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Canakinumab Reduces CV Outcomes in High Risk Patients

The results of a randomized, double-blind trial have shown that canakinumab (CAN), an interleukin-1β inhibitor, given as 150 mg every 3 months, resulted in a significantly lower rate of recurrent cardiovascular events (in high-risk CV patients), independent of lipid-level lowering. (Citation source https://buff.ly/2xGZi01)

The results of the CANTOS study (ClinicalTrials.gov number, NCT01327846) were simultaneously published in NEJM, Lancet and were presented at the European Society of Cardiology meeting in Barcelona.

The study involved 10,061 patients with a prior myocardial infarction and elevated high sensitivity C-reactive protein (CRP) of 2.0 mg/L or more. The trial compared 3 doses of canakinumab (50 mg, 150 mg, and 300 mg) with placebo. The primary end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death over 48 months.

At 2 years CRP levels decreased in a dose dependent fashion (compared to PBO). Canakinumab did not affect lipid levels.

With a median follow-up of 3.7 years, the incidence rate for the primary end point was:

  • PBO: 4.50 events per 100 person-years
  • CAN 50 mg: 4.11 events per 100 person-years (HR 0.93 (95% confidence interval [CI], 0.80 to 1.07; P=0.30);
  • CAN 150 mg: 3.86 events per 100 person-years (HR 0.85 (95% CI, 0.74 to 0.98; P=0.021);
  • CAN 300 mg: 3.90 events per 100 person-years (HR 0.86 (95% CI, 0.75 to 0.99; P=0.031).

Only the 150-mg dose met the prespecified threshold for statistical significance for the primary end point. It also met the secondary end point of hospitalization for unstable angina that led to urgent revascularization (HR 0.83; 95% CI, 0.73 to 0.95; P=0.005).

Interestingly CAN was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P=0.31).

Exploratory analyses also revealed canakinumab reduced total cancer deaths, especially lung cancer. The effects were dose dependent.

Some have suggested these results as "modest" especially in light of the excessive cost of chronic canakinumab therapy in the multitudes of at risk individuals.  Nonetheless, these data support the theory that inflammation is a major driver to cardiovascular risk, even in patients without inflammatory diseases like rheumatoid arthritis (RA).

Large cohort trials in rheumatoid arthritis (RA) patients have shown substantial reduction in myocardial infarction and major cardiovascular events (MACE) when patients were treated with prolonged methotrexate or TNF inhibition. (https://buff.ly/2wMC38j)

These findings have lead Ridker P and others to devise trials to examine if control of inflammation may lead to better cardiovascular outcomes in high risk, non-RA patients (http://buff.ly/2iQEigL).

The CANTOS trial is the first of 3 large trials that assess if DMARDs or biologics will lower systemic inflammation sufficiently to avoid major CV events.

Trials that are currently ongoing include the CIRT trial (with methotrexate) and a trial of hydroxychloroquine (http://buff.ly/2iQFi4g).  All are placebo controlled trials designed to assess intervention effects on CV outcomes in high risk individuals.

Cardiology Trials Assessing DMARD/Biologic Effects on CV Outcomes

Cardiology Trials Assessing DMARD/Biologic Effects on CV Outcomes

Study

CIRT

CANTOS

OXI

Title

CV Inflammation Reduction Trial

Canakinumab Anti-inflammatory Thrombosis Outcomes Study

Hydroxychloroquine for the Prevention of CV Events in Myocardial Infarction

DMARD, Interventions

Methotrexate (15-20/wk), PBO

Canakinumab (50,150,300mg), PBO

Hydroxychloroquine (400mg) or PBO

Patients enrolled (N)

CAD, MI, DM, MS

(7000)

Post MI, CAD w/ hsCRP > 2.0mg/dl 

(17400)

Post-MI patients

(2500)

Endpoint

Major CVE, Mortality

Time to major CVE (MI, CVA, CVD death)

360 events - Death, MI, hospitalization for unstable angina, urgent PTCA, CABG

Start date

April 2013

April 2011

February 2016

Completion

December 2018

February 2017

June 2018

ClinicalTrials.gov

NCT01594333

NCT01900600

NCT02648464

 

Disclosures: 
The author has received compensation as an advisor or consultant on this subject

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