 0.0% of those with renal impairment, and 4.8% of those with severe moderate renal impairment. In patients taking warfarin, VTE and associated deaths occurred in renal impairment. 2.6% of those with normal renal function, 1.6% of those with mild renal impairment, and 4.1% of moderate renal impairment. In patients taking rivaroxaban, major bleeding In patients taking dabigatran etexilate, major occurred in 0.8% of those with normal renal bleeding occurred in 0.3% of those with normal function, 1.4% of those with mild renal renal function, 1.8% of those with mild renal impairment, 0.9% of those with moderate renal impairment, and 5.7% of those with moderate impairment, and 0% of those with severe renal renal impairment. In patients taking warfarin, impairment. In patients taking warfarin, major major bleeding occurred in 1.1% of those with bleeding occurred in 1.0% of those with normal normal renal function, 3.0% of those with mild renal function, 3.0% of those with mild renal renal impairment, and 4.4% of those with impairment, 3.9% of those with moderate renal moderate renal impairment. impairment, and 9.1% of those with severe renal impairment. EINSTEIN-DVT ¼ Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Deep Vein Thrombosis; EINSTEIN-PE ¼ Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Acute Symptomatic Pulmonary Embolism; RE-COVER ¼ Randomized Trial of Dabigatran Versus Warfarin in the Treatment of Acute Venous Thromboembolism; VTE ¼ venous thromboembolism. * Major bleeding was defined according to the International Society on Thrombosis Haemostasis bleeding scale.

Because edoxaban offers a 30-mg half-dose for the patient populations described above and other medically fragile patients (specifically defined as those with a CLCR of 30e50 mL/min, those with a weight 60 kg, or those receiving concomitant treatment with strong P-gp inhibitors), an independent study was conducted to determine the efficacy and safety profile of this reduced dosage. Published results of this study exhibited similar rates of recurrent VTE and bleeding between the fragile patients in the 30-mg group and those in the 60-mg study group. Specifically, recurrent VTE occurred in 3.0% of the 30-mg group and 3.2% of 60-mg group, whereas major or CRNM bleeding occurred in 7.9% of 30-mg group and 8.6% of the 60mg group.29 When comparing this fragile edoxaban population to fragile patients receiving warfarin, 30 mg of edoxaban resulted in similar rates of recurrent

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VTE (3.0% for edoxaban and 4.2% for warfarin) and a reduced rate of bleeding (7.9% for edoxaban and 12.8% for warfarin).29 These results indicate that not only did edoxaban 30 mg maintain the efficacy of edoxaban 60 mg but also it was more tolerable than warfarin in medically fragile patients.

Extended Treatment of VTE Although guidelines recommend a 3- to 6-month regimen of anticoagulant treatment after diagnosed VTE, patients with a higher risk of VTE recurrence may be prescribed extended or lifelong anticoagulation therapy. Extended treatment with a VKA only amplifies its characteristic drawbacks, prolonging the needed for dietary restrictions and frequent laboratory monitoring. To simplify extended anticoagulation therapy, 3 NOACs (apixaban, dabigatran etexilate, and

13

Clinical Therapeutics rivaroxaban) were investigated against placebo in Phase III clinical trials for the prolonged treatment of VTE.

Study Design To confirm the clinical benefit of extended anticoagulation with a NOAC versus the standard 3to 6-month regimen, each of these 3 medications underwent Phase III clinical trials to determine their superior efficacy compared with placebo in lower-risk patients for whom there is clinical equipoise regarding the continuation or cessation of anticoagulant therapy. For patients who carry an increased risk of recurrent VTE and would be explicitly indicated for extended anticoagulation with a VKA, dabigatran etexilate was further investigated against warfarin.

Study Findings The EINSTEIN-Extension and Twice-daily Oral Direct Thrombin Inhibitor Dabigatran Etexilate in the Long Term Prevention of Recurrent Symptomatic VTE (RE-SONATE) studies confirmed rivaroxaban's and dabigatran etexilate's superiority versus placebo in the prevention of recurrent VTE.5,30 Similar findings were evident in the AMPLIFY-EXTENSION trial, which investigated apixaban at both 2.5 and 5 mg. Both doses were superior to placebo in reducing the risk of recurrent VTE.31 Furthermore, trial results from these 3 studies indicate that apixaban, dabigatran etexilate, and rivaroxaban were all associated with similar risks of major bleeding when compared with placebo. Undergoing further evaluation in the Phase III, Randomised, Multicenter, Double-blind, Parallel-group, Active Controlled Study to Evaluate the Efficacy and Safety of Oral Dabigatran Etexilate (150 mg Bid) Compared to Warfarin (INR 2.0e3.0) for the Secondary Prevention of Venous Thromboembolism (RE-MEDY) study, dabigatran etexilate was found to be noninferior to standard warfarin therapy for extended anticoagulation and was associated with a decreased rate of bleeding.30 Results of these trials are given in Table VI. In comparing NOAC and aspirin treatments for patients in equipoise regarding the need for continued anticoagulation, the Reduced-dosed Rivaroxaban in the Long-term Prevention of Recurrent Symptomatic VTE (EINSTEIN CHOICE) trial found that rivaroxaban (at the treatment dose of 20 mg/d and the prophylactic dose of 10 mg/d) was more effective

14

than aspirin 100 mg in the extended prevention of recurrent VTE and was associated with a similar rate of bleeding. Specifically, recurrent VTE occurred in 1.5% of patients taking Rivaroxaban 20 mg, 1.2% of patients taking rivaroxaban 10 mg, and 4.4% of patients taking aspirin 100 mg (HR ¼ 0.34; 95% CI, 0.20e0.59 for rivaroxaban 20 mg vs aspirin 100 mg; HR ¼ 0.26; 95% CI, 0.14e0.47 for rivaroxaban 10 mg vs aspirin 100 mg, P < 0.001 for both comparisons).32 Rates of major bleeding were 0.5% in the rivaroxaban 20-mg group, 0.4% in the rivaroxaban 10-mg group, and 0.3% in the aspirin 100-mg group.32

Prophylactic Treatment After Major Orthopedic Surgery VTE is a potentially fatal complication that can occur in patients after major orthopedic operations, such as total knee or hip arthroplasties. As such, thromboprophylaxis for at least 10 days after major orthopedic joint replacement surgery is now standard practice. However, as the mean length of stay in the hospital has decreased to 3 to 4 days, an oral anticoagulant regimen that is easily administered in an outpatient setting is ideal. Acknowledging this, all 4 NOACs were investigated for their efficacy regarding thromboprophylaxis in patients after major orthopedic joint replacement surgery.

