Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Drugs
Published in: Drugs 7/2012

01-05-2012 | Adis Drug Evaluation

Dabigatran Etexilate

A Review of its Use for the Prevention of Venous Thromboembolism after Total Hip or Knee Replacement Surgery

Authors: Celeste B. Burness, Kate McKeage

Published in: Drugs | Issue 7/2012

Login to get access

Abstract

Dabigatran etexilate (Pradaxa®, Pradax™, Prazaxa®) is indicated for the primary prevention of venous thromboembolic (VTE) events in adults who have undergone elective total hip replacement (THR) or total knee replacement (TKR) surgery. This article reviews the clinical efficacy and tolerability of oral dabigatran etexilate in patients undergoing major orthopaedic surgery, as well as summarizing its pharmacological properties and results of a cost-utility analysis. The discussion of clinical trial data focuses on comparative trials with the EU approved dosage regimen of once-daily subcutaneous enoxaparin sodium 40mg.
Dabigatran etexilate is an oral prodrug of the potent, rapidly acting, reversible, competitive inhibitor of thrombin, dabigatran. Dabigatran has predictable and consistent anticoagulant effects and does not require routine coagulation monitoring or dose titration.
In the large, randomized, double-blind, phase III, noninferiority trials, RE-MODEL, RE-NOVATE and RE-NOVATE II, oral dabigatran etexilate, at dosages of 150 and 220 mg once daily, initiated postoperatively was shown to be noninferior to subcutaneous enoxaparin sodium 40 mg once daily (initiated prior to surgery) with regard to the incidence of the composite of total VTE events and all-cause mortality in patients undergoing TKR or THR surgery.
In general, oral dabigatran etexilate was well tolerated in clinical trials of patients undergoing major orthopaedic surgery. There were no significant between-group differences in bleeding complications, including major bleeding, clinically relevant non-major bleeding or minor bleeding between the dabigatran etexilate or enoxaparin sodium groups.
In addition, a cost-utility analysis from the perspective of the UK National Health Service indicated that dabigatran etexilate 220 mg once daily is dominant (i.e. more effective and less costly) to enoxaparin sodium 40 mg once daily in patients undergoing THR or TKR.
Additional head-to-head comparisons would be beneficial to more definitively position dabigatran etexilate relative to other available oral treatment options for VTE prophylaxis, such as rivaroxaban and apixaban. In the meantime, dabigatran etexilate offers a convenient, effective and generally well tolerated treatment option for the prophylaxis of VTE in patients undergoing TKR and THR surgery.
Literature
1.
National Collaborating Centre for Acute and Chronic Conditions. National Institute for Health and Clinical Excellence clinical guideline 92: venous thromboembolism. Reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in patients admitted to hospital [online]. Available from URL: http://​guidance.​nice.​org.​uk/​CG92 [Accessed 2012 Apr 13]
2.
Falck-Ytter Y, Francis CW, Johanson NA, 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 practice guidelines. Chest 2012 Feb; 141 (2 Suppl.): e278S-325S
3.
Turpie AGG, Esmon C. Venous and arterial thrombosis: pathogenesis and the rationale for anticoagulation. Thromb Haemost 2011; 105 (4): 586–96PubMedCrossRef
4.
Kahn SR, Ginsberg JS. Relationship between deep venous thrombosis and the postthrombotic syndrome. Arch Intern Med 2004; 164 (1): 17–26PubMedCrossRef
5.
Schulman S, Majeed A. A benefit-risk assessment of dabigatran in the prevention of venous thromboembolism in orthopaedic surgery. Drug Saf 2011; 34 (6): 449–63PubMedCrossRef
