Old and new anticoagulants

Summary

Vitamin-K-antagonists (VKA) and heparins have been complementary anticoagulants for prevention and treatment of thrombosis for almost 70 years. In contrast to heparins, VKA have not been modified pharmacologically, however treatment surveillance has improved by introducing INR and self-monitoring/management. Disclosure of the molecular basis of interaction with VKORC1, the target enzyme of VKA, has helped to better understand coumarin sensitivity and resistance. New oral anticoagulants have now been approved and stimulated expectations in patients and physicians to get rid of the burdening frequent controls of VKA without loss of efficacy and safety.

This review will summarize the development and profile of the new substances. Main difference compared to VKA is their direct mode of action against one clotting factor which is factor IIa in dabigatran and factor Xa in rivaroxaban and other “xabanes” currently under intensive investigation. Half lifes of the new anticoagulants are much shorter than that of the mainly used coumarins (phenprocoumon, warfarin), making “anticoagulation bridging” unnecessary before surgery. Therapeutic width of direct thrombin inhibitors and factor Xa inhibitors is broader and they are given at fixed doses. Clinical studies in thromboprophylaxis, thromboembolism and atrial fibrillation indicate at least non-inferiority or even superior efficacy compared with enoxaparin and VKA at comparable safety outcomes. Limitations of the new substances may arise from gastrointestinal side effects, mode of metabolism and route of elimination. Specific antidots are not available for none of them.

Undoubtedly, the new oral anticoagulants are very promising. But, although thousands of study patients already have been treated, there are questions to be answered such as treatment adherence in absence of monitoring, safety and efficacy in risk patients, dosage adjustment and interactions with other drugs, before conclusions can be drawn towards their potential to replace VKA.

Zusammenfassung

Vitamin-K-Antagonisten (VKA) und Heparine waren fast 70 Jahre lang komplementäre Antikoagulanzien für die Prävention und Therapie von Thrombosen. Im Gegensatz zu den Heparinen wurden die VKA pharmakologisch nicht verändert, aber die Möglichkeiten der Therapieüberwachung verbesserten sich mit Einführung des INR-Bestimmung und des Selbstmonitorings. Die Entdeckung der molekularen Grundlagen des Vitamin-K-Epoxid-Reduktase Komplexes (VKORC1), dem Schlüsselenzym der Interaktion mit VKA, hat das Verständnis für Phänomene wie Cumarinsensitivität und -resistenz entscheidend erweitert. Neue Substanzen wurden mittlerweile entwickelt und zugelassen. Sie haben sowohl bei Patienten als auch Ärzten große Erwartungen geweckt, in naher Zukunft die häufigen und belastenden INR-Kontrollen nicht mehr zu benötigen.

Diese Übersichtsarbeit fasst die Entwicklung und das Profil der neuen Substanzen zusammen. Ihr wesentlicher Unterschied im Vergleich zu den VKA besteht darin, dass sie direkt gegen einen einzelnen Gerinnungsfaktor gerichtet sind, Faktor IIa (Thrombin) im Falle von Dabitgatran und Faktor Xa bei Rivaroxaban und anderen „Xabanen”, die derzeit invensiv untersucht werden. Die Halbwertzeiten der neuen Antikoagulanzien sind wesentlich kürzer als die der überwiegend verwendeten VKA (Phenprocoumon, Warfarin), womit ein „Antikoagulations-Bridging” z. B. präoperativ unnötig würde. Die therapeutische Breite von Thrombin- und Faktor-Xa-Inhibitoren ist größer und sie werden in fixer Dosierung appliziert. Klinische Studien aus den Bereichen Thromboseprophylaxe, Therapie von Thromboembolien und Vorhoffflimmern weisen zumindest Nicht-Unterlegenheit, wenn nicht sogar bessere Effektivität im Vergleich zu Enoxaparin und VKA nach, bei vergleichbaren Sicherheitsendpunkten. Limitierungen der neuen Substanzen könnten sich auf Grund gastrointestinaler Nebenwirkungen, Art der Metabolisierung und dem Eliminierung ergeben. Ein spezifisches Antidot steht für keine der Substanzen zur Verfügung.

Unzweifelhaft sind die neuen oralen Antikoagulanzien sehr vielversprechend. Dennoch bleiben offene Fragen, obwohl schon tausende von Patienten unter Studienbedingungen behandelt wurden, z. B. die nach der Therapieadhärenz bei nicht mehr erfolgendem Monitoring, Effektivität und Sicherheit bei Risikopatienten sowie Dosisanpassung und Interaktion mit anderen Medikamenten. Erst nach deren Beantwortung wird eine abschließende Bewertung möglich sein, ob die neuen Substanzen geeignet sind, die Vitamin-K-Antagonisten zu ersetzen.

Keywords

Vitamin K antagonists - heparins - direct oral thrombin inhibitors - factor Xa inhibitors - clinical trials

Schlüsselwörter

Vitamin-K-Antagonisten - Heparine - direkte orale Thrombininhibitoren - Faktor-Xa-Inhibito ren - klinische Studien

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