Dabigatran etexilate: A new oral thrombin inhibitor

Circulation

Volumn 123, Issue 13, 2011, Pages 1436-1450

  Hankey, Graeme J ^a   Eikelboom, John W ^b  

^a ROYAL PERTH HOSPITAL   (Australia)

^b MCMASTER UNIVERSITY   (Canada)

Author keywords

anticoagulants; atrial fibrillation; dabigatran etexilate; direct thrombin inhibitor; stroke

Indexed keywords

ACETYLSALICYLIC ACID; DABIGATRAN ETEXILATE; ENOXAPARIN; WARFARIN; XIMELAGATRAN;

ABDOMINAL PAIN; AMINOTRANSFERASE BLOOD LEVEL; ARTICLE; BLEEDING; BRAIN HEMORRHAGE; DEEP VEIN THROMBOSIS; DRUG ABSORPTION; DRUG EFFICACY; DRUG EXCRETION; DRUG FORMULATION; DRUG HALF LIFE; DRUG MECHANISM; DRUG METABOLISM; DRUG OVERDOSE; DRUG SAFETY; DRUG WITHDRAWAL; DYSPEPSIA; GASTROINTESTINAL HEMORRHAGE; HEART ATRIUM FIBRILLATION; HUMAN; LIVER TOXICITY; LUNG EMBOLISM; PRIORITY JOURNAL; RISK BENEFIT ANALYSIS; SIDE EFFECT; VENOUS THROMBOEMBOLISM;

ADMINISTRATION, ORAL; ANIMALS; ANTICOAGULANTS; ANTITHROMBIN PROTEINS; BENZIMIDAZOLES; HUMANS; PRODRUGS; PYRIDINES; RANDOMIZED CONTROLLED TRIALS AS TOPIC; THROMBIN; VENOUS THROMBOEMBOLISM;

EID: 79954456496     PISSN: 00097322     EISSN: 15244539     Source Type: Journal    
DOI: 10.1161/CIRCULATIONAHA.110.004424     Document Type: Article

References (74)

1. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med. 2007;146:857-867. (Pubitemid 351650486)
2. Sun JCJ, Davidson MJ, Lamy A, Eikelboom JW. Antithrombotic management of patients with prosthetic heart valves: current evidence and future trends. Lancet. 2009;374:565-576.
3. Hurlen M, Abdelnoor M, Smith P, Erickssen J, Arnesen H. Warfarin, aspirin, or both after myocardial infarction. N Engl J Med. 2002;347: 969-974.
4. Gross PL, Weitz JI. New anticoagulants for treatment of venous thromboembolism. Arterioscler Thromb Vasc Biol. 2008;28:380-386.
5. Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest. 2008;133:160S-198S. (Pubitemid 351892967)
6. Baker WL, Cios DA, Sander SD, Coleman CI. Meta-analysis to assess the quality of warfarin control in atrial fibrillation patients in the United States. J Manag Care Pharm. 2009;15:244-252.
7. International Warfarin Pharmacogenetics Consortium. Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl J Med. 2009;360:753-764.
8. Eckman MH, Rosand J, Greenberg SM, Gage BF. Cost-effectiveness of using pharmacogenetic information in warfarin dosing for patients with nonvalvular atrial fibrillation. Ann Intern Med. 2009;150:73-83.
9. Go AS, Hylek EM, Chang Y, Phillips KA, Henault LE, Capra AM, Jensvold NG, Selby JV, Singer DE. Anticoagulation therapy for stroke prevention in atrial fibrillation: how well do randomized trials translate into clinical practice? JAMA. 2003;290:2685-2692. (Pubitemid 37475596)
10. Nieuwlaat R, Capucci A, Camm AJ, Olsson SB, Andresen D, Davies DW, Cobbe S, Breithardt G, Le Heuzey JY, Prins MH, Lévy S, Crijns HJ; European Heart Survey Investigators. Atrial fibrillation management: a prospective survey in ESC member countries: the Euro Heart Survey on Atrial Fibrillation. Eur Heart J. 2005;26:2422-2434. (Pubitemid 41552972)
11. Birman-Deych E, Radford MJ, Nilasena DS, Gage BF. Use and effectiveness of warfarin in Medicare beneficiaries with atrial fibrillation. Stroke. 2006;37:1070-1074.
12. Weitz JI, Hirsh J, Samama MM. New antithrombotic drugs: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest. 2008;133:234S-256S. (Pubitemid 351892968)
13. Eriksson BI, Quinlan DJ, Eikelboom JW. Novel oral factor Xa and thrombin inhibitors in the management of thromboembolism. Annu Rev Med. 2011;62:41-57.
14. Huntington JA, Baglin TP. Targeting thrombin: rational drug design from natural mechanism. Trends Pharmacol Sci. 2003;24:589-595. (Pubitemid 37357143)
15. Eriksson BI, Quinlan DJ, Weitz JI. Comparative pharmacodynamics and pharmacokinetics of oral direct thrombin and factor Xa inhibitors in development. Clin Pharmacokinet. 2009;48:1-22.
16. Testa L, Bhindi R, Agostoni P, Abbate A, Zoccai GG, Van Gaal WJ. The direct thrombin inhibitor ximelagatran/melagatran: a systematic review on clinical applications and an evidence based assessment of risk benefit profile. Expert Opin Drug Saf. 2007;6:397-406. (Pubitemid 351308168)
17. Di Nisio M, Middledrorp S, Buller HR. Direct thrombin inhibitors. N Engl J Med. 2005;353:1028-1040. (Pubitemid 41262337)
18. Baetz BE, Spinler SA. Dabigatran etexilate: an oral direct thrombin inhibitor for prophylaxis and treatment of thromboembolic diseases. Pharmacotherapy. 2008;28:1354-1373.
19. Eisert WG, Hauel N, Stangier J, Wienen W, Clemens A, Van Ryn J. Dabigatran: an oral novel potent reversible nonpeptide inhibitor of thrombin. Arterioscler Thromb Vasc Biol. 2010;30:1885-1889.
20. Van Ryn J, Hauel N, Waldman L, Wienen W. Dabigatran inhibits both clot-bound and fluid-phase thrombin in vitro: comparison to heparin and hirudin [abstract 570]. Arterioscler Thromb Vasc Biol. 2008:28: e136-e137.
21. Weitz JI, Hudoba M, Massel D, Maraganore J, Hirsh J. Clot-bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin III-independent inhibitors. J Clin Invest. 1990;86:385-391. (Pubitemid 20271869)
22. Weitz JI, Leslie B, Hudoba M. Thrombin binds to soluble fibrin degradation products where it is protected from inhibition by heparinantithrombin but susceptible to inactivation by antithrombin-independent inhibitors. Circulation. 1998;97:544-552. (Pubitemid 28090683)
