IL-6 receptor inhibitor improves myocardial salvage in STEMI: ASSAIL-MI
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Tocilizumab, an interleukin-6 receptor inhibitor, improved myocardial salvage in patients with first-time acute STEMI compared with placebo, according to the ASSAIL-MI trial presented at the European Society of Cardiology Congress.
“Our findings suggest that IL-6 receptor inhibition is an interesting therapeutic target on top of conventional medical treatment,” Anne Kristine Anstensrud, MD, cardiologist at Oslo University Hospital in Norway, told Healio. “In a subpopulation analysis, patients admitted to hospital within 3 to 6 hours after onset of symptoms were shown to have a benefit of the IL-6 receptor inhibition. Overall, the study medication was safe and well tolerated.”
In this multicenter, randomized clinical trial, researchers analyzed data from 199 patients who presented with 6 hours of chest pain, had ST-segment elevation and were indicated for urgent coronary angiography with the intent to reperfuse a potentially occluded vessel. After hospital admission, patients were randomly assigned a single infusion of tocilizumab (Actemra, Genentech; mean age, 62 years; 79% men) or placebo (mean age, 60 years; 89% men). Both groups received their assigned treatments before undergoing PCI.
“It has been shown with interleukin-6 inhibition with tocilizumab reduces the inflammatory response after NSTEMI and diminishes the release of troponin T particularly in those undergoing PCI, suggesting that tocilizumab can have a protective effect on the ischemia reperfusion injury,” Anstensrud said during the presentation.
The primary endpoint was myocardial salvage index, which was measured by cardiac MRI between 3 and 7 days after randomization. Secondary endpoints included final infarct size after 6 months, area under the receiver operating characteristic curve (AUC) for troponin T during index hospitalization, AUC of C-reactive protein during index hospitalization, and safety and tolerability.
Follow-up was conducted through 6 months and include cardiac MRI, echocardiography and blood samples, in addition to safety measurements.
The myocardial salvage index in patients assigned tocilizumab was 69% compared with 64% in those assigned placebo (adjusted between-group difference, 5.6 percentage points; P = .042).
In a prespecified subgroup analysis, the treatment effect of tocilizumab was greater in patients with symptom onset of more than 3 hours compared with those with symptom onset of 3 hours or less (P for interaction = .034). There was also a trend toward the treatment effect being greater in men than women (P for interaction = .053).
The final infarct size in patients assigned tocilizumab was 12.6 g compared with 15 g in those assigned placebo, but the difference did not reach statistical significance (P = .08). The AUC for troponin T also did not reach statistical significance, although the level was higher in the placebo group compared with the tocilizumab group (2,357 ng/L/h vs. 1,614 ng/L/h; P = .13). The AUC for CRP was lower in the tocilizumab group compared with the placebo group (1.9 mg/L/h vs. 8.6 mg/L/h; P < .001).
“As expected, there was a significant difference in CRP [favoring] tocilizumab,” she said.
Other factors did not differ between both groups including N-terminal pro-B-type natriuretic peptide, left ventricular end-diastolic volume, serious adverse events and infections requiring hospitalization.
“The ASSAIL-MI trial was a phase 2 trial,” Anstensrud said in an interview. “Further research is needed both to evaluate the effect in a larger study population according to clinical endpoints, but also to select patients that might have the most beneficial effect of the anti-inflammatory treatment.”
Perspective
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Peter Libby, MD
The cytokine IL-6 occupies a pivotal place in inflammatory signaling implicated in CVD. IL-6 is the last step in a pro-inflammatory pathway that starts with the NLR3P inflammasome, a multimeric assembly in cells that specializes in sensing danger signals, for example atherosclerosis-related triggers such as cholesterol crystals.
The inflammasome activates the pro-inflammatory cytokine interleukin-1 beta, which in turn induces IL-6. IL-6 can elicit the acute phase response in hepatocytes which stimulates these cells to increase their production of fibrinogen, the precursor of clots and of plasminogen activator inhibitor-1 the major blocker of our endogenous fibrinolytic system. The proteins directly affect thrombus formation and persistence. IL-6 also strongly induces CRP, which we can measure as an index of inflammatory status that correlates well with first and recurrent CV events. Thus, IL-6 represents an attractive therapeutic target in ischemic heart disease. In an important pilot study, Ola Kleveland, MD, PhD, and colleagues studied the effect of administration the IL-6 receptor antagonist tocilizumab on biomarkers in patients with non-STEMI (Kleveland O, et al. Eur Heart J. 2016;doi:10.1093/eurheartj/ehw171). They found reductions in CRP and in troponin T, particularly in those who underwent PCI. Given these promising pilot results and no indication for safety concern, the Norwegian team of investigators designed ASSAIL-MI which administered tocilizumab to individuals who were having first acute STEMI (Anstensrud AK, et al. Open Heart. 2019;doi:10.1136/openhrt-2019-001108).
The researchers used MRI to assess myocardial salvage and studied almost 200 patients who presented within 6 hours of symptom onset. They found a modest benefit on the primary endpoint of myocardial salvage. Patients receiving tocilizumab had a salvage index of 69% compared with 64% in those treated with placebo. The calculated infarct size, however, did not achieve a statistically significant decline. Nor did troponin T release drop in tocilizumab-treated individuals.
We have been seeking an anti-inflammatory therapy that can provide benefit beyond standard pharmacologic treatment and primary PCI in patients with STEMI. This pioneering study provides an important proof of principle that an anti-inflammatory therapy may improve clinical outcomes in this group of patients. The anti-inflammatory therapy appeared safe during 6 months of follow-up. The challenge remains to find a group in which anti-inflammatory treatment will provide added clinical benefit and show reduced recurrent events in long term follow-up. For example, in a pre-specified subgroup analysis, it appeared that tocilizumab might provide greater benefit if administered within the first 3 hours following initial symptoms. ASSAIL-MI thus points the way towards further development of anti-inflammatory therapy that will improve outcomes in patients with STEMI.
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