e-5555 and Myocardial-Infarction

Atherothrombosis and its clinical manifestations are among the leading causes of death in the developed world. The current standard-of-care antiplatelet therapy for the treatment of such events comprises aspirin and a thienopyridine or ticagrelor. However, recurrent ischemic events due to residual cardiovascular risk are a common phenomenon in these patients. It is believed that this residual risk is caused, at least in part, by thrombin, which signals through protease-activated receptors (PARs) and especially PAR-1. Thus, PAR-1 antagonism could represent an effective approach in the treatment of atherothrombotic disease. In this context, two potent and selective agents have been developed, vorapaxar and atopaxar. However, only vorapaxar has completed phase 3 clinical trials. In the present review, the main pharmacodynamic and pharmacokinetic properties of the PAR-1 antagonists are briefly described and the latest clinical data on vorapaxar are presented.

Topics: Clinical Trials as Topic; Coronary Artery Bypass; Drug Therapy, Combination; Hemorrhage; Humans; Imines; Lactones; Myocardial Infarction; Percutaneous Coronary Intervention; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Pyridines; Receptor, PAR-1; Receptors, Thrombin; Stents; Stroke; Thrombosis

Ischemic heart disease remains the number one cause of death in the world despite advances in invasive and pharmacologic therapies. An ongoing area of research is the central role of platelets in atherothrombosis. Many therapeutic strategies have been developed over the last few decades affecting different platelet receptors to alter platelet-mediated thrombosis including targeting the receptors for thromboxane A(2), adenosine diphosphate, and fibrinogen. However, despite the use of pharmacologic agents directed at these pathways, residual morbidity and mortality still exist. Therefore, identifying agents that more favorably balance a reduction in ischemic events while minimizing bleeding events is an ongoing mission. Thrombin is known to be the most potent stimulant of platelet-mediated thrombosis whose action on the platelet is through a family of receptors known as the protease-activated receptors (PARs). Activation through the PAR-1 receptor, in particular, results in an early and intense response by the platelet to thrombin, and it is the primary thrombin receptor on platelets, thus making it a potentially desirable target for therapy. Most recently, two PAR-1 antagonists, atopaxar and vorapaxar, have been tested in clinical trials. Generally, the results show a reduction in ischemic event rates, but an increase in bleeding event rates. This article will summarize the current state of the literature and consider the role these drugs might play in the future for the prevention of ischemic heart disease events.

Topics: Acute Coronary Syndrome; Blood Platelets; Coronary Artery Disease; Hemorrhage; Humans; Imines; Lactones; Myocardial Infarction; Platelet Activation; Platelet Aggregation Inhibitors; Pyridines; Receptor, PAR-1; Thrombin; Treatment Outcome

Thrombin receptor antagonists blocking protease-activated receptor-1 (PAR-1) on platelets represent a new class of oral antiplatelet agents for patients with atherothrombotic disease manifestations.. We investigated the safety and efficacy of PAR-1 antagonists in patients with coronary artery disease (CAD).. Randomized, placebo-controlled trials of the PAR-1 antagonists atopaxar or vorapaxar in CAD patients were identified. The primary safety endpoint was the composite of Thrombolysis In Myocardial Infarction (TIMI) clinically significant bleeding. The primary efficacy endpoint was the composite of death, myocardial infarction (MI) or stroke.. A total of 41 647 patients from eight trials were included. PAR-1 antagonists were associated with higher risks of TIMI clinically significant (odds ratio [OR] 1.48, 95% confidence interval [CI] 1.39-1.57, P < 0.001), major (OR 1.46, 95% CI 1.28-1.67, P < 0.001) and minor (OR 1.67, 95% CI 1.40-2.00, P < 0.001) bleeding than placebo in the fixed-effects model. PAR-1 antagonists reduced the composite of death, MI or stroke as compared with placebo (OR 0.87, 95% CI 0.81-0.92, P < 0.001), driven by a lower risk of MI (OR 0.85, 95% CI 0.78-0.92, P < 0.001). Conversely, PAR-1 antagonists and placebo did not differ in terms of risk of death (OR 0.99, 95% CI 0.90-1.09, P = 0.81) or stroke (OR 0.96, 95% CI 0.84-1.10, P = 0.59).. PAR-1 antagonists decrease ischemic events in patients with CAD as compared with placebo, mainly driven by a reduction in MI, at the cost of an increased risk of clinically significant bleeding.

Topics: Blood Platelets; Chi-Square Distribution; Coronary Artery Disease; Evidence-Based Medicine; Hemorrhage; Humans; Imines; Lactones; Myocardial Infarction; Odds Ratio; Platelet Aggregation Inhibitors; Pyridines; Randomized Controlled Trials as Topic; Receptor, PAR-1; Risk Assessment; Risk Factors; Stroke; Treatment Outcome

Atopaxar (E5555) is a reversible protease-activated receptor-1 thrombin receptor antagonist that interferes with platelet signaling. The primary objective of the Lessons From Antagonizing the Cellular Effects of Thrombin-Acute Coronary Syndromes (LANCELOT—ACS) trial was to evaluate the safety and tolerability of atopaxar in patients with ACS.. Six hundred and three subjects were randomized within 72 hours of non-ST-elevation ACS to 1 of 3 doses of atopaxar (400-mg loading dose followed by 50, 100, or 200 mg daily) or matching placebo. The incidence of Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) major or minor bleeding did not differ significantly between the combined atopaxar and placebo groups (3.08% versus 2.17%, respectively; P=0.63), and there was no dose-related trend (P=0.80). The incidence of CURE major bleeding was numerically higher in the atopaxar group compared with the placebo group (1.8% versus 0%; P=0.12). The incidence of cardiovascular death, myocardial infarction, stroke, or recurrent ischemia was similar between the atopaxar and placebo arms (8.03% versus 7.75%; P=0.93). The incidence of CV death, MI, or stroke was 5.63% in the placebo group and 3.25% in the combined atopaxar group (P=0.20). Dose-dependent trends for efficacy were not seen. Atopaxar significantly reduced ischemia on continuous ECG monitoring (Holter) at 48 hours compared with placebo (relative risk, 0.67; P=0.02). Transient dose-dependent transaminase elevation and relative QTc prolongation were observed with the highest doses of atopaxar.. In patients after ACS, atopaxar significantly reduced early ischemia on Holter monitoring without a significant increase in major or minor bleeding. Larger trials are required to fully establish the efficacy and safety of atopaxar.. URL: http://www.ClinicalTrials.gov. Unique identifier: NCT00548587.

Topics: Acute Coronary Syndrome; Aged; Death, Sudden, Cardiac; Female; Hemorrhage; Humans; Imines; Incidence; Liver Diseases; Male; Middle Aged; Myocardial Infarction; Platelet Aggregation Inhibitors; Pyridines; Receptors, Thrombin; Risk Factors; Secondary Prevention; Stroke