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.

METHODS AND 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.

TRIAL REGISTRATION NUMBER:

(EudraCT 2010-019527-58, ISRCTN82061264).

• Authors: S R Alam, S C Lewis, V Zamvar, R Pessotto, M R Dweck, A Krishan, K Goodman, K Oatey, R Harkess, L Milne, S Thomas, N M Mills, C Moore, S Semple, O Wiedow, C Stirrat, S Mirsadraee, D E Newby, P A Henriksen
• Journal: Heart (British Cardiac Society) (Heart) Vol. 101 Issue 20 Pg. 1639-45 (Oct 2015) ISSN: 1468-201X [Electronic] England
• PMID: 26310261 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Chemical References

• Elafin
• Protease Inhibitors
• Recombinant Proteins

Topics

• Coronary Artery Bypass (adverse effects)
• Coronary Artery Disease (surgery)
• Double-Blind Method
• Elafin (administration & dosage)
• Follow-Up Studies
• Humans
• Infusions, Intravenous
• Intraoperative Complications (drug therapy, etiology)
• Intraoperative Period
• Magnetic Resonance Imaging, Cine
• Myocardial Reperfusion Injury (diagnosis, drug therapy, etiology)
• Protease Inhibitors (administration & dosage)
• Recombinant Proteins
• Retrospective Studies