Thromboembolism involving the arterial or venous circulation

Transcription

1 Update on Antithrombotic Therapy Update on Antithrombotic Therapy New Anticoagulants John W. Eikelboom, MBBS; Jeffrey I. Weitz, MD Thromboembolism involving the arterial or venous circulation or arising from the heart is a common cause of morbidity and mortality. Rapidly acting parenteral anticoagulants, such as heparin, are used for the prevention and initial treatment of thromboembolism and during revascularization procedures, 1 whereas the slower-acting vitamin K antagonists (VKAs) are used for long-term therapy. 2 The introduction of low-molecular-weight heparin (LMWH) and fondaparinux has simplified parenteral anticoagulant therapy, and these agents have replaced heparin for many indications. 3 Development of new oral anticoagulants to replace VKAs has been slower than that of parenteral agents. Ximelagatran, an oral thrombin inhibitor, was briefly licensed in Europe but was withdrawn in 2006 because of potential hepatic toxicity. 4 Although this set the field back for several years, the situation has changed with the recent introduction of dabigatran etexilate, a new oral thrombin inhibitor, and rivaroxaban, an oral factor Xa (fxa) inhibitor. 3 Licensed in Europe and Canada for prevention of venous thromboembolism (VTE) in patients undergoing hip or knee arthroplasty, dabigatran etexilate and rivaroxaban streamline out-of-hospital thromboprophylaxis because the drugs can be given once daily in fixed doses without coagulation monitoring. The greater unmet medical need, however, is to find a replacement for VKAs for long-term therapy, particularly stroke prevention in patients with atrial fibrillation (AF). The results of the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) trial, which compared dabigatran etexilate with warfarin for stroke prevention in patients with AF, demonstrate that the new oral anticoagulants have the potential to be more effective and safer than VKAs. 5 If these results are replicated with other agents and in additional clinical settings, then oral thrombin and fxa inhibitors will soon replace VKAs. This article (1) outlines the limitations of established parenteral and oral anticoagulants, (2) describes the potential advantages of the new agents, (3) briefly reviews the pharmacology and clinical trial results with new anticoagulants in advanced stages of development, and (4) provides perspective on the opportunities and challenges with the new parenteral and oral anticoagulants. Limitations of Existing Anticoagulants The introduction of LMWH and fondaparinux simplified the initial management of arterial or venous thrombosis because these agents can be given subcutaneously without coagulation monitoring. 3 Furthermore, the risk of heparin-induced thrombocytopenia is lower with LMWH than with heparin and nonexistent with fondaparinux. Nonetheless, the need for daily subcutaneous injection limits the long-term use of LMWH or fondaparinux. Other drawbacks include their potential for accumulation in patients with renal impairment, the lack of an antidote, and the risk of catheter thrombosis when these agents are used as the sole anticoagulant in patients undergoing percutaneous coronary intervention (PCI). With its long half-life, the lack of antidote is particularly problematic for fondaparinux. Protamine sulfate only partly neutralizes the anticoagulant activity of LMWH and has no effect on that of fondaparinux. 3 In patients undergoing PCI, bivalirudin is a safe and effective alternative to heparin. Bivalirudin can be used in patients with heparin-induced thrombocytopenia and is not associated with catheter thrombosis. Its short half-life precludes the need for an antidote in most clinical situations, but bivalirudin can accumulate in patients with renal impairment. 6,7 An advantage of heparin and bivalirudin over fondaparinux or enoxaparin in the PCI setting is the capacity to titrate the dose according to the results of point-of-care coagulation tests. VKAs, such as warfarin, represent the only orally active anticoagulants that are licensed for long-term use. Although effective, these agents have numerous limitations (Table 1). These include a slow onset of action, variable dose requirements reflecting, at least in part, common genetic polymorphisms that influence their metabolism, differences in dietary intake of vitamin K, and numerous drug drug interactions that increase or decrease their anticoagulant effect. 8 Consequently, routine coagulation monitoring is necessary to ensure that the international normalized ratio (INR) is therapeutic because overanticoagulation is associated with an increased risk of hemorrhage, whereas underanticoagulation increases the risk of thrombosis. Such monitoring is inconvenient for patients and physicians and costly for the healthcare system. Furthermore, even with monitoring, the INR is frequently outside the therapeutic range. 9 Although anticoagulation clinics or home From the Department of Medicine, McMaster University (J.W.E., J.I.W.), and Department of Biochemistry and Medical Sciences and Henderson Research Centre (J.I.W.), Hamilton, Ontario, Canada. Correspondence to Dr Jeffrey Weitz, Henderson Research Centre, 711 Concession St, Hamilton, Ontario, L8V1C3, Canada. jweitz@thrombosis.hhscr.org (Circulation. 2010;121: ) 2010 American Heart Association, Inc. Circulation is available at DOI: /CIRCULATIONAHA

2 1524 Circulation April 6, 2010 Table 1. Limitations of Oral VKAs Table 2. Advantages of New Oral Anticoagulants Limitation Slow onset and offset of action Interindividual variability in anticoagulant effect Narrow therapeutic index Food and drug interactions Reduce synthesis of all vitamin K dependent proteins Clinical Implications Need for bridging with a rapidly acting anticoagulant Variability in dosing requirements Need for routine coagulation monitoring Dietary precautions; need for routine coagulation monitoring Risk of skin necrosis in patients with protein C or S deficiency; potential for osteoporosis INR monitoring improves the control of therapy with VKAs, these are not available for all patients. The many limitations of VKAs have resulted in their underuse for stroke prevention in eligible patients with AF, 10 thereby creating a large unmet need that has prompted the development of new oral anticoagulants with potential advantages over existing agents (Table 2). Potential Advantages of New Anticoagulants Although the need for new parenteral anticoagulants is less pressing than that for replacements of VKAs, several new parenteral anticoagulants are in advanced stages of development (Figure). Designed to be more specific for fxa than LMWH, AVE5026, an ultralow-molecular-weight heparin, mainly targets fxa 11 ; idrabiotaparinux, a synthetic pentasaccharide, 12 and otamixaban 13 selectively target fxa; and RB006, an anticoagulant RNA aptamer, 14 specifically targets factor IXa. All of the new parenteral agents have a rapid onset of action and produce a