Non-vitamin K antagonist oral anticoagulants in cardiovascular disease management: evidence and unanswered questions

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1 Journal of Clinical Pharmacy and Therapeutics, 2014, 39, doi: /jcpt Review Article Non-vitamin K antagonist oral anticoagulants in cardiovascular disease management: evidence and unanswered questions J. W. Cheng* PharmD, MPH and G. Barillari MD *MCPHS University, Brigham and Women s Hospital, Boston, MA, USA and Centre for Haemorrhagic and Thrombotic Diseases, University Hospital, Udine, Udine, Italy Received 24 January 2013, Accepted 27 November 2013 Keywords: apixaban, dabigatran, rivaroxaban, thromboembolic disorders SUMMARY What is known and objective: Anticoagulation is important in the management of cardiovascular disorders; however, traditional anticoagulants such as heparins and vitamin K antagonists (VKAs) have limitations, including parenteral administration with the former and the need for coagulation monitoring and dose adjustments with the latter. Three non- VKA oral anticoagulants (OACs), dabigatran, rivaroxaban and apixaban, are available for the prevention of stroke in patients with atrial fibrillation (AF) and may change clinical practice. This article reviews current knowledge and important unanswered questions on the use of these agents in patients with cardiovascular disease. Methods: A literature search was performed using PubMed and the search terms dabigatran, rivaroxaban, apixaban, AF and acute coronary syndrome (ACS). Peer-reviewed, published clinical trials, review articles, relevant treatment guidelines and prescribing information documents were identified and reviewed for relevance. Results and discussion: Dabigatran is an oral direct thrombin inhibitor; rivaroxaban and apixaban are oral direct Factor Xa inhibitors. These agents have a quicker onset and offset of action, more predictable pharmacokinetic and pharmacodynamic profiles, and fewer drug drug interactions than VKAs, allowing use of fixed doses. For the prevention of stroke in patients with AF, the non-vka OACs were either non-inferior or superior to warfarin with similar or improved bleeding profiles, particularly with respect to reductions in intracranial haemorrhage. In patients with ACS receiving dual antiplatelet therapy, the addition of rivaroxaban significantly reduced the rate of death from cardiovascular causes, myocardial infarction or stroke without increasing fatal bleeding, but led to higher rates of major bleeding. Dose reductions with non-vka OACs are mandated in certain circumstances in patients with AF, such as moderate renal impairment. Contraindications include creatinine clearance <15 ml/min (<30 ml/min for dabigatran in Europe and Canada) and moderate or severe hepatic impairment, but patients can be transitioned to other anticoagulants if appropriate. It is unknown which non-vka OAC is optimal for stroke prevention in patients with AF, although factors such as Correspondence: J. W. Cheng, MCPHS University, 179 Longwood Avenue, Boston, MA , USA. Tel.: ; fax: ; judy.cheng@mcphs.edu co-medications (e.g. dabigatran may be preferred if a patient is taking a co-medication that is a strong cytochrome P450 3A4 inhibitor) and renal function (rivaroxaban and apixaban depend less on renal clearance than dabigatran) will be important for individual patients. Addition of rivaroxaban to antiplatelet therapy for prevention of recurrent events in patients with recent ACS is approved in Europe for patients at the highest risk (with elevated cardiac biomarkers) and must take into account the increased risk of major bleeding. Although routine coagulation monitoring is not required, an understanding of which assays are appropriate for each non-vka OAC and how they are affected is important. In a bleeding emergency, non-specific prohaemostatic agents are suggested to reverse the action of the non-vka OACs, but more clinical data are needed. What is new and conclusion: Non-VKA OACs provide similar or improved efficacy and, on current evidence, improved safety. They provide greater convenience, compared with traditional anticoagulants for the prevention of stroke in patients with AF. Rivaroxaban may be of benefit to selected high-risk patients with ACS. Selection of the most appropriate non-vka OAC will depend on individual patient factors. WHAT IS KNOWN AND OBJECTIVE Atrial fibrillation (AF) and acute coronary syndrome (ACS) are prevalent and serious conditions. Along with venous thromboembolism (VTE) and stroke, ACS is a common cause of cardiovascular mortality, 1 and AF the most common cardiac dysrhythmia 2 is associated with increased cardiovascular mortality, stroke and hospitalization. 3 Anticoagulants are pivotal in the management of thromboembolic diseases. Until recently, vitamin K antagonists (VKAs), of which warfarin and acenocoumarol are the most commonly used, were the only oral anticoagulants (OACs) available for the prevention of stroke in patients with AF, but interpatient variability in dose response, slow onset and offset of action, and extensive drug and food interactions complicate their use. 4 The 9th edition of the American College of Chest Physicians (ACCP) evidence-based clinical practice guidelines on antithrombotic and thrombolytic therapy recommends non-vka OACs for patients with non-valvular AF and an intermediate-to-high risk of stroke. 5 VKAs have not routinely been used in patients after ACS events. Currently, dual antiplatelet therapy with acetylsalicylic acid (ASA) plus a thienopyridine, such as clopidogrel, is the standard management strategy for the treatment of these patients. However, because recurrence rates are 2014 John Wiley & Sons Ltd 118

2 still high, the potential of anticoagulants to improve outcomes has been investigated. Recently, three direct non-vka OACs have become available in Europe, the United States (US) and Canada for the prevention of stroke and systemic embolism in patients with AF (Table 1). Dabigatran etexilate is an oral, direct thrombin inhibitor, 6 8 whereas rivaroxaban and apixaban are both oral, direct Factor Xa inhibitors Rivaroxaban has also recently been approved in the European Union (EU) for prevention of atherothrombotic events in patients with a recent ACS event and elevated biomarkers. 15 This review will discuss the pharmacology of the non-vka OACs, and consider their potential role in the management of AF and ACS and the practical application of these agents in clinical practice. METHODS Peer-reviewed clinical trials, review articles and relevant treatment guidelines were identified from MEDLINE and Current Content database (both 1966 to July 2013) using the search terms apixaban, dabigatran, rivaroxaban, atrial fibrillation, acute coronary syndrome, pharmacokinetics and pharmacodynamics. Prescribing information documents from the EU, Canada and the United States were reviewed. Citations from available articles and congress abstracts were reviewed for additional references; however, only randomized, phase III clinical trials are discussed. MECHANISM OF ACTION AND CLINICAL PHARMACOLOGY Mechanism of action of non-vitamin K antagonist oral anticoagulants VKAs target several non-activated factors in the coagulation cascade, whereas non-vka OACs inhibit single, specific, activated factors (Fig. 1). Unlike heparins and the indirect Factor Xa inhibitor fondaparinux, they do not require antithrombin to exert their effect. 16 Dabigatran is a selective, direct thrombin (Factor IIa) inhibitor that is administered orally as a prodrug (dabigatran etexilate) and has a low affinity for, and inhibitory activity against, other enzymes in the coagulation cascade. 17 Dabigatran prevents the conversion of fibrinogen into fibrin and thrombus formation. 6 Rivaroxaban and apixaban are oral, selective, direct, reversible Factor Xa inhibitors. 18,19 They inhibit free, prothrombinase-bound and clot-bound Factor Xa by binding directly and selectively to the active site of the serine endopeptidase, preventing thrombin generation. 18,20 Factor IIa and Factor Xa were chosen as targets for the non-vka OACs because these factors are found at or after the common junction of the intrinsic and extrinsic coagulation pathways (Fig. 1). 16 Pharmacokinetics Selected pharmacokinetic parameters and chemical structures for dabigatran etexilate, rivaroxaban and apixaban are shown in Table 1. Oral dabigatran etexilate is absorbed rapidly but has low oral bioavailability. 21 In the liver, the prodrug dabigatran etexilate is converted into its active metabolite, dabigatran, by esterase-catalysed hydrolysis. 6 Approximately 20% of dabigatran is conjugated by glucuronosyltransferases to active glucuronide conjugates. Unabsorbed dabigatran etexilate is excreted in the faeces after oral administration, whereas dabigatran absorbed into the blood is removed via the kidneys. 21 Rivaroxaban is absorbed rapidly and, unlike dabigatran, does not require a prodrug because of high oral bioavailability. 22 Elimination is rapid, with no pharmacologically active circulating metabolites detected in plasma. 23 Approximately two-thirds of the administered dose is metabolized to inactive metabolites, with half then excreted renally and the other half via the hepatobiliary route. The remaining one-third of the rivaroxaban dose undergoes direct renal excretion as unchanged drug in the urine. 23 Apixaban also has a high bioavailability after oral administration. 12,24 The clearance of apixaban is balanced between metabolism by cytochrome P450 (CYP) 3A4 to inactive metabolites and intestinal (~46 56%), renal (~24 29%) and biliary (<3%) excretion. 12,24 Thus, the proportion of active drug cleared by renal mechanisms for rivaroxaban and apixaban is considerably less than for dabigatran, which has implications for dosing in patients with renal impairment. By comparison, VKAs are almost entirely excreted via metabolic processes. 12 The influence of key patient demographic factors is summarized in Table 1. Female subjects have approximately 40 50% higher exposure to dabigatran etexilate compared with males, 6 probably caused by gender-related differences in muscle mass which affect creatinine clearance (CrCl). 25 Pharmacokinetics were similar between Japanese and Caucasian patients. 26 Moderate hepatic impairment (Child Pugh B) does not affect the pharmacokinetics of dabigatran etexilate. 27 In subjects with severe renal impairment (CrCl < 30 ml/min), the mean terminal elimination half-life was double that of healthy volunteers with normal renal function (28 vs 14 h, respectively). 28 The extent of absorption of dabigatran etexilate is similar when taken with and without food. 6 Rivaroxaban was found to have predictable pharmacokinetics across a wide range of doses in healthy volunteers and patients undergoing total hip or knee replacement. 22,29,30 Age, 31,32 gender, 32,33 extremes of body weight 34 and mild (Child Pugh A) hepatic impairment 9,35 do not affect the pharmacokinetics of rivaroxaban to a clinically relevant extent. Parameters are also broadly similar between Caucasian and Chinese subjects, 33,36 although modelling data in Japanese patients with AF indicated a higher exposure compared with Caucasian patients for a 20 mg dose. 37 Exposure increased with decreasing renal function compared with controls, whereas maximum plasma concentration (C max ) was relatively unaffected. 38 Taking 10 mg rivaroxaban with food does not significantly affect rivaroxaban pharmacokinetics 9 ; however, decreased bioavailability and absorption rate with increasing dose led to lower C max and area under the concentration time curve (AUC) in the fasted state. 39,40 This does not occur when doses of rivaroxaban greater than 10 mg are taken with food. 9,41 For apixaban, moderate increases in exposure resulting from low body weight, 42 female gender and age older than 65 years have been reported, 12 whereas ethnicity did not affect apixaban pharmacokinetics. 12 Exposure increased with decreasing renal function. 12 Mild or moderate (Child Pugh A or B) hepatic impairment does not appear to affect apixaban pharmacokinetics, 12 and food does not affect its absorption. 43 Overall, dabigatran, rivaroxaban and apixaban have predictable pharmacokinetics with effects caused by normal demographic variables that are largely not of clinical relevance and modest compared with VKAs. There are relevant specific effects (e.g. increasing exposure with decreasing renal function, food effect with rivaroxaban) that must be taken into account, but fixed doses can be given without the need for routine coagulation monitoring in most patients. Conversely, VKAs exhibit high interindividual 119

