title: Randomized, double-blind, placebo-controlled, international trial of the oral IIb/IIIa antagonist lotrafiban in coronary and cerebrovascular disease.
abstract: BACKGROUND
  This is the primary report of the large-scale evaluation of lotrafiban, an orally administered IIb/IIIa receptor antagonist, a unique trial with respect to the platelet antagonist, protocol design, and inclusion of cerebrovascular disease in a significant proportion of patients.
  
  
  RESULTS
  Patients with vascular disease were randomized to lotrafiban 30 or 50 mg BID on the basis of age and predicted creatinine clearance or placebo in addition to aspirin at a dose ranging from 75 to 325 mg/d at the discretion of the physician-investigator. Follow-up was for up to 2 years. The primary end point was the composite of all-cause mortality, myocardial infarction, stroke, recurrent ischemia requiring hospitalization, and urgent revascularization. Of 9190 patients enrolled from 23 countries and 690 hospitals, 41% had cerebrovascular disease at the time of entry, and 59% had coronary artery disease. Death occurred in 2.3% of placebo-assigned patients and 3.0% of lotrafiban-group patients (hazard ratio 1.33, 95% CI 1.03 to 1.72, P=0.026), and the cause of excess death was vascular related. There was no significant difference in the primary end point (17.5% compared with 16.4%, respectively; hazard ratio 0.94, 95% CI 0.85 to 1.03, P=0.19). Serious bleeding was more frequent in the lotrafiban group (8.0% compared with 2.8%; P<0.001). Serious bleeding was more common among patients who received higher doses of aspirin (>162 mg/d), with or without lotrafiban.
  
  
  CONCLUSIONS
  Lotrafiban, an orally administered platelet glycoprotein IIb/IIIa blocker, induced a 33% increase in death rate, which was vascular in origin and not affected by the type of atherosclerotic involvement at entry to the trial. Although the dose of aspirin was not randomly assigned, the finding of increased bleeding with doses >162 mg/d is noteworthy.
authors.affiliation: Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA. topole@ccf.org
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Topol
authors.forename: Donald
authors.initials: D
authors.lastname: Easton
authors.forename: Robert A
authors.initials: RA
authors.lastname: Harrington
authors.forename: Pierre
authors.initials: P
authors.lastname: Amarenco
authors.forename: Robert M
authors.initials: RM
authors.lastname: Califf
authors.forename: Carmen
authors.initials: C
authors.lastname: Graffagnino
authors.forename: Stephen
authors.initials: S
authors.lastname: Davis
authors.forename: Hans-Christophe
authors.initials: HC
authors.lastname: Diener
authors.forename: James
authors.initials: J
authors.lastname: Ferguson
authors.forename: Desmond
authors.initials: D
authors.lastname: Fitzgerald
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Granett
authors.forename: Ashfaq
authors.initials: A
authors.lastname: Shuaib
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Koudstaal
authors.forename: Pierre
authors.initials: P
authors.lastname: Theroux
authors.forename: Frans
authors.initials: F
authors.lastname: Van de Werf
authors.forename: Kristina
authors.initials: K
authors.lastname: Sigmon
authors.forename: Karen
authors.initials: K
authors.lastname: Pieper
authors.forename: Marc
authors.initials: M
authors.lastname: Vallee
authors.forename: James T
authors.initials: JT
authors.lastname: Willerson
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001241:Aspirin / Q000009:adverse effects / Q000627:therapeutic use; D001569:Benzodiazepines / Q000009:adverse effects* / Q000627:therapeutic use; D002561:Cerebrovascular Disorders / Q000188:drug therapy* / Q000401:mortality; D003327:Coronary Disease / Q000188:drug therapy* / Q000401:mortality; D003404:Creatinine / Q000097:blood / Q000652:urine; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D010880:Piperidines / Q000009:adverse effects* / Q000627:therapeutic use; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D016016:Proportional Hazards Models; D018570:Risk Assessment; D016896:Treatment Outcome
chemical_list: D010880:Piperidines; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D001569:Benzodiazepines; D003404:Creatinine; C412702:lotrafiban; D001241:Aspirin