predictable anticoagulant effect, which, in the case of idrabiotaparinux and RB006, can be rapidly neutralized by intravenous administration of avidin, a biotin-binding protein, or RB007, a complementary aptamer, respectively. The new oral anticoagulants in the most advanced stages of development target either thrombin or fxa (Figure). As the final effector in blood coagulation, thrombin is a logical target for new anticoagulants. Thrombin not only converts fibrinogen to fibrin but also amplifies its own generation by feedback activation of factors V, VIII, and XI. Thrombin also is a potent platelet agonist. Therefore, thrombin inhibition not only attenuates fibrin formation but also reduces thrombin generation and platelet activation. Direct thrombin inhibitors have potential efficacy advantages over indirect inhibitors, such as heparin or LMWH. Whereas indirect thrombin inhibitors are limited in their capacity to inhibit fibrin-bound thrombin, direct thrombin inhibitors inactivate fibrin-bound thrombin and free thrombin equally well. 15,16 This endows direct thrombin inhibitors with the capacity to better suppress thrombus growth because thrombi harbor thrombin, and fibrin-bound thrombin is an important trigger of thrombus expansion. The evidence supporting thrombin as a target for new oral anticoagulants initially came from studies with ximelagatran. Ximelagatran underwent extensive phase III evaluation for Advantage Rapid onset of action Predictable anticoagulant effect Specific coagulation enzyme target Low potential for food interactions Low potential for drug interactions Clinical Implications No need for bridging No need for routine coagulation monitoring Low risk of off-target adverse effects No dietary precautions Few drug restrictions several indications, including the prevention and treatment of VTE and stroke prevention in patients with AF. For all of these indications, fixed-dose, unmonitored ximelagatran was shown to be not inferior to conventional anticoagulant therapy. More recent confirmation of the suitability of thrombin as a target comes from studies with dabigatran etexilate, which was not inferior to once-daily enoxaparin for thromboprophylaxis after hip or knee arthroplasty 17 and to warfarin for treatment of VTE, 18 and was superior to warfarin for prevention of stroke and systemic embolism in patients with AF. 5 In contrast to ximelagatran, dabigatran is not hepatotoxic. fxa is also a good target for new oral anticoagulants. Factor X is positioned at the convergence of the extrinsic and intrinsic pathways of coagulation, and, when activated, 1 molecule of fxa can generate 1000 thrombin molecules. 19 Fondaparinux has been shown to be effective for the prevention and treatment of VTE 20 and for the prevention of recurrent ischemia in patients with acute coronary syndrome (ACS), 21,22 providing proof of principle that fxa is an attractive target. Direct fxa inhibitors may have an advantage over indirect inhibitors, such as fondaparinux, because direct fxa inhibitors not only inhibit free fxa but also inhibit fxa assembled within the prothrombinase complex. 23 New Anticoagulants The new parenteral and oral anticoagulants are discussed separately. With each agent, the pharmacology is reviewed briefly, as are the results of clinical trials. New Parenteral Anticoagulants The pharmacological characteristics of the new parenteral anticoagulants that are in advanced stages of development are compared in Table 3. AVE5026 As an ultralow-molecular-weight heparin with a mean molecular weight of 2400, AVE5026 primarily targets fxa and has only a minimal effect on thrombin. 11 When given subcutaneously, the half-life of AVE5026 is 16 to 20 hours, enabling once-daily administration. AVE5026 is excreted renally, and, like fondaparinux, its anticoagulant effects are not neutralized by protamine sulfate. 11 On the basis of the results of the phase II Prevention of Venous Thromboembolism in Patients Undergoing Elective Total Knee Replacement Surgery (TREK) study involving 690 patients undergoing knee arthroplasty, 24 a 20-mg dose of AVE5026 was selected for further evaluation. An extensive

3 Eikelboom and Weitz New Anticoagulants 1525 Figure. Classification of established anticoagulants and new anticoagulants that were recently licensed for use or are in advanced stages of clinical development. fixa indicates factor IXa. *Indirectly inhibit coagulation by interacting with antithrombin. AVE5026 is an ultralow-molecular-weight heparin that primarily inhibits fxa and has minimal activity against thrombin. phase III program is comparing AVE5026 with enoxaparin for VTE prevention in 9000 patients undergoing hip, knee, or abdominal surgery and in 3200 cancer patients receiving chemotherapy (Table 4). Idrabiotaparinux A hypermethylated derivative of fondaparinux, idrabiotaparinux binds antithrombin with high affinity and has a half-life of 130 hours. 12 Consequently, idrabiotaparinux is given subcutaneously on a once-weekly basis. The drug is excreted unchanged by the kidneys. Idrabiotaparinux differs from idraparinux in that it contains a biotin moiety that enables reversal with intravenous avidin. Avidin, a protein derived from egg white, binds the biotin moiety with high affinity to form a complex that is cleared rapidly by the kidneys. 12 The initial phase III trial program evaluated the effectiveness and safety of idraparinux for the treatment of VTE and for stroke prevention in AF. The Van Gogh deep vein thrombosis (DVT) trial compared 3 to 6 months of idraparinux (2.5 mg given once weekly by subcutaneous injection) with conventional anticoagulant therapy (LMWH followed by a VKA dose adjusted to achieve an INR of 2 to 3) in 2904 patients with acute DVT. 32 At 3 months, the incidence of recurrent VTE (nonfatal or fatal) was similar in the 2 treatment groups, a result that satisfied the prespecified noninferiority criterion (2.9% and 3.0%, respectively; P for noninferiority). Idraparinux was associated with significantly fewer major plus clinically relevant nonmajor bleeds than conventional therapy (4.5% and 7.0%, respectively; P 0.004). The Van Gogh pulmonary embolism (PE) trial compared 3 to 6 months of idraparinux with conventional anticoagulant therapy (intravenous heparin followed by a VKA dose adjusted to achieve an INR of 2 to 3) in 2215 patients with acute PE. 32 The rate of recurrent VTE was Table 3. Comparison of Pharmacological Characteristics of AVE5026, Idrabiotaparinux, Otamixaban, and RB006 Characteristic AVE5026 Idrabiotaparinux Otamixaban RB006 Target fxa* fxa fxa Factor IXa Antithrombin dependent Yes Yes No No Dosing Subcutaneous, fixed, Subcutaneous, fixed, Intravenous infusion Intravenous infusion once daily once weekly Half-life h 130 h 25 min Not reported Renal clearance, % No Routine coagulation monitoring No No No No Antidote No Yes, avidin No Yes, RB007 Drug interactions Nil known Nil known Nil known Nil known *AVE5026 primarily inhibits fxa and has minimal thrombin-inhibitory activity.

