- Question
- Does inhibiting inflammation with low-dose methotrexate, as an alternative to interleukin-1β blockade with canakinumab, reduce atherosclerotic cardiovascular events?
- Design
- Randomized, double-blind, placebo-controlled, event-driven trial of 4786 patients, funded by the NHLBI. It was stopped after a median follow-up of 2.3 years.
- Population
- Patients with previous myocardial infarction or multivessel coronary disease who also had type 2 diabetes or the metabolic syndrome.
- Intervention
- Oral low-dose methotrexate (target dose of 15 to 20 mg weekly) plus 1 mg of folate daily.
- Control
- Matching placebo given once weekly, also with 1 mg of folate daily.
- Primary outcome
- Composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death; near the end of the trial, before unblinding, hospitalization for unstable angina leading to urgent revascularization was added.
- Results
- The final primary end point occurred in 201 patients on methotrexate and 207 on placebo (HR 0.96; 95% CI 0.79 to 1.16). The original primary end point occurred in 170 vs. 167 patients (HR 1.01; 95% CI 0.82 to 1.25). Methotrexate did not lower interleukin-1β, interleukin-6, or C-reactive protein levels compared with placebo.
- Safety
- Methotrexate was associated with elevated liver-enzyme levels, reduced leukocyte counts and hematocrit levels, and a higher incidence of non-basal-cell skin cancers than placebo.
- Conclusion
- In patients with stable atherosclerosis, low-dose methotrexate did not reduce inflammatory markers or cardiovascular events compared with placebo.
- Why it matters
- The result showed that not every anti-inflammatory strategy lowers cardiovascular risk and that low-dose methotrexate is not an option for preventing atherosclerotic events, unlike what was seen with selective interleukin-1β blockade.
Card generated automatically with AI from the abstract of the original publication and the trial registry; every figure was checked against those sources. It may contain errors: verify the data at the source before using it for clinical decisions.
Generated on October 14, 2026