6.
Rico JIA, Pitarch JVL, Fernandez JAP. Topical issues in venous thromboembolism. Drugs 2010; 70 Suppl. 2: 11–8CrossRef
7.
Eriksson BI, Dahl OE. Prevention of venous thromboem-bolism following orthopaedic surgery: clinical potential of direct thrombin inhibitors. Drugs 2004; 64 (6): 577–95PubMedCrossRef
8.
9.
Garnock-Jones KP. Dabigatran etexilate: a review of its use in the prevention of stroke and systemic embolism in patients with atrial fibrillation. Am J Cardiovasc Drugs 2011; 11 (1): 57–72PubMedCrossRef
10.
Stangier J. Clinical pharmacokinetics and pharmaco-dynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet 2008; 47 (5): 285–95PubMedCrossRef
11.
Eriksson BI, Quinlan DJ, Weitz JI. Comparative pharmaco-dynamics and pharmacokinetics of oral direct thrombin and factor Xa inhibitors in development. Clin Pharmacokinet 2009; 48 (1): 1–22PubMedCrossRef
12.
13.
14.
Wienen W, Stassen J-M, Priepke H, et al. In-vitro profile and ex-vivo anticoagulant activity of the direct thrombin inhibitor dabigatran and its orally active prodrug, dabiga-tran etexilate. Thromb Haemost 2007 Jul; 98 (1): 155–62PubMed
15.
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 subjects. Br J Clin Pharmacol 2007 Sep; 64 (3): 292–303PubMedCrossRef
16.
van Ryn J, Hauel N, Waldmann L, et al. Dabigatran inhibits both clot-bound and fluid phase thrombin in vitro: compared to heparin and hirudin [abstract no. P570]. Arte-rioscler Thromb Vasc Biol 2008; 28 (6): e136-7
17.
Stangier J, Stahle H, Rathgen K. Pharmacokinetics and pharmacodynamics of the direct oral thrombin inhibitor dabigatran in healthy elderly subjects. Clin Pharmacokinet 2008 Jan; 47 (1): 47–59PubMedCrossRef
18.
Liesenfeld K-H, Schafer HG, Troconiz IF, et al. Effects of the direct thrombin inhibitor dabigatran on ex vivo coagulation time in orthopaedic surgery patients: a population model analysis. BrJ Clin Pharmacol 2006; 62 (5): 527–37CrossRef
19.
Stangier J, Wetzel K, Wienen W, et al. Measurement of the pharmacodynamic effect of dabigatran etexilate: thrombin clotting time [abstract no. PP-TH-134]. Thromb Haemost 2009; 7 Suppl. 2: 978
20.
Green L, Lawrie AS, Patel R, et al. The effect of total hip/knee replacement surgery and prophylactic dabigatran on thrombin generation and coagulation parameters. Thromb Res. Epub 2012 Jan 13
21.
Ring A, Clemens A, Rathgen K, et al. Dabigatran does not prolong the QTc interval with supratherapeutic exposure: a thorough QTc study. J Am Coll Cardiol 2011 Apr 5; 57 (14 Suppl.): E56
22.
Hartter S, Yamamura N, Stangier J, et al. Pharmacokinetics and pharmacodynamics in Japanese and Caucasian subjects after oral administration of dabigatran etexilate. Thromb Haemost 2012 Feb; 107 (2): 260–9PubMedCrossRef
23.
Stangier J, Eriksson BI, Dahl OE. Pharmacokinetic profile of the oral direct thrombin inhibitor dabigatran etexilate in healthy volunteers and patients undergoing total hip replacement. J Clin Pharmacol 2005; 45 (5): 555–63PubMedCrossRef
24.
Stangier J, Rathgen K, Stahle H, et al. Coadministration of dabigatran etexilate and atorvastatin: assessment of potential impact on pharmacokinetics and pharmaco-dynamics. Am J Cardiovasc Drugs 2009; 9 (1): 59–68PubMedCrossRef
25.
Troconiz IF, Tillmann C, Liesenfeld KH, et al. Population pharmacokinetic analysis of the new oral thrombin inhibitor dabigatran etexilate (BIBR 1048) in patients undergoing primary elective total hip replacement surgery. J Clin Pharmacol 2007 Mar; 47 (3): 371–82PubMedCrossRef
26.
Stangier J, Rathgen K, Stahle H, et al. Influence of renal impairment on the pharmacokinetics and pharmaco-dynamics of oral dabigatran etexilate: an open-label, parallel-group, single-centre study. Clin Pharmacokinet 2010 Apr 1; 49 (4): 259–68PubMedCrossRef