4 1526 Circulation April 6, 2010 Table 4. Phase III Randomized Controlled Trials of New Anticoagulants for VTE Prevention Drug Hip Arthroplasty Knee Arthroplasty Hip Fracture Medical Surgical AVE5026 SAVE-HIP1 (2320) TREK (690) 24 SAVE-HIP2 (1000) SAVE-VEMED (12 300)* SAVE-ABDO (4400) SAVE-KNEE (1060) SAVE-HIP3 (454) SAVE-ONCO (3200) Dabigatran etexilate RE-NOVATE (3494) 25 RE-MODEL (2076) RE-NOVATE II (1920) RE-MOBILIZE (2615) 27 Rivaroxaban RECORD1 (4542) 28 RECORD3 (2531) MAGELLAN (8000)... RECORD2 (2509) 30 RECORD4 (3148) 31 Apixaban ADVANCE3 (5406) ADVANCE1 (3202)... ADOPT (6524)... ADVANCE2 (3053) SAVE-HIP1 indicates Thromboembolism in Patients Undergoing Total Hip Replacement Surgery; SAVE-HIP2, Evaluation of AVE5026 as Compared to Enoxaparin for the Prevention of Thromboembolism in Patients Undergoing Hip Fracture Surgery; SAVE-HIP3, Evaluation of AVE5026 as Compared to Placebo for the Extended Prophylaxis of Venous Thromboembolism in Patients Having Undergone Hip Fracture Surgery; SAVE-KNEE, Evaluation of AVE5026 as Compared to Enoxaparin for the Prevention of Thromboembolism in Patients Undergoing Elective Knee Replacement Surgery; SAVE-VEMED, Evaluation of AVE5026 in the Prevention of Venous Thromboembolism in Acutely Ill Medical Patients with Restricted Mobility; SAVE-ONCO, Evaluation of AVE5026 in the Prevention of Venous Thromboembolism in Cancer Patients Undergoing Chemotherapy; SAVE-ABDO, Evaluation of AVE5026 as Compared to Enoxaparin for the Prevention of Venous Thromboembolism in Patients Undergoing Major Abdominal Surgery; MAGELLAN, Evaluation of AVE5026 as Compared to Enoxaparin for the Prevention of Venous Thomboembolic Event (VTE) Prophylaxis in Medically Ill Patients; ADOPT, Study of Apixaban for the Prevention of Thrombosis-related Events in Patients with Acute Medical Illness. The planned or final number of subjects included in the trials is provided in parentheses. Data are obtained from unless indicated otherwise. *SAVE-VEMED was terminated before recruitment was completed. Medical patients receiving cancer chemotherapy. significantly higher with idraparinux than with conventional therapy (3.4% and 1.6%, respectively; P 0.50 for noninferiority), a finding that did not meet the noninferiority criterion. Again, there were fewer major plus clinically relevant nonmajor bleeds with idraparinux (5.8% and 8.2%, respectively; P 0.02). The Van Gogh extension study compared 6 months of idraparinux (2.5 mg given once weekly) with placebo in 1215 patients with VTE who had been treated for 6 months with idraparinux or a VKA. 33 The rate of recurrent VTE was significantly lower with idraparinux than with placebo (1.0% and 3.7%, respectively; P 0.002), but the risk of major plus clinically relevant nonmajor bleeding was higher (4.5% and 1.5%, respectively; P 0.001), including 3 fatal intracranial bleeds in the idraparinux-treated group. The AMADEUS trial compared idraparinux (2.5 mg once weekly) with a VKA (dose adjusted to an INR of 2 to 3) for prevention of thromboembolism in patients with AF. 34 The trial was stopped early after 4576 patients had been followed for a mean of 10.7 months because of an excess of clinically relevant bleeds with idraparinux compared with a VKA (19.7 and 11.3/100 patient-years, respectively; P ), including a significant increase in intracranial bleeds (1.1 and 0.4/100 patient-years, respectively; P 0.014). The risk of stroke or systemic embolism with idraparinux was similar to that with a VKA (0.9 and 1.3/100 patient-years, respectively; P for noninferiority). Although the results with idraparinux suggest that it is an effective anticoagulant, concerns about the risk of bleeding prompted the development of idrabiotaparinux, a reversible form of the drug. The findings of the Bioequipotency Study of SSR126517E and Idraparinux in Patients With Deep Venous Thrombosis of the Lower Limbs (EQUINOX) bioequivalence study suggest that idrabiotaparinux and idraparinux are similarly effective for DVT treatment and that the anticoagulant effect of idrabiotaparinux can be rapidly reversed with intravenous avidin. 3 Building on this information, 2 large phase III trials were designed to evaluate idrabiotaparinux for treatment of VTE and for stroke prevention in AF. The Clinical Study Assessing SSR126517E Injections Onceweekly in Pulmonary Embolism Therapeutic Approach (CASSIOPEA) trial is comparing 3 to 6 months of idrabiotaparinux (3 mg given subcutaneously once weekly) with conventional anticoagulation therapy for prevention of recurrent VTE in 3200 patients with acute PE (Table 4). The Evaluation of Weekly Subcutaneous Biotinylated Idraparinux Versus Oral Adjusted-dose Warfarin to Prevent Stroke and Systemic Thromboembolic Events in Patients with Atrial Fibrillation (BOREALIS-AF) trial (Table 5), which compared the same idrabiotaparinux regimen with warfarin for prevention of stroke or systemic embolism in patients with AF, was stopped early, but the results are not yet available. Otamixaban A parenteral direct fxa inhibitor, otamixaban has a rapid onset of action, produces a predictable anticoagulant effect, and has a short half-life, and 25% of the drug is cleared by the kidneys. 35 These features render otamixaban an attractive candidate to replace heparin in patients with ACS. 36 This possibility was evaluated in the Study of Otamixaban Versus Unfractionated Heparin (UFH) and Eptifibatide in Non-ST Elevation Acute Coronary Syndrome (SEPIA-ACS) 1 Thrombolysis in Myocardial Infarction (TIMI) 42, a phase II dose-finding study that compared 5 different doses of otamixaban with the combination of heparin plus eptifibatide for the prevention of major cardiovascular events in 3241 patients with non ST-segment elevation ACS. 13 All of the patients received aspirin and clopidogrel, and 62.7% underwent PCI. Although the rates of the primary efficacy outcome, a composite of death, myocardial infarction, urgent revascularization, or bailout glycoprotein IIb/IIIa use at 7 days, were not significantly different across the 5 doses of otamixaban or compared with heparin plus eptifibatide, rates

