ro-48-3657 and Syndrome

Platelet membrane glycoprotein IIb/IIIa inhibitors, a new class of potent antiplatelet agents, have been used in the treatment of acute coronary syndromes as well as in the prevention of complications after percutaneous coronary interventions. Approximately 50,000 patients with coronary artery disease have been enrolled in randomized studies of glycoprotein IIb/IIIa inhibitors. The purpose of this article is to review the pharmacology of glycoprotein IIb/IIIa inhibitors, the results of the clinical trials using these agents, and their current use in percutaneous coronary interventions and the treatment of acute coronary syndromes.

Topics: Abciximab; Acetates; Acute Disease; Administration, Oral; Alanine; Angioplasty, Balloon, Coronary; Antibodies, Monoclonal; Anticoagulants; Benzamidines; Coronary Disease; Eptifibatide; Hemorrhage; Humans; Immunoglobulin Fab Fragments; Myocardial Infarction; Oximes; Peptides; Piperidines; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Pyrrolidines; Randomized Controlled Trials as Topic; Stents; Syndrome; Thrombocytopenia; Thrombolytic Therapy; Tirofiban; Tyrosine

Platelet aggregation plays a central role in the pathogenesis of thrombosis and the acute coronary syndromes. When given intravenously, potent selective antagonists of fibrinogen binding to the glycoprotein (GP) IIb/IIIa receptor, the final common pathway for platelet aggregation, have been effective in the treatment of acute coronary syndromes. Their benefit ceases, however, with the end of the infusion. Aspirin reduces the incidence of secondary vascular events by 25% to 30% after an acute coronary syndrome, and clopidogrel provides modest improvement over aspirin. However, both are relatively weak antiplatelet agents that each block only one of many pathways to platelet activation and surface membrane expression of the competent GP IIb/IIIa receptor. With the success of the intravenous GP IIb/IIIa antagonists in the acute setting, recent interest has focused on the potential benefit of oral GP IIb/IIIa antagonists used long-term for secondary prevention. The oral agents tested in phase III studies thus far have not performed up to expectations, however. The following paper reviews these studies and the implications of their results.

Topics: Alanine; Angina, Unstable; Aspirin; Benzamidines; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Humans; Myocardial Infarction; Oximes; Piperidines; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Pyrrolidines; Syndrome; Treatment Outcome

We studied stent thrombosis in 4,607 patients with acute coronary syndromes who received a coronary stent as part of routine care during 2 trials of aspirin versus sibrafiban for secondary prevention. In these patients, stent thrombosis occurred more often than in previous patients who underwent elective percutaneous coronary intervention. These patients and their outcomes may be more representative of patients with typical acute coronary syndromes undergoing stenting in clinical practice.

Topics: Acute Disease; Aspirin; Causality; Coronary Disease; Coronary Thrombosis; Female; Humans; Incidence; Male; Middle Aged; Multivariate Analysis; Myocardial Ischemia; Oximes; Piperidines; Platelet Aggregation Inhibitors; Postoperative Complications; Stents; Syndrome

Sibrafiban is a double prodrug that is converted to the inactive single prodrug and to the active IIb/IIIa antagonist following oral administration. Pharmacokinetics (PK) and pharmacodynamics (PD) of oral sibrafiban and its metabolites were evaluated in patients postacute coronary syndrome receiving once- or twice-daily sibrafiban for up to 28 days at several dose levels. Mean peak concentrations of sibrafiban were < 5 ng/mL. Peak single prodrug concentrations occurred 1.7 +/- 1.0 (mean +/- SD) hours after sibrafiban dosing. Total apparent plasma clearance of the single prodrug was 40 +/- 15 L/h, and the elimination half-life was 2.3 +/- 0.8 hours. Mean values of the steady-state pharmacokinetics for total concentrations of the active drug over all doses were: time to peak plasma concentration, 5.0 +/- 1.7 hours; apparent clearance, 13.9 +/- 3.9 L/h; and half-life, 11.0 +/- 2.8 hours. Once-daily dosing resulted in high peak-trough excursions in active drug concentrations: trough concentrations were 21% +/- 6% of peak. Twice-daily dosing resulted in an AUC for the active drug on Day 28 that was 168% +/- 36% of that on Day 1, and steady-state trough concentrations were 54% +/- 10% of peak with sustained inhibition of platelet aggregation. Dose-adjusted steady-state active drug concentrations increased with increasing age and with decreasing renal function and body weight.

Topics: Acute Disease; Administration, Oral; Adult; Age Factors; Aged; Aged, 80 and over; Amidines; Area Under Curve; Body Weight; Coronary Disease; Double-Blind Method; Female; Glomerular Filtration Rate; Heterocyclic Compounds; Humans; Male; Metabolic Clearance Rate; Middle Aged; Oximes; Piperidines; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Prodrugs; Syndrome

Despite progress, atherosclerotic vascular disease remains a major cause of morbidity and mortality. Intravenous therapy with platelet glycoprotein (GP) IIb/IIIa receptor antagonists improves outcome in patients with acute coronary syndromes (ACS). Whether potent long-term antiplatelet therapy with oral GP IIb/IIIa antagonists will further improve outcome at a dose that is tolerable in long-term treatment is unknown.. SYMPHONY (Sibrafiban versus aspirin to Yield Maximum Protection from ischemic Heart events post-acute cOroNary syndromes) was a randomized, double-blind, aspirin-controlled trial with 2 concentration regimens of sibrafiban, an oral peptidomimetic GP IIb/IIIa antagonist, for long-term treatment instead of aspirin in patients after an ACS. Patients were eligible for SYMPHONY if they presented within 7 days of an ACS (>/=20 minutes of ischemic symptoms), had been clinically stable for at least 12 hours, and met one of the following inclusion criteria: ST-segment depression or elevation of at least 0.5 mm or new left bundle branch block with the ACS or elevated creatinine kinase MB more than the upper limit of normal and >3% of total creatine kinase or, if creatine kinase MB was not measured, an elevated level of troponin T or I. Approximately 9000 patients post ACS were randomized 1:1:1 to treatment with either aspirin (80 mg every 12 hours) or high-dose or low-dose sibrafiban every 12 hours. Assignment of tablet strength (3, 4.5, or 6 mg) within the sibrafiban arms was based on body weight and renal function to achieve a target steady-state plasma concentration. The duration of study drug therapy was 90 days. Patients who had intracoronary stenting during the course of the study initially received a blinded stent medication assignment for 2 to 4 weeks based on their initial randomization as follows: aspirin/ticlopidine 250 mg twice daily, low-dose sibrafiban/ticlopidine placebo twice daily, and high-dose sibrafiban/ticlopidine placebo twice daily. After the second interim safety assessment by the Data and Safety Monitoring Board the stent regimen for the low-dose group was modified to include ticlopidine 250 mg twice daily.. The primary efficacy end point of SYMPHONY was the 90-day incidence of a composite of all-cause mortality, myocardial infarction or reinfarction, and severe recurrent ischemia. A clinical events classification committee was established to determine the end points of reinfarction and severe recurrent ischemia. The primary safety end points were the incidence of major bleeding or minor bleeding and the combined incidence of major and minor bleeding. Bleeding classification was done by computer algorithm. Tolerability was assessed by the rate of study drug discontinuation from bleeding.

Topics: Angina, Unstable; Aspirin; Clinical Trials, Phase III as Topic; Double-Blind Method; Humans; Myocardial Infarction; Oximes; Piperidines; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Prodrugs; Randomized Controlled Trials as Topic; Research Design; Syndrome; Treatment Outcome