Cardiovascular Inflammation Reduction Trial - CIRT

Contribution To Literature:

The CIRT trial showed that low-dose methotrexate does not reduce IL-1β, IL-6, hsCRP, or CV events compared with placebo among patients with established CAD and either DM or metabolic syndrome or both.


The goal of the trial was to assess the safety and benefit of using low-dose methotrexate among patients with stable coronary artery disease (CAD) and either diabetes mellitus (DM) or metabolic syndrome or both.

Study Design

Eligible patients were randomized in a 1:1 fashion to either low-dose methotrexate 15-20 mg weekly (n = 1,716) or placebo (n = 1,695). All patients received folic acid 1 mg. The dose of methotrexate was adjusted based on labs and symptoms.   

Inclusion criteria:

  • Aged ≥18 years
  • Have suffered a documented myocardial infarction (MI) or have multivessel CAD on an angiogram at any time in the past
  • Have completed any planned coronary revascularization procedures associated with the qualifying event
  • Have been on a stable secondary prevention regimen for a minimum of 60 days
  • Have either type 2 DM or metabolic syndrome
  • No contraindication to low-dose methotrexate (American College of Rheumatology 2010 guidelines)
  • Total number of enrollees: 4,786
  • Duration of follow-up: 4 years
  • Mean patient age: 66 years
  • Percentage female: 19%

Other salient features/characteristics:

  • Prior MI: 60.8%, multivessel CAD: 39.2%
  • DM: 34%, metabolic syndrome: 32%, both DM and metabolic syndrome: 34%
  • Low-density lipoprotein: 68 mg/dl, high-density lipoprotein: 41 mg/dl
  • High-sensitivity C-reactive protein (hsCRP): 1.5 mg/L

Principal Findings:

The primary outcome of major adverse cardiac events (MACE), for low-dose methotrexate vs. control, was 3.4/100 person-years vs. 3.4/100 person-years, hazard ratio 1.01, 95% confidence interval 0.82-1.25, p = 0.91.

MACE plus hospitalization for unstable angina requiring unplanned revascularization was 4.1% vs. 4.3%, p = 0.67.

Secondary outcomes, for methotrexate vs. control:

  • Methotrexate increased ALT, AST and reduced white blood cell count, hematocrit, and hemoglobin levels, but did not affect interleukin(IL)-1β, IL-6, or hsCRP
  • All-cause mortality: 1.8% vs. 1.6%, p = 0.32
  • HF hospitalization: 0.95% vs. 1.06%, p = 0.54
  • MI: 2.3% vs. 2.3%, p = 0.95
  • Any infection: 62.4% vs. 56.0%, p = 0.004


The results of this trial indicate that low-dose methotrexate did not reduce IL-1β, IL-6, hsCRP, or CV events compared with placebo among patients with established CAD and either diabetes or metabolic syndrome or both. Despite using a low dose, patients receiving methotrexate had a higher incidence of side effects such as transaminitis, leucopenia, anemia, and infections.

Unlike CANTOS, this trial did not mandate high residual inflammation among enrolled patients. Canakinumab significantly reduced IL-1β, IL-6, and hsCRP in the CANTOS trial, and demonstrated a CV benefit independent of lipid lowering. Future trials focusing on the role of anti-inflammatory agents on CV events will need to ensure that the right pathway(s) are selected as targets.


Ridker PM, Everett BM, Pradhan A, et al., on behalf of the CIRT Investigators. Low-Dose Methotrexate for the Prevention of Atherosclerotic Events. N Engl J Med 2019;380:752-62.

Presented by Dr. Paul M. Ridker at the American Heart Association Annual Scientific Sessions (AHA 2018), Chicago, IL, November 10, 2018.

Clinical Topics: Diabetes and Cardiometabolic Disease, Prevention, Atherosclerotic Disease (CAD/PAD)

Keywords: AHA Annual Scientific Sessions, AHA18, Angina, Unstable, Atherosclerosis, Coronary Artery Disease, C-Reactive Protein, Diabetes Mellitus, Type 2, Inflammation, Metabolic Syndrome, Methotrexate, Myocardial Infarction, Interleukin 1 Receptor Antagonist Protein, Primary Prevention, Secondary Prevention

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