Anti-Inflammatory Therapy With Canakinumab for the Prevention of Hospitalization for Heart Failure

Circulation. 2019 Mar 5;139(10):1289-1299. doi: 10.1161/CIRCULATIONAHA.118.038010.

Abstract

Background: Subclinical inflammation is associated with an increased risk of heart failure and with adverse prognosis in patients with established heart failure. Yet, treatments specifically directed at reducing inflammation in patients with heart failure have not yet shown improved clinical outcomes. We tested the hypothesis that the interleukin-1β inhibitor canakinumab would prevent hospitalization for heart failure (HHF) and the composite of HHF or heart failure-related mortality.

Methods: We randomized 10 061 patients with prior myocardial infarction and high-sensitivity C-reactive protein ≥2 mg/L to canakinumab 50, 150, or 300 mg or placebo, given subcutaneously once every 3 months. In total, 2173 (22%) reported a history of heart failure at baseline. We tested the hypothesis that canakinumab prevents prospectively collected HHF events and the composite of HHF or heart failure-related mortality.

Results: A total of 385 patients had an HHF event during a median follow-up of 3.7 years. Patients who had HHF were older, had higher body mass index, and were more likely to have diabetes mellitus, hypertension, and prior coronary bypass surgery. As anticipated, median (quartile 1, 3) baseline concentrations of high-sensitivity C-reactive protein were higher among those who had HHF during follow-up than those who did not (5.7 [3.5, 9.9] mg/L versus 4.2 [2.8, 6.9] mg/L, respectively; P<0.0001). The unadjusted hazard ratios for HHF with each dose of canakinumab compared with placebo were 1.04 (95% CI, 0.79-1.36) for 50 mg, 0.86 (95% CI, 0.65-1.13) for 150 mg, and 0.76 (95% CI, 0.57-1.01) for 300 mg ( P for trend=0.025). The composite of HHF or heart failure-related mortality was also reduced by canakinumab, with unadjusted hazard ratios of 1.00 (95% CI, 0.78-1.29) for 50 mg, 0.88 (95% CI, 0.68-1.13) for 150 mg, and 0.78 (95% CI, 0.60-1.02) for 300 mg ( P for trend=0.042).

Conclusions: These randomized double-blind placebo-controlled data suggest that therapy with canakinumab, an interleukin-1β inhibitor, is related to a dose-dependent reduction in HHF and the composite of HHF or heart failure-related mortality in a population of patients with prior myocardial infarction and elevations in high-sensitivity C-reactive protein.

Clinical trial registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01327846.

Keywords: clinical trial [publication type]; heart failure; inflammation.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Anti-Inflammatory Agents / adverse effects
  • Anti-Inflammatory Agents / therapeutic use*
  • Antibodies, Monoclonal, Humanized / adverse effects
  • Antibodies, Monoclonal, Humanized / therapeutic use*
  • Biomarkers / blood
  • C-Reactive Protein / metabolism
  • Disease Progression
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Female
  • Heart Failure / blood
  • Heart Failure / drug therapy*
  • Heart Failure / mortality
  • Heart Failure / physiopathology
  • Humans
  • Inflammation Mediators / blood
  • Male
  • Middle Aged
  • Patient Admission*
  • Prospective Studies
  • Protective Factors
  • Risk Factors
  • Time Factors
  • Treatment Outcome

Substances

  • Anti-Inflammatory Agents
  • Antibodies, Monoclonal, Humanized
  • Biomarkers
  • Inflammation Mediators
  • canakinumab
  • C-Reactive Protein

Associated data

  • ClinicalTrials.gov/NCT01327846