27.
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 Dec; 48 (12): 1411–9PubMedCrossRef
28.
Eriksson BI, Dahl OE, 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 Nov; 5 (11): 2178–85
29.
Eriksson BI, Dahl OE, Rosencher N, et al. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial. Lancet 2007 Sep 15; 370 (9591): 949–56PubMedCrossRef
30.
RE-MOBILIZE Writing Committee, Ginsberg JS, Davidson BL, et al. Oral thrombin inhibitor dabigatran etexilate vs North American enoxaparin regimen for prevention of venous thromboembolism after knee arthroplasty surgery. J Arthroplasty 2009 Jan; 24 (1): 1–9PubMedCrossRef
31.
Eriksson BI, Dahl OE, Huo MH, et al. Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II): a randomised, double-blind, non-inferiority trial. Thromb Haemost 2011; 105 (4): 721–9PubMedCrossRef
32.
Eriksson BI, Dahl OE, Ahnfelt L, et al. Dose escalating safety study of a new oral direct thrombin inhibitor, dabi-gatran etexilate, in patients undergoing total hip replacement: BISTRO I. J Thromb Haemost 2004 Sep; 2 (9): 1573–80PubMedCrossRef
33.
Eriksson BI, Dahl OE, Buller HR, et al. 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 Jan; 3 (1): 103–11PubMedCrossRef
34.
Fuji T, Fuijita S, Ujihira T, et al. Dabigatran etexilate prevents venous thromboembolism after total knee arthroplasty in Japanese patients with a safety profile comparable to placebo. J Arthroplasty 2010; 25 (8): 1267–74PubMedCrossRef
35.
Friedman RJ, Dahl OE, Rosencher N, et al. Dabigatran versus enoxaparin for prevention of venous thromboem-bolism after hip or knee arthroplasty: a pooled analysis of three trials. Thromb Res 2010; 126 (3): 175–82PubMedCrossRef
36.
Wolowacz SE, Roskell NS, Plumb JM, et al. 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 (1): 77–85PubMed
37.
Dahl OE, Kurth AA, Rosencher N, et al. Thromboprophy-laxis with dabigatran etexilate in patients over seventy-five years of age with moderate renal impairment undergoing or knee replacement. Int Orthop 2012 Apr; 36 (4): 741–8PubMedCrossRef
38.
Boehringer Ingelheim International GmbH. A phase III, randomised, parallel-group, double-blind, active controlled study to investigate the efficacy and safety of two different dose regimens of orally administered dabigatran etexilate capsules [150 or 220mg once daily starting with a half dose (i.e. 75 or 110 mg) on the day of surgery] compared to subcutaneous enoxaparin 40mg once daily for 8 +/− 2 days, in prevention of venous thromboembolism in patients with primary elective total knee replacement surgery: RE-MODEL (Thromboembolism prevention after knee surgery) [Boehringer Ingelheim trial number 1160.25]. Clinical trial synopsis [online]. Available from URL: http://​trials.​boehringer-ingelheim.​com/​res/​trial/​data/​pdf/​1160.​25_​U06-1617.​pdf [Accessed 2012 Apr 13]
39.
Boehringer Ingelheim International GmbH. A phase III, randomized, parallel-group, double-blind, active controlled study to investigate the efficacy and safety of two different dose regimens (75 mg day 1 followed by 150 mg day 2-completion, and 110mg day 1 followed by 220 mg day 2-completion) of dabigatran etexilate administered orally (capsules), compared to enoxaparin 30mg twice a day subcutaneous for 12–15 days in prevention of venous thromboembolism in patients with primary elective total knee replacement surgery [Boehringer Ingelheim trial number 1160.24]. Clinical trial synopsis [online]. Available from URL: http://​trials.​boehringer-ingelheim.​com/​res/​trial/​data/​pdf/​1160.​24_​U06-1616.​pdf [Accessed 2012 Apr 13]
40.
