Ghrelin for Neuroprotection in Post-Cardiac Arrest Coma: A Randomized Clinical Trial

Abstract

Importance: Out-of-hospital cardiac arrest survival rates have markedly risen in the last decades, but neurological outcome only improved marginally. Despite research on more than 20 neuroprotective strategies involving patients in comas after cardiac arrest, none have demonstrated unequivocal evidence of efficacy; however, treatment with acyl-ghrelin has shown improved functional and histological brain recovery in experimental models of cardiac arrest and was safe in a wide variety of human study populations.

Objective: To determine safety and potential efficacy of intravenous acyl-ghrelin to improve neurological outcome in patients in a coma after cardiac arrest.

Design, setting, and participants: A phase 2, double-blind, placebo-controlled, multicenter, randomized clinical trial, Ghrelin Treatment of Comatose Patients After Cardiac Arrest: A Clinical Trial to Promote Cerebral Recovery (GRECO), was conducted between January 18, 2019, and October 17, 2022. Adult patients 18 years or older who were in a comatose state after cardiac arrest were assessed for eligibility; patients were from 3 intensive care units in the Netherlands. Expected death within 48 hours or unfeasibility of treatment initiation within 12 hours were exclusion criteria.

Interventions: Patients were randomized to receive intravenous acyl-ghrelin, 600 μg (intervention group), or placebo (control group) within 12 hours after cardiac arrest, continued for 7 days, twice daily, in addition to standard care.

Main outcomes and measures: Primary outcome was the score on the Cerebral Performance Categories (CPC) scale at 6 months. Safety outcomes included any serious adverse events. Secondary outcomes were mortality and neuron-specific enolase (NSE) levels on days 1 and 3.

Results: A total of 783 adult patients in a coma after cardiac arrest were assessed for eligibility, and 160 patients (median [IQR] age, 68 [57-75] years; 120 male [75%]) were enrolled. A total of 81 patients (51%) were assigned to the intervention group, and 79 (49%) were assigned to the control group. The common odds ratio (OR) for any CPC improvement in the intervention group was 1.78 (95% CI, 0.98-3.22; P = .06). This was consistent over all CPC categories. Mean (SD) NSE levels on day 1 after cardiac arrest were significantly lower in the intervention group (34 [6] μg/L vs 56 [13] μg/L; P = .04) and on day 3 (28 [6] μg/L vs 52 [14] μg/L; P = .08). Serious adverse events were comparable in incidence and type between the groups. Mortality was 37% (30 of 81) in the intervention group vs 51% (40 of 79) in the control group (absolute risk reduction, 14%; 95% CI, -2% to 29%; P = .08).

Conclusions and relevance: In patients in a coma after cardiac arrest, intravenous treatment with acyl-ghrelin was safe and potentially effective to improve neurological outcome. Phase 3 trials are needed for conclusive evidence.

Trial registration: Clinicaltrialsregister.eu: EUCTR2018-000005-23-NL.

Figure 1.. Flow Diagram of Patients Through This Study

^aShorter treatment due to death or discharge to other hospital or home not included. ^bIntervention group: due to temperature deviation of freezer. ^cControl group: due to death before study medication administration.

Figure 2.. Cerebral Performance Category (CPC) Scores at 6 Months

The unadjusted common odds ratio for any improvement in the intervention group was 1.78 (95% CI, 0.98-3.22; P = .06). Scores on the CPC scale range from 1 to 5, with 1 indicating no or mild neurologic disability; 2, moderate disability; 3, severe disability; 4, coma; and 5, death.

Figure 3.. Subgroup Analyses

Based on the electroencephalogram at 12 and 24 hours after cardiac arrest, a classification of severity of encephalopathy was made. The trial was not powered to analyze subgroups, and these results should be considered exploratory. Black squares indicate point estimates of effects; dotted vertical line, no effect. OR indicates odds ratio.