Canakinumab Anti-Inflammatory Thrombosis Outcomes Study - CANTOS

Apr 04, 2022
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Presenter/Author:
Paul M. Ridker, MD, MPH, FACC
Author/Summarized by Author:
Anthony A. Bavry, MD, MPH, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Novartis Pharmaceuticals
Date Presented:
04/04/2022
Date Published:
09/28/2020
Date Updated:
04/04/2022
Original Posted Date:
08/27/2017
References

Contribution To Literature:

Highlighted text has been updated as of April 4, 2022.

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). The reduction in the primary outcome was the same among those with diabetes (hazard ratio [HR] 0.85, 95% confidence interval [CI] 0.70-1.03), those with pre-diabetes (HR 0.86, 95% CI 0.70-1.06), and those with normoglycemia (HR 0.81, 95% CI 0.49-1.35).

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)
  • Incident diabetes: similar among the four treatment groups (log rank p = 0.84).

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 cardiac 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).

Total cardiovascular events, defined as cardiovascular death, MI, stroke, and coronary revascularization, occurred in 8.4/100 person-years of the 50 mg group vs. 8.3/100 person-years of the 150 mg group vs. 8.2/100 person-years of the 300 mg group vs. 10.4/100 person-years of the placebo group (p = 0.004 for 50 mg group, p = 0.002 for 150 mg group, p = 0.001 for 300 mg group vs. placebo).

Chronic kidney disease substudy:

Among those with estimated glomerular filtration rate (eGFR) <60 cc/min/1.73 m2, canakinumab vs. placebo was associated with a reduction in major adverse vascular events (HR 0.82, 95% CI 0.68-1.00, p = 0.05) and among those with estimated glomerular filtration rate ≥60 cc/min/1.73 m2, canakinumab vs. placebo was associated with a reduction in major adverse vascular events (HR 0.86, 95% CI 0.77-0.97, p = 0.01). The greatest benefit was observed among those who achieved hsCRP <2 mg/L (HR 0.68, 95% CI 0.53-0.86, p = 0.0015).

Hazard ratios for cardiovascular mortality stratified by baseline renal function and CRP:

  • Preserved eGFR/low hsCRP, 1.0 (referent)
  • Preserved eGFR/high hsCRP, 1.49
  • Reduced eGFR/low hsCRP, 3.00
  • Reduced eGFR/high hsCRP, 4.08

Hazard ratios for cardiovascular mortality stratified by baseline renal function and low-density lipoprotein cholesterol (LDL-C):

  • Preserved eGFR/low LDL-C, 1.0 (referent)
  • Preserved eGFR/high LDL-C, 1.13
  • Reduced eGFR/low LDL-C, 2.96
  • Reduced eGFR/high LDL-C, 3.28

Modulation of interleukin-6 and interleukin-18: Among those who experienced an on-treatment reduction in interleukin-6 below the median value, there was a 32% reduction in major adverse events for canakinumab vs. placebo (p < 0.0001). Canakinumab was not associated with a change in interleukin-18; however, interleukin-18 levels were associated with cardiovascular risk. For example, the highest tertile of interleukin-18 compared with the lowest tertile was associated with a 1.3-fold increased hazard for major adverse cardiac events (p = 0.0095).

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 not associated with a reduction in incident diabetes. Canakinumab was effective at reducing hsCRP in a dose-response relationship. Canakinumab was effective among those with chronic kidney disease, especially those who achieved the greatest reduction in hsCRP. Residual inflammatory risk is a significant determinant of recurrent cardiovascular risk. 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:

Presented by Dr. Paul Ridker at the American College of Cardiology Annual Scientific Session (ACC 2022), Washington, DC, April 4, 2022.

Everett BM, McFadyen JG, Thuren T, Libby P, Glynn RJ, Ridker PM. Inhibition of Interleukin-1β and Reduction in Atherothrombotic Cardiovascular Events in the CANTOS Trial. J Am Coll Cardiol 2020;76:1660-70.

Editorial Comment: Roubille F, Huet F, Duflos C. Total Burden of Events: A New Standard Stressing the Positive Impact of Inflammation Modulation. J Am Coll Cardiol 2020;76:1671-3.

Ridker PM, MacFadyen JG, Thuren T, Libby P, on behalf of the CANTOS Trial Group. Residual inflammatory risk associated with interleukin-18 and interleukin-6 after successful interleukin-1β inhibition with canakinumab: further rationale for the development of targeted anti-cytokine therapies for the treatment of atherothrombosis. Eur Heart J 2019;Sep 1:[Epub ahead of print].

Ridker PM, Libby P, MacFadyen JG, et al. 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;39:3499-3507.

Editorial: Klingenberg R, Lüscher TF. CANTOS: a seductive song with several verses. Eur Heart J 2018;39:3508-10.

Presented by Dr. Paul M. Ridker at the European Society of Cardiology Congress, Munich, Germany, August 26, 2018.

Everett BM, Donath MY, Pradhan AD, et al. Anti-Inflammatory Therapy With Canakinumab for the Prevention and Management of Diabetes. J Am Coll Cardiol 2018;Mar 12:[Epub ahead of print].

Presented by Dr. Brendan Everett at the American College of Cardiology Annual Scientific Session (ACC 2018), Orlando, FL, March 12, 2018.

Presented by Dr. Paul Ridker at the American College of Cardiology Annual Scientific Session (ACC 2018), Orlando, FL, March 11, 2018.

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 2018;391:319-28.

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.

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

Keywords: ACC22, ACC Annual Scientific Session, ESC18, ESC Congress, ACC18, AHA Annual Scientific Sessions, AHA17, Antibodies, Monoclonal, Anti-Inflammatory Agents, Atherosclerosis, Cholesterol, LDL, C-Reactive Protein, Diabetes Mellitus, Dyslipidemias, ESC2017, Inflammation, Interleukin-6, Interleukins, Kidney Failure, Chronic, Myocardial Infarction, Primary Prevention, Thrombosis, Sepsis, Stroke


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