23. Stangier J, Stähle H, Rathgen K, Führ R. Pharmacokinetics and pharmacodynamics of the direct oral thrombin inhibitor dabigatran in healthy elderly subjects. Clin Pharmacokinet. 2008;47:47-59. (Pubitemid 350260888)
24. Stangier J, Rathgen K, Stähle H, Gannser 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;64:292-303. (Pubitemid 47283865)
25. Troconiz IF, Tillmann C, Liesenfeld KH, Schafer HG, Stangier J. Population pharmacokinetic analysis of the new oral thrombin inhibitor dabigatran etexilate (BIBR 148) in patients undergoing primary elective total hip replacement surgery. J Clin Pharmacol. 2007;47:371-382. (Pubitemid 46294714)
26. Blech S, Ebner T, Lidwig-Schwellinger E, Sangier J, Roth W. The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans. Drug Metab Disposition. 2008;36:386-399. (Pubitemid 351185753)
27. Ebner T, Wagner K, Wienen W. Dabigatran acylglucuronide, the major human metabolite of dabigatran: in vitro formation, stability, and pharmacological activity. Drug Metab Dispos. 2010;38:1567-1575.
28. Stangier J, Stähle 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;48:1411-1419.
29. Wolowacz SE, Roskell NS, Maciver F, Beard SM, Robinson PA, Plumb JM, Dolan G, Brenkel IJ. Economic evaluation of dabigatran etexilate for the prevention of venous thromboembolism after total knee and hip replacement surgery. Clin Ther. 2009;31:194-212.
30. Wolowacz SE, Roskell NS, Plumb JM, Clemens A, Noack H, Robinson PA, Dolan G, Brenkel IJ. Economic evaluation of dabigatran etexilate for the prevention of venous thromboembolism in patients over age 75 years or with moderate renal impairment undergoing total knee or hip replacement surgery. Thromb Haemost. 2010;103:360-371.
31. Freeman JV, Zhu RP, Owens DK, Garber AM, Hutton DW, Go AS, Wang PJ, Turakhia MP. Cost-effectiveness of dabigatran compared with warfarin for stroke prevention in atrial fibrillation. Ann Intern Med. 2011;154:1-11.
32. Stangier J, Rathgen K, Stähle 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;259-268.
33. Stangier J, Rathgen K, Stähle H, Reseki K, Körnicke T, Roth W. Coadministration of dabigatran etexilate and atorvastatin. Am J Cardiovasc Drugs. 2009;9:59-68.
34. Van Ryn J, Standier J, Liesenfeld K-H, Haertter S, Wienen W, Feuring M, Clemens A. Dabigatran etexilate: a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost. 2010;103:1116-1127.
35. Liesenfeld K-H, Schäfer HG, Troconiz IF, Tillmann C, Eriksson BI, Stangier J. Effects of the direct thrombin inhibitor dabigatran on ex vivo coagulation time in orthopedic surgery patients: a population model analysis. Br J Clin Pharmacol. 2006;62:527-537. (Pubitemid 44571573)
36. Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet. 2008; 47:285-295. (Pubitemid 351508116)
37. Stangier J, Clemens A. Pharmacology, pharmacokinetics and pharmacodynamics of dabigatran etexilate an oral direct thrombin inhibitor. Clin Appl Thromb/Hemost. 2009;15:9S-16S.
38. Van Ryn J, Ruehl D, Priepke H, Wienen W. Reversibility of the anticoagulant effect of high doses of the direct thrombin inhibitor dabigatran, by recombinant factor VIIa or activated prothrombin complex concentrate [abstract 0370]. Haematologica. 2008;93(suppl 1):148.
39. Eriksson BI, Dahl OE, Ahnfelt L, Kalebo P, Stangier J, Nehmiz G, Hermansson K, Kohlbrenner V. Dose escalating safety study of a new oral direct thrombin inhibitor, dabigatran etexilate, in patients undergoing total hip replacement: BISTRO I. J Thromb Haemost. 2004;2:1573-1580. (Pubitemid 40186173)
40. Eriksson BI, Dahl OE, Buller HR, Hettiarachchi R, Rosencher N, Bravo ML, Ahnfelt L, Piovella F, Stangier J, Kalebo P, Reilly P. A new oral direct thrombin inhibitor, dabigatran etexilate, compared with enoxaparin for prevention of thromboembolic events following total hip or knee replacement: the BISTRO II randomized trial. J Thromb Haemost. 2005;3:103-111. (Pubitemid 41647122)
