IL-1 Blockade in Patients With Heart Failure With Preserved Ejection Fraction

Abstract

Background Enhanced inflammation may lead to exercise intolerance in heart failure with preserved ejection fraction. The aim of the current study was to determine whether IL (interleukin)-1 blockade with anakinra improved cardiorespiratory fitness in heart failure with preserved ejection fraction. Methods and Results Thirty-one patients with heart failure with preserved ejection fraction and CRP (C-reactive protein) >2 mg/L were randomized to anakinra (100 mg subcutaneously daily, N=21) or placebo (N=10) for 12 weeks. We measured peak oxygen consumption (Vo2), ventilatory efficiency (VE/Vco2 slope), and high-sensitivity CRP and NT-proBNP (N-terminal pro-B-type natriuretic peptide) at 4, 12, and 24 weeks. Twenty-eight patients completed ≥2 visits, 18 women (64%), 27 (96%) obese. There were no differences in peak Vo2 or VE/Vco2 slope between groups at baseline. Peak Vo2 was not changed after 12 weeks of anakinra (from 13.6 [11.8-18.0] to 14.2 [11.2-18.5] mL·kg-1·min-1, P=0.89), or placebo (14.9 [11.7-17.2] to 15.0 [13.8-16.9] mL·kg-1·min-1, P=0.40), without significant between-group differences in changes at 12 weeks (-0.4 [95% CI, -2.2 to +1.4], P=0.64). VE/Vco2 slope was also unchanged with anakinra (from 28.3 [27.2-33.0] to 30.5 [26.3-32.8], P=0.97) or placebo (from 31.6 [27.3-36.9] to 31.2 [27.8-33.4], P=0.78), without significant between-group differences in changes at 12 weeks (+1.2 [95% CI, -1.8 to +4.3], P=0.97). Within the anakinra-treated patients, high-sensitivity CRP and NT-proBNP levels were lower at 4 weeks compared with baseline ( P=0.026 and P=0.022 versus placebo [between-group analysis], respectively). Conclusions Treatment with anakinra for 12 weeks failed to improve peak Vo2 and VE/Vco2 slope in a group of obese heart failure with preserved ejection fraction patients. The favorable trends in high-sensitivity CRP and NT-proBNP with anakinra deserve exploration in future studies. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT02173548.

Keywords: cardiorespiratory fitness; exercise test; heart failure; inflammation; interleukin-1; natriuretic peptides; oxygen consumption.

Figures

Figure 1.. Screening and enrollment of patients.

CPX indicates cardiopulmonary exercise test; and hsCRP, high-sensitivity C-reactive protein.

Figure 2.. Effects of treatment on peak oxygen consumption (Vo2) and minute ventilation-carbon dioxide production slope (VE/Vco2 slope).

Treatment with anakinra was not associated with any significant changes, or differences in change vs placebo, in peak Vo2 or the VE/Vco2 slope at 4 wk nor at 12 wk (coprimary end points) or after 12-wk washout (all P values >0.05 at timexgroup interaction analysis). There were no significant changes in peak Vo2 or the VE/Vc02 slope at 4 and 12 wk compared with baseline in either group (all P>0.05). Column height reflects median and bar reflects interquartile range.

Figure 3.. Effects of treatment on exercise time.

There were no statistically significant differences between-group changes in exercise time comparing anakinra and placebo (P=0.96). Within the anakinra-treated patients, treadmill exercise time was longer at 4 wk (+48 s, P=0.004 for within-group) and 12 wk (+27 s, P=0.009 for within-group) vs baseline. After 12 wk of cessation of anakinra therapy, exercise time was not different than the baseline levels (+2 s, P=0.95). Column height reflects median and bar reflects interquartile range.

Figure 4.. Changes in CRP (C-reactive protein) during the 12 wk of anakinra treatment.

CRP levels were lower after 4 and 12 wk of anakinra (P=0.026 and P=0.033, respectively, vs placebo [between-group analysis—timexgroup interaction]). No significant changes in CRP levels were seen at any time point in the placebo group (all P>0.05 vs baseline [within-group analysis]), whereas CRP levels were lower at 4 wk (−65%, P=0.009 vs baseline [within-group analysis]) and at 12 wk (−52%, P=0.009 vs baseline [within-group analysis]) in the anakinra group, with levels returning closer to baseline after 12 wk of stopping treatment (P=0.048 vs baseline [within-group analysis]). Column height reflects median and bar reflects interquartile range.

Figure 5.. Changes in NT-proBNP (N-terminal pro-B-type natriuretic peptide).

There was a significantly greater reduction in NT-proBNP levels with 4 wk of anakinra than placebo (P=0.022 [between-group analysis—timexgroup interaction]). There were no changes in NT-proBNP levels in the placebo group at any time point (all P>0.16 vs baseline [within-group analysis]), whereas NT-proBNP levels were lower at 12 wk in the anakinra group (−42% vs baseline, P=0.029 for within-group; however, P>0.05 for timexgroup interaction). Column height reflects median and bar reflects interquartile range.

Figure 6.. Changes in functional capacity and quality of life questionnaires.

There were no significant differences in baseline Duke Activity Status Index (DASI) score of Minnesota Living With Heart Failure Questionnaire (MLWHFQ) score and physical domain score between the groups at baseline, and there were no significant between-groups differences on the effects of treatments on any of the outcomes of interest. Patients randomized to treatment with anakinra reported significantly higher perceived functional capacity, as assessed by the DASI question-naire at follow-up (within-group analysis), and quality of life, as shown by the physical domain scores of the MLWHFQ and comprehensive MLWHFQ score (within-group analysis), whereas no placebo-treated patients did not (within-group analysis); however, none of the differences in anakinra vs placebo changes reached statistical significance (timexgroup interaction). Column height reflects median and bar reflects interquartile range.