Factor Xa inhibitors New anticoagulants for secondary haemostasis
|
|
- Bonnie Atkinson
- 6 years ago
- Views:
Transcription
1 260 Schattauer 2009 Review Factor Xa inhibitors New anticoagulants for secondary haemostasis E. Perzborn Cardiovascular Pharmacology, Pharma R&D Discovery Research, Bayer Schering Pharma AG, Wuppertal, Germany Keywords Factor Xa inhibitors, anticoagulants, thrombosis Summary Oral factor Xa (FXa) inhibitors are a promising alternative to current anticoagulants. This paper reviews the latest developments of oral direct FXa inhibitors and focuses on those which have been approved for the prevention of venous thromboembolism (VTE) after total hip or knee replacement or are in advanced development and have passed phase II (proof of principle) testing. The most advanced drugs are apixaban, betrixaban, edoxaban, eribaxaban, rivaroxaban, LY517717, TAK-442, and YM150. Rivaroxaban (Xarelto ) is the first direct FXa inhibitor which has recently been approved for the prevention of VTE in adult patients after elective hip or knee replacement in several countries, including the European Union and Canada. Rivaroxaban has a flat dose-dependent anticoagulant response with a wide therapeutic window and low potential for drug-drug and drug-food interactions. Rivaroxaban can be given in fixed doses without coagulation monitoring. This review describes the pharmacodynamic and pharmacokinetic profiles and the results of clinical trials with FXa inhibitors in the prevention and treatment of thromboembolic disorders. Correspondence to: Elisabeth Perzborn PhD Cardiovascular Pharmacology Pharma R&D Discovery Research Bayer Schering Pharma AG Aprather Weg 18a, Wuppertal, Germany Tel. +49/(0)202/ , Fax +49/(0)202/ elisabeth.perzborn@bayerhealthcare.com Schlüsselwörter Faktor-Xa-Hemmer, Thrombose Antikoagulanzien, Zusammenfassung Orale Faktor-Xa(FXa)-Hemmer sind viel versprechende Alternativen zu den gebräuchlichen Antikoagulanzien. In diesem Artikel werden Neuentwicklungen im Bereich der oralen direkten FXa-Hemmer vorgestellt mit Schwerpunkt auf solchen, die zur Prävention venöser Thromboembolien (VTE) nach Hüft- oder Kniegelenkersatz zugelassen sind oder sich in einem fortgeschrittenen Entwicklungsstadium befinden und die Phase-II-Studien zum Nachweis der Wirksamkeit (proof of principle) durchlaufen haben. Apixaban, Betrixaban, Edoxaban, Eribaxaban, Rivaroxaban, LY517717, TAK-442 und YM150 sind die am weitesten entwickelten FXa-Hemmer. Rivaroxaban (Xarelto ) ist der erste direkte FXa-Hemmer, der u. a. in der Europäischen Union und in Kanada zur Prävention von VTE nach elektivem Hüft- oder Kniegelenksersatz bei Erwachsenen zugelassen ist. Für Rivaroxaban wurde eine flach verlaufende dosisabhängige antikoagulatorische Wirkung gezeigt. Sein breites therapeutisches Fenster und geringes Potenzial für Wechselwirkungen mit Pharmaka und Nahrungsmitteln erlaubt die Gabe in fixer Dosis ohne Überwachung der Blutgerinnung. Diese Übersicht beschreibt das pharmakodynamische und pharmakokinetische Profil sowie die Ergebnisse klinischer Studien mit FXa- Hemmern zur Prävention und Behandlung von Thromboembolien. Faktor-Xa-Inhibitoren neue Antikoagulanzien der sekundären Hämostase Hämostaseologie 2009; 29: A key strategy in the discovery and development of new anticoagulants is the targeting of specific enzymes in the coagulation pathway. One approach is to inhibit thrombin generation through inhibition of the coagulation factor Xa (FXa). FXa plays a pivotal role in the blood coagulation pathway ( Fig. 1). Factor X (FX) is activated by the intrinsic and the extrinsic pathways in response to vascular injury or blood stasis. FXa combines with factor Va in the presence of calcium ions on an activated phospholipide surface to form the prothrombinase complex. The prothrombinase complex is more efficient than free FXa activating prothrombin to thrombin (35). Thrombin then catalyses the cleavage of fibrinogen to fibrin, the activation of factor XIII (which cross-links and stabilizes fibrin), the activation of platelets and the feedback activation of upstream coagulation factors (19), resulting in the amplification of its own formation (33, 34). Because of the key position of FXa in the coagulation pathway, the development of FXa inhibitors is an important approach in the search for novel antithrombotic therapies. This paper focuses on oral direct FXa inhibitors in clinical development that have been shown to be effective in venous thromboembolism (VTE) prevention in patients after total hip (THR) or knee (TKR) replacement. Indirect FXa inhibitors The first selective FXa inhibitor was fondaparinux (Arixtra ) which was shown to be effective and safe in patients with acute coronary syndrome (ACS) and VTE. However, because it is an indirect FXa inhibitor, its effects depend on the level of antithrombin (AT) and fondaparinux cannot be administered orally. Other parenteral indirect FXa inhibitors, like idraparinux and idrabiotaparinux (biotiny- Hämostaseologie 3/2009
2 Perzborn: FXa inhibitors 261 lated idraparinux) are currently at different stages of clinical development. Oral direct FXa inhibitors Several oral direct FXa inhibitors are at different stages of clinical development for the short and long term prevention and treatment of thromboembolic diseases. These include apixaban, betrixaban, edoxaban, eribaxaban, rivaroxaban, LY517717, TAK-442, and YM150. Rivaroxaban has recently been approved for the prevention of VTE in adult patients after total hip or knee replacement (THR, TKR) in several countries, including the European Union and Canada. These new, small molecule FXa inhibitors are AT-independent inhibitors and bind direct to the active FXa site, thereby blocking the interaction of FXa with its substrate prothrombin. AT-independent inhibitors have the potential to inhibit free FXa, prothrombinase and clot-bound FXa activity (10, 42). Fondaparinux, an indirect AT-dependent FXa inhibitor, does not inhibit FXa in the prothrombinase complex at clinically relevant concentrations (36). The direct action of the new FXa inhibitors might mean that their action is more predictable and that they are more effective. Rivaroxaban Fig. 1 Schematic representation of the coagulation cascade, illustrating the pivotal role of factor Xa Rivaroxaban (Xarelto, Bayer Schering Pharma AG) is a direct competitive FXa inhibitor (inhibitory constant [K i ] = 0.4 nmol/l) with > fold greater selectivity for FXa than other serine proteases (41). It is a reversible (k off s 1 ) FXa inhibitor with a rapid onset of action (k on M 1 s 1 ) (44). It inhibits prothrombinase (IC nmol/l) (41) and clot-bound (IC nmol/l) (9) FXa activity in plasma. In human plasma, it inhibits thrombin generation by inhibiting FXa, generated via both the intrinsic and extrinsic coagulation pathways (17, 20). In addition, rivaroxaban concentration-dependently inhibits thrombin generation in the presence of thrombomodulin in human plasma, suggesting that it does not interfere with the thrombin-thrombomodulin-apc system, and therefore does not suppress the negative feedback reaction by activated protein C (40). In vivo, rivaroxaban given prophylactically had potent and consistent antithrombotic effects in venous (5, 39, 41) and arterial (21, 39, 41) thrombosis models in mice, rats and rabbits. In a rabbit model, rivaroxaban reduced the deposition of radiolabeled fibrinogen into preformed clots in the jugular vein (5). Bleeding times in rats and rabbits were not significantly affected at antithrombotic doses (41). Rivaroxaban has high oral bioavailability and a rapid onset of action, reaching maximum plasma concentrations hours after administration (27, 28). It has a half-life of up to 9 hours in healthy young subjects (28) and hours in healthy elderly subjects (26). Rivaroxaban is eliminated via two routes: one-third unchanged in the urine, and two-thirds after metabolic degradation, half of which is excreted via the kidney, half via the faecal route (48). Rivaroxaban shows nearly linear pharmacokinetics up to 15 mg with no significant accumulation following repeat dosing. The plasma concentrations and pharmacodynamic effects of rivaroxaban (inhibition of FXa activity and prolongation of prothrombin time [PT]) correlate closely in healthy subjects and patients undergoing major orthopedic surgery (37, 38). RECORD program Rivaroxaban has recently been approved for the prevention of VTE after THR and TKR in several countries, based on the results of the phase III RECORD program, which comprised four large studies in more than patients. In all of the RECORD studies, the primary efficacy endpoint (total VTE) was the composite of deep venous thrombosis (DVT), nonfatal pulmonary embolism (PE) and allcause mortality. A main secondary efficacy endpoint was major VTE: the composite of proximal DVT, nonfatal PE and VTE-related death. The primary safety endpoint was major bleeding, defined as bleeding event that was fatal, occurred in a critical organ (e. g. retroperitoneal, intracranial, intraocular, or intraspinal bleeding) or requiring reoperation, or extrasurgical-site bleeding that was associated with a fall in hemoglobin of 2 g/dl or more, or required an infusion of two or more units of blood ( Tab. 1). RECORD2 investigated the efficacy and safety of extended thromboprophylaxis with rivaroxaban (5 weeks) compared with shortterm enoxaparin (10 14 days) in patients undergoing THR (24). The results of this Schattauer 2009 Hämostaseologie 3/2009
