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.

Description:

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

Interpretation:

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.

References:

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 2018;Nov 10:[Epub ahead of print].

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 X, Methotrexate, Myocardial Infarction, Interleukin 1 Receptor Antagonist Protein, Primary Prevention, Secondary Prevention


< Back to Listings