CANTOS - Canakinumab for patients with previous MI

in ,

Ridker PM, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. NEJM 2017

Bottom line:

  • In patients with prior MI & hsCRP >2 mg/L, canakinumab reduced the risk of non-fatal coronary events (NNT ~160/year), but increased the risk of fatal infections (NNH ~1000/year).

  • Due to unresolved issues of cost & feasibility of use of this therapy, CANTOS has limited direct applicability to real-world practice, but serves as a proof of concept for anti-inflammatory therapy to reduce the risk of ASCVD.

 

Patients (n=10,061 after 17,482 were screened)

  • Included
    • Hx of MI
    • High-sensitivity CRP 2 mg/L or higher
  • Exclusion
    • Hx of chronic/recurrent infection
    • Previous CA
    • Known/suspected immunocompromised
    • Hx/high risk of TB or HIV-related disease
    • Ongoing use of other systemic anti-inflammatory tx
  • Baseline characteristics
    • 61 y
    • Female 26%
    • STEMI 54%, NSTEMI 34%, unknown 12%
    • Previous PCI 66%, CABG 14%
    • HF 22%
    • CV risk factors: Smoker 23%, HTN ~80%, diabetes ~40%
    • Labs
      • Median hsCRP 4.2 mg/L
      • LDL-C 2.1 mmol/L
    • Meds
      • ACEI/ARB ~80%
      • Anti-ischemic therapy 92%
      • Statin ~90%

Interventions

  • Interventions: Canakinumab 50 mg, 150 mg or 300 mg subcutaneously q3 months
    • 300 mg dose group: 300 mg q2 weeks x2 doses, then q3 months
  • Control: Matching placebo
     

Results @ median 3.7 years

Labs

  • hsCRP reduction: 50 mg (26%), 150 mg (37%), 300 mg (41%)
  • LDL, HDL: No effect

Efficacy

  • Primary outcome (CV death, MI or stroke):
    • Canakinumab 150 mg: 14.0% over follow-up (incidence rate: 3.86 per 100 patient-years)
    • Placebo: 16.0% over follow-up (incidence rate: 4.50 per 100 patient-years)
    • HR 0.85 (0.74-0.98), NNT 50 (NNT ~160/y)
  • Secondary efficacy outcome (primary + unstable angina hospitalization leading to unplanned revascularization):
    • Canakinumab 150 mg: 4.29 per 100 patient-years
    • Placebo: 5.13 per 100 patient-years
    • HR 0.83 (0.73-0.95)
  • Death: Canakinumab 150 mg 2.73/100 pt-y, placebo 2.97/100 pt-y, HR 0.92 (0.78-1.09)
  • MI: Canakinumab 150 mg 1.90/100 pt-y, placebo 2.43/100 pt-y, HR 0.76 (0.62-0.92)
  • Stroke: HR 0.98 (0.71-1.35)
  • Revascularization: Canakinumab 150 2.49/100 pt-y, placebo 3.61/100 pt-y, HR 0.68 (0.58-0.81)
  • Note: For brevity, I only include the efficacy data for the 150-mg dose here (50 mg generally ineffective/less effective, & 300 mg similar to 150 mg)

Safety/tolerance

  • Discontinued study drug: Canakinumab 18.7%, placebo 18.1%
  • Serious adverse events: Canakinumab 11.8/100 pt-y, placebo 12/100 pt-y, p=0.79
  • Serious adverse event from infection: Canakinumab 3.1/100 pt-y, placebo 2.9/100 pt-y, p=0.14
  • Fatal infection or sepsis: Canakinumab 0.3/1000 pt-y, placebo 0.2/100 pt-y, p=0.02

Considerations

  • Low risk of bias
    • Central, computerized randomization (allocation concealed)
    • Participants, clinicians & investigators blinded
    • 0.3% lost to follow-up
  • Generalizability
    • Eligibility criteria for this trial are broad (any prior MI + hsCRP >2 mg/L) & primarily excluded patients at high risk of adverse effects of immunosuppressive therapy, though enrolled patients had a relatively high risk of ASCVD (~4%/year in the placebo group)
  • Currently, canakinumab is approved under the organ drug status for rare diseases, & is priced at $200,000/year (US price in USD)