After Total Knee Arthroplasty The optimal thromboprophylactic strategy for patients after a total knee arthroplasty (TKA) has not been established, and different guidelines exist in the United States, Europe, and Japan. Specifically, the FDA recommends that in the United States patients receive 30 mg of subcutaneous enoxaparin every 12 hours (twice daily) beginning 12 to 24 hours before surgery and continuing until 10 to 14 days after wound closure. European recommendations state that patients should have 40 mg of subcutaneous enoxaparin once daily starting 12 hours before surgery and again until 10 to 14 days after wound closure. Recommendations in Japan are slightly different and state that patients should be administered subcutaneous enoxaparin 2000 IU (equivalent to 20 mg) twice daily beginning 24 to 36 hours before surgery and lasting for the next 11 to 14 days. Apixaban, dabigatran etexilate, and rivaroxaban all underwent 2 separate Phase III clinical trials to determine their efficacy versus US and European

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Table VI. Trial results for the extended treatment of acute VTE. Variable

Apixaban (AMPLIFYEXT31)

Dabigatran Etexilate RE-SONATE30

RE-MEDY30

Rivaroxaban (EINSTEINEXT5)

Rivaroxaban 20 mg/d vs Dabigatran etexilate Apixaban 2.5 mg or 5 mg Dabigatran etexilate placebo for 6 or 12 150 mg twice daily vs 150 mg twice daily vs twice daily vs placebo months placebo for 6 months warfarin for 6e36 for 12 months months Rivaroxaban (n ¼ 602), Dabigatran etexilate Dabigatran etexilate Patients Apixaban (n ¼ 840 at placebo (n ¼ 594) (n ¼ 1430), warfarin (n ¼ 681), placebo 2.5 mg, n ¼ 813 at (n ¼ 1426) (n ¼ 662) 5 mg), placebo (n ¼ 829) Results Recurrent VTE or death Recurrent VTE occurred Recurrent VTE occurred Recurrent VTE occurred in 1.3% of patients in 1.8% of patients in 0.4% of patients occurred in 1.7% of receiving rivaroxaban receiving dabigatran receiving dabigatran patients receiving and 7.1% of patients etexilate and 1.3% of apixaban 2.5 mg, 1.7% etexilate and 5.6% of those receiving warfarin receiving placebo patients receiving of patients receiving placebo (HR ¼ 0.08; (HR ¼ 1.44; 95% CI, apixaban 5 mg, and (HR ¼ 0.18; 95% CI, 0.78e2.64; P ¼ 0.01) 95% CI, 0.02e0.25; 8.8% of patients 0.09e0.39; P < 0.001) P < 0.001) receiving placebo (−7.2% difference in risk for 2.5 mg; 95% CI, 5.0e9.3; −7.0% difference in risk for 5 mg; 95% CI, 4.9e9.1; P < 0.001 for both comparisons) Major bleeding occurred Major bleeding Major bleeding occurred Major bleeding in 0.7% of patients occurred in 0.9% of occurred in 0.3% of in 0.2% of patients receiving rivaroxaban patients receiving patients receiving receiving apixaban and 0 patients receiving dabigatran etexilate dabigatran etexilate 2.5 mg, 0.1% of placebo (P ¼ 0.11) and 1.8% of those and 0 patients patients receiving receiving warfarin receiving placebo apixaban 5 mg, and (HR ¼ 0.52; 95% CI, 0.5% of patients 0.27e1.02) receiving placebo Outcome Superior efficacy with a Superior efficacy with a Noninferior efficacy with Superior efficacy with a similar safety profile fewer major bleeding similar safety profile significantly higher risk of major bleeding events

Dosing

AMPLIFY-EXT ¼ Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy Extension; EINSTEIN-EXT ¼ Oral Direct Factor Xa Inhibitor Rivaroxaban Extension; HR ¼ hazard ratio; RE-MEDY ¼ Phase III, Randomised, Multicenter, Double-blind, Parallel-group, Active Controlled Study to Evaluate the Efficacy and Safety of Oral Dabigatran Etexilate (150 mg Bid) Compared to Warfarin (INR 2.0e3.0) for the Secondary Prevention of Venous Thromboembolism; RE-SONATE ¼ Twice-daily Oral Direct Thrombin Inhibitor Dabigatran Etexilate in the Long Term Prevention of Recurrent Symptomatic VTE; VTE ¼ venous thromboembolism. Major bleeding was defined according to the International Society on Thrombosis Haemostasis bleeding scale.

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15

Clinical Therapeutics recommendations. The efficacy of edoxaban was evaluated only against the Japanese guidelines. The results of each trial are summarized in Table VII. With respect to US recommendations for thromboprophylaxis after TKA (subcutaneous enoxaparin 30 mg twice daily), dabigatran etexilate at doses of 150 and 220 mg/d, as well as apixaban 2.5 mg twice daily, each failed to find noninferiority versus the recommended enoxaparin treatment.33,34 Of note, both apixaban and dabigatran etexilate were noninferior to subcutaneous enoxaparin 40 mg/ d as per European recommendations.35,36 In all Phase III trials concerning the thromboprophylaxis after TKAs, these medications exhibited similar rates of bleeding compared with the enoxaparin regimens for both US and European guidelines.33e36 In contrast, rivaroxaban 10 mg/d was superior to standard enoxaparin treatments recommended in the United States and Europe.37,38 In addition, prophylactic therapy with rivaroxaban exhibited similar rates of bleeding as enoxaparin treatment.37,38 Studied against the Japanese recommendations for thromboprophylaxis after TKA, edoxaban 30 mg once daily exhibited superior efficacy versus enoxaparin 2000 IU (20 mg) twice daily in the Phase III Studying Thrombosis After Replacement Surgery (STARS) E-3 study.39 Rates of bleeding between the edoxaban and enoxaparin treatment groups were similar.39