3 Table 1. Pharmacokinetic parameters of dabigatran etexilate, rivaroxaban and apixaban in healthy adults (median values given to nearest integer) Dabigatran etexilate Rivaroxaban Apixaban Pradaxa â /Pradax â (Boehringer Ingelheim) Xarelto â (Bayer HealthCare/ Janssen Pharmaceuticals) Eliquis â (Bristol-Myers Squibb/Pfizer) Chemical structure Approval date (year. month) for patients with AF (EU/Canada/US) / / / / / / Other licensed indications Prevention of VTE in patients undergoing hip or knee replacement surgery (EU/ Canada only) Prevention of VTE in patients undergoing hip or knee replacement surgery Treatment of DVT and PE and prevention of recurrent DVT and PE Prevention of recurrent events in patients with recent ACS (combined with antiplatelets; EU only) Prodrug Yes No No Absolute bioavailability (%) a, Maximum concentration (ng/ml) 110 b, a 173 c, c,24 Time to maximum concentration (h) Apparent half-life (h) ~12 12 Prevention of VTE in patients undergoing hip or knee replacement surgery (EU/Canada only) Apparent clearance (L/h) Renal excretion (%) 85 d,6 66 e, Population pharmacokinetic effects Age, gender, body weight and ethnicity Increased exposure with age >75 years; 40 50% increase in exposure for women vs men 6 No relevant effects 9 ; higher exposure in Japanese vs Caucasian patients with AF for 20 mg dose 37 Moderate/no effects 12,42 Renal function Half-life doubled with CrCl 30 ml/min Exposure increased by 44%, 52% and 64% for vs controls 28 CrCl 50 79, and <30 ml/min, respectively, vs controls 38 Exposure increased by 16%, 29% and 44% for CrCl 51 80, and ml/min, respectively, vs controls 12 (continued) 120

4 Table 1 (continued) Apixaban Rivaroxaban Dabigatran etexilate Eliquis â (Bristol-Myers Squibb/Pfizer) Xarelto â (Bayer HealthCare/ Janssen Pharmaceuticals) Pradaxa â /Pradax â (Boehringer Ingelheim) No relevant effect with mild/moderate impairment (Child Pugh A/B) 12 Hepatic function No relevant effect with mild/moderate impairment (Child Pugh A/B) 6,27 No relevant effect with mild impairment (Child Pugh A); relevant increase in pharmacodynamic effect with moderate impairment (Child Pugh B) 9,35 No effect 43 Food No effect on bioavailability but increases time Nonlinear absorption with increasing doses to maximum concentration by 2 h 6 above 10 mg in fasted state 39,40 ; corrected by taking dose with food 9,41 a 10 mg oral dose. b 150 mg oral dose. c 20 mg oral dose. d After intravenous administration. e 50% active drug, 50% inactive metabolites. ACS, acute coronary syndrome; AF, atrial fibrillation; CrCl, creatinine clearance; DVT, deep vein thrombosis; EU, European Union; PE, pulmonary embolism; US, United States; VTE, venous thromboembolism. pharmacokinetic variability and require regular monitoring and dose adjustments. 16 Pharmacodynamics Maximum thrombin inhibition with dabigatran occurs concurrently with C max after dosing, and inhibition is maintained for at least 8 h. 44 In healthy volunteers, time curves for activated partial thromboplastin time (aptt), prothrombin time (PT), thrombin time and ecarin clotting time (ECT) were prolonged in a dosedependent manner after dabigatran treatment, and thrombin time and ECT exhibited the greatest sensitivity and correlation with dose. 44 Age, hepatic dysfunction and renal impairment did not affect the pharmacodynamic response to dabigatran. 27,28,45 A chromogenic assay for dabigatran (Hyphen BioMed, Neuville-sur- Oise, France) is now available. 46 Routine use of this assay for clinical monitoring of dabigatran should be investigated further. Rivaroxaban inhibits Factor Xa activity in a dose-dependent manner, with maximum inhibition occurring approximately 3 h after dosing. 29 Inhibition of Factor Xa is maintained for approximately 12 h after doses of 10, 20 and 30 mg. 29 Prolongation (in seconds) of median PT and aptt (to a lesser degree) is also dose dependent, 29 and the extent of PT prolongation depends on the thromboplastin reagent used. 47 If PT is used, prolongation should be read in seconds, and the international normalized ratio (INR) should not be used. Factor Xa-specific chromogenic assays are able to quantitatively measure rivaroxaban exposure with dosedependent results, provided appropriate calibration over a wide range of plasma concentrations is performed. 48 Of these, the COAMATIC â Heparin (DiaPharma, West Chester, OH, USA), Technochrom â anti-xa (Technoclone, Vienna, Austria) and modified STA â Rotachrom â (Diagnostica Stago, Asnieres-sur-Seine, France) assays have been shown to provide accurate results over a wide range of rivaroxaban concentrations. 49,50 Maximum anti- Factor Xa inhibition with apixaban is reached with C max after 3 4 h, and inhibition is maintained throughout the dosing interval. 12 Apixaban prolongs aptt and PT, but these changes are small and variable. By contrast, anti-factor Xa chromogenic assays, such as STA Rotachrom, are sensitive to apixaban, with plasma concentrations exhibiting a linear and reproducible correlation with anti-factor Xa activity. 12 Renal impairment and mild-to-moderate hepatic impairment appear not to impact this relationship. Overall, compared with warfarin, the non-vka OACs have a rapid onset and offset of action (within a few hours of initiating or discontinuing treatment); warfarin takes at least 24 h to have an effect on patients and requires up to 5 days to wash out. 12 Quantitative, calibrated Factor IIa and Factor Xa assays are probably the optimal means of monitoring anticoagulant activity, although an appropriate generic coagulation assay may be used if properly calibrated. Conversion of the results of the latter to an INR value is not appropriate for any non-vka OAC because the INR is calibrated specifically for use with VKAs. However, routine monitoring should not be necessary in most clinical circumstances if non-vka OACs are used in patients similar to those enrolled in clinical trials, because of the predictable pharmacodynamic effects of these agents. Drug interactions Drug interactions are summarized in Table 2. Dabigatran etexilate, but not dabigatran, is a substrate of P-glycoprotein (P-gp); neither 121

