Der Internist

, Volume 51, Issue 12, pp 1571–1581 | Cite as

Neue orale Antikoagulanzien

Werden sie die Vitamin-K-Antagonisten verdrängen?
Arzneimitteltherapie

Zusammenfassung

Langjährige praktische Erfahrung unter Einbeziehung des Patienten, gepaart mit intensiver wissenschaftlicher Begleitung, haben die Vitamin-K-Antagonisten zu einem Eckpfeiler der dauerhaften Prophylaxe und Therapie internistischer Erkrankungen werden lassen. Bekannte Limitationen in der Pharmakokinetik und -dynamik, umständlich erscheinende Therapiekontrolle auf der einen sowie die bevorstehende Verfügbarkeit innovativer Produkte mit gezielter Antikoagulationshemmung ohne Kontrollbedarf auf der anderen Seite fordern eine aktuelle Bestandsaufnahme. Für die perioperative Endoprothetik konnte für den direkten Thrombininhibitor Dabigatranetexilat sowie die Faktor-Xa-Inhibitoren Rivaroxaban und Apixaban inzwischen der Effektivitätsnachweis im Vergleich zu niedermolekularen Heparinen erbracht werden; zur kurzfristigen Thromboseprophylaxe bei internistischen Erkrankungen wird ihre Wirksamkeit zurzeit untersucht. Für die langfristige Gabe (6 bzw. 24 Monate) zur Therapie tiefer Beinvenenthrombosen bzw. zur Schlaganfallprophylaxe bei Vorhofflimmern existieren bereits Daten für den direkten Thrombininhibitor Dabigatranetexilat, dessen Effektivität im Vergleich zu Vitamin-K-Antagonisten bei ähnlichem Sicherheitsprofil in Abhängigkeit der Dosierung gleich oder überlegen ist. Allerdings werden die langjährig erprobten Vitamin-K-Antagonisten weiterhin so lange die Basis der oralen Antikoagulationstherapie darstellen, bis offene Fragen z. B. bezüglich unzureichender Therapieadhärenz (Abbruchrate bis 20%) oder existierender Arzneimittelinteraktionen der neuen Konkurrenzprodukte beantwortet sind.

Schlüsselwörter

Dabigatranetexilat Rivaroxaban Apixaban Thrombose Vorhofflimmern 

New oral anticoagulants

Better than vitamin K antagonists?

Abstract

Many years of practical use and intensive scientific research have allowed vitamin K antagonists to become a cornerstone of treatment of internal diseases. Nevertheless, limitations in pharmacokinetics and -dynamics of vitamin K antagonists and the availability of new drugs in regard to a targeted anticoagulation therapy ask for a new review of the situation. Proof of effectiveness for the perioperative prophylaxis of venous thrombosis after hip and knee replacement has already been achieved for the direct thrombin inhibitor dabigatran etexilate as well as for the factor Xa inhibitors rivaroxaban und apixaban compared to low molecular weight heparins. These new drugs are now also investigated in patients with internal diseases. For the long-term application (6 or 12 months) concerning the treatment of venous thrombosis and/or stroke prophylaxis in patients with atrial fibrillation data is already available for the direct thrombin inhibitor dabigatran etexilate. Depending on its dosage its effectiveness in comparison with vitamin K antagonists is equal or even better without disadvantages in safety. However, vitamin K antagonists will remain the standard oral anticoagulation until open questions regarding e.g. insufficient therapy adherence (with termination rates up to 20%) or problems with drug interactions of the new competitive products have been completely answered.

Keywords

Dabigatran etexilate Rivaroxaban Apixaban Thrombosis Atrial fibrillation 

Notes

Interessenkonflikt

Prof. Dr. H. Völler erhielt Vortragshonorare der Firmen Pfizer Pharma GmbH und Boehringer Ingelheim Pharma GmbH & Co. Prof. Dr. S. Alban ist als Referentin für die Firma Bayer Vital GmbH tätig und erhielt im Jahr 2007 Beratungshonorar von der Firma Boehringer Ingelheim. Dr. D. Westermann gibt an, keinen Interessenkonflikt zu haben.

