ro-48-3657 and Acute-Disease

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

The central role of platelet-rich thrombus in the pathogenesis of acute coronary syndromes (ACSs) is well-known. Glycoprotein IIb/IIIa (Gp IIb/IIIa) receptor antagonists are potent inhibitors of platelet function that may be expected to affect favorably the natural history of ACSs.. To define the optimal role of Gp IIb/IIIa inhibitors in treatment strategies for ACSs.. A MEDLINE search was performed to identify all English-language articles regarding use of Gp IIb/IIIa inhibitors in ACSs published between 1966 and June 2000. In addition, relevant abstracts from the annual meetings of the American Heart Association, American College of Cardiology, and the European Society of Cardiology were reviewed.. Only studies of 500 or more patients were included. Of 15 studies identified, 10 randomized, placebo-controlled, double-blind trials of Gp IIb/IIIa inhibitors in ACSs were selected for review.. Data quality was determined by publication in the peer-reviewed literature or presentation at an official cardiology society-sponsored meeting, as well as by verification with the primary author.. Three members of this class of drugs are available for intravenous use. Abciximab, eptifibatide, and tirofiban hydrochloride, each have data demonstrating their value in improving the outcomes of patients presenting with ACSs. Current evidence supports use of these drugs in both conservative and invasive treatment strategies. Glycoprotein IIb/IIIa-blocking therapy is safe, and with proper precautions, bleeding risks can be minimized. Biological differences exist among these agents, but as of yet, no head-to-head comparisons have been made of their clinical efficacy. Unlike intravenous Gp IIb/IIIa inhibitors, available data regarding any role of oral Gp IIb/IIIa inhibitors are not favorable.. Current data indicate that intravenous Gp IIb/IIIa inhibitor therapy merits a prominent role in the initial management of patients with ACSs. JAMA. 2000;284:1549-1558.

Topics: Abciximab; Acute Disease; Alanine; Angina, Unstable; Angioplasty, Balloon, Coronary; Antibodies, Monoclonal; Anticoagulants; Benzamidines; Drug Therapy, Combination; Eptifibatide; Heparin, Low-Molecular-Weight; Humans; Immunoglobulin Fab Fragments; Myocardial Infarction; Oximes; Peptides; Piperidines; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Pyrrolidines; Randomized Controlled Trials as Topic; Stents; Tirofiban; Tyrosine

The baseline characteristics, complications, and survival of 489 black and 6,890 non-black patients with acute coronary syndromes were studied. Important racial differences were observed in demographic features, atherosclerosis risk factors, and treatment strategies; however, despite these differences, no independent difference was observed in clinical outcomes according to race. The 1-year mortality rate was 2.9% for black patients and 2.5% for non-black patients (p = 0.93).

Topics: Acute Disease; Aged; Black or African American; Coronary Disease; Double-Blind Method; Female; Humans; Male; Middle Aged; Multivariate Analysis; Oximes; Piperidines; Platelet Aggregation Inhibitors; Prognosis; Retrospective Studies; Risk Factors

Stroke is a rare but serious event that complicates the course of patients with acute coronary syndromes (ACS). The type, outcome, and risk factors of stroke occurring in stabilized patients with ACS have not been previously reported.. We evaluated stroke incidence, subtypes, and outcomes, in addition to demographics and clinical risk characteristics associated with stroke among patients enrolled in the Sibrafiban versus Aspirin to Yield Maximum Protection from Ischemic Heart Events Post-acute Coronary Syndromes (SYMPHONY) and 2nd SYMPHONY trials.. Of 15,904 stabilized patients with ACS, 113 (0.71%) had a stroke over a median follow-up of 90 days. The majority of strokes occurred within 30 days of presentation, and the time course for stroke occurrence paralleled that of myocardial (re)infarction. Most strokes were ischemic (78%), and 52% resulted in moderate or severe disability or death. Patients with stroke were older and more often had hypertension, diabetes, peripheral vascular disease, and atrial fibrillation. Among patients with stroke who had cardiac catheterization, percutaneous coronary intervention, or coronary artery bypass grafting, stroke occurred predominantly after the procedure. No difference in occurrence or type of stroke was observed in the assigned treatment groups. In multivariable modeling age, heart failure, prior stroke, left bundle branch block, and systolic blood pressure predicted the occurrence of stroke.. In patients stabilized after presenting with a spectrum of ACS and treated with sibrafiban and/or aspirin, stroke occurred in fewer than 1% within 90 days but carried a significant mortality and morbidity risk.

