Dabigatran - A new chapter in anticoagulation

Cardiovascular and Hematological Agents in Medicinal Chemistry

Volumn 10, Issue 2, 2012, Pages 116-123

  Ahmed, Shameer ^a   Levin, Vadim ^a   Malacoff, Robert ^a   Martinez, Matthew W ^a  

^a LEHIGH VALLEY HOSPITAL   (United States)

Author keywords

Anticoagulation; Atrial fibrillation; BISTRO trial; Chemical structure; Dabigatran; Diract thrombin inhibitors; PETRO trial; Pharmacodynamics; Pharmacokinetics; Re Ly trial; RECOVER trial; Stroke warfarin

Indexed keywords

ACETYLSALICYLIC ACID; AMIODARONE; ANTIFIBRINOLYTIC AGENT; BIBR 1087; BIBR 951; CLARITHROMYCIN; CLOPIDOGREL; DABIGATRAN; DABIGATRAN ETEXILATE; ENOXAPARIN; GLUCURONIC ACID; PANTOPRAZOLE; QUINIDINE; UNCLASSIFIED DRUG; VERAPAMIL; WARFARIN;

ABDOMINAL PAIN; ACUTE CORONARY SYNDROME; ALLERGIC REACTION; ANTICOAGULATION; CARDIAC PATIENT; CATALYSIS; CHEMICAL STRUCTURE; DIARRHEA; DIZZINESS; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG DOSE ESCALATION; DRUG EFFECT; DRUG MECHANISM; DRUG STRUCTURE; DRUG WITHDRAWAL; DYSPEPSIA; GASTROINTESTINAL HEMORRHAGE; GLOMERULUS FILTRATION RATE; HEADACHE; HEART ATRIUM FIBRILLATION; HUMAN; HYDROLYSIS; INTERNATIONAL NORMALIZED RATIO; KIDNEY FAILURE; KIDNEY FUNCTION; MULTICENTER STUDY (TOPIC); NAUSEA; NONHUMAN; PALLOR; PARTIAL THROMBOPLASTIN TIME; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); POST HOC ANALYSIS; PRURITUS; REVIEW; STROKE; SWELLING; THROMBIN TIME; VENOUS THROMBOEMBOLISM;

EID: 84860433567     PISSN: 18715257     EISSN: 18756182     Source Type: Journal    
DOI: 10.2174/187152512800388911     Document Type: Review

References (36)

