The Effects of METhotrexate Therapy on the Physical Capacity of Patients With ISchemic Heart Failure: A Randomized Double-Blind, Placebo-Controlled Trial (METIS Trial)

Abstract

Background The cytokine hypothesis suggests that there is an association between chronic heart failure (CHF) and inflammation. Methotrexate could improve CHF patients' clinical status, especially those with ischemic etiology. Methods and Results METIS is a randomized, double-blinded trial studying 50 patients with ischemic CHF given methotrexate (7.5 mg) or placebo, plus folic acid (5 mg), for 12 weeks. The primary end point was the difference in 6-minute walk test (6MWT) distance before and after treatment. We also evaluated functional class (NYHA), Short-Form 36 protocol quality of life, C-reactive protein (CRP), incidence of adverse effects, and the combined incidence of death, myocardial infarction, stroke, hospitalization, and need for myocardial revascularization. There was no significant difference between groups in distance covered in the 6MWT: the methotrexate group improved by 24.5 ± 39.5 m, the placebo group by 21.3 ± 43.7 m ( P = .80). The NYHA scores improved in 66.7% of the methotrexate group patients and in 50.0% of the placebo group ( P = .2). SF-36 scores indicated improved mental health in the placebo group. There were no significant differences in CRP levels, the combined outcome, or adverse events. Conclusions These results show that the methotrexate group tended toward improved NYHA scores and that there were no significant changes in 6MWT results or secondary assessments.