Literatur

  1. 1.
    Ahrens I, Lip GY, Peter K (2010) New oral anticoagulant drugs in cardiovascular disease. Thromb Haemost 104:49–60PubMedGoogle Scholar
  2. 2.
    Aktionsplan des Bundesministeriums für Gesundheit zur Verbesserung der Arzneimitteltherapiesicherheit (AMTS) in Deutschland (2010). http://www.akdae.de/AMTS/index.html, gesehen 28.07.2010Google Scholar
  3. 3.
    Alban S (2008) Pharmacological strategies for inhibition of thrombin activity. Curr Pharm Des 14:1152–1175CrossRefPubMedGoogle Scholar
  4. 4.
    Ansell J, Hirsh J, Hylek E et al (2008) Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8 Edition). Chest 133(6 Suppl):299S–339SCrossRefPubMedGoogle Scholar
  5. 5.
    Carreiro J, Ansell J (2008) Apixaban, an oral direct Factor Xa inhibitor: awaiting the verdict. Expert Opin Investig Drugs 17:1937–1945CrossRefPubMedGoogle Scholar
  6. 6.
    Connolly SJ, Ezekowitz MD, Yusuf S et al (2009) Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 361:1139–1151CrossRefPubMedGoogle Scholar
  7. 7.
    Eikelboom JW, Weitz JI (2010) New anticoagulants. Circulation 121:1523–1532CrossRefPubMedGoogle Scholar
  8. 8.
    European Medicines Agency (2008) CHMP assessment report for Pradaxa, INN dabigatran etexilate. Procedure No. EMEA/H/C/829. Doc.Ref.: EMEA/174363/2008. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000829/human_med_000981.jsp&murl=menus/medicines/medicines.jsp&mid=WC0b01ac058001d124. Gesehen 28.08.2010Google Scholar
  9. 9.
    European Medicines Agency (2008) CHMP assessment report for Xarelto; INN rivaroxaban. Procedure No. EMEA/H/C/000944. Doc.Ref.: EMEA/543519/2008. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000944/human_med_001155.jsp&murl=menus/medicines/medicines.jsp&mid=WC0b01ac058001d124#. Accessed: 28.08.2010Google Scholar
  10. 10.
    Fetsch T, Bauer P, Engberding R et al (2004) Prevention of atrial fibrillation after cardioversion: results of the PAFAC trial. Eur Heart J 25:1385–1394CrossRefPubMedGoogle Scholar
  11. 11.
    Fuster V, Rydén LE, Cannom DS et al (2006) ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation-executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients with Atrial Fibrillation). Eur Heart J 27:1979–2030CrossRefPubMedGoogle Scholar
  12. 12.
    Geerts WH, Bergqvist D, Pineo GF et al (2008) Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8 Edition). Chest 133:381S–453SCrossRefPubMedGoogle Scholar
  13. 13.
    Gladstone DJ, Bui E, Fang J et al (2009) Potentially preventable strokes in high-risk patients with atrial fibrillation who are not adequately anticoagulated. Stroke 40:235–240CrossRefPubMedGoogle Scholar
  14. 14.
    Gorin L, Fauchier L, Nonin E et al (2010) Antithrombotic treatment and the risk of death and stroke in patients with atrial fibrillation and a CHADS2 score=1. Thromb Haemost 103:833–840PubMedGoogle Scholar
  15. 15.
    Hankowitz J, Bramlage P (2010) Pharmaka zur Thrombozyten- und Gerinnungshemmung in der Behandlung des akuten Koronarsyndroms. Kardiologe 4:239–248CrossRefGoogle Scholar
  16. 16.
    Hart RG, Pearce LA, Aguilar MI (2007) Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 146:857–867PubMedGoogle Scholar
  17. 17.
    Heneghan C, Alonso-Coello P, Garcia-Alamino JM et al (2006) Self-monitoring of oral anticoagulation: a systematic review and meta-analysis. Lancet 367:404–411CrossRefPubMedGoogle Scholar
  18. 18.
    Hohnloser SH, Pajitnev D, Pogue J et al (2007) Incidence of stroke in paroxysmal versus sustained atrial fibrillation in patients taking oral anticoagulation or combined antiplatelet therapy: an ACTIVE W Substudy. J Am Coll Cardiol 50:2156–2161CrossRefPubMedGoogle Scholar
  19. 19.
    Jurk K, Kehrel BE (2005) Platelets and the new comprehension of haemostasis. Hamostaseologie 25:39–49PubMedGoogle Scholar
  20. 20.
    Kirchhof P, Bax J, Blomstrom-Lundquist C et al (2009) Early and comprehensive management of atrial fibrillation: executive summary of the proceedings from the 2nd AFNET-EHRA consensus conference ‚research perspectives in AF’. Eur Heart J 30:2969c–2977cCrossRefGoogle Scholar