3 262 Perzborn: FXa inhibitors Tab. 1 Incidence of venous thromboembolism and bleeding events across the four RECORD studies (11, 24, 29, 46) endpoint RECORD1 (THR)* RECORD2 (THR)* RECORD3 (TKR)* RECORD4 (TKR) efficacy endpoints % (n) total VTE, (primary endpoint) enoxaparin enoxaparin 30 mg bid 5 weeks days 5 weeks days days 3.7 (58/1558) p< (18/1595) enoxa - parin 9.3 (81/869) p< (17/864) enoxa - parin 18.9 (166/878) p<0.001 rivaroxaban* rivaroxaban rivaroxaban rivaroxaban 9.6 (79/824) 10.1 (97/959) p= (67/965) safety endpoints (bleeding events) % (n) major VTE symptomatic VTE major bleeding (primary endpoint) clinically relevant non-major bleeding (33/1678) p< (11/2206) p= (2/2224) 2.4 (54/2224) 0.2 (4/1686) 0.3 (6/2193) 0.3 (6/2209) 2.9 (65/2209) 5.1 (49/962) p< (15/1207) p=0.004 <0.1 (1/1229) 2.7 (33/1229) 0.6 (6/961) 0.2 (3/1212) <0.1 (1/1228) 3.3 (40/1228) 2.6 (24/925) p=0.01 (24/1217) p= (6/1239) 2.3 (28/1239) 1.0 (9/908) 0.7 (8/1201) 0.6 (7/1220) 2.7 (33/1220) all p-values for efficacy calculated from absolute risk reduction; THR: total hip replacement; TKR: total knee replacement; VTE: venous thromboembolism; *dosage once daily: enoxaparin 40 mg; rivaroxaban 10 mg (22/1112) p= (18/1508) p= (4/1508) (30/1508) 1.2 (13/1122) 0.7 (11/1526) 0.7 (10/1526) 2.6 (39/1526) study demonstrated that extended prophylaxis with 10 mg rivaroxaban once daily (qd) given orally was superior to short-term prophylaxis with 40 mg enoxaparin qd given subcutaneously for the prevention of total, major and symptomatic VTE, after THR ( Tab. 1). Even though rivaroxaban was given for three weeks longer than enoxaparin, the incidence of major bleeding at five weeks was 0.1% in both groups. This study confirmed the benefits of extended prophylaxis over short-term prophylaxis and the safety of its use. RECORD1 and RECORD 3 were designed to compare 10 mg rivaroxaban qd with 40 mg enoxaparin qd for days (extended prophylaxis) after THR (RECORD1) (29) and days (short-term prophylaxis) after TKR (RECORD3) (46). In both studies, rivaroxaban was significantly more effective than enoxaparin in the prevention of total VTE ( Tab. 1). RECORD 3 also showed a statistically significant reduction in major and symptomatic VTE, and RECORD1 a statistically significant reduction in major VTE ( Tab. 1). The incidence of major bleeding in RECORD 1 and 3 showed no significant differences between rivaroxaban and enoxaparin ( Tab. 1). RECORD4 compared the efficacy and safety of 10 mg rivaroxaban orally qd with 30 mg enoxaparin twice daily (bid), both for days, in patients undergoing TKR (46). Rivaroxaban was significantly more effective than enoxaparin for the primary efficacy endpoint (total VTE), with no significant difference between the rates of major bleeding in the two groups ( Tab. 1). ODIXa, EINSTEIN, MAGELLAN, ROCKET AF, ATLAS The efficacy and safety of rivaroxaban in the treatment of VTE were assessed in two phase IIb studies: ODIXa-DVT (2) and EINSTEIN-DVT (7). These studies demonstrated that rivaroxaban is effective and has a similar safety profile compared to standard therapy in the treatment of acute symptomatic DVT ( Tab. 2). An initial intensified regimen (15 mg rivaroxaban bid for three weeks) followed by longterm treatment with 20 mg qd was selected for investigation in three phase III studies 1 on the efficacy and safety of rivaroxaban in VTE: EINSTEIN-DVT, -PE, - EXTENSION. A further phase III study 2 (MAGELLAN) is investigating the efficacy and safety of prophylaxis with 10 mg rivaroxaban qd for up to five weeks compared with short-term enoxaparin in hospitalized acute medically ill patients. 20 mg rivaroxaban qd is being compared with warfarin in the prevention of stroke in approximately patients with atrial fibrillation (AF) in a phase III study 3 (ROCKET AF). Finally, a phase III study investigating secondary prevention in patients with ACS, ATLAS 2 TIMI 51, was started in late Two dosages of rivaroxaban, 2.5 and 5 mg bid, are being investigated, based on the results of a phase IIb study, the ATLAS ACS TIMI 46 study, which assessed safety and efficacy in about 3500 patients with recent ACS 4 (18). Apixaban Apixaban (Bristol-Myers Squibb) is a smallmolecule, oral, direct FXa inhibitor that selectively and reversibly inhibits free FXa (K i = 0.08 nmol/l) (50). Apixaban rapidly reacts with FXa (k on = M/s), binds with high affinity (K i = 0.3 nmol/l at 37 C), and noncompetitively inhibits prothrombin activation (32). The human plasma concentration required to double the prothrombin Hämostaseologie 3/2009 Schattauer 2009
4 Perzborn: FXa inhibitors 263 Tab. 2 Efficacy and safety results of the ODIXa-DVT (2) and EINSTEIN-DVT (7) studies DVT study rivaroxaban enoxaparin + VKA 10 mg bid 20 mg bid 30 mg bid 40 mg qd ODIXa improvement in thrombus burden without recurrent VTE at 3 weeks, n (%) recurrent DVT, PE, and VTE-related death at 3 months, n (%) major bleeding, n (%) EINSTEIN recurrent VTE and thrombus deterioration at 3 months, n (%) major bleeding, n (%) (n=100) 53 (53.0) (n=106) 2 (1.9) (n=119) 2 (1.7) (n=98) 58 (59.2) (n=100) 2 () (n=117) 2 (1.7) (n=115) 7 (6.1) (n=135) 1 (0.7) (n=109) 62 (56.9) (n=111) 2 (1.8) (n=121) 4 (3.3) (n=112) 6 (5.4) (n=134) 2 (1.5) (n=112) 49 (43.8) (n=114) 3 (2.6) (n=121) 2 (1.7) (n=121) 8 (6.6) (n=136) 0 (0.0) (n=109) 50 (45.9) (n=112) 1 (0.9) (n=126) 0 (0.0) LMWH/heparin + VKA (n=101) 10 (9.9) (n=137) 2 (1.5) bid: twice daily; DVT: deep vein thrombosis; LMWH: low molecular weight heparin; qd: once daily; PE: pulmonary embolism; VKA: vitamin K antagonist; VTE: venous thromboembolism time and the partial thromboplastin time is 3.6 and 7.4 μmol/l (50). Dose-dependent antithrombotic efficacy has been demonstrated in rabbit models of arteriovenous shunt thrombosis, venous thrombosis and electrically-mediated carotid arterial thrombosis (50). Apixaban was shown to be effective in the prevention of experimental thrombosis at doses that preserve hemostasis in rabbits (50). Apixaban has high oral bioavailability in chimpanzees (51%) and dogs (88%), has a half-life of approximately 8 15 hours in humans, low metabolic clearance, and multiple pathways of elimination, including renal and intestinal excretion (22, 14). Indications, studies Apixaban is currently being evaluated in a number of indications, including the prevention and treatment of VTE (comprising DVT and PE), the prevention of stroke in patients with AF, and the prevention of cardiovascular events in ACS. The phase II APROPOS trial with apixaban (total daily dosage 5 20 mg qd or bid) vs. enoxaparin or warfarin for VTE prevention after TKR has demonstrated similar efficacy for apixaban, enoxaparin and warfarin in the reduction of the incidence of the primary efficacy endpoint (30). Based on these results, apixaban is currently being evaluated in phase III studies for the prevention of VTE after major orthopedic surgery (the ADVANCE program). ADVANCE-1 investigated the efficacy and safety of 2.5 mg apixaban orally bid compared with 30 mg enoxaparin s.c. bid for the prevention of VTE in patients undergoing TKR ( Tab. 3). Apixaban did not meet the specified criteria for non-inferiority compared with enoxaparin with respect to the primary efficacy endpoint (a composite of symptomatic or asymptomatic DVT, PE and all-cause mortality) (31). The rate of the primary efficacy endpoint was 9.0% in the apixaban group and 8.9% in the enoxaparin group (p > 0.05). The rate of major bleeding with apixaban was 0.7% and with enoxaparin 1.4% (p = 0.054). ADVANCE-2 5 (2.5 mg apixaban bid versus 40 mg enoxaparin qd) is currently under way in patients undergoing TKR. A third study, AD- VANCE-3 6, is assessing extended prophylaxis (35 days) with 2.5 mg apixaban bid and 40 mg enoxaparin qd in patients undergoing THR. The Botticelli-DVT phase II study for the treatment of acute symptomatic DVT examined the efficacy and safety of 5 and 10 mg apixaban bid and 20 mg qd compared with a low- molecular-weight