CANTOS

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Ridker PM, et al. "Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease". The New England Journal of Medicine. 2017. 377(12):1119-1131.
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Clinical Question

Among patients with a history of myocardial infarction and a high-sensitivity C-reactive protein level of ≥ 2mg/L, does treatment with canakinumab (a monoclonal antibody targeting interleukin-1β) reduce the rate of recurrent cardiovascular events when compared with placebo?

Bottom Line

Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months was associated with 0.6% absolute reduction in cardiovascular events, driven by a comparable reduction in nonfatal MI. Use of canakinumab was also associated with 0.13% absolute increase in fatal infection.

Major Points

The inflammatory hypothesis posits that inflammation mediates the development of atherosclerotic plaque and its progression to myocardial infarction.[1] The role of inflammation in atherosclerosis is supported by previous data demonstrating higher incidence of cardiovascular events in patients with higher levels of inflammatory markers.[2][3] No evidence to date has demonstrated effective prevention of cardiovascular events with antiinflammatory therapy independent of lipid-lowering effects.

The Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) trial randomized 10,061 patients with previous MI and hsCRP ≥ 2mg/L in a 1:1:1:1.5 (placebo) ratio to one of three doses of canakinumab (a monoclonal antibody targeting interleukin-1β) or placebo. As compared with placebo, canakinumab reduced hsCRP level from baseline in a dose-dependent manner through 48 months, without reduction in the LDL-C level. At a median follow-up of 3.7 years, the 150-mg dose was associated with a 0.6% absolute reduction in the primary end point (composite of MI, stroke, or cardiovascular death), which was driven largely by the reduction in the incidence of MI. A comparable modest treatment benefit in a secondary end point that additionally included hospitalization for unstable angina requiring urgent revascularization was also observed in the 150-mg dose. In a pooled analysis, canakinumab groups were observed to have a 0.13% absolute increase in fatal infection.

The findings of CANTOS not only provide strong evidence in support of the inflammatory hypothesis of atherothrombosis, but also encouragingly demonstrate that this pathway is actionable and that reduction of inflammatory activity with canakinumab results in a reduction in cardiovascular events. However, given the modest effect size, lack of mortality benefit, and increased rate of fatal infection, the widespread use of canakinumab in patients at high risk for recurrent cardiovascular events with high inflammatory markers will likely need to wait until results are replicated and the risk-benefit tradeoff as well as cost-effectiveness are clarified.

The 2018 CIRT study was a related, NIH-funded trial run by the same group as CANTOS. CIRT randomized adults with CHD to methotrexate or placebo. It was closed early for lack of efficacy.

Guidelines

As of October 2017, no guidelines have been published that reflect the results of this trial.

Design

  • Randomized, double-blind, placebo-controlled, event-driven phase 3 trial
  • N=10,061 randomized in a 1:1:1:1.5 ratio
    • Canakinumab (n=6,717)
      • 50 mg (n=2,170)
      • 150 mg (n=2,284)
      • 300 mg (n=2,263)
    • Placebo (n=3,344)
  • Setting: 1,132 study locations in 40 countries in the US and abroad
  • Enrollment: 2011-2014
  • Median follow-up: 3.7 years
  • Analysis: Intention-to-treat
  • Primary outcome: Nonfatal myocardial infarction, any nonfatal stroke, or cardiovascular death

Population

Inclusion Criteria

  • Age ≥18 years
  • hsCRP ≥2 mg/L
  • MI in prior 30 days: History of clinical symptoms consistent with myocardial ischemia associated with elevation of cardiac biomarkers above the 99th percentile of the upper reference limit (preferably troponin) OR development of new pathological Q waves regardless of symptoms

Exclusion Criteria

  • Pregnancy or nursing women or women of child-bearing potential
  • Any of the following:
    • Planned coronary revascularization (PCI or CABG) or any other major surgical procedure
    • Major non-cardiac surgical or endoscopic procedure in the prior 6 months
    • Multi-vessel CABG surgery within the past 3 years
    • Qualifying MI is secondary to PCI or CABG
    • NYHA class IV HF
    • Uncontrolled hypertension (SBP >160 mmHg or DBP >100 mmHg at Visit 1 (these patients could be re-screened after modification of antihypertensive medications)
    • Uncontrolled diabetes
    • Nephrotic syndrome, eGFR <30 mL/min/1.73 m2, or kidney transplant
    • Liver disease
    • Prior malignancy other than basal cell skin carcinoma
  • Alcohol or substance abuse
  • Prior or current TB infection or any risk factors for TB, including:
    • High-risk residence (e.g., jail, homeless shelter, or chronic care facility), substance abuse, or health-care workers with unprotected exposure
    • Close contact with a person with TB in the prior 12 months
  • Immunocompromised state (e.g., advanced HIV or immunosuppressive medications)
  • Live vaccinations within 3 months prior to the randomization visit or live vaccinations planned during the trial
  • Hypersensitivity to study medications
  • Participation in another trial with an investigational drug in prior 30 days
  • Non-CVD life-limiting illness

