Long-Term Effects of Methotrexate on Cardiovascular Outcomes and Left Ventricular Function in ST-Segment Elevation Myocardial Infarction: A Five-Year Follow-Up of the TETHYS Trial

INTRODUCTION: Inflammation plays a central role in myocardial infarction (MI) and subsequent cardiac remodeling. The TETHYS study assessed the long-term effects of methotrexate (MTX) in ST-segment elevation MI patients, focusing on ventricular function and major cardiovascular events. METHODS: This was a prospective, observational follow-up study of 81 patients from the TETHYS trial, randomized to receive either MTX or placebo. The primary objective was to evaluate the long-term effects of MTX on cardiovascular outcomes using a win ratio (WR) approach, including death, reinfarction, stroke, rehospitalization, and the difference in left ventricular ejection fraction (LVEF) at 5 years. The secondary objective was to assess LVEF improvement after 180 days. A WR analysis was performed to assess cardiovascular outcomes. LVEF changes over time were analyzed using ANCOVA for repeated measures. Statistical significance was set at p < 0.05. RESULTS: MTX treatment resulted in significantly fewer wins in the WR analysis compared to placebo (WR 0.56, 95% CI: 0.34-0.93, p = 0.026). There was no significant difference in LVEF trajectory over time (p = 0.308). However, MTX showed a significant improvement in LVEF when comparing 180 days to 3 months: 0.009% (MTX) versus -0.105% (placebo), p = 0.020. CONCLUSIONS: MTX did not improve long-term cardiovascular outcomes and was associated with more adverse events compared to placebo. No significant differences were found in LVEF trajectory over time. A transient improvement in LVEF was observed at 180 days but did not translate to better long-term outcomes.