41. Eriksson BI, Dahl OE, Rosencher N, Kurth AA, Van Dijk CN, Frostick SP, Kalebo P, Christiansen AV, Hantel S, Hettiarachchi R, Schnee J, Buller HR. Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. J Thromb Haemost. 2007;5:2178-2185. (Pubitemid 47617868)
42. Eriksson BI, Dahl OE, Rosencher N, Kurth AA, Van Dijk CN, Frostick SP, Prins MH, Hettiarachchi R, Hantel S, Schnee J, Buller HR. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial. Lancet. 2007;370:949-956. (Pubitemid 47393577)
43. Ginsberg JS, Davidson BL, Comp PC, Francis CW, Friedman RJ, Huo MH, Lieberman JR, Muntz JE, Raskob GE, Clements ML, Hantel S, Schnee JM, Caprini JA. Oral thrombin inhibitor dabigatran etexilate vs North American enoxaparin regimen for prevention of venous thromboembolism after knee arthroplasty surgery. J Arthroplasty. 2009;24:1-9.
44. Eriksson BI, Dahl OE, Huo MH, Kurth AA, Hantel S, Hermansson K, Schnee JM, Friedman RJ, the RE-NOVATE II Study Group. Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II). A randomised, double-blind, noninferiority trial. Thromb Haemost. 2011;105(4). [Epub ahead of print].
45. Schulman S, Kearon C, Kakkar A, Mismetti P, Schellong S, Ericksson H. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361:2342-2352.
46. Ezekowitz MD, Reilly PA, Nehmiz G, Simmers TA, Nagarakanti R, Parcham-Azad K, Pedersen KE, Lionetti DA, Stangier J, Wallentin L. Dabigatran with or without concomitant aspirin compared with warfarin alone in patients with nonvalvular atrial fibrillation (PETRO study). Am J Cardiol. 2007;100:1419-1426. (Pubitemid 47576022)
47. Ezekowitz MD, Connolly S, Parekh A, Reilly PA, Varrone J, Wang S, Oldgren J, Themeles E, Wallentin L, Yusuf S. Rationale and design of RE-LY: randomized evaluation of long-term anticoagulant therapy, warfarin, compared with dabigatran. Am Heart J. 2009;157:805-810.
48. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener H-C, Joyner CD, Wallentin L; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139-1151.
49. Connolly SJ, Ezekowitz MD, Yusuf S, Reilly PA, Wallentin L; Randomized Evaluation of Long-Term Anticoagulation Therapy Investigators. Newly identified events in the RE-LY trial [letter to the editor]. N Engl J Med. 2010;363:1875-1876.
50. Stiles S. Oral anticoagulants REDEEMed? Daily dabigatran "safe" with dual antiplatelets after MI. http://www.theheart.org/article/1026791.do. Accessed September 24, 2010.
51. Gustafsson D, Nystrom J-E, Carlsson S, Bredberg U, Eriksson U, Gyzander E, Elg M, Antonsson T, Hoffmann K-J, Ungell A-L, Sorensen H, Nagard S, Abrahamsson A, Bylund R. The direct thrombin inhibitor melagatran and its oral prodrug H376/95: intestinal absorption properties, biochemical and pharmacodynamic effects. Thromb Res. 2001;101:171-181. (Pubitemid 32176022)
52. Sergent O, Ekroos K, Lefeuvre-Orfila L, Rissel M, Forsberg G-B, Oscarsson J, Andersson TB, Lagadic-Gossman L. Ximelagatran increases membrane fluidity and changes membrane lipid composition in primary human hepatocytes. Toxicol In Vitro. 2009;23:1305-1310.
53. Wolowacz SE, Roskell NS, Plumb JM, Caprini JA, Eriksson BI. Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty: a meta-analysis. Thromb Haemost. 2009;101:77-85.
54. Hankey GJ, Eikelboom. Antithrombotic drugs for patients with ischaemic stroke and transient ischaemic attack to prevent recurrent major vascular events. Lancet Neurol. 2010;9:273-284.
55. US FDA Advisory Committee Briefing Document. August 27, 2010; page 155. http://www.fda.gov/downloads/AdvisoryCommittees/ CommitteesMeetingMaterials/ Drugs/CardiovascularandRenalDrugs AdvisoryCommittee/UCM226009.pdf?bcsi scan 33FB12C90BF1B18A-1. Accessed December 20, 2010.
56. US FDA Advisory Committee Addendum to Clinical Review for NDA 22-512: risk of myocardial infarction. September 2, 2010. http:// www.fda.gov/downloads/ AdvisoryCommittees/CommitteesMeeting Materials/Drugs/ CardiovascularandRenalDrugsAdvisoryCommittee/ UCM226012.pdf. Accessed December 20, 2010.