1. Hirsh, J.; Bauer, K.A.; Donati, M.B.; Gould, M.; Samama, M.M.; Weitz, J.I. Parenteral anticoagulants: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest, 2008, 133(6 Suppl.), 141S-159S.
2. Ma, T.K.; Yan, B.P.; Lam, Y.Y. Dabigatran etexilate versus warfarin as the oral anticoagulant of choice? A review of clinical data. Pharmacol. Ther., 2011, 129(2), 185-194.
3. Francis, C.W.; Berkowitz, S.D.; Comp, P.C.; Lieberman, J.R.; Ginsberg, J.S.; Paiement, G.; Peters, G.R.; Roth, A.W.; McElhattan, J.; Colwell, C.W., Jr. Comparison of ximelagatran with warfarin for the prevention of venous thromboembolism after total knee replacement. N. Engl. J. Med., 2003, 349(18), 1703-1712.
4. Hrebickova, L.; Nawarskas, J.J.; Anderson, J.R. Ximelagatran: a new oral anticoagulant. Heart Dis., 2003, 5(6), 397-408.
5. Stangier, J.; Rathgen, K.; Stahle, H.; Gansser, 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(3), 292-303.
6. Blech, S.; Ebner, T.; Ludwig-Schwellinger, E.; Stangier, J.; Roth, W. The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans. Drug Metab. Dispos., 2008, 36(2), 386-399.
7. Stangier, J.; Clemens, A. Pharmacology, pharmacokinetics, and pharmacodynamics of dabigatran etexilate, an oral direct thrombin inhibitor. Clin. Appl. Thromb. Hemost., 2009, (15 Suppl. 1), 9S-16S.
8. Stangier, J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin. Pharmacokinet., 2008, 47(5), 285-295.
9. Stangier, J.; Stahle, H.; Rathgen, K.; Fuhr, R. Pharmacokinetics and pharmacodynamics of the direct oral thrombin inhibitor dabigatran in healthy elderly subjects. Clin. Pharmacokinet., 2008, 47(1), 47-59.
10. 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-centre study. Clin. Pharmacokinet., 2010, 49(4), 259-268.
11. Bates, S.M.; Weitz, J.I. The mechanism of action of thrombin inhibitors. J. Invasive. Cardiol., 2000, (12 Suppl. F), 27F-32F.
12. Di Nisio, M.; Middeldorp, S.; Buller, H.R. Direct thrombin inhibitors. N. Engl. J. Med., 2005, 353(10), 1028-1040.
13. Fenyvesi, T.; Jorg, I.; Harenberg, J. Monitoring of anticoagulant effects of direct thrombin inhibitors. Semin. Thromb. Hemost., 2002, 28(4), 361-368.
14. van Ryn, J.; Stangier, J.; Haertter, S.; Liesenfeld, K.H.; 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(6), 1116-127.
15. Callas, D.D.; Fareed, J. Comparative anticoagulant effects of various thrombin inhibitors, as determined in the ecarin clotting time method. Thromb. Res., 1996, 83(6), 463-468.
16. Wienen, W.; Stassen, J.M.; Priepke, H.; Ries, U.J.; Hauel, N. In-vitro profile and ex-vivo anticoagulant activity of the direct thrombin inhibitor dabigatran and its orally active prodrug, dabigatran etexilate. Thromb. Haemost., 2007, 98(1), 155-162.
17. Eriksson, B.I.; Dahl, O.E.; 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(9), 1573-1580.
18. Eriksson, B.I.; Dahl, O.E.; Buller, H.R.; Hettiarachchi, R.; Rosencher, N.; Bravo, M.L.; 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(1), 103-111.
19. Eriksson, B.I.; Dahl, O.E.; Rosencher, N.; Kurth, A.A.; van Dijk, C.N.; Frostick, S.P.; Prins, M.H.; Hettiarachchi, R.; Hantel, S.; Schnee, J.; Buller, H.R. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomized, double-blind, non inferiority trial. Lancet, 2007, 370(9591), 949-956.
20. Eriksson, B.I.; Dahl, O.E.; Rosencher, N.; Kurth, A.A.; van Dijk, C.N.; Frostick, S.P.; Kalebo, P.; Christiansen, A.V.; Hantel, S.; Hettiarachchi, R.; Schnee, J.; Buller, H.R. 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(11), 2178-2185.
21. Geerts, W.H.; Pineo, G.F.; Heit, J.A.; Bergqvist, D.; Lassen, M.R.; Colwell, C.W.; Ray, J.G. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest, 2004, 126(3 Suppl.), 338S-400S.
22. Eriksson, B.I.; Dahl, O.E.; Huo, M.H.; Kurth, A.A.; Hantel, S.; Hermansson, K.; Schnee, J.M.; Friedman, R.J. 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), 721-729.
