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provided by Elsevier - Publisher Connector Journal of the American College of Cardiology Vol. 56, No. 25, 2010 © 2010 by the American College of Cardiology Foundation ISSN 0735-1097/$36.00 Published by Elsevier Inc. doi:10.1016/j.jacc.2010.09.017

STATE-OF-THE-ART PAPER

Novel for Stroke Prevention in Atrial Fibrillation Current Clinical Evidence and Future Developments

Stephan H. Schirmer, MD, PHD,* Magnus Baumhäkel, MD,* Hans-Ruprecht Neuberger, MD, PHD,* Stefan H. Hohnloser, MD,† Isabelle C. van Gelder, MD, PHD,‡§ Gregory Y. H. Lip, MD,ʈ Michael Böhm, MD* Homburg/Saar and Frankfurt, Germany; Groningen and Utrecht, the Netherlands; and Birmingham, England, United Kingdom

Atrial fibrillation (AF) is the most common cardiac rhythm disorder and a major risk factor for ischemic stroke. therapy using or vitamin K antagonists (VKA) is currently prescribed for prevention for ischemic stroke in patients with AF. A narrow therapeutic range and the need of regular monitoring of its antico- agulatory effect impair effectiveness and safety of VKA, causing a need for alternative drugs. Re- cently developed anticoagulants include direct antagonists such as or factor Xa inhibitors such as , , , and . Currently, data from a phase III clinical trial are avail- able for dabigatran only, which show the direct thrombin antagonist to be at least noninferior in efficacy to VKA for the prevention of stroke and systemic embolism in patients with AF. This review focuses on current advances in the development of directly acting oral anticoagulant drugs and their potential to replace the VKA class of drugs in patients with AF. (J Am Coll Cardiol 2010;56:2067–76) © 2010 by the American College of Cardiol- ogy Foundation

Atrial fibrillation (AF) affects more than 1% of the general for ischemic stroke, irrespective of temporal pattern of AF, population, and its prevalence rises up to 10% in people whether paroxysmal, persistent, or permanent (4–7), and older than 80 years of age (1–2). It is estimated that nearly importantly, AF-related stroke confers a significantly in- 16 million people will suffer from AF in the U.S. by 2050 creased mortality and morbidity compared with non-AF (3). AF is known to be a substantial independent risk factor causes of stroke (8–10). Apart from its impact on health and survival, AF imposes an enormous economic burden. It is estimated that AF causes yearly direct and indirect costs of From the *Klinik für Innere Medizin III (Kardiologie, Angiologie und Internistische $66 billion per year (11). Intensivmedizin), Universitätsklinikum des Saarlandes, Homburg/Saar, Germany; †Klinik für Kardiologie, Abteilung für klinische Elektrophysiologie, J. W. Goethe Currently, aspirin and vitamin K antagonists (VKA) are Universität, Frankfurt, Germany; ‡Department of Cardiology, University Medical the only approved antithrombotic therapies for stroke pre- Center Groningen, University of Groningen, Groningen, the Netherlands; §Inter- university Cardiology Institute of the Netherlands, Utrecht, the Netherlands; and the vention in patients with AF (12). VKA therapy is clearly ʈ University of Birmingham Centre for Cardiovascular Sciences, City Hospital, recommended in patients with a CHADS2 (congestive Birmingham, England, United Kingdom. The authors were funded by the Deutsche heart failure, hypertension, age Ͼ75 years, diabetes, and Forschungsgemeinschaft (KFO 196) and by the the Wissenschaftsministerium des Saarlandes (Klinische Studiengruppe). Drs. Baumhäkel, Böhm, and Lip have received previous stroke/transient ischemic attack) score of 2 or honoraria from Boehringer Ingelheim and Bayer. Dr. Baumhäkel has received support for higher. At a CHADS2 score of 1, VKA may be preferred animal studies by Bayer A6, Boehringer, Pfizer, and Servier. Dr. Neuberger receives speaker fees from Boehringer Ingelheim. Dr. Hohnloser reports receiving consulting fees over aspirin if the thromboembolic risk is judged higher from Sanofi-Aventis, Cardiome, ARYx, Bristol-Myers Squibb, Boehringer Ingelheim, than that of bleeding complications, or if other stroke risk and MSD; research grants from Sanofi-Aventis and St. Jude Medical; and lecture fees factors (e.g., female sex, vascular disease, and so on) that are from Sanofi-Aventis, St. Jude Medical, Cardiome, Boehringer Ingelheim, Bristol-Myers Squibb, and MSD. Dr. van Gelder reports receiving consulting fees from Sanofi-Aventis, not included in the CHADS2 score are considered, which Boehringer Ingelheim, and Cardiome, research grants from Medtronic, Biotronik, and St. has been expressed as the CHA2DS2-VASc (CHADS2– Jude Medical, and lecture fees from Sanofi-Aventis, Boehringer Ingelheim, and vascular disease, age 65 to 74 years, sex category) score Medtronic. Dr. Lip has received funding from Boehringer, Pfizer/Bristol-Myers Squibb, Sanofi, Astellas, Merck, Portola, Biotronic, Daiichi-Sankyo, and AstraZeneca. Dr. Böhm (13,14). receives research support and speaker honoraria from AstraZeneca, Boehringer Ingelheim, The use of VKA, however, necessitates regular anticoag- Pfizer, and Sanofi-Aventis. Manuscript received June 25, 2010; revised manuscript received September 13, ulation monitoring. Interactions of with food and 2010, accepted September 23, 2010. other drugs also hamper its use. Intensity of oral anticoag- 2068 Schirmer et al. JACC Vol. 56, No. 25, 2010 Novel Anticoagulants in Atrial Fibrillation December 14/21, 2010:2067–76