heparin or fondaparinux and a vitamin K antagonist. All three doses of apixaban were considered similar to the comparators. The result of this study led to the phase III ARISTOLE study for the prevention of stroke or systemic embolism in patients with AF (6). The ARISTOTLE 7 trial is investigating whether 5 mg apixaban bid is as effective as warfarin in preventing stroke and systemic embolism in subjects with AF and risk factors for stroke. The AVERROES 8 trial is investigating whether 5 mg apixaban bid (2.5 bid in selected patients) are superior to mg acetylsalicylic acid qd in preventing stroke or systemic embolism in patients with AF and at least one additional risk factor. Apixaban is also currently under investigation in two phase III studies for the treatment of VTE. The AMPLIFY trial 9 is evaluating the effects of 10 mg apixaban bid for 7 days followed by 5 mg bid for 6 months in preventing VTE recurrence or death in patients with DVT or PE compared to standard therapy (enoxaparin followed by warfarin). The AMPLIFY-EXT 10 trial is evaluating the effects of 2.5 and 5.0 mg apixaban bid for 12 months in preventing VTE recurrence or death in patients who have completed their treatment for DVT or PE. A phase III trial on the prevention of VTE in patients hospitalized for an acute medical illness (ADOPT 11 ) is comparing 2.5 mg apixaban bid for 30 days followed by 6 14 days placebo with 40 mg enoxaparin qd for 6 14 days followed by 30 days placebo. A phase II trial, ADVOCATE 12, is investigating VTE prevention in cancer patients. In a randomized, double-blind, phase II trial (APPRAISE-1), patients with ACS received ASA in combination with 2.5 mg apixaban bid or 10 mg qd for 26 weeks. Co-administration of clopidogrel was at the physician s discretion. Apixaban 10 mg bid and apixaban 20 mg qd was discontinued early due to excess bleeding in patients receiving apixaban and dual antiplatelet therapy. Results showed non-significant relative risk reductions in cardiovascular events of 27% in the 2.5 mg group and 38% in the 10 mg group Schattauer 2009 Hämostaseologie 3/2009
5 264 Perzborn: FXa inhibitors Tab. 3 Other direct factor Xa inhibitors in clinical development apixaban betrixaban edoxaban VTE prevention after major orthopaedic surgery (phase III) ADVANCE-1 TKR (n = 3202) (31) apixaban enoxaparin p value primary efficacy outcome composite of symptomatic or asymptomatic DVT, PE and all-cause mortality 15 mg 40 mg primary efficacy outcome VTE incidence 20% 15% 10% primary safety outcomes major bleeding 0% 0% 2% CRNM bleeding 0% 2% 5% VTE prevention in TKR patients (phase II) (n = 523) (15) edoxaban placebo 5 mg 15 mg 30 mg 60 mg primary efficacy outcome VTE incidence 29.5% (p<0.01) primary safety outcome major bleeding and clinically relevant bleeding 9.0% 8.9% NS primary safety outcome major bleeding 0.7% 1.4% NS VTE prevention in TKR patients (phase II) EXPERT (n = 215) (45) betrixaban enoxaparin 2.9% (p=0.445) 26.1% (p<0.001) 4.7% (p=1.00) 12.5% (p<0.001) 3.9% (p=1.00) 9.1% (p<0.001) 4.7% (p=1.00) STARTS THR phase IIb (n = 950) (43) edoxaban dalteparin 15 mg 30 mg 60 mg 90 mg primary efficacy outcome VTE incidence 28.2% 21.2% 15.2% 10.6% 43.8% primary safety outcome major and CRNM bleeding 1.6% 1.8% 2.2% 2.3% 0% stroke prevention in patients with AF phase II (n = 1146) (49) edoxaban warfarin 30 mg qd 60 mg qd 30 mg bid 60 mg bid primary safety outcome major and CRNM bleeding 3% 4.7% 7.8% (p<0.05) 10.6% (p=0.002) 3.2% VTE: venous thromboembolism; DVT: deep vein thrombosis; PE: pulmonary embolism; THR: total hip replacement; TKR: total knee replacement; NS: non-significant; CNRM: clinically relevant non-major; AF: atrial fibrillation; qd: once daily; bid: twice daily ADVANCE-1: apixaban 2.5 mg bid; or enoxaparin 30 mg bid for 10 days; EXPERT: betrixaban 15 or 40 mg bid; or enoxaparin 30 mg bid for days; edoxaban phase II: edoxaban 5, 15, 30 or 60 mg qd; or placebo for days; STARTS: edoxaban 15, 30, 60 or 90 mg qd; or dalteparin for 7 10 days; phase II stroke prevention in patients with AF: edoxaban 30 or 60 mg qd and bid; or warfarin (INR 2 3) for 3 months 48.3% 3.9% compared with placebo (4). The incidence of major bleeding plus clinically relevant nonmajor bleeding was 5.7% in the 2.5 mg bid group, 7.9% for 10 mg qd, and 3% for placebo patients. A phase III study with 5 mg apixaban bid (APPRAISE-2 13 ) was started recently. Betrixaban Betrixaban (PRT ; Portola Pharmaceuticals) is a further, orally active, site-directed, competitive FXa inhibitor that selectively inhibits free FXa (K i = nmol/l) (47). It has a bioavailability of 47%, and a half-life of about 20 h (47, 45). In vivo dosedependent antithrombotic activity has been shown in arterial and venous thrombosis models in rats, rabbits and baboons (1). Clearance is primarily by biliary excretion with limited metabolism and minimal renal excretion (less than 5% of an administered dose) (47, 45). A phase II, randomized, openlabel VTE prevention trial (EXPERT) in patients undergoing TKR provided proof of principle for 15 and 40 mg betrixaban bid and showed a good safty profile (45). The primary efficacy endpoint was the incidence of VTE (symptomatic DVT or PE, or asymptomatic DVT) on days VTE occurred in 20% (15 mg) and 15.4% (40 mg) of patients receiving betrixaban, and in 10% of those receiving enoxaparin. Major bleeding events were not observed in either betrixaban group, but occurred in 2% of patients in the enoxa - parin group. Hämostaseologie 3/2009 Schattauer 2009
6 Perzborn: FXa inhibitors 265 A phase II study (EXPLORE-Xa 14 ) to investigate the safety, tolerability and efficacy of 40, 60, and 80 mg betrixaban qd (doubleblind) compared to warfarin (open-label, dose-adjusted) for 3 months in patients with atrial fibrillation has started recruitment. Edoxaban Edoxaban (DU-176b; Daiichi Sankyo) is an oral, direct and competitive FXa inhibitor. FXa is inhibited with K i values of 0.56 nmol/l for free FXa and 2.98 nmol/l for prothrombinase with a > fold selectivity for FXa (16). In human plasma, edoxaban doubles the prothrombin time and activated partial thromboplastin time at concentrations of and μmol/l. In vivo, edoxaban dose-dependently inhibited thrombus formation in rat and rabbit thrombosis models, and the bleeding time in rats was not significantly prolonged at an antithrombotic dose (16). It is rapidly absorbed (median t max h), with a plasma half-life of 9 11h and a bioavailability of about 45% (51). In healthy volunteers, a single 60 mg dose of edoxaban reduced ex vivo thrombus formation in a flow chamber under venous and arterial flow conditions for up to 5 h (51). A placebo-controlled, phase II study in patients undergoing TKR showed that edo - xaban dose-dependently reduced VTE without increases in major or clinically relevant bleeding ( Tab. 3) (15). The incidence in placebo patients was 48.3%, and was reduced by edoxaban to 29.5% (5 mg qd), 26.1% (15 mg qd), 12.5% (30 mg qd), and 9.1% (60 mg qd). The results of a randomized, double-blind, phase IIb study (STARTS II) comparing edoxaban with dalteparin in patients undergoing THR were reported recently (43). The incidence of VTE on dalteparin was 43.8% and was dose-dependently lower on edoxaban: 28.2% (15 mg qd), 21.2% (30 mg qd), 15.2% (60 mg qd), and 10.6% (90 mg qd) (Table 3). There were no major or clinically relevant bleeding events associated with dalteparin. The rate of major or clinically relevant bleeding for edoxaban was 1.6% (15 mg qd), 1.8% (30 mg qd), 2.2% (60 mg qd), and 2.3% (90 mg qd). Edoxaban in qd and bid regimens was also assessed in a phase II study for the prevention of stroke in patients with AF compared with standard warfarin therapy for 3 months ( Tab. 3) (49). A significantly higher incidence of major and clinically relevant nonmajor bleeding events was observed in patients who received 30 and 60 mg bid edoxaban (7.8 and 10.6%) than in those given warfarin (3.2%). In contrast, the incidence of major and clinically relevant non-major bleeding events with the 30 and 60 mg qd edoxaban regimen (3.0 and 4.7%) was similar to that with warfarin (3.2 %). A phase III trial comparing low-dose and high-dose edoxaban with warfarin for 24 months in patients with AF (ENGAGE AFTIMI ) has been started. YM150 YM150 (Astellas Pharma Inc) is a once-daily, orally active FXa inhibitor (K i = 0.31 nmol/l). It has shown antithrombotic effects at doses that did not prolong bleeding time in animal models of venous and arterial thrombosis; this in vivo activity is also shared with its major metabolite YM (K i = 0.02 nmol/l) (23). At present, only limited preclinical, phase I and phase IIa clinical data are available. Two phase II trials for the prevention of VTE after