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

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Novel Anticoagulants for Stroke Prevention in Atrial Fibrillation Current Clinical Evidence and Future Developments View metadata, citation and similar papers at core.ac.uk brought to you by CORE 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 Anticoagulants 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. Antithrombotic therapy using aspirin 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 anticoagulant drugs. Re- cently developed anticoagulants include direct thrombin antagonists such as dabigatran or factor Xa inhibitors such as rivaroxaban, apixaban, betrixaban, and edoxaban. 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 warfarin 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 heparin, 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 heparins, 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 hirudin 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 Clopidogrel contrast, argatroban, ximelagatran, 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
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