After Total Hip Arthroplasty Recommendations in most countries, including North America and Europe, regarding thromboprophylaxis after total hip arthroplasty (THA) include a subcutaneous injection of enoxaparin 40 mg once daily beginning the evening before surgery and continuing for a minimum duration of 10 days. There is also speculation that an extended prophylactic regimen of up to 35 days would be beneficial. Of note, although a subcutaneous regimen of enoxaparin 30 mg twice daily is alternatively used in some countries and is approved by the FDA, this dosage is less frequently used and is not approved for an extended 35-day prophylactic regimen. Once again, because the typical duration of hospital stay is only between 3 and 4 days, adherence to a parenteral anticoagulant regimen is difficult, and an oral treatment would be preferred in an outpatient setting. In Phase III clinical studies, apixaban 2.5 mg twice daily, dabigatran etexilate 150 and 220 mg/d, and

16

rivaroxaban 10 mg/d were each evaluated against subcutaneous enoxaparin 40 mg once daily for a period of 35 days. Study results revealed apixaban and dabigatran etexilate (at both 150- and 220-mg doses) were noninferior to the standard enoxaparin therapy and exhibited similar rates of bleeding.40,41 Rivaroxaban was additionally determined to be clinically superior to enoxaparin 40 mg/d without an increase in adverse events or rates of bleeding.42 The numerical results of these Phase III trials are given in Table VIII. Extended anticoagulation with rivaroxaban was further evaluated against the short-term 10- to 14day Enoxaparin therapy recommended by FDA guidelines. In the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD) 2 trial, rivaroxaban 10 mg/d for 40 days was compared with enoxaparin 40 mg/d for 10 to 14 days. Results of this study indicated the superior efficacy of long-term rivaroxaban as compared with short-term enoxaparin therapy.43 Once again, there were similar rates of bleeding between the study groups.43 As with the other Phase III trial concerning edoxaban's efficacy in thromboprophylaxis after orthopedic surgery, the STARS J-V trial compared edoxaban 30 mg taken once daily to the Japanese guideline of enoxaparin 2000 IU (20 mg) twice daily. Edoxaban 30 mg/d exhibited superior efficacy with a similar rate of bleeding for patients after THA.44 Edoxaban additionally underwent further Phase III testing to determine its efficacy against enoxaparin in patients undergoing hip fracture surgery (HFS) for medial or lateral femoral neck fractures. Revealing a decreased incidence of major or CRNM bleeding (3.4% of patients taking edoxaban vs 6.5% of patients taking enoxaparin) and a slightly increased number of thromboembolic events (6.5% of patients taking edoxaban patients vs 3.7% of patients taking enoxaparin) Edoxaban exhibited results comparable to the Japanese standard of enoxaparin for patients undergoing HFS.45 However, because the power of the study was low (n ¼ 92), no official statistical comparison could be made. Additional research was also conducted on the safety profile of half-dose edoxaban 15 mg for thromboprophylaxis in patients with severe renal impairment (CRCL 15e30 mL/min) after lower-limb orthopedic operations, including

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Table VII. Variable

Trial results for thromboprophylaxis following total knee arthroplasty.* Apixaban ADVANCE 1

33

Dabigatran Etexilate ADVANCE 2

35

RE-MOBILIZE

34

RE-MODEL

36

Edoxaban (STARS E-339)

Rivaroxaban RECORD 438

RECORD 337

Apixaban 2.5 mg twice daily vs enoxaparin 30 mg twice daily for 10e14 days

Dabigatran etexilate 150 mg or 220 mg twice daily vs enoxaparin 40 mg/ enoxaparin 40 mg/ enoxaparin 30 d for 6e10 days d for 10e14 days mg twice daily for 12e15 days

Patients

Apixaban (n ¼ 1599), enoxaparin (n ¼ 1596)

Apixaban (n ¼ 1501), enoxaparin (n ¼ 1508)

Results

VTE or death occurred in 9.0% of patients taking apixaban and 8.8% of patients taking enoxaparin (RR ¼ 1.02; 95% CI, 0.78e1.32)

VTE or death occurred in 15% of patients taking apixaban and 24% of patients taking enoxaparin (RR ¼ 0.62; 95% CI, 0.51e0.74; P < 0.0001)

Major or CRNM bleeding occurred in 2.9% of

Major or CRNM bleeding occurred

Dabigatran etexilate (n ¼ 871 at 150 mg, n ¼ 857 at 220 mg), enoxaparin (n ¼ 868) VTE or death occurred in 33.7% of patients taking dabigatran etexilate 150 mg, 31.1% of patients taking dabigatran etexilate 150 mg, and 25.3% of patients taking enoxaparin (8.4% risk difference for 150 mg; 95% CI; 3.4e13.33; P ¼ 0.0009; 5.8% risk difference for 220 mg; 95% CI, 0.8e10.8; P ¼ 0.0234) Major bleeding Major bleeding Major bleeding occurred in 0.6% occurred in 1.3% occurred in

