5233Interleukin-1 blockade with Anakinra in ST-segment elevation acute myocardial infarction: Results from the VCUART3 study
Authors: Abbate A , Trankle C R , Lipinski M J , Kadariya D , Canada J M , Carbone S , Buckley L F , Appleton D , Wohlford G F , Medina De Chazal H , Chiabrando J G , Roberts C , Turlington J S , Abouzaki N A , Van Tassell B 
Published: October 2019

Abstract

Background
ST-segment elevation myocardial infarction (STEMI) is associated with an intense inflammatory response that predicts an increased risk of death and heart failure (HF). In the current study we tested whether anakinra, a recombinant Interleukin-1 (IL-1) receptor antagonist, given once daily (standard dose) or twice daily reduced systemic inflammation in patients with STEMI.

Methods
We enrolled patients with STEMI within 12 hours of presentation at 3 sites. After revascularization, patients were randomly assigned to receive anakinra 100 mg twice daily, anakinra 100 mg once daily alternating with placebo once daily every 12 hours, or placebo twice daily, for 14 days in a 1:1:1 ratio. The primary efficacy outcome was the area under the curve for C-reactive protein levels (CRP-AUC) using a high-sensitivity assay at 14 days comparing anakinra (both arms) versus placebo followed by a comparison between each of the anakinra arms with placebo. Two pre-specified exploratory clinical efficacy endpoints, adjudicated by a blinded event committee, were assessed: a composite endpoint of all-cause death for any reason or incidence of HF (defined as new-onset HF requiring hospitalization or a new prescription of a loop diuretic, D+HF) and a composite endpoint of death and HF hospitalization (D+HHF) at 1 year. Data are expressed as median and interquartile range or number and percentage. Kaplan-Meyer survival curves were compared using Log-rank test (Mantel-Cox). (ClinicalTrials.gov number, NCT01950299)

Results
Of 311 patients screened, 99 subjects (80 [81%] males, 57 [58%] Caucasians, 55 [49–62] years of age) were randomly assigned to anakinra twice daily (N=31), anakinra once daily (N=33) or placebo (N=35). There were no significant imbalances in the demographic characteristics between groups (all P>0.05). The CRP-AUC was significantly lower in the anakinra group than in the placebo group (67 [39–120] versus 214 [131–394] mg/dl, P<0.001; and P<0.001 for each anakinra arm versus placebo separately, without significant differences between the two anakinra arms, P=0.41). Treatment with anakinra was associated with a significant reduction versus placebo in the incidence of D+HF (6/64 [9.4%] versus 9/35 [25.7%], P=0.046), and of D+HHF (0/64 [0] versus 4/35 [11.4%], P=0.011), without any significant difference between the two anakinra arms. Anakinra was not associated with any treatment-related serious adverse events, nor with excess infections compared with placebo (14.1% vs 14.3%, P=0.87).

Conclusions
Among patients with STEMI, IL-1 blockade significantly reduced the systemic inflammatory response compared with placebo, without any significant difference between standard or high dose regimens. Prespecified exploratory analyses on clinical endpoints demonstrate reduced incidence of HF and reduced HF hospitalizations, supporting the concept of beneficial effects with IL-1 blockade in patients with acute myocardial infarction.

Acknowledgement/Funding
Funded by NHLBI 1R34HL121402; Drug supply from Swedish Orphan Biovitrum