Dabigatran Etexilate: An Oral Direct Thrombin Inhibitor for the Management of Thromboembolic Disorders

Clinical Therapeutics

Volumn 34, Issue 4, 2012, Pages 766-787

  Cheng, Judy W M ^a,b   Vu, Huyen ^a  

^a MASSACHUSETTS COLLEGE OF PHARMACY AND HEALTH SCIENCES   (United States)

^b BRIGHAM AND WOMEN S HOSPITAL   (United States)

Author keywords

Atrial fibrillation; Dabigatran etexilate; Venous thromboembolism

Indexed keywords

AMIODARONE; CLOPIDOGREL; DABIGATRAN ETEXILATE; ENOXAPARIN; KETOCONAZOLE; PANTOPRAZOLE; QUINIDINE; RIFAMPICIN; VERAPAMIL; WARFARIN;

ADVERSE OUTCOME; BLEEDING; CARDIOVERSION; DRUG ANTAGONISM; DRUG BLOOD LEVEL; DRUG COST; DRUG MECHANISM; DRUG METABOLISM; DYSPEPSIA; GASTRITIS; GROUPS BY AGE; HEART ATRIUM FIBRILLATION; HIP ARTHROPLASTY; HUMAN; KIDNEY DISEASE; LIVER DYSFUNCTION; LOADING DRUG DOSE; RECURRENT DISEASE; REVIEW; SEX DIFFERENCE; VENOUS THROMBOEMBOLISM;

ADULT; AGED; AREA UNDER CURVE; BENZIMIDAZOLES; BIOLOGICAL AVAILABILITY; FEMALE; HUMANS; MALE; PRODRUGS; PYRIDINES; RANDOMIZED CONTROLLED TRIALS AS TOPIC; THROMBOEMBOLISM;

EID: 84859583311     PISSN: 01492918     EISSN: 1879114X     Source Type: Journal    
DOI: 10.1016/j.clinthera.2012.02.022     Document Type: Review

References (66)