Major bleeding Major bleeding occurred in 0.7% occurred in

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A.A. Coulis and W.C. Mackey

Edoxaban 30 mg/ Rivaroxaban 10 mg/d vs d vs enoxaparin 2000 enoxaparin 30 mg enoxaparin 40 mg/d for twice-daily for 11 IU 13e17 days e15 days (20 mg) twice daily for 11e14 days Rivaroxaban Rivaroxaban Dabigatran etexilate Edoxaban (n ¼ 1254), (n ¼ 1584), (n ¼ 360), (n ¼ 703 at enoxaparin enoxaparin enoxaparin 150 mg, (n ¼ 1277) (n ¼ 1564) (n ¼ 356) n ¼ 679 at 220 mg), enoxaparin (n ¼ 694) VTE or death DVT or PE occurred VTE or death VTE or death occurred in occurred in 6.9% in occurred in 40.5% 9.6% of of patients taking 7.4% of patients of patients taking patients taking rivaroxaban and taking dabigatran rivaroxaban 10.1% of patients edoxaban and etexilate 150 mg, and 18.9% of taking enoxaparin 13.9% of 36.4% of patients patients taking (absolute risk patients taking taking dabigatran enoxaparin reduction ¼ enoxaparin etexilate 220 mg, (absolute risk 3.19%; 95% (RR reduction ¼ and 37.7% of reduction ¼ CI, 0.71e5.67; 46.8%; patients taking 1.6%; 95% CI, P ¼ 0.0118) P ¼ 0.010) enoxaparin 0.4e2.8; (absolute risk P ¼ 0.01) 2.8% for 150 mg; 95% CI, −3.1- to 8.7; risk difference, −1.3% for 220 mg; 95% CI, −7.3 to 4.6)

Dosing

(Continued )

Variable

Apixaban ADVANCE 133 patients taking apixaban and 4.3% of patients taking enoxaparin (P ¼ 0.03)

Outcome Inferior efficacy with reduced rates of bleeding

Dabigatran Etexilate ADVANCE 235

RE-MOBILIZE34

RE-MODEL36

Edoxaban (STARS E-339)

1.1% of patients of patients taking of patients taking taking dabigatran dabigatran edoxaban and etexilate 150 mg, etexilate 150 mg, 0.3% of 1.5% of patients 0.6% of patients patients taking taking dabigatran taking dabigatran enoxaparin etexilate 220 mg, etexilate 220 mg, (P ¼ 0.373) and 1.3% of and 1.4% of patients taking patients taking enoxaparin enoxaparin Noninferior efficacy Inferior efficacy with Noninferior efficacy Superior efficacy with with similar rates similar rates of without increased similar rates of of bleeding bleeding rates of bleeding bleeding in 4% of patients taking apixaban and 5% of patients taking enoxaparin (P ¼ 0.09)

Rivaroxaban RECORD 438 of patients taking rivaroxaban and 0.3% of patients taking enoxaparin (P ¼ 0.1096)

RECORD 337 0.6% of patients taking rivaroxaban and 0.5% of patients taking enoxaparin

Superior efficacy Superior efficacy with similar with similar rates rates of of bleeding bleeding

ADVANCE ¼ Apixaban Versus Enoxaparin For Thromboprophylaxis After Knee Replacement; CRNM ¼ clinically relevant nonmajor; DVT ¼ deep vein thrombosis; PE ¼ pulmonary embolism; RECORD ¼ Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes; RE-MOBILIZE ¼ Prevention of Venous Thromboembolism After Total Knee Arthroplasty; RE-MODEL ¼ Prevention of Venous Thromboembolism After Total Knee Replacement; RR ¼ relative risk; STARS ¼ Studying Thrombosis After Replacement Surgery; VTE ¼ venous thromboembolism. * Major bleeding and CRNM bleeding were defined according to the International Society on Thrombosis Haemostasis bleeding scale.

Clinical Therapeutics

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Table VII.

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Table VIII.

Trial results for thromboprophylaxis after total hip arthroplasty.*

Variable Apixaban (ADVANCE340)

Dabigatran Etexilate RE-NOVATE41

RE-NOVATE II51

Edoxaban (STARS JV44)

Rivaroxaban RECORD 142

RECORD 243

Dabigatran etexilate Dabigatran etexilate Edoxaban 30 mg/d vs Rivaroxaban 10 mg/ Rivaroxaban 10 mg/ Apixaban 2.5 mg d for 40 days vs enoxaparin 2000 IU d vs enoxaparin 150 or 220 mg/d vs 220 mg/f vs twice daily vs enoxaparin 40 mg/ enoxaparin 40 mg/ enoxaparin 40 mg/ enoxaparin 40 mg/ (20 mg) twice daily 40 mg/d for 35 d for 10e14 days days for 11e14 days d for 35 days d for 35 days d for 35 days Rivaroxaban Patients Apixaban (n ¼ 2708), Dabigatran etexilate Dabigatran etexilate Edoxaban (n ¼ 225), Rivaroxaban (n ¼ 1252), (n ¼ 2266), enoxaparin (n ¼ 1010), (n ¼ 1163 at enoxaparin enoxaparin enoxaparin (n ¼ 248) enoxaparin 150 mg, (n ¼ 2699) (n ¼ 1257) (n ¼ 2275) (n ¼ 1003) n ¼ 1146 at 220 mg), enoxaparin (n ¼ 1154) VTE or death occurred VTE or death occurred VTE occurred in 2.4% VTE or death occurred VTE or death occurred Results DVT, PE, or death occurred in 1.4% of in 8.6% of patients in 2.0% of patients in 1.1% of patients of patients taking in 7.7% of patients taking dabigatran patients taking taking rivaroxaban edoxaban and 6.9% taking rivaroxaban taking dabigatran apixaban and 3.9% etexilate 150 mg, and 9.3% of and 2.6% of of patients taking etexilate and 8.8% 6.0% of patients of patients taking patients taking patients taking enoxaparin of patients taking taking dabigatran enoxaparin enoxaparin enoxaparin (absolute enoxaparin (risk etexilate 220 mg, (RR ¼ 0.36; 95% (absolute risk (absolute risk difference, −4.5%; difference, −1.1%; CI, 0.22e0.54; reduction, 7.3%; reduction, 2.6%; 95% CI, −3.8 to 1.6; 95% CI. −8.6 and 6.7% of P < 0.001) 95% CI, 2.0e9.4; 95% CI, 1.5e3.7; to −0.09; P < 0.0001) patients taking P < 0.0001) P < 0.001) P < 0.001) patients (1.9% difference in risk for 150 mg; 95% CI, −0.6 to 4.4; −0.7% difference in risk for 220 mg; 95% CI, −2.9 to 1.6) Major or CRNM Major bleeding Major or CRNM Major bleeding Major bleeding Major or CRNM occurred in 0.3% of bleeding occurred occurred in 1.3% of occurred in 1.4% of bleeding occurred bleeding occurred in 3.4% of patients patients taking in 2.6% of patients patients taking patients taking in 4.8% of patients