Boehringer Ingelheim International GmbH. A phase III randomised, parallel-group, double-blind, active controlled study to investigate the efficacy and safety of two different dose regimens of orally administered dabigatran etexilate capsules [150 or 220mg once daily starting with half dose (i.e. 75 or 110 mg) on the day of surgery] compared to subcutaneous enoxaparin 40mg once daily for 28-35 days, in prevention of venous thromboembolism in patients with primary elective total hip replacement surgery: RE-NOVATE (Extended thromboembolism prevention after hip surgery) [Boehringer Ingelheim trial number 1160.48]. Clinical trial synopsis [online]. Available from URL: http://​trials.​boehringer-ingelheim.​com/​res/​trial/​data/​pdf/​1160.​48_​U06-161819325.​pdf [Accessed 2012 Apr 13]
41.
Boehringer Ingelheim International GmbH. A phase III randomised, parallel group, double-blind, active controlled study to investigate the efficacy and safety of orally administered 220mg dabigatran etexilate capsules (110 mg administered on the day of surgery followed by 220 mg once daily) compared to subcutaneous 40 mg enoxaparin once daily for 28-35 days in prevention of venous throm-boembolism in patients following primary elective total hip arthroplasty (RE-NOVATE II) [Boehringer Ingelheim trial number 1160.64/U10-1392-01]. Clinical trial synopsis [online]. Available from URL: http://​trials.​boehringer-ingelheim.​com/​res/​trial/​data/​pdf/​1160.​64_​U10-139219703.​pdf [Accessed 2012 Apr 13]
42.
Eriksson BI, Kurth AA, Friedman RJ, et al. Risk of bleeding with dabigatran etexilate in patients undergoing major orthopaedic surgery is not increased by concomitant use of non-steroidal antiinflammatory drugs or acetylsalicylic acid [abstract no. PP-MO-167]. J Thromb Haemost 2009 Jul; 7 Suppl. S2: 374
43.
Rosencher N, Noack H, Feuring M, et al. Type of anaesthesia did not affect the efficacy and safety of dabigatran etexilate compared with enoxaparin for primary venous thromboembolism prevention following total knee or hip replacement surgery [abstract no. 6AP5-6]. Eur J Anaes-thesiol 2009; 26 Suppl. 45: 94
44.
Barsness GW, Smith JS, Eriksson BI, et al. Evaluation of the acute coronary syndrome safety profile of dabigatran etexilate in patients undergoing major orthopedic surgery [abstract no. 14413]. Circulation 2011; 124 Suppl.
45.
Wolowacz SE, Roskell NS, 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 (1): 194–212PubMedCrossRef
46.
Wolowacz SE, Roskell NS, Plumb JM, 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 (2): 360–71PubMedCrossRef
47.
Zaniolo O, Pradelli L. Economic performance of dabigatran etexilate for primary VTE prevention following total hip and knee replacement surgery in Italy [abstract no. PCV66]. Value Health 2010 Nov; 13 (7): A353
48.
Mateus C, Wolowacz S, Pereira JA. Cost-effectiveness of dabigatran etexilate for the primary prevention of venous thromboembolism in total hip and knee replacement in Portugal [abstract no. PCV39]. Value Health 2009 May; 12 (3): A148
49.
Boersma C, Kappelhoff BS, Postma MJ. Dabigatran etexilate is cost-saving for the primary prevention of venous thromboembolic events following major orthopaedic surgery in the Netherlands [abstract no. PCV114]. Value Health 2009 Oct; 12 (7): A334
50.
Gonzalez-Rojas N, Vieta A, Monreal M, et al. Economic analysis of dabigatran etexilate for the primary prevention of venous thromboembolism following total hip or knee replacement in Spain [abstract no. PMS38]. Value Health 2009 Oct; 12 (7): A440
51.
Bradley-Kennedy C, Wolowacz SE, Roskell NS, et al. Cost-effectiveness of dabigatran etexilate in Canada for the primary prevention of venous thromboembolism in patients undergoing total hip replacement surgery [abstract no. PP-WE-470]. J Thromb Haemost 2009; 7 Suppl. 2: 786