5 Fig. 1. The coagulation cascade and targets of VKAs, non-vka OACs and AP agents. Common VKAs include warfarin, acenocoumarol and phenprocoumon. Heparins: unfractionated heparin, low molecular weight heparins (e.g. enoxaparin, dalteparin, nadroparin, tinzaparin, certoparin, reviparin, ardeparin, panaparin, bemiparin). Common APs include acetylsalicylic acid, thienopyridines (e.g. clopidogrel, ticlopidine, prasugrel) and ticagrelor. Coagulation factors are designated by Roman numerals, and the suffix a indicates the active form. AP, antiplatelet; AT, antithrombin; OAC, oral anticoagulant; TF, tissue factor; VKA, vitamin K antagonist dabigatran etexilate nor dabigatran is metabolized by the CYP system, nor do they appear to inhibit or induce CYP enzyme activity. 6 According to the European Summary of Product Characteristics, dabigatran etexilate does not significantly affect the pharmacokinetics of atorvastatin, digoxin or diclofenac or vice versa. 6 Concomitant administration of the proton pump inhibitor pantoprazole led to a decrease in the mean AUC of approximately 30%, but this was not considered clinically relevant. 6 Ranitidine did not reduce the bioavailability of dabigatran etexilate. 6 Dabigatran and clopidogrel had no clinically relevant pharmacokinetic or pharmacodynamic effects on each other. However, if a loading dose of clopidogrel (300 mg or 600 mg) was administered, dabigatran AUC and C max at steady state increased by 30 40%. 51 For drug interactions with P-gp inducers and inhibitors, the maximum increase in dabigatran bioavailability was observed with ketoconazole (~150%). 6 After multiple dosing of verapamil (120 mg twice or four times daily), there was a 50 60% increase in dabigatran bioavailability. Consistent with all interactions between dabigatran etexilate and P-gp inhibitors, which should occur primarily in the gut, when verapamil was administered 2 h before dabigatran etexilate intake, there was only a marginal (<20%) increase in dabigatran bioavailability. 52 Clarithromycin did not significantly affect dabigatran pharmacokinetics. 6 However, after 7 days of pretreatment with rifampicin (600 mg once daily [od]), dabigatran AUC and C max were reduced by 66% and 67%, respectively. These parameters returned to dabigatran-only values 7 days after cessation of rifampicin. 53 Rivaroxaban is eliminated via CYP3A4- and P-gp-dependent pathways. 54 Because of a potential increase in exposure and pharmacodynamic effects, the concomitant use of rivaroxaban with strong inhibitors of both CYP3A4 and P-gp (e.g. ketoconazole and ritonavir) should be avoided. 9,55 Substances that strongly inhibit only one rivaroxaban elimination pathway and those that moderately inhibit both pathways have a lesser effect. Caution should be used when administering rivaroxaban with strong CYP3A4 inducers (e.g. rifampicin) because of the potential reduction in rivaroxaban plasma concentrations. 9,55 Rivaroxaban absorption was not affected by changes in gastric ph induced by ranitidine or antacid, 40 nor were the pharmacokinetics of rivaroxaban affected by digoxin or atorvastatin. 56 Administration of 500 mg naproxen with rivaroxaban does not appear to prolong bleeding time to a clinically significant extent compared with naproxen alone, but some individuals may experience a more pronounced pharmacodynamic response (i.e. increased risk of bleeding). 57 The bioavailability and pharmacokinetics of rivaroxaban do not appear affected by the concomitant administration of clopidogrel (300 mg loading dose, followed by 75 mg maintenance dose), although a clinically relevant increase in bleeding time was observed. 58 No clinically relevant pharmacodynamic interaction was observed with the co-administration of rivaroxaban and ASA compared with ASA alone (ASA 500 mg loading dose, followed by 100 mg the day after). 59 Compared with enoxaparin, rivaroxaban has a similar and rapid onset of action, and the combination of both these agents was associated with enhanced pharmacodynamic effects. 60 One study in healthy volunteers demonstrated that rivaroxaban did not interact with midazolam, and rivaroxaban exposure was only moderately affected by co-administration with erythromycin, clarithromycin and fluconazole. 55 Rivaroxaban was able to be co-administered with CYP3A4 and/or P-gp substrates or moderate inhibitors but not with strong combined CYP3A4, P-gp and breast cancer resistance protein inhibitors such as azole antimycotics

6 Table 2. Summary of drug interactions with the non-vka oral anticoagulants Name of concomitant drug Dabigatran etexilate (P-gp substrate) Rivaroxaban (CYP3A4 and P-gp substrate) Apixaban (CYP3A4 and P-gp substrate) Azole antimycotics Ketoconazole Clinically relevant increase in dabigatran exposure. 6 Concomitant administration of P-gp inhibitors (e.g. amiodarone, verapamil, quinidine, ketoconazole, dronedarone, clarithromycin and ticagrelor) is expected to result in increased dabigatran plasma concentrations Clinically relevant increase in rivaroxaban PK/PD effects; avoid co-administration of rivaroxaban and ketoconazole, itraconazole, voriconazole or posaconazole or any other strong inhibitors of both CYP3A4 and P-gp 9,55 Fluconazole No clinically relevant effects 9,55 HIV protease inhibitors Ritonavir Clinically relevant increase in rivaroxaban PK/PD effects; avoid co-administration with ritonavir or other HIV protease inhibitors (and other strong inhibitors of both CYP3A4 and P-gp) 55 Anti-infectives Erythromycin No clinically relevant effects 55 Clarithromycin Clinically relevant effects cannot be exluded 6 No clinically relevant effects 55 Rifampicin Anticoagulants Enoxaparin Warfarin Decrease in dabigatran exposure and maximum concentration with steady-state rifampicin 6 Non-steroidal anti-inflammatory/antiplatelet drugs Diclofenac No effect 6 Naproxen Acetylsalicylic acid Clopidogrel Possible increased gastrointestinal bleeding risk 6 No clinically relevant PK/PD effects at steady state 6 Potentially relevant decrease in rivaroxaban PK/PD effects; strong CYP3A4 inducers (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital or St John s wort) should be administered with rivaroxaban with caution 9 No PK effect but additive PD effect could lead to increased risk of bleeding 60 No PK effect but additive PD effect could lead to increased risk of bleeding 9 No PK effect but some individuals may have more pronounced PD responses 57 No clinically relevant interaction but potential for increased risk of bleeding 9,59 No overall PK/PD effect but a relevant increase in bleeding time was observed in a subset of patients 9,58 Cardiac drugs Atorvastatin No clinically relevant effect 6 No clinically relevant effect 56 Digoxin No clinically relevant effect 6 No clinically relevant effect 56 Verapamil Increase in dabigatran bioavailability and exposure of potential clinical relevance 6 Clinically relevant increase in apixaban PK/PD effects; avoid co-administration of apixaban and any strong inhibitors of both CYP3A4 and P-gp 12 Potentially relevant decrease in apixaban exposure and maximum concentration with steady-state rifampicin 12 Additive PD effect could lead to increased risk of bleeding 12 Non-clinically relevant increase in apixaban exposure 12 No clinically relevant effect but potential for increased risk of bleeding 12 No clinically relevant interaction 12 Expected increase in apixaban exposure and maximum concentration (but to a lesser extent than strong combined CYP3A4 and P-gp inhibitors) 12 Atenolol No clinically relevant effect 12 Stomach acid regulators Pantoprazole No clinically relevant effect 6 Ranitidine No clinically relevant effect 6 No clinically relevant effect 40 Sedatives Midazolam No clinically relevant effect 55 Diltiazem Increase in apixaban exposure and maximum concentration (but to a lesser extent than strong combined CYP3A4 and P-gp inhibitors) 12 Famotidine No clinically relevant effect 61 CYP3A4, cytochrome P450 3A4; HIV, human immunodeficiency virus; P-gp, P-glycoprotein; PD, pharmacodynamics; PK, pharmacokinetics; VKA, vitamin K antagonist. 123