5 Eikelboom and Weitz New Anticoagulants 1527 Table 5. Phase III Randomized Controlled Trials of New Anticoagulants for Indications Other Than VTE Prevention Anticoagulant VTE Treatment ACS AF Idrabiotaparinux CASSIOPEA (3200)... BOREALIS-AF (9600) Dabigatran etexilate RE-COVER I (2564) 18 RE-LY (18 113) 5,40 RE-COVER II (2500) RELY-ABLE ( 6000) RE-MEDY (2400) RE-SONATE (1800) AZD ASSURE (15 000) Rivaroxaban EINSTEIN-DVT (2900) ATLAS (16 000) Japanese AF (1280) EINSTEIN-PE (3300) ROCKET-AF (14 000) EINSTEIN-Extension (1065) Apixaban Apixaban VTE (2900) APPRAISE2 (10 800) AVERROES (5600) Apixaban VTE extension (2430) ARISTOTLE (15 000) Edoxaban ENGAGE AF TIMI 48 (16 500) RE-COVER indicates Efficacy and Safety of Dabigatran Compared to Warfarin for 6 Month Treatment of Acute Symptomatic Venous Thromboembolism; RE-MEDY, Secondary Prevention of Venous Thromboembolism; RE-SONATE, Twice-daily Oral Direct Thrombin Inhibitor Dabigatran Etexilate in the Long Term Prevention of Recurrent Symptomatic VTE; EINSTEIN-DVT, Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Acute Symptomatic Deep-Vein Thrombosis Without Symptomatic Pulmonary Embolism; EINSTEIN-PE, Oral Direct Factor Xa Inhibitor Rivaroxaban In Patients With Acute Symptomatic Pulmonary Embolism With Or Without Symptomatic Deep-Vein Thrombosis; EINSTEIN-EXTENSION, Once-Daily Oral Direct Factor Xa Inhibitor Rivaroxaban In The Long-Term Prevention Of Recurrent Symptomatic Venous Thromboembolism In Patients With Symptomatic Deep-Vein Thrombosis Or Pulmonary Embolism; ATLAS ACS, Rivaroxaban in Combination With Aspirin Alone or With Aspirin and a Thienopyridine in Subjects With Acute Coronary Syndromes; APPRAISE-2, Apixaban for Prevention of Acute Ischemic and Safety Events; RELY-ABLE, Long Term Multicenter Extension of Dabigatran Treatment in Patients With Atrial Fibrillation Who Completed RE-LY Trial; ROCKET-AF, Randomized Double Blind Study Comparing Once-Daily Oral Rivaroxaban With Adjusted Dose Oral Warfarin for the Prevention of Stroke in Patients With Nonvalvular Atrial Fibrillation; AVERROES, Apixaban versus acetylsalicylic acid to prevent stroke in atrial fibrillation patients who have failed or are unsuitable for vitamin K antagonist treatment. The planned or final number of subjects included in the trials is provided in parentheses. Data are obtained from unless indicated otherwise. were numerically lowest with the 2 intermediate doses of otamixaban. The lowest-dose otamixaban arm was stopped early because of excess thrombotic complications, and the rates of thrombotic complications were numerically higher with all doses of otamixaban than with heparin plus eptifibatide. Otamixaban was associated with a significant dosedependent increase in the primary safety outcome, non coronary artery bypass graft surgery related TIMI major or minor bleeding, but bleeding rates with intermediate doses of otamixaban were similar to those with heparin plus eptifibatide. On the basis of these results, the SEPIA ACS1 TIMI 42 investigators have proposed further evaluation of intermediate doses of otamixaban in a phase III trial. RB006 An RNA aptamer that targets factor IXa with high affinity and specificity, RB006 has been formulated to have an extended half-life. 14 When given intravenously to healthy volunteers or patients with stable coronary artery disease, RB006 produces a rapid and dose-proportional anticoagulant effect that is immediately reversed by intravenous administration of RB007, the complementary oligonucleotide antidote. 37,38 RB006 is not cleared renally and does not appear to be immunogenic. By targeting factor IXa, RB006 has the potential to inhibit the activation of coagulation induced by exposure of blood to artificial surfaces, such as stents or cardiac bypass circuits. Therefore, as an aptamer/antidote pair, RB006/RB007 has the potential to replace heparin and protamine sulfate in patients undergoing cardiopulmonary bypass surgery. RB006 may also be useful for patients at high risk of bleeding and for those with renal impairment. In the ongoing phase IIa Feasibility and Safety Study Comparing REG1 Anticoagulation System With Unfractionated Heparin in Elective PCI (REVERSAL-PCI) study, the efficacy and safety of RB006/ RB007 are being compared with those of heparin in 26 patients undergoing elective PCI. New Oral Anticoagulants Oral Thrombin Inhibitors Dabigatran Etexilate Dabigatran etexilate, a prodrug of dabigatran, which reversibly inhibits the active site of thrombin, has an oral bioavailability of 6%. 39 After oral administration, dabigatran etexilate is rapidly and completely converted to dabigatran by esterases. Plasma levels of dabigatran peak 2 hours after drug administration. Dabigatran has a half-life of 14 to 17 hours, which permits once- or twice-daily administration, and 80% of the drug is excreted unchanged by the kidneys. Dabigatran etexilate is a substrate of the P-glycoprotein (P-gp) transporter. This efflux transporter is highly expressed in the intestine and kidneys, and coadministration of potent P-gp inhibitors, such as quinidine, can increase plasma levels of dabigatran by reducing its clearance. 37 Consequently, quinidine is contraindicated in patients taking dabigatran