Dosing

A.A. Coulis and W.C. Mackey

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(continued on next page)

(Continued )

Variable Apixaban (ADVANCE340)

Dabigatran Etexilate RE-NOVATE41

RE-NOVATE II51

Edoxaban (STARS JV44)

Rivaroxaban RECORD 142

RECORD 243

taking rivaroxaban rivaroxaban and dabigatran etexilate dabigatran etexilate taking edoxaban and 2.8% of 0.1% of patients and 3.7% of and 0.9% of 150 mg, 2.0% of patients taking taking enoxaparin patients taking patients taking patients taking enoxaparin (P ¼ 0.18) enoxaparin dabigatran etexilate enoxaparin (P ¼ 0.25) (P ¼ 0.475) (P ¼ 0.40) 220 mg, and 1.6% of patients taking enoxaparin (P ¼ 0.60 for 150 mg; P ¼ 0.44 for 220 mg) Outcome Superior efficacy with Noninferior efficacy Noninferior efficacy Superior efficacy with Superior efficacy with Superior efficacy with low rates of similar rates of with similar rates of with similar rates of similar rates of similar rates of bleeding bleeding bleeding bleeding bleeding bleeding taking apixaban and 5.0% of patients taking enoxaparin (−0.2% absolute difference in risk; 95% CI, −1.4 to 1.0)

ADVANCE ¼ Apixaban Versus Enoxaparin For Thromboprophylaxis After Knee Replacement; CRNM ¼ clinically relevant nonmajor; DVT ¼ deep vein thrombosis; PE ¼ pulmonary embolism; RECORD ¼ Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes; RE-MOBILIZE ¼ Prevention of Venous Thromboembolism After Total Knee Arthroplasty; RE-MODEL ¼ Prevention of Venous Thromboembolism After Total Knee Replacement; RR ¼ relative risk; STARS ¼ Studying Thrombosis After Replacement Surgery; VTE ¼ venous thromboembolism. * Major bleeding and CRNM bleeding were defined according to the International Society on Thrombosis Haemostasis bleeding scale.

Clinical Therapeutics

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Table VIII.

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A.A. Coulis and W.C. Mackey TKA, THA, and HFS. Reporting similar rates of bleeding between patients taking edoxaban 15 mg with severe renal impairment (20.7%), patients with severe renal impairment taking fondaparinux 1.5 mg (40.0%), and patients with mild-to-moderate renal impairment taking edoxaban 30 mg (33.3%), this study suggests that edoxaban 15 mg/d is similarly tolerated in this patient population.46 However, given these high rates of bleeding, a larger study is needed to confirm these results and assess the possible clinical tolerability concerns of these regimens.

Prophylactic Treatment for Acutely Ill Medical Patients Patients hospitalized for acute medical illnesses, such as pneumonia, stroke, or heart failure, pose an increased risk of VTE that is often compounded by additional risk factors, such as prolonged immobilization, age 75 years, or a history of previous VTE. Current guidelines regarding such high-risk patients, hereafter referred to as acutely ill medical patients, recommends the use of a low-dose 6- to 10-day parenteral anticoagulant regimen (typically subcutaneous enoxaparin 40 mg/d). Because this treatment is rarely extended beyond hospital discharge, the trend toward shorter hospital stays means that many acutely ill medical patients receive anticoagulant therapy for a shorter duration than recommended. Investigating the benefit of extended thromboprophylaxis in this patient population, the Extended Prophylaxis for Venous Thromboembolism in Acutely Ill Medical Patients With Prolonged Immobilization (EXCLAIM) trial revealed that enoxaparin 40 mg/d for 40 days exhibited a reduced incidence of VTE compared with placebo and was the first study to indicate that extended anticoagulation for acutely ill medical patients may be advantageous.47 However, because daily enoxaparin injections are not ideal in the outpatient setting, the Apixaban Dosing to Optimize Protection from Thrombosis (ADOPT) and Multicenter, Randomized, Parallel Group Efficacy and Safety Study for the Prevention of Venous Thromboembolism in Hospitalized Acutely Ill Medical Patients Comparing Rivaroxaban With Enoxaparin (MAGELLAN) researchers investigated whether an extended anticoagulant regimen with oral apixaban or rivaroxaban could be effective.

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Study Design Phase III clinical trials were conducted to compare an extended anticoagulation regimen with apixaban or rivaroxaban to the short-term enoxaparin 40-mg regimen that is currently recommended. Each NOAC was administered at their respective doses for 30 to 40 days. Enoxaparin 40 mg was given via subcutaneous injection for 6 to 14 days. In its investigation of rivaroxaban, the MAGELLAN study performed 2 efficacy analyses: a noninferiority study at day 10 of administration and a superiority study at day 35. In this way, the MAGELLAN researchers explored whether rivaroxaban was as effective as enoxaparin in the short-term prophylaxis of acutely ill medical patients as well as whether extended treatment with this medication exhibited clinical benefit.

Study Findings In their respective Phase III clinical trials, an extended regimen of apixaban 2.5 mg twice daily or rivaroxaban 10 mg/d were each compared to enoxaparin 40 mg/d for the extended thromboprophylaxis in acutely ill medical patients. In their investigations of apixaban, the ADOPT48 trial revealed that this medication did not exhibit superior efficacy to enoxaparin therapy. Furthermore, apixaban was associated with significantly more bleeding events.48 Although rivaroxaban was also associated with an increased rate of bleeding in the MAGELLAN trial, it was determined to be noninferior to enoxaparin 40 mg/d at the 10-day efficacy analysis and had superior efficacy at the conclusion of 35 days.49 Results for these 3 trials are given in Table IX.