orthopedic surgery have been completed. In a phase IIa study for the prevention of VTE after THR, mg YM150 qd was shown to be safe, well tolerated and effective (12). A phase IIb study, ONYX-2, to determine the optimal dose of YM150 (5 120 mg qd) for the prevention of VTE after THR, has recently been completed (13). The incidence of the primary efficacy endpoint (composite of DVT, symptomatic VTE, PE and death up to days 7 10 of prophylaxis) ranged from 31.7% to 13.3%, and decreased significantly with increasing doses of YM150. Further phase II studies have been started to evaluate the safety and tolerability of escalating oral doses of YM150 compared with enoxaparin in patients undergoing TKR (PEARL-1 16 ), and the safety and efficacy of qd and bid dosing regimens of YM150 compared with warfarin in patients undergoing TKR (PEARL 17 ). A double-blind, dose-finding phase II study 18 to investigate the pharmacokinetics and pharmacodynamics of YM150 in patients with AF has been recently completed. LY LY difumarate (Eli Lilly) is an oral, direct FXa inhibitor with a K i for FXa of nmol/l and an elimination half-life of about 25 h in healthy subjects; it is eliminated mainly in faeces (47). In a randomized, double-blind, dose-escalation study in patients undergoing TKR or THR, total VTE rates were 19% for 100 mg LY517717, 19% for 125 mg, and 16% for 150 mg compared with 21% for 40 mg enoxaparin qd (3). The incidence of bleeding events was similar for LY and enoxaparin. No information on future studies is available. Eribaxaban Eribaxaban (PD ; Pfizer) has a high affinity for human FXa (K i = 0.32 nmol/l) (25). In vivo antithrombotic activity has been demonstrated in an AV shunt model in rabbits (25). Clinical data from a dose-ranging study with eribaxaban in the prevention of VTE in TKR patients have recently been presented (8). All doses were well tolerated. VTE frequency was as follows (eribaxaban dose in mg): 37.1% (0.1), 37.1% (0.3), 28.8% (0.5), 19.2% (1.0), 14.3% (2.5), 1.4% (4.0), and 11.1% (10.0) compared with 18.1% for 30 mg enoxaparin s.c. bid. A dose-related increase in the incidence of total bleeding, driven mainly by minor bleeding, was not statistically significant. No further studies have been reported. TAK-442 TAK-442 (Takeda Pharmaceutical) is a further orally active, direct FXa inhibitor. A phase II dose-ranging study 19 to evaluate the efficacy and safety of TAK-442 (10, 40, 80 mg qd and bid) in subjects undergoing TKR has been recently completed, and a further phase NCT , 1 NCT , 1 NCT , 2 NCT , 3 NCT , 4 NCT , 5 NCT , 6 NCT ), 7 NCT , 8 NCT , 9 NCT , 10 NCT , 11 NCT , 12 NCT , 13 NCT , 14 NCT , 15 NCT , 16 NCT , 17 NCT , 18 NCT , 19 NCT , 20 NCT Schattauer 2009 Hämostaseologie 3/2009
7 266 Perzborn: FXa inhibitors II study 20 in subjects with ACS is ongoing. No pharmacodynamic or pharmacokinetic data are available. Conclusion The efficacy and safety of new oral, direct FXa inhibitors in recent clinical studies potentially heralds a new era for anticoagulation. The positive results showed for the prevention of VTE in patients undergoing THR and TKR surgery have led to the approval of the direct factor Xa inhibitor rivaroxaban for these indications. Several FXa inhibitors are currently being investigated in chronic use indications such as the prevention of stroke in patients with AF, the secondary prevention of ACS and treatment of VTE. In future, anticoagulant treatment will favour oral agents with a wide therapeutic window and predictable anticoagulant response that do not need routine monitoring. Emerging data suggest that direct FXa inhibitors are effective antithrombotic agents for short-term usage and promising agents for long-term usage. Since they have shown a predictable pharmacological profile, are given orally, and do not require routine coagulation monitoring, these new agents are likely to improve anticoagulation treatment in thromboembolic disorders and reduce the burden associated with long-term treatment. References 1. Abe K, Siu G, Edwards S et al. Animal models of thrombosis help predict the human therapeutic concentration of PRT54021, a potent oral factor Xa inhibitor. Blood 2006; 108: A Agnelli G, Gallus A, Goldhaber et al. Treatment of proximal deep-vein thrombosis with the oral direct Factor Xa inhibitor rivaroxaban (BAY ): the ODIXa-DVT (oral direct Factor Xa inhibitor BAY in patients with acute symptomatic deepvein thrombosis) study. Circulation 2007; 116: Agnelli G, Haas S, Ginsberg JS et al. A phase II study of the oral factor Xa inhibitor LY for the prevention of venous thromboembolism after hip or knee replacement. J Thromb Haemost 2007; 5: Alexander JH. Safety of the factor Xa inhibitor, Apixaban, in combination with antiplatelet therapy after acute coronary syndrome: Results of the AP- PRAISE-I dose guiding trial. Presented at ESC Biemond BJ, Perzborn E, Friederich PW et al. Prevention and treatment of experimental thrombosis in rabbits with rivaroxaban (BAY ) an oral, direct Factor Xa inhibitor. Thromb Haemost 2007; 97: Buller H, Deitchman D, Prins M et al. Efficacy and safety of the oral direct factor Xa inhibitor apixaban for symptomatic deep vein thrombosis. The Botticelli DVT dose-ranging study. J Thromb Haemost 2008; 6: Buller HR, Lensing AW, Prins MH et al. A doseranging study evaluating once-daily oral administration of the factor Xa inhibitor Rivaroxaban in the treatment of patients with acute symptomatic deep vein thrombosis. The EINSTEIN-DVT Dose-Ranging Study. Blood 2008; 112: Cohen AT, Armstrong D, Gazdzik T et al. An adaptive-design dose-ranging study of PD , a new oral factor Xa inhibitor, for thromboprophylaxis after total knee replacement surgery. Blood 2008; 112: A Depasse F, Busson J, Mnich J et al. Effect of BAY a novel, oral, direct Factor Xa inhibitor on clot-bound Factor Xa activity in vitro. J Thromb Haemost 2005; 3: P Eisenberg PR, Siegel JE, Abendschein DR et al. Importance of factor Xa in determining the procoagulant activity of whole-blood clots. J Clin Invest 1993; 91: Eriksson BI, Borris LC, Friedman RJ et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med 2008; 358: Eriksson BI, Turpie AGG, Lassen MR et al. A dose escalation study of YM150, an oral direct factor Xa inhibitor, in the prevention of venous thromboembolism in elective primary hip replacement surgery. J Thromb Haemost 2007; 5: Eriksson BI, Turpie AGG, Lassen MR et al. Once daily YM150, an oral direct Factor Xa inhibitor, for prevention of venous thromboembolism in patients undergoing elective primary hip replacement. Blood 2007; 110: A Frost C, Yu Z, Nepal S et al. Apixaban, an oral direct Factor Xa inhibitor: single-dose safety, pharmacokinetics and pharmacodynamics in healthy volunteers. J Thromb Haemost 2007; 5 (Suppl 1): P-M Fuji T, Fujita S, Tachibana S et al. Randomized, double-blind, multi-dose efficacy, safety and bio - marker study of the oral factor Xa inhibitor DU-176b compared with placebo for prevention of venous thromboembolism in patients after total knee arthroplasty. Blood 2008; 112: Furugohri T, Isobe K, Honda Y et al. DU-176b, a potent and orally active factor Xa inhibitor: In vitro and in vivo pharmacological profiles. J Thromb Haemost 2008; 6: Gerotziafas GT, Elalamy I, Depasse F et al. In vitro inhibition of thrombin generation, after tissue factor pathway activation, by the oral, direct Factor Xa inhibitor rivaroxaban. J Thromb Haemost 2007; 5: Gibson CM, Mega JL, Hammett CJ et al. Randomized Comparison of Rivaroxaban, an Oral Direct Factor Xa Inhibitor, with Placebo in Patients with Acute Coronary Syndromes: The ATLAS ACS-TIMI 46 Trial. Circulation 2008; 118: Gomez K, McVey JH, Tuddenham E. Inhibition of coagulation by macromolecular complexes. Haematologica 2005; 90: Graff J, von Hentig N, Misselwitz F et al. Effects of the oral, direct Factor Xa inhibitor rivaroxaban on platelet-induced thrombin generation and prothrombinase activity. J Clin Pharmacol 2007; 47: Haertlein B, Parry TJ, Chen C et al. Rivaroxaban an oral, direct factor Xa inhibitor prevents arterial thrombotic occlusion in electrolytically injured rat carotid arteries. Blood 2007; 110: A He K, He B, Grace JE et al. Preclinical pharmacokinetic and metabolism of apixaban, a potent and selective Factor Xa inhibitor. Blood 2006; 108: A Iwatsuki Y, Shigenaga T, Moritani Y et al. Biochemical and pharmacological profiles of YM150, an oral direct Factor Xa inhibitor. Blood 2006; 108: A Kakkar AK, Brenner B, Dahl OE et al. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet 2008; 372: Kohrt JT, Bigge CF, Bryant JW et al. The discovery of (2R,4R)-N-(4-chlorophenyl)-N-(2-fluoro- 4-(2-oxopyridin-1(2H)-yl)phenyl)-4-methoxypyrrolidine-1,2-dicarboxamide (PD ), an orally efficacious factor Xa inhibitor. Chem Biol Drug Des 2007; 70: Kubitza D, Becka M, Roth A et al. Dose-escalation study of the pharmacokinetics and pharmacodynamics of rivaroxaban in healthy elderly subjects. Curr Med Res Opin 2008; 24: Kubitza D, Becka M, Voith B et al. Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY , an oral, direct factor Xa inhibitor. Clin Pharmacol Ther 2005; 78: Kubitza D, Becka M, Wensing G et al. Safety, pharmacodynamics, and pharmacokinetics of BAY an oral, direct Factor Xa inhibitor after multiple dosing in healthy male subjects. Eur J Clin Pharmacol 2005; 61: Lassen MR, Ageno W, Borris LC et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med 2008; 358: Lassen MR, Davidson BL, Gallus A et al. The efficacy and safety of apixaban, an oral, direct factor Xa inhibitor, as thromboprophylaxis in patients following total knee replacement. J Thromb Haemost 2007; 12: Lassen MR, Gallus AS, Pineo GF et al. Randomized double-blind comparison of apixaban with enoxaparin for thromboprophylaxis after knee replacement: the ADVANCE-1 trial. Blood 2008; 112: A Luettgen JM, Wang Z, Seiffert DA et al. Inhibition of measured thrombin generation in human plasma by apixaban: A predictive mathematical model based on experimentally determined rate constants. J Thromb Haemost 2006; 5 (Suppl 1): P-T Mann KG, Butenas S, Brummel K. The dynamics of thrombin formation. Arterioscler Thromb Vasc Biol 2003; 23: Mann KG, Brummel K, Butenas S. What is all that thrombin for? J Thromb Haemost 2003; 1: Mann KG, Jenny RJ, Krishnaswamy S. Cofactor proteins in the assembly and expression of blood clotting enzyme complexes. Annu Rev Biochem 1988; 57: McKenzie CR, Abendschein DR, Eisenberg PR. Sustained inhibition of whole-blood clot procoagulant activity by inhibition of thrombus-associated factor Xa. Arterioscler Thromb Vasc Biol 1996; 16: Hämostaseologie 3/2009 Schattauer 2009
8 Perzborn: FXa inhibitors Mueck W, Becka M, Kubitza D et al. Population model of the pharmacokinetics and pharmacodynamics of rivaroxaban an oral, direct Factor Xa inhibitor in healthy subjects. Int J Clin Pharmacol Ther 2007; 45: Mueck W, Eriksson BI, Bauer KA et al. Population pharmacokinetics and pharmacodynamics of rivaroxaban an oral, direct factor xa inhibitor in patients undergoing major orthopaedic surgery. Clin Pharmacokinet 2008; 47: Perzborn E, Arndt B, Fischer E et al. Antithrombotic effects of rivaroxaban an oral, direct Factor Xa inhibitor in animal models of arterial and venous thrombosis: comparison with enoxaparin, an antithrombin-dependent anticoagulant. Eur Heart J 2006; 27 (Suppl): P Perzborn E, Harwardt M. Direct thrombin inhibitors, but not factor Xa inhibitors, enhance thrombin formation in human plasma by interfering with the thrombin thrombomodulin protein C system. Blood 2008; 112: A Perzborn E, Strassburger J, Wilmen A et al. In vitro and in vivo studies of the novel antithrombotic agent BAY an oral, direct Factor Xa inhibitor. J Thromb Haemost 2005; 3: Prager NA, Abendschein DR, McKenzie CR et al. Role of thrombin compared with factor Xa in the procoagulant activity of whole blood clots. Circulation 1995; 92: Raskob G, Cohen A, Eriksson B et al. Randomized double-blind multi-dose trial of the oral factor-xa inhibitor DU-176b versus LMW heparin (dalteparin) for prevention of venous thromboembolism after total hip replacement. Eur Heart J 2008; 29: Tersteegen A, Schmidt S, Burkhardt N. Rivaroxaban an oral, direct factor Xa inhibitor binds rapidly to factor Xa. J Thromb Haemost 2007; 5 (Suppl 2): P-W Turpie AGG, Bauer KA, Davidson BL et al. A randomized evaluation of betrixaban, an oral factor Xa inhibitor, for prevention of thromboembolic events after total knee replacement (EXPERT). Thromb Haemost 2009; 101: Turpie AGG, Bauer KA, Davidson BL et al. Once- Daily Oral Rivaroxaban Compared with Subcutaneous Enoxaparin Every 12 Hours for Thromboprophylaxis after Total Knee Replacement: REC- ORD4. Blood 2008; 112: A Turpie AGG. New oral anticoagulants in atrial fibrillation. Eur Heart J 2008; 29: Weinz C, Schwartz T, Pleiss U et al. Metabolism and distribution of [14C] BAY an oral, direct Factor Xa inhibitor in rat, dog and human. Drug Metab Rev 2004; 36: A Weitz JI, Connolly SJ, Kunitada S et al. Randomized, parallel group, multicenter, multinational study evaluating safety of DU-176b compared with warfarin in subjects with non-valvular atrial fibrillation. Blood 2008; 112: A Wong PC, Crain EJ, Xin B et al. Apixaban, an oral, direct and highly selective factor Xa inhibitor: in vitro, antithrombotic and antihemostatic studies. J Thromb Haemost 2008; 6: Zafar MU, Vorchheimer DA, Gaztanaga J et al. Antithrombotic effects of factor Xa inhibition with DU-176b: Phase-I study of an oral, direct factor Xa inhibitor using an ex-vivo flow chamber. Thromb Haemost 2007; 98: Hämostaseologie 3/2009
This paper reviews the potential cost-effectiveness
n reports n Cost-Effectiveness of Rivaroxaban After Total Hip or Total Knee Arthroplasty Louis M. Kwong, MD, FACS Abstract Venous thromboembolism (VTE) following joint replacement surgery represents an
More informationa unit of Dr Bharat S Mody Director Chief Arthroplasty Surgeon Centre for Knee & Hip Surgery Dr Pankaj Patni Orthopaedic Surgeon Dr Sunil Dewangan
Centre for Knee & Hip Surgery Arthroscopy a unit of Arthroplasty Dr Bharat S Mody Director Chief Arthroplasty Surgeon Dr Sunil Dewangan Dr Prakash Tekwani Dr Rahul Khanna Dr Pankaj Patni Orthopaedic Surgeon
More informationBayer R&D Investor Day 2005
Science For A Better Life HealthCare Bayer R&D Investor 25 December 8, 25 London Bayer R&D Investor 25 BAY 59-7939: A Novel, ral, Direct Factor Xa Inhibitor Frank Misselwitz Head of Therapeutic Area Cardiovascular,
More informationReview Article Current Status of New Anticoagulants in the Management of Venous Thromboembolism
Advances in Hematology Volume 2012, Article ID 856341, 7 pages doi:10.1155/2012/856341 Review Article Current Status of New Anticoagulants in the Management of Venous Thromboembolism Roberto C. Montoya
More informationThe novel anticoagulants: entering a new era. BOUNAMEAUX, Henri. Abstract
Article The novel anticoagulants: entering a new era BOUNAMEAUX, Henri Abstract During the past five decades, anticoagulant therapy has consisted of rapidly acting parenteral drugs (unfractionated heparin
More informationNEW ORAL ANTICOAGULANTS FOR VENOUS THROMBOEMBOLISM PROPHYLAXIS IN THE FOOT AND ANKLE
NEW ORAL ANTICOAGULANTS FOR VENOUS THROMBOEMBOLISM PROPHYLAXIS IN THE FOOT AND ANKLE Matthew Q. McCammon, DPM INTRODUCTION Venous thromboembolism (VTE) is a common cause of morbidity and mortality. Each
More informationThe Lancet Publishes Results from the Landmark Phase III Rivaroxaban Study RECORD2
News Release Bayer HealthCare AG Corporate Communications 51368 Leverkusen Germany Phone +49 214 30 1 www.news.bayer.com Venous Blood Clot Prevention after Hip Replacement Surgery: The Lancet Publishes
More informationDirect anticoagulation therapy
Direct anticoagulation therapy Pan-Arab Meeting & Saudi Society of Hematology Dr Ihab Alhemaidi MBBS MRCP(Lond UK) FRCPath. Fellow of the Royal Society of Medicine Consultant Adult hematology/bmt Section
More informationTiming the First Postoperative Dose of Anticoagulants Lessons Learned From Clinical Trials
[ Commentary ] Timing the First Postoperative Dose of Anticoagulants Lessons Learned From Clinical Trials Jeremy S. Paikin, MD ; Jack Hirsh, MD ; Noel C. Chan, MBBS ; Jeffrey S. Ginsberg, MD ; Jeffrey
More informationAnticoagulation in VTE The Haematologist s Perspective. Dr. M.D. Maina FRCP Edin.
Anticoagulation in VTE The Haematologist s Perspective Dr. M.D. Maina FRCP Edin. Disclosures None The coagulation process that leads to haemostasis involves a complex set of reactions involving approximately
More informationISIS PHARMACEUTICALS. ISIS-FXI Rx Program Update. Webcast December 8, 2014
ISIS PHARMACEUTICALS ISIS-FXI Rx Program Update Webcast December 8, 2014 Introduction Stan Crooke, M.D., Ph.D. CEO and Chairman, Isis Pharmaceuticals 2 Forward Looking Language Statement This presentation
More informationContinuing Education for Pharmacists
Continuing Education for Pharmacists Oral anticoagulation without protimes: A review of two emerging agents that may come to market. Lindsay Davis, Pharm.D. (Acute Care Pharmacy Resident, Phoenix VA Medical
More informationDOACs: When and how to measure their anticoagulant effect
DOACs: When and how to measure their anticoagulant effect Stavroula Tsiara MD, PhD, FRCP Associate Professor of Internal Medicine University of Ioannina, Greece NOACs NOACs, TSOACs, DOACs (ISTH) Target
More informationNew Insights into the Diagnosis & Management of Venous Thromboembolism (VTE) Michael Miller, M.D.