1. Ansell J., Hirsh J., Hylek E., et al. 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.
2. Hirsh J., O'Donnell M., Eikelboon J.W. Beyond unfractionated heparin and warfarin: current and future advances. Circulation 2007, 116:552-560.
3. Nutescu E.A., Wittkowsky A.K. Direct thrombin inhibitors for anticoagulation. Ann Pharmacother 2004, 38:99-109.
4. Spinler S.A., Wittkowsky A.K., Nutescu E.A., Smythe M.A. Anticoagulation monitoring part 2: unfractionated heparin and low-molecular-weight heparin. Ann Pharmacother 2005, 39:1275-1285.
5. DiNisio M., Middeldrorp S., Buller H.R. Direct thrombin inhibitors. N Engl J Med 2005, 353:1028-1040.
6. Gulseth M.P. Ximelagatran: an orally active direct thrombin inhibitor. Am J Health Syst Pharm 2005, 62:1451-1467.
7. Oral anticoagulant dabigatran etexilate approved in Canada Accessed May 3, 2011. http://www.pslgroup.com/dg/223ad6.htm.
8. FDA News Release: FDA approves Pradaxa to prevent stroke in people with atrial fibrillation US Food and Drug Administration, Accessed May 3, 2011. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm230241.htm.
9. Falck-Ytter Y., Francis C.W., Johanson N.A., et al. Prevention of VTE in orthopedic surgery patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practical Guidelines. Chest 2012, 141(Suppl 2):e278S-e325s.
10. th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012, 141(Suppl 2):e419S-e494S.
11. Goldhaber S.Z. Pulmonary embolism. Lancet 2004, 363:1295-1305.
12. Blann A.D., Lip G.Y. Venous thromboembolism. BMJ 2006, 332:215-219.
13. Zhan C., Miller M.R. Excess length of stay, charges, and mortality attributable to medical injuries during hospitalization. JAMA 2003, 290:1868-1874.
14. 2011 Heart Disease and Stroke Statistics (online) American Heart Association, Accessed May 3, 2011. http://circ.ahajournals.org/cgi/reprint/CIR.0b013e3182009701.
15. Ryder K.M., Benjamin E.J. Epidemiology and significance of atrial fibrillation. Am J Cardiol 1999, 89:131R-138R.
16. Wann L.S., Curtis A.B., January C.T., et al. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (updating the 2006 guideline). Circulation 2011, 123:104-123.
17. th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012, 141(Suppl 2):e531S-e575S.
18. Cairns J.A., Connolly S., McMurtry S., et al. Canadian Cardiovascular Society Atrial Fibrillation Guidelines 2010: prevention of stroke and systemic thromboembolism in atrial fibrillation and flutter. Can J Cardiol 2011, 27:74-90.
19. Guidelines for the management of atrial fibrillation. Eur Heart J 2010, 31:2369-2429. The Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology.
20. Eriksson B., Quinlan D. Oral anticoagulants in development, focus on thromboprophylaxis in patients undergoing orthopaedic surgery. Drugs 2006, 66:1411-1429.
21. Hauel N., Nar H., Priepke H., et al. Structure-based design of novel potent nonpeptide thrombin inhibitors. J Med Chem 2002, 45:1757-1766.
22. Blech S., Ebner T., Ludwig-Schwellinger E., et al. The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans. Drug Metab Dispos 2008, 36:386-399.
23. Stangier J., Eriksson B.I., Dahl O.E., et al. Pharmacokinetic profile of the oral direct thrombin inhibitor dabigatran etexilate in health volunteers and patients undergoing total hip replacement. J Clin Pharmacol 2005, 45:555-563.
24. Stangier J., Rathgen K., Stahle H., et al. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subject. Br J Clin Pharmacol 2007, 64:292-303.
25. Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet 2008, 47:285-295.
26. Dabigatran Etexilate Advisory Committee Briefing Document Boehringer Ingelheim, Accessed May 4, 2011. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/UCM226009.pdf.
27. Stangier J., Stahle H., Rathgen K., Fuhl R. Pharmacokinetics and pharmacodynamics of the direct oral thrombin inhibitor dabigatran in healthy elderly subjects. Clin Pharmacokinet 2008, 47:47-59.
28. Pradaxa (dabigatran etexilate). US prescribing information, updated March 2011 Accessed February 21, 2012. http://bidocs.boehringer-ingelheim.com/BIWebAccess/ViewServlet.ser?docBase=renetnt&folderPath=/Prescribing%20Information/PIs/Pradaxa/Pradaxa.pdf.
29. Stangier J., Stahle H., Rathgen K., et al. 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.
30. 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-center study. Clin Pharmacokinet 2010, 49:259-268.
31. Eriksson B.I., Dahl O.E., Ahnfelt L., et al. 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.
32. Eriksson B.I., Dahl O.E., Buller R., et al. A new oral direct thrombin inhibitor, dabigatran etexilate, compared with enoxaparin for prevention of thromboembolic events following total hip or knee replacement: BISTRO II randomized trial. J Thromb Haemost 2005, 3:103-111.
33. Eriksson B.I., Dahl O.E., Rosencher N., et al. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomized, double-blind, non-inferiority trial. Lancet 2007, 370:949-956.
34. Eriksson B.I., Dahl O.E., Rosencher N., et al. 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.
35. Enoxaparin (Lovenox) US Prescribing Information Updated April 20,2011, Accessed March 8, 2012. http://products.sanofi.us/lovenox/lovenox.html#section-5.1.
36. 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. The RE-MOBLIZE Writing Committee.
37. Schulman S., Kearon C., Kakkar A.K., et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009, 361:2342-2352.
38. Ezekowitz M.D., Reilly P.A., Nehmiz G., et al. Dabigatran with or without concomitant aspirin compared with warfarin alone in patients with novalvular atrial fibrillation (PETRO study). Am J Cardiol 2007, 100:1419-1426.
