AHA 2018 — Low-dose methotrexate does not confer preventive benefit in atherosclerosis

  • Hao Cheng, MD
  • Conference Reports
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  • Low-dose methotrexate confers no benefit to cardiac events for patients with stable atherosclerotic disease.

Why this matters

  • Inflammation is causally related to atherothrombosis.
  • Canakinumab, a monoclonal antibody, resulted in a lower rate of cardiovascular events than placebo in a previous randomized trial (CANTOS).
  • This study determines whether low-dose methotrexate confers a similar benefit.

Study design

  • Randomized, double-blind trial of low-dose methotrexate (at a target dose of 15-20 mg weekly) vs placebo.
  • Patients were included if they had previous myocardial infarction or multivessel coronary disease who additionally had either type 2 diabetes or the metabolic syndrome.
  • Primary endpoints were a composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death as well as hospitalization for unstable angina that led to urgent revascularization.

Key results

  • 4786 patients were randomly assigned with a median follow-up of 2.3 years.
  • Methotrexate did not result in lower interleukin-1β, interleukin-6, or C-reactive protein levels than placebo.
  • The original primary endpoint occurred in 170 patients in the methotrexate group and in 167 in the placebo group (incidence rate, 3.46 vs 3.43 per 100 person-years; HR [CI 95%] = 1.01 [0.82-1.25]).
  • Methotrexate was associated with:
    • Elevations in liver-enzyme levels, P<.001.>
    • Reductions in leukocyte counts and hematocrit levels, P<.001.>
    • Higher incidence of non–basal-cell skin cancers, P=.002.


  • Lower inflammatory markers compared with CANTOS study.

Expert comment

  • "How could these two studies [CIRT and CANTOS] be different? Well . . . the HsCRP (inflammatory risk) in CIRT is 1.5 mg. In CANTOS, it's 4.2 mg... In addition, the mean LDL-C was reduced to 68 mg/dL in CIRT whereas the group in CANTOS had a mean of 82 mg/dL. So the group in CANTOS is arguably higher risk and has a greater presence of [inflammation]."  Sidney C. Smith, Jr., MD, Professor of Medicine, University of North Carolina.