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 (STEMI) 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 five 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) vs. -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. .