Topics: Acute Disease; Aged; Angina, Unstable; Angioplasty, Balloon, Coronary; Aspirin; Coronary Artery Bypass; Female; Follow-Up Studies; Humans; Incidence; Male; Middle Aged; Myocardial Infarction; Oximes; Piperidines; Platelet Aggregation Inhibitors; Proportional Hazards Models; Recurrence; Risk Factors; Stroke

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

Inhibitors of the platelet glycoprotein IIb/IIIa receptor given intravenously have been shown to be effective in reducing ischemic complications after coronary angioplasty and in unstable angina, making this a promising new class of agents for the treatment and prevention of ischemic events in patients with acute coronary syndromes. Sibrafiban (Ro 48-3657) is an oral, peptidomimetic, selective antagonist of the glycoprotein IIb/IIIa receptor.. The Thrombolysis in Myocardial Infarction (TIMI) 12 trial was a phase II, double-blind, dose-ranging trial designed to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of sibrafiban in 329 patients after acute coronary syndromes. In the PK/PD cohort of TIMI 12, 106 patients were randomized to receive one of seven dosing regimens of sibrafiban, ranging from 5 mg daily to 10 mg twice daily for 28 days. In the safety cohort, 223 patients were randomized to one of four dose regimens of sibrafiban (ranging from 5 mg twice daily to 15 mg once daily) or aspirin for 28 days. High levels of platelet inhibition were achieved: mean peak values ranged from 47% to 97% inhibition of 20 micromol/L ADP-induced platelet aggregation on day 28 across the seven doses. Twice-daily dosing provided more sustained platelet inhibition (mean inhibition, 36% to 86% on day 28), whereas platelet inhibition returned to baseline levels by 24 hours with once-daily dosing. Major hemorrhage occurred in 1.5% of patients treated with sibrafiban and in 1.9% of patients treated with aspirin. Protocol-defined "minor" bleeding, usually mucocutaneous, occurred in 0% to 32% of patients in the various sibrafiban groups and in none of the patients treated with aspirin. Minor bleeding was related to total daily dose (P=.002), once- versus twice-daily dosing (P<.0001), renal function (P<.0001), and presentation with unstable angina (P<.01).. The oral glycoprotein IIb/IIIa antagonist sibrafiban achieved effective, long-term platelet inhibition with a clear dose-response but at the expense of a relatively high incidence of minor bleeding. Oral IIb/IIIa inhibition deserves further study as a new treatment strategy in patients after acute coronary syndromes.

Topics: Acute Disease; Administration, Oral; Aged; Cohort Studies; Coronary Disease; Dose-Response Relationship, Drug; Double-Blind Method; Female; Hemorrhage; Humans; Male; Middle Aged; Oximes; Piperidines; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Recurrence

The secondary prevention benefit of therapy with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) has been clearly demonstrated; however, the role of early initiation of statins after acute coronary syndromes (ACSs) is unknown.. To evaluate the association of early statin initiation (< or = 7 days) after ACS with 90-day and 1-year outcomes.. Observational cohort from databases of 2 randomized clinical trials, SYMPHONY and 2nd SYMPHONY.. Nine hundred thirty-one clinical centers in 37 countries.. A total of 12,365 ACS patients randomized from August 1997 to August 1999 who were not taking statins prior to the index ACS and who either started statin therapy early (median, 2.0 [interquartile range, 1.0-3.1] days after ACS; n = 3952) or survived more than 5 days after ACS and never received statin therapy (n = 8413).. Ninety-day incidence of death; death or myocardial infarction (MI); and death, MI, or severe recurrent ischemia; as well as 1-year incidence of death.. Ninety-day and 1-year unadjusted mortality comparison suggested early statin benefit (1.2% for early statins vs 2.1% for no statins; hazard ratio [HR], 0.58; 95% confidence interval [CI], 0.42-0.81 for 90-day comparisons and 2.3% for early statins vs 4.4% for no statins; HR, 0.52; 95% CI, 0.40-0.68 for 1-year comparison). However, no benefit was evident for 90-day death or MI (6.5% vs 6.9%; HR, 0.95; 95% CI, 0.82-1.11) or death, MI, or severe recurrent ischemia (9.2% vs 8.9%; HR, 1.04; 95% CI, 0.92-1.18). After propensity and covariate adjustment, there were no 90-day or 1-year differences between the early-statin group and the no-statin group. The 90-day adjusted HR for death was 1.08 (95% CI, 0.75-1.56); for death or MI, 1.08 (95% CI, 0.91-1.29); and for death, MI, or severe recurrent ischemia, 1.15 (95% CI, 0.99-1.34). One-year mortality-adjusted HR was 0.99 (95% CI, 0.73-1.33). Among 2711 patients with core laboratory lipid analysis, early statin was associated with higher adjusted risk for death or death or MI at cholesterol levels below treatment guidelines but was more favorable at higher levels.. In this study, there was no relationship between early initiation of statin therapy and improved outcomes although our subset analysis suggests that outcomes after early statin initiation may vary with cholesterol levels. Confirmation of early treatment effects of statins on outcomes awaits the results of adequately powered randomized clinical trials.

Topics: Acute Disease; Aged; Angina, Unstable; Aspirin; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lipoproteins; Male; Middle Aged; Myocardial Infarction; Oximes; Piperidines; Platelet Aggregation Inhibitors; Proportional Hazards Models; Randomized Controlled Trials as Topic; Survival Analysis; Treatment Outcome