General Review The New Era of Anticoagulation Nedaa Skeik, Kyle K. Rumery, and Gabriel T. Rodriguez, Minneapolis, Minnesota

Warfarin has been approved by the U.S. Food and Drug Administration for medical use as an anticoagulant for more than 60 years. Although it has been an effective anticoagulant, its use is accompanied by several pitfalls, which has led to research and the discovery of new additional groups of anticoagulants: direct thrombin inhibitors, such as dabigatran, and direct factor Xa inhibitors, such as rivaroxaban and apixaban. These new anticoagulants are fast-acting, noninferior to warfarin in preventing stroke in patients with nonvalvular atrial fibrillation, and do not require monitoring. More data are accumulating to support their use in the prevention and management of venous thromboembolism. This article reviews the literature on these novel anticoagulants, including their pharmacokinetics and treatment indications.

INTRODUCTION Warfarin was first used in 1948 as a pesticide before the U.S. Food and Drug Administration (FDA) approved it for medical use as an anticoagulant in 1954. Warfarin works through inhibiting vitamin K epoxide reductase, an enzyme that reduces oxidized vitamin K after it has facilitated the carboxylation of coagulation proteins for factors II, VII, IX, and X.1 When used to treat patients with atrial fibrillation, a condition affecting more than 2 million Americans, warfarin has been shown in randomized controlled trials to reduce the incidence of ischemic strokes by 65% compared with placebo.2 However, several compelling problems are associated with the use of warfarin, including variability of its effect among individuals, the need for frequent international normalized ratio (INR) checks to ensure therapeutic levels are maintained (achieved 66% of the time in the United States according to Abbott Northwestern Hospital and Minneapolis Heart Institute Research Foundation, Minneapolis, MN. Correspondence to: Nedaa Skeik, Vascular Medicine Specialist, Abbott Northwestern Hospital, Minneapolis Heart Institute, Vascular Medicine, 800 East 28th Street, Suite H 2000, Minneapolis, MN 55407, USA; E-mail: [email protected] Ann Vasc Surg 2014; 28: 503–514 http://dx.doi.org/10.1016/j.avsg.2013.07.013 Ó 2014 Elsevier Inc. All rights reserved. Manuscript received: July 11, 2013; manuscript accepted: July 31, 2013; published online: January 10, 2014.

the Randomized Evaluation of Long-Term Anticoagulant Therapy [RE-LY] trial), dietary restrictions, and numerous drugedrug interactions.3,4 These problems have resulted in compliance issues, especially among elderly patients, with 26% of patients age 80 years or older discontinuing the use of warfarin within the first year, 81% of whom stopped because of safety concerns.5 The problems associated with warfarin use, however, have resulted in active, ongoing research to identify alternative anticoagulation therapies that are able to provide the benefits of warfarin without its associated problems. This research has led to the discovery of two treatment alternatives: direct thrombin inhibitors and direct factor Xa (FXa) inhibitors. This article provides an in-depth review of the relevant medical literature, which assesses the efficacy of these new anticoagulation treatment modalities.

DIRECT THROMBIN INHIBITORS Thrombin is a key protein in the chemical process of coagulation and was considered an important target for researchers, because it activates factors V, VIII, XI, and XIII and fibrinogen.6,7 It also promotes platelet aggregation via activation of protease receptors on its membrane. Several FDA-approved direct thrombin inhibitors are available in intravenous form, and currently one is available in oral form. The 503

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currently available intravenous forms include hirudin, bivalirudin, lepirudin, and desirudin, which are mostly used to manage heparin-induced thrombocytopenia. Examples of oral direct thrombin inhibitors include ximelagatran and dabigatran etexilate.8 Ximelagatran was the first available oral thrombin inhibitor; however, its marketing approval was withdrawn in several European and South American countries because of the discovered adverse effect of hepatotoxicity.9 This review of thrombin inhibitors is therefore focused on the comparative efficacy of dabigatran.

DABIGATRAN (PRADAXAÒ) In 2010, dabigatran became the first oral anticoagulant approved by the FDA in more than 50 years (approved October 2010), receiving specific approval for preventing stroke and systemic embolism (SE) in patients with nonvalvular atrial fibrillation (NVAF).4 It received FDA approval based on data from the RE-LY trial using dabigatran etexilate.10 The approved dosages in the United States are 150 mg (creatinine clearance [CrCl], > 30 mL/ min) and 75 mg (CrCl, 15e30 mL/min), both twice daily.11 A third dose, 110 mg, was approved for use in Europe, but is not available in the United States. Unlike the 150 and 110 mg doses, the 75 mg dose is based entirely on pharmacokinetic profiling rather than clinical evidence.11 Dosing information is not currently available for patients with a CrCl < 15 mL/min, women who are pregnant or nursing, and children.11 Mechanism of Action and Pharmacology Dabigatran is a prodrug that is converted to its active form, etexilate ester.4 Maximum concentration is achieved within 1e2 hr postadministration, and the half-life in healthy patients is 12e17 hr after multiple doses, although it varies depending on renal function.11 As CrCl decreases, mean half-life increases substantially.4 Although its duration of action is 24 hr in patients with normal renal function, its effect can last up to 5 days in patients with renal insufficiency.12 Approximately 35% of dabigatran remains bound to human plasma proteins, and 80% is excreted via the renal system. Absolute bioavailability is approximately 3e7%.11 Dabigatran etexilate is a substrate of the efflux permeability glycoprotein transporter (P-gp) and it is not a substrate, inhibitor, or inducer of CYP450 enzymes.4 Excretion of dabigatran is promoted by the high expression of efflux transporter P-gp in the intestines and kidneys. P-gp inhibitors, such as

