IL-6 inhibition improves myocardial salvage in post-MI setting, ASSAIL-MI trial.

Patients with STEMI undergoing PCI who received an intravenous dose of tocilizumab, an inhibitor of the inflammatory cytokine interkleukin-6 (IL-6), prior to their procedure appeared to have more viable myocardium when compared to patients receiving placebo, has been shown in the recent ASSAIL-MI study published in JACC this month.

Prompt myocardial revascularization with percutaneous coronary intervention (PCI) reduces infarct size and improves outcomes in patients with ST-segment elevation myocardial infarction (STEMI). However, as much as 50% of the loss of viable myocardium may be attributed to the reperfusion injury and the associated inflammatory response.

This study sought to evaluate the effect of the interleukin-6 receptor inhibitor tocilizumab on myocardial salvage in acute STEMI. The ASSAIL-MI trial was a randomized, double-blind, placebo-controlled trial. Patients admitted with STEMI within 6 h of symptom onset were randomized in a 1:1 fashion to promptly receive a single infusion of 280 mg tocilizumab or placebo. The primary endpoint was the myocardial salvage index as measured by magnetic resonance imaging after 3 to 7 days.

The myocardial salvage index was larger in the tocilizumab group than in the placebo group. Microvascular obstruction was less extensive in the tocilizumab arm, but there was no significant difference in the final infarct size between the tocilizumab arm and the placebo arm (7.2% vs. 9.1% of myocardial volume, p = 0.08). Adverse events were evenly distributed across the treatment groups.

While there was no significant difference in the final infarct size at 6 months, the adjusted myocardial salvage index, which accounts for the extent to which ischemic myocardium recovers after reperfusion—and was the trial's primary endpoint—was significantly higher among patients treated with tocilizumab.

This study expands on some of the recent successes of different anti-inflammatory therapies in various cardiovascular disease settings. For example, the COLCOT trial showed that colchicine lowered the risk of ischemic cardiovascular events in patients who recently had an MI, while the LoDoCo2 trial showed it was effective in patients with chronic coronary disease. In CANTOS, the human monoclonal antibody canakinumab was also effective, albeit modestly so, at reducing the risk of major cardiovascular events in patients with stable coronary artery disease.

"What we're aiming for is to reduce the size of the area at risk that ends up being irreversibly damaged," lead investigator Kaspar Broch said. "Obviously, if you have a large area at risk and you reduce that irreversible damage by a lot, you'd expect to see a benefit in terms of outcomes. But in order to see a difference in outcomes, you'd have to have rather large MIs in the first place, larger than we had in our study. Our problem was that we had patients with rather small MIs, and then you'd need to have a large number of patients to show a difference in outcomes."

This is not the first time that tocilizumab, a human monoclonal antibody used mainly for the treatment of rheumatoid arthritis and systemic juvenile idiopathic arthritis, and now in select COVID-19 patients, has been tested in patients with cardiovascular disease. In 2016, the same researchers conducted a small study in patients with NSTEMI and showed that tocilizumab reduced C-reactive protein (CRP) levels by 50% in the days after the intervention.

In an editorial, Paul Ridker, MD (Brigham and Women's Hospital, Boston, MA), says ASSAIL-MI and the previous study of tocilizumab in NSTEMI patients suggest that the "second frontier" for anti-inflammatory agents might be the setting of acute coronary ischemia and reperfusion injury. "Moving anti-inflammatory interventions from stable atherosclerosis into acute ischemia is of considerable clinical relevance, although mechanisms likely differ and relate more to ischemia/reperfusion injury and the consequences of plaque rupture than to atherosclerotic progression," he writes.

Source: JACC J Am Coll Cardiol. 2021 Apr, 77 (15) 1845–1855.