Dabigatran etexilate - 2010 - PDF - Boehringer Ingelheim

Dabigatran
etexilate
Background information – For medical media outside the US only
What is
dabigatran etexilate?
Dabigatran etexilate is a novel reversible oral direct
thrombin inhibitor that provides its anticoagulant
effect by specifically and selectively blocking the
activity of thrombin (both free and clot bound). 1,2
Thrombin is the central enzyme in clot (thrombus)
formation, responsible for the conversion of
fibrinogen to fibrin.
Dabigatran etexilate
key characteristics
• Does not require routine coagulation monitoring
or dose titration3-5 • Predictable and consistent anticoagulant
effect 5,6
• Rapid onset / offset of action 5
• Low potential for drug-drug interactions 7-9
• No food-drug interactions and dosing
independent of meals or dietary restrictions10 1

Dabigatran etexilate
the role of thrombin
Thrombin is an enzyme in the blood that causes blood to clot by facilitating the
conversion of the protein fi brinogen to fi brin. Thrombin clips a small piece off the large
protein fi brinogen, causing it to assemble into large fi brous networks, converting fi brinogen
from a soluble substance into insoluble fi brin. These networks of fi brin strands then trap
blood cells, leading to the formation of blood clots or thrombi.
Mechanism of action
Direct thrombin inhibitors (DTIs) block
• All anticoagulants work by directly or indirectly inhibiting both thrombin circulating which and plays clot-bound a key thrombin role in thrombus
formation 1,11,12
• Unlike other anticoagulants, the effects of direct
thrombin inhibitors such as dabigatran etexilate
are limited to thrombin. 1,13
Dabigatran etexilate works by:
• specifi cally and selectively binding to thrombin,
thereby blocking its activity13 • blocking both free and clot-bound thrombin,
providing more effective thrombin inhibition than
heparins (which block mainly free thrombin) 1,2
• binding with existing thrombin, the starting
point for up-regulation of the clotting factors
which are responsible for additional thrombin
production 1,2,13
• interfering with thrombin and its effects on the
coagulation cascade, e.g.: 1,13
− conversion of fi brinogen to fi brin by
thrombin
− platelet activation by thrombin (thrombin is the most potent stimulus for platelet activation) 1
− activation of clotting Factors V, Viii and xi by thrombin (even small amounts of thrombin can
initiate the up-regulation of these clotting factors). 14,15
effi cacy and safety
Prevention of venous thrombeombolism (Vte) in patients following total knee or
hip replacement
• Dabigatran etexilate provides VTE prevention comparable to enoxaparin after total knee or hip
replacement 16
• Results from the RE-NOVATE ®17 , RENOVATE II ®18 and RE-MODEL16 trials showed that dabigatran etexilate
was as effective as enoxaparin at preventing VTE and all-cause mortality16 • Dabigatran etexilate’s safety profi le is comparable to enoxaparin after total knee or hip replacement 16
• Low incidence of major bleeding events, similar to enoxaparin. 16
Background information – For medical media outside the US only
Antithrombin
Heparin
Conversion of
fibrinogen to fibrin
Blood clot
Thrombin generation
Clot-bound thrombin
Adapted from Eikelboom J et al. J Am Coll Cardiol 2003;41:70S–8S
Amplification
DTIs: dabigatran
etexilate
DTIs: dabigatran
etexilate
Direct thrombin inhibitors (DTIs) block both circulating and clotbound
thrombin
2