Annals of Vascular Surgery

amiodarone, dronedarone, quinidine, ketoconazole, and verapamil, inhibit excretion of dabigatran, leading to an increase in circulating drug levels.4 In contrast, inducers of P-gp (e.g., rifampin) reduce circulating drug levels by promoting excretion of dabigatran. Therefore, inducers such as quinine, systemic ketoconazole, and rifampin should be avoided in patients receiving dabigatran. The largest increase in levels of circulating dabigatran has been observed when verapamil or dronedarone are given 1 hr before dabigatran; however, a negligible increase in dabigatran concentration occurs if either of these P-gp inhibitors is given 2 hr after dabigatran ingestion.4 Common Side Effects The most common side effects of dabigatran are gastrointestinal-related, including dyspepsia, abdominal pain, epigastric discomfort, acid reflux, esophagitis, erosive gastritis, gastric hemorrhage, and gastrointestinal ulcer.10 Hypersensitivity reactions are far less common, occurring in < 0.1% of patients. Based on data from the RE-LY trial, the discontinuation rate for dabigatran during the first and second year of use is 16% and 21%, respectively, versus 10% and 17% for warfarin.10 Finally, hepatitis risk from dabigatran, 150 mg, was similar to that associated with warfarin (1.9% and 2.2%, respectively).10

CLINICAL USE Stroke Prophylaxis for Patients with NVAF Dabigatran, 110 mg, was noninferior (P < 0.001), whereas the 150 mg dose was superior to warfarin (P < 0.001) in preventing ischemic stroke or embolism.10 Furthermore, dabigatran in both doses was associated with less risk of hemorrhagic stroke (P < 0.001 for both doses) (Table I). Risk of major bleeds was significantly lower with dabigatran, 110 mg (P ¼ 0.003), and similar with 150 mg (P ¼ 0.31) compared with warfarin.10 Although dabigatran, 110 mg, had a similar risk for gastrointestinal bleeding as warfarin (P ¼ 0.43), the risk was significantly higher with dabigatran, 150 mg (P < 0.001) (Table I).10 Age-related Safety A subanalysis of the RE-LY trial by Eikelboom et al.13 investigated the risk of bleeding with dabigatran, 110 and 150 mg, compared with warfarin based on age. In patients younger than 75 years,

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Table I. Rates of ischemic stroke or embolism and rates of hemorrhagic stroke for dabigatran versus warfarin based on the RE-LY trial data

Warfarin Dabigatran, 110 mg bid Dabigatran, 150 mg bid

Rate of ischemic stroke or embolism

Rate of hemorrhagic stroke

1.69%/year 1.53%/year (P < 0.001 for noninferiority) 1.11%/year (P < 0.001 for superiority)

0.38%/year 0.12%/year (P < 0.001) 0.10%/year (P < 0.001)

dabigatran had a lower risk of major bleeding (P < 0.001 for both doses), whereas those aged 75 years or older on dabigatran, 110 mg, had a similar risk (P ¼ 0.89; P for interaction < 0.001), and patients on 150 mg displayed a trend toward higher risk of major bleeding (P ¼ 0.07; P for interaction < 0.001).13 The interaction with age was observed for extracranial (especially gastrointestinal) but not intracranial bleeding. The risk of intracranial bleeding was consistently reduced with dabigatran compared with warfarin, regardless of the dose and age. Hart et al.14 found that fewer instances of fatal (P < 0.01) or traumatic (P < 0.05) intracranial hemorrhage occurred among those assigned to dabigatran, 150 and 110 mg, compared with those on warfarin, whereas Diener et al.15 found that dabigatran was still effective in patients with a history of previous transient ischemic attack or stroke. Periprocedural Use Healey et al.16 examined the periprocedural bleeding risk in patients in the RE-LY trial. They studied bleeding rates from 7 days before to 30 days after invasive procedures, which included pacemaker/ defibrillator implantation, dental procedures, diagnostic procedures, cataract removal, colonoscopy, joint replacement, coronary artery bypass grafting (CABG) with valve, carotid endarterectomy, peripheral angioplasty, and limb amputation. The last dose of dabigatran at either 110 or 150 mg was given an average of 49 hr before the procedure, compared with 114 hr in patients on warfarin. No significant difference was seen in the rates of periprocedural major bleeding between patients receiving either dose of dabigatran or warfarin (P ¼ 0.28).16 However, significantly less periprocedural bleeding risk was associated with dabigatran at 110 and 150 mg compared with warfarin when the anticoagulant was discontinued within 48 hr of the given procedure (P < 0.001 for both).16 Bassiouny et al.17 investigated the use of dabigatran, 150 mg, and warfarin to prevent thromboembolic and hemorrhagic events during pulmonary vein isolation for atrial fibrillation and found that