New Insights into the Diagnosis & Management of Venous Thromboembolism (VTE) Michael Miller, M.D. Professor of Cardiovascular Medicine University of Maryland School of Medicine Copyright A.P. Wheeler 2009
More informationClinical Study Synopsis
Clinical Study Synopsis This file is posted on the Bayer HealthCare Clinical Trials Registry and Results website or on the website www.clinicalstudyresults.org hosted by the Pharmaceutical Research and
More informationLOW MOLECULAR WEIGHT HEPARIN THE STANDARD VALUE
LOW MOLECULAR WEIGHT HEPARIN THE STANDARD VALUE ANASTASIOS V. KOROMPILIAS, MD ORTHOPAEDIC DEPARTMENT, MEDICAL SCHOOL UNIVERSITY OF IOANNINA, IOANNINA, GREECE MAJOR ORTHOPAEDIC SURGERY POSTOPERATIVE CLASSIFIED
More informationUpdate on the Direct Oral Anticoagulants (DOACs)
Update on the Direct Oral Anticoagulants (DOACs) J. Randle Adair DO, PhD Internal Medicine New Mexico Cancer Center & Co-Chair, Anticoagulation Subcommittee Presbyterian Healthcare Services (PHS) Attending,
More informationNovel Anti-coagulant Agents. David G Hovord BA MB BChir FRCA Clinical Assistant Professor University of Michigan
Novel Anti-coagulant Agents David G Hovord BA MB BChir FRCA Clinical Assistant Professor University of Michigan Objectives Provide an overview of the normal coagulation, including perioperative testing
More informationLVHN Scholarly Works. Lehigh Valley Health Network. Joseph G. Ottinger RPh, MS, MBA, BCPS Lehigh Valley Health Network,
Lehigh Valley Health Network LVHN Scholarly Works Department of Pharmacy Retrospective Evaluation of Delayed Administration of Fondaparinux in Providing Comparable Safety and Efficacy Outcomes in Patients
More informationNew Anticoagulants Linda Liu, M.D.
Difficult Task New Anticoagulants Professor UCSF Dept of Anesthesia 15 minutes! Emphasis on 2 new oral anticoagulants Dabigatran Rivaroxaban Relation to anesthesia Rapid reversal Regional anesthesia UC
More informationFactor Xa is a coagulation factor that acts at the convergence
DVT: A New Era in Anticoagulant Therapy Rivaroxaban: A New Oral Factor Xa Inhibitor Elisabeth Perzborn, Susanne Roehrig, Alexander Straub, Dagmar Kubitza, Wolfgang Mueck, Volker Laux Downloaded from http://atvb.ahajournals.org/
More informationSYNOPSIS. Clinical Study Report for Study CV Individual Study Table Referring to the Dossier
Name of Sponsor/Company: Bristol-Myers Squibb Name of Finished Product: Individual Study Table Referring to the Dossier (For National Authority Use Only) Name of Active Ingredient: SYNOPSIS Clinical Study
More informationOmar A. Elkashef, MD
DVT Prophylaxis in Orthopedic Surgery By Omar A. Elkashef, MD Kasr Al- aini About VTE Venous thromboembolism encompasses deep vein thrombosis (DVT) and pulmonary embolism VTE is common and PE is a potentially
More informationVenous Thromboembolism Prophylaxis after Major Elective Orthopedic Surgery
Venous Thromboembolism Prophylaxis after Major Elective Orthopedic Surgery Tony Wan, MD, FRCPC Clinical Instructor, Division of General Internal Medicine Department of Medicine, University of British Columbia
More informationAdvances in oral anticoagulation treatment: the safety and efficacy of rivaroxaban in the prevention and treatment of thromboembolism
352040620712453067AGG TurpieTherapeutic Advances in Hematology 2012 Therapeutic Advances in Hematology Review Advances in oral anticoagulation treatment: the safety and efficacy of rivaroxaban in the prevention
More informationManaging the Risks Associated with Anticoagulant Therapy. Steve McGlynn Specialist Principal Pharmacist (Cardiology) NHS Greater Glasgow and Clyde
Managing the Risks Associated with Anticoagulant Therapy Steve McGlynn Specialist Principal Pharmacist (Cardiology) NHS Greater Glasgow and Clyde Background Identified as high risk medicines Wide range
More informationInhibitors of propagation of coagulation: factors V and X
British Journal of Clinical Pharmacology DOI:10.1111/j.1365-2125.2011.04001.x Inhibitors of propagation of coagulation: factors V and X Vincenzo Toschi 1 & Maddalena Lettino 2 1 Department of Hematology
More informationUW Medicine Alternative Monitoring for Antithrombotic Agents
Tags: monitoring alternative monitoring SUMMARY OF ANTICOAGULATION LAB TESTS AT UWMedicine Description Order Code Specimen Collection Availability Turn-Around Time Anti Xa Based Tests antixa for heparin
More informationNew Anticoagulants. Kenneth A. Bauer
New Anticoagulants Kenneth A. Bauer Traditional anticoagulant drugs, including unfractionated heparin and warfarin, have several limitations. New anticoagulants have been developed that target a single
More informationEvidence Update Evidence update on the use of oral anticoagulants in clinical practice
1-10 Evidence Update Evidence update on the use of oral anticoagulants in clinical practice Chandima Kulathilake 1 1Department of Pathology, Faculty of Medical Sciences, University of Sri Jayewardenepura,
More informationScottish Medicines Consortium
Scottish Medicines Consortium fondaparinux, 2.5mg/0.5ml, solution for injection (Arixtra ) No. (287/06) GlaxoSmithKline 7 July 2006 The Scottish Medicines Consortium has completed its assessment of the
More informationClinical Study Synopsis
Clinical Study Synopsis This file is posted on the Bayer HealthCare Clinical Trials Registry and Results website or on the website www.clinicalstudyresults.org hosted by the Pharmaceutical Research and
More informationReview Article New Oral Anticoagulants for Thromboprophylaxis after Elective Total Hip and Knee Arthroplasty
Thrombosis Volume 2010, Article ID 280731, 9 pages doi:10.1155/2010/280731 Review Article New Oral Anticoagulants for Thromboprophylaxis after Elective Total Hip and Knee Arthroplasty Richard J. Friedman
More information3 : 34. Pankaj Manoria, P C Manoria, Bhopal
3 : 34 Newer Antithrombins and anticoagulants Introduction Thrombosis is a leading cause of morbidity and mortality but for decades, anticoagulant therapy has usually consisted of unfractionate heparin
More informationUse of modified intention to treat analysis in studies of direct oral anticoagulants and risk of selection bias.
Use of modified intention to treat analysis in studies of direct oral anticoagulants and risk of selection bias. Tristan Rainville, MD, a Madeleine Durand, MD, MSc, b Mikhael Laskine, MD, MSc, b a Centre
More informationMark Crowther, MD, MSc, FRCPC. Co-authors. Professor of Medicine, McMaster University, Canada
Reversal of Enoxaparin-Induced Anticoagulation in Healthy Subjects by Andexanet Alfa (PRT064445), An Antidote for Direct and Indirect fxa Inhibitors A Phase 2 Randomized, Double-Blind, Placebo Controlled
More informationOverview of Reversal Agents in Development
Overview of Reversal Agents in Development Michael B Streiff, MD FACP Associate Professor of Medicine and Pathology Medical Director, Johns Hopkins Anticoagulation Service Chairman, VTE Guideline Committee,National
More informationBevyxxa (betrixaban) NEW PRODUCT SLIDESHOW
Bevyxxa (betrixaban) NEW PRODUCT SLIDESHOW Introduction Brand name: Bevyxxa Generic name: Betrixaban Pharmacological class: Factor Xa inhibitor Strength and Formulation: 40mg, 80mg; caps Manufacturer:
More informationDOACs Can Be Reversed!