7 Similar to rivaroxaban, apixaban is a substrate of CYP3A4 and P-gp, but is not a major inhibitor or inducer of either. 12 Co-administration of the CYP3A4 and P-gp inducer rifampicin (oral 600 mg od) with 10 mg oral apixaban resulted in 54% and 42% lower apixaban AUC and C max, respectively. A single dose of 100 mg atenolol also reduced exposure to 10 mg apixaban, lowering C max and AUC by 18% and 15%, respectively. Co-administration of 400 mg od oral ketoconazole and apixaban produced a 16-fold increase in apixaban C max and a 2-fold increase in AUC. 12 The administration of 360 mg od oral diltiazem with a single oral dose of 10 mg apixaban resulted in a 13-fold and 14 fold increase in apixaban C max and AUC, respectively. 12 Concomitant administration of a 500 mg single dose of naproxen and apixaban led to 16-fold and 15-fold increases in C max and AUC, respectively. 12 Co-administration of apixaban and enoxaparin did not affect enoxaparin activity. Pharmacokinetic and pharmacodynamic analyses of concomitant apixaban and ASA, either alone (325 mg) or in combination with 75 mg clopidogrel (162 mg ASA), did not reveal a significant interaction. 12 Famotidine, a gastric acid suppressant, did not affect the pharmacokinetics of apixaban. 61 Overall, the non-vka OACs have a considerably lower potential for food and drug interactions compared with VKAs. 16 The most important drugs to avoid with non-vka OACs are drugs that strongly compete with both elimination pathways (CYP3A4 and P-gp) for the Factor Xa inhibitors and the P-gp pathway for dabigatran. Co-administration with other anticoagulants would be expected to have an additive pharmacodynamic effect and increase bleeding risk and should be avoided unless switching between agents PHASE III CLINICAL TRIALS OF DIRECT ORAL ANTICOAGULANTS IN CARDIOVASCULAR DISEASE Prevention of stroke and systemic embolism in patients with atrial fibrillation Phase III trials conducted in patients with non-valvular AF, who were receiving non-vka OACs, were all randomized, parallelgroup, active-control studies. The RE-LY trial was a noninferiority study of blinded dabigatran [110 mg twice daily (bid) or 150 mg bid] compared with open-label dose-adjusted warfarin (Table 3). 62 The ROCKET AF trial was an open-label, non-inferiority study that compared 20 mg od rivaroxaban (15 mg od in patients with CrCl ml/min) with doseadjusted warfarin. 63 The ARISTOTLE trial was a double-blind, non-inferiority study, in which patients received either apixaban (5 mg bid, or 25 mg bid in selected patients) or dose-adjusted warfarin. 64 A second apixaban trial (AVERROES) was a doubleblind superiority study that compared 5 mg bid apixaban (25 mg bid in selected patients) with ASA ( mg at the investigator s discretion) in patients that warfarin was unsuccessful in or in patients who were unsuitable for warfarin. 65 All four studies included patients with one or more risk factors for stroke. The mean CHADS 2 score was 21 for the ARISTOTLE, AVERROES and RE-LY trials, but was higher for patients in ROCKET AF (35) Efficacy events. In RE-LY, the lower dose of dabigatran (110 mg bid) was non-inferior to warfarin for the primary endpoint of stroke or systemic embolism, whereas the higher dose (150 mg bid) was superior. The rate of haemorrhagic stroke was significantly lower for both dabigatran doses. 62 A long-term, multicentre extension of dabigatran treatment in patients who completed RE-LY (RELY-ABLE) reported a higher rate of major bleeding with 150 mg bid dabigatran compared with 110 mg bid and similar rates of stroke and death after a further 23 years of treatment (Table 3). 66 In ROCKET AF, patients with non-valvular AF received either 20 mg od rivaroxaban (15 mg od in patients with CrCl ml/min) or warfarin adjusted to therapeutic INR. 20 mg od rivaroxaban was non-inferior to warfarin for the prevention of stroke and systemic embolism (primary efficacy outcome; Table 3). The parallel Japanese J ROCKET AF study demonstrated non-inferiority between Japan-specific rivaroxaban (15 mg od or 10 mg od in patients with CrCl ml/min) and warfarin regimens for the same primary outcomes (Table 3). 67 In the ARISTOTLE study, apixaban significantly reduced the risk of stroke and systemic embolism, with the difference primarily driven by a significant reduction in haemorrhagic stroke and a significant reduction in the risk of death from all causes (Table 3). 64 Rates of death from cardiovascular causes and myocardial infarction (MI) were similar between apixaban and warfarin. 64 In AVERROES, apixaban significantly reduced the rate of stroke or systemic embolism and the risk of cardiovascular-related hospitalization compared with ASA, whereas the rates of MI, vascular death and all-cause mortality were similar (Table 3). 65 Bleeding events. Rates of major and non-major clinically relevant bleeding were significantly lower with apixaban compared with warfarin (P < 0001), 64 and similar bleeding rates were also observed between rivaroxaban and warfarin (P = 044). 63 Compared with warfarin, the incidence of major bleeding was significantly lower for 110 mg bid dabigatran (P = 0003) 62 and 5 mg bid apixaban (P < 0001), 64 and similar for 150 mg bid dabigatran (P =031) 62 and 20 mg od rivaroxaban (P = 058). 63 The annual rate of intracranial bleeding was significantly lower than with warfarin for both dabigatran doses (P < 0001), 62 rivaroxaban (P = 002) 63 and apixaban (P < 0001). 64 By contrast, gastrointestinal bleeding was significantly more frequent with 150 mg bid dabigatran (P < 0001) 62 and 20 mg od rivaroxaban (P < 0001), 63 but similar for 110 mg bid dabigatran (P = 043) 62 and 5 mg bid apixaban (P = 037). 64 In addition, rates of lifethreatening bleeding with 110 mg bid and 150 mg bid dabigatran (P < 0001 and P = 004, respectively) 62 and fatal bleeding with 20 mg od rivaroxaban (P = 0003) 63 and 5 mg bid apixaban (P-value not reported) 64 were lower compared with warfarin. In AVERROES, rates of major bleeding were similar between the apixaban and ASA groups (P = 057). 65 Non-bleeding events. In patients with AF, the discontinuation rate at 1 year was 15 16% for dabigatran compared with 10% for warfarin (P < 0001), % for rivaroxaban (vs 222%; P-value not reported) 63 and 253% for apixaban (vs 275%; P = 0001). 64 An elevated incidence of dyspepsia was observed for dabigatran compared with warfarin (110 mg bid, 118% and 150 mg bid, 113% vs 58%; P < 0001). 62 Rates of elevated liver enzyme levels were similar between all agents and warfarin. The incidence of acute MI was generally low and similar to warfarin for apixaban (P = 037) 64 and rivaroxaban (P = 012), 63 but was significantly increased with 150 mg dabigatran (P = 0048). 62 Compared with ASA, fewer patients treated with apixaban had a serious adverse event (P < 0001), primarily because of fewer nervous system disorders

8 Table 3. Published and ongoing phase III, randomized clinical trials of dabigatran, rivaroxaban and apixaban for the prevention of stroke and systemic embolism in patients with non-valvular AF Outcomes Trial name Study design Patients (randomized/ analysed for efficacy) Interventions Treatment duration Primary efficacy Secondary efficacy Primary safety Secondary safety RE-LY 62 Multicentre, randomized, single-blind, active-control, non-inferiority RELY-ABLE 66 Multicentre, randomized, double-blind, long-term safety ROCKET AF 63 Multicentre, randomized, double-blind, double-dummy, active-control, non inferiority J-ROCKET AF 67 Multicentre, randomized, double-blind, double-dummy, active-control, non-inferiority (Japanese patients) Patients with AF and 1 risk factor for stroke (n = ) Patients 18 years who complete RE-LY At moderateto-high risk of stroke with ECGdocumented AF (n = / ) At moderate-tohigh risk of stroke with ECGdocumented AF (n = 1280/ 1278) Dabigatran etexilate oral 110 mg bid or 150 mg bid vs warfarin oral (INR 20 30) od Dabigatran etexilate oral 110 mg bid or 150 mg bid Rivaroxaban oral 20 mg od (15 mg od in patients with CrCl ml/min) or warfarin adjusted to maintain an INR of Rivaroxaban oral 15 mg od (10 mg od in patients with CrCl ml/min) or warfarin adjusted to Japanese guidelines (INR for patients <70 years or INR for patients 70 years) Median 2 years Median 23 years after the end of RE-LY Median 590 days 30 months Stroke or systemic embolism: 15% vs 11% vs 17% per year (P < 0001 for non-inferiority vs warfarin; P < 0001 for superiority with dabigatran 150 mg bid vs warfarin) Stroke or systemic embolism: 16% and 15% per year (HR 091; 95% CI ) Stroke or systemic embolism (per protocol population): 17% vs 22% per year (P < 0001 for non-inferiority) Stroke or non-cns systemic embolism (per protocol on-treatment population): 13% vs 26% (P = 005) All-cause mortality: 38% vs 36% vs 41% per year (P = 013 and P=0051 for superiority vs warfarin) MI: 07% vs 07% vs 05% per year (P = 007 and P = 0048) Haemorrhagic stroke: 01% and 01% per year Stroke or systemic embolism (ITT population): 21% vs 24% per year (P < 0001 for non inferiority) MI 09% vs 11% per year (P = 012) Stroke, non-cns systemic embolism or vascular death: 18% vs 29% (HR 065; 95% CI ) Stroke, non-cns systemic embolism, MI or vascular death: 22% vs 30% (HR 074; 95% CI ) Major bleeding: 27% vs 31% vs 34% per year (P = 0003 and P=031 vs warfarin) Major bleeding: 30% and 37% per year (HR 126; 95% CI ) Major and non-major clinically relevant bleeding: 149% vs 145% per year (P = 044) Major and non-major clinically relevant bleeding: 180% vs 164% per year (P < 0001 for non-inferiority) Any bleeding: 146% vs 164% vs 181% per year (P < 0001 and P = 0002 vs warfarin) Intracranial bleeding: 023% vs 030% vs 074% per year (P < 0001 vs warfarin) GI bleeding: 11% vs 15% vs 10% per year (P = 043 and P < 0001 vs warfarin) Life-threatening bleeding: 12% vs 15% vs 18% (P < 0001 and P = 004) Death: 31% and 30% per year (HR 097; 95% CI ) Major bleeding: 36% vs 34% per year (P = 058) Intracranial haemorrhage: 05% vs 07% per year (P = 002) Fatal bleeding: 02% vs 05% per year (P = 0003) GI bleeding: 32% vs 22% per year (P < 0001) Major bleeding: 30% vs 36% (HR 085; 95% CI ) Intracranial haemorrhage: 08% vs 16% (continued) 125

