November 12, 2016

NEW ORLEANS — Giving the glucagonlike peptide-1 (GLP-1) analog exenatide (Byetta, AstraZeneca) to comatose patients after out-of-hospital cardiac arrest (OHCA) had no effect on a marker of neurological injury during the first 72 hours after admission, in a new study.

"The present trial suggests that exenatide for out-of-hospital cardiac-arrest patients administered after reperfusion has limited neuroprotective effects," the authors conclude.

The study did, however, show that giving the drug in a timely manner was feasible, with 96% of patients given treatment within 240 minutes of return of spontaneous circulation. This shows that other pharmacological interventions can be tested in a similar setup, the researchers state.

The study also found an unexpected effect on mortality. While there was only a minor difference in mortality from neurological injury, there was a nonsignificant 10% reduction in all-cause mortality in the exenatide group.

The study was presented on November 12 at the American Heart Association 2016 Scientific Sessions and was simultaneously published online in Circulation.

Lead author Sebastian Wiberg, MD, from Rigshospitalet, Copenhagen, Denmark, commented to Medscape Medical News: "We did not find any differences on our primary end point, which was the neuron-specific enolase [NSE] values used as a surrogate marker of neurological damage. In this light, we believe that the nonsignificant differences in mortality and poor neurological function after 180 days is likely a play of chance. We plan to conduct a number of post hoc analyses on the associations between exenatide and hemodynamic function and blood glucose levels. For future trials we plan to examine other pharmacological and nonpharmacological interventions in a similar logistical setup at our institutions."

In the Circulation paper, the authors note that note that the overall mortality after out-of-hospital cardiac arrest is about 90%. Although the in-hospital mortality after successful resuscitation and admission to an intensive care unit has decreased in the past decade, 30% to 50% of admitted patients do not survive until hospital discharge, and the leading cause of death is anoxic brain injury.

They explain that the mechanisms causing neurological damage involve ischemia, reperfusion injury, and apoptosis, all of which result in tissue degeneration and corresponding loss of neurological function. Preclinical data suggest that these deleterious processes can be modified for up to 6 hours. "Therefore, identification of new treatment options for active neuroprotection in addition to targeted temperature management will be intuitively beneficial."

GLP-1 analogs are approved for the treatment of type 2 diabetes mellitus, but they have also been suggested to have anti-inflammatory and neuroprotective effects, Dr Wiberg et al say. In animal models, GLP-1 analogs ameliorated neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis and reduced the final infarct volume in stroke and MI models, they report.

In humans, exenatide given before revascularization after MI resulted in increased myocardial salvage, and in patients with a short duration of ischemia, exenatide treatment resulted in a smaller final infarct size.

The current study measured levels of NSE, a glycoprotein and widely used biomarker released from dying neurons into the bloodstream. The concentration of NSE in blood is correlated to the size of a given cerebral insult, and high levels have been shown to be predictors of poor outcome after out-of-hospital cardiac arrest.

For the study, 120 comatose patients resuscitated from OHCA were randomized to 17.4-µg exenatide or placebo over a 6.25-hour infusion, in addition to standardized intensive care including targeted temperature management.

Results showed that there were no significant differences in the primary efficacy end point — area under the NSE curve or a composite end point of death and poor neurological function after 180 days — between groups. Adverse events were rare, with no significant difference between groups.

The median blood glucose 8 hours after admission in patients receiving exenatide was lower than that in patients receiving placebo.

While there were no significant differences in secondary end points, including mortality and poor neurological function, there was a nonsignificant absolute difference of 10% in 180-day mortality in favor of exenatide, which was largely driven by mortality in the first 30 days.

The absolute difference in mortality was 4% at 7 days and 11% at 30 days. There was only a minor difference in mortality from neurological injury between the two allocation groups (76% vs 64%, n=1), suggesting that the effect of exenatide on mortality, if present, is not caused by neuroprotection but may be associated with other factors such as anti-inflammatory effects, glucose-dependent glucose regulation, and cardioprotection, the researchers say.

The study was supported by the Danish Heart Foundation and the Research Foundation for Copenhagen University Hospital and Odense University Hospital. The authors have no relevant financial relationships.

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Circulation. Published online November 12, 2016. Abstract

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