total hemorrhagic and thromboembolic events were similar (P ¼ 0.59 and P ¼ 0.53 prematching and postmatching, respectively). Southworth et al.18 proposed that, given the heightened awareness of dabigatran as a new drug on the market, the higher reported rates of bleeding with dabigatran might merely reflect the greater likelihood of reporting a bleeding event in a patient receiving dabigatran than in one receiving warfarin. Ultimately, the mini-sentinel assessment by the FDA indicated that bleeding rates associated with new use of dabigatran were no higher than those of new use of warfarin, a finding that is consistent with results from the RE-LY trial.19,20 Myocardial Infarction and Other Cardiac Risks Controversy continues about the risk of myocardial infarction (MI) with dabigatran use. Although results from the original RE-LY trial revealed some increased risk for MI in patients who received 150 mg of dabigatran versus warfarin (P ¼ 0.048), a subanalysis found no significant difference in the incidence of clinical MI for either dabigatran 110 or 150 mg compared with warfarin (P ¼ 0.10 for 110 mg; P ¼ 0.09 for 150 mg; P ¼ 0.06 combined).10,21 Furthermore, annual rates of a composite of stroke, SE, MI, unstable angina, CABG, percutaneous coronary intervention, cardiac arrest, and cardiac death was lower for dabigatran 150 mg versus warfarin (P ¼ 0.03), although not for dabigatran 110 mg (P ¼ 0.24).21 Finally, ‘‘net clinical benefit’’ events, including all strokes, SE, MI, pulmonary embolism (PE), major bleeding, and allcause death, occurred at a significantly lower rate with dabigatran, 150 mg, compared with warfarin (P ¼ 0.02).21 Uchino and Hernandez22 conducted a metaanalysis of 7 randomized control trials of dabigatran in the management of NVAF and venous thromboembolism (VTE). In contrast to RE-LY trial findings, they reported that dabigatran was associated with a higher risk of MI or acute coronary syndrome (ACS) compared with controls, which included warfarin, enoxaparin, or placebo (P ¼ 0.03).22 Although the

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relative risk of MI increase was 33% and the relative risk reduction for death was 11% with dabigatran compared with control, the absolute increased risk was very small (0.27%), and the absolute risk reduction was only 0.05%.22 Consequently, the study does not provide convincing evidence of clinically significant harm from cardiac ischemic events when comparing treatment with dabigatran versus warfarin. However, the possibility of increased cardiac risk associated with dabigatran use should be further investigated, especially if it continues to be used in populations at high risk of MI or ACS. Finally, the RE-DEEM (RandomizEd Dabigatran Etexilate Dose Finding Study in Patients With Acute Coronary Syndromes Post Index Event With Additional Risk Factors for Cardiovascular Complications Also Receiving Aspirin and Clopidogrel) trial investigated the role of dabigatran at 50, 75, and 110 mg in combination with dual antiplatelet therapy in the management of ACS and found a dose-dependent increase in bleeding events without significant thrombotic benefit, except for a significant reduction of coagulation activity as measured by D-dimer concentration (P < 0.001).23 Management of VTE The RE-NOVATE (A Phase III Randomised, Parallel Group, Double-blind, Active Controlled Study to Investigate the Efficacy and Safety of Two Different Dose Regimens of Orally Administered Dabigatran Etexilate Capsules [150 or 220 mg Once Daily Starting With Half Dose (75 or 110 mg) on the Day of Surgery] Compared to Subcutaneous Enoxaparin 40 mg Once Daily for 28-35 Days, in Prevention of Venous Thromboembolism in Patients With Primary Elective Total Hip Replacement Surgery) and RE-MODEL ([Thromboembolism Prevention After Knee Surgery]. Two Different Dose Regimens of Orally Administered Dabigatran Etexilate Capsules [150 or 220 mg Once Daily Starting With a Half Dose (i.e.75 or 110 mg) on the Day of Surgery] Compared to Subcutaneous Enoxaparin 40 mg Once Daily for 6-10 Days) trials investigated the use of dabigatran, 220 and 150 mg, versus enoxaparin for VTE prevention after total hip and knee replacement, respectively.24,25 Both dabigatran doses were noninferior to enoxaparin in preventing VTE (RE-NOVATE: P < 0.0001 for 220 mg, P < 0.0001 for 150 mg; RE-MODEL: P ¼ 0.0003 for 220 mg, P ¼ 0.017 for 150 mg), with no significant difference in major bleeding rates (RENOVATE: P ¼ 0.44 for 220 mg, P ¼ 0.60 for 150 mg; RE-MODEL: P ¼ 0.82 for 220 mg, P ¼ 1.0 for 150 mg).24,25

Annals of Vascular Surgery

Hankey et al.4 conducted a meta-analysis of the effect of dabigatran, 220 mg once daily versus enoxaparin, 40 mg once daily or 30 mg twice daily in reducing the risk of total VTE, all-cause mortality, and major bleeding among patients undergoing knee or hip replacement, and found similar prevention of total VTE and all-cause mortality and similar risk of major bleeding. In addition, the RE-COVER (A Phase III, Randomised, Double Blind, Parallelgroup Study of the Efficacy and Safety of Oral Dabigatran Etexilate 150 mg Twice Daily Compared to Warfarin (INR 2.0-3.0) for 6 Month Treatment of Acute Symptomatic Venous Thromboembolism (VTE), Following Initial Treatment (5-10 Days) With a Parenteral Anticoagulant Approved for This Indication) study investigated the role of dabigatran, 150 mg versus warfarin in the treatment of acute VTE.26 Dabigatran was noninferior (P < 0.001) to warfarin in terms of 6-month recurrent VTE and VTE death, without increased major bleeding risk (hazard ratio [HR] with dabigatran, 0.82; 95% confidence interval [CI], 0.45e1.48). The RE-MEDY and RE-SONATE trials investigated the extended use of dabigatran, 150 mg, warfarin (RE-MEDY), or placebo (RE-SONATE) in preventing VTE and found that dabigatran was noninferior to warfarin (P ¼ 0.01), with a lower risk of major or clinically relevant bleeding than warfarin.27 In the RE-SONATE study, recurrent VTE in the dabigatran group was significantly lower than in the placebo group (P < 0.001); however, an increase in major or clinically relevant bleeding in the dabigatran group was reported (HR, 2.92; 95% CI, 1.52e5.60).27 Use with Mechanical Heart Valves The RE-ALIGN trial attempted to compare the safety and pharmacokinetics of dabigatran versus warfarin in patients with mechanical heart valves.28 The trial, however, was prematurely discontinued because of concerns about the increased risk of valve thrombosis and major bleeding with dabigatran. Price et al.29 reported two cases of mechanical valve (one aortic, the other mitral) thrombosis in patients switched from warfarin to dabigatran. Based on this evidence, dabigatran is contraindicated in patients with mechanical heart valves. Monitoring Several options are currently available for monitoring patients on dabigatran, although this is generally not indicated nor required to ensure efficacy.30 However, circumstances arise in which monitoring may be useful, including overdosing,