DISCUSSION Overall, the NOACs offer a simplified anticoagulation regimen that generally has noninferiority in efficacy and similar rates of bleeding when compared with standard therapy throughout multiple studies in the published literature. In the absence of head-to-head trials directly comparing each NOAC, patient preference for certain medication characteristics may be valuable in determining the anticoagulation regimen that is most appropriate for an individual. Although each NOAC treatment was well tolerated among most patients, because dabigatran etexilate

21

Clinical Therapeutics

Table IX. Variable Dosing Patients Results

Trial results for thromboprophylaxis in acutely ill medical patients.* Apixaban (ADOPT48)

Rivaroxaban (MAGELLAN49)

Apixaban 2.5 mg twice daily for 30 days vs enoxaparin 40 mg/d for 6e14 days Apixaban (n ¼ 3255), enoxaparin (n ¼ 3273) VTE and associated death occurred in 2.71% of patients taking apixaban and 3.06% of patients taking enoxaparin (RR ¼ 0.87; 95% CI, 0.62 e1.23; P ¼ 0.44)

Major bleeding occurred in 0.47% of patients taking apixaban patients and 0.19% of patients taking enoxaparin (RR ¼ 2.58; 95% CI, 1.02 e7.24; P ¼ 0.04)

Outcome

Did not have superior efficacy with significantly more bleeding events

Rivaroxaban 10 mg/d for 31e39 days vs enoxaparin 40 mg/d for 6e14 days Rivaroxaban (n ¼ 4050), enoxaparin (n ¼ 4051) At day 10, VTE occurred in 2.7% of patients taking rivaroxaban and 2.7% of patients taking enoxaparin (RR ¼ 0.97; 95% CI, 0.71 e1.31; P ¼ 0.003); at day 35, VTE occurred in 4.4% of patients taking rivaroxaban and 5.7% of patients taking enoxaparin (RR ¼ 0.77; 95% CI, 0.62e0.96; P ¼ 0.02) At day 10, major bleeding occurred in 2.8% of patients taking rivaroxaban and 1.2% of patients taking enoxaparin; at day 35, major bleeding occurred in 4.1% of patients taking rivaroxaban and 1.7% of patients taking enoxaparin At day 10, noninferior efficacy with increased rates of bleeding; at day 35, superior efficacy with increased rates of bleeding

ADOPT ¼ Apixaban Dosing to Optimize Protection from Thrombosis; MAGELLAN ¼ Multicenter, Randomized, Parallel Group Efficacy and Safety Study for the Prevention of Venous Thromboembolism in Hospitalized Acutely Ill Medical Patients Comparing Rivaroxaban With Enoxaparin; RR ¼ relative risk. * Major bleeding was defined according to the International Society on Thrombosis Haemostasis bleeding scale.

was associated with an adverse effect of dyspepsia, this medication may not be the first choice for those sensitive to gastric upset. In addition, because apixaban and dabigatran etexilate require twice-daily dosing, edoxaban or rivaroxaban may be better suited for patients who prefer a medication with once-daily administration. Tailoring the prescribed therapy to fit these patient preferences may promote medication adherence. Excluding those with severe hepatic or renal impairment as well as breastfeeding mothers, the NOACs can administered to a wide variety of patient populations and only exhibit serious drug interactions with strong dual P-gp and CYP3A4 inducers or inhibitors. Owing to its renal clearance without CYP metabolism, dabigatran etexilate may be the best NOAC option for patients with impaired hepatic function or those requiring concomitant

22

administration with a medication affecting CYP3A4 activity. Offering a variety of dosing options, edoxaban and apixaban are valuable treatment alternatives for patients still indicated for NOAC therapy but who may be highly sensitive to treatment. However, only half-dosed edoxaban was explicitly studied and found to be tolerable and effective in patients with mild-to-moderate renal impairment, a low weight, or concomitant administration with strong P-gp inhibitors. Although apixaban is available in 2.5-, 5-, or 10-mg tablets, reduced doses were not specifically studied in Phase III clinical trials. Further research is needed before a decreased dose of apixaban can confidently be prescribed for vulnerable patient populations. Because the ability to quickly reverse the effects of anticoagulation continues to be of clinical interest, the approval of andexanet alfa and idarucizumab as

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A.A. Coulis and W.C. Mackey antidotes is especially important for patients taking apixaban, dabigatran etexilate, or rivaroxaban who are at risk of serious bleeding or who may require emergency surgery. However, because edoxaban remains without a specific reversal agent, use of this medication in high-risk patient populations poses an increased chance of irreversible bleeding.

Treatment of Acute VTE\ Because apixaban and rivaroxaban were approved as monotherapies, this opportunity for a simplified oral regimen would be especially ideal for patients who do not require hospitalization and are stable for outpatient management. However, patients who were initially started on parenteral treatment with LMWH or UFH are not optimal candidates for subsequent treatment with apixaban or rivaroxaban. This is confirmed by the poor outcome of patients taking rivaroxaban in the subgroup analysis of early switchers from the XALIA trial. For such patients, dabigatran etexilate or edoxaban would be superior choices. This is especially applicable for patients with pronounced symptoms of VTE who were initially hospitalized and administered inpatient anticoagulation. With dabigatran etexilate or edoxaban, such patients would be able to begin a NOAC anticoagulation regimen at discharge after initial heparin treatment. The efficacy and tolerability of NOAC anticoagulation for the treatment of acute VTE were substantially supported with multiple Phase III trials, 3 of which were able to reproduce and confirm the initial noninferiority results. Although only one Phase III trial exists for edoxaban, the sample size should be noted. With almost twice as many trial participants as the others, the data supporting edoxaban's noninferiority to warfarin is of similar strength to the other NOACs with 2 confirmatory trials. Of additional note, as the EINSTEIN-PE study sampled the largest number of individuals with diagnosed PE (n ¼ 4832), almost twice as many as in other trials, it presents the strongest supporting data concerning anticoagulation treatment for acute PE. For this reason, in the absence of additional preferential factors affecting a clinician's decision, rivaroxaban may be the first choice of treatment for patients with PE. However, head-to-head studies directly comparing the safety profiles and effectiveness of

