Early use of tocilizumab (Actemra) does not reduce myocardial infarct size but modestly increases myocardial salvage in patients with acute ST-segment elevation myocardial infarction (STEMI), results of the ASSAIL-MI trial suggest.
"We're among the first to show that you can actually affect the reperfusion injury through anti-inflammatory treatment — it's sort of a new attack point for treatments in STEMI," lead author Kaspar Broch, MD, PhD, Oslo University Hospital Rikshospitalet, Oslo, Norway, told theheart.org | Medscape Cardiology. "What we do now is reperfuse as soon as we can and then add drugs in order to prevent new events, but we don't really attack the reperfusion injury that occurs when you perform PCI, which has been shown to actually account for some 50% of the final injury."
The phase 2, proof-of-concept study was prompted by the team's earlier work in non-STEMI patients, in which a single dose of the interleukin-6 (IL-6) receptor antagonist cut C-reactive protein (CRP) levels by more than 50% during hospitalization and reduced troponin T release after percutaneous coronary intervention (PCI).
For ASSAIL-MI, Broch and colleagues randomly assigned 199 patients presenting with acute STEMI within 6 hours of symptom onset to a single intravenous injection of 280 mg tocilizumab or placebo during PCI. Patients, study personnel, and caretakers were blinded to treatment. Data were available for 195 patients for the primary endpoint of myocardial salvage index.
As reported today in the Journal of the American College of Cardiology, tocilizumab was associated with a higher adjusted myocardial salvage index on cardiac MRI 3 to 7 days after PCI than placebo (69.3% vs 63.6%; P = .04).
The extent of microvascular obstruction was less with tocilizumab (0% vs 4%; P = .03), as was the area under the curve of C-reactive protein during hospitalization (1.9 vs 8.6 mg/L/hr; P < .001).
The final infarct size at 6 months was 21% lower in the tocilizumab group but the difference did not reach statistical significance (7.2% vs 9.1% of left ventricular mass; P = .08).
There were no between-group differences in troponin T area under the curve during hospitalization (1614 vs 2357 ng/L/hr; P = .13), N-terminal pro-B-type natriuretic peptide concentrations at 6 months (79 vs 63 ng/L; P = .25), or baseline-adjusted left ventricular end-diastolic volume at 6 months (157 vs 160 ml; P = .54).
Subgroup analyses suggested the positive effect of tocilizumab on myocardial salvage index is limited to patients presenting at least 3 hours after symptom onset vs ≤3 hours (P = .034), with a trend for greater benefit among men vs women (P = .053).
Broch noted that the absolute effect of tocilizumab on myocardial necrosis was smaller than anticipated when the trial was designed, which may explain the lack of significant reduction in infarct size.
"We were aiming for patients with larger infarctions than we actually ended up with, which is partly due to the strict inclusion criteria and the fact that with modern treatments, patients don't end up with large myocardial infarctions," he said. "But if they had been larger, I think that 20% absolute reduction would have meant a lot in terms of clinical events."
The study also used a very modest dose of tocilizumab, compared with that used for inflammatory diseases, to minimize a potential negative effect on myocardial healing, for instance, myocardial ruptures, Broch said. "I'm not sure whether you gain anything by giving a larger dose."
Serious adverse events were similar in the tocilizumab and placebo groups (19 v 15; P = .57). There were no myocardial ruptures, and no patient died or developed heart failure. Low-density lipoprotein, triglycerides, and liver enzymes increased in the tocilizumab group but were similar at 3 and 6 months.
"IL-6 is a central cytokine involved in all stages of plaque growth, progression, and rupture," Paul Ridker, MD, MPH, of the Brigham and Women's Hospital in Boston, Massachusetts, and a long-standing investigator in inflammation and atherothrombosis, told theheart.org | Medscape Cardiology. "These preliminary data in STEMI, like the authors' prior data in non-STEMI, are consistent with the idea that inhibiting IL-6 could have clinical benefit, a concept that will be taken into a major cardiovascular outcomes trial later this year."
The cardiovascular outcomes trial, known as ZEUS, will test the novel IL-6 inhibitor ziltivekimab among more than 6000 very high-risk atherosclerosis patients who have moderate to severe chronic kidney disease and high sensitivity CRP greater than 2 mg/L, he noted.
Moving beyond IL-1b blockade as done in CANTOS to direct downstream inhibition of IL-6 represents a "logical next scientific step" in the development of anti-inflammatory therapies for acute ischemia and chronic atherosclerosis, Ridker, who led the CANTOS trial, noted in an accompanying accompanying editorial.
"Preventive cardiologists, however, need not wait until outcome trials are complete to use this evolving biological knowledge to their patient's advantage," he writes. "As recently confirmed in the pages of the Journal, exercise, smoking cessation, and a healthy diet reduce both C-reactive protein and IL-6, and clearly have lifelong benefits. Our immediate task is thus to incorporate inflammation inhibition through lifestyle management into our daily practice."
The study was supported by the South-Eastern Norway Regional Health Authority, Central Norway Regional Health Authority, and Roche, which provided the medicinal products and an unrestricted grant. Broch has disclosed no relevant financial relationships. Ridker has received investigator-initiated research grant support from Kowa, Novartis, Amarin, Pfizer, and the National Heart, Lung, and Blood Institute; and has served as a consultant to Novartis, Janssen, Agepha, Flame, Civi Biopharma, Inflazome, Corvidia, Novo Nordisk, SOCAR, IQVIA, and AstraZeneca.
J Am Coll Cardiol. Published online April 12, 2021. Abstract, Editorial
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