Abbreviations ulation is closely related to out- Clinical Data on Direct Thrombin Inhibitors and Acronyms come, with the necessity to Mechanisms of action. In contrast to factor Xa inhibitors, maintain a narrow therapeutic acute coronary direct thrombin inhibitors have more diverse effects on the ؍ ACS range as measured by the inter- syndrome(s) coagulation. They prevent fibrin formation, thrombin- national normalized ratio (INR) atrial fibrillation mediated activation of factors V, VIII, XI, and XIII, and ؍ AF of2to3(15). Even within the twice daily thrombin-induced platelet aggregation. The latter is in ؍ .b.i.d setting of a randomized controlled contrast to unfractionated , which is known to ؍ CI confidence interval trial, patients are within the ther- activate platelets (21,22). Similarly to factor Xa inhibitors, international apeutic range for only two-thirds ؍ INR normalized ratio tissue factor–induced thrombin generation is attenuated by of the time (16), and in daily thrombin inhibitors (23). Also in contrast to , direct ؍ RR relative risk clinical practice, therapeutic thrombin inhibitors have the capacity to act on fibrin-bound vitamin K range is achieved to an even ؍ VKA antagonists thrombin (24), causing a more efficient inhibition than lesser extent (17). Furthermore, indirect thrombin inhibitors acting further upstream in the ؍ VTE venous oral anticoagulation using warfa- thromboembolism coagulation cascade (Fig. 1). In theory, this effect can also rin is associated with a significant increase the risk of bleeding. risk of major bleeding (approxi- Among direct thrombin inhibitors, monovalent com- mately 2%/year). Importantly, more recent data suggest that pounds can be distinguished from bivalent inhibitors. Biva- also antiplatelet therapy confers a similar (BAFTA [Birming- lent direct thrombin inhibitors include and bivaliru- ham Atrial Fibrillation Treatment of the Aged] study) (18)or din, both of which have to be applied intravenously. In even greater (ACTIVE-W [Atrial fibrillation contrast, , , and dabigatran are uni- Trial with Irbesartan for prevention of Vascular Events]) (19) valent direct thrombin inhibitors, the latter 2 having been risk of major bleeding, with aspirin or aspirin– developed for oral use. clopidogrel combination therapy, respectively. Because of Ximelagatran. Ximelagatran was first evaluated in ortho- the difficulties of warfarin therapy and the large number pedic trials, where it showed superiority over warfarin (25). of patients in need of anticoagulation in AF, alternative Its efficacy in stroke prevention in patients with AF was therapeutic strategies have long been sought after. demonstrated in 2 large, phase III studies, the open-label Commonly used anticoagulants such as unfractionated and low molecular weight heparin act by binding to anti- thrombin and inhibiting both thrombin and activated factor Xa. Direct inhibition of factor Xa and of thrombin are particularly interesting approaches. The former might cause more coagulation-specific effects, whereas the latter might have beneficial effects outside the coagulation cascade, e.g., by interfering with the effects of thrombin on PAR (protease activated receptor) receptors on plate- lets, endothelial cells, or vascular smooth muscle cells (20)(Fig. 1). Thus, novel anticoagulant drugs were developed with the aim of an orally available compound that did not require monitoring of the anticoagulatory effect but could be ap- plied at a fixed dose. A small number of anticoagulants have reached phase III clinical studies for use in AF. Usually, the safety and efficacy of novel anticoagulants are first tested in patients undergoing elective hip or knee replacement sur- gery. This approach is particularly suitable for anticoagulant drug development because of study populations with a relatively high rate of thrombotic events and the possibility Figure 1 Coagulation Cascade of monitoring bleeding events in a hospital environment. Both the intrinsic coagulation pathway (involving factors XII, XI, IX, and VIII) as Among the factor Xa inhibitors, apixaban, betrixaban, well as the extrinsic pathway (involving factor VII) end in the same common edoxaban, and rivaroxaban are the most advanced com- pathway, the activation of to factor Xa. Together with factor Va, factor Xa forms the prothrombinase complex that activates prothrombin (factor II) to pounds. A phase III clinical trial comparing apixaban to thrombin (factor IIa). In contrast to indirect anticoagulants such as heparins, aspirin in patients unsuitable for VKA has recently been which require III to inhibit factor Xa or factor IIa, the novel, orally stopped. In the comparison to VKA, dabigatran currently is available inhibitors directly inhibit for Xa or factor IIa. Thrombin not only acti- vates fibrinogen into fibrin (factor Ia), but also activates factors V, VII, VIII, IX, the furthest developed oral direct thrombin inhibitor and and XIII. Blocking thrombin thus efficiently inhibits coagulation. Figure illustra- the only novel anticoagulant for which data from a phase III tion by Craig Skaggs. trial for stroke prevention in AF are available. JACC Vol. 56, No. 25, 2010 Schirmer et al. 2069 December 14/21, 2010:2067–76 Novel Anticoagulants in Atrial Fibrillation