6 1528 Circulation April 6, 2010 etexilate. Coadministration of dabigatran etexilate and amiodarone, a weak P-gp inhibitor, increases dabigatran levels by 50% without significantly affecting those of amiodarone. On the basis of the results of phase II studies showing that dabigatran etexilate is effective for VTE prevention, 2 doses were taken forward into phase III for thromboprophylaxis after hip or knee arthroplasty: 220 or 150 mg once daily, starting with a half dose of 110 or 75 mg on the first day. The European-approved dose of enoxaparin, 40 mg once daily with the first dose given in the evening before surgery, was used as the comparator in the Dabigatran Etexilate 150 mg or 220 mg once daily versus Enoxaparin 40 mg once daily for Prevention of Thrombosis After Knee Surgery (RE- MODEL) 26 and Dabigatran Etexilate Compared With Enoxaparin in Prevention of VTE Following Total Hip Arthroplasty (RE-NOVATE) 25 trials, whereas the dose of enoxaparin approved in North America, 30 mg twice daily starting 12 to 24 hours after surgery, was the comparator in the Dabigatran Etexilate versus Enoxaparin in Prevention of VTE Post Total Knee Replacement (RE-MOBILIZE) trial 27 (Table 4). In all 3 trials, the primary efficacy end point was total VTE, a composite of venographically detected or symptomatic DVT, nonfatal PE, and all-cause mortality. In the RE-MODEL trial involving 2076 patients undergoing knee arthroplasty, 6 to 10 days of either dose of dabigatran etexilate had efficacy similar to that of enoxaparin (220 mg dabigatran, 31%; 150 dabigatran, 34%; enoxaparin, 25%). The incidence of major bleeding did not differ significantly among the 3 groups (1.3%, 1.5%, and 1.3%, respectively). 26 In the RE-NOVATE trial involving 3494 patients undergoing hip arthroplasty, treatment with either dose of dabigatran etexilate for 28 to 35 days had efficacy similar to that of enoxaparin (220 mg dabigatran, 6.0%; 150 mg dabigatran, 8.6%; enoxaparin, 6.7%). The incidence of major bleeding did not differ significantly among the 3 groups (2.0%, 1.3%, and 1.6%, respectively). 25 In the RE- MOBILIZE study of 2615 patients undergoing knee arthroplasty, treatment with either dose of dabigatran etexilate for 12 to 15 days was statistically inferior to a similar duration of treatment with enoxaparin (220 mg dabigatran, 31%; 150 mg dabigatran, 34%; enoxaparin, 25%). The incidence of major bleeding did not differ significantly among the 3 groups (0.6%, 0.6%, and 1.4%, respectively). 27 A fourth phase III trial, the RE-NOVATE II trial, is comparing 28 to 35 days of treatment with dabigatran 220 mg once daily with an equal duration of treatment with enoxaparin (40 mg once daily) for VTE prevention after hip arthroplasty. Dabigatran etexilate is licensed in Europe and Canada for VTE prevention after elective hip or knee arthroplasty. The 220-mg dose of dabigatran etexilate is recommended for the majority of patients, whereas the 150-mg dose is reserved for patients also taking amiodarone and for those at higher risk for bleeding, such as patients older than 75 years or with a creatinine clearance 50 ml/min. Dabigatran etexilate has been evaluated for prevention of stroke or systemic embolism in patients with AF and is under investigation for initial and extended treatment of VTE (Table 5). The RE-LY trial investigators randomized patients with AF and at least 1 additional risk factor for stroke to receive dabigatran etexilate (at doses of 110 or 150 mg twice daily) or warfarin, which was adjusted to achieve an INR of 2 to 3. Administration of dabigatran etexilate and warfarin was open label, but patients and investigators were blinded to dabigatran etexilate dose, and adjudicators were blinded to all treatments. 5,40 Rates of the primary efficacy outcome, stroke or systemic embolism, were 1.69%/year in the warfarin group, 1.53%/year in the group that received 110 mg of dabigatran (P for noninferiority), and 1.11%/ year in the group given 150 mg of dabigatran (P for both noninferiority and superiority). The rate of major bleeding was 3.36%/year in the warfarin group compared with 2.71%/year in the group receiving 110 mg of dabigatran (P 0.003) and 3.11%/year in the group receiving 150 mg of dabigatran (P 0.31). The rate of hemorrhagic stroke was 0.38%/year in the warfarin group compared with 0.12%/year with 110 mg of dabigatran (P 0.001) and 0.10%/year with 150 mg of dabigatran (P 0.001). The mortality rate was 4.13%/year in the warfarin group compared with 3.75%/year with 110 mg of dabigatran (P 0.13) and 3.64%/year with 150 mg of dabigatran (P 0.051). There was no signal for liver toxicity or other adverse events with dabigatran etexilate except for an increase in dyspepsia compared with warfarin. At the completion of the RE-LY trial, patients in the dabigatran etexilate group were offered an opportunity to continue in the RELY-ABLE study, a long-term open-label extension trial (Table 5). After it was shown that dabigatran etexilate was effective for VTE prevention