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bleeding events, surgery, and compliance assessment. Direct drug concentration monitoring is ideal but not routinely available. Because dabigatran inhibits the final step of both coagulation cascades, it leads to the prolongation of the following tests: prothrombin time (PT), INR, activated partial thromboplastin time (aPTT), thrombin clotting time (TT), and ecarin clotting time (ECT).31 The correlation with dabigatran concentration, however, varies among these tests. For example, correlation is poor with PT/INR but is better with TT and ECT. Thrombin clotting time exhibits a linear correlation with dabigatran levels, but may be too sensitive, displaying off-scale at low drug concentrations.31 Unfortunately, ECT has limited availability and kits are not standardized for dabigatran; therefore, it is not feasible for emergency monitoring. Activated partial thromboplastin time is widely available, and its correlation with dabigatran concentration is curvilinear, but its results are highly variable, particularly with high concentrations of dabigatran.31 However, when aPTT is normal, dabigatran has almost certainly cleared from the system and conditions are safe to proceed with a procedure. The HemoclotÒ test (thrombin inhibitor assay), although not widely available, is similar to TT, but with a plasma dilution of 1:8 to 1:20, which is indicative of better correlation.31 Another promising new test used at the authors’ institution is the chromogenic antifactor II assay, which is based on the fact that the quantity of the color emitted by the released chromogenic p-nitroaniline that results from thrombin cleavage is inversely proportional to the concentration of dabigatran. Management of Bleeding As mentioned, bleeding is a serious complication of dabigatran, and therefore drug reversal and bleeding management is very important. No specific antidote is currently available.30 Time is not the antidote, because dabigatran has a half-life of 12e17 hr. Fresh frozen plasma does not provide adequate reversal management, because clotting times are prolonged as a result of inhibition and not factor deficiency.31 Instead, and based on the site, bleeding may be corrected with pressure, red blood cell transfusion, endoscopic procedures, and/or pressors. Dabigatran is a lipophilic molecule, and therefore is absorbable by activated charcoal if given within 1e2 hr of ingestion.31 Hemodialysis is another option; however, because 35% of the drug is bound to plasma protein, only 60% is dialyzable.30 Currently no solid evidence suggests that plasmapheresis and hemofiltration are effective methods of dabigatran reversal.

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Prothrombin complex concentrates (PCC) contain factors II, VII, IX, and X and have been shown to stop bleeding in rabbits, but have no impact on dabigatran-induced clotting assay.32 Activated PCC reversed the bleeding time prolongation caused by dabigatran.31 Recombinant factor VIIa (60 mg/kg) reduced the tail bleeding in a rat model with dabigatran, but only partially restored aPTT.31 Prothrombin complex concentrate, active PCC, and recombinant factor VIIa should only be used as a last resort, and patients with a high risk for thrombosis should be monitored for disseminated intravascular coagulation after infusion. Periprocedural Management and Anticoagulant Conversion No consensus exists about how to manage periprocedural anticoagulation in patients on dabigatran.4,31 However, different protocols have been created based on surgical bleeding risk, patient thrombotic risk, and renal function. The authors’ institution discontinues dabigatran 1e2 days before surgery in patients with high thrombotic risk and normal renal function who are scheduled for low-bleed-risk procedures, and discontinues dabigatran up to 5e7 days before highbleed-risk procedures in patients with low thrombotic risk and renal insufficiency. When thrombotic risk is high, greater consideration is given to using a bridging agent, such as heparin, based on the package insert warning.11 Postprocedural recommendations include deep vein thrombosis (DVT) prophylaxis, and resuming dabigatran once complete hemostasis is confirmed. In cases with continuous high risk of bleeding, temporary warfarin use might be considered, because it has a slow onset and is reversible.31 Conversion from warfarin to dabigatran requires discontinuation of warfarin and initiation of dabigatran when INR is < 2.0.11 Warfarin is started 3 days before discontinuation of dabigatran for CrCl  50 mL/min, 2 days before for CrCl 30e50 mL/min, and 1 day if CrCl is 15e30 mL/min, with no recommendations for CrCl  15 mL/min.11 When converting from parenteral anticoagulant to dabigatran, dabigatran may be started 2 hr before or at the time of discontinuation of the parenteral anticoagulant. Finally, when converting from dabigatran, initiation of the parenteral anticoagulants should be delayed for 12 hr after the last dose of dabigatran if CrCl  30 mL/min and 24 hr if CrCl < 30 mL/min.11

DIRECT FACTOR XA INHIBITORS Factor Xa activation is a crucial step for coagulation because it converges both intrinsic and extrinsic

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pathways. Therefore, inhibiting FXa has been an ideal goal for anticoagulation therapies.33 Indirect FXa inhibitors (e.g., low-molecular-weight heparin and fondaparinux) act as cofactors to proteases, like antithrombin, enhancing FXa inhibition and preventing clot formation, whereas direct FXa inhibitors bind directly to FXa to inhibit coagulation.33 However, direct inhibitors have an advantage through blocking clot-bound FXa, which induces a stronger anticoagulation effect.34,35 Consequently, multiple direct FXa inhibitors have been developed, such as rivaroxaban, apixaban, betrixaban, and edoxaban.