SPORTIF III (Stroke Prevention Using an Oral Throm- 40 mg o.d. for Prevention of Thrombosis After Knee Surgery] bin Inhibitor in Atrial Fibrillation) trial (26) and the trial) (33). When compared with a higher dose scheme of double-blind SPORTIF V trial (27), which followed-up enoxaparin (2 ϫ 30 mg daily) in the RE-MOBILIZE 3,410 patients (70.2 Ϯ 8.6 years) for 17 months and 3,922 (Dabigatran Etexilate vs Enoxaparin in Prevention of VTE patients (71.6 Ϯ 9.1 years) for 20 months, respectively. In Post Total Knee Replacement) trial, dabigatran for 12 to 15 SPORTIF V, the annual risk for stroke or systemic embo- days was inferior in the prevention of VTE in 1,896 patients lism (composite primary end point) was 1.6% with ximel- age 66 Ϯ 10 years (34). In a pooled analysis of all 3 trials, agatran compared with 1.2% to 2.3% for warfarin (27). At Friedman et al. (35) found noninferiority and similar the same time, bleeding was less frequent with ximelagatran bleeding rates of dabigatran compared with enoxaparin. A than with warfarin (1.9% vs. 2.5%). Ximelagatran has also recent Cochrane meta-analysis on total hip and knee re- been investigated in secondary prevention after acute myo- placements concluded direct thrombin antagonist to be as cardial infarction, where it reduced a combined end point of effective as low molecular weight heparin or VKA in the mortality, reinfarction, and stroke when compared with prevention of VTE (36). placebo (28). However, hepatotoxicity, as indicated by a A trial investigating treatment of acute VTE in 2,539 relevant (more than 3 times the upper limit of normal) patients age 55 Ϯ 15 years (the RE-COVER trial) recently increase in alanine aminotransferase, was observed in several demonstrated noninferior efficacy (end point: recurrent studies in up to 6.1% compared with 0.8% in patients symptomatic, objectively confirmed VTE and related death) receiving warfarin. As a consequence, ximelagatran was of a fixed dose of dabigatran (150 mg twice daily [b.i.d.]) to withdrawn from all markets and from further development warfarin with a similar major bleeding profile during 6 in February 2006. months of therapy (37). Investigations analyzing the effects Dabigatran. Dabigatran is a direct reversible thrombin of dabigatran on long-term prevention of recurrent and of inhibitor. Its oral pro-drug, dabigatran etexilate, which is acute symptomatic VTE are currently recruiting patients converted by serum esterases to dabigatran, has a bioavail- (Twice-Daily Oral Direct Thrombin Inhibitor Dabigatran ability of 6.5%, a half-life of 12 to 17 h and is renally Etexilate in the Long Term Prevention of Recurrent Symp- excreted by approximately 80% (29). Although it does not tomatic VTE: NCT00558259; Secondary Prevention of require regular dose monitoring, anticoagulant status can be Venous Thrombo Embolism: NCT00329238; and Phase assessed by measuring thrombin clotting time or ecarin III Study Testing Efficacy and Safety of Oral Dabigatran clotting time, which might be valuable in case of bleeding Etexilate vs Warfarin for 6 m Treatment for Acute Symp- (30). Although the activated partial thromboplastin time tomatic VTE: NCT00680186, respectively). may not be suitable for the precise quantification of antico- Following the noninferiority studies in the prevention of agulant effect at high plasma concentrations of dabigatran, it VTE after orthopedic surgery, the safety and effectiveness of may be useful to indicate excessive anticoagulant effects in dabigatran in stroke prevention in 502 patients with AF was emergency situations (30). first investigated in the PETRO (Prevention of Embolic A large study program, called the (RE-VOLUTION and ThROmbotic events) phase II trial that suggested program) was initiated to investigate the effect of dabigatran reduction of thromboembolic events with dabigatran doses in different settings (prevention and treatment of venous of 150 or 300 mg twice daily (38). Subsequently, stroke thromboembolism [VTE], prevention of stroke in AF, and prevention was tested in the large, phase III RE-LY secondary prevention of [ACS]). (Randomized Evaluation of Long-term anticoagulation Phase III testing of dabigatran started with trials to prevent therapY) trial that included 18,113 patients with AF VTE after orthopedic surgery. In