Canakinumab Anti-Inflammatory Thrombosis Outcomes 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)

Results of secondary analysis addressing relationship of hsCRP reduction to event reduction: Among patients who were randomized to canakinumab and achieved on-treatment hsCRP <2 mg/L, there was a reduction in major adverse cardiovascular events (HR 0.75, 95% CI 0.66-0.85, p < 0.0001), compared with no benefit among those with on-treatment hsCRP ≥2 mg/L (HR 0.90, 95% CI 0.79-1.02, p = 0.11).

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.

The amount of hsCRP reduction from canakinumab might provide a mechanism for predicting the clinical response from this medication.

References:

Ridker PM, MacFadyen JG, Everett BM, Libby P, Thuren T, Glynn RJ, on behalf of the CANTOS Trial Group. Relationship of C-reactive protein reduction to cardiovascular event reduction following treatment with canakinumab: a secondary analysis from the CANTOS randomised controlled trial. Lancet 2017;Nov 13:[Epub ahead of print].

Presented by Dr. Paul M. Ridker at the American Heart Association Annual Scientific Sessions (AHA 2017), Anaheim, CA, November 13, 2017.

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;390:1833-42.

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


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