New direct thrombin inhibitors

  • Alessandro Squizzato
  • Francesco Dentali
  • Luigi Steidl
  • Walter Ageno
IM - Review

Abstract

Direct thrombin inhibitors (DTIs) are a class of anticoagulants that bind selectively to thrombin and block its interaction with its substrates. Dabigatran etexilate and AZD0837, the new generation of DTIs, are now under intense development, and are potentially of great interest for internists. Dabigatran etexilate is a potent, non-peptidic small molecule that specifically and reversibly inhibits both free and clot-bound thrombin by binding to the active site of thrombin molecule. It has been already licensed in the European Union and in Canada for the prevention of VTE in patients undergoing hip- and knee-replacement surgery. Ongoing trials are evaluating its efficacy and safety for the treatment of deep venous thrombosis and pulmonary embolism, primary and secondary prevention of VTE, prevention of systemic embolism in patients with non-valvular atrial fibrillation, and prevention of cardiac events in patients with acute coronary syndromes. AZD0837 is the prodrug of ARH06737, a potent, competitive, reversible inhibitor of free and fibrin-bound thrombin. At present, only limited, preclinical, phase I and phase II clinical data have been presented. The drug has now entered a phase III clinical program in the population of patients with atrial fibrillation. Their properties and the oral administration render these compounds, theoretically, more convenient than both vitamin K antagonist and low molecular weight heparins. However, only reports from clinical practice patterns over the next months and years will tell us how and when to use the new DTIs.

Keywords

Anticoagulants Thrombin inhibitors Dabigatran Venous thromboembolism Atrial fibrillation 

Notes

Acknowledgments

The authors did not receive any financial support to write this manuscript.

Conflict of interest statement

The authors declare that they have no conflict of interest related to the publication of this manuscript.

References

  1. 1.
    Di Nisio M, Middeldorp S, Buller HR (2005) Direct thrombin inhibitors. N Engl J Med 353:1028–1040CrossRefPubMedGoogle Scholar
  2. 2.
    Weitz JI, Hirsh J, Samama MM (2008) New antithrombotic drugs: American College of Chest Physicians evidence-based clinical practice guidelines (8th edn). Chest 133:234–256CrossRefGoogle Scholar
  3. 3.
    Eriksson BI, Quinlan DJ, Weitz JI (2009) Comparative pharmacodynamics and pharmacokinetics of oral direct thrombin and factor Xa inhibitors development. Clin Pharmacokinet 48:1–22CrossRefPubMedGoogle Scholar
  4. 4.
    European Medicines Agency (EMEA). European public assessment report: Pradaxa [online]. Available at URL:http://www.emea.europa.eu
  5. 5.
    Gustafsson D, Elg M (2003) The pharmacodynamics and pharmacokinetics of the oral direct thrombin inhibitor ximelagatran and its active metabolite melagatran: a mini-review. Thromb Res 109(Suppl 1):S9–S15CrossRefPubMedGoogle Scholar
  6. 6.
    Mungall D (2002) BIBR-1048 Boehringer Ingelheim. Curr Opin Invest Drugs 3:905–907Google Scholar
  7. 7.
    Stangier J, Rathgen K, Stahle H et al (2007) The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol 64:292–303CrossRefPubMedGoogle Scholar
  8. 8.
    Sanford M, Plosker GL (2008) Dabigatran etexilate. Drugs 68:1699–1709CrossRefPubMedGoogle Scholar
  9. 9.
    Stangier J, Rathgen K, Stähle H, Reseski K, Körnicke T, Roth W (2009) Coadministration of dabigatran etexilate and atorvastatin: assessment of potential impact on pharmacokinetics and pharmacodynamics. Am J Cardiovasc Drugs 9:59–68PubMedGoogle Scholar
  10. 10.
    Wienen W, Stassen JM, Priepke H, Ries UJ, Hauel N (2007) Effects of the direct thrombin inhibitor dabigatran and its orally active prodrug, dabigatran etexilate, on thrombus formation and bleeding time in rats. Thromb Haemost 98:333–338PubMedGoogle Scholar
  11. 11.
    Eriksson BI, Dahl OE, Rosencher N et al (2007) Oral dabigatran etexilate versus subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. J Thromb Haemost 5:2178–2185CrossRefPubMedGoogle Scholar
  12. 12.
    Eriksson BI, Dahl OE, Rosencher N, RE-NOVATE Study Group et al (2007) Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomized, double-blind, non-inferiority trial. Lancet 370:949–956CrossRefPubMedGoogle Scholar
  13. 13.
    RE-MOBILIZE Writing Committee, Ginsberg JS, Davidson BL, Comp PC, Francis CW, Friedman RJ, Huo MH, Lieberman JR, Muntz JE, Raskob GE, Clements ML, Hantel S, Schnee JM, Caprini JA (2009) The oral thrombin inhibitor dabigatran etexilate vs the North American enoxaparin regimen for the prevention of venous thromboembolism after knee arthroplasty surgery. J Arthroplasty 2:1–9Google Scholar
  14. 14.
    Wolowacz SE, Roskell NS, Plumb JM, Caprini JA, Eriksson BI (2009) Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty. A meta-analysis. Thromb Haemost 101:77–85PubMedGoogle Scholar
  15. 15.
    Ezekowitz MD, Reilly PA, Nehmiz G, Simmers TA, Nagarakanti R, Parcham-Azad K, Pedersen KE, Lionetti DA, Stangier J, Wallentin L (2007) Dabigatran with or without concomitant aspirin compared with warfarin alone in patients with nonvalvular atrial fibrillation (PETRO Study). Am J Cardiol 100:1419–1426CrossRefPubMedGoogle Scholar
  16. 16.
    Ezekowitz MD, Connolly S, Parekh A, Reilly PA, Varrone J, Wang S, Oldgren J, Themeles E, Wallentin L, Yusuf S (2009) Rationale and design of RE-LY: randomized evaluation of long-term anticoagulant therapy, warfarin, compared with dabigatran. Am Heart J 157:805–810CrossRefPubMedGoogle Scholar
  17. 17.
    Lip GYH et al (2009) The oral direct thrombin inhibitor AZD0837 for the prevention of stroke and systemic embolism in patients with atrial fibrillation: a phase II randomized dose-guiding, safety and tolerability study. Abstract 1021 presented at the 58th Annual Scientific Sessions of the American College of Cardiology (ACC), in Orlando, Florida, 29–31 March 2009Google Scholar
  18. 18.
    Cullberg M, Eriksson U, Wernevik L et al (2007) Effect of ketoconazole and grapefruit juice on the pharmacokinetics of the oral direct thrombin inhibitor AZD0837 [abstract n. 205]. Basic Clin Pharmacol Toxicol 101:130Google Scholar

Copyright information

© SIMI 2009

Authors and Affiliations

  • Alessandro Squizzato
    • 1
    • 2
  • Francesco Dentali
    • 1
  • Luigi Steidl
    • 1
  • Walter Ageno
    • 1
  1. 1.Department of Clinical MedicineUniversity of InsubriaVareseItaly
  2. 2.U.O. Medicina I, Ospedale di CircoloVareseItaly

Personalised recommendations