Improving antiplatelet therapy for atherothrombotic disease

Summary

Morbidity and mortality in patients with atherothrombotic disease remain high despite the use of antiplatelet therapy with aspirin and an ADP receptor antagonist. Selective inhibition of the principal protease-activated receptor (PAR)-1 for thrombin, the most potent agonist for platelet activation, represents a promising novel strategy to reduce thrombosis and ischaemic events. SCH 530348, a potent thrombin receptor antagonist (TRA) selective for PAR-1, has been evaluated in preclinical studies, demonstrating complete and sustained inhibition of thrombin/TRAP-induced platelet aggregation without a concomitant increase in the risk of bleeding. Phase 2 studies in patients undergoing non-urgent or urgent PCI showed that treatment with SCH 530348 in addition to the standard of care (aspirin plus an ADP receptor antagonist) is not associated with an increased risk of TIMI bleeding and is well tolerated, with a rate of adverse events comparable to standard therapy alone. These studies also demonstrated that the use of SCH 530348 in combination with aspirin and an ADP receptor antagonist may reduce the incidence of major adverse cardiac events, specifically periprocedural myocardial infarction, vs aspirin plus an ADP receptor antagonist alone. On the basis of these encouraging results, 2 ongoing large phase 3 randomized trials are evaluating the efficacy and safety of SCH 530348 in combination with the standard-of-care therapy in ≈35 000 patients with NSTE ACS or established atherosclerosis.

Zusammenfassung

Morbidität und Mortalität von Patienten mit arthero thrombotischen Erkrankungen sind weiter hoch, trotz verbreitetem Einsatz anti-thrombozytärer Therapie mit Aspirin und ADPRezeptor-Antagonisten. Die selektive Hem-mung des bedeutsamsten Rezeptors für Thrombin (PAR-1) auf Thrombozyten stellt eine neuartige und vielversprechende Strategie zur Reduktion thrombotischer und ischämischer Ereignisse dar. SCH 530348, ein hochwirksamer, Thrombinrezeptor-Antagonist (TRA) selektiv für den Rezeptor PAR-1 ist in präklinischen und klinischen Studien geprüft worden. Präklinisch fand sich eine rasche, vollständige und nachhaltige Hemmung der Thrombin/ TRAP-induzierten Plättchenagregation ohne erhöhtes Blutungsrisiko. Eine aktuelle, klinische Phase-II-Studie an 1020 Patienten mit elektiver oder Notfall-PCI sowie konservativer Therapie konnte zeigen, dass eine Therapie mit SCH 530348 zusätzlich zur Standardtherapie (inkl. Aspirin und ADP-Rezeptor-Antagonist) ausgezeichnet vertragen wurde und nicht mit einer erhöhten Rate an Blutungen (nach TIMI-Skala) assoziiert war. Die Rate an unerwünschten Arzneimittelwirkungen entsprach der Standardtherapie allein. Weiterhin ließ sich in dieser Studie unter Therapie mit SCH 530348 in Kombination mit Aspirin und ADP-Antagonisten und ein Trend zur Reduktion kardiovaskulärer Ereignisse, insbesondere von Myokardinfarkten gegenüber der Stan-dardtherapie allein nachweisen. Auf Grundlage dieser vielversprechenden Daten untersuchen zurzeit zwei groß angelegte, randomisierte Phase-III-Studien die Wirksamkeit und Sicherheit von SCH 530348 (in Kombination mit Standardtherapie) an mehr als 35 000 Patienten mit N-STEMI-ACS sowie in der Sekundärprophylaxe bei Patienten mit vorbekannten artherothrombotischen Erkrankungen.

Keywords

Atherothrombosis - antiplatelet therapy - PAR-1 - SCH 530348 - thrombin receptor antagonist

Schlüsselwörter

Artherothrombose - antithrombozytäre Therapie - PAR-1 - SCH 530348 - Thrombinrezeptor-Antagonist

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