Baseline Characteristics

  • Demographics: Age 61 years, female 25.7%
  • PMH: DM 40.0%, prior PCI 66.7%, prior CABG 14.0%
  • Medications: Antithrombotic agents 95.0%, lipid-lowering agents 93.4%, anti-ischemia agents 91.4%, renin-angiotensin inhibitors 79.7%
  • Labs: Median hsCRP 4.20 mg/L, median LDL cholesterol 82.4 mg/dL (2.13 mmol/L)

Interventions

  • Participants were randomized to a group:
  • Canakinumab - 1 of 3 doses:
    • Canakinumab 50 mg
    • Canakinumab 150 mg
    • Canakinumab 300 mg
  • Placebo
  • All doses of canakinumab and placebo were administered subcutaneously once every 3 months; for the 300 mg dose, the regimen was 300 mg every 2 weeks for the first two doses, then once every 3 months.
  • All participants received standard of care
  • Extension phase - Patients who participated in the extension phase remain on their pivotal phase blinded assigned treatment arm for the first three extension phase visits (Month 0 to Month 6). After the database from the pivotal study is locked they are switched to an open-label dose of 150 mg canakinumab at the fourth extension visit (Month 9).

Outcomes

Primary Outcome

Myocardial infarction, stroke, or cardiovascular death
Placebo: 4.50 per 100 person-yr
Canakinumab 50 mg: 4.11 per 100 person-yr (HR 0.93; 95% CI 0.80–1.07; P=0.30 [> threshold P=0.02115])
Canakinumab 150 mg: 3.86 per 100 person-yr (HR 0.85; 95% CI 0.74–0.98; P=0.02075 [< threshold P=0.02115])
Canakinumab 300 mg: 3.90 per 100 person-yr (HR 0.86; 95% CI 0.75–0.99; P=0.0314 [> threshold P=0.01058])