in the phase II Boehringer Ingelheim Study in ThROmbosis (BISTRO) trials, 41,42 a 150-mg twicedaily dose was selected for comparison with dose-adjusted warfarin (target INR 2 to 3) in an extensive phase III VTE treatment program involving 9000 patients (Table 5). All of the trials in this program use a double-blind and doubledummy design. The RECOVER-1 investigators 18 randomised 2564 patients with acute VTE to dabigatran etexilate (150 mg twice daily) or warfarin (dose-adjusted to an INR of 2 to 3) for 6 months after initial treatment with a parenteral anticoagulant. Rates of the primary efficacy outcome, recurrent symptomatic VTE and VTE-related death, were 2.4% and 2.1% in th dabigatran and warfarin groups, respectively (P for non-inferiority). Rates of major bleeding were 1.6% and 1.9% in the dabigatran and warfarin groups, respectively, and rates of any bleeding were 16.1% and 21.9%, respectively. The results of other VTE treatment trials with dabigatran will be available in 2010 or Dabigatran etexilate has also been evaluated in the phase II Dose Finding Study for Dabigatran Etexilate in Patients with Acute Coronary Syndrome (RE-DEEM) study in ACS to determine whether it reduces the risk of recurrent ischemia when given in conjunction with antiplatelet drugs. It is unclear whether a phase III trial will be performed for this indication. AZD0837 A prodrug with oral bioavailability of 20% to 50%, AZD0837 is rapidly metabolized in the liver to its active form, H The half-life of H is 9 hours after a single

7 Eikelboom and Weitz New Anticoagulants 1529 Table 6. Comparison of Pharmacological Features of Rivaroxaban, Apixaban, and Edoxaban Characteristic Rivaroxaban Apixaban Edoxaban Target fxa fxa fxa Prodrug No No No Bioavailability, % Dosing Fixed, once daily* Fixed, twice daily Fixed, once daily Half-life 7 11 h 12 h 9 11 h Renal clearance, % Routine coagulation monitoring No No No Drug interactions Potent inhibitors of CYP3A4 and P-gp Potent inhibitors of CYP3A4 Potent inhibitors of CYP3A4 and P-gp CYP-3A4 indicates cytochrome p-450 3A4. *A twice-daily regimen is being evaluated in patients with ACS. Half of renally cleared rivaroxaban is cleared as unchanged drug and half as inactive metabolites. Potent inhibitors of both CYP3A4 and P-glycoprotein include azole antifungals (eg, ketoconazole, itraconazole, voriconazole, posaconazole) and protease inhibitors, such as ritonavir. Potent inhibitors of CYP3A4 include azole antifungals, macrolide antibiotics (eg, clarithromycin), and protease inhibitors (eg, atanazavir). dose in healthy volunteers, but development of an extendedrelease formulation enables once-daily administration. 39 Only limited phase II evaluation of AZD0837 has been undertaken, and the dose being compared with warfarin (target INR 2 to 3) in the phase III AZD0837 Compared to Warfarin for the Prevention of Stroke and Systemic Embolic Events in Atrial Fibrillation (ASSURE) trial for the prevention of stroke or systemic embolism in patients with AF (Table 5) was selected on the basis of preliminary biomarker data and previous experience with ximelagatran. Randomization into the ASSURE trial was halted in 2009 and it is unclear whether there will be further development of AZD0837. Oral fxa Inhibitors The oral fxa inhibitors are small molecules that bind reversibly to the active site of fxa. Although numerous agents in this class are under development, those in the most advanced stages are rivaroxaban, apixaban, and edoxaban (Table 6). Rivaroxaban An active compound with an oral bioavailability of 80%, rivaroxaban has a rapid onset of action and a half-life of 7 to 11 hours. 38 Rivaroxaban has a dual mode of elimination; one third is cleared as unchanged drug via the kidneys, one third is metabolized by the liver via CYP3A4-dependent and -independent pathways with the metabolites then excreted in the feces, and one third is metabolized in the liver with the inactive metabolites then eliminated via the kidneys. Rivaroxaban is a substrate for P-gp, and concomitant administration of potent inhibitors or both P-gp and CYP3A4, such as ketoconazole or ritonavir, is contraindicated because they increase plasma drug levels. 39 After promising results in the phase II Oral Direct Factor Xa Inhibitor (ODIXa) VTE prevention studies, the phase III RECORD trial program evaluated the efficacy and safety of rivaroxaban compared with enoxaparin in patients undergoing hip or knee arthroplasty (Table 4). The dose of rivaroxaban in all 4 RECORD trials was 10 mg once daily started 6 to 8 hours after wound closure. The Europeanapproved dose of enoxaparin, 40 mg once daily (with the first dose given in the evening before surgery), was used as the comparator in the RECORD 1, 2, and 3 trials, whereas the North American approved dose of enoxaparin (30 mg twice daily starting 12 to 24 hours after surgery) was the comparator in the RECORD 4 trial. 31 The primary efficacy end point in all of the trials was total VTE, a composite of symptomatic or asymptomatic DVT, nonfatal PE, and allcause mortality. In the RECORD 1 trial, which included 4541 patients undergoing hip arthroplasty, a 31- to 39-day course of rivaroxaban significantly reduced the incidence of total VTE compared with an equal duration of treatment with enoxaparin (1.1% and 3.7%, respectively; P 0.001). 