9 Table 3 (continued) Outcomes Trial name Study design Patients (randomized/ analysed for efficacy) Interventions Treatment duration Primary efficacy Secondary efficacy Primary safety Secondary safety ARISTOTLE 64 Multicentre, randomized, double-blind, active-controlled, non-inferiority/ superiority AVERROES 65 Multicentre, randomized, double-blind, active-controlled, superiority Patients with AF with 1 risk factor for stroke (n = / ) Aged 50 years with AF and 1 risk factor for stroke who met the criteria for, but were not suitable for, warfarin (n = 5599) Apixaban oral 5 mg a bid vs warfarin oral (INR 20 30) od Apixaban oral 5 mg a bid vs ASA oral mg od Median 18 years Median 11 years Stroke or systemic embolism: 13% vs 16% per year (P = 001) Stroke or systemic embolism: 16% vs 37% per year (P < 0001) All-cause mortality: 35% vs 39% per year (P = 0047) MI: 053% vs 061% per year (P = 037) Stroke, systemic embolism or death: 46% vs 72% per year (P < 0001) Stroke, systemic embolism, MI or vascular death: 42% vs 64% per year (P < 0001) Major bleeding: 21% vs 31% per year (P < 0001) Major bleeding: 14% vs 12% per year (P = 057) Major or non-major clinically relevant bleeding: 41% vs 60% per year (P < 0001) Intracranial bleeding: 03% vs 08% per year (P < 0001) GI bleeding: 08% vs 09% per year (P = 037) Intracranial bleeding: 04% vs 04% per year (P = 069) GI bleeding: 04% vs 04% per year (P = 071) a 25 mg in patients with two or more of the following: age 80 years, body weight 60 kg or serum creatinine level 15 mg/dl. AF, atrial fibrillation; ASA, acetylsalicylic acid; bid, twice daily; CI, confidence interval; CNS, central nervous system; CrCl, creatinine clearance; CV, cardiovascular; ECG, electrocardiogram; GI, gastrointestinal; HR, hazard ratio; INR, international normalized ratio; ITT, intention to treat; MI, myocardial infarction; od, once daily. 126

10 Prevention of ischaemic events in patients with acute coronary syndrome ATLAS ACS 2 TIMI 51 was a placebo-controlled study of rivaroxaban in patients with ACS. 68 When administered with concurrent dual antiplatelet therapy, rivaroxaban was superior to placebo for the prevention of death from cardiovascular causes, MI or stroke (Table 4). Rivaroxaban was also superior to placebo for the reduction of death from cardiovascular causes alone and allcause mortality and significantly reduced the risk of stent thrombosis. This was associated with an increase in the rates of major bleeding not related to coronary artery bypass grafting (P < 0001) and intracranial haemorrhage (P = 0009); however, it was not associated with an increase in fatal bleeding (P = 066) or other adverse events for the combined data for the 25 mg bid and 5 mg bid doses of rivaroxaban. 68 The 25 mg bid dose of rivaroxaban was associated with fewer fatal bleeding events compared with the 5 mg bid dose (P = 004). APPRAISE-2 compared 5 mg bid apixaban (25 mg bid in selected patients) with placebo, in addition to standard antiplatelet therapy, in patients with a recent ACS. 69 The trial was discontinued early because of higher rates of bleeding with apixaban without evidence of a reduction in ischaemic events (Table 4). NON-VITAMIN K ANTAGONIST ORAL ANTICOAGULANTS IN CLINICAL PRACTICE: PRACTICAL ASPECTS Official dosing information for dabigatran, rivaroxaban and apixaban is provided in Table 5. Although broadly aligned, some subtle differences exist between the European, Canadian and US prescribing instructions. Contraindications Dabigatran is not recommended in Europe for patients with CrCl < 30 ml/min, 6 whereas in the United States, dabigatran is indicated for stroke prevention in patients with AF who have CrCl ml/min (but not less) at a reduced dose of 75 mg bid. 6 None of the three agents (dabigatran, rivaroxaban and apixaban) should be used in patients with CrCl <15 ml/min, in those who are aged younger than 18 years, in pregnant or breastfeeding women, in patients with a high bleeding risk, or in those with clinically active bleeding Dabigatran and apixaban may be used with caution in patients with mild or moderate hepatic impairment (Child Pugh A/ B), but not more severe impairment; rivaroxaban is contraindicated for patients with Child Pugh B or C. Concomitant use of strong CYP3A4 and P-gp inhibitors is contraindicated for rivaroxaban and apixaban, whereas dabigatran is only affected by P-gp inhibitors. Concomitant use of dronedarone with rivaroxaban should be avoided because of a lack of clinical data. Dronedarone is not recommended with dabigatran in Europe or Canada, because of increased dabigatran exposure. Concurrent use of other anticoagulants, antiplatelet agents or non-steroidal anti-inflammatory drugs is not permitted with dabigatran and apixaban, whereas rivaroxaban can be co-administered with these agents with caution Surgical interventions Given their short half-lives, non-vka OACs can be discontinued up to 24 h (or approximately two half-lives) prior to a planned surgical intervention in patients with normal renal function, compared with patients receiving VKAs. 70,71 This offers an advantage when a relatively urgent surgical procedure is required. However, a delay of up to 5 days may be required in patients with renal compromise who have a moderate or high risk of bleeding (Table 5). Unlike VKAs, no antidotes exist to reverse the effect of these agents. After surgery, anticoagulation can be restarted once normal haemostasis has been re-established; no parenteral anticoagulant bridging is required. Transitioning between non-vitamin K antagonist oral anticoagulants and other anticoagulants If patients with AF are transitioned from a VKA to dabigatran, the VKA should be discontinued and dabigatran initiated when INR is < If the patient is transitioning from dabigatran to a VKA, the starting time of the VKA should be based on the patient s CrCl (Table 5). 6 In patients with AF, when transitioning from VKA to rivaroxaban, the VKA should be discontinued and rivaroxaban initiated as soon as the INR is 30 to avoid inadequate anticoagulation When transitioning from rivaroxaban to VKA, the European guidance is to give both agents concurrently until the INR is Because rivaroxaban affects INR measurement, INR values obtained during co-administration with a VKA are not useful for determining the appropriate VKA dose. When the patient changes therapy from warfarin to apixaban, the INR should be <20; for a change from apixaban to warfarin, apixaban should be continued for 2 days after initiating VKA therapy and continued until the INR is CURRENT AND FUTURE QUESTIONS Choice of non-vitamin K antagonist oral anticoagulant for patients with atrial fibrillation Dabigatran, 62 rivaroxaban 63 and apixaban 64 have all shown similar efficacy for the prevention of stroke in patients with AF; however, because of the difference in study designs and populations (e.g. different mean CHADS 2 score), a direct comparison is not possible. Therefore, the question of which agent is optimal remains unanswered. Data suggest that non-vka OACs lower the risk of intracranial haemorrhage and seem to decrease the overall risk of major bleeding compared with standard interventions. 62,64,72 By contrast, there is the potential for an increased risk of gastrointestinal bleeding and a possible increased risk of MI with dabigatran. 64 Apixaban and rivaroxaban may be better tolerated than dabigatran, which can cause considerable dyspepsia. 62 Drug interactions, although fewer than with VKAs, must be considered when choosing between the non-vka OACs. Dabigatran may be more appropriate for patients taking concomitant strong CYP3A4 inhibitors because it is not cleared via this pathway. Conversely, dabigatran is more likely to be affected by strong P-gp inhibitors than rivaroxaban or apixaban. Patients with renal impairment Dabigatran has the greatest dependence on renal elimination, and dose adjustments are recommended in various circumstances (Table 5); however, these doses have not been tested in clinical trials of patients with AF. In contrast, the 15 mg od dose of rivaroxaban used in patients with AF plus moderate or severe renal impairment (CrCl ml/min) was clinically validated in ROCKET AF. 63 There are no data in patients with CrCl 127

11 Table 4. Phase III, randomized clinical trials of rivaroxaban and apixaban for the prevention of cardiovascular events in patients with recent ACS Outcomes Trial name Study design Patients (randomized/ analysed for primary outcome) Interventions Treatment duration Primary efficacy Other efficacy Primary safety Other safety ATLAS ACS 2 Multicentre, randomized, TIMI double-blind, placebocontrolled, superiority APPRAISE-2 69 Multicentre, randomized, double-blind, placebocontrolled, non-inferiority Recent ACS Standard antiplatelet therapy a plus rivaroxaban oral 25 mg bid or 5 mg bid or placebo Recent acute ACS and 2 risk factors for recurrent ischaemic events (n = 7392) Standard antiplatelet therapy a plus apixaban oral 25 mg c or 5 mg bid or placebo Mean 311 months Death from CV causes, MI or stroke: 89% b vs 107% (P = 0008) Median 175 days (apixaban) and 185 days (placebo) CV-related death, MI or ischaemic stroke: 132 per 100 patient-years vs 140 per 100 patient-years (P = 051) Death from any cause: 29% vs 45% (P = 0002) Death from CV causes: 27% vs 41% (P = 0002) CV-related death, MI, ischaemic stroke or unstable angina: 169 per 100 patient-years vs 180 per 100 patient-years (P = 043) Major bleeding not related to coronary artery bypass grafting: 21% vs 06% (P < 0001) Major bleeding: 24 per 100 patient-years vs 09 per 100 patient-years (P = 0001) Intracranial haemorrhage: 06% vs 02% (P = 0009) Fatal bleeding: 03% c vs 02% (P = 066) Intracranial bleeding: 06 per 100 patient-years vs 02 per 100 patient-years (P = 003) Fatal bleeding: 03 per 100 patient-years vs 0 a ASA monotherapy or ASA plus a thienopyridine. b Both rivaroxaban doses combined. c In selected patients. ACS, acute coronary syndrome; bid, twice daily; CV, cardiovascular; MI, myocardial infarction. 128