Secondary Outcomes

Myocardial infarction, stroke, hospitalization for unstable angina that led to unplanned revascularization, or cardiovascular death
Placebo: 5.13 per 100 person-yr
Canakinumab 50 mg: 4.56 per 100 person-yr (HR 0.90; 95% CI 0.78–1.03; P=0.12)
Canakinumab 150 mg: 4.29 per 100 person-yr (HR 0.83; 95% CI 0.73–0.95; P=0.00525 [< threshold P=0.00529])
Canakinumab 300 mg: 4.25 per 100 person-yr (HR 0.83; 95% CI 0.72–0.94; P=0.004)
Myocardial infarction, stroke, or death from any cause
Placebo: 5.56 per 100 person-yr
Canakinumab 50 mg: 5.17 per 100 person-yr (HR 0.94; 95% CI 0.83–1.07; P=0.35)
Canakinumab 150 mg: 4.77 per 100 person-yr (HR 0.85; 95% CI 0.75–0.96; P=0.01)
Canakinumab 300 mg: 4.88 per 100 person-yr (HR 0.87; 95% CI 0.77–0.99; P=0.03)
Myocardial infarction
Placebo: 2.43 per 100 person-yr
Canakinumab 50 mg: 2.20 per 100 person-yr (HR 0.94; 95% CI 0.78–1.15; P=0.56)
Canakinumab 150 mg: 1.90 per 100 person-yr (HR 0.76; 95% CI 0.62–0.92; P=0.005)
Canakinumab 300 mg: 2.09 per 100 person-yr (HR 0.84; 95% CI 0.70–1.02; P=0.07)
Stroke
Placebo: 0.74 per 100 person-yr
Canakinumab 50 mg: 0.73 per 100 person-yr (HR 1.01; 95% CI 0.72–1.41; P=0.95)
Canakinumab 150 mg: 0.74 per 100 person-yr (HR 0.98; 95% CI 0.71–1.35; P=0.91)
Canakinumab 300 mg: 0.60 per 100 person-yr (HR 0.80; 95% CI 0.57–1.13; P=0.20)
Hospitalization for unstable angina that led to unplanned revascularization
Placebo: 0.69 per 100 person-yr
Canakinumab 50 mg: 0.48 per 100 person-yr (HR 0.70; 95% CI 0.47–1.03; P=0.07)
Canakinumab 150 mg: 0.44 per 100 person-yr (HR 0.64; 95% CI 0.44–0.94; P=0.02)
Canakinumab 300 mg: 0.40 per 100 person-yr (HR 0.58; 95% CI 0.39–0.86; P=0.006)
Cardiovascular death
Placebo: 1.44 per 100 person-yr
Canakinumab 50 mg: 1.18 per 100 person-yr (HR 0.80; 95% CI 0.62–1.03; P=0.083)
Canakinumab 150 mg: 1.26 per 100 person-yr (HR 0.88; 95% CI 0.70–1.12; P=0.30)
Canakinumab 300 mg: 1.33 per 100 person-yr (HR 0.93; 95% CI 0.75–1.18; P=0.55)
Death from any cause
Placebo: 2.97 per 100 person-yr
Canakinumab 50 mg: 2.85 per 100 person-yr (HR 0.94; 95% CI 0.80–1.11; P=0.48)
Canakinumab 150 mg: 2.73 per 100 person-yr (HR 0.92; 95% CI 0.78–1.09; P=0.33)
Canakinumab 300 mg: 2.76 per 100 person-yr (HR 0.94; 95% CI 0.80–1.10; P=0.42)
Median change in hsCRP from baseline at 48 months
Placebo: -17.1%
Canakinumab 50 mg: -43.4% (P<0.001)
Canakinumab 150 mg: -54.1% (P<0.001)
Canakinumab 300 mg: -57.8% (P<0.001)
Median change in IL-6 from baseline at 12 months
Placebo: 3.49%
Canakinumab 50 mg: -19.1% (P<0.001)
Canakinumab 150 mg: -33.8% (P<0.001)
Canakinumab 300 mg: -37.7% (P<0.001)
Median change in LDL-C from baseline at 48 months
Placebo: -1.4%
Canakinumab 50 mg: 0.0% (P=0.19)
Canakinumab 150 mg: 1.7% (P=0.004)
Canakinumab 300 mg: -2.8% (P=0.67)
Median change in HDL-C from baseline at 48 months
Placebo: -2.25%
Canakinumab 50 mg: 0.00% (P=0.008)
Canakinumab 150 mg: 0.00% (P<0.001)
Canakinumab 300 mg: 0.00% (P<0.001)
Median change in TG from baseline at 48 months
Placebo: -3.2%
Canakinumab 50 mg: 1.7% (P=0.026)
Canakinumab 150 mg: 7.5% (P<0.001)
Canakinumab 300 mg: 2.3% (P=0.021)

Adverse Events

Serious adverse event
Placebo: 11.96 per 100 person-yr
Canakinumab all doses: 11.82 per 100 person-yr (P=0.79)
Serious adverse event of infection
Placebo: 2.86 per 100 person-yr
Canakinumab all doses: 3.14 per 100 person-yr (P=0.14)
Fatal infection or sepsis
Placebo: 0.18 per 100 person-yr
Canakinumab all doses: 0.31 per 100 person-yr (P=0.02)
Cancer
Placebo: 1.88 per 100 person-yr
Canakinumab all doses: 1.75 per 100 person-yr (P=0.38)
Fatal cancer
Placebo: 0.64 per 100 person-yr
Canakinumab all doses: 0.45 per 100 person-yr (P=0.02)

Criticisms

  • Over 40% of recruited patients were excluded from the trial (most commonly due to low hsCRP but 35% of excluded patients due to concomitant illness or TB risk), limiting generalizability
  • Very modest treatment effect raises question of clinical significance
  • Given very similar treatment effect and borderline statistical significance of the 300mg dose for the primary endpoint, the ideal dose (150mg vs. 300mg) of canakinumab in this population remains unclear

Funding

This investigator-driven clinical trial was sponsored by Novartis. The sponsor was responsible for data collection.

Further Reading

  1. Ross R. "Atherosclerosis–an inflammatory disease." The New England Journal of Medicine. 1999;340:115-126.
  2. Ridker PM et al. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N. Engl. J. Med. 1997. 336:973-9.
  3. Ridker PM et al. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N. Engl. J. Med. 2000. 342:836-43.