Usefulness of Canakinumab to Improve Exercise Capacity in Patients With Long-Term Systolic Heart Failure and Elevated C-Reactive Protein

Abstract

Interleukin-1β (IL-1β) is a cytokine involved in atherothrombosis and is known to depress cardiac function. We hypothesized that blocking IL-1β in patients with symptomatic systolic heart failure (HF) would improve their cardiorespiratory fitness. The purpose of the study was to measure changes in peak oxygen consumption (VO2) in 30 patients with prior myocardial infarction, high-sensitivity C-reactive protein ≥ 2 mg/l and HF with left ventricular ejection fraction (LVEF) < 50% enrolled in the Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) in an independent single center substudy. We measured peak VO2 before and after 3 and 12 months of treatment with Canakinumab every 3 months (50, 150, or 300mg subcutaneously) or placebo, and measured LVEF before and after 12 months. In December 2013, the CANTOS study announced early termination of enrollment, halting enrollment for this substudy after only 15 patients, of which 3 were assigned to placebo and 12 to Canakinumab (50mg [1; 7%], 150mg [5; 33%], 300mg [6; 40%]). Patients treated with Canakinumab had a significant improvement in peak VO2, from 19.2 to 22.8 ml/kg/min at 3 months (p = 0.023 within-group changes, p = 0.026 for time_x_group interaction versus placebo [primary end point]), and an improvement in LVEF 38% (33-43) to 44% (38-52) at 12 months (p = 0.012 for within-group changes). No significant changes were seen in the placebo group. In conclusion, the findings of this small prespecified secondary analysis of the CANTOS trial support the positive results of the overall study, and confirm IL-1 as a potential therapeutic target in HF. https://ichgcp.net/clinical-trials-registry/NCT01900600.

Copyright © 2018 Elsevier Inc. All rights reserved.

Figures

Figure 1. Interval changes in peak oxygen consumption with Canakinumab.

Individual patient values are shown according to Canakinumab dose (triangle = 50 mg [n = 1]; squares = 150 mg [n = 5]; circles = 300 mg [n= 6]). Panel A shows changes in peak oxygen consumption (VO2) at 3 months, *p = 0.023 for within group changes versus baseline, and p = 0.026 versus placebo at time_x_group interaction at 3 months. Of the 3 doses, only Canakinumab 150 mg (squares) was associated with a significant increase in peak VO2 at 3 months (from 18.4 [13.6—21.6] to 22.5 [16.8—24.4], p = 0.043 with a median increase of +3.5 [+1.8/+4.5] ml/kg/min). Panel B shows changes in VO2 at 12 months. Panel C shows changes in left ventricular ejection fraction (LVEF) at 12 months. **p = 0.012 for within group changes versus baseline, and p = 0.30 versus placebo at time_x_group interaction. Of the 3 doses, only Canakinumab 150 mg was associated with a significant increase in LVEF at 12 months (from 38% [31—46] to 46% [42—57], p = 0.043 with a median increase of +12% [+3/+17]).

Figure 2

Interval changes in peak oxygen consumption in patients treated with placebo are shown (circles). Panel A shows changes in peak oxygen consumption (VO2) at 3 months and 12 months (Of the 3 patients, only 1 patient had peak VO2 measured at 12 months). Panel B shows changes in left ventricular ejection fraction in the 3 patients at echocardiography at 12 months.