CIRT

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Ridker PM, et al. "Low-dose methotrexate for the prevention of atherosclerotic events". The New England Journal of Medicine. 2018. epub 2018-11-10:1-11.
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Clinical Question

In patients with established atherosclerotic heart disease (previous MI or multivessel coronary disease plus either type 2 diabetes or metabolic syndrome), does low-dose methotrexate reduce cardiac events compared to placebo?

Bottom Line

In patients with established atherosclerotic heart disease (previous MI or multivessel coronary disease plus either type 2 diabetes or metabolic syndrome), low-dose methotrexate failed to reduce the primary endpoint of nonfatal MI, nonfatal stroke, hospitalization for unstable angina leading to revascularization, or cardiovascular death after 2.3 years.

Major Points

Inflammation has been shown to be a causal factor in the progression of atherosclerotic heart disease. In the CANTOS trial, selective inhibition of Interleukin-1B, a potent activator of innate immunity, with the monoclonal antibody canakinumab led to a reduction in cardiovascular events among patients with a history of MI and residually elevated c-reactive protein without exerting significant effects on lipid levels or blood pressure. However, widespread utilization of canakinumab remains limited by high cost and lack of experience with clinical use. In contrast, methotrexate is a low-cost, widely-utilized immunosuppressant with a long track record of safe use among patients with rheumatic disease, representing a possible alternative method of achieving modulation of inflammation to reduce cardiovascular events in patients with established atherosclerotic heart disease.

The 2018 Cardiovascular Inflammation Reduction Trial (CIRT) trial randomized 4,786 patients with either low-dose methotrexate (15-20MG once weekly) or placebo. At median 2.3 years (after termination of the study early for lack of efficacy), there was no difference in the primary endpoint of nonfatal MI, nonfatal stroke, hospitalization for unstable angina leading to revascularization, or cardiovascular death (4.13 per 100 person-years with methotrexate versus 4.31 per 100 person-years with placebo). At 8 months, there was no noticeable reduction from baseline in inflammatory markers including c-reactive protein, interleukin-1B, or interleukin 6 with methotrexate therapy. There was a modest increase in the incidence of cytopenias, elevated liver function tests, and non-basal cell skin cancers in patients randomized to methotrexate.

In summary, the CIRT trial suggests no benefit to the use of low-dose methotrexate in patients with established atherosclerotic heart disease, and rather a modest but significant increase in adverse effects including non-basal cell skin cancers. Of note, in contrast to CANTOS, enrollment in CIRT did not require a residually elevated c-reactive protein level, and the median level at enrollment was relatively low at 1.6mg/L; thus, lack of benefit may have been related to enrollment of patients with limited inflammatory activity to target. Given lack of significant reduction in surrogate markers for inflammatory activity with methotrexate, there also remains the possibility that a more effective dose may have had benefit, although this would require further dedicated study. Alternatively, it is possible that the downstream targets of methotrexate are simply not critical to the inflammatory component of atherosclerotic disease progression.

Guidelines

As of November 2018, no guidelines have been published that reflect the results of this trial.

Design

  • Multicenter, randomized, double-blind, placebo-controlled
  • N=4786
    • Low-dose methotrexate (N=2391)
    • Placebo (N=2395)
  • Setting: 417 centers in North America
  • Enrollment: April 4, 2013 - March 13, 2018
  • Median follow-up: 2.3 years
  • Analysis: Intention-to-treat
  • Primary Outcome: Nonfatal MI, nonfatal stroke, hospitalization for unstable angina leading to revascularization, cardiovascular death

Population

Inclusion Criteria

  • Age ≥ 18 years
  • Myocardial infarction in the past and/or multivessel coronary disease by angiography
  • Type 2 diabetes and/or metabolic syndrome
  • Completed all planned revascularization procedures
  • Medically stable for 60 days from index MI, surgical procedure or other significant illness

Exclusion Criteria

  • Chronic liver disease
  • Chronic inflammatory condition such as lupus or rheumatoid arthritis, ulcerative colitis, or Crohn's disease
  • Chronic infectious disease
  • Interstitial lung disease or pulmonary fibrosis
  • Myeloproliferative disease in the past 5 years
  • HIV positive
  • Requirement or intolerance to methotrexate
  • History of non-basal cell malignancy or treatment for lymphoproliferative disease within 5 years
  • Requirement for use of drugs that alter folate metabolism
  • History of alcohol abuse or unwillingness to limit consumption to less than 4 drinks per week
  • Women of childbearing potential (even if using oral contraception) or intention to breastfeed
  • Men who plan to father children during the study period or are unwilling to use contraception
  • Life expectancy < 3 years or unlikely to comply in judgment of investigator
  • Chronic use of oral or IV steroid therapy or other immunosuppressive or biologic response modifiers
  • History of hepatitis B or C
  • Chronic pericardial effusion, pleural effusion, or ascites
  • NYHA class IV heart failure

Baseline Characteristics

From the placebo group.