the RE-NOVATE (39,40). In RE-LY, patients were randomized to receive (Dabigatran Etexilate Compared With Enoxaparin in Pre- either a fixed dose of 110- or 150-mg dabigatran b.i.d. or vention of VTE Following Total Hip Arthroplasty) study, warfarin at an adjusted dose to reach an INR of 2.0 to 3.0 150 mg and 220 mg of dabigatran once daily were nonin- (Table 1)(40). The primary outcome at a median follow-up ferior to 40-mg enoxaparin daily for 33 days (end point: of 2 years, stroke or systemic embolism, occurred as often in composite of VTE and death) without a significant increase patients taking 110-mg dabigatran b.i.d. as in patients on in bleeding in 3,494 patients age 64 Ϯ 11 years following warfarin (1.5% vs. 1.7%, relative risk [RR]: 0.91, 95% total hip replacement (31). The recently presented RE- confidence interval [CI]: 0.74 to 1.11, p ϭ 0.34), and less NOVATE II trial also showed extended thromboprophy- often (1.1%, RR: 0.66, 95% CI: 0.53 to 0.82, p Ͻ 0.001) in laxis after hip arthroplasty in 2,055 patients using 220-mg those taking 150-mg dabigatran b.i.d. (Fig. 2). Importantly, dabigatran for 28 to 35 days to be noninferior (same end hemorrhagic stroke occurred significantly less often in point as RE-NOVATE) to 40-mg enoxaparin (32). Also, patients on low-dose (0.12% per year, RR: 0.31, 95% CI: after total knee replacement, dabigatran proved to be non- 0.17 to 0.56; p Ͻ 0.001) and on high-dose dabigatran inferior (end point: composite of VTE and death) to (0.10% per year, RR: 0.26, 95% CI: 0.14 to 0.49; p Ͻ 0.001) enoxaparin in 2,076 patients age 68 Ϯ 9 years, followed-up compared with patients taking warfarin (0.38% per year). A for 3 months after 6 to 10 days of treatment (RE-MODEL comparable rate of major bleeding was observed in those [Dabigatran Etexilate 150 or 220 mg o.d. vs. Enoxaparin patients on high-dose dabigatran and in patients taking 00Schirmer 2070 oe nioglnsi tilFibrillation Atrial in Anticoagulants Novel

ComparisonTable 1 Comparison of the Hitherto of the Conducted Hitherto or Conducted Ongoing Phase or Ongoing III Trials Phase in AF III Trials in AF al. et

Drug Study Name Patients Primary End Point Secondary End Points Follow-Up Results (Primary End Point) Comments Dabigatran RE-LY 18,113 patients Composite: stroke/ 1. Myocardial infarction Event-driven (n ϭ 450), Low-dose dabigatran equally Open-label warfarin 110 mg/150 mg AF systemic embolism 2. Pulmonary embolism Ͼ12 months effective, high dose b.i.d. 1 risk factor 3. Hospitalization superior to warfarin Warfarin 50% VKA naive 4. Total mortality

INR 2–3 CHADS2 0–1: c. 32% 5. Cardiovascular mortality CHADS2 2: c. 35% CHADS2 Ն3: c. 33% Rivaroxaban ROCKET-AF 14,000 patients Composite: stroke/ 1. Composite: TIA/ Event-driven (n ϭ 405), Study completed January Double-dummy design with 20 mg o.d. AF systemic embolism all-cause mortality/ Ͼ14 months 2010, data awaited sham INR Warfarin moderate/high risk vascular mortality/ end 2010

INR 2–3 CHADS2 2: 10% myocardial infarction CHADS2 Ն3: 90% Apixaban ARISTOTLE 18,205 patients Composite: stroke/ 1. Composite: stroke/ Event-driven (n ϭ 448), Patient recruitment Double-dummy design with sham 5 mg b.i.d. AF systemic embolism systemic embolism/ Ͼ12 months completed, study end INR, stroke diagnosis by Warfarin 1 risk factor all-cause mortality expected April 2011 neurologists INR 2–3 Both VKA naive/non-naive 2. Composite: stroke/ systemic embolism/ all-cause mortality/ major bleeding 3. Composite: stroke/ systemic embolism/ major bleeding/ myocardial infarction Apixaban AVERROES 5,600 patients Composite: stroke/ 1. Time from first dose of Event-driven, 36 months Apixaban superior to aspirin, Prematurely stopped after 5 mg b.i.d. AF systemic embolism study drug to first no increased risk of evidence of superiority of Aspirin Ն1 risk factor occurrence of ischemic bleeding study drug to aspirin 81–32 mg o.d. Intolerant/unsuitable for VKA stroke, hemorrhagic stroke, systemic embolism, myocardial infarction, or vascular death Edoxaban ENGAGE-AF– 20,500 patients (estimated) Composite: stroke/ 1. Composite: stroke/ Time frame: 24 months Study completion expected 30 mg/60 mg o.d. TIMI 48 AF systemic embolism systemic embolism/ March 2012

Warfarin Moderate risk (CHADS2 Ն2) all-cause mortality 2. Major bleeding eebr1/1 2010:2067–76 14/21, December

AF ϭ atrial fibrillation; ARISTOTLE ϭ Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation; AVERROES ϭ A Phase III Study of Apixaban in Patients With Atrial Fibrillation; b.i.d. ϭ twice daily; CHADS2 ϭ (congestive heart failure, hypertension, age Ͼ75 years, diabetes, and previous stroke/transient ischemic attack); ENGAGE-AF ϭ Global Study to Assess the Safety and Effectiveness of DU-176b vs Standard Practice of Dosing With Warfarin in Patients With Atrial Fibrillation; INR ϭ international normalized ratio; o.d. ϭ daily; 2010 25, No. 56, Vol. JACC RE-LY ϭ Randomized Evaluation of Long-term anticoagulation therapY; ROCKET-AF ϭ Randomized, Double-Blind Study Comparing Once Daily Oral Rivaroxaban With Adjusted-Dose Oral Warfarin for the Prevention of Stroke in Subjects With Non-Valvular Atrial Fibrillation; VKA ϭ . JACC Vol. 56, No. 25, 2010 Schirmer et al. 2071 December 14/21, 2010:2067–76 Novel Anticoagulants in Atrial Fibrillation

