The effect of interleukin-1 receptor antagonist therapy on markers of inflammation in non-ST elevation acute coronary syndromes: the MRC-ILA Heart Study

Abstract

AimsAcute coronary syndromes (ACSs) are driven by inflammation within coronary plaque. Interleukin-1 (IL-1) has an established role in atherogenesis and the vessel-response to injury. ACS patients have raised serum markers of inflammation. We hypothesized that if IL-1 is a driving influence of inflammation in non-ST elevation ACS (NSTE-ACS), IL-1 inhibition would reduce the inflammatory response at the time of ACS.Methods and resultsA phase II, double-blinded, randomized, placebo-controlled, study recruited 182 patients with NSTE-ACS, presenting <48 h from onset of chest pain. Treatment was 1:1 allocation to daily, subcutaneous IL-1receptor antagonist (IL-1ra) or placebo for 14 days. Baseline characteristics were well matched. Treatment compliance was 85% at 7 days. The primary endpoint (area-under-the-curve for C-reactive protein over the first 7 days) was: IL-1ra group, 21.98 mg day/L (95%CI 16.31–29.64); placebo group, 43.5 mg day/L (31.15–60.75) (geometric mean ratio = 0.51 mg/L; 95%CI 0.32–0.79; P = 0.0028). In the IL-1ra group, 14-day achieved high-sensitive C-reactive protein (P < 0.0001) and IL-6 levels (P = 0.02) were lower than Day 1. Sixteen days after discontinuation of treatment (Day 30) high-sensitive C-reactive protein levels had risen again in the IL-1ra group [IL-1ra; 3.50 mg/L (2.65–4.62): placebo; 2.21 mg/L (1.67–2.92), P = 0.022]. MACE at Day 30 and 3 months was similar but at 1 year there was a significant excess of events in the IL-1ra group.ConclusionIL-1 drives C-reactive protein elevation at the time of NSTE-ACS. Following 14 days IL-1ra treatment inflammatory markers were reduced. These results show the importance of IL-1 as a target in ACS, but also indicate the need for additional studies with anti-IL-1 therapy in ACS to assess duration and safety.Clinical Trial RegistrationEUCTR: 2006-001767-31-GB: .

Dietary Docosahexaenoic Acid Reduces Oscillatory Wall Shear Stress, Atherosclerosis, and Hypertension, Most Likely Mediated via an IL‐1–Mediated Mechanism

“…This combined with a reduction in TLR‐4 levels and an increase in IL‐1ra levels in DHA‐fed mice all suggest DHA is acting via an IL‐1 mechanism (Figure 8). Furthermore, and of potential clinical relevance, unpublished data from the IL‐A HEART study82, 83 in our group show that in a post hoc secondary analysis of blood pressure data, systolic and diastolic blood pressure and mean arterial pressure decreased in the group receiving IL‐1ra (baseline versus day 14: 131.4±2.4 versus 124.7±1.6 mm Hg, systolic, P <0.01; 75.2±1.5 versus 71.1±1.2 mm Hg, diastolic, P =ns; 93.9±1.7 versus 88.6±1.2 mm Hg, mean arterial pressure, P <0.05; n=76 patients [IL‐1ra] and n=71 [placebo], t test). Given other recent data,84 we speculate that strategies to block IL‐1 signaling directly could modulate hypertension.…”

Inflammatory and fibrotic responses of cardiac fibroblasts to myocardial damage associated molecular patterns (DAMPs)

“…Small-scale clinical trials have also sought to evaluate the effect of IL-1 inhibition on inflammation and cardiac remodelling in stable-STEMI and non-STEMI patients [155,156], reporting that IL-1 inhibition reduced post-MI inflammation but had little effect on cardiac function in the longer term. This may relate to the relatively mild inflammatory phenotype in these patient cohorts compared with less stable STEMI patients, in which IL-1 blockade was more effective [157].…”

Innate Immune Mechanisms in Myocardial Infarction - An Update

“…In apolipoprotein E-defficient (ApoE -/-) mice with induced AMI, antibody-mediated IL-1β signaling blockade dampened the exacerbated myelopoesis triggered by the ischemic injury, leading to a lower degree of myocardial inflammation and improved cardiac function at 3 weeks after the infarction (25). Recently, the MRC-ILA Heart study, a phase II double-blinded randomized placebo-controlled trial tested the effects of the recombinant IL-1β receptor antagonist Anakinra on systemic inflammation and prognosis in 182 non-ST-elevation acute coronary syndrome (NSTE-ACS) survivors (57). The treatment, administered in the acute 14-day period immediately after the AMI, significantly reduced the levels of the inflammatory biomarker C-reactive protein (CRP) at 7 and 14 days compared to placebo (57).…”

“…Recently, the MRC-ILA Heart study, a phase II double-blinded randomized placebo-controlled trial tested the effects of the recombinant IL-1β receptor antagonist Anakinra on systemic inflammation and prognosis in 182 non-ST-elevation acute coronary syndrome (NSTE-ACS) survivors (57). The treatment, administered in the acute 14-day period immediately after the AMI, significantly reduced the levels of the inflammatory biomarker C-reactive protein (CRP) at 7 and 14 days compared to placebo (57). However, the incidence of major adverse cardiovascular events (MACE) at 1-year was higher in the active treatment group, suggesting that IL-1β blockade should not be used clinically in the immediate post-AMI period.…”