1 DOACs Can Be Reversed! AC Forum 14 th National Conference April 21, 2017 Adam Cuker, MD, MS Perelman School of Medicine University of Pennsylvania 2 Full disclosures (last 12 months) Research support
More informationReal-world data confirm clinical trial outcomes for rivaroxaban in orthopaedic patients
REVIEW ARTICLE Real-world data confirm clinical trial outcomes for rivaroxaban in orthopaedic patients Louis Kwong, MD a and Alexander G.G. Turpie, MD, FRCP, FACP, FACC, FRCPC b a Department of Orthopaedic
More informationPROPHYLAXIS IN THE ORTHOPEDIC PATIENT: Martin H. Ellis MD Hematology Institute and Blood Bank Meir Medical Center Kfar Saba
VENOUS THROMBOEMBOLISM PROPHYLAXIS IN THE ORTHOPEDIC PATIENT: Martin H. Ellis MD Hematology Institute and Blood Bank Meir Medical Center Kfar Saba OVERVIEW Biochemistry of coagulation Pathogenesis of VTE
More informationDirect Oral Anticoagulants Vs. Enoxaparin for Prevention of Venous Thromboembolism Following Orthopedic Surgery: A Dose Response Meta-analysis
Citation: Clin Transl Sci (2017) 10, 260 270; C 2017 ASCPT. All rights reserved doi:10.1111/cts.12471 ARTICLE Direct Oral Anticoagulants Vs. Enoxaparin for Prevention of Venous Thromboembolism Following
More informationBETRIXABAN TO PREVENT PE, DVT, STROKE: MEDICALLY ILL PATIENTS Samuel Z. Goldhaber, MD Director, Thrombosis Research Group Section Head, Vascular
BETRIXABAN TO PREVENT PE, DVT, STROKE: MEDICALLY ILL PATIENTS Samuel Z. Goldhaber, MD Director, Thrombosis Research Group Section Head, Vascular Medicine Cardiovascular Division Brigham and Women s Hospital
More informationANTICOAGULANT THERAPY ANTICOAGULANT THERAPY REVISITED Thrombosis is a complication of underaggressive anticoagulant therapy
ANTICOAGULANT THERAPY REVISITED 2004 or, Which one(s) of these (#$%$#!@#^) drugs should be the one(s) I use, and for what? ANTICOAGULANT THERAPY One of most common treatments in hospital & out 2 nd most
More informationTHE NOVEL ORAL ANTICOAGULANTS
IDEAL ANTITHROMBOTIC AGENT THE NOVEL ORAL ANTICOAGULANTS Kristin Jochmans MD, PhD Dienst Hematologie - Universitair Ziekenhuis Brussel Efficacious (in arterial and venous disease) Safe (no toxicity low
More informationVenous thromboembolism (VTE) comprises deepvein
At a Glance Original Research Practical Implications p 107 Author Information p 110 Full text and PDF www.ajpblive.com Economic Model Comparing Rivaroxaban and Enoxaparin for Post-Orthopedic VTE Prophylaxis
More informationNew Oral Anticoagulants:
New Oral Anticoagulants: A Brief Review Joseph J. Mazza, MD, MACP; Steven H. Yale, MD, FACP ABSTRACT This manuscript represents a brief review of the current oral anticoagulants that have come on the scene
More informationThe Future of Medical Therapy for Venous Thromboemboli
Supplement issue Joseph A. Caprini, MD, MS, RVT Department of Surgery, Evanston Northwestern Healthcare, Evanston, Illinois, USA; Northwestern University Feinberg School of Medicine, Chicago, Illinois,
More informationRelative Effects of Two Different Enoxaparin Regimens as Comparators Against Newer Oral Anticoagulants. Meta-analysis and Adjusted Indirect Comparison
CHEST Original Research ANTITHROMBOTIC THERAPY Relative Effects of Two Different Enoxaparin Regimens as Comparators Against Newer Oral Anticoagulants Meta-analysis and Adjusted Indirect Comparison Chun
More informationNew Drug Evaluation: Betrixaban Capsules
Copyright 2012 Oregon State University. All Rights Reserved Drug Use Research & Management Program Oregon State University, 500 Summer Street NE, E35 Salem, Oregon 97301-1079 Phone 503-947-5220 Fax 503-947-1119
More informationStudy population The study population comprised patients undergoing major hip or knee surgery.
Pharmacoeconomic analysis of fondaparinux versus enoxaparin for the prevention of thromboembolic events in orthopedic surgery patients Dranitsaris G, Kahn S R, Stumpo C, Paton T W, Martineau J, Smith R,
More informationA BS TR AC T. n engl j med 363;26 nejm.org december 23,
The new england journal of medicine established in 1812 december 23, 2010 vol. 363 no. 26 Apixaban versus Enoxaparin for Thromboprophylaxis after Hip Replacement Michael Rud Lassen, M.D., Alexander Gallus,
More informationAntithrombotic Therapy Current Status and Future Directions. Pieter Willem Kamphuisen Vasculaire Geneeskunde AMC Amsterdam
Antithrombotic Therapy Current Status and Future Directions Pieter Willem Kamphuisen Vasculaire Geneeskunde AMC Amsterdam Disclosures Research Support Employee Consultant Current studies Wyeth, CSL Behring,
More informationA Pilot Study Comparing Hospital Readmission Rates In Patients Receiving Rivaroxaban or Enoxaparin After Orthopedic Surgery
A Pilot Study Comparing Hospital Readmission Rates In Patients Receiving Rivaroxaban or Enoxaparin After Orthopedic Surgery Melissa A. Herschman, PharmD, BCPS; Frank S. Rigelsky, PharmD, BCPS; and Sandra
More informationManaging Coagulation Abnormalities Linda Liu, M.D.
Managing Coagulation Abnormalities Professor UCSF Dept of Anesthesia UC SF 1 Difficult Task Coagulation Abnormalities 30 minutes Emphasis on 2 new oral anticoagulants Dabigatran Rivaroxaban UC SF 2 UC
More informationAnalysis of the Anticoagulant Market
MEDICAL DEVICES PHARMACEUTICALS CHEMICALS FOOD & BEVERAGE ELECTRONICS Analysis of the Anticoagulant Market VPG Publications, Consulting, Clients www.vpgcorp.com VPG Market Research Reports www.vpgmarketresearch.com
More informationDevelopment of New Anticoagulants: Present and Future
Development of New Anticoagulants: Present and Future Job Harenberg, M.D. 1 ABSTRACT Anticoagulant drugs are the most frequently hospital-prescribed compounds in many countries and are used with the intention
More informationDeep dive into anticoagulant reversal In 20 minutes so we won t dive too deep. Mark Crowther on behalf many Some slides modified from other sources
Deep dive into anticoagulant reversal In 20 minutes so we won t dive too deep Mark Crowther on behalf many Some slides modified from other sources 1 Disclosures Major disclosure: Paid consulting with Portola,
More informationCDEC FINAL RECOMMENDATION
CDEC FINAL RECOMMENDATION APIXABAN (Eliquis Bristol-Myers Squibb Canada and Pfizer Canada) Indication: Venous Thromboembolic Events Recommendation: The Canadian Drug Expert Committee (CDEC) recommends
More informationBetrixaban (Bevyxxa) A Direct-Acting Oral Anticoagulant Factor Xa Inhibitor
Betrixaban (Bevyxxa) A Direct-Acting Oral Anticoagulant Factor Xa Inhibitor Jessica W. Skelley, PharmD, BCACP; Angela R. Thomason, PharmD, BCPS; and Jeffery C. Nolen, PharmD Candidate INTRODUCTION Venous
More informationNewer oral anticoagulants for VTE and their relevance in India
Newer oral anticoagulants for VTE and their relevance in India 17/1/2014 M.Valliappan Senior Resident Department of Pulmonary Medicine Objectives Need for new drugs Individual drugs and their evidences
More informationSession 1 Topics. Vascular Phase of Hemostasis. Coagulation Pathway. Action of Unfractionated Heparin. Laboratory Monitoring of Anticoagulant Therapy
~~Marshfield Labs Presents~~ Laboratory Monitoring of Anticoagulant Therapy Session 1 of 4 Session 1 Topics Review of coagulation and the vascular phase of hemostasis Unfractionated heparin Low molecular
More informationApixaban or Enoxaparin for Thromboprophylaxis after Knee Replacement
The new england journal of medicine original article Apixaban or Enoxaparin for Thromboprophylaxis after Knee Replacement Michael Rud Lassen, M.D., Gary E. Raskob, Ph.D., Alexander Gallus, M.D., Graham
More informationThe history of anticoagulation. Mike Greaves [1949-] University of Aberdeen
The history of anticoagulation Mike Greaves [1949-] University of Aberdeen Disclosure I have avoided financial support from the pharmaceutical industry for around 7 years The history of heparin 1916 Heparin
More informationChallenges of VTE Prophylaxis in. Orthopaedics. Prevalence of DVT in Orthopaedic Surgery Without Prophylaxis
Grand Rounds Scripps Green Hospital May 5, 2010 Challenges of VTE Prophylaxis in Orthopaedics C. W. Colwell, Jr., M.D. At Scripps Clinic Challenges of VTE Prophylaxis in Orthopaedics I have a potential
More informationLina Al-Lawama. Rama Al-Ashqar. Malik Al-Zohlof
2 Lina Al-Lawama Rama Al-Ashqar Malik Al-Zohlof Anticoagulant drugs Recap Last lecture we were talking about antiplatelet drugs, we mentioned 5 drugs : Aspirin which is used alone with patents that have
More informationUP AND COMING ANTICOAGULANTS AND HEMOSTASIS AGENTS
UP AND COMING ANTICOAGULANTS AND HEMOSTASIS AGENTS Jeffrey I Weitz, MD, FRCP(C), FACP Professor of Medicine and Biochemistry McMaster University Canada Research Chair in Thrombosis Heart & Stroke Foundation/
More informationTHE MICHELANGELO OASIS 5 PROGRAM. MichelAngelo : The Creation of Man (Fragment of the Sistine Chapel ceiling- Detail) ( )
THE MICHELANGELO OASIS 5 PROGRAM MichelAngelo : The Creation of Man (Fragment of the Sistine Chapel ceiling- Detail) (1511-12) Key Steps in Coagulation Pathway Intrinsic pathway Extrinsic pathway 1 Xa
More informationReverse the New Anticoagulants? Mitchell J Daley, PharmD, BCPS
Reverse the New Anticoagulants? Mitchell J Daley, PharmD, BCPS Clinical Pharmacy Specialist, Critical Care University Medical Center Brackenridge / Dell Seton Medical Center at the University of Texas
More informationSee Important Reminder at the end of this policy for important regulatory and legal information.