Figure 4 All-Cause Mortality in the RE-LY Trial Figure 2 Cumulative Hazard Rates for the Primary End Point (Stroke or Systemic Embolism) in the RE-LY Trial The 12% reduction (95% CI: 0.77 to 1.00) in all-cause mortality with 150-mg The end point occurred in 1.69% per year in the warfarin group versus 1.53% (3.6%) dabigatran compared with warfarin (4.1%) almost reached statistical with 110-mg dabigatran taken twice daily (RR: 0.91, 95% CI: 0.74 to 1.11, significance (p ϭ 0.051). Adapted, with permission, from Connolly et al. (39). p Ͻ 0.001 for noninferiority) and in 1.11% per year in the 150-mg dabigatran Abbreviations as in Figure 2. group (RR: 0.66, 95% CI: 0.53 to 0.82, p Ͻ 0.001 for superiority). Adapted, with permission, from Connolly et al. (39). CI ϭ confidence interval; RE-LY ϭ Randomized Evaluation of Long-term anticoagulation therapy; RR ϭ relative risk. in all subgroups of AF patients at low, moderate, or high risk of stroke (41). Analyzing the primary end point (stroke or systemic embolism) of the RE-LY study in relation to warfarin (RR: 0.93, 95% CI: 0.81 to 1.07, p ϭ 0.31). There the time-in-therapeutic range of patients treated with was a lower bleeding rate in patients taking the lower dose warfarin showed that beneficial effects of dabigatran over of dabigatran (RR: 0.80, 95% CI: 0.69 to 0.93, p ϭ 0.003). warfarin were consistent irrespective of INR control. For Total bleeding was reduced with both 110- and 150-mg the end points cardiovascular events and total mortality, dabigatran (Fig. 3). In detail, intracranial bleeding was dabigatran was superior to warfarin at low time-in- reduced from 0.7% with warfarin to 0.3% with high-dose therapeutic range (42). and to 0.2% with low-dose dabigatran. Gastrointestinal For unknown reasons, an increased rate of myocardial bleeding, however, was increased from 1.0% per year with infarction was seen with dabigatran compared with warfarin warfarin to 1.1% with low-dose and to 1.5% with high-dose (0.7% vs. 0.5%), which reached statistical significance for dabigatran. Importantly, there was a reduction in all-cause high-dose (p ϭ 0.048), but not low-dose (p ϭ 0.07) mortality with 150-mg dabigatran compared with warfarin dabigatran. Upcoming subanalyses of RE-LY will deliver (RR: 0.88) that almost reached statistical significance (p ϭ answers on the combination therapy of aspirin and dabig- 0.051) (Fig. 4) and a significant reduction in vascular atran. A subanalysis on patients undergoing cardioversion, mortality (RR: 0.85, p ϭ 0.04). A recent RE-LY subanaly- presented at the meeting of the American College of sis showed that dabigatran is at least noninferior to warfarin Cardiology in March 2010, showed similarly low rates of strokes of stroke in patients treated with dabigatran or warfarin (43). Recently, a phase II trial investigating the effect of a 6-month treatment of dabigatran etexilate on top of aspirin and clopidogrel in 1,878 patients with ACS has been carried out (RE-DEEM [Dose Finding Study for Dabigatran Etexilate in Patients With Acute Coronary Syndrome] trial). Its results, which suggest that using additional anti- platelet therapy with dabigatran in patients after percutane- ous coronary intervention is safe, were first presented at the American Heart Association Scientific Sessions 2009. This is of relevance in a relatively large group of patients with AF Figure 3 Total Bleeding in the RE-LY Trial undergoing percutaneous coronary intervention for stable Total bleeding was significantly reduced with both 150-mg (16.4% per year, RR: coronary artery disease or ACS (44). 0.91, 95% CI: 0.86 to 0.97, p ϭ 0.002) and 110-mg (14.6% per year, RR: Notably, no significant rise in liver enzymes was noted 0.78, 95% CI: 0.74 to 0.83, p Ͻ 0.001) dabigatran compared with warfarin during the entire dabigatran study program. The pharma- (18.2% per year). Adapted, with permission, from Connolly et al. (39). Abbrevia- tions as in Figure 2. cokinetic profile of dabigatran shows no interaction with cytochrome P450 enzymes. However, P-glycoprotein- 2072 Schirmer et al. JACC Vol. 56, No. 25, 2010 Novel Anticoagulants in Atrial Fibrillation December 14/21, 2010:2067–76 inhibitors such as amiodarone, verapamil or quinidine, all prevention of VTE only. The first phase III trial comparing used in patients with AF, may lead to an increased plasma these drugs to VKA for stroke prevention in AF concentration of dabigatran and thus increase bleeding risk. (ROCKET-AF [Randomized, Double-Blind Study Com- Up to approximately 80% of dabigatran is eliminated via the paring Once Daily Oral Rivaroxaban With Adjusted-Dose kidneys, which is why the drug may accumulate when renal Oral Warfarin for the Prevention of Stroke in Subjects function is abnormal. However, a recent