• ASSAIL-MI Trial: IL-6 Inhibition with Tocilizumab Increased Myocardial Salvage by 5.6% vs. Placebo in STEMI Patients

    The interleukin-6 (IL-6) inhibitor tocilizumab increased myocardial salvage by 5.6% versus placebo in ST-segment elevation myocardial infarction (STEMI) patients in the Norwegian ASSAIL-MI trial.

    The positive effects seemed to be limited to patients presenting more than 3 hours after symptom onset, however.

    Findings from the study – which received funding from the drug's manufacturer Roche – were published online on Monday and in the April 20 issue of the Journal of the American College of Cardiology.

    The authors, led by the University of Oslo's Kaspar Broch, MD, PhD, and Anne Kristine Anstensrud, MD, noted that despite prompt revascularization with percutaneous coronary intervention improving mortality and morbidity rates in STEMI, “the residual morbidity is substantial.”

    The “area at risk” is the volume of myocardium rendered ischemic by the coronary occlusion, they said, adding that myocardial salvage – the extent to which the ischemic myocardium recovers after reperfusion – is a key component in outcomes.

    “As much as 50% of the loss of viable myocardium may be attributed to the reperfusion injury and the associated inflammatory response,” they said.

    The researchers, therefore, set out to evaluate tocilizumab – an IL-6 drug with anti-inflammatory properties – in acute STEMI to assess myocardial salvage potential in the ASSAIL-MI (Assessing the effect of Anti-IL-6 treatment in Myocardial Infarction) trial.

    The double-blind, placebo-controlled study randomized consenting patients, who had been admitted to one of three high-volume treatment centers in Norway with STEMI within 6 hours of symptom onset between March 2017 and February 2020, to receive either a single infusion of 280 mg tocilizumab (99 evaluable patients) or placebo (96 evaluable patients) in a 1:1 fashion.

    Coronary angiography was performed in all patients, and the mean door-to-balloon time was 23 ± 10 minutes. No patients died during 6 months of follow-up.

    Myocardial salvage index – the study’s primary endpoint – was measured by magnetic resonance imaging after 3 to 7 days.

    The tocilizumab group had higher myocardial salvage index scores, at 69.3% ± 19.3%, which the researchers said was a 5.6% between-group difference (95% confidence interval [CI]: 0.2 to 11.3; p = 0.04) with the placebo cohort’s score of 63.6% ± 20.8%.

    “This effect seemed to be limited to patients with symptom onset (more than 3 hours) before PCI,” however, the researchers stressed.

    The mean myocardial salvage index was 1.6% for those with symptom onset of 3 hours or less before percutaneous coronary intervention (PCI; 95% CI: -5.3 to -8.4; p = 0.36), but was 14.6% for patients undergoing PCI more than 3 hours after symptom onset (95% CI: 4.7 to 24.5; p = 0.034).

    The extent of microvascular obstruction was 0% (interquartile range [IQR]: 0% to 14%) in the tocilizumab arm compared to 4% (IQR: 0% to 18%) in the placebo group – a significant difference (p = 0.03) – as was the difference in C-reactive protein area under the curve (AUC, mg/l/h), at 1.9 (0.9 to 4.9) in the tocilizumab-dosed patients compared to 8.6 (5.0 to 17.9) in placebo group (p < 0.001), the researchers added.

    However, the 21% difference between the final infarct size at 6 months in the tocilizumab and placebo arms was not significant (7.2% vs. 9.1% of myocardial volume, p = 0.08). The troponin T AUC (ng/l/h) during hospitalization was also numerically lower in those dosed with tocilizumab, but with no statistical difference (p = 0.13).

    There were no between-group differences in the baseline-adjusted left ventricular volume or the plasma concentration of = N-terminal proB-type natriuretic peptide (NT-proBNP) at 6 months.

    Meanwhile, adverse events were evenly distributed across the treatment groups, and most were mild and deemed not to be associated with the study drug. Serious events in a total of 19 tocilizumab and 15 placebo patients (p = 0.57) included myocardial infarction, coronary artery bypass grafting, subarachnoid hemorrhage, resuscitated ventricular fibrillation, ventricular tachycardia, chest pain and ischemic stroke.

    “Notably, there were no myocardial ruptures,” the researchers said.

    “This randomized trial showed that prompt, intravenous treatment with the IL-6 inhibitor tocilizumab may improve myocardial salvage in patients presenting with acute STEMI,” the researchers said.

    Still, they stressed that the clinical significance observed in the increase of myocardial salvage with tocilizumab treatment is uncertain and called for larger studies, which could also help find an optimized dose and focus on patients presenting several hours after symptom onset.

    In an accompanying editorial, Harvard Medical School’s Paul M. Ridker, MD, MPH, said: “Moving beyond IL-1b blockade” – as done in the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) trial – “to direct downstream inhibition of IL-6 represents a logical next scientific step in the development of anti-inflammatory therapies for both acute ischemia and chronic atherosclerosis.”

    He added that preventive cardiologists “need not wait” until outcome studies are completed to “use this evolving biological knowledge to their patient’s advantage,” calling on practitioners to adopt lifestyle management practices to aid inflammation inhibition by reducing C-reactive protein and IL-6, including exercise, smoking cessation, and a healthy diet. 

    Sources:

    Broch K, Anstensrud AK, Woxholt S, et al. Randomized Trial of Interleukin-6 Receptor Inhibition in Patients With Acute ST-Segment Elevation Myocardial Infarction. J Am Coll Cardiol 2021;77:1845–55.

    Ridker PM. Inhibiting Interleukin-6 to Reduce Cardiovascular Event Rates: A Next Step for Atherothrombosis Treatment and Prevention. J Am Coll Cardiol 2021;77:1856-8.

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