title: Perioperative elafin for ischaemia-reperfusion injury during coronary artery bypass graft surgery: a randomised-controlled trial.
abstract: BACKGROUND
  Elafin is a potent endogenous neutrophil elastase inhibitor that protects against myocardial inflammation and injury in preclinical models of ischaemic-reperfusion injury. We investigated whether elafin could inhibit myocardial ischaemia-reperfusion injury induced during coronary artery bypass graft (CABG) surgery.
  
  
  RESULTS
  In a randomised double-blind placebo-controlled parallel group clinical trial, 87 patients undergoing CABG surgery were randomised 1:1 to intravenous elafin 200 mg or saline placebo administered after induction of anaesthesia and prior to sternotomy. Myocardial injury was measured as cardiac troponin I release over 48 h (area under the curve (AUC)) and myocardial infarction identified with MRI. Postischaemic inflammation was measured by plasma markers including AUC high-sensitive C reactive protein (hs-CRP) and myeloperoxidase (MPO). Elafin infusion was safe and resulted in >3000-fold increase in plasma elafin concentrations and >50% inhibition of elastase activity in the first 24 h. This did not reduce myocardial injury over 48 h (ratio of geometric means (elafin/placebo) of AUC troponin I 0.74 (95% CI 0.47 to 1.15, p=0.18)) although post hoc analysis of the high-sensitive assay revealed lower troponin I concentrations at 6 h in elafin-treated patients (median 2.4 vs 4.1 μg/L, p=0.035). Elafin had no effect on myocardial infarction (elafin, 7/34 vs placebo, 5/35 patients) or on markers of inflammation: mean differences for AUC hs-CRP of 499 mg/L/48 h (95% CI -207 to 1205, p=0.16), and AUC MPO of 238 ng/mL/48 h (95% CI -235 to 711, p=0.320).
  
  
  CONCLUSIONS
  There was no strong evidence that neutrophil elastase inhibition with a single-dose elafin treatment reduced myocardial injury and inflammation following CABG-induced ischaemia-reperfusion injury.
  
  
  BACKGROUND
  (EudraCT 2010-019527-58, ISRCTN82061264).
authors: British Heart Foundation/Centre for Population Health Sciences, University of Edinburgh Centre for Cardiovascular Science, Edinburgh, UK.
authors: S R
authors: SR
authors: Alam
authors: Edinburgh Clinical Trials Unit, University of Edinburgh, Western General Hospital, Edinburgh, UK.
authors: S C
authors: SC
authors: Lewis
authors: Department of Cardio-thoracic Surgery, Edinburgh Royal Infirmary, Edinburgh, UK.
authors: V
authors: V
authors: Zamvar
authors: Department of Cardio-thoracic Surgery, Edinburgh Royal Infirmary, Edinburgh, UK.
authors: R
authors: R
authors: Pessotto
authors: British Heart Foundation/Centre for Population Health Sciences, University of Edinburgh Centre for Cardiovascular Science, Edinburgh, UK.
authors: M R
authors: MR
authors: Dweck
authors: Edinburgh Clinical Trials Unit, University of Edinburgh, Western General Hospital, Edinburgh, UK.
authors: A
authors: A
authors: Krishan
authors: Edinburgh Clinical Trials Unit, University of Edinburgh, Western General Hospital, Edinburgh, UK.
authors: K
authors: K
authors: Goodman
authors: Edinburgh Clinical Trials Unit, University of Edinburgh, Western General Hospital, Edinburgh, UK.
authors: K
authors: K
authors: Oatey
authors: Edinburgh Clinical Trials Unit, University of Edinburgh, Western General Hospital, Edinburgh, UK.
authors: R
authors: R
authors: Harkess
authors: Edinburgh Clinical Trials Unit, University of Edinburgh, Western General Hospital, Edinburgh, UK.
authors: L
authors: L
authors: Milne
authors: Edinburgh Clinical Trials Unit, University of Edinburgh, Western General Hospital, Edinburgh, UK.
authors: S
authors: S
authors: Thomas
authors: British Heart Foundation/Centre for Population Health Sciences, University of Edinburgh Centre for Cardiovascular Science, Edinburgh, UK.
authors: N M
authors: NM
authors: Mills
authors: Department of Cardio-thoracic Surgery, Edinburgh Royal Infirmary, Edinburgh, UK.
authors: C
authors: C
authors: Moore
authors: Clinical Research Imaging Centre, University of Edinburgh, Edinburgh, UK.
authors: S
authors: S
authors: Semple
authors: Department of Dermatology, University of Kiel, Kiel, Germany.
authors: O
authors: O
authors: Wiedow
authors: British Heart Foundation/Centre for Population Health Sciences, University of Edinburgh Centre for Cardiovascular Science, Edinburgh, UK.
authors: C
authors: C
authors: Stirrat
authors: Clinical Research Imaging Centre, University of Edinburgh, Edinburgh, UK.
authors: S
authors: S
authors: Mirsadraee
authors: British Heart Foundation/Centre for Population Health Sciences, University of Edinburgh Centre for Cardiovascular Science, Edinburgh, UK Clinical Research Imaging Centre, University of Edinburgh, Edinburgh, UK.
authors: D E
authors: DE
authors: Newby
authors: British Heart Foundation/Centre for Population Health Sciences, University of Edinburgh Centre for Cardiovascular Science, Edinburgh, UK.
authors: P A
authors: PA
authors: Henriksen
mesh_terms: D001026:Coronary Artery Bypass / Q000009:adverse effects*; D003324:Coronary Artery Disease / Q000601:surgery*; D004311:Double-Blind Method; D053492:Elafin / Q000008:administration & dosage*; D005500:Follow-Up Studies; D006801:Humans; D007262:Infusions, Intravenous; D007431:Intraoperative Complications / Q000188:drug therapy* / Q000209:etiology; D007432:Intraoperative Period; D019028:Magnetic Resonance Imaging, Cine; D015428:Myocardial Reperfusion Injury / Q000175:diagnosis / Q000188:drug therapy* / Q000209:etiology; D011480:Protease Inhibitors / Q000008:administration & dosage; D011994:Recombinant Proteins; D012189:Retrospective Studies
chemical_list: D053492:Elafin; D011480:Protease Inhibitors; D011994:Recombinant Proteins