The effect of interleukin-1 receptor antagonist therapy on markers of inflammation in non-ST elevation acute coronary syndromes : the MRC-ILA Heart Study
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Aims: Acute 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 results: A 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. Conclusion: IL-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.
Morton , A C , Rothman , A M K , Greenwood , J P , Gunn , J , Chase , A , Clarke , B , Hall , A S , Fox , K , Foley , C , Banya , W , Wang , D , Flather , M D & Crossman , D C 2015 , ' The effect of interleukin-1 receptor antagonist therapy on markers of inflammation in non-ST elevation acute coronary syndromes : the MRC-ILA Heart Study ' European Heart Journal , vol 36 , no. 6 , pp. 377-84 . DOI: 10.1093/eurheartj/ehu272
European Heart Journal
© The Authors 2014. Published by Oxford University Press on behalf of the European Society of Cardiology. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact firstname.lastname@example.org
This work was supported by UK Medical Research Council Experimental Medicine Grant number G0502131 and a UK Medical Research Council Clinical Research Training Fellowship MR/K002406/1 (A.M.K.R.). IL-1ra (Anakinra) and matching placebo were donated by Amgen Corporation. Funding to pay the Open Access publication charges for this article was provided by the University of Sheffield.
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