RIVAROXABAN (XARELTOÒ) Mechanism of Action and Pharmacology Rivaroxaban is an oral direct FXa inhibitor that binds with a high affinity and selectivity.36 Studies have shown the versatile ability of rivaroxaban to block both free and clot-bound FXa.36,37 Rivaroxaban is taken once daily and is rapidly absorbed, with a quick onset of 1e4 hr postingestion. Elimination of ingested rivaroxaban involves hepatic metabolism and renal excretion (66%), resulting in a half-life of 10 hr in healthy individuals.38e40 CYP3A4/5 and P-gp enzymes interact with rivaroxaban, creating particular drug interactions.41 P-gp inhibitors (e.g., ketoconazole, ritonavir, clarithromycin, erythromycin, fluconazole) increase rivaroxaban plasma levels, whereas Pgp inducers (e.g., carbamazepine, phenytoin, rifampin, St. John’s wort) decrease rivaroxaban plasma levels. In addition, concomitant use with certain antithrombotics has not been shown to alter pharmacokinetics but may increase bleeding risk.41 Lastly, rivaroxaban has been associated with rare adverse reactions, including agranulocytosis, thrombocytopenia, bleedings, jaundice, cholestasis, cytolytic hepatitis, and allergic reactions.42

CLINICAL USE In the United States, rivaroxaban was first approved for VTE prophylaxis in patients undergoing total hip replacement (10 mg/d, beginning 6e8 hr through 35 days postoperation) and knee replacement (10 mg/d, beginning 6e8 hr through 12 days postoperation).42e46 It later received approval for ischemic stroke prevention in patients with NVAF (20 or 15 mg/d if CrCl 15e20 mL/min).42,47 Rivaroxaban was eventually approved for management of VTE.42,48e50 Contraindications for rivaroxaban include hypersensitivity, active major bleeding, hepatic

Annals of Vascular Surgery

impairment (Child-Pugh class B or C), CrCl < 15 mL/min for thromboembolism/stroke prophylaxis, and CrCl < 30 mL/min for DVT prophylaxis.42e50 Stroke Prophylaxis for Patients with NVAF The ROCKET-AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) trial investigated rivaroxaban for ischemic stroke prevention in patients with NVAF.47 Compared with therapeutic warfarin administration, rivaroxaban was noninferior for the primary efficacy outcome, a composite of stroke or SE (P < 0.001), and provided similar risk for major or clinically relevant nonmajor bleeding (P ¼ 0.44 for primary safety outcomes).47 Moreover, intracranial hemorrhages and fatal bleeding occurred less often with rivaroxaban (P ¼ 0.02 and P ¼ 0.003, respectively).47 Subsequent studies further analyzed rivaroxaban for particular subgroups within the ROCKET-AF trial.53,54 Low-dose rivaroxaban (15 mg) was found to be equally effective for thromboprophylaxis in patients with NVAF with renal insufficiency (CrCl 30e49 mL/min; P ¼ 0.76).53 Although patients with renal insufficiency experienced higher bleeding rates than those with normal renal function, rivaroxaban and warfarin resulted in similar bleeding risks (P ¼ 0.76), with less fatal bleeding events in the rivaroxaban group (P ¼ 0.047).53 Lastly, a history of prior stroke did not significantly alter the primary efficacy (composite of stroke or SE) or safety (major or clinically relevant nonmajor bleeding) outcomes of rivaroxaban compared with warfarin (P ¼ 0.047 and P ¼ 0.23, respectively).54 Management of VTE Four studies from the RECORD (REgulation of Coagulation in ORthopedic Surgery to Prevent Deep Venous Thrombosis and Pulmonary Embolism) program compared rivaroxaban with enoxaparin in patients after total hip replacement and total knee replacement.43e46,51 In all four studies, rivaroxaban was superior to enoxaparin for total VTE prevention (composite of symptomatic DVT, nonfatal PE, and all-cause mortality) with no significant increases in major bleeding (< 0.7% in each study).51 These findings led to FDA approval of rivaroxaban for VTE prevention in patients after total knee and hip replacement.51,52 The EINSTEIN investigators assessed rivaroxaban for the treatment and secondary prevention of

