To investigate the effects of early upstream antithrombotic therapy administration (ATTA) in ST‐segment elevation myocardial infarction (STEMI) patients with prolonged transport times to primary percutaneous intervention (PPCI) on major clinical outcomes.

It remains unclear whether early upstream administration of aspirin, ticagrelor, and unfractionated heparin (UFH) confers additional benefits compared with in‐hospital administration.

Between 2015 and 2018, we performed PPCI in 709 included consecutive STEMI patients. We compared 482 STEMI patients who received aspirin, ticagrelor, and UFH loading in a non‐PCI capable spoke hospital before transfer (NPHT) versus 227 prehospital triage setting (PTS) STEMI patients who received in‐ambulance aspirin, followed by ticagrelor and UFH in the hub catheterization laboratory. The primary outcome was the presence of a pre‐PPCI TIMI flow 2–3 in the infarct related artery (IRA). The secondary outcomes included definite acute stent thrombosis and hemorrhagic complications.

The median times from ticagrelor and heparin administration to angiography in the NPHT group and the PTS group were 80.5 min (Interquartile Range (IQR) 68.5–94) and 10 min (IQR 5–15) respectively (p < .0001). Using inverse probability of treatment weighting to minimize heterogeneity between groups, we showed significant differences for the primary outcome (44.6 versus 18.5%, p < .0001) and for definite acute stent thrombosis (0.6 versus 2.6%, p = .03), with no difference in the combined in‐hospital BARC 2–5 bleeding events (1.9 versus 3.5%, p = .18) in the NPHT versus the PTS group, respectively.

In this single‐center retrospective cohort study, after adjusting for baseline covariates, early upstream ATTA with aspirin, ticagrelor, and UFH was associated with greater pre‐PPCI TIMI flow and less definite acute stent thrombosis in STEMI patients, without increased bleeding risk.