Overview of Direct Thrombin Inhibitors in Clinical Practice

ABSTRACT

Novel anticoagulants have been developed that specifically target activated coagulation factor X or thrombin. This article reviews the present state of direct thrombin inhibitors, including compounds that are administered parenterally (lepirudin, bivalirudin, argatroban, napsagatran, and Melagatran [AstraZeneca, Mölndal, Sweden]) and those that can be given orally (ximelagatran and dabigatran etexilate). Lepirudin and argatroban (in the United States but not in all European countries) are licensed for treatment of heparin-induced thrombocytopenia (HIT) (argatroban also for prophylaxis), whereas bivalirudin is approved as an alternative to heparin in patients undergoing percutaneous coronary interventions (PCI) and argatroban for PCI in patients with HIT. Napsagatran development has ceased, and ximelagatran has not been granted approval by the U.S. Food and Drug Administration and was withdrawn from European market a few months after its initial registration due to liver toxicity. The compound with the most advanced development among the oral direct thrombin inhibitors at the present time is dabigatran etexilate, for which promising phase III data already exist for the indication of thromboprophylaxis following major orthopedic surgery.

KEYWORDS

Oral anticoagulants - direct thrombin inhibitors - lepirudin - argatroban - dabigatran

REFERENCES

• 1 Ansell J, Hirsh J, Poller L, Bussey H, Jacobson A, Hylek E. The pharmacology and management of the vitamin K antagonists: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.  Chest. 2004;  126(suppl) 204S-233S
• 2 Weitz J I, Hirsh J, Samama M M. New anticoagulant drugs: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.  Chest. 2004;  126(suppl) 265S-286S
• 3 Organisation to Assess Strategies for Ischemic Syndromes (OASIS-2) Investigators . Effect of recombinant hirudin (lepirudin) compared with heparin on death, myocardial infarction, refractory angina, and revascularization procedures in patients with acute myocardial ischemia without ST elevation: a randomized trial.  Lancet. 1999;  353 429-438
• 4 Eriksson B I, Wille-Jorgensen P, Kalebo P et al.. A comparison of recombinant hirudin with a low-molecular-weight heparin to prevent thromboembolic complications after total hip replacement.  N Engl J Med. 1997;  337 1329-1335
• 5 Bittl J A, Chaitman B R, Feit F, Kimball W, Topol E J. Bivalirudin versus heparin during coronary angioplasty for unstable or postinfarction angina: final report reanalysis of the Bivalirudin Angioplasty Study.  Am Heart J. 2001;  142 952-959
• 6 Stone G W, McLaurin B T, Cox D A ACUITY Investigators et al.. Bivalirudin for patients with acute coronary syndromes.  N Engl J Med. 2006;  355 2203-2216
• 7 Yeh R W, Jang I K. Argatroban: update.  Am Heart J. 2006;  151 1131-1138
• 8 Bounameaux H, Ehringer H, Hulting J, Rasche H, Rapold H J, Zultak M. An exploratory trial of two dosages of a novel synthetic thrombin inhibitor (napsagatran, Ro 46–6240) compared with unfractionated heparin for treatment of proximal deep-vein thrombosis. Results of the European multicenter ADVENT trial.  Thromb Haemost. 1997;  78 997-1002
• 9 Cohen A T, Hirst C, Sherril B, Holmes P, Fidan D. Meta-analysis of trials comparing ximelagatran with low molecular weight heparin for prevention of venous thromboembolism after major orthopaedic surgery.  Br J Surg. 2005;  92 1335-1344
• 10 Fiessinger J N, Huisman M V, Davidson B L et al.. Ginsberg JS for the THRIVE Treatment Study Investigators. Ximelagatran versus low-molecular-weight heparin and warfarin for the treatment of deep-vein thrombosis. A randomized controlled trial.  JAMA. 2005;  293 681-689
• 11 Schulman S, Wahlander K, Lundström T, Clason S B. Eriksson H for the THRIVE III Investigators. Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran.  N Engl J Med. 2003;  349 1713-1721
• 12 Diener HC for the Executive Steering Committee of the SPORTIF III and V Investigators . Stroke prevention using the oral direct thrombin inhibitor ximelagatran in patients with non-valvular atrial fibrillation. Pooled analysis from the SPORTIF III and V studies.  Cerebrovasc Dis. 2006;  21 279-293
• 13 Wallentin L, Wilcox R G, Weaver W D ESTEEM Investigators et al.. Oral ximelagatran for secondary prophylaxis after myocardial infarction: the ESTEEM randomized controlled trial.  Lancet. 2003;  352 789-797
• 14 Testa L, Bhindi R, Agostini P, Abbate A, Zoccai G G, van Gaal W J. 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
• 15 Eriksson B I, Dahl O E, Rosencher N RE-NOVATE Study Group et al.. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial.  Lancet. 2007;  370 949-956
• 16 Eriksson B I, Dahl O E, Rosencher N RE-MODEL Study Group et al.. Oral dabigatran etexilate vs. enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial.  J Thromb Haemost. 2007;  5 2178-2185
• 17 Friedman R J, Caprini J A, Comp P C et al.. Dabigatran etexilate versus enoxaparin in preventing venous thromboembolism following total knee arthroplasty.  J Thromb Haemost. 2007 (suppl 2);  , Abstract O-W-051
• 18 Caprini J A, Hwang E, Hantel S, Schnee J, Eriksson B I. The oral direct thrombin inhibitor, dabigatran etexilate, is effective and safe for prevention of major venous thromboembolism following major orthopedic surgery.  J Thromb Haemost. 2007;  (suppl 2) , Abstract O-W-050
• 19 Weitz J I. Factor Xa or thrombin: is thrombin a better target?.  J Thromb Haemost. 2007;  5(suppl 1) 65-67
• 20 Ansell J. Factor Xa or thrombin: is factor Xa a better target?.  J Thromb Haemost. 2007;  5(suppl 1) 60-64