57. Lip GY, Lane DA. Does warfarin for stroke thromboprophylaxis protect against MI in atrial fibrillation patients? Am J Med. 2010;123:785-789.
58. Wallentin L, Yusuf S, Ezekowitz MD, Alings M, Flather M, Franzosi MG, Pais P, Dans A, Eikelboom J, Oldgren J, Pogue J, Reilly PA, Yang S, Connolly SJ; RE-LY investigators. Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial. Lancet. 2010;376:975-983.
59. Diener H-C, Connolly SJ, Ezekowitz MD, Wallentin L, Reilly PA, Yang S, Xavier D, Di Pasquale G, Yusuf S; RE-LY Study Group. Dabigatran compared with warfarin in patients with atrial fibrillation and previous transient ischaemic attack or stroke: a subgroup analysis of the RE-LY trial. Lancet Neurol. 2010;9:1157-1163.
60. Roskell NS, Lip GYH, Noack H, Clemens A, Plumb JM. Treatments for stroke prevention in atrial fibrillation: a network meta-analysis and indirect comparisons versus dabigatran etexilate. Thromb Haemost. 2010; 104:1106-1115.
61. Stiles S. Warfarin, move over: dabigatran gets unanimous thumbs-up from FDA advisory panel. http://www.theheart.org/article/1123797.do. Accessed September 21, 2010.
62. Wood S, O'Riordan M. FDA approves dabigatran for stroke prevention, embolism, in AF patients. http://www.theheart.org/article/1138703.do. Accessed October 25, 2010.
63. PRADAX™ (dabigatran etexilate) gains approval in Canada for stroke prevention in atrial fibrillation. http://www.seekingmedia.com.au/ news.php?newsid-1640&g-1. Accessed December 20, 2010.
64. Medi C, Hankey GJ, Freedman SB. Stroke risk and antithrombotic strategies in atrial fibrillation. Stroke. 2010;41:2705-2713.
65. RELY-ABLE long term multi-center extension of dabigatran treatment in patients with atrial fibrillation who completed RE-LY trial. http:// www.clinicaltrials.gov/ct2/show/NCT00808067?term-RELY&rank-2. Accessed October 6, 2010.
66. Jungbauer L, Dobias C, Stöllberger C, Weidinger F. The frequency of prescription of P-glycoprotein-affecting drugs in atrial fibrillation. J Thromb Haemost. 2010;8:2069-2070.
67. Eikelboom JW, Weitz JI. Update on antithrombotic therapy: new anticoagulants. Circulation. 2010;121:1523-1532.
68. ROCKET AF Study Investigators. Rivaroxaban-Once Daily, oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation: rationale and design of the ROCKET AF study. Am Heart J. 2010;159:340-347.e1.
69. Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation (ARISTOTLE). http://www.clinicaltrials.gov/ct2/show/NCT00412984? term- ARISTOTLE&rank-1. Accessed October 6, 2010.
70. Connolly SJ, Eikelboom J, Joyner C, Diener H-C, Hart R, Golitsyn S, Flaker G, Avezum A, Hohnloser SH, Diaz R, Talajic M, Zhu J, Pais P, Budaj A, Parkhomenko A, Jansky P, Commerford P, Tan RS, Sim KH, Lewis BS, Mieghem WV, Lip GYH, Kim JH, Lanas-Zanetti F, Gonzalez-Hermosillo A, Dans AL, Munawar M, O'Donnell M, Lawrence J, Lewis G, Afzal R, Yusuf S, for the AVERROES Steering Committee and Investigators. Apixaban in patients with atrial fibrillation. New Engl J Med. 2011;364:806-817.
71. Global Study to Assess the Safety and Effectiveness of DU-176b vs Standard Practice of Dosing With Warfarin in Patients With Atrial Fibrillation (EngageAFTIMI48). http://www.clinicaltrials.gov/ct2/show/ NCT00781391?term- ENGAGEAFTIMI48&rank-1 Accessed October 6, 2010.
72. Schirmer SH, Baumhäkel M, Neuberger H-R, Hohnloser SH, Van Gelder IC, Lip GYH, Böhm M. Novel anticoagulants for stroke prevention in atrial fibrillation. J Am Coll Cardiol. 2010;56:2067-2076.
73. Hankey GJ, Eikelboom JW. What do the results of the PRoFESS trial teach us? Lancet Neurol. 2008;7:860-862.
74. Wann LS, Curtis AB, Ellenbogen KA, Estes NAM 3rd, Ezekowitz MD, Jackman WM, January CT, Lowe JE, Page RL, Slotwiner DJ, Stevenson WG, Tracy CM, writing on behalf of the 2006 ACC/AHA/ESC Guidelines for the Management of Patients With Atrial Fibrillation Writing Committee. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (update on dabigatran): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2011; 123:1144-1150.