Dabigatran etexilate
Key indications under investigation
The extensive RE-VOLUTION ® clinical trial programme is evaluating the efficacy and safety of dabigatran
etexilate against current standard therapies in five major therapeutic areas in over 38,000 patients globally.
RE-VOLUTION ® trials Indication under investigation Status
RE-NOVATE ®
RE-NOVATE ® II
RE-MODEL TM
RE-MOBILIZE ®
RE-LY ®
RE-COVER TM &
RECOVER TM II
RE-MEDY TM
RE-SONATE TM
RE-DEEM TM
Primary prevention of VTE following hip
replacement surgery
Primary prevention of VTE following knee
replacement surgery
Primary prevention of VTE following knee
replacement surgery
Prevention of stroke in patients with
non-valvular AF
Treatment of acute VTE
Secondary prevention of VTE
Secondary prevention of VTE
Current licensed indication
Secondary prevention of cardiac events in
patients with acute coronary syndrome
Background information – For medical media outside the US only
Completed and published 17
Completed 18
Completed and published 16
Completed and published 19
Completed. Results published in the New
England Journal of Medicine, 2009 20,21
Completed and published22 Ongoing
Ongoing
Ongoing
Completed
Based on the results of RE-NOVATE ® and RE-MODEL, 13,14 dabigatran etexilate has already been approved
in 75 countries for the primary prevention of blood clots (venous thromboembolic events) in adults who
have undergone elective total hip or elective total knee replacement surgery. 4
The registration process for dabigatran etexilate in the indication of prevention of stroke and systemic
embolism in patients with atrial fibrillation is underway in the US, Europe, Canada, Australia, Japan and
additional countries. The FDA has granted priority review designation for dabigatran etexilate. Boehringer
Ingelheim expects to launch dabigatran etexilate for the prevention of stroke and systemic embolisms in AF
in first countries by end of 2010 or beginning of 2011.
Disclaimer
Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation prevention. This
information is provided for medical education purposes only.
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Dabigatran etexilate
references
1. Di Nisio M, Middeldorp S, Büller HR, et al. Direct thrombin inhibitors. N Engl J Med 2005;353:1028–40.
2. van Ryn J, et al. Dabigatran inhibits both clot-bound and fluid-phase thrombin in vitro: comparison to heparin and hirudin. Arterioscler Thromb
Vasc Biol 2008; 28:e136–7
3. Stangier J, et al. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy
male subjects. Br J Pharmacol 2007;64:292-303
4. Pradaxa, Summary of Product Characteristics, 2008
5. Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet
2008;47:285–95
6. Stangier J, et al. Pharmacokinetics and pharmacodynamics of the direct oral thrombin inhibitor dabigatran in healthy elderly subjects. Clin
Pharmacokinet 2008;28:47-59
7. 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;36:386–99
8. Stangier J, et al. Coadministration of the oral direct thrombin inhibitor dabigatran etexilate and atorvastatin has little impact on the
pharmacokinetics and pharmacodynamics of either drug. J Thromb Haemost 2007; 5(Suppl2):Abstract P-W.671
9. Stangier J, et al. Coadministration of dabigatran etexilate and atorvastatin: assessment of potential impact on pharmacokinetics and
pharmacodynamics. Am J Cardiovasc Drugs 2009;9:59-68
10. Stangier J, Eriksson BI, Dahl OE, et al. Pharmacokinetic Profile of the Oral Direct Thrombin Inhibitor Dabagitran Etexilate in Healthy Volunteers
and Patients Undergoing Total Hip Replacement. J Clin Pharmacol 2005;45:555–63
11. Ansell J. et al. The pharmacology and management of the Vitamin K Antagonists: the seventh ACCP conference on antithrombotic and
thrombolytic therapy. Chest 2004; 126:949-956
12. Gurm HS, Bhatt DL. Thrombin, an ideal target for pharmacological inhibition: a review of direct thrombin inhibitors. Am J Heart 2005;
149:S43-S53
13. Sobera LA et al. Dabigatran/Dabigatran etexilate Drugs Future 2005; 30:877-885
14. Ansell J et al. Advances in therapy and the management of antithrombotic drugs for venous thromboembolism. Hematol Am Soc 2000:266-284
15. Mc Rae SJ, Ginsberg JS. New anticoagulants for venous thromboembolic disease. Curr Opin Cardiol 2005; 20:502-508
16. 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;5:2178–85
17. 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;370:949–56
18. Eriksson BI, et al. Dabigatran versus enoxaparin for thromboprophylaxis after primary hip arthroplasty: The RE-NOVATE II randomised trial.
Presented at the Annual Congress of the European Haematology, 12th June 2010.
19. RE-MOBILIZE Writing Committee. 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
20. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139–1151
21. Ezekowitz MD, Connolly S, Parekh A et al. Rationale and design of RE-LY: Randomized evaluation of long-term anticoagulant therapy, warfarin,
compared with dabigatran. Am Heart J 2009;157: 805-10
22. Schulman S, Kearon C, Kakkar AK, et al. Dabigatran etexilate versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med
2009;361:2342-52
For more information, contact:
Dr reinhard Malin
Boehringer Ingelheim GmbH
Phone: +49/6132/7790815
Fax: +49/6132/77 66 01
E-mail: press@boehringer-ingelheim.com
Background information – For medical media outside the US only
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