23. Ginsberg, J.S.; Davidson, B.L.; Comp, P.C.; Francis, C.W.; Friedman, R.J.; Huo, M.H.; Lieberman, J.R.; Muntz, J.E.; Raskob, G.E.; Clements, M.L.; Hantel, S.; Schnee, J.M.; Caprini, J.A. Oral thrombin inhibitor dabigatran etexilate vs North American enoxaparin regimen for prevention of venous thromboembolism after knee arthroplasty surgery. J. Arthroplasty., 2009, 24(1), 1-9.
24. Eriksson, B.I.; Friedman, R.J. Dabigatran etexilate: pivotal trials for venous thromboembolism prophylaxis after hip or knee arthroplasty. Clin. Appl. Thromb. Hemost., 2009, (15 Suppl. 1), 25S-31S.
25. Schulman, S.; Kearon, C.; Kakkar, A.K.; Mismetti, P.; Schellong, S.; Eriksson, H.; Baanstra, D.; Schnee, J.; Goldhaber, S.Z. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N. Engl. J. Med., 2009, 361(24), 2342-2352.
26. Go, A.S.; Hylek, E.M.; Borowsky, L.H.; Phillips, K.A.; Selby, J.V.; Singer, D.E. Warfarin use among ambulatory patients with nonvalvular atrial fibrillation: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study. Ann. Intern. Med., 1999, 131(12), 927-934.
27. Wolf, P.A.; D'Agostino, R.B.; Belanger, A.J.; Kannel, W.B. Probability of stroke: a risk profile from the Framingham Study. Stroke, 1991, 22(3), 312-318.
28. Rosamond, W.; Flegal, K.; Furie, K.; Go, A.; Greenlund, K.; Haase, N.; Hailpern, S.M.; Ho, M.; Howard, V.; Kissela, B.; Kittner, S.; Lloyd-Jones, D.; McDermott, M.; Meigs, J.; Moy, C.; Nichol, G.; O'Donnell, C.; Roger, V.; Sorlie, P.; Steinberger, J.; Thom, T.; Wilson, M.; Hong, Y. Heart disease and stroke statistics--2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation, 2008, 117(4), e25-e146.
29. Ezekowitz, M.D.; Reilly, P.A.; Nehmiz, G.; Simmers, T.A.; Nagarakanti, R.; Parcham-Azad, K.; Pedersen, K. E.; Lionetti, D. A.; 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(9), 1419-1426.
30. Connolly, S.J.; Ezekowitz, M.D.; Yusuf, S.; Eikelboom, J.; Oldgren, J.; Parekh, A.; Pogue, J.; Reilly, P.A.; Themeles, E.; Varrone, J.; Wang, S.; Alings, M.; Xavier, D.; Zhu, J.; Diaz, R.; Lewis, B.S.; Darius, H.; Diener, H.C.; Joyner, C.D.; Wallentin, L. Dabigatran versus warfarin in patients with atrial fibrillation. N. Engl. J. Med., 2009, 361(12), 1139-1151.
31. Connolly, S.J.; Ezekowitz, M.D.; Yusuf, S.; Reilly, P.A.; Wallentin, L. Newly identified events in the RE-LY trial. N. Engl. J. Med., 2010, 363(19), 1875-1876.
32. Nagarakanti, R.; Ezekowitz, M.D.; Oldgren, J.; Yang, S.; Chernick, M.; Aikens, T.H.; Flaker, G.; Brugada, J.; Kamensky, G.; Parekh, A.; Reilly, P.A.; Yusuf, S.; Connolly, S.J. Dabigatran versus warfarin in patients with atrial fibrillation: an analysis of patients undergoing cardioversion. Circulation, 2011, 123(2), 131-136.
33. Oldgren, J.; Alings, M.; Darius, H.; Diener, H.C.; Eikelboom, J.; Ezekowitz, M.D.; Kamensky, G.; Reilly, P.A.; Yang, S.; Yusuf, S.; Wallentin, L.; Connolly, S.J. Risks for stroke, bleeding, and death in patients with atrial fibrillation receiving dabigatran or warfarin in relation to the CHADS2 score: a subgroup analysis of the RELY trial. Ann. Intern. Med., 2011, 155(10), 660-667, W204.
34. Guyatt, G.H.; Norris, S.L.; Schulman, S.; Hirsh, J.; Eckman, M.H.; Akl, E.A.; Crowther, M.; Vandvik, P.O.; Eikelboom, J.W.; McDonagh, M.S.; Lewis, S.Z.; Gutterman, D.D.; Cook, D.J.; Schunemann, H.J. Methodology for the development of antithrombotic therapy and prevention of thrombosis guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest, 2012, 141(2 Suppl.), 53S-70S.
35. Beasley, B.N.; Unger, E.F.; Temple, R. Anticoagulant options--why the FDA approved a higher but not a lower dose of dabigatran. N. Engl. J. Med., 2011, 364(19), 1788-1790.
36. Oldgren, J.; Budaj, A.; Granger, C.B.; Khder, Y.; Roberts, J.; Siegbahn, A.; Tijssen, J.G.; Van de Werf, F.; Wallentin, L. Dabigatran vs. placebo in patients with acute coronary syndromes on dual antiplatelet therapy: a randomized, double-blind, phase II trial. Eur. Heart J., 2011, 32(22), 2781-2789.