title: Risk of intracranial haemorrhage with combined fibrinolytic and glycoprotein IIb/IIIa inhibitor therapy in acute myocardial infarction. Dichotomous response as a function of age in the GUSTO V trial.
abstract: BACKGROUND
  Intracranial haemorrhage is an important limitation to pharmacologic reperfusion therapy for acute myocardial infarction. The combination of a glycoprotein IIb/IIIa inhibitor, half-dose plasminogen activator and reduced-dose heparin has been evaluated as an alternative to standard fibrinolytic therapy in this setting.
  
  
  RESULTS
  We evaluated the relation between univariate and multivariate predictors of intracranial haemorrhage and the effect of treatment with either reteplase alone (10 U bolus twice, 30 min apart) with standard-dose heparin (5000 U bolus followed by an infusion of 1000 Uh(-1)for patients > or =80 kg and 800 Uh(-1)for those <80 kg) or combination therapy with abciximab (0.25mg/kg bolus and 0.125 microg/kg/min for 12h) and half-dose reteplase (two boluses of 5U 30 min apart) with reduced-dose heparin (60 Ukg(-1)bolus, maximum 5000 U, followed by an infusion of 7 Ukg(-1)h(-1)) in the 16 588 patients randomized in the GUSTO V trial. Overall, the incidence of intracranial haemorrhage was similar in the two groups (0.6% vs 0.6%; OR 1.05, 95% CI 0.71, 1.56). The median (25th-75th) time from drug administration to intracranial haemorrhage was 5.5 (3.4-11) hours with combination therapy and 9.2 (5.9-22) hours with reteplase (P=0.048). Among the multivariable predictors of intracranial haemorrhage, only age showed a significant interaction with treatment effect (age per treatment interaction chi-square 4.60, P=0.032) with a lower risk of combination therapy for younger patients and a higher risk for the elderly.
  
  
  CONCLUSIONS
  Although no additional risk of intracranial haemorrhage has been observed with combination therapy in the whole population, a significant age pertreatment interaction exists, with a lower risk with combination therapy in younger patients, and a higher risk in the elderly.
authors.affiliation: Department of Cardiology, Niguarda Hospital, Milan, Italy. stefano.savonitto@fastwebnet.it
authors.forename: S
authors.initials: S
authors.lastname: Savonitto
authors.forename: P W
authors.initials: PW
authors.lastname: Armstrong
authors.forename: A M
authors.initials: AM
authors.lastname: Lincoff
authors.forename: G
authors.initials: G
authors.lastname: Jia
authors.forename: C A
authors.initials: CA
authors.lastname: Sila
authors.forename: J
authors.initials: J
authors.lastname: Booth
authors.forename: P
authors.initials: P
authors.lastname: Terrosu
authors.forename: C
authors.initials: C
authors.lastname: Cavallini
authors.forename: H D
authors.initials: HD
authors.lastname: White
authors.forename: D
authors.initials: D
authors.lastname: Ardissino
authors.forename: R M
authors.initials: RM
authors.lastname: Califf
authors.forename: E J
authors.initials: EJ
authors.lastname: Topol
mesh_terms: D000077284:Abciximab; D000911:Antibodies, Monoclonal / Q000009:adverse effects*; D004359:Drug Therapy, Combination; D005260:Female; D005343:Fibrinolytic Agents / Q000009:adverse effects*; D006493:Heparin / Q000009:adverse effects; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000009:adverse effects*; D020300:Intracranial Hemorrhages / Q000139:chemically induced*; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy*; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects; D011994:Recombinant Proteins / Q000009:adverse effects*; D012307:Risk Factors; D010959:Tissue Plasminogen Activator / Q000009:adverse effects*
chemical_list: D000911:Antibodies, Monoclonal; D005343:Fibrinolytic Agents; D007140:Immunoglobulin Fab Fragments; D010975:Platelet Aggregation Inhibitors; D011994:Recombinant Proteins; D006493:Heparin; C087896:reteplase; D010959:Tissue Plasminogen Activator; D000077284:Abciximab