28 In the RECORD 2 trial involving 2509 patients undergoing total hip arthroplasty, a 31- to 39-day course of rivaroxaban significantly reduced the incidence of total VTE compared with a 10- to 14-day course of enoxaparin followed by 21 to 25 days of placebo (2.0% and 9.3%, respectively; P 0.001). 30 The RECORD 3 trial included 2531 patients undergoing knee arthroplasty. A 10- to 14-day course of treatment with rivaroxaban significantly reduced the incidence of total VTE compared with an equal duration of treatment with enoxaparin (9.6% and 18.9%, respectively, P 0.001). 29 Finally, in the RECORD 4 trial involving 3148 patients undergoing knee arthroplasty, a 10- to 14-day course of treatment with rivaroxaban significantly reduced the incidence of total VTE compared with an equal duration of enoxaparin at the higher 30-mg twice-daily dose (6.9% and 10.1%, respectively; P 0.012). 31 In both the RECORD 2 and 3 trials, rivaroxaban significantly reduced the incidence of symptomatic VTE compared with enoxaparin. 29,30 Rivaroxaban did not increase bleeding in any of the trials, but a pooled analysis of the 4 RECORD trials revealed a small but significant increase in major plus clinically relevant nonmajor bleeding with rivaroxaban. On the basis of these results, rivaroxaban is licensed in Europe and Canada for the prevention of VTE in patients undergoing elective hip or knee arthroplasty. Rivaroxaban is undergoing evaluation in phase III trials for VTE prevention in 8000 medically ill patients (Table 4) and for prevention of stroke or systemic embolism in patients with AF, initial and long-term VTE treatment in 7000 patients, and the prevention of recurrent ischemia in patients with ACS (Table 5). Apixaban An active drug, apixaban is absorbed rapidly, and maximal plasma concentrations are achieved 3 hours after oral administration. 39 The drug is cleared with a terminal half-life of 8 to 14 hours. Apixaban is eliminated via multiple pathways, including hepatic metabolism via CYP3A4 and renal and intestinal excretion. Concomitant treatment with potent inhibitors of CYP3A4 is contraindicated in apixaban-treated patients. 39

8 1530 Circulation April 6, 2010 On the basis of the results of a phase II study in patients undergoing knee arthroplasty, the phase III Apixaban for the Prevention of Thrombosis-related Events (ADVANCE) program is comparing a 2.5-mg twice-daily dose of apixaban (started in the morning of the day after surgery) with enoxaparin in patients undergoing knee or hip arthroplasty. In ADVANCE 1, 46 which involved 3202 patients undergoing knee arthroplasty, a 12-day course of apixaban had efficacy similar to an equal duration of treatment with enoxaparin (30 mg twice daily) with total VTE rates of 8.9% and 9.0%, respectively. Major bleeding rates were 0.7% with apixaban and 1.4% with enoxaparin (P 0.053). Despite similar efficacy, apixaban did not meet the prespecified noninferiority goal because the event rates were lower than expected. The ADVANCE 2 trial, 47 which included 3053 patients undergoing total knee arthroplasty, compared the same apixaban regimen with an equal duration of treatment with enoxaparin at a dose of 40 mg once daily. In this trial, apixaban significantly reduced total VTE compared with enoxaparin (15.1% and 24.4%, respectively; P 0.001) and was associated with a trend for less bleeding (3.5% and 4.8%, respectively; P 0.09). The ADVANCE 3 trial is comparing 5 weeks of treatment with apixaban 2.5 mg twice daily with an equal duration of treatment with enoxaparin (40 mg once daily) for VTE prevention in 5406 patients undergoing hip arthroplasty. Apixaban is presently undergoing evaluation in phase III trials for VTE prevention in 6500 medically ill patients (Table 4), prevention of stroke or systemic embolism in 2 large phase III trials involving patients with AF, initial and long-term VTE treatment in 5000 patients, and prevention of recurrent ischemia in patients with ACS (Table 5). Edoxaban An active drug that is rapidly absorbed, edoxaban has a half-life of 9 to 11 hours. 39 Edoxaban has a dual mechanism of elimination; approximately one third is eliminated via the kidney, and the remainder is excreted in the feces. In phase II studies, edoxaban has been evaluated for VTE prevention and for stroke prevention in AF. In the phase II study in AF, once-daily dosing regimens were associated with less bleeding than twice-daily regimens. Building on this finding, the ongoing phase III Global Study to Assess the Safety and Effectiveness of DU-176b versus Standard Practice of Dosing With Warfarin in Patients With Atrial Fibrillation (ENGAGE-AF)-TIMI 48 trial is comparing 2 doses of edoxaban (30 or 60 mg once daily) with warfarin in patients with AF (Table 5). Other Oral fxa Inhibitors Other oral fxa inhibitors under development include betrixaban, YM150, and TAK442. Betrixaban has the unique features of a 15-hour half-life and extrarenal clearance. Betrixaban and YM150 are undergoing phase II evaluation for stroke prevention in AF, whereas TAK442 is undergoing phase II evaluation for prevention of recurrent ischemia in ACS patients. 3 Conclusions and Future Directions Although the unmet needs for parenteral anticoagulants have diminished with the introduction of LMWH and fondaparinux, some problems persist. LMWH and fondaparinux are problematic in patients with severe renal impairment, and the lack of an antidote can be an issue with fondaparinux and, to a lesser extent, with LMWH. The recent problem with heparin contamination with oversulfated chondroitin sulfate highlights the advantage of synthetic drugs, such as fondaparinux. 