Clinical Policy: (Fragmin) Reference Number: CP.PHAR.225 Effective Date: 05.01.16 Last Review Date: 02.18 Line of Business: Commercial, Medicaid Coding Implications Revision Log See Important Reminder
More informationPharmacology Lecture 5. Anticoagulants
Pharmacology Lecture 5 Anticoagulants General overview Anti-thrombotic Drugs Antiplatlets Anticoagulants Fibrinolytics Anticoagulants Indirect Thrombin Inhibitors Anti-thrombotic effect is exerted by interaction
More informationHIBOR. 1st Prophilaxis. Acute phase treatment. Pentasaccharide. Long-term 2ª ACOs UFH LMWH LMWH LMWH. Competitors
HIBOR Competitors 1st Prophilaxis LMWH Pentasaccharide Long-term Profilaxis treatment 2ª ACOs LMWH Acute phase treatment UFH LMWH Unfractionated heparin (UFH) Discovered by J. Mc Lean in 1916. Later named
More informationApheresis Anticoagulant Removal. Oluwatoyosi Onwuemene, MD MS May 6th, 2017
Apheresis Anticoagulant Removal Oluwatoyosi Onwuemene, MD MS May 6th, 2017 Talk Outline Case presentation Factors associated with drug removal TPE s effects on hematologic parameters Anticoagulant properties
More informationThe legally binding text is the original French version TRANSPARENCY COMMITTEE OPINION. 18 January 2012
The legally binding text is the original French version TRANSPARENCY COMMITTEE OPINION 18 January 2012 ELIQUIS 2.5 mg, film-coated tablets B/10 (CIP code: 419 454-4) B/20 (CIP code: 419 455-0) B/60 (CIP
More informationLinking in silico and in vitro experiments to identify and evaluate a biomarker for enoxaparin activity
Linking in silico and in vitro experiments to identify and evaluate a biomarker for enoxaparin activity Abhishek Gulati What is enoxaparin? Low molecular weight heparin anticoagulant Used to minimise the
More informationVenous thromboembolism (VTE) Can Biomarkers Help to Guide Duration of Therapy After VTE? New Chest Guidelines 2016
Venous thromboembolism (VTE) Can Biomarkers Help to Guide Duration of Therapy After VTE? Marlene Grenon, MD Associate Professor of Surgery University of California San Francisco UCSF Vascular Surgery Symposium
More informationDrug Monograph. Metabolism CYP-independent hydrolysis
Drug Monograph Brand Name: Bevyxxa Generic Name: Betrixaban Manufacturer 1-3 : Portola Pharmaceuticals, Inc Available as 40 and 80mg capsules ($1,800 for #100) Drug Class 1-3 : Direct Oral Anticoagulant
More informationA specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa
A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa Lu G, Deguzman FR, Hollenbach SJ, et al. Department of Biology, Portola Pharmaceuticals Inc.,
More informationSR123781A: A New Once-Daily Synthetic Oligosaccharide Anticoagulant for Thromboprophylaxis After Total Hip Replacement Surgery
Journal of the American College of Cardiology Vol. 51, No. 15, 2008 2008 by the American College of Cardiology Foundation ISSN 0735-1097/08/$34.00 Published by Elsevier Inc. doi:10.1016/j.jacc.2008.03.007
More informationApixaban versus Enoxaparin for Thromboprophylaxis in Medically Ill Patients
original article Apixaban versus for Thromboprophylaxis in Medically Ill Patients Samuel Z. Goldhaber, M.D., Alain Leizorovicz, M.D., Ajay K. Kakkar, M.D., Ph.D., Sylvia K. Haas, M.D., Ph.D., Geno Merli,
More informationFactor Xa or thrombin: is factor Xa a better target?
Journal of Thrombosis and Haemostasis, 5 (Suppl. 1): 60 64 INVITED REVIEW Factor Xa or thrombin: is factor Xa a better target? J. ANSELL Boston University School of Medicine, Boston, MA, USA To cite this
More informationManagement of Bleeding in the Anticoagulated Patient Short Snappers CSIM 2015 Elizabeth Zed, MD, FRCPC October 17, 2015
+ Management of Bleeding in the Anticoagulated Patient Short Snappers CSIM 2015 Elizabeth Zed, MD, FRCPC October 17, 2015 + Disclosures Off label use of PCC and apcc will be discussed My centre participates
More informationAdvances in the Treatment and Prevention of Venous Thromboembolism The New World After Heparin
Advances in the Treatment and Prevention of Venous Thromboembolism The New World After Heparin ROBERT J. GOTTLIEB, M.D. Hematology/Oncology Physicians of Lancaster ABSTRACT Venous thromboembolism (VTE)
More informationBivalirudin (Angiomax ) vs. Heparin during Peripheral Vascular Interventions: Which is Better and How to Decide?
Bivalirudin (Angiomax ) vs. Heparin during Peripheral Vascular Interventions: Which is Better and How to Decide? Vinod Nair MD FACC FSCAI Cardiovascular Ins6tute of the South, Houma Financial Disclosure:
More informationArt by C. Michael Gibson, MS, MD
P o rto l a 2 0 14 the art of science for the benefit of patients Art by C. Michael Gibson, MS, MD creating innovation. breakthrough medicines. value. creating a growth company 100+ strong Portola Pharmaceuticals
More informationTHE PHARMA INNOVATION - JOURNAL Dabigatran Etexilate: A Drug Update
Received: 25-02-2013 Accepted: 26-04-2013 ISSN: 2277-7695 CODEN Code: PIHNBQ ZDB-Number: 2663038-2 IC Journal No: 7725 Vol. 2 Issue 3 2013 Online Available at www.thepharmajournal.com THE PHARMA INNOVATION
More informationSee Important Reminder at the end of this policy for important regulatory and legal information.
Clinical Policy: (Arixtra) Reference Number: CP.PHAR.226 Effective Date: 05.01.16 Last Review Date: 02.19 Line of Business: Commercial, HIM-Medical Benefit, Medicaid Coding Implications Revision Log See
More informationTuesday, March 20, Oppenheimer & Co. Annual Healthcare Conference
ca Tuesday, March 20, 2018 Oppenheimer & Co. Annual Healthcare Conference Forward-Looking Statements This presentation contains forward-looking statements within the meaning of the Private Securities Litigation
More informationNew anticoagulants for the prevention and treatment of venous thromboembolism
REVIEW New anticoagulants for the prevention and treatment of venous thromboembolism Simon J McRae Jeffrey S Ginsberg Department of Medicine, McMaster University, Hamilton, ON, Canada Abstract: Anticoagulant
More informationIn Hospital Bleeding Management
In Hospital Bleeding Management Geno J Merli, MD, MACP, FSVM, FHM Professor Medicine & Surgery Co-Director Jefferson Vascular Center Sidney Kimmel Medical College Thomas Jefferson University Hospitals
More informationSee Important Reminder at the end of this policy for important regulatory and legal information.
Clinical Policy: (Arixtra) Reference Number: CP.PHAR.226 Effective Date: 07.01.18 Last Review Date: 02.18 Line of Business: Oregon Health Plan Coding Implications Revision Log See Important Reminder at
More informationOTE. Betrixaban: A New Oral Anticoagulant for Extended- Duration Thromboprophylaxis. Vol. 33, Issue 8 May Established 1985
HAR Vol. 33, Issue 8 May 2018 M A N OTE Established 1985 : A New Oral Anticoagulant for Extended- Duration Thromboprophylaxis Justin Muklewicz, harmd Candidate in this issue : A New Oral Anticoagulant
More informationDo novel oral anticoagulants do better than standard therapy in the treatment of deep vein thrombosis?
Review 218 Do novel oral anticoagulants do better than standard therapy in the treatment of deep vein thrombosis? M. Brodmann Division of Angiology, Medical University Graz, Austria Keywords Deep vein
More informationDose Selection in Drug Development and Regulation: Possible Future Direction. Richard Lalonde and Donald Stanski Pfizer and AstraZeneca
Dose Selection in Drug Development and Regulation: Possible Future Direction Richard Lalonde and Donald Stanski Pfizer and AstraZeneca Overview What is the problem and how did we get here Examples of the
More informationMehta Hiren R et al. IRJP 2 (4)
INTERNATIONAL RESEARCH JOURNAL OF PHARMACY ISSN 2230 8407 Available online http://www.irjponline.com Review Article XIMELAGATRAN: A NEW DIRECT THROMBIN INHIBITOR Mehta Hiren R 1 *, Patel Paresh B 2, Galani
More informationAnticoagulants are widely used for the prevention and
Review Translational Success Stories highlight how basic discoveries have led to clinical advances, such as the use of new drugs or diagnostic modalities in patients. This initiative reflects the renewed
More informationRIVAROXABAN FOR THE PREVENTION OF VENOUS THROMBOEMBOLISM
RIVAROXABAN FOR THE PREVENTION OF VENOUS THROMBOEMBOLISM Produced by Authors School of Health and Related Research (ScHARR), The University of Sheffield Matt Stevenson, Senior Operational Researcher, ScHARR,
More informationHemostasis/Thrombosis IV
Hemostasis/Thrombosis IV Antithrombotic Therapy Antithrombotic Therapy Mainstay of battle against thromboembolic disease Hot area of new drug research Cannot inhibit clot formation without increased risk
More informationOral Rivaroxaban for Symptomatic Venous Thromboembolism
T h e n e w e ngl a nd j o u r na l o f m e dic i n e original article Oral for Symptomatic Venous Thromboembolism The EINSTEIN Investigators* A BS TR AC T Background, an oral factor Xa inhibitor, may
More informationVenous thromboembolism (VTE) is a common complication
Enoxaparin Versus Dabigatran or Rivaroxaban for Thromboprophylaxis After Hip or Knee Arthroplasty Results of Separate Pooled Analyses of Phase III Multicenter Randomized Trials Menno V. Huisman, MD, PhD*;
More information