Original Investigation
Inhibition of Interleukin-1β and Reduction in Atherothrombotic Cardiovascular Events in the CANTOS Trial

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Abstract

Background

Inflammation reduction with the interleukin (IL)-1β inhibitor canakinumab significantly reduces the first major adverse cardiovascular event in patients with prior myocardial infarction (MI) and residual inflammatory risk (high-sensitivity C-reactive protein ≥ 2 mg/l). However, the effect of canakinumab on the total number of cardiovascular events, including recurrent events collected after a first event, is unknown.

Objectives

This study sought to determine whether randomly allocated canakinumab would reduce the total burden of serious cardiovascular events.

Methods

We randomized 10,061 patients to placebo or canakinumab 50 mg, 150 mg, or 300 mg once every 3 months and compared the rates of the composite of all serious cardiovascular events (MI, stroke, coronary revascularization, and cardiovascular death) in active versus placebo groups. We used negative binomial regression to account for correlations among repeated events in the same person and to estimate rate ratios and 95% confidence intervals.

Results

During a median of 3.7 years of follow-up, 3,417 total serious cardiovascular events occurred in 2,003 individuals among the 10,061 unique patients randomized. Canakinumab reduced the rates of total serious cardiovascular events, with rates per 100 person-years in the placebo, 50 mg, 150 mg, and 300 mg canakinumab groups of 10.4, 8.4, 8.3, and 8.2, respectively. The corresponding rate ratios (95% confidence intervals) compared with placebo were 0.80 (0.69 to 0.93) for 50 mg, 0.79 (0.68 to 0.92) for 150 mg, and 0.78 (0.67 to 0.91) for 300 mg.

Conclusions

Anti-inflammatory therapy with canakinumab significantly reduced the total number of cardiovascular events in patients with prior MI and evidence of residual inflammatory risk. (Cardiovascular Risk Reduction Study [Reduction in Recurrent Major CV Disease Events] (CANTOS); NCT01327846

Key Words

canakinumab
coronary artery disease
inflammation
NLRP3 inflammasome
prevention

Abbreviations and Acronyms

CI
confidence interval
hsCRP
high-sensitivity C-reactive protein
IL
interleukin
MACE
major adverse cardiovascular events (MI, stroke, cardiovascular death)
MACE+
major adverse cardiovascular events plus unstable angina requiring unplanned coronary revascularization
MI
myocardial infarction

Cited by (0)

Funded by Novartis Pharmaceuticals, Basel, Switzerland. The sponsor of the CANTOS trial was involved in the design of the trial protocol and the collection of trial data. Dr. Everett has served as a consultant to and received grant support from Novartis for work unrelated to the CANTOS trial; has received significant grants from the National Heart, Lung, and Blood Institute during the study; has received significant personal fees from Amgen; and has received modest personal fees from Amarin, Gilead, Merck, and Roche Diagnostics outside the present work. Dr. Thuren is an employee of and holds stock in Novartis Pharmaceuticals. Dr. Libby has served as an unpaid consultant to, or has been involved in clinical trials for Amgen, AstraZeneca, Esperion Therapeutics, Ionis Pharmaceuticals, Kowa Pharmaceuticals, Novartis, Pfizer, Sanofi-Regeneron, and XBiotech, Inc.; has been a member of the scientific Advisory Board for Amgen, Corvidia Therapeutics, DalCor Pharmaceuticals, IFM Therapeutics, Kowa Pharmaceuticals, Olatec Therapeutics, Medimmune, Novartis, and XBiotech, Inc.; serves on the Board of XBiotech, Inc.; his laboratory has received research funding in the past 2 years from Novartis; and has been an unpaid consultant to and has received research grant support from Novartis Pharmaceuticals. Dr. Glynn has received research grant support to conduct the CANTOS trial from Novartis Pharmaceuticals; and has been an unpaid consultant to Novartis. Dr. Ridker has served as the Principal Investigator of the CANTOS trial; and has served as a consultant to Novartis, Inflazome, Agepha, and Corvidia. Ms. MacFadyen has reported that she has no relationships relevant to the contents of this paper to disclose.

The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC author instructions page.

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© 2020 by the American College of Cardiology Foundation. Published by Elsevier.