RE-LY subanalysis With Non-Valvular Atrial Fibrillation]) is still in progress. presented at the annual meeting of the American College of Rivaroxaban. Rivaroxaban has a bioavailability of 80%, a Cardiology in March 2010 suggests that an interaction plasma half-life of 7 to 11 h, and is metabolized in the liver between renal function and treatment was not evident after by two-thirds, whereas one-third undergoes unchanged adjustment for age (45). The benefit of dabigatran versus renal excretion (53). Phase III orthopedic trials have dem- warfarin in reducing major bleeding was shown to be onstrated noninferior or even superior efficacy in VTE significantly attenuated with increasing age. However, the prevention of rivaroxaban compared with enoxaparin. For reduction in hemorrhagic stroke with dabigatran remained example, rivaroxaban led to RR reductions of 70% to 78% of unaffected by age (46). the primary end point (composite of deep vein thrombosis, Since March 2008, use of dabigatran for the prevention of nonfatal pulmonary embolism, or death) compared with VTE after elective hip and knee replacement has been enoxaparin in the RECORD1 (Rivaroxban [10 mg] Given approved by the accreditation authorities in Europe. An Once Daily in Patients Undergoing Total Hip Replacement economic analysis comparing dabigatran to enoxaparin in Compared to Enoxaparin) study, which compared both after hip replacement provided re- drugs over a 5-week period in 4,541 patients (mean age 63 duced costs with the oral thrombin inhibitor, which were years) after total hip replacement (54), and in the mainly due to high application costs of enoxaparin (47). In RECORD2 study using enoxaparin for 2 weeks and rivar- patients with AF otherwise requiring VKA therapy, cost oxaban for 5 weeks in 2,509 patients age 62 Ϯ 14 years (55). analyses will have to show how far the difference in drug After total knee replacement, rivaroxaban was superior to price will be counterweighed by the omitted expenses of enoxaparin (end point composite of any deep vein throm- regular anticoagulation monitoring. Total cost effectiveness bosis, nonfatal pulmonary embolism, or death) when com- of dabigatran will be favorable over warfarin if costs of pared over a period of 14 days post-operatively in 2,531 disabling stroke could indeed be reduced because of superior patients (mean age 68 years) in the RECORD3 (56) and efficacy of the drug. A cost analysis for dabigatran in AF, 3,148 (age 65 Ϯ 10 years) patients in the RECORD4 (57) however, has yet to be done. Another direct thrombin study, the latter trial comparing rivaroxaban to 2 ϫ 30-mg antagonist currently investigated, known as AZD0837, has enoxaparin. Results of the EINSTEIN (Oral Direct Factor shown promising data in phase II studies in AF, where it Xa Inhibitor Rivaroxaban In Patients With Acute Symp- was noninferior to warfarin while showing a reduced bleed- tomatic Deep-Vein Thrombosis Without Symptomatic ing risk (48,49). Pulmonary Embolism: Einstein-DVT Evaluation) study, which included 3,449 patients treated for acute deep vein thrombosis, were presented at the annual meeting of the Clinical Data on Oral Factor Xa Inhibitors European Society of Cardiology in August 2010. The study Mechanisms of action. By inhibiting factor Xa, generation showed noninferiority of rivaroxaban compared with enox- of thrombin from prothrombin is attenuated. Besides, tissue aparin/warfarin with comparable safety profiles. Another factor–induced thrombin generation is inhibited (50). As a phase III investigation in the prevention of primary VTE consequence, prothrombin time increases with factor Xa with rivaroxaban (MAGELLAN [Venous Thromboem- inhibition in a dose-dependent fashion. Parenterally appli- bolic Event (VTE) Prophylaxis in Medically Ill Patients] cable factor Xa inhibitors—, —are study) is currently being performed. Following approval for indirect (i.e., they require antithrombin as a cofactor). use after orthopedic surgery in Europe, the U.S. Food and Otamixaban is a novel intravenously applicable direct factor Drug Administration halted its favorable review because of Xa inhibitor with promising results for use after myocardial some safety concerns in the EINSTEIN-extension study, infarction (51). The focus of this review, however, lies on where a nonsignificant increase in major bleeding and in the development of oral anti-factor Xa agents with the liver enzymes had been noted with rivaroxaban (58). potential to replace VKAs as anticoagulants in AF. A The effect of rivaroxaban in AF is currently investigated growing number of direct factor Xa inhibitors have entered in the phase III ROCKET AF study, in which more than clinical testing in recent years. The lack of induction of a 14,000 patients have been randomized to receive 20 mg of release of platelet factor 4 and the lack of platelet activation rivaroxaban daily or warfarin, dose-adjusted to an INR of in the presence of heparin-induced thrombocytopenia anti- 2.0 to 3.0 (Table 1)(59). Its results are