  21. 21.
    Lamassa M, Di Carlo A, Pracucci G et al (2001) Characteristics, outcome, and care of stroke associated with atrial fibrillation in Europe: data from a multicenter multinational hospital-based registry (The European Community Stroke Project). Stroke 32:392–398PubMedGoogle Scholar
  22. 22.
    Lassen MR, Raskob GE, Gallus A et al (2010) Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet 375:807–815CrossRefPubMedGoogle Scholar
  23. 23.
    Lohrmann J, Becker RC (2008) New anticoagulants – the path from discovery to clinical practice. N Engl J Med 358:2827–2829CrossRefPubMedGoogle Scholar
  24. 24.
    Lopes RD, Alexander JH, Al-Khatib SM et al (2010) Apixaban for reduction in stroke and other ThromboemboLic events in atrial fibrillation (ARISTOTLE) trial: design and rationale. Am Heart J 159:331–339CrossRefPubMedGoogle Scholar
  25. 25.
    Monroe DM, Hoffman M (2006) What does it take to make the perfect clot? Arterioscler Thromb Vasc Biol 26:41–48CrossRefPubMedGoogle Scholar
  26. 26.
    Nabauer M, Gerth A, Limbourg T et al (2009) The Registry of the German Competence NETwork on Atrial Fibrillation: patient characteristics and initial management. Europace 11:423–434CrossRefPubMedGoogle Scholar
  27. 27.
    Nieuwlaat R, Capucci A, Camm AJ et al (2005) Atrial fibrillation management: a prospective survey in ESC member countries: the Euro Heart Survey on Atrial Fibrillation. Eur Heart J 26:2422–2434CrossRefPubMedGoogle Scholar
  28. 28.
    Patten M, Maas R, Bauer P et al (2004) Suppression of paroxysmal atrial tachyarrhythmias – results of the SOPAT trial. Eur Heart J 25:1395–1404CrossRefPubMedGoogle Scholar
  29. 29.
    Perzborn E, Kubitza D, Misselwitz F (2007) Rivaroxaban. A novel, oral, direct factor Xa inhibitor in clinical development for the prevention and treatment of thromboembolic disorders. Hamostaseologie 27:282–289PubMedGoogle Scholar
  30. 30.
    Pfizer/Bristol-Myers Squibb (2010) AVERROES study of investigational agent apixaban closes early due to clear evidence of efficacy. http://media.pfizer.com/files/news/press_releases/2010/averroes_apixaban_061010.pdf, accessed 09.06.2010Google Scholar
  31. 31.
    Phillips KW, Ansell J (2010) The clinical implications of new oral anticoagulants: will the potential advantages be achieved? Thromb Haemost 103:34–39PubMedGoogle Scholar
  32. 32.
    Raghavan N, Frost CE, Yu Z et al (2009) Apixaban metabolism and pharmacokinetics after oral administration to humans. Drug Metab Dispos 37:74–81CrossRefPubMedGoogle Scholar
  33. 33.
    ROCKET AF Study Investigators (2010) Rivaroxaban-once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation: rationale and design of the ROCKET AF study. Am Heart J 159:340–347CrossRefGoogle Scholar
  34. 34.
    Schulman S, Kearon C, Kakkar AK et al (2009) Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 361:2342–2352CrossRefPubMedGoogle Scholar
  35. 35.
    Walraven C van, Hart RG, Connolly S et al (2009) Effect of age on stroke prevention therapy in patients with atrial fibrillation: the atrial fibrillation investigators. Stroke 40:1410–1416CrossRefPubMedGoogle Scholar
  36. 36.
    Wang L, Zhang D, Raghavan N et al (2010) In vitro assessment of metabolic drug-drug interaction potential of apixaban through cytochrome P450 phenotyping, inhibition, and induction studies. Drug Metab Dispos 38:448–458CrossRefPubMedGoogle Scholar
  37. 37.
    Wolowacz SE, Roskell NS, Plumb JM et al (2010) 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 103:360–371PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  1. 1.FESC, Klinik am SeeRehabilitationszentrum für Innere MedizinRüdersdorfDeutschland
  2. 2.Pharmazeutisches InstitutChristian-Albrechts-Universität zu KielKielDeutschland
  3. 3.Centrum für Herz-, Kreislauf- und Gefäßmedizin, Medizinische Klinik II – Kardiologie und PulmologieCharité – Universitätsmedizin BerlinBerlinDeutschland

Personalised recommendations