title: In vitro inhibition of platelet aggregation in response to increasing concentrations of tirofiban in patients with significant renal insufficiency.
abstract: BACKGROUND
  Patients with impaired renal function are a growing subset at higher risk for cardiovascular complications due to vasculopathic state, inducing accelerated atherosclerosis and arteriosclerosis. These patients are at increased risk for complications after coronary interventions, especially major bleeding events. As a result, this at-risk population of patients has not been well studied in most of the major clinical trials evaluating coronary interventions. Of particular interest is the optimal dosing of glycoprotein IIb-IIIa inhibitors in the setting of acute myocardial infarction. In this study, we attempted to find the in vitro concentration of tirofiban required to inhibit platelet aggregation to <10% in patients with moderate to severe renal insufficiency.
  
  
  METHODS
  A total of 21 patients were divided into two groups based on estimated creatinine clearance (group 1 <46ml/min; group 2 >46ml/min). Platelet-rich plasma from each subject was then incubated in vitro with increasing concentrations of tirofiban (25, 37.5, and 50ng/ml), and light transmission aggregometry assay was used to assess the degree of platelet aggregation in response to adenosine diphosphate (ADP).
  
  
  RESULTS
  Patients in group 1 had a baseline platelet aggregation of 45%, which decreased to 10% at a 25.0ng/ml concentration of tirofiban; the effect was enhanced to a platelet aggregation of <5% at higher doses. In contrast, subjects in group 2 with creatinine clearance >or=46ml/min had an average platelet aggregation inhibition of 12% with 50ng/ml of tirofiban.We found a significant decrease in platelet aggregation in group 2 at 25, 37.5, and 50ng/ml of tirofiban (p<0.05) in comparison with group 1.
  
  
  CONCLUSIONS
  Our data indicate that patients with moderate to severe renal dysfunction suppress their platelet aggregation to <10% with 25ng/ml of tirofiban, one-third of the standard effective dose for patients with normal renal function.We suggest further clinical trials to define an objective means to calculate proper renal dosing of glycoprotein IIb-IIIa inhibitors in these patients to prevent potentially fatal complication of major hemorrhagic events.
authors.affiliation: Section of Cardiology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Mahboob
authors.initials: M
authors.lastname: Alam
authors.forename: Rafael
authors.initials: R
authors.lastname: Gonzalez
authors.forename: Ariel
authors.initials: A
authors.lastname: Delarosa
authors.forename: Jaromir
authors.initials: J
authors.lastname: Bobek
authors.forename: Hisham
authors.initials: H
authors.lastname: Dokainish
authors.forename: Nasser
authors.initials: N
authors.lastname: Lakkis
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology; D000293:Adolescent; D000328:Adult; D000368:Aged; D016009:Chi-Square Distribution; D003404:Creatinine / Q000378:metabolism; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors; D053657:Platelet-Rich Plasma; D051437:Renal Insufficiency / Q000097:blood* / Q000188:drug therapy*; D012307:Risk Factors; D000077466:Tirofiban; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D014443:Tyrosine; D000244:Adenosine Diphosphate; D003404:Creatinine; D000077466:Tirofiban