Background and objectiveAlthough recommended for the treatment of acute heart failure (AHF), the use of intravenous (IV) nitroglycerin (NTG) is supported by scarce and contradicting evidence. In the current analysis, we have assessed the impact of IV NTG administration by EMS or in emergency department (ED) on outcomes of AHF patients. MethodsWe analyze AHF patients included by 45 hospitals that were delivered to ED by EMS. Patients were grouped according to whether treatment with IV NTG was started by EMS before ED admission (preED-NTG), during the ED stay (ED-NTG) or were untreated with IV NTG (no-NTG, control group). In-hospital, 30-day and 365-day all-cause mortality, prolonged hospitalization (>7 days) and 90-day post-discharge combined adverse events (ED revisit, hospitalization or death) were compared in EMS-NTG and ED-NTG respect to control group. ResultsWe included 8424 patients: preED-NTG = 292 (3.5%), ED-NTG = 1159 (13.8%) and no-NTG = 6973 (82.7%). preED-NTG group had the most severely decompensated cases of AHF (p < 0.001) but it had lower in-hospital (OR = 0.724, 95%CI = 0.459–1.114), 30-day (HR = 0.818, 0.576–1.163) and 365-day mortality (HR = 0.692, 0.551-0.869) and 90-day post-discharge events (HR = 0.795, 0.643–0.984) than control group. ED-NTG group had mortalities similar to control group (in-hospital: OR = 1.164, 0.936–1.448; 30-day: HR = 0.980, 0.819–1.174; 365-day: HR = 0.929, 0.830–1.039) but significantly decreased 90-day post-discharge events (HR = 0.870, 0.780–0.970). Prolonged hospitalization rate did not differ among groups. Five different analyses confirmed these findings. ConclusionsEarly prehospital IV NTG administration was associated with lower mortality and post-discharge events, while IV NTG initiated in ED only improved post-discharge event rate. Further studies are needed to assess the role of early prehospital administration of IV NTG to patients with AHF.