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VTE.48e50 EINSTEIN compared rivaroxaban and enoxaparin with vitamin K antagonist (VKA) therapy for secondary VTE prevention in patients with acute DVT.48 Rivaroxaban had noninferior efficacy to enoxaparin/VKA for recurrent VTE (P < 0.001), without significant differences in major bleeding rates (P ¼ 0.73).48 In addition, EINSTEIN-EXT found that extended treatment (6e12 months) of rivaroxaban was superior to placebo for recurrent VTE prevention (P < 0.001), with no increase in nonfatal major bleeds (P ¼ 0.11).48,49 The EINSTEIN PE trial was a similar study that investigated rivaroxaban versus enoxaparin/VKA for the treatment of patients with acute PE.50 Rivaroxaban was noninferior to enoxaparin/VKA for preventing recurrent VTE (P ¼ 0.003), without significant differences in major or clinically relevant nonmajor bleeding events (P ¼ 0.23).50 Based on the EINSTEIN studies, rivaroxaban gained FDA approval for the management of acute DVT and PE. For the management of VTE, rivaroxaban is given at 15 mg twice daily for 2 weeks, with a subsequent dose of 20 mg daily for a duration determined by the VTE recurrent risk.42 In the MAGELLAN study, rivaroxaban was studied in hospitalized patients requiring VTE prophylaxis.55 Standard (10 ± 4 days) and extended treatments (35 ± 4 days) of rivaroxaban were noninferior (P ¼ 0.003) and superior (P ¼ 0.02), respectively, to enoxaparin for VTE prevention. However, both rivaroxaban treatment groups had increased bleeding risk compared with the enoxaparin group (P < 0.001 for both).55 Acute Coronary Syndrome The ATLAS ACS 2eTIMI 51 study was initiated to assess the secondary thromboprophylaxis of rivaroxaban in patients with ACS.56 Low doses of rivaroxaban (5 and 10 mg) markedly reduced mortality rates from cardiovascular causes and stroke compared with placebo (P ¼ 0.008). However, both rivaroxaban doses increased risks for major bleeding (P < 0.001) and intracranial hemorrhage (P ¼ 0.009), whereas rates of fatal bleeds were similar (P ¼ 0.66 for both doses).56 Despite these promising findings, more clinical data are required to approve rivaroxaban for patients who are acutely ill and those with ACS. Monitoring Rivaroxaban does not have a specific assay for monitoring; however, several assays can be used to assess the drug level. The PT and aPTT assays are routine tests used for most anticoagulants, but these assays

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give variable measurements for rivaroxaban and are therefore unsuitable for accurate monitoring.57 However, PT in seconds shows some correlation with the level of direct Xa inhibitors such as rivaroxaban and apixaban. A normal PT level rules out clinically significant levels of the direct factor Xa inhibitor.57 Other clot-based assays, HepTest and ACT, are available, but have yet to be studied with rivaroxaban.57 The anti-FXa assay is a different method that involves the enzymatic cleavage of a synthetic substrate and can directly determine the amount of FXa present in the sample. These tests show promising results for rivaroxaban and can measure a large plasma level range (0e500 ng/mL). However, a standardized assay is still needed for routine rivaroxaban monitoring. Reversal and Bleeding Management Despite the advantages rivaroxaban has over traditional VKAs, one current disadvantage with rivaroxaban is the absence of a specific antidote. In the event of a bleeding complication, standard protocol calls for applying pressure at the site and use of red blood cell transfusion and pressors, and with gastrointestinal bleeding, an endoscopic procedure may be necessary. Delivery of fresh frozen plasma may not reverse rivaroxaban effects, because clotting times are prolonged as a result of inhibition and not factor deficiencies. Prothrombin complex concentrates were initially proposed as a possible antidote, because Eerenberg et al.32 found that they immediately reversed anticoagulant effects in healthy patients receiving rivaroxaban. Thus, although the use of PCCs shows promise as a reversing agent for rivaroxaban, further clinical research is required. Periprocedural Management and Anticoagulant Conversion Similar to dabigatran, rivaroxaban does not have consensus protocols for periprocedural anticoagulation management. However, a specific set of treatment protocols is used at the authors’ institution. These protocols are based on the bleeding risk associated with a given procedure, the thrombotic risk, and the patient’s renal and liver functions. The preoperative management of patients scheduled for highbleed-risk procedures may require discontinuation of rivaroxaban up to 5 days before the procedure for patients with CrCl  50 mL/min and low thrombosis risk, whereas low-bleeding-risk procedures may not require medication discontinuation until 1e2 days before the procedure for patients with

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Table II. Novel anticoagulant pharmacology comparison

Mechanism of Action T ½ in hour T-max Metabolism

Dabigatran

Rivaroxaban

Apixaban

Direct thrombin inhibitor

Direct Factor X inhibitor

Direct Factor X inhibitor

12 e 17 hours ½ e 2 hours 80% renal

Average 10 hours 1 e 4 hours 1/3 excreted unchanged in urine 2/3 excreted inactive in urine and feces Interaction P-gp CYP3A4/5, CYP2J2, P-gp and ATP-binding cassette G2 (ABCG2) Side Effects Bleeding Bleeding GI side effects including GI Agranulocytosis, bleed Thrombocytopenia, Stevens Johnson Active bleed, Contraindication Active bleed Child Pugh B-C CrCl< 15 CrCl < 30 in DVT prophylaxis Prosthetic valves CrCl < 15 in NVAF Prosthetic valves Level aPTT!, TT, ECT PT in seconds Monitoring Hemoclot, dabigatran level Anti-factor Xa level Management No specific antidote, Charcoal if No specific antidote, Charcoal if within 2 hours PCC, APCC, of Bleeding within 2 hours, APCC rFVIIa (FEIBA), PCC, rFVIIa Not dialyzable Dialyzable

8 e 15 hours 1 e 3 hours Renal 27% Liver 73%

CYP3A4 and P-gp

Bleeding Nausea Skin rash Low BP Active bleed Severe liver disease Prosthetic valves

