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The best combination of access site and anticoagulant used during primary percutaneous coronary intervention (PCI) in patients presenting with ST segment elevation myocardial infarction is not known.We conducted a retrospective cohort study of all patients >18 years of age who underwent primary PCI in 2 large regional ST segment elevation myocardial infarction centers in Massachusetts between 2012 and 2014. The cohort was divided into 3 groups: bival/fem, hep/rad, or off-protocol, based on anticoagulation and access used. We used multiple logistic regression model to compare major cardiovascular events—major adverse cardiovascular events (MACE) and bleeding complications between the 2 on-protocol groups (bival/fem and hep/rad).Of the 1074 patients in this study, there were 443 (41%), 501 (47%), and 130 (12%) patients in bival/fem, hep/rad, and off-protocol groups, respectively. There were significantly higher number of cardiogenic shock patients in the bival/fem compared to the hep/rad group (6.5% vs. 3.0%, P < 0.001). There was a trend toward reduced MACE in the hep/rad group compared to bival/fem (2.8 % vs. 5.1%, P = 0.068). When cardiogenic shock patients are excluded, there is no significant difference in mortality rates (bival/fem: 2.7% vs. hep/rad: 1.0%, P = 0.07) or bleeding complications between the groups (hep/rad: 4.5% vs. bival/fem: 2.1%, P = 0.06).In patients undergoing primary PCI, there was a trend toward reduced inpatient MACE with the use of heparin and radial access compared with bivalirudin with femoral access. In patients without cardiogenic shock, there is no significant difference in mortality or bleeding rates between the 2 groups.