Zukünftiges Indikationspotenzial eines oralen Thrombininhibitors

Zusammenfassung

Herkömmliche Antikoagulanzien haben zu signifikanten Fortschritten in der Medizin geführt, sind aber mit zahlreichen Unzulänglichkeiten verbunden. Insbesondere bei der Langzeitantikoagulation mit Vitamin-K-Antagonisten limitieren sie die Anwendung im klinischen Alltag (Gründe: verzögertes Einsetzen und Abklingen der Wirkung, geringe therapeutische Breite, Notwendigkeit der individuellen laborkontrollierten Dosierung, Wechselwirkungen mit Pharmaka und Nahrungsmitteln). Auf der Suche nach neuen Antithrombotika mit verbessertem Wirk- und Sicherheitsprofil wurde der orale direkte Thrombininhibitor Ximelagatran entwickelt, der in fester Dosierung ohne routinemäßige Gerinnungskontrollen eingesetzt werden kann und keine der genannten Unzulänglichkeiten besitzt. Die vorliegenden klinischen Phase-II-Daten sind sehr ermutigend. Nach Abschluss des klinischen Entwicklungsprogramms zur Prävention und Therapie venöser Thromboembolien, zur Prävention des Schlaganfalls bei Vorhofflimmern und im Rahmen der Therapie des akuten Koronarsyndroms wären weitere Untersuchungen wünschenswert, z.B. zur Langzeitprophylaxe nach Hochrisikoeingriffen, bei chronischer peripherer arterieller Verschlusskrankheit, Myokardinfarkt, linksventrikulären Thromben und bei Patienten mit künstlichen Herzklappen oder Thrombophilie sowie als alternatives Antikoagulans bei heparininduzierter Thrombozytopenie und zur Prävention thromboembolischer Komplikationen in der Onkologie. Wegen der mitogenen Wirkung von Thrombin bei der Tumorzellproliferation wären außerdem experimentelle Untersuchungen zur Wirkung von Ximelagatran hinsichtlich einer potenziellen Hemmung der Thrombin-getriggerten Onkogenese interessant.

Summary

By the use of conventional anticoagulants, significant improvements were achieved in all fields of medicine. Although efficacious and widely used, their use is limited in several respects. In particular, the use of vitamin K antagonists is restricted in the clinical routine setting. The main reasons are the delayed on- and off-set of action, the narrow therapeutic window, the necessity of individual laboratory-controlled dosing, and interactions with food ingredients and drugs. The search for new antithrombotics with an improved safety/efficacy profile led to the development of the direct oral thrombininhibitor ximelagatran. It can be administered without routine monitoring of coagulation parameters and does not possess any of the previously mentioned limitations. The results from clinical phase II studies obtained so far are very encouraging. After completion of the clinical development program focussing on prevention and treatment of venous thromboembolism, on stroke prevention in atrial fibrillation and on acute coronary syndromes, it is desirable to continue with investigations with regard to long-term prophylaxis in high risk surgery, in chronic peripheral artery disease, in patients with left ventricular thrombi, artificial heart valves, or thrombophilia, as an alternative anticoagulant in heparin induced thrombocytopenia and for prevention of thromboembolic complications in oncology. Because of the mitogenic effects of thrombin on the proliferation of tumour cells, additional experimental studies aiming at a potential inhibition of thrombin-triggered oncogenesis is of uttermost interest.

Schlüsselwörter

Orale Thrombininhibition - Ximelagatran - Thrombose - Schlaganfallprophylaxe

Keywords

Oral thrombin inhibition - Ximelagatran - thromboembolism - prevention of stroke

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