'Dramatic' Inflammation Reduction After OHCA With Tocilizumab

Marlene Busko

November 24, 2020

Comatose patients resuscitated after an out-of-hospital cardiac arrest (OHCA) who received an infusion of tocilizumab (RoActemra), an antibody that blocks interleukin-6 (IL-6) receptors, had reduced systemic inflammatory response and cardiac injury in a small pilot study.

There was a "very dramatic effect" in C-reactive protein (CRP) levels, which were reduced by more than 84% with tocilizumab vs placebo in the first 72 hours after the comatose patients were admitted to hospital, Martin A. S. Meyer, MD, from Copenhagen University Hospital, Denmark, reported.

He presented findings from the Interleukin-6 Receptor Antibodies for Modulating the Systemic Inflammatory Response After Out-of-Hospital Cardiac Arrest (IMICA) study — a pilot trial that involved 80 patients — in a late-breaking resuscitation science session at the virtual American Heart Association (AHA) Scientific Sessions 2020.

"The IMICA trial demonstrated that it is feasible to reduce systemic inflammation after OHCA and demonstrated cardioprotective benefits when examining biomarkers of cardiac infarction/injury and myocardial stress in patients treated with tocilizumab," Meyer told theheart.org | Medscape Cardiology.

The trial was not powered to show a potential difference in mortality or neurologic outcome, he noted. "We do, however, find it reassuring from a safety perspective that it appears safe to administer tocilizumab to these critically ill patients," he said.

What remains to be determined, he said, "is whether this translates into clinical benefits for the patients, and as we find these results promising, we are looking into the possibility of a larger-scale trial aimed at this."

Invited to comment, Romergryko G. Geocadin, MD, said, "The point that is exciting here is there is probably a potential, if it crosses the blood-brain barrier, that it may be complementary to therapeutic hypothermia [targeted temperature management], and at this stage, we need all the help we can get.

"Therapeutic hypothermia may be working, but the number needed to treat is 1 out of 6 patients. What's going to happen to the other five? So there's a lot that still needs to be done," said Geocardin, professor of neurology, Johns Hopkins University, Baltimore, Maryland, who was lead author of a July 2019 AHA scientific statement, "Standards for Studies of Neurological Prognostication in Comatose Survivors of Cardiac Arrest."

"This research I think is headed in the right direction," he added. "I hope they will be able to elucidate whether and how much of this crossed the blood-brain barrier and what is the direct effect on the brain itself, in terms of mitigation of the IL-6 inflammation of the brain."

"To our knowledge, there is no concluding evidence on whether tocilizumab crosses the blood-brain barrier in humans," Meyer responded. "However, an animal study in rhesus monkeys revealed a low degree of penetration of the blood-brain barrier after IV administration. Yet, tocilizumab has been suggested as a possible treatment of, eg, autoimmune encephalitis.

"We are currently looking into the prospects of repeating this intervention in a larger trial," he said, although "the design is yet to be finalized."

Reduce Inflammation, Cardiac Injury?

Patients with OHCA who are resuscitated but remain in a coma at hospital admission have a high risk for morbidity and mortality from post–cardiac arrest syndrome (PCAS), Meyer and colleagues explain in an article describing the study protocol.

Systemic inflammation is a major component of PCAS, and elevated levels of circulating IL-6, a proinflammatory cytokine, are associated with worse outcomes in OHCA patients.

The researchers aimed to see whether tocilizumab would reduce systemic inflammation after OHCA and thereby also possibly mitigate organ injury.

The trial included 80 patients who had OHCA of a presumed cardiac cause and had return of spontaneous circulation (ROSC) but were comatose.

At admission, the patients were randomly assigned to receive a single injection of tocilizumab (8 mg/kg, for a maximum of 800 mg) or placebo in addition to standard care, which included targeted temperature management of 36° C for 24 hours.

The patients in both groups had similar characteristics. The mean age of the patients was 63 years; 82% were men, and 92% had a shockable rhythm. Time to ROSC was about 19 minutes.

The primary endpoint was reduction in CRP levels, which, along with leukocyte levels, were measured at admission and 24, 48, and 72 hours.

Secondary endpoints included levels of troponin T (TNT) and creatinine kinase myocardial band (CKMB), markers of cardiac injury/infarction, which were measured at admission and 6, 12, 24, 36, 48, and 72 hours; NT-proBNP, a marker of myocardial stress, measured at admission and 48 hours; and neuron-specific enolase (NSE), a marker of cerebral injury, measured at 48 and 72 hours.

Levels of CRP, leucocytes, CKMB, TNT, and NT-proBNP were significantly lower over the 72-hour period in patients who received tocilizumab compared to patients who received placebo (all P < .01).

Finding a "decrease in CRP meant that we had blocked the IL-6 receptors sufficiently to decrease CRP production, irrespective of circulating levels of IL-6," said Meyer.

However, levels of NSE were similar in both groups, as were rates of favorable neurologic outcome (cerebral performance category score, 1–2; 60%) and 180-day survival (65%).

Meyer and Geocadin have disclosed no relevant financial relationships.

American Heart Association (AHA) Scientific Sessions 2020: Abstract LBRS. Presented November 14, 2020.

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