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

Morton AC, Rothman AMK, Greenwood JP, et al.
European Heart Journal, 2015; 36: 377–384; doi:10.1093/eurheartj/ehu272

Background

Inflammation within coronary plaque is associated with acute coronary syndromes (ACS) and atherosclerosis, as a chronic inflammatory condition, is the primary cause of ACS [1]. Exacerbations of the inflammatory process may lead to plaque rupture. This can be followed by thrombosis and subsequent myocardial ischaemia [2]. Additionally, myocardial injury after an ischaemic event can elicit a local and systemic inflammation. The intensity of the systemic response also predicts adverse events [3].
Interleukin-1 (IL-1) has an established role in atherogenesis. Patients with ACS have higher levels of IL-1, which induces IL-6 production [4], and both are known to stimulate C-reactive protein. Serum IL-6 levels are elevated in patients with ACS [5], which is independently associated with increased mortality [6]. IL-1 signalling can be blocked in man by human recombinant IL-1 receptor antagonist (IL-1ra) [7]. It was 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.
The present study, therefore, examined the effect of the specific inhibitor of IL-1r anakinra on C-reactive protein levels in patients with NSTE-ACS. This phase II, double-blinded, randomized, placebo controlled study enrolled 182 patients presenting within 48 hours after the onset of chest pain. Patients were treated with either daily subcutaneous 100mg anakinra or placebo for 14 days. Serum high-sensitive C-reactive protein (hs-CRP) over the first 7 days was the primary endpoint.

Main results

• Hs-CRP (primary endpoint) in treatment group in the first 7 days was lower with active treatment: 21.98 mg day/L (95%CI: 16.31–29.64), as compared with the placebo group, 43.5 mg day/L (95%CI: 31.15–60.75) (geometric mean ratio= 0.51 mg/L; 95%CI: 0.32–0.79; P=0.0028).
• After 14-days hs-CRP (1.74 [95%CI: 1.28-2.39] vs. 4.60 [95%CI: 3.21-6.59], P= 0.0001) and IL-6  (2.51 [95%CI: 2.04-3.08] vs. 3.82 [95%CI: 2.82-5.16], P= 0.022) levels were lower in the treatment  than in the placebo group.
• Sixteen days after discontinuation of treatment, hs-CRP levels had risen again in the treatment group (3.50 mg/L, 95%CI: 2.65-4.62)), while levels declined further in the placebo group (2.21 mg/L, 95%CI: 1.67-2.92, P=0.022].
• Major adverse cardiovascular events at day 30 and 3 months were similar but after 1 year there were significantly more events in the treatment group (13 [18.9%] vs. 4 [5.4%], P=0.0233), which was mostly driven by a trend towards more MI (8 [11.4%] vs. 2 [2.7%], P=0.0581).

Conclusion

This is the first randomised trial to investigate the effects of anakinra in NSTE-ACS patients, which demonstrated a suppression of inflammation markers (hs-CRP and IL-6) after 14 days of treatment with the IL-1ra. This study shows that IL-1 is a key mediator in the hs-CRP elevation that occurs at the time of NSTE-ACS. The results also showed that a 14-day treatment was insufficient to achieve durable suppression of inflammation. The CANTOS study [8], the large prospective study of long term IL-1 inhibition in patients with CAD, may further clarify this topic.

Editorial comment [9]

Abbate and Dinarello state that “Whereas it is clear that elevated CRP levels predicts poor outcomes in patients with ACS, it is not clear whether reducing CRP levels reduces subsequent events. Although the data from the MRC-ILA Heart Study do not support the hypothesis of a beneficial effect of IL-1 blockade in ACS, one must consider the obvious limitations of a small sample size with a small number of events. Moreover, lacking the details of clinical outcomes for secondary endpoints, the interpretation of the MRC-ILA Heart Study remains uncertain” [..]

“The MRC-ILA Heart Study shows that 14 days of 100 mg daily anakinra significantly reduced CRP levels at 7 and 14 days but not at 30 days. These findings probably are the result of two concurrent
mechanisms: the spontaneous reduction in the placebo group and a loss of inhibition in the anakinra group after cessation” [..]
“One fundamental question generated from the MRC-ILA Heart is whether a 14-day treatment is sufficient. Since by day 30, regardless of group allocation, most patients had reduced levels of CRP, one may argue that prolonged treatment is not needed, or not in those with low CRP levels. In contrast, given the underlying chronic vessel inflammatory process, prolonged treatment may be needed”. [..] 
“In conclusion, the MRC-ILA Heart Study investigators have contributed greatly to the understanding of whether the acute inflammatory response in NSTEMI is IL-1 mediated, and the answer is a clear
yes. More studies are now needed to address whether inhibition of the acute inflammatory response with IL-1 blockers will reduce morbidity and mortality”.

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