PT in seconds Anti-factor Xa level No specific antidote, Charcoal if 2e6 hours PCC, APCC, rVIIa Not dialyzable

APCC, Activated prothrombin complex concentrates, FEIBA, Factor eight inhibitor bypass activity, rFVIIa. Recombinant activated clotting factor VII, BP, blood pressure, P-gp, permeability glycoprotein, PCC, Prothrombin complex concentrates, CrCl, creatinine clearance, DVT, deep vein thrombosis, AF, atrial fibrillation, GI, gastrointestinal, T1/2, half-life,Tmax, peak concentration.

high thrombotic risk and CrCl > 50 mL/min. Unfortunately, coagulation assays capable of documenting complete elimination of rivaroxaban are not yet available. The decision regarding the timing of medication discontinuation, therefore, requires careful consideration and should be made on a case-bycase basis. Rivaroxaban may be restarted as soon as hemostasis is achieved. Conversion from warfarin to rivaroxaban requires patients to discontinue warfarin and initiate rivaroxaban use once INR is < 3.0.42 Although clinical studies have not investigated the conversion from rivaroxaban to warfarin, the authors’ institution recommends that warfarin administration begin 1e3 days before rivaroxaban discontinuation based on the creatinine clearance. For patients converting from parenteral anticoagulants to rivaroxaban, the first dose can be administered 0e2 hr before the next parenteral anticoagulant dose. Conversion from rivaroxaban to parenteral anticoagulants involves discontinuing rivaroxaban and simultaneously starting new parenteral anticoagulants.

APIXABAN (ELIQUISÒ) Apixaban is another direct FXa inhibitor that was approved in May 2012 in Europe for thromboembolic prophylaxis in patients with NVAF. It was subsequently approved by the FDA in December 2012 for the same indication (5.0 or 2.5 mg, twice daily).58 Pharmacodynamics Apixaban is an oral agent administered twice daily with a high oral bioavailability (>50% across different animal models) and a 12-hr half-life in humans.59,60 The drug metabolized in the kidneys (z25%) and liver (75%), and has drug interactions mainly with potent CYP3A4 and P-glycoprotein transporter inhibitors.59,60

CLINICAL USE Stroke Prophylaxis for Patients with NVAF The AVERROES trial compared the use of apixaban (5 mg, twice daily) versus aspirin (81e324 mg,

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Table III. Novel anticoagulant indications comparison Dabigatran

FDA Approved Indications

Evidence for NVAF in Comparison to Warfarin

Rivaroxaban

Apixaban

NVAF NVAF VTE prophylaxis with THR/TKR VTE treatment & prevention ROCKET AF: non-inferior ARISTOTLE: superior RE-LY: 110 mg, (stroke) (stroke) non-inferior 150 mg, superior (ischemic stroke) RE-NOVATE/RE-NOVATE RECORD 1 & 2: superior ADVANCE-3: superior II: non-inferior

NVAF

VTE Prophylaxis for Hip Replacement vs. Enoxaparin VTE Prophylaxis for Knee RE-MODEL/RE-MOBILIZE: Replacement vs. non-inferior Enoxaparin VTE Prophylaxis in Medical Inpatients vs. Enoxaparin Acute VTE management vs. RE-COVER: non-inferior LMWH/VKA VTE risk reduction after RE-MEDY: non-inferior initial management vs. warfarin RE-SONATE: superior vs. placebo

RECORD 3 & 4: superior Lassen et al.68: non-inferior

MAGELLAN: non-inferior at 10 days Superior at 35 days EINSTEIN: non-inferior AMPLIFY: non-inferior EINSTEIN EXT: superior vs. placebo

AMPLIFY-EXT: superior vs. placebo

FDA, United States Food and Drug Administration; NVAF, nonvalular atrial fibrillation; THR/TKR, total hip replacement/total knee replacement; VTE, venous thromboembolism; RE-LY, Randomized Evaluation of Long-Term Anticoagulant Therapy trial; REDEEM, RandomizEd Dabigatran Etexilate Dose Finding Study in Patients With Acute Coronary Syndromes Post Index Event With Additional Risk Factors for Cardiovascular Complications Also Receiving Aspirin and Clopidogrel: Multi-centre, Prospective, Placebo Controlled, Cohort Dose Escalation Study; RE-NOVATE, A Phase III Randomised, Parallel Group, Double-blind, Active Controlled Study to Investigate the Efficacy and Safety of Two Different Dose Regimens of Orally Administered Dabigatran Etexilate Capsules [150 or 220 mg Once Daily Starting With Half Dose (75 or 110 mg) on the Day of Surgery] Compared to Subcutaneous Enoxaparin 40 mg Once Daily for 28-35 Days, in Prevention of Venous Thromboembolism in Patients With Primary Elective Total Hip Replacement Surgery; RE-MODEL, Two Different Dose Regimens of Orally Administered Dabigatran Etexilate Capsules [150 or 220 mg Once Daily Starting With a Half Dose (i.e.75 or 110 mg) on the Day of Surgery] Compared to Subcutaneous Enoxaparin 40 mg Once Daily for 6-10 Days; RE-COVER, A Phase III, Randomised, Double Blind, Parallel-group Study of the Efficacy and Safety of Oral Dabigatran Etexilate 150 mg Twice Daily Compared to Warfarin (INR 2.0-3.0) for 6 Month Treatment of Acute Symptomatic Venous Thromboembolism (VTE), Following Initial Treatment (5-10 Days) With a Parenteral Anticoagulant Approved for This Indication; RECORD, REgulation of Coagulation in ORthopedic Surgery to Prevent Deep Venous Thrombosis and Pulmonary Embolism; ROCKET-AF, Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation; RESONATE, Twicedaily Oral Direct Thrombin Inhibitor Dabigatran Etexilate in the Long-term Prevention of Recurrent Symptomatic Proximal Venous Thromboembolism in Patients With Symptomatic Deep-vein Thrombosis or Pulmonary Embolism; RE-MEDY, A 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 2.0-3.0) for the Secondary Prevention of Venous Thromboembolism; MAGELLAN, Rivaroxaban Compared with Enoxaparin for the Prevention of Venous Thromboembolism in Acutely Ill Medical Patients; EINSTEIN trial, Oral Rivaroxaban for Symptomatic Venous Thromboembolism; ARISTOTLE, Apixaban versus Warfarin in Patients with Atrial Fibrillation; ADVANCE-3, Apixaban versus Enoxaparin for Thromboprophylaxis after Hip Replacement; AMPLIFY, Apixaban for the Treatment of Acute Venous Thromboembolism; AMPLIFY-EXT, Apixaban for Extended Treatment of Venous Thromboembolism.

