Abstract
BACKGROUND: Inflammation plays a central role in the pathophysiology of ST-elevation myocardial infarction (STEMI), being associated with larger infarct size (IS) and worse left ventricular remodeling (LVR). Methotrexate (MTX) is a potent anti-inflammatory drug with potential benefits in the treatment of STEMI. Experimental studies have suggested that a formulation of MTX incorporated into lipid nanoemulsion (LDE-MTX) could be beneficial and safe. OBJECTIVES: To evaluate the efficacy and safety of LDE-MTX in patients with STEMI. METHODS: Randomized, double-blinded, placebo-controlled, proof-of-concept study. Patients were randomized 4 ± 2 days after first anterior STEMI to receive LDE-MTX (40 mg/m(2) intravenous infusion) or LDE-placebo weekly for 6 weeks. The primary efficacy endpoint was left ventricle end-diastolic volume (LVEDV) assessed by cardiac magnetic resonance at 90 ± 7 days post-randomization; the main secondary endpoints were changes in LVEDV, other LVR parameters and IS. RESULTS: Due to the COVID-19 pandemic the study was stopped prematurely, with 32 randomized patients (15 LDE-placebo, 17 LDE-MTX) completing the protocol. At 90 days, there was no difference in LVEDV between groups. Among other secondary endpoints, there appeared to be a greater reduction of IS (%LV) in favor of the LDE-MTX group (-3.9 ± 6.9 vs -9.4 ± 8.4, p = 0.030). LDE-MTX was well tolerated. CONCLUSIONS: In patients with STEMI, LDE-MTX appears to be safe but did not influence LVEDV and other LVR parameters, although it possibly reduced infarct size at 90 days. These hypothesis-generating results support further investigation of a novel nanomedicine approach to STEMI in larger trials.