Canakinumab Anti-Inflammatory Thrombosis Outcome Study - CANTOS

Contribution To Literature:

The CANTOS trial showed that canakinumab (150 mg) was superior to placebo at preventing adverse cardiac events.

Description:

The goal of the trial was to evaluate canakinumab compared with placebo among patients with a history of myocardial infarction (MI) and elevated high-sensitivity C-reactive protein (hsCRP). Canakinumab is a monoclonal antibody targeting interleukin-1β.

Study Design

  • Randomized
  • Parallel
  • Stratification

Patients with MI and elevated hsCRP were randomized to canakinumab 50 mg (n = 2,170) vs. canakinumab 150 mg (n = 2,284) vs. canakinumab 300 mg (n = 2,263) vs. placebo (n = 3,344). The study drug was administered subcutaneously once every 3 months.

  • Total number of enrollees: 10,061
  • Duration of follow-up: median 3.7 years
  • Mean patient age: 61 years
  • Percentage female: 26%
  • Percentage with diabetes: 40%
  • Median low-density lipoprotein cholesterol: 82 mg/dl

Inclusion criteria:

  • History of MI
  • hsCRP ≥2 mg/L

Exclusion criteria:

  • Chronic or recurrent infection
  • High risk for tuberculosis or HIV
  • History of cancer
  • Immunocompromised state
  • Systemic use of anti-inflammatory treatment

Principal Findings:

The primary outcome, incidence of cardiovascular death, MI, or stroke, occurred in 4.11/100 person-years of the 50 mg group vs. 3.86/100 person-years of the 150 mg group vs. 3.90/100 person-years of the 300 mg group vs. 4.50/100 person-years of the placebo group (p = 0.02 for 150 mg group vs. placebo; other comparisons nonsignificant).

Secondary outcomes:

  • hsCRP reduction from baseline vs. placebo: 26% greater in the 50 mg group, 37% greater in the 150 mg group, and 41% greater in the 300 mg group (p < 0.001 for all comparisons with placebo)
  • Fatal infection or sepsis: 0.31/100 person-year in the combined canakinumab vs. 0.18/100 person-year in the placebo group (p = 0.02)

Interpretation:

Among patients with a history of MI and elevated hsCRP, canakinumab was effective at preventing adverse cardiac events over a median of 3.7 years. The only dose that achieved significance after multiplicity-adjusted threshold for statistical significance was the 150 mg group. Canakinumab was effective at reducing hsCRP in a dose-response relationship. Canakinumab was associated with an increased risk of fatal infection or sepsis despite exclusion of patients with chronic or recurrent infection.

References:

Ridker PM, Everett BM, McFadyen JG, et al., on behalf of the CANTOS Trial Group. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 2017;377:1119-31.

Editorial: Harrington RA. Targeting Inflammation in Coronary Artery Disease. N Engl J Med 2017;377:1197-8.

Ridker PM, McFadyen JG, Thuren T, et al., on behalf of the CANTOS Trial Group. Effect of interleukin-1β inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial. Lancet 2017;Aug 27:[Epub ahead of print].

Presented by Dr. Paul M. Ridker at the European Society of Cardiology Congress, Barcelona, Spain, August 27, 2017.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Lipid Metabolism, Nonstatins, Novel Agents

Keywords: Antibodies, Monoclonal, Anti-Inflammatory Agents, Atherosclerosis, Cholesterol, LDL, C-Reactive Protein, Dyslipidemias, ESC Congress, ESC2017, Inflammation, Myocardial Infarction, Primary Prevention, Thrombosis, Sepsis, Stroke


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