Safety of edoxaban, an oral factor Xa inhibitor, in Asian patients with non-valvular atrial fibrillation

Namsik Chung; Hui-Kyung Jeon; Li-Ming Lien; Wen-Ter Lai; Hung-Fat Tse; Wook-Sung Chung; Tsong-Hai Lee; Shih-Ann Chen

doi:10.1160/TH10-07-0451

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2011; 105(03): 535-545
DOI: 10.1160/TH10-07-0451

New Technologies, Diagnostic Tools and Drugs

Schattauer GmbH

Safety of edoxaban, an oral factor Xa inhibitor, in Asian patients with non-valvular atrial fibrillation

Namsik Chung

¹Severance Hospital, Yonsei University College of Medicine No. 134, Sinchon-dong, Seodaemun-gu, Seoul, Korea

,

Hui-Kyung Jeon

²Uijeongbu St. Mary’s Hospital, Catholic University of Korea No. 65–1, Kumoh-dong, Uijeongbu City, Kyungki-do, Korea

,

Li-Ming Lien

³Shin Kong Wu Ho-Su Memorial Hospital No. 95, Shihlin District, Taipei, Taiwan

,

Wen-Ter Lai

⁴Chung-Ho Memorial Hospital, Kaohsiung Medical University No.100, Kaohsiung, Taiwan

,

Hung-Fat Tse

⁵Queen Mary Hospital No. 102, Hong Kong, China

,

Wook-Sung Chung

⁶St. Mary’s Hospital No. 62, Yeouido-dong, Yeongdeungpo-gu, Seoul, Korea

,

Tsong-Hai Lee

⁷Chang Gung Memorial Hospital – Linko No. 5, Kuei Shan, Taoyuan, Taiwan

,

Shih-Ann Chen

⁸Taipei Veterans General Hospital No. 201, Sec. 2, Taipei 112, Taiwan

› Institutsangaben

Abstract

Summary

Edoxaban is an oral, reversible, direct factor Xa inhibitor in phase III clinical development for the prevention of stroke in atrial fibrillation (AF). A phase II study was undertaken to evaluate the safety and efficacy of edoxaban in Asian patients with non-valvular AF with CHADS₂ score ≥1. In a multicentre, active-controlled, double-blind edoxaban and open-label warfarin, parallel-group study, a total of 235 patients from four Asian countries were randomly assigned to edoxaban 30 mg qd, 60 mg qd or warfarin dose adjusted to international normalised ratio of 2–3 for three months. The primary endpoint was the incidence of centrally adjudicated all bleeding events (major, clinically relevant non-major and minor). Secondary endpoints included thromboembolic events, biomarkers of thrombus formation and all adverse events (AEs). The incidence of all bleeding events (95% CI) was 20.3% (12.9, 30.4) for edoxaban 30 mg, 23.8% (15.8, 34.1) for edoxaban 60 mg, and 29.3% (20.2, 40.4) for warfarin. A subgroup analysis suggested low body weight (≤60 kg) may affect the incidence of bleeding events with edoxaban. The incidence of study drug-related AEs was 22% for edoxaban 30 mg, 29% for edoxaban 60 mg and 33% for warfarin. No thromboembolic events occurred in any treatment group. In conclusion, this phase II study found a trend for a reduction in the incidence of all bleeding events in Asian AF patients with edoxaban 30 mg and 60 mg compared with warfarin. Adverse events were similar between the edoxaban 60-mg and warfarin groups and were lower with the edoxaban 30-mg group.

ClinicalTrials.gov number: NCT00806624

Keywords

Edoxaban - non-valvular atrial fibrillation - factor Xa inhibitor - anticoagulant - warfarin