expected to become bodies have suggested factor Xa inhibitors such as rivaroxa- available by late 2010. An important feature of the ban may be potential drugs for the management of patients ROCKET AF trial is the fact that is was performed in a with heparin-induced thrombocytopenia (52). Phase III double-blind manner, with computer-generated sham INR data on factor Xa inhibitors is currently available for the values provided for patients on rivaroxaban. In contrast to JACC Vol. 56, No. 25, 2010 Schirmer et al. 2073 December 14/21, 2010:2067–76 Novel Anticoagulants in Atrial Fibrillation an open-label study design, this eliminates treatment bias, 2,809 patients treated with apixaban showed a 56% reduc- although the advantages of double-blind trials in examining tion in stroke or systemic embolism without excessive risk of anticoagulants have recently been challenged (60). increased bleeding compared with aspirin. In the recently completed phase II ATLAS ACS–TIMI 46 Betrixaban. Another factor Xa antagonist, betrixaban, has (Rivaroxaban in Combination With Aspirin Alone or With so far only been tested in phase II studies, where it has Aspirin and a in Patients With Acute demonstrated safety in the EXPERT (A randomized eval- Coronary Syndromes) trial, increasing doses of rivaroxaban uation of betrixaban, an oral factor Xa inhibitor, for pre- as secondary prevention of major cardiovascular events in vention of thromboembolic events after total knee replace- 3,491 patients with ACS resulted in dose-dependent in- ment) trial in 215 patients after total knee replacement (68). creases of bleeding but reduction of the secondary end point The results of the phase II trial of betrixaban in AF have of death, myocardial infarction and stroke (61), warranting been presented at the annual meeting of the American the larger phase III trial ATLAS–TIMI 51, which is College of Cardiology in March 2010, where betrixaban was currently recruiting patients. also shown to be safe, with a dose-dependent risk of Apixaban. In a phase III investigation to prevent throm- bleeding comparable to that of warfarin (EXPLORE-Xa boembolism after total knee replacement (ADVANCE-1 [Phase 2 Study of the Safety, Tolerability and Pilot Efficacy [Study of an Investigational Drug for the Prevention of of Oral Factor Xa Inhibitor Betrixaban Compared to Thrombosis-Related Events Following Knee Replacement Warfarin] trial) (45). Importantly, betrixaban is the only Surgery]), the use of 2.5-mg apixaban twice daily failed to new anticoagulant that is excreted almost unchanged meet the noninferiority criteria (primary end point: com- through bile with minimal renal excretion (Ͻ5%), making it posite of deep vein thrombosis, nonfatal pulmonary embo- particularly suitable for use in patients with renal failure. lism, and death) when compared with 2 ϫ 30-mg enoxapa- Edoxaban. Of the latest of the new anticoagulants, edoxa- rin daily for 10 to 14 days in 3,195 patients (mean age 66 ban, 1 phase I trial has been published so far (69). A phase years), albeit resulting in a lower risk of bleeding (62). In III study comparing its effects to warfarin in patients with another phase III trial to prevent VTE after knee replace- AF is currently being performed (ENGAGE-AF–TIMI 48 ment in 3,057 patients with a mean age of 66 years, the trial [Global Study to Assess the Safety and Effectiveness of ADVANCE-2 trial, apixaban was superior to 40-mg enox- DU-176b vs. Standard Practice of Dosing With Warfarin in aparin daily for 10 to 14 days without an increase in Patients With Atrial Fibrillation]: NCT00781391)(Table 1). bleeding (63). Other phase III investigations of apixaban for Also, a phase III trial comparing edoxaban to warfarin for the primary prevention (ADOPT [Study of Apixaban for the treatment of VTE, the Edoxaban Hokusai-VTE study the Prevention of Thrombosis-Related Events in Patients (Comparative Investigation of Low Molecular Weight With Acute Medical Illness]: NCT00457002) or treatment (LMW) Heparin/Edoxaban Tosylate (DU176b) Versus of deep venous thrombosis and pulmonary embolism (Effi- (LMW) Heparin/Warfarin in the Treatment of Symptom- cacy and Safety Study of Apixaban for the Treatment of atic Deep-Vein Blood Clots and/or Lung Blood Clots: Deep Vein Thrombosis or Pulmonary Embolism: NCT00986154), is actively recruiting patients. NCT00643201) are currently recruiting patients. Other compounds. Other factor Xa inhibitors in clinical In a phase II study (APPRAISE [Apixaban for Preven- development include YM150 (70), which is being examined tion of Acute Ischemic and Safety Events] study) in 1,715 in a phase II trial in AF (A Study Evaluating Safety and patients with ACS, apixaban led to a dose-dependent Tolerability of YM150 Compared to Warfarin in Subjects increase in bleeding and a trend towards a reduction of With Atrial Fibrillation: NCT00938730) and LY-517717, recurrent ischemic events (64). A phase III trial is currently which has hitherto only been investigated in knee arthro- recruiting participants (Phase III Acute Coronary Syn- plasty (71). drome [APPRAISE-2]: NCT00831441). A large phase III trial in patients with AF, the ARISTOTLE Potential Limitations (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation) trial comparing apixaban to warfarin, is cur- Some of the advantages of the newly developed drugs might rently being conducted (Table 1). Enrolment of 18,206 translate into disadvantages in clinical practice. The nonre- patients has been completed, and study results are expected quirement for regular anticoagulation monitoring also pro- in April 2011 (65). The AVERROES study (A Phase III vides a lack of laboratory monitoring in case of bleeding or Study of Apixaban in Patients With Atrial Fibrillation: thrombosis. Thus, patient adherence cannot be tested as it NCT00496769), which compared apixaban to aspirin (end can with VKA. Some of the novel agents require twice daily point: composite of stroke or systemic embolism, see also dosing, again potentially lowering effectiveness of the Table 1) in patients with AF unsuitable for VKA therapy drug in patients with low compliance. Similarly, rather (66), was halted prematurely because of a superior efficacy of fast onset and offset of the novel compounds compared the study drug in reducing thromboembolic events (67). with VKA may translate into a disadvantage in these The results were presented at the annual meeting of the patients. Antidotes have not been developed yet for drugs European Society of Cardiology in August 2010. A total of that have almost reached bedside of patients with AF, 2074 Schirmer et al. JACC Vol. 56, No. 25, 2010 Novel Anticoagulants in Atrial Fibrillation December 14/21, 2010:2067–76 although strategies for overdose treatment, e.g., charcoal them have proven to be at least noninferior to warfarin or therapy and hemodialysis in dabigatran overdose, have heparin in the prevention or treatment of AF-unrelated been proposed (30). thromboembolism. In AF, dabigatran was the first to provide data from a phase III trial, making it an alternative Thrombin and Vascular Pathophysiology: to VKA. Although the novel anticoagulants are all very Beyond Anticoagulation attractive in theory, data from large clinical trials are of critical importance as was strikingly demonstrated in the Apart from its role as the effector molecule of the coagula- tion cascade, thrombin exerts other, often detrimental case of ximelagatran. Further studies will show whether effects in cardiovascular pathophysiology. Outside of blood other drugs such as the factor Xa inhibitors can raise similar clotting, thrombin acts via protease-activated receptors hopes to replace the VKAs for stroke prevention in patients (PAR) and thrombomodulin, both of which become up- with AF. Conclusions on differences in effectiveness and safety regulated upon vascular injury as in atherosclerosis. Endo- between different new compounds will, however, be limited as thelial dysfunction is the primary event in atherosclerosis long as head-to-head comparisons have not been carried out (72). Thrombin has a negative effect on endothelial func- (for a comparison of the study designs, see Table 1). Safety tion, inhibiting nitric oxide (NO) production and increasing profiles will play a decisive role in the race for the most endothelin expression by stimulating endothelin converting successful anticoagulant, when efficacy data of most currently enzyme via a Rho/ROCK and ERK pathways, respectively developed compounds show superiority to VKA. Future clin- (73). A stimulatory effect of thrombin on arginase contrib- ical analyses will show whether direct factor Xa or thrombin utes to reduced NO bioavailability (74). Inhibition of inhibitors have additional beneficial cardiovascular effects as endothelial nitric oxide synthase and impairment of endo- suggested by pre-clinical data. thelial function by thrombin suggest that thrombin inhibi- tors potentially exert antiatherosclerotic effects (73). Reprint requests and correspondence: Dr. Stephan H. Schirmer, The thrombin receptor PAR1 is essential for leukocyte Klinik für Innere Medizin III, Kardiologie, Angiologie und recruitment and inflammation (75). Inflammatory cell re- Internistische Intensivmedizin, Universitätsklinikum des Saarlan- ␤ cruitment into atherosclerotic plaques might therefore be des, Kirrberger Stra e, 66424 Homburg/Saar, Germany. E-mail: inhibited by thrombin antagonists. AF is commonly found [email protected]. in patients suffering from atherosclerosis, and inflammatory cells contribute to atherosclerotic plaque instability (76,77). Potentially, patients with atherosclerotic disease and AF REFERENCES benefit from a thrombin inhibitor–caused reduction of 1. Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial inflammation in the atherosclerotic plaque. 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Rationale and design of AVERROES: apixaban versus acetylsalicylic acid to prevent stroke in Key Words: anticoagulants y atrial fibrillation y thrombin inhibitor.