daily) in patients with NVAF unsuitable for VKA therapy.61 Compared with aspirin, apixaban significantly reduced rates of stroke and SE (P < 0.001) without significantly increasing major bleeding events or intracranial hemorrhages (P ¼ 0.57), resulting in fewer overall deaths (P ¼ 0.07).62 This effect was consistent in patients with or without a

history of stroke (P ¼ 0.17), without enhanced major bleeding risks.62 In the ARISTOTLE trial, thromboprophylaxis with apixaban (5 mg, twice daily) was compared with warfarin in patients with NVAF.62 Apixaban was superior to warfarin in preventing recurrent stroke or SE (P ¼ 0.01).63 In terms of safety, apixaban resulted

512 Skeik et al.

in fewer major bleeds (P < 0.001), hemorrhagic or ischemic strokes (P < 0.001 and P ¼ 0.42, respectively), and deaths from any cause (P ¼ 0.047).63 Management of VTE The ADVANCE-3 trial compared the use of apixaban, 2.5 mg twice daily with enoxaparin, 40.0 mg subcutaneously every 24 hr for thromboprophylaxis after hip replacement.64 Primary outcome was a composite of asymptomatic or symptomatic DVT, nonfatal PE, or death. Lassen et al.64 found that apixaban was superior to enoxaparin in preventing primary outcome events in these patients (P < 0.01). Additionally, no increase in bleeding was seen in patients on apixaban compared with enoxaparin. Previously, Lassen et al.65 conducted a similar study to evaluate the efficacy and safety of apixaban at 5, 10, or 20 mg daily and twice daily versus both enoxaparin and warfarin for thromboprophylaxis in patients after total knee replacement. The primary efficacy outcome was a composite of VTE and allcause mortality, with major bleeding as a primary safety outcome. A dose-dependent decrease in the rate of primary efficacy outcome was observed with apixaban (P ¼ 0.09 with daily/twice daily regimens combined; P ¼ 0.19 for daily and P ¼ 0.13 for twice daily dosing), whereas all dosages of apixaban had lower rates of primary efficacy events compared with enoxaparin or warfarin.65 However, a dosedependent increase in bleeding events was also observed within the groups receiving apixaban daily (P ¼ 0.01) and twice daily (P ¼ 0.02).65 The AMPLIFY trial compared apixaban (at a dose of 10 mg twice daily for 7 days, followed by 5 mg twice daily for 6 months) with conventional therapy (subcutaneous enoxaparin, followed by warfarin) in 5,395 patients with acute VTE. The primary outcome was VTE and related mortality. Safety outcome was major bleeding alone and major bleeding plus clinically relevant nonmajor bleeding. Apixaban was found to be noninferior to conventional therapy (P < 0.001) for primary outcome and superior (P < 0.001) for safety outcome.66 The AMPLIFY-EXT trial compared apixaban, 2.5 and 5.0 mg twice daily versus placebo for the extended treatment of VTE after 6e12 months of initial anticoagulation and found a significant decrease in recurrent VTE in patients on both dosages of apixaban (P < 0.001), without any increase risk of major bleeds.67 Monitoring Similar to rivaroxaban, no specific laboratory testing is available to monitor the level of apixaban. More

Annals of Vascular Surgery

research is needed to validate anti-Xa assays specific for apixaban. Periprocedural Management and Anticoagulant Conversion No consensus exists on periprocedural anticoagulation management in regard to apixaban. The authors’ follows similar protocols as outlined in the rivaroxaban section, and tends to take liver function in consideration, because abnormal liver function would delay the clearance of apixaban.

SUMMARY The relevant medical literature provides ample and convincing data supporting the use of novel anticoagulants in the management of NVAF, and perhaps VTE in the near future. Although the rate of intracranial hemorrhage is lower when these novel anticoagulants are used, the important work to find a specific antidote for bleeding reversal must be continued. No head-to-head study has yet compared the safety and efficacy of the novel anticoagulants; however, Tables II and III summarize the differences between these medications. Dabigatran, 150 mg, results in more gastrointestinal side effects and bleeding, and increased major bleeding risk in patients older than 75 years, whereas apixaban has the best safety profile and has demonstrated some mortality benefit. Rivaroxaban is currently the only novel anticoagulant with FDA approval for VTE prevention and management.

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