"Prompt revascularization - i.e., recanalization of the occluded artery - is key to reducing the degree of heart muscle damage after acute myocardial infarction," Dr. Kaspar Broch of Oslo University Hospital in Rikshospitalet told Reuters Health by email.
"However, somewhat paradoxically, the reperfusion itself causes further damage to the cells in the heart through...ischemia-reperfusion injury, whereby the return of oxygenated blood generates highly toxic oxygen radicals," he explained. "These oxygen species damage the cells directly, but also elicit an inflammatory overshoot that may further wound the myocardium."
"Our hypothesis," he said, "was that targeted anti-inflammatory treatment with the IL-6 inhibitor tocilizumab might ameliorate this injury and increase myocardial salvage."
He noted that the group's previous small trial in non-STEMI patients who underwent PCI showed that tocilizumab reduced inflammation, as reflected by circulating levels of CRP, and also myocardial injury, as reflected by circulating troponin T (https://bit.ly/32taChz). "The trial suggested that tocilizumab could protect against reperfusion injury," he said. "These results prompted the (current) trial."
As reported in the Journal of the American College of Cardiology, for the phase-2 ASSAIL-MI trial, 199 patients (mean age, 61; about 85% men) with STEMI were randomized within six hours of symptom onset to a single infusion of 280 mg tocilizumab or placebo.
The myocardial salvage index (primary endpoint) was larger in the tocilizumab than in the placebo group, with an adjusted between-group difference of 5.6 percentage points.
Microvascular obstruction was less extensive in the tocilizumab arm; however, there was no significant difference in the final infarct size at six months between tocilizumab and placebo (7.2% vs. 9.1% of myocardial volume).
Heterogeneity of the treatment effect was observed regarding the time from symptom onset. Notably, the positive effect of tocilizumab on the primary endpoint seemed to be limited to patients presenting more than three hours after symptom onset.
Although men seemed to benefit from tocilizumab more than women did, the interaction between sex and treatment was of borderline statistical significance.
Adverse events were similar across the treatment groups. Most were mild and deemed not associated with the study drug. There were 19 serious AEs in the tocilizumab group and 15 in the placebo group, but no myocardial ruptures.
Dr. Broch said, "While the ASSAIL-MI trial met its primary endpoint and suggests that the reperfusion injury is amenable to treatment, thus opening up a new target for treatment in acute MI, it is too early to start using this drug in clinical practice."
"Fortunately, we did not observe any safety concerns in our trial, but inclusion criteria were strict and the number of patients limited," he said. "We are currently planning new studies to further explore the effect of IL6 inhibition in MI, which will hopefully culminate in a large trial with clinical endpoints."
Dr. Paul Ridker of Brigham and Women's Hospital in Boston, author of a related editorial, commented by email to Reuters Health, "IL-6 is a central cytokine crucial in many steps of the atherosclerotic process, and these exciting preliminary data using tocilizumab are consistent with the hypothesis that inhibiting IL-6 can alter surrogate outcomes after myocardial infarction."
"What is not known is whether this approach will translate into a real clinical benefit for patients," he said. "Thus, our group is now launching a major cardiovascular outcomes trial...that will compare the novel IL-6 inhibitor ziltivekimab to placebo among 6,000 atherosclerosis patients with chronic kidney disease and elevated hsCRP, a group with very high unmet need."
The study was supported in part by Roche, which also provided the tocilizumab used in the trial.
SOURCE: https://bit.ly/32wLTZP and https://bit.ly/3mYTcD0 Journal of the American College of Cardiology, online April 12, 2021.
By Marilynn Larkin
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