title: Increased benefit of alteplase in patients with ischemic stroke and a high body temperature.
abstract: BACKGROUND
  In observational studies, a high body temperature has been associated with unfavorable outcome. In in vitro studies, the fibrinolytic activity of alteplase decreased 5% per degree Celsius reduction in temperature. The modifying effect of body temperature on treatment with alteplase in patients with acute ischemic stroke is unclear. We assessed the influence of baseline body temperature on the effect of alteplase on functional outcome in patients with acute ischemic stroke, included in the Paracetamol (Acetaminophen) in Stroke (PAIS) trial.
  
  
  METHODS
  PAIS was a randomized, double-blind clinical trial to assess the effect of high-dose paracetamol on functional outcome in patients with acute stroke. For this study, we selected all patients with ischemic stroke and randomization within 6 h of symptom onset. We estimated the effect of treatment with alteplase on the modified Rankin Scale score at 3 months with ordinal logistic regression, stratified by baseline body temperature. We made adjustments for confounding factors and expressed associations as adjusted odds ratios (aOR) with 95% confidence intervals (CI). We also tested for interaction between treatment with alteplase and body temperature.
  
  
  RESULTS
  We included 647 of the 1,400 patients in PAIS in our study. Treatment with alteplase was associated with improved functional outcome at 3 months (aOR 1.51, 95% CI 1.09-2.08). In the 286 patients (44%) with a baseline body temperature of 37.0°C or higher, alteplase was associated with a larger effect (aOR 2.13, 95% CI 1.28-3.45) than in patients with a temperature below 37.0°C (aOR 1.11, 95% CI 0.71-1.69). A test for interaction between body temperature and alteplase did not reach statistical significance (p = 0.18).
  
  
  CONCLUSIONS
  Patients with ischemic stroke and a high body temperature may have a larger benefit of treatment with alteplase than patients with lower body temperatures. These findings are in line with those from in vitro studies, in which lowering temperature decreased the fibrinolytic activity of the enzyme alteplase. This interaction should be explored further in randomized clinical trials of thrombolytic therapy or modification of body temperature. Trials of therapeutic hypothermia should be controlled for treatment with thrombolytics, and trials of thrombolytic treatment should consider body temperature as a potential effect modifier.
authors: Department of Neurology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
authors: Inger
authors: I
authors: de Ridder
authors: Heleen
authors: H
authors: den Hertog
authors: Maarten
authors: M
authors: van Gemert
authors: Diederik
authors: D
authors: Dippel
authors: Bart
authors: B
authors: van der Worp
mesh_terms: D000082:Acetaminophen / Q000627:therapeutic use; D000368:Aged; D000369:Aged, 80 and over; D058633:Antipyretics / Q000627:therapeutic use; D001831:Body Temperature / Q000187:drug effects; D002545:Brain Ischemia / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D004311:Double-Blind Method; D005260:Female; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D020521:Stroke / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D015912:Thrombolytic Therapy; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D058633:Antipyretics; D005343:Fibrinolytic Agents; D000082:Acetaminophen; D010959:Tissue Plasminogen Activator