The Effect of interleukin-1 Receptor Antagonist Therapy on Markers of Inflammation in non-ST Elevation Acute Coronary Syndromes: The MRC-ILA Heart Study

Eur Heart J. 2015 Feb 7;36(6):377-84. doi: 10.1093/eurheartj/ehu272. Epub 2014 Jul 30.

Abstract

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.

Clinical trial registration euctr: 2006-001767-31-GB: www.clinicaltrialsregister.eu/ctr-search/trial/2006-001767-31/GB.

Keywords: Drugs; Interleukins; Myocardial infarction.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Coronary Syndrome / drug therapy*
  • Area Under Curve
  • Biomarkers / metabolism
  • C-Reactive Protein / metabolism
  • Double-Blind Method
  • Female
  • Humans
  • Interleukin 1 Receptor Antagonist Protein / therapeutic use*
  • Interleukin-6 / metabolism
  • Male
  • Middle Aged
  • Receptors, Interleukin-1 / antagonists & inhibitors*
  • Treatment Outcome
  • Troponin / metabolism
  • von Willebrand Factor / metabolism

Substances

  • Biomarkers
  • Interleukin 1 Receptor Antagonist Protein
  • Interleukin-6
  • Receptors, Interleukin-1
  • Troponin
  • von Willebrand Factor
  • C-Reactive Protein