52.
Bradley-Kennedy C, Wolowacz SE, Roskell NS, et al. Cost-effectiveness of dabigatran etexilate in Canada for the primary prevention of venous thromboembolism (VTE) in patients undergoing total knee replacement surgery (TKR) [abstract no. PP-WE-471]. J Thromb Haemost 2009; 7 Suppl. 2: 786
53.
Holmes M, Carroll C, Papaioannou D. Dabigatran etexilate for the prevention of venous thromboembolism in patients undergoing elective hip or knee surgery: a NICE single technology appraisal. Pharmacoeconomics 2012 Feb 1; 30 (2): 137–46PubMedCrossRef
54.
55.
Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest 2008; 133 (6 Suppl.): 381–453SCrossRef
56.
57.
58.
59.
Duggan ST. Rivaroxaban: a review of its use for the prophylaxis of venous thromboembolism after total hip or knee replacement surgery. Am J Cardiovasc Drugs 2012 Feb 1; 12 (1): 57–72PubMedCrossRef
60.
Ufer M. Comparative efficacy and safety of the novel oral anticoagulants dabigatran, rivaroxaban and apixaban in preclinical and clinical development. Thromb Haemost 2010 Mar; 103 (3): 572–85PubMedCrossRef
61.
62.
63.
Harper P, Young L, Merriman E. Bleeding risk with dabigatran in the frail elderly [letter]. N Engl J Med 2012 Mar 1; 366 (9): 864–6PubMedCrossRef
64.
65.
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 (6): 1116–27
66.
van Ryn J, Dorr B, Kaspereit F, et al. Beriplex P/N reverses bleeding in an acute renal injury model after dabigatran overdose in rabbits [abstract no. 486]. Pathophysiol Haemost Thromb 2010; 57 Suppl. 1: A94
67.
van Ryn J, Schurer J, Kink-Eiband M, et al. The successful reversal of dabigatran-induced bleeding by coagulation factor concentrates in a rat tail bleeding model do not correlate with ex vivo markers of anticoagulation [abstract no. 2316]. Blood 2011; 118 (21)
68.
Eerenberg ES, Kamphuisen PW, Sijpkens MK, et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation 2011 Oct 4; 124 (14): 1573–9PubMedCrossRef
69.
Stangier J, Feuring M. Using the HEMOCLOT direct thrombin inhibitor assay to determine plasma concentrations of dabigatran. Blood Coagul Fibrinolysis 2012 Mar; 23 (2): 138–43PubMedCrossRef
70.
Maratea D, Fadda V, Trippoli S, et al. Prevention of venous thromboembolism after major orthopedic surgery: indirect comparison of three new oral anticoagulants. J Thromb Haemost 2011; 9 (9): 1868–70PubMedCrossRef
71.
72.
Loke YK, Kwok CS. Dabigatran and rivaroxaban for prevention of venous thromboembolism: systematic review and adjusted indirect comparison. J Clin Pharm Ther 2011; 36 (1): 111–24PubMedCrossRef
73.
Huisman MV, Quinlan DJ, Dahl OE, et al. Enoxaparin versus dabigatran or rivaroxaban for thromboprophylaxis after hip or knee arthroplasty: results of separate pooled analyses of phase III multicenter randomized trials. Circ Cardiovasc Qual Outcomes 2010; 3 (6): 652–60PubMedCrossRef
74.
Metadata
Title
Dabigatran Etexilate
A Review of its Use for the Prevention of Venous Thromboembolism after Total Hip or Knee Replacement Surgery
Authors
Celeste B. Burness
Kate McKeage
Publication date
01-05-2012
Publisher
Springer International Publishing
Published in
Drugs / Issue 7/2012
Print ISSN: 0012-6667
Electronic ISSN: 1179-1950
DOI
https://doi.org/10.2165/11209080-000000000-00000

Other articles of this Issue 7/2012

Drugs 7/2012 Go to the issue

Adis Drug Profile

Bevacizumab Combination Therapy

Adis Drug Profile

Bevacizumab in Ovarian Cancer

Adis Drug Evaluation

Dihydroartemisinin/Piperaquine

Therapy In Practice

Assessment and Medication Management of Paediatric Obsessive-Compulsive Disorder

Correspondence

Pharmacotherapy for Breakthrough Cancer Pain

Correspondence

The Author’s Reply