Interleukin-1 Blockade in Acute Decompensated Systolic Heart Failure: Results of the Anakinra in Decompensated Heart Failure Pilot Study

Background: The inflammatory response in acute decompensated heart failure (ADHF) may contribute to the progression of the disease, complication, and re-hospitalization. Interleukin-1 (IL-1) has been identified as a potential therapeutic target in HF. We hypothesized that IL-1 blockade, with Anakinra (Kineret™, Swedish Orphan Biovitrum), would quench the acute inflammatory response in patients with ADHF. Methods: We randomized 30 patients with ADHF, reduced left ventricular ejection fraction (LVEF<40%), and elevated C reactive protein (CRP) levels (≥5 mg/l) to either Anakinra 100 mg twice daily for 3 days followed by once daily for 11 days or matching placebo, in a 1:1 double blinded fashion. We measured CRP and IL-6 plasma levels using high-sensitivity assays, daily for 5 days, and then again at 14 days and evaluated the area-under-the-curve (AUC) and interval change (delta). Results: Treatment with Anakinra was well tolerated: there were 7 adverse events in 6 patients treated with Anakinra and 12 in 10 patients treated with placebo (OR 0.33 [0.08-1.48, P=0.15). Two patients in the Anakinra group and 5 in the placebo group suspended treatment prematurely (OR 0.31 [0.05-1.93], P=0.21). When compared with placebo, Anakinra did not reduce the CRP-AUC at 4 days (primary endpoint) or at 14 days, while it significantly reduced the IL-6-AUC at 4 and 14 days (Table). Two patients in the Anakinra group and 3 patients in the placebo group experienced worsening HF or readmission for HF (OR 0.61 [0.09-4.34], P=0.62). In patients with paired baseline and day 14 echocardiograms (N=14), Anakinra was associated with a greater recovery in LVEF vs placebo (+10% [+3/+14] vs 0 [-16%/+5%], P=0.020, respectively). Conclusions: IL-1 blockade with Anakinra in patients with ADHF appears to be safe and is associated with a blunted inflammatory response. Further studies are warranted to determine whether this anti-inflammatory effect translates into improved clinical outcomes.