12 Table 5. Dosing schedules, recommendations and contraindications for dabigatran, 6 8 rivaroxaban 9 11 and apixaban for the prevention of stroke in patients with nonvalvular AF and for rivaroxaban in patients with ACS 9 (from the European Summary of Product Characteristics, Canadian product monograph and US Prescribing Information) Indication Dosing schedule Dose adjustments Contraindications Transitioning to/from Surgical interventions Shelf life Dabigatran Prevention of stroke and systemic embolism in patients with non-valvular AF a,b,c who have 1 risk factor for stroke a,d in whom anticoagulation is appropriate b Europe/Canada/US 150 mg bid Europe/Canada A reduced dose of 220 mg od (or 110 mg bid) should be given to patients: Age 80 years Receiving concomitant verapamil, ASA and/ or clopidogrel A reduced dose of 220 mg od should be considered based on benefit risk analysis in patients: Age years With CrCl ml/min With gastritis, oesophagitis or gastroesophageal reflux At high risk of bleeding US A reduced dose of 75 mg bid in patients with CrCl ml/min Age <18 years CrCl <30 ml/min (Europe and Canada) or CrCl <15 ml/min (US) Hypersensitivity to the active substance or any of the excipients Clinically significant active bleeding or a lesion or condition at significant risk of major bleeding Hepatic impairment or liver disease expected to impact survival (Europe and Canada only) Concomitant treatment with other anticoagulants (except when switching) or systemic ketoconazole, cyclosporine, itraconazole, tacrolimus or quinidine or dronedarone (Europe and Canada only) Pregnancy or breast feeding VKA to dabigatran: stop VKA and start dabigatran when INR <20 Dabigatran to VKA: CrCl 50 ml/min, use VKA for 3 days before discontinuing dabigatran CrCl ml/min, use VKA for 2 days before discontinuing dabigatran US only, CrCl ml/min, use VKA for 1 day before discontinuing dabigatran Europe/Canada High risk of bleeding or major surgery: stop dabigatran 2 days (CrCl 80 ml/min), 2 3 days (CrCl ml/min) or 4 days (CrCl ml/min) before Standard risk surgery: stop dabigatran 24 h (CrCl 80 ml/min), 1 2 days (CrCl ml/min) or 2 3 days (CrCl ml/min) before Resume dabigatran only once haemostasis is restored US Stop dabigatran 1 2 days (CrCl 50 ml/min) or 3 5 days (CrCl <50 ml/min) before Consider longer time for major surgery, spinal puncture or spinal/epidural catheter or if complete haemostasis required Europe/ Canada/US Use within 4 months after bottle is opened (continued) 129

13 Table 5 (continued) Indication Dosing schedule Dose adjustments Contraindications Transitioning to/from Surgical interventions Shelf life Rivaroxaban Prevention of stroke and systemic embolism in patients with non-valvular AF a,b,c who have 1 risk factor for stroke a,d (in whom anticoagulation is appropriate b ) Prevention of atherothrombotic events in patients with recent ACS and elevated biomarkers, combined with standard single or dual antiplatelet therapy a 20 mg od CrCl ml/min: oral 15 mg od Europe/Canada/US Age <18 years CrCl <15 ml/min Hypersensitivity to the active substance or any of the excipients e Clinically significant active bleeding or lesions at risk of clinically significant bleeding Europe and Canada only Concomitant treatment with strong inhibitors of both CYP3A4 and P-gp (systemic azole antimycotics f or HIV protease inhibitors g ) Concomitant dronedarone (Europe only) Hepatic disease associated with coagulopathy and clinically relevant bleeding risk, including cirrhotic patients with Child Pugh B or C Malignant neoplasms at high risk of bleeding Pregnancy or breast feeding Europe/US VKA to rivaroxaban: stop VKA and start rivaroxaban when INR 30 Canada VKA to rivaroxaban: stop VKA and start rivaroxaban when INR 25 Europe/Canada Rivaroxaban to VKA: co-administer both agents until INR 20 US Rivaroxaban to VKA: Stop rivaroxaban and begin both a parenteral anticoagulant and VKA at the time of the next scheduled rivaroxaban dose; stop parenteral agent when target INR range reached 25 mg bid None As above Not applicable As above Europe/Canada/US Stop rivaroxaban 24 h before Restart once postsurgical haemostasis established Canada For patients at high bleeding risk or for major surgery, consider stopping rivaroxaban 2 4 days before 3 years (continued) 130

14 Table 5 (continued) Indication Dosing schedule Dose adjustments Contraindications Transitioning to/from Surgical interventions Shelf life Apixaban Prevention of stroke and systemic embolism in patients with non-valvular AF who have 1 risk factor for stroke a,b,c 5 mg bid None Age <18 years CrCl <15 ml/min Hepatic disease associated with coagulopathy and clinically relevant bleeding risk Severe hepatic impairment or dialysis Elevated liver enzymes (ALT/AST >29 ULN) or total bilirubin 159 ULN Hypersensitivity to the active substance or any of the excipients e Clinically significant active bleeding Concomitant strong CYP3A4 and P-gp inhibitors (systemic azole antimycotics f or HIV protease inhibitors g ) Increased bleeding risk for other reasons h Pregnancy or breast feeding Europe/Canada/US Warfarin to apixaban: stop VKA and start apixaban when INR <20 Europe/Canada Apixaban to warfarin: continue apixaban for 2 days after initiating VKA therapy until INR 20 US Apixaban to warfarin: stop apixaban and start parenteral anticoagulant and VKA when next apixaban dose is scheduled; stop parenteral agent when INR reaches target range Europe/Canada/US Moderate or high bleeding risk: stop apixaban 48 h before Low bleeding risk: stop apixaban 24 h before Restart once haemostasis established 3 years a Approved in Europe. b Approved in Canada. c Approved in United States. d Such as congestive heart failure, hypertension, age 75 years, diabetes mellitus, prior stroke or transient ischaemic attack. e Rivaroxaban and apixaban contain lactose. f Including ketoconazole, itraconazole, voriconazole and posaconazole. g e.g. ritonavir. h Including: congenital or acquired bleeding disorders, uncontrolled severe arterial hypertension, active ulcerative gastrointestinal disease, recent gastrointestinal ulcerations, vascular retinopathy, recent intracranial or intracerebral haemorrhage, intraspinal or intracerebral vascular abnormalities, recent brain, spinal or ophthalmological surgery, bronchiectasis, history of pulmonary bleeding, bacterial endocarditis, thrombocytopenia, platelet disorders, history of haemorrhagic stroke. ACS, acute coronary syndrome; AF, atrial fibrillation; ALT, alanine aminotransferase; ASA, acetylsalicylic acid; AST, aspartate aminotransferase; bid, twice daily; CrCl, creatinine clearance; CYP3A4, cytochrome P450 3A4; HIV, human immunodeficiency virus; INR, international normalized ratio; od, once daily; P-gp, P-glycoprotein; ULN, upper limit of normal; US, United States; VKA, vitamin K antagonist. 131