39. Connolly S.J., Ezekowitz M.D., Yusuf S., et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009, 361:1139-1151.
40. Fuji T., Fujita S., Ujihira T., Sato T. Dabigatran etexilate prevents venous thromboembolism after total knee arthroplasty in Japanese patients with a safety profile comparable to placebo. J Arthroplasty 2010, 25:1267-1274.
41. Friedman R.J., Dahl O.E., Rosencher N., et al. Dabigatran versus enoxaparin for prevention of venous thromboembolism after hip or knee arthroplasty: a pooled analysis of three trials. Thrombosis Res 2010, 126:175-182.
42. Huisman M.V., Quinlan D.L., Dahl O.E., Schulman S. Enoxaparin versus dabigatran or rivaroxaban for thromboprophylaxis after hip or knee arthroplasty: results of separate pooled analyses of Phase III multicenter randomized trials. Cir Cardiovasc Qual Outcomes 2010, 3:652-660.
43. Wolowacz S.E., Roskell N.S., Plumb J.M., et al. Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty. Thromb Haemost 2009, 101:77-85.
44. Trkulja V., Kolundzic R. Rivaroxaban vs dabigatran for thromboprophylaxis after joint replacement surgery: exploratory indirect comparison based on meta-analysis of pivotal clinical trials. Croat Med J 2010, 51:113-123.
45. Salazar C.A., Malaga G., Malasquez G. Direct thrombin inhibitors versus vitamin K antagonists or low molecular weight heparins for prevention of venous thromboembolism following total hip or knee replacement. Cochrane Database Syst Rev 2010, 4. CD005981.
46. Wallentin L., Yusuf S., Ezekowitz M.D., et al. 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.
47. Ford G.A., Choy A.M., Deedwania P., et al. Direct thrombin inhibition and stroke prevention in elderly patients with atrial fibrillation: experience from the SPORTIF III and V trials. Stroke 2007, 38:2965-2971.
48. Diener H.C., Connolly S.J., Ezekowitz M.D., et al. Dabigatran compared with warfarin in patients with atrial fibrillation and previous transient ischemic attack or stroke: a subgroup analysis of the RE-LY trial. Lancet Neurol 2010, 9:1157-1163.
49. Ezekowitz M.D., Wallentin L., Connolly S.J., et al. Dabigatran and warfarin in vitamin K antagonist-naïve and experienced cohorts with atrial fibrillation. Circulation 2010, 122:2246-2252.
50. Arnold A.Z., Mick M.J., Mazurek R.P., et al. Role of prophylactic anticoagulation for direct current cardioversion in patients with atrial fibrillation or atrial flutter. J Am Coll Cardiol 1992, 19:851-855.
51. Design of a clinical trial for the assessment of cardioversion using transesophageal echocardiography (ACUTE multicenter study). Am J Cardiol 1998, 81:877-883. Steering and Publications Committee of the ACUTE Study.
52. Nagarakanti R., Ezekowitz M.D., Oldgren J., et al. Dabigatran versus warfarin in patients with atrial fibrillation: an analysis of patients undergoing cardioversion. Circulation 2011, 123:131-136.
53. Pradaxa (dabigatran etexilate). European prescribing information, updated March 2009 HYPERLINK, and, Accessed March 8, 2012. http://www.pradaxa.co.uk/index-professional.php.
54. Boehringer Ingelheim. Pradaxa (dabigatran etexilate) Canadian product monograph. Updated October 26, 2010.
55. FDA Drug Safety Communication: Special storage and handling requirements must be followed for Pradaxa (dabigatran etexilate mesylate) capsules US Food and Drug Administration, Accessed March 8, 2012. http://www.boehringer-ingelheim.ca/content/dam/internet/opu/ca_EN/documents/humanhealth/product_monograph/Pradax-pm.pdf.
56. Elkenboom J.W., Wallentin L., Connolly S.J., et al. Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial. Circulation 2011, 123:2363-2372.
57. Van Ryn J., Stangier J., Haertter S., et al. Dabigatran etexilate-a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 2010, 103:1116-1127.
58. Wolowacz S.E., Roskell N.S., Plumb J.M., et al. Economic evaluation of dabigatran etexilate for the prevention of venous thromboembolism in patients aged over 75 years or with moderate renal impairment undergoing total knee or hip replacement. Thromb Haemost 2010, 103:360-371.
59. Eerenberg E.S., Kamphuisen P.W., Sijpkens M.K., et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in health subjects. Circulation 2011, 124. 1573-159.
60. Wolowacz S.E., Roskell N.S., Maciver F., et al. Economic evaluation of dabigatran etexilate for the prevention of venous thromboembolism after total knee and hip replacement surgery. Clin Ther 2009, 31:194-212.
61. McCullagh L., Tilson L., Walsh C., Barry M. A cost-effective model comparing rivaroxaban and dabigatran etexilate with enoxaparin sodium as thromboprophylaxis after total hip and total knee replacement in the Irish healthcare setting. Pharmacoeconomics 2009, 27:829-846.
62. Freeman J.V., Zhu R.P., Owens D.K., et al. Cost effectiveness of dabigatran compared with warfarin for stroke prevention in atrial fibrillation. Ann Intern Med 2011, 154:1-11.
63. Sorensen S.V., Kansal A.R., Connolly S., et al. Cost-effectiveness of dabigatran etexilate for the prevention of stroke and systemic embolism in atrial fibrillation: a Canadian payer perspective. Thromb Haemost 2011, 105:743-932.
64. Turpie G.G., Bauer K.A., Eriksson B.I., et al. Fondaparinux vs. enoxaparin for the prevention of venous thromboembolism in major orthopedic surgery: a meta-analysis of four randomized double-blind studies. Arch Intern Med 2002, 162:1833-1840. Steering Committee of the Pentasaccharide Orthopedic Prophylaxis Studies.
65. Pradaxa wholesale price Accessed March 8, 2012. http://www.drugstore.com/pradaxa/bottle-60-150mg-capsules/qxn00597013554.
66. Agnelli G., Eriksson B.I., Cohen A.T., et al. Safety assessment of new antithrombotic agents: lessons from EXTEND study on ximelagatran. Throm Res 2009, 123:488-497.