Abstract 18369: Interleukin-1 Blockade Improves Exercise Capacity in Heart Failure With Preserved Ejection Fraction (HFpEF): Results of the D-HART Study

Abstract

Treatment options remain limited for patients with heart failure and preserved ejection fraction (HFpEF). Reduced exercise capacity is a common finding in HFpEF. Peak oxygen consumption (peak VO2) represents a gold standard for functional capacity and is a strong independent predictor of adverse outcomes. HFpEF patients also exhibit high levels of systemic inflammation that may be associated with mechanisms of diastolic dysfunction. We enrolled 12 patients with symptomatic HFpEF (LVEF>50% and evidence of abnormal LV relaxation, filling, diastolic distensibility, or diastolic stiffness) and elevated hsCRP (>2 mg/L). Patients were randomized to 14 day crossover treatment with daily subcutaneous injections of IL-1 receptor antagonist (anakinra); 100 mg or matching placebo in a double blind fashion ( NCT01542502 ). The pre-specified primary endpoint was change in peak VO2. Cardiopulmonary exercise testing was performed at baseline and upon completion of each treatment course. We observed a significant improvement in peak VO2 (+1.1 vs -0.1 ml•kg-1•min-1, P=0.009) and the oxygen uptake efficiency slope (+0.23 vs +0.09, P=0.006) and a significant reduction in hsCRP (-84% vs -10%, P=0.006) upon completion of anakinra treatment versus placebo. Correlative studies also revealed significant associations between changes in peak VO2 and hsCRP (R=-0.60, P=0.002). Improvements in ventilator efficiency (VE/VCO2 slope) were limited to patients with above median values for ventilator efficiency (VE/VCO2 slope>26), suggesting that maximum benefits may occur in patients with impaired baseline function. These findings support the hypothesis that systemic inflammation and exercise intolerance in HFpEF are, at least in part, IL-1-dependent and provide the rationale for larger randomized clinical trials to confirm the benefits of IL-1 blockade in patients with HFpEF.