15 <15 ml/min for any non-vka OAC. Of the three agents, clearance of apixaban is the least dependent on renal function. Patients with acute coronary syndrome on dual antiplatelet therapy Rivaroxaban is now approved in the EU (but not in the United States) at a dose of 25 mg bid, to be added to standard single or dual antiplatelet therapy for the prevention of atherothrombotic events in patients with a recent ACS and elevated cardiac biomarkers. 15 In a randomized study in healthy volunteers, ASA did not affect the pharmacokinetics of rivaroxaban, suggesting that there is no clinically relevant interaction between the two drugs. 59 In addition, the pharmacokinetics of rivaroxaban were unaffected by steady-state clopidogrel in healthy volunteers; however, a clinically relevant increase in bleeding time was observed. 58 In ATLAS ACS 2 TIMI 51, the combination of rivaroxaban and standard medical therapy for patients with ACS (including lowdose ASA) resulted in increases in the rates of major bleeding (not related to coronary artery bypass grafting) and intracranial haemorrhage; however, this treatment caused no major increase in fatal bleeding compared with antiplatelet therapy alone. 68 Given the increased bleeding risk when an anticoagulant is added to antiplatelet therapy, it will be vital to correctly identify patients whose high likelihood of recurrent cardiovascular events means they will probably benefit from rivaroxaban in this setting. Monitoring and reversal of anticoagulant activity Unlike the VKAs, dabigatran, rivaroxaban and apixaban have predictable pharmacokinetics and pharmacodynamics and do not require routine coagulation monitoring or dose adjustments. This could be particularly important, not only from a healthcare resource perspective, but also given the known correlation between the challenges presented by treatment with VKAs and poor adherence to therapy. 4 However, given the higher costs of non-vka OACs, transitioning patients who are well controlled on VKAs may not be justifiable. Laboratory measurement of non- VKA OACs may be required in circumstances such as haemostatic emergencies, renal insufficiency, imminent surgery or administration of interacting medications. Pharmacists will probably take an active role in such measurement. Anti-Factor Xa chromogenic assays are the tests of choice for rivaroxaban and apixaban, 48 but they require standardization and may not be readily available. In addition, anti-factor IIa chromogenic assays are emerging for the quantification of dabigatran activity. PT, read in seconds, linearly and dose dependently relates to rivaroxaban concentrations when using a high-sensitivity test with rivaroxaban calibrators and controls. 47 The responsiveness of PT to dabigatran is linear but sensitivity is low, whereas apixaban correlates poorly. 48 ECT 73 and thrombin time 48 are appropriate for the measurement of dabigatran activity, but their availability is limited. The standardization of such tests must improve, and more studies are needed to determine their in vivo efficacy. Although standard bleeding management approaches are advised for non-critical bleeding in patients receiving non-vka OACs, urgent reversal of anticoagulation may be required during a bleeding emergency Prothrombin complex concentrates (PCCs), fresh frozen plasma, activated prothrombin complex concentrate (apcc) or, in some cases, recombinant activated Factor VII (rfviia) can be used as reversal agents for VKAs, but few clinical studies have investigated the ability of these agents to reverse the action of non-vka OACs, and further randomized trials are needed. Some animal models indicate that PCC can reverse the activity of Factor Xa and Factor IIa inhibitors In addition, both apcc and rfviia may effectively reverse the effects of Factor Xa inhibitors, but rfviia appears less effective with thrombin inhibitors. In healthy volunteers, only rivaroxaban activity was completely reversed by PCC. 77,78 If reversal is required, apcc, rfviia, concentrates of Factors II, IX and X or dialysis are suggested for dabigatran 6 8 ; PCC, apcc or rfviia for rivaroxaban 9 ; and rfviia for apixaban. 12 Pharmacists will be important participants in the formulation of drug-specific emergency bleeding management protocols for non-vka OACs. 79 Recently, the first animal studies of a specific antidote for the Factor Xa inhibitors, PRT064445, have been published. This agent restored haemostasis in a liver laceration model in rabbits treated with rivaroxaban and dose dependently and completely corrected increased blood loss in rats treated with enoxaparin or fondaparinux. 80 Studies in patients are planned. In addition, an antidabigatran antibody, adabi-fab, is now in phase II clinical trials. 81 WHAT IS NEW AND CONCLUSIONS Apixaban, dabigatran and rivaroxaban may provide greater convenience than VKAs for many patients, pharmacists and physicians. Selection of the most appropriate OAC (including warfarin) for individual patients will depend on indication, co-morbidities (especially renal impairment), potential drug interactions and even social factors, such as the patients ability to comply with INR monitoring and meet medical costs. ACKNOWLEDGEMENTS AND DISCLOSURES Stephen Purver, a medical writer, provided editorial support for the development of the manuscript, with funding from Bayer HealthCare Pharmaceuticals and Janssen Scientific Affairs, LLC. SOURCE OF FUNDING This manuscript was developed with support from Bayer Health- Care Pharmaceuticals and Janssen Scientific Affairs, LLC. The authors received no direct funding from the sponsors and had full control of the content of the manuscript. CONFLICT OF INTEREST Both of the authors have no conflict of interests. REFERENCES 1. Goldhaber SZ. Pulmonary embolism thrombolysis: a clarion call for international collaboration. J Am Coll Cardiol, 1992;19: Fuster V, Ryden LE, Cannom DS et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee 132

16 to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation, 2006;114:e257 e Roger VL, Go AS, Lloyd-Jones DM et al. Heart disease and stroke statistics update: a report from the American Heart Association. Circulation, 2012;125:e2 e Ageno W, Gallus AS, Wittkowsky A, Crowther M, Hylek EM, Palareti G Oral anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest, 2012;141:e44S e88s. 5. You JJ, Singer DE, Howard PA et al. Antithrombotic therapy for atrial fibrillation: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest, 2012;141:e531S e575s. 6. Boehringer Ingelheim International GmbH. Pradaxa â (dabigatran etexilate) Summary of Product Characteristics Available at: GB/document_library/EPAR_-_Product_ Information/human/000829/WC pdf (accessed 5 November 2013). 7. Boehringer Ingelheim Pharmaceuticals Inc. Pradaxa â (dabigatran etexilate) Prescribing Information Available at: label/2013/022512s017lbl.pdf (accessed 23 October 2013). 8. Boehringer Ingelheim Canada Ltd. Pradax TM (dabigatran etexilate mesilate) Product Monograph Available at: internet/opu/ca_en/documents/human health/product_monograph/pradax-pm. pdf (accessed 11 November 2013). 9. Bayer Pharma AG. Xarelto â (rivaroxaban) Summary of Product Characteristics Available at: docs/en_gb/document_library/epar_-_ Product_Information/human/000944/WC pdf (accessed 1 November 2013). 10. Janssen Pharmaceuticals Inc. Xarelto â (rivaroxaban) Prescribing Information Available at: gov/drugsatfda_docs/label/2013/ s004lbl.pdf (accessed 23 July 2013). 11. Bayer Inc. Product Monograph (Canada) Available at: files/xarelto-pm-eng-28aug pdf?# (accessed 18 December 2013). 12. Bristol-Myers Squibb, Pfizer EEIG. Eliquis â (apixaban) Summary of Product Characteristics Available at: europa.eu/docs/en_gb/document_library/ EPAR_-_Product_Information/human/ /WC pdf (accessed 22 October 2013). 13. Bristol-Myers Squibb Company, Pfizer Inc. Eliquis â (apixaban) Prescribing Information Available at: fda.gov/drugsatfda_docs/label/2012/ s000lbl.pdf (accessed 23 October 2013). 14. Bristol-Myers Squibb Canada Inc, Pfizer Canada Inc. Eliquis (apixaban) Product Monograph Available at: pm_pdf/eliquis_en_pm.pdf (accessed 11 November 2013). 15. Medscape. EU Approves Xarelto for Secondary Prevention after an ACS Available at: viewarticle/ (accessed 3 July 2013). 16. Eikelboom JW, Weitz JI. New anticoagulants. Circulation, 2010;121: Hauel NH, Nar H, Priepke H, Ries U, Stassen JM, Wienen W. Structure-based design of novel potent nonpeptide thrombin inhibitors. J Med Chem, 2002;45: Perzborn E, Roehrig S, Straub A, Kubitza D, Misselwitz F. The discovery and development of rivaroxaban, an oral, direct Factor Xa inhibitor. Nat Rev Drug Discov, 2011;10: 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: Wong PC, Pinto DJ, Zhang D. Preclinical discovery of apixaban, a direct and orally bioavailable factor Xa inhibitor. J Thromb Thrombolysis, 2011;31: Blech S, Ebner T, Ludwig-Schwellinger E, Stangier J, Roth W. The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans. Drug Metab Dispos, 2008;36: Kubitza D, Becka M, Voith B, Zuehlsdorf M, Wensing G. Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY , an oral, direct Factor Xa inhibitor. Clin Pharmacol Ther, 2005;78: Weinz C, Schwarz T, Kubitza D, Mueck W, Lang D. Metabolism and excretion of rivaroxaban, an oral, direct Factor Xa inhibitor, in rats, dogs and humans. Drug Metab Dispos, 2009;37: Raghavan N, Frost CE, Yu Z et al. Apixaban metabolism and pharmacokinetics after oral administration to humans. Drug Metab Dispos, 2009;37: Rule AD, Bailey KR, Schwartz GL, Khosla S, Lieske JC, Melton LJ III. For estimating creatinine clearance measuring muscle mass gives better results than those based on demographics. Kidney Int, 2009;75: H artter S, Yamamura N, Stangier J, Reilly PA, Clemens A. Pharmacokinetics and pharmacodynamics in Japanese and Caucasian subjects after oral administration of dabigatran etexilate. Thromb Haemost, 2012;107: Stangier J, Stahle H, Rathgen K, Roth W, Shakeri-Nejad K. Pharmacokinetics and pharmacodynamics of dabigatran etexilate, an oral direct thrombin inhibitor, are not affected by moderate hepatic impairment. J Clin Pharmacol, 2008;48: Stangier J, Rathgen K, Stahle H, Mazur D. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-centre study. Clin Pharmacokinet, 2010;49: Kubitza D, Becka M, Wensing G, Voith B, Zuehlsdorf M. 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: 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: Kubitza D, Becka M, Roth A, Mueck W. Dose-escalation study of the pharmacokinetics and pharmacodynamics of rivaroxaban in healthy elderly subjects. Curr Med Res Opin, 2008;24: Kubitza D, Becka M, Roth A, Mueck W. The influence of age and gender on the pharmacokinetics and pharmacodynamics of rivaroxaban an oral, direct Factor Xa inhibitor. J Clin Pharmacol, 2013;53: Jiang J, Hu Y, Zhang J et al. Safety, pharmacokinetics and pharmacodynamics of single doses of rivaroxaban - an oral, direct Factor Xa inhibitor - in elderly Chinese subjects. Thromb Haemost, 2010;103: Kubitza D, Becka M, Zuehlsdorf M, Mueck W. Body weight has limited influence on the safety, tolerability, pharmacokinetics, or pharmacodynamics of rivaroxaban (BAY ) in healthy subjects. J Clin Pharmacol, 2007;47: Kubitza D, Roth A, Becka M et al. Effect of hepatic impairment on the pharmacokinetics and pharmacodynamics of a single dose of rivaroxaban an oral, direct Factor Xa inhibitor. Br J Clin Pharmacol, 2013;76: Zhao X, Sun P, Zhou Y et al. Safety, pharmacokinetics and pharmacodynamics of single/multiple doses of the oral, direct Factor Xa inhibitor rivaroxaban in healthy 133

