Systemic Inflammation and Cardiorespiratory Fitness in Heart Failure: A Pooled Analysis of Anakinra Clinical Trials

BACKGROUND Systemic inflammation, defined by C-reactive protein (CRP) ≥2 mg/L, is common in heart failure (HF) and its resolution is associated with better outcomes. We evaluated whether resolution of systemic inflammation was associated with improved peak oxygen consumption (VO 2 ) in patients with HF with reduced (HFrEF) or preserved ejection fraction (HFpEF). METHODS Patients from five phase II clinical trials treated with anakinra, recombinant interleukin-1 receptor antagonist, or placebo, were pooled and stratified by CRP ≥ or <2.0 mg/L at longest follow-up. Change in treadmill peak VO 2 was the primary endpoint. Doppler echocardiography was also performed. RESULTS Among 166 patients (77% HFrEF, 23% HFpEF), baseline CRP was 6.1 (3.1 to 13.2) mg/L, and 47% had CRP <2 mg/L after 12 [6 to 24] weeks of treatment. Peak VO 2 improved more in those with inflammation resolution (+1.5 [+0.1 to +4.1] vs +0.7 [-0.8 to +1.9] mL·kg −1 ·min −1 , p =0.003). On-treatment CRP correlated with change in peak VO 2 (R=-0.26, p =0.0008), with every 1 mg/L difference in CRP corresponding to +0.1 mL·kg⁻¹·min⁻¹. Anakinra treatment led to greater CRP reduction (-3.5 [-8.3 to -2.0] vs -0.6 [-3.7 to -0.8] mg/L; p <0.0001) and more frequently on-treatment CRP <2 mg/L (53% vs 33%, OR: 2.3 [95% CI 1.1-4.4]; p =0.03), although many patients failed to achieve resolution, and treatment was not associated with greater change in peak VO 2 . A sensitivity analysis showed an even greater improvement in peak VO 2 in those with on-treatment CRP <1 mg/L (+1.9 [+0.3 to +4.7] mL·kg −1 ·min −1 ). CONCLUSION Resolution of systemic inflammation was associated with a greater improvement in peak VO 2 in patients with HF. Anakinra decreased CRP levels, increasing inflammation resolution, but failed to achieve resolution in nearly half of the cases.