DALLAS – Interleukin-1 blockade resulted in significantly improved exercise capacity and a corresponding reduction in systemic inflammation in patients with heart failure with preserved ejection fraction in the small, pilot D-HART study.
"These results confirm the role of IL-1 in regulating cardiovascular function and provide the first evidence that an IL-1-targeted therapeutic strategy may be valuable in HFpEF [heart failure with preserved ejection fraction]," Benjamin W. Van Tassell, Pharm.D., declared at the American Heart Association scientific sessions.
The findings are welcome given that there are no approved therapies for HFpEF, which accounts for at least half of all cases of heart failure, noted Dr. Van Tassell of Virginia Commonwealth University, Richmond.
D-HART was a randomized, double-blind, placebo-controlled study involving 12 patients with symptomatic HFpEF and high levels of systemic inflammation as reflected in their elevated baseline high-sensitivity C-reactive protein levels. Patients were placed on 14 days of daily subcutaneous injections of the IL-1 antagonist anakinra (Kineret) at 100 mg or placebo, then crossed over to the other study arm. Half of the subjects had New York Heart Association (NYHA) class II heart failure, the other half class III.
Since heart failure is a syndrome of exercise intolerance secondary to impaired cardiac function, Dr. Van Tassell and his coinvestigators chose change in peak oxygen consumption (VO2) as the primary study endpoint. The median peak VO2 during the anakinra phase of the study was 16.3 mL/kg per minute, which was a 1.2–mL/kg per minute or 8% improvement over the peak value on placebo.
The improvement in peak VO2 correlated with a sharp reduction in high-sensitivity C-reactive protein (hsCRP), a surrogate marker for IL-1 activity. From a baseline of 7.5 mg/L, hsCRP levels plunged by 84% after 14 days on anakinra compared to 10% with placebo.
Ventilatory efficiency (VE) improved with IL-1 blockade as evidenced by a significant increase in the oxygen uptake efficiency slope. However, the VE/VCO2 slope – another measure of ventilatory efficiency – improved significantly with anakinra only in the five patients with above-median values at baseline. Their 12% improvement in this metric during IL-1 inhibition implies that maximum benefit occurs in patients with impaired baseline function, according to Dr. Van Tassell.
He added that these encouraging findings from D-HART provide a sound basis for larger confirmatory randomized trials evaluating IL-1 inhibition in patients with HFpEF. Anakinra is approved for the treatment of rheumatoid arthritis.
D-HART was supported by the American Heart Association and university funds. Dr. Van Tassell reported having no financial conflicts of interest.