e-5555 and Coronary-Thrombosis

Patients with acute coronary syndrome (ACS) usually receive acetylsalicylic acid plus an adenosine diphosphate (ADP) receptor inhibitor to reduce the long-term risk of recurrent events. However, patients receiving standard antiplatelet prophylaxis still face a substantial risk of recurrent events. Strategies involving 3 antithrombotic agents with different modes of action have now been tested. In Thrombin Receptor Antagonists for Clinical Event Reduction (TRA-CER), compared with standard care alone, bleeding complications including intracranial hemorrhage (ICH) were increased with the addition of vorapaxar, without efficacy benefit. In Trial to Assess the Effects of SCH 530348 in Preventing Heart Attack and Stroke in Patients With Atherosclerosis (TRA 2°P-TIMI 50), the addition of vorapaxar reduced recurrent events compared with standard care in stable patients with prior myocardial infarction. This study was terminated early in patients with prior stroke owing to excess ICH, though an increased risk of ICH or fatal bleeding was not detected in patients with prior myocardial infarction. The Apixaban for Prevention of Acute Ischemic and Safety Events 2 (APPRAISE-2) trial of standard-dose apixaban added to standard care in patients with ACS was also stopped early owing to excess serious bleeding. However, in Rivaroxaban in Combination With Aspirin Alone or With Aspirin and a Thienopyridine in Patients With Acute Coronary Syndromes (ATLAS ACS 2 TIMI 51), fatal bleeding or fatal ICH did not increase with low-dose rivaroxaban added to low-dose acetylsalicylic acid-based standard care compared with standard care alone. In that trial, a significant reduction of recurrent vascular events was shown with 3 antithrombotic regimens compared with standard care. Therefore, depending on drug dose and patient population, further reductions in recurrent vascular events after ACS may be possible in future clinical practice, with a favorable benefit-risk profile.

Topics: Acute Coronary Syndrome; Anticoagulants; Benzimidazoles; beta-Alanine; Clinical Trials as Topic; Coronary Thrombosis; Dabigatran; Hemorrhage; Humans; Imines; Lactones; Morpholines; Platelet Activation; Platelet Aggregation Inhibitors; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Secondary Prevention; Thiophenes; Thrombin

Platelet activation and aggregation is a complex and key process in thrombus formation after the rupture of an atherosclerotic plaque, which can lead to an acute coronary syndrome. Aspirin, an irreversible inhibitor of thromboxane A(2) synthesis, in combination with an inhibitor of P2Y(12) ADP platelet receptors (clopidogrel, prasugrel or ticagrelor), represents the current standard of care of antiplatelet therapy for patients with acute coronary syndrome and in those patients undergoing percutaneous coronary intervention. Despite the benefit of these agents, the risk of thrombotic events and bleeding complications may still occur while on such antiplatelet treatment regimens, thus representing an important limitation. Thrombin is one of the most important platelet activators. The inhibition of thrombin-mediated platelet activation by means of protease-activated receptor-1 inhibitors represents an attractive therapeutic option for patients with atherothrombotic disease processes. This article provides an overview on atopaxar (E5555), an orally active protease-activated receptor-1 antagonist that has recently completed Phase II clinical investigation.

Topics: Acute Coronary Syndrome; Animals; Clopidogrel; Coronary Artery Disease; Coronary Thrombosis; Humans; Imines; Platelet Activation; Platelet Aggregation Inhibitors; Pyridines; Receptors, Thrombin; Ticlopidine