17 Chinese subjects. Br J Clin Pharmacol, 2009; 68: Tanigawa T, Kaneko M, Hashizume K et al. Model-based dose selection for phase III rivaroxaban study in Japanese patients with non-valvular atrial fibrillation. Drug Metab Pharmacokinet, 2013;28: Kubitza D, Becka M, Mueck W et al. Effects of renal impairment on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban, an oral, direct Factor Xa inhibitor. Br J Clin Pharmacol, 2010;70: Mueck W, Becka M, Kubitza D, Voith B, Zuehlsdorf M. 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: Kubitza D, Becka M, Zuehlsdorf M, Mueck W. Effect of food, an antacid, and the H2 antagonist ranitidine on the absorption of BAY (rivaroxaban), an oral, direct Factor Xa inhibitor, in healthy subjects. J Clin Pharmacol, 2006;46: Stampfuss J, Kubitza D, Becka M, Mueck W. The effect of food on the absorption and pharmacokinetics of rivaroxaban. Int J Clin Pharmacol Ther, 2013;51: Upreti VV, Wang J, Barrett YC et al. Effect of extremes of body weight on the pharmacokinetics, pharmacodynamics, safety and tolerability of apixaban in healthy subjects. Br J Clin Pharmacol, 2013;76: Frost C, Wang J, Nepal S et al. Apixaban, an oral, direct Factor Xa inhibitor: single-dose safety, pharmacokinetics, pharmacodynamics and food effect in healthy subjects. Br J Clin Pharmacol, 2013;75: Stangier J, Rathgen K, Stahle H, Gansser D, Roth W. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol, 2007;64: Stangier J, St ahle H, Rathgen K, Fuhr R. Pharmacokinetics and pharmacodynamics of the direct oral thrombin inhibitor dabigatran in healthy elderly subjects. Clin Pharmacokinet, 2008;47: Stangier J, Feuring M. Using the HEMO- CLOT direct thrombin inhibitor assay to determine plasma concentrations of dabigatran. Blood Coagul Fibrinolysis, 2012;23: Samama MM, Martinoli JL, Le Flem L et al. Assessment of laboratory assays to measure rivaroxaban an oral, direct Factor Xa inhibitor. Thromb Haemost, 2010;103: Lindhoff-Last E, Samama MM, Ortel TL, Weitz JI, Spiro TE. Assays for measuring rivaroxaban: their suitability and limitations. Ther Drug Monit, 2010;32: Mani H, Rohde G, Stratmann G et al. Accurate determination of rivaroxaban levels requires different calibrator sets but not addition of antithrombin. Thromb Haemost, 2012;108: Samama MM, Contant G, Spiro TE et al. Evaluation of the anti-factor Xa chromogenic assay for the measurement of rivaroxaban plasma concentrations using calibrators and controls. Thromb Haemost, 2012;107: Hartter S, Sennewald R, Schepers C, Baumann S, Fritsch H, Friedman J. Pharmacokinetic and pharmacodynamic effects of comedication of clopidogrel and dabigatran etexilate in healthy male volunteers. Eur J Clin Pharmacol, 2013;69: Hartter S, Sennewald R, Nehmiz G, Reilly P. Oral bioavailability of dabigatran etexilate (Pradaxa â ) after co-medication with verapamil in healthy subjects. Br J Clin Pharmacol, 2013;75: H artter S, Koenen-Bergmann M, Sharma A et al. Decrease in the oral bioavailability of dabigatran etexilate after co-medication with rifampicin. Br J Clin Pharmacol, 2012; 74: Lang D, Freudenberger C, Weinz C. In vitro metabolism of rivaroxaban an oral, direct Factor Xa inhibitor in liver microsomes and hepatocytes of rat, dog and man. Drug Metab Dispos, 2009;37: Mueck W, Kubitza D, Becka M. Co-administration of rivaroxaban with drugs that share its elimination pathways: pharmacokinetic effects in healthy subjects. Br J Clin Pharmacol, 2013;76: Kubitza D, Becka M, Roth A, Mueck W. Absence of clinically relevant interactions between rivaroxaban - an oral, direct Factor Xa inhibitor - and digoxin or atorvastatin in healthy subjects. J Int Med Res, 2012;40: Kubitza D, Becka M, Mueck W, Zuehlsdorf M. Rivaroxaban (BAY ) - an oral, direct Factor Xa inhibitor - has no clinically relevant interaction with naproxen. Br J Clin Pharmacol, 2007;63: Kubitza D, Becka M, Mueck W, Schwers S. Effect of co-administration of rivaroxaban and clopidogrel on bleeding time, pharmacodynamics and pharmacokinetics: a phase I study. Pharmaceuticals (Basel), 2012;5: Kubitza D, Becka M, Mueck W, Zuehlsdorf M. Safety, tolerability, pharmacodynamics, and pharmacokinetics of rivaroxaban an oral, direct Factor Xa inhibitor are not affected by aspirin. J Clin Pharmacol, 2006;46: Kubitza D, Becka M, Schwers S, Voith B. Investigation of pharmacodynamic and pharmacokinetic interactions between rivaroxaban and enoxaparin in healthy male subjects. Clin Pharmacol Drug Dev, 2013;2: Upreti VV, Song Y, Wang J et al. Effect of famotidine on the pharmacokinetics of apixaban, an oral direct Factor Xa inhibitor. Clin Pharmacol, 2013;5: Connolly SJ, Ezekowitz MD, Yusuf S et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med, 2009;361: Patel MR, Mahaffey KW, Garg J et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med, 2011;365: Granger CB, Alexander JH, McMurray JJ et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med, 2011; 365: Connolly SJ, Eikelboom J, Joyner C et al. Apixaban in patients with atrial fibrillation. N Engl J Med, 2011;364: Connolly SJ, Wallentin L, Ezekowitz MD et al. The long-term multicenter observational study of dabigatran treatment in patients with atrial fibrillation (RELY- ABLE) study. Circulation, 2013;128: Hori M, Matsumoto M, Tanahashi N et al. Rivaroxaban vs. warfarin in Japanese patients with atrial fibrillation the J- ROCKET AF study. Circ J, 2012;76: Mega JL, Braunwald E, Wiviott SD et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med, 2012; 366: Alexander JH, Lopes RD, James S et al. Apixaban with antiplatelet therapy after acute coronary syndrome. N Engl J Med, 2011;365: Gogarten W, Vandermeulen E, Van Aken H, Kozek S, Llau JV, Samama CM. Regional anaesthesia and antithrombotic agents: recommendations of the European Society of Anaesthesiology. Eur J Anaesthesiol, 2010;27: Sie P, Samama CM, Godier A et al. Surgery and invasive procedures in patients on long-term treatment with direct oral anticoagulants: thrombin or Factor-Xa inhibitors. Recommendations of the Working Group on Perioperative Haemostasis and the French Study Group on Thrombosis and Haemostasis. Arch Cardiovasc Dis, 2011;104: The EINSTEIN PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med, 2012;366:

18 73. Samama MM, Guinet C. Laboratory assessment of new anticoagulants. Clin Chem Lab Med, 2011;49: Gruber A, Carlsson S, Kotze HF, Marzec U, Sarich TC, Hanson SR. Hemostatic effect of activated factor VII without promotion of thrombus growth in melagatran-anticoagulated primates. Thromb Res, 2007;119: Godier A, Miclot A, Le Bonniec B et al. Evaluation of prothrombin complex concentrate and recombinant activated Factor VII to reverse rivaroxaban in a rabbit model. Anesthesiology, 2012;116: Pragst I, Zeitler SH, Doerr B et al. Reversal of dabigatran anticoagulation by prothrombin complex concentrate (Beriplex P/N) in a rabbit model. J Thromb Haemost, 2012;10: Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation, 2011;124: Marlu R, Hodaj E, Paris A, Albaladejo P, Crackowski JL, Pernod G. Effect of nonspecific reversal agents on anticoagulant activity of dabigatran and rivaroxaban. A randomised crossover ex vivo study in healthy volunteers. Thromb Haemost, 2012;108: Peacock WF, Gearhart MM, Mills RM. Emergency management of bleeding associated with old and new oral anticoagulants. Clin Cardiol, 2012;35: Lu G, DeGuzman FR, Hollenbach SJ et al. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation Factor Xa. Nat Med, 2013;19: Schiele F, van Ryn J, Canada K et al. A specific antidote for dabigatran: functional and structural characterization. Blood, 2013;121: Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet, 2008;47:

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