Modulation of the interleukin-6 signalling pathway and incidence rates of atherosclerotic events and all-cause mortality: analyses from the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS)

Eur Heart J. 2018 Oct 7;39(38):3499-3507. doi: 10.1093/eurheartj/ehy310.

Abstract

Aims: Canakinumab, a monoclonal antibody targeting interleukin (IL)-1β, reduces rates of recurrent cardiovascular events without lowering lipids. It is uncertain, however, to what extent these beneficial cardiovascular outcomes are mediated through interleukin-6 (IL-6) signalling, an issue with substantial pathophysiologic consequences and therapeutic implications.

Methods and results: A total of 4833 stable atherosclerosis patients in the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) had IL-6 levels measured before randomization and after treatment with placebo or one of three doses of canakinumab (50 mg, 150 mg, or 300 mg) given subcutaneously once every 3 months. Participants were followed for up to 5 years (median follow-up 3.7 years). Compared with those allocated to placebo, CANTOS participants receiving canakinumab who achieved on-treatment IL-6 levels below the study median value of 1.65 ng/L experienced a 32% reduction in major adverse cardiovascular events [MACE, multivariable adjusted hazard ratio (HRadj) 0.68, 95% confidence interval (CI) 0.56-0.82; P < 0.0001], a 30% reduction in MACE plus the additional endpoint of hospitalization for unstable angina requiring urgent revascularization (MACE+, HRadj 0.70, 95% CI 0.59-0.84; P < 0.0001), a 52% reduction in cardiovascular mortality (HRadj 0.48, 95% CI 0.34-0.68; P < 0.0001), and a 48% reduction in all-cause mortality (HRadj 0.52, 95% CI 0.40-0.68; P < 0.0001) with prolonged treatment. In contrast, those with on-treatment IL-6 levels equal to or above 1.65 ng/L after taking the first dose of canakinumab had no significant benefit for any of these endpoints. These differential findings based on the magnitude of IL-6 response were seen in analyses alternatively based on tertiles of on-treatment IL-6 levels, and in analyses using a statistical inference approach to estimate the effect of treatment among individuals who would achieve a targeted IL-6 level.

Conclusion: CANTOS provides proof of concept evidence in humans that modulation of the IL-6 signalling pathway, at least with canakinumab, associates with reduced cardiovascular event rates, independent of lipid lowering.

Clinical trial registration: ClinicalTrials.gov NCT01327846.

Publication types

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

MeSH terms

  • Aged
  • Antibodies, Monoclonal / administration & dosage
  • Antibodies, Monoclonal / therapeutic use*
  • Antibodies, Monoclonal, Humanized
  • Atherosclerosis / blood*
  • Atherosclerosis / complications
  • Atherosclerosis / drug therapy*
  • Cardiovascular Diseases / blood
  • Cardiovascular Diseases / mortality
  • Cardiovascular Diseases / prevention & control*
  • Cause of Death
  • Double-Blind Method
  • Drug Administration Schedule
  • Female
  • Humans
  • Incidence
  • Injections, Subcutaneous
  • Interleukin-1beta / antagonists & inhibitors*
  • Interleukin-1beta / immunology
  • Interleukin-6 / blood*
  • Male
  • Middle Aged
  • Proof of Concept Study
  • Secondary Prevention
  • Signal Transduction*

Substances

  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • IL6 protein, human
  • Interleukin-1beta
  • Interleukin-6
  • canakinumab

Associated data

  • ClinicalTrials.gov/NCT01327846