Heart failure with reduced ejection fraction (HFrEF) patients who land in the hospital with flare-ups often show high inflammation levels marked by C-reactive protein (CRP) above 2 mg/L, which signals poor recovery chances. 
Researchers tested whether anakinra, the interleukin-1 blocker commonly used for arthritis, could lower inflammation faster and improve peak oxygen consumption (VO2), a strong measure of exercise ability, in these patients. 
The study published in the Circulation: Heart Failure randomized 102 adults recently hospitalized for HFrEF in a 2:1 ratio to receive daily 100 mg subcutaneous anakinra (68 patients) or placebo (34 patients) for a full 24 weeks, while all participants continued their standard heart failure medications. The main goal focused on the change in peak VO2 at the 24-week mark, with 84 patients providing complete data (57 on anakinra and 27 on placebo).
Exercise Capacity Improves Across Both Treatment Groups
All patients in the study experienced a meaningful improvement in their peak VO2 levels over the trial period, rising from a median of 13.0 mL/kg/min (Q1 10.9, Q3 17.0) to 14.9 mL/kg/min (Q1 12.0, Q3 18.0), which reached statistical significance with a P-value less than 0.001 across the entire cohort. Those receiving anakinra saw a median increase of 1.5 mL/kg/min (95% CI from -0.2 to +3.4), while the placebo group achieved a similar gain of 1.2 mL/kg/min (95% CI from +0.5 to +3.9), resulting in no significant difference between the two arms with a P-value of 0.40 and a median difference of just +0.30 mL/kg/min (95% CI from -1.70 to +0.90). 
This finding suggests that optimizing standard therapies like beta-blockers, ARNIs, and SGLT2 inhibitors likely drove the fitness gains rather than the addition of anakinra.
Anakinra Shows Modest Impact on Inflammation Markers
CRP levels dropped substantially in both groups during the study, with anakinra-treated patients experiencing a 76% reduction (Q1 -87%, Q3 -36%) compared to a 48% reduction in the placebo group (Q1 -77%, Q3 +14%), which approached but did not fully reach statistical significance between groups at a P-value of 0.050. About 47% of anakinra patients reached CRP below 2 mg/L versus 37% in placebo, though this difference did not prove significant (P=0.48). Importantly, patients who achieved CRP under 2 mg/L demonstrated larger VO2 improvements at +2.6 mL/kg/min (Q1 +0.7, Q3 +4.6) compared to +1.0 mL/kg/min (Q1 -0.3, Q3 +1.9) for those remaining at or above 2 mg/L (P=0.007), along with fewer HFrEF-related events (8% versus 26%, P=0.045).
Safety Profile Remains Favorable Without New Concerns
The trial reported no unexpected serious side effects linked to anakinra treatment, and rates of HFrEF hospitalizations or other events stayed comparable between the anakinra and placebo groups. Anakinra proved tolerable through daily injections, with no increased infection risks despite its immune-modulating action, aligning with safety data from its use in rheumatoid arthritis settings.
Clinical Implications Guide Future Heart Failure Management
Standard medical therapy alone resolves much of the inflammation and supports VO2 recovery in decompensated HFrEF patients, while anakinra provides only a borderline benefit on CRP without meaningfully enhancing exercise capacity or other key outcomes. 
Physicians should prioritize full optimization of guideline-directed medical therapy first and monitor CRP trends closely, as levels below 2 mg/L correlate strongly with better functional gains and fewer rehospitalizations.