  • Demographics: Age 66.0 years, female 18.2%, nonwhite 20.9%
  • Comorbidities: smoker 11.3%, BMI 31.3, HTN 90.6%, hx MI 60.9%, multivessel coronary disease 39.1%, DM 34.4%, metabolic syndrome 32.6%, CHF 13.9%, hx PCI 59.3%, hx CABG 43.1%, family history of premature CAD 25.3%
  • Medications: ACEi/ARB 72.0%, statin 85.7%, beta blocker 79.5%, antiplatelet 85.8%
  • Biomarkers: Total cholesterol 140.9, LDL 68.0, HDL 41.0, hsCRP 1.50, IL-1B 1.46, IL-6 2.30, a1c 6.5

Interventions

  • Patients randomized 1:1 to low-dose methotrexate or matching placebo
  • Eligible patients underwent open-label run-in phase lasting 5-8 weeks during which they received 1mg oral folic acid daily, along with oral methotrexate once weekly in doses increasing sequentially from 5MG to 10MG to 15MG.
    • Patients who experienced adverse effects or laboratory abnormalities during the run-in phase were excluded
    • Patients who tolerated 15MG dose without adverse effects or laboratory abnormalities for two consecutive weeks proceeded to randomization
  • Randomized stratified by site, type of index event, time since index event, and status with respect to risk factors
  • All patients took folic acid 1MG daily
  • At 4 months, dose of study drug was increased to 20MG weekly (or matching placebo)
  • A computerized algorithm (based on levels of centrally measured laboratory values and reported symptoms, assessed every 2 months) was used to adjust the dose of study drug in a standardized manner

Outcomes

Comparisons are low-dose methotrexate versus placebo

Primary Outcomes

Nonfatal MI, nonfatal stroke, hospitalization for unstable angina requiring revascularization
201 (4.13%) vs. 207 (4.31%); HR 0.96 (95% CI 0.79-1.16); p = 0.67

Secondary Outcomes

Death from any cause
96 (1.80%) vs. 83 (1.55%); HR 1.16 (95% CI 0.87-1.56)
Primary outcome or any coronary revascularization
278 (5.86%) vs. 288 (6.15%); HR 0.95 (95% CI 0.81-1.12)
Hospitalization for congestive heart failure
48 (0.95%) vs. 53 (1.06%); HR 1.06 (95% CI 0.60-1.31)
Nonfatal MI
113 (2.29%) vs. 114 (2.32%); HR 0.99 (95% CI 0.76-1.29)

Safety Outcomes

Serious adverse event
569 (13.5/100 person-yr) vs. 549 (13.0/100 person-yr); p = 0.52
Any cancer
52 (1.03/100 person-yr) vs. 30 (0.60/100 person-yr); p = 0.02
Elevated ALT
49 (0.97/100 person-yr) vs. 17 (0.34/100 person-yr); p < 0.001
Leukopenia
241 (5.14/100 person-yr) vs. 172 (3.63/100 person-yr); p < 0.001

Subgroup Analyses

  • There were no significant interactions according to type of index event, time since index event, status with respect to diabetes or the metabolic syndrome at the time of enrollment, time spent enrolled in the trial, or levels of baseline high-sensitivity c-reactive protein

Criticisms

  • Run-in phase lasting 5-8 weeks reduces generalizability, as only patients who are known to tolerate methotrexate initiation were included in the study
  • Lack of decrease in inflammatory markers at 8 months with the administered dose of methotrexate does not exclude the possibility that a more effective dose may result in achievement of suppression of inflammatory activity and reduction in cardiovascular outcomes
  • Unlike CANTOS, there was no requirement for elevated inflammatory markers at study entry, and thus median hsCRP at enrollment was low (1.6mg/L versus 4.2mg/L in CANTOS). Thus, lack of residual inflammatory activity in many enrolled patients may have contributed to lack of observed effect with methotrexate.

Funding

  • Study supported by the NHLBI

Further Reading