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the 4 NOACs in the treatment of PE are needed to more firmly establish this. When considering tolerability, all 4 NOACs had similar or reduced major bleeding profiles when compared with standard therapy. Apixaban was the only medication that exhibited a clinically relevant reduction in the risk of major bleeding. While this indirect comparison should be interpreted with caution, it is reasonable to postulate that apixaban may be a logical anticoagulant option for patients for whom there are bleeding concerns. In addition, the NOACs maintained their overall noninferiority and similar tolerability in subgroup analyses of multiple vulnerable patient populations. However, only edoxaban offers a reduced dosing option with published evidence supporting its use for medically fragile patients. In the event that edoxaban is not an option for patients with mild-to-moderate renal impairment or advanced age, subgroup analyses support the use of dabigatran etexilate and rivaroxaban. Because individuals with severe renal function (CRCL <30 mL/min) were excluded from the original studies, further research is needed before either of these medications can be confidently prescribed for this patient population. Although NOAC anticoagulation in patients with active cancer may be a valuable alternative to VKAs, only edoxaban was further investigated against the recommended long-term LMWH monotherapy. In the absence of published data establishing the noninferiority of the other 3 medications, edoxaban should be the first-choice in NOAC anticoagulation for patients with active cancer. In addition, patients with advanced cancer and a life expectancy of <3 months, many of whom require the recommended long-term LMWH regimen, were excluded from the original Phase III trials and subsequent analyses. Therefore, further research is needed before NOAC anticoagulation can be recommended for this population. NOAC anticoagulation may have the greatest clinical benefit in patients who require prolonged or life-long therapy. With no dietary restrictions or need for routine coagulation monitoring, long-term NOAC therapy would impose little effect on patients’ activities of daily living. Although long-term therapy with aspirin also exhibits these lifestyle benefits, it was inferior to rivaroxaban in the EINSTEIN CHOICE trial. For these reasons, in patients for

23

Clinical Therapeutics whom there is clinical equipoise regarding the continuation or cessation of anticoagulation, apixaban, dabigatran etexilate, or rivaroxaban would be valuable options. Because dabigatran etexilate is the only medication with published evidence on its noninferiority to warfarin in the extended treatment of VTE and additionally was associated with a lower risk of major bleeding, it is the logical oral anticoagulant for patients who require extended anticoagulant therapy.

VTE Prophylaxis In the case of thromboprophylaxis after a TKA, rivaroxaban exhibited superiority over both US- and European-recommended enoxaparin regimens without increased rates of bleeding. Because rivaroxaban 10 mg/d was the only medication with clinically proven superiority over the FDA recommended enoxaparin 30 mg twice daily in the United States, it may be the NOAC of choice, offering a simple and effective treatment alternative. If solely considering the European standard of care, apixaban and dabigatran etexilate may also be valuable options because of their proven noninferiority compared with enoxaparin 40 mg/d. Although the Phase III trial of edoxaban seemed promising, its unique study characteristics must be taken into consideration. Most obviously, edoxaban's superiority was established against a thromboprophylactic regimen that is not recommended for patients in the United States or Europe. Enoxaparin 2000 IU (20 mg) twice daily is a lower anticoagulant dose than used in the West and is adjusted for the lower mean weight of Japanese patients. Of note, the mean weight of studied participants in the edoxaban trial was 60.2 kg.39 For reference, mean weights of participants in the apixaban and rivaroxaban studies were 78 and 80.7 kg, respectively.39 For this reason, although edoxaban exhibited favorable results in the Japanese population, these data cannot be extrapolated for US or European patients and do not indicate superiority with respect to Western guidelines. Phase III analyses of apixaban and rivaroxaban found superior efficacies and similar safety profiles compared with enoxaparin 40 mg/d after THA. Although each of these studies investigated their results for 35 days as recommended by current guidelines, this lengthy parenteral anticoagulation

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regimen is rarely administered in clinical practice and LMWH therapy is often discontinued at hospital discharge. Because apixaban and rivaroxaban were superior without increasing the risk of bleeding, these medications would be ideal for the recommended 35 days. Confirming the benefit of long-term NOAC anticoagulation over short-term enoxaparin, the RECORD 2 trial found that rivaroxaban 10 mg/d for 40 days was superior to enoxaparin 40 mg/d for 10 to 14 days with a lower risk of bleeding. Although unable to prove superiority like apixaban and rivaroxaban, through its reported noninferiority and reduced dosing option, dabigatran etexilate could fill a crucial niche in NOAC thromboprophylaxis after THA. Further investigation conducted in an independent study revealed that when dabigatran etexilate 150 mg was administered once daily to patients with moderate renal impairment (CLCR <50 mL/min), the steady-state drug concentration in this population was in a similar and therapeutic range to those with mild renal impairment (CLCR of 50-80 mL/min) receiving dabigatran etexilate 220 mg in the Oral Dabigatran Versus Enoxaparin for Thromboprophylaxis After Primary Total Hip Arthroplasty (RE-NOVATE II) trial (47.5 ng/mL in patients taking 150 mg; interquartile range, 29.6e71.2 ng/mL vs 32.0 ng/mL in patients taking 220 mg; interquartile range, 19.4e55.0 ng/mL).50,51 Offering a tolerable and effective reduced dosing option, dabigatran etexilate 150 mg could be indicated for medically fragile patients, such as those with moderate renal impairment or elderly patients. Because this encompasses a significant portion of patients receiving a THA, dabigatran etexilate 150 mg is an important option for thromboprophylaxis. Although the STARS J-V trial indicated the similar tolerability and superior efficacy of edoxaban therapy for thromboprophylaxis after THA, these results were compared against the Japanese guidelines, which recommends a lower dose of enoxaparin. In addition, the mean weight of the STARS J-V study participants was 57.5 kg, approximately 20 kg lower than the other Phase III trials (mean weight in the RECORD 1 trial for patients taking rivaroxaban was 78 kg).44 However, because edoxaban continues to exhibit favorable results in supplemental avenues of study, namely in the thromboprophylactic treatment of patients after HFS and in the successful half-dose