48 Although the risk of heparin-induced thrombocytopenia is eliminated with fondaparinux, the drug can trigger antibody formation, which could be problematic if patients are switched to heparin or LMWH. 49 New synthetic parenteral anticoagulants that are eliminated extrarenally can be reversed readily and do not cause thrombocytopenia may have advantages over existing agents in certain situations. Anticoagulant aptamer/antidote pairs, such as RB007/RB008, possess all of these desirable features. The greatest unmet medical need is for oral anticoagulants that are simpler to administer than VKAs. The promising results with dabigatran etexilate and rivaroxaban in patients undergoing hip or knee arthroplasty have already helped to streamline out-of-hospital thromboprophylaxis, but it is the favorable results of the RE-LY trial that are likely to revolutionize our approach to long-term anticoagulant therapy. With fewer strokes and less intracranial bleeding with the higher-dose dabigatran etexilate regimen compared with warfarin and less bleeding yet similar efficacy with the lower-dose regimen, we now have the opportunity to tailor therapy according to patient needs. In addition, the availability of simple, fixed-dose, unmonitored therapy should increase the use of anticoagulant therapy in patients with AF at risk for stroke. Despite the optimism, the transition from VKAs to new oral anticoagulants is likely to be gradual because VKAs are effective and entrenched in clinical practice and because the cost of the new agents is likely to be high. New oral anticoagulants will be least affordable in developing countries, where the need to replace VKAs is highest because of the growing burden of AF and valvular heart disease and the lack of resources and infrastructure to monitor VKAs in the majority of affected patients. Is thrombin or fxa a better target for new anticoagulants? All anticoagulants inhibit coagulation by blocking thrombin generation, thrombin activity, or both. The results of studies with dabigatran etexilate, fondaparinux, rivaroxaban, and apixaban validate both thrombin and fxa as targets for new anticoagulants, and there is no convincing evidence that one target is better than the other. Head-to-head comparisons will be needed to determine whether there are meaningful differences in efficacy and safety among the new oral agents, but such studies are unlikely to be performed in the near future because of potential commercial risks. Indirect comparisons across trials are problematic because of confounding due to differences in patients, interventions, and outcomes. Therefore, each agent will need to be assessed independently. Concerns about hepatic safety prompted the withdrawal of ximelagatran and heightened awareness about potential offtarget side effects. Dabigatran etexilate is not hepatotoxic,

9 Eikelboom and Weitz New Anticoagulants 1531 indicating that this is not a class effect with thrombin inhibitors. None of the other new oral anticoagulants in advanced stages of development has yet to demonstrate evidence of liver toxicity, but long-term data are still needed. Recognition that bleeding is associated with adverse outcomes in patients with cardiovascular disease and concern about the lack of antidotes have focused attention on the risk of bleeding with the new oral anticoagulants. To minimize this risk, dose selection for most of the new agents has been rigorous to optimize the balance between efficacy and safety. Never have there been so many choices of new parenteral and oral anticoagulants. Although targeted parenteral anticoagulants with antidotes may simplify treatment of patients at high risk for bleeding, new oral anticoagulants that can be given in fixed doses without coagulation monitoring offer the most promise. Streamlining oral therapy will increase the uptake of anticoagulant prophylaxis in patients with AF, thereby decreasing death and disability from stroke. The search for replacements for VKAs appears to be nearing completion. Sources of Funding No funding was received for the preparation of this manuscript. Dr Eikelboom is the recipient of the Tier II Canada Research Chair in Cardiovascular Medicine, and Dr Weitz holds the Heart and Stroke Foundation of Ontario/J. Fraser Mustard Chair in Cardiovascular Research and the Tier I Canada Research Chair in Thrombosis. Disclosures Dr Eikelboom has served on advisory boards and/or received honoraria from companies that develop and market new anticoagulants, including AstraZeneca, Bayer, Boehringer Ingelheim, Bristol- Myers Squibb, Daiichi-Sankyo, Eisai, GlaxoSmithKline, and Sanofi- Aventis. Dr Weitz has served on advisory boards and/or received honoraria from AstraZeneca, Bayer, Bristol-Myers Squibb, Pfizer, Daiichi-Sankyo, Eisai, Merck, Sanofi-Aventis, Schering-Plough, GlaxoSmithKline, Takeda, and The Medicines Company. References 1. Hirsh J, Bauer KA, Donati MB, Gould M, Samama MM, Weitz JI. Parenteral anticoagulants: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest. 2008; 133:141S 159S. 2. Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest. 2008;133:160S 198S. 3. Weitz JI, Hirsh J, Samama MM. New antithrombotic drugs: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest. 2008;133:234S 256S. 4. Testa L, Bhindi R, Agostoni P, Abbate A, Zoccai GG, Van Gaal WJ. 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