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Referenzen

References
1 Albers GW, Dalen JE, Laupacis A. et al. Antithrombotic therapy in atrial fibrillation. Chest 2001; 119 (Suppl. 01) 194S-206S.
2 Go AS, Hylek EM, Phillips KA. et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. J Am Med Assoc 2001; 285: 2370-2375.
3 Benjamin EJ, Wolf PA, D’Agostino RB. et al. Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation 1998; 98: 946-952.
4 Flegel KM, Shipley MJ, Rose G. Risk of stroke in non-rheumatic atrial fibrillation. Lancet 1987; 1: 526-529.
5 Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation.. Analysis of pooled data from five randomized controlled trials. Arch Intern Med 1994; 154: 1449-1457.
6 Hart RG, Benavente O, McBride R. et al. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis. Ann Intern Med 1999; 131: 492-501.
7 Thromboembolic prophylaxis in 3575 hospitalized patients with atrial fibrillation.. The Clinical Quality Improvement Network (CQIN) Investigators. Can J Cardiol 1998; 14: 695-702.
8 Waldo AL, Becker RC, Tapson VF. et al. Hospitalized patients with atrial fibrillation and a high risk of stroke are not being provided with adequate anticoagulation. J Am Coll Cardiol 2005; 46: 1729-1736.
9 Go AS, Hylek EM, Borowsky LH. et al. Warfarin use among ambulatory patients with nonvalvular atrial fibrillation: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study. Ann Intern Med 1999; 131: 927-934.
10 Hylek EM, D’Antonio J, Evans-Molina C. et al. Translating the results of randomized trials into clinical practice: the challenge of warfarin candidacy among hospitalized elderly patients with atrial fibrillation. Stroke 2006; 37: 1075-1080.
11 Birman-Deych E, Radford MJ, Nilasena DS. et al. Use and effectiveness of warfarin in Medicare beneficiaries with atrial fibrillation. Stroke 2006; 37: 1070-1074.
12 Friberg L, Hammar N, Ringh M. et al. Stroke prophylaxis in atrial fibrillation: who gets it and who does not? Report from the Stockholm Cohort-study on Atrial Fibrillation (SCAF-study). Eur Heart J 2006; 27: 1954-1964.
13 Ingelgard A, Hollowell J, Reddy P. et al. What are the barriers to warfarin use in atrial fibrillation?: Development of a questionnaire. J Thromb Thrombolysis 2006; 21: 257-265.
14 Gattellari M, Worthington J, Zwar N. et al. Barriers to the use of anticoagulation for nonvalvular atrial fibrillation: a representative survey of Australian family physicians. Stroke 2008; 39: 227-230.
15 Fuster V, Ryden LE, Cannom DS. et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation--executive summary: 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 to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation). J Am Coll Cardiol 2006; 48: 854-906.
16 Ogata K, Mendell-Harary J, Tachibana M. et al. Clinical safety, tolerability, pharmacokinetics, and pharmacodynamics of the novel factor Xa inhibitor edoxaban in healthy volunteers. J Clin Pharmacol 2010; 50: 743-753.
17 Samama MM, Wolzt M, Ogata K, Mendell J, Kunitada S. Effect of edoxaban (DU-176b) on thrombin generation and platelet activation in shed and venous blood with fondaparinux as active comparator. Eur Heart J 2009; 30: 331 (Poster P2105).
18 Suzuki S, Yamashita T, Kato T. et al. Incidence of major bleeding complication of warfarin therapy in Japanese patients with atrial fibrillation. Circ J 2007; 71: 761-765.
19 Gage BF, Waterman AD, Shannon W. et al. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. J Am Med Assoc 2001; 285: 2864-2870.
20 Newcombe RG. Two-sided confidence intervals for the single proportion: comparison of seven methods. Stat Med 1998; 17: 857-872.
21 Newcombe RG. Interval estimation for the difference between independent proportions: comparison of eleven methods. Stat Med 1998; 17: 873-890.
22 Rosendaal FR, Cannegieter SC, van der Meer FJ. et al. A method to determine the optimal intensity of oral anticoagulant therapy. Thromb Haemost 1993; 69: 236-239.
23 Yasaka M, Inoue H, Kawai Y. et al. Randomized, parallel group, warfarin control, multicenter phase II study evaluating safety of DU-176b in Japanese subjects with non-valvular atrial fibrillation (NVAF). Boston, MA: XXII Congress of The International Society on Thrombosis and Haemostasis (ISTH); July 11–16, 2009. J Thromb Haemost 2009; 7: 376 (Abstract).
24 Weitz JI, Connolly SJ, Patel I. et al. Randomised, parallel-group, multicentre, multinational phase 2 study comparing edoxaban, an oral factor Xa inhibitor, with warfarin for stroke prevention in patients with atrial fibrillation. Thromb Haemost 2010; 104: 633-641.
25 Daiichi Sankyo I. TIMI Study Group.. Global Study to Assess the Safety and Effectiveness of DU-176b vs Standard Practice of Dosing With Warfarin in Patients With Atrial Fibrillation (EngageAFTIMI48). Clinicaltrials.gov, US National Institutes of Health. Updated November 19, 2009. http://www.clinicaltrials.gov/ct2/show/NCT00781391?term=00781391&rank=1 Accessed December 3, 2009.