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A.A. Coulis and W.C. Mackey adjustment for patients with severe renal impairment (CRCL of 15e30 mL/min), further evaluation is warranted to establish edoxaban's place in Western medical practice. Furthermore, the potential exhibited by edoxaban highlights areas of study that are currently lacking for the other oral anticoagulants. When considering the clinical role of NOACs in thromboprophylaxis after major orthopedic surgery, additional avenues of study should include their effectiveness compared with aspirin. Offering the same lifestyle benefits and ease of oral administration, the relative low-cost and convenience of over-the-counter aspirin would make it a valuable anticoagulant option. Investigating this possibility, the Extended Venous Thromboembolism Prophylaxis Comparing Rivaroxaban to Aspirin Following Total Hip and Knee Arthroplasty (EPCAT II) trial established the noninferiority of aspirin 81 mg/ d versus rivaroxaban 10 mg/d for the prevention of recurrent VTE after TKA or THA. Numerically, VTE occurred in 0.64% of the aspirin group and in 0.70% of the rivaroxaban group (0.06 difference in percentage points; 95% CI, −0.55 to 0.66; P < 0.001 for noninferiority and P ¼ 0.84 for superiority), whereas major bleeding complications occurred in 0.47% and 0.29% of the aspirin and rivaroxaban groups, respectively (0.18 difference in percentage points; 95% CI, −0.65 to 0.29; P ¼ 0.42).52 However, subgroup analysis of patients who were undergoing long-term aspirin therapy before surgery revealed higher rates of bleeding for those in the aspirin group. Specifically, the trial results indicated that for this subgroup of 885 patients, 0.7% in both the rivaroxaban and aspirin groups experienced a recurrent VTE, whereas 0.23% of the rivaroxaban group and 0.94% of the aspirin group experienced major bleeding events.52 These results suggest that for patients already undergoing long-term aspirin therapy, an additional dose of aspirin 81 mg for VTE prophylaxis is not recommended. Although it seems that thromboprophylaxis with rivaroxaban would be advantageous for such patients, further research is needed to establish the safety profiles and efficacy of the NOACs (especially apixaban, dabigatran etexilate, and edoxaban) compared with aspirin therapy. In addition to major orthopedic surgery, apixaban and rivaroxaban were evaluated for efficacy and tolerability in the thromboprophylaxis of acutely ill

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medical patients with varied results. In Phase III clinical trials, apixaban failed to establish superiority with respect to the recommended enoxaparin regimen of 40 mg once daily for 6e14 days. Speaking to the potential of apixaban, ADOPT trial researchers state that their study was underpowered and insist that no clinically directive conclusion can be drawn from their results. Specifically, the authors postulate that the study conditions, namely the required ultrasonographic screening for VTE even in the absence of symptoms and continued enoxaparin treatment for the full recommended 6 to 14 days, do not accurately portray clinical practice.48 Acknowledging this, although apixaban is not currently indicated for the extended thromboprophylaxis in acutely ill medical patients, further research that better represents clinical conditions is warranted. In addition to the favorable results, the study design of the MAGELLAN trial provides the greatest support for the use of rivaroxaban in the thromboprophylaxis of acutely ill medical patients. Establishing its noninferiority at day 10 indicates that oral rivaroxaban is as effective as subcutaneous enoxaparin, the short-term anticoagulant regimen recommended by current guidelines. Because most patients remain in the hospital for <5 days and it is standard practice to discontinue enoxaparin injections on hospital discharge, oral rivaroxaban would be a much simpler option. Furthermore, it was the only NOAC that has superiority versus placebo in an extended 35-day thromboprophylactic regimen. However, because this medication was associated with increased risks of bleeding, the benefit to risk ratio must be considered by the physician.

CONCLUSION Overall, Phase III and postmarketing VTE treatment and prophylaxis trials found that NOACs can effectively simplify anticoagulation therapy for a wide range of patients. With no restriction on dietary intake and administered in fixed-oral doses that do not require routine monitoring, these medications are ideal for the outpatient setting. Although not addressed in this review, additional factors, such as patient satisfaction and overall cost of treatment, should be considered. Offering a brief insight into additional benefits that may be associated with NOAC therapy, subgroup analysis of the EINSTEIN

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Clinical Therapeutics trials indicated that patients taking rivaroxaban reported greater treatment satisfaction.53 In addition, researchers investigating financial implications calculated that during a 5-year period it cost a mean of $2488 less per patient to treat with rivaroxaban than with standard enoxaparin or warfarin therapy.54 Although these results seem promising, they were not the primary focus of the original study and should be read with caution. However, these factors are important aspects of treatment that should be subject to rigorous study. In light of the results described above, it now seems reasonable for clinicians to consider NOACs as first-line agents for treatment and prophylaxis of venous thromboembolic disease in most patients and to consider the relative merits of the available NOACs in tailoring their choices for individual clinical scenarios. Although heparins and VKAs may still be recommended for selected patients, their role is rapidly diminishing, especially when longer-term therapy is required.

ACKNOWLEDGMENTS Dr. John Castellot of the Tufts University School of Medicine provided valuable guidance in the editing of this manuscript. Author contributions are as follows: Alexis Coulis: methodology, investigation, and writing (original draft); William Mackey: conceptualization, methodology, writing (review and editing), and supervision.

CONFLICTS OF INTEREST The authors have indicated that they have no conflicts of interest regarding the content of this article.

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Address correspondence to: Alexis A. Coulis, MS, Tufts University School of Medicine, 145 Harrison Ave, Boston, MA 02111, USA. E-mail: Alexis. [email protected]

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