Treatment Effects of Interleukin-6 Receptor Antibodies for Modulating the Systemic Inflammatory Response After Out-of-Hospital Cardiac Arrest (The IMICA Trial)

Abstract

Background: Out-of-hospital cardiac arrest (OHCA) patients who remain comatose after initial resuscitation are at high risk of morbidity and mortality due to the ensuing post cardiac arrest syndrome (PCAS). Systemic inflammation constitutes a major component of PCAS, and interleukin-6 (IL-6) levels are associated with PCAS severity. The IL-6 receptor antagonist tocilizumab could potentially dampen inflammation in PCAS. The objective of the present trial was to determine the efficacy of tocilizumab to reduce systemic inflammation after OHCA of presumed cardiac cause and thereby potentially mitigate organ injury. Methods: Eighty comatose OHCA patients were randomized 1:1 in a double-blinded placebo-controlled trial to a single infusion of tocilizumab or placebo in addition to standard of care including targeted temperature management. Blood samples were sequentially drawn during the initial 72h. Primary endpoint: reduction in C-reactive protein (CRP) response from baseline till 72h in patients treated with tocilizumab evaluated by mixed model analysis for a treatment-by-time interaction. Secondary endpoints (main): marker of inflammation: leukocytes, markers of myocardial injury: Creatine Kinase Myocardial Band (CKMB), Troponin T (TnT), and N-terminal pro B-type natriuretic peptide (NT-proBNP); marker of brain injury: neuron-specific enolase (NSE); these secondary endpoints were analyzed by mixed model analysis. Results: The primary endpoint of reducing the CRP response by tocilizumab was achieved as there was a significant treatment-by-time interaction, p<0.0001, and a profound effect on CRP levels. Systemic inflammation was reduced by treatment with tocilizumab as both CRP and leukocyte levels were markedly reduced, tocilizumab vs placebo at 24h: -84% [-90%;-76%] and -34% [-46%;-19%] respectively, both p<0.001. Myocardial injury was also reduced documented by reductions in CKMB and TnT; active vs. placebo at 12h: -36% [-54%;-11%] and -38% [-53%;-19%], respectively, both p<0.01. NT-proBNP was similarly reduced by active treatment; tocilizumab vs placebo at 48h: -65% [-80%;-41%], p<0.001. There were no differences in survival or neurological outcome. Conclusions: Treatment with tocilizumab resulted in a significant reduction in systemic inflammation and myocardial injury in comatose resuscitated OHCA patients. Clinical Trial Registration: URL: https://clinicaltrials.gov; Unique identifier: NCT03863015

The inflammatory response is related to circulatory failure after out-of-hospital cardiac arrest: A prospective cohort study

“…However, a recent study on reducing inflammation and myocardial injury after OHCA with the IL-6 receptor blocker tocilizumab, found promising effects on biomarker release, but was underpowered for detecting change in mortality [37]. Complement inhibition might also be an alternative therapeutic approach in the future [38].…”

Impact of rewarming rate on interleukin-6 levels in patients with shockable cardiac arrest receiving targeted temperature management at 33 °C: the ISOCRATE pilot randomized controlled trial

“…Higher IL6 values have been reported to be associated with higher mortality, worse PCAS, and CPC of 3-5 at 12 months [11,12]. In a clinical RCT of patients with OHCA, the IL6-receptor antagonist tocilizumab decreased systemic inflammation and myocardial injury without improving the functional outcome, which was not, however, the primary endpoint [28,29]. Finally, the IL6 half-life of less than 1 h means that rapid changes in IL6 levels can be readily detected by serial assays [30].…”

Association of red cell distribution width with mortality in cardiac arrest patients: a retrospective analysis based on the MIMIC-IV database

“…It is worth noting that the secondary injury after ROSC is much more harmful than the primary ischemic injury [24]. Besides, systematic in ammation is crucial in the development of post-CA syndrome [25]. Several previous reports have shown that increased RDW level relates to a lot of misregulations including senescence, oxidative stress, systemic in ammation, malnutrition, and impaired kidney function [26,27].…”