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Current guidelines recommend prasugrel hydrochloride and ticagrelor hydrochloride as preferred therapies for patients with acute coronary syndrome (ACS) treated with percutaneous coronary intervention (PCI). However, it is not well known how frequently these newer agents are being used in clinical practice or how adherence varies among the platelet adenosine diphosphate P2Y12 receptor (P2Y12) inhibitors.To determine trends in use of the different P2Y12 inhibitors in patients who underwent PCI from 2008 to 2016 in a large cohort of commercially insured patients and differences in patient adherence and costs among the P2Y12 inhibitors.A retrospective cohort study used administrative claims from a large US national insurer (ie, UnitedHealthcare) from January 1, 2008, to December 1, 2016, comprising patients aged 18 to 64 years hospitalized for PCI who had not received a P2Y12 inhibitor for 90 days preceding PCI. The P2Y12 inhibitor filled within 30 days of discharge was identified from pharmacy claims.Proportion of patients filling prescriptions for P2Y12 inhibitors within 30 days of discharge by year, as well as medication possession ratios (MPRs) and total P2Y12 inhibitor copayments at 6 and 12 months for patients who received drug-eluting stents.A total of 55 340 patients (12 754 [23.0%] women; mean [SD] age, 54.4 [7.1] years) who underwent PCI were included in this study. In 2008, 7667 (93.6%) patients filled a prescription for clopidogrel bisulfate and 521 (6.4%) filled no P2Y12 inhibitor prescription within 30 days of hospitalization. In 2016, 2406 (44.0%) patients filled clopidogrel prescriptions, 2015 (36.9%) filled either prasugrel or ticagrelor prescriptions, and 1045 (19.1%) patients filled no P2Y12 inhibitor prescription within 30 days of hospitalization. At 6 months, mean MPRs for patients who received a drug-eluting stent filling clopidogrel, prasugrel, and ticagrelor prescriptions were 0.85 (interquartile range [IQR], 0.82-1.00), 0.79 (IQR, 0.66-1.00), and 0.76 (IQR, 0.66-0.98) (P < .001), respectively; mean copayments for a 6 months’ supply were $132 (IQR, $47-$203), $287 (IQR, $152-$389), and $265 (IQR, $53-$387) (P < .001), respectively. At 12 months, mean MPRs for clopidogrel, prasugrel, and ticagrelor were 0.76 (IQR, 0.58-0.99), 0.71 (IQR, 0.49-0.98), and 0.68 (IQR, 0.41-0.94) (P < .001), respectively; mean total copayments were $251 (IQR, $100-$371), $556 (IQR, $348-$730), and $557 (IQR, $233-$744) (P < .001), respectively.Between 2008 and 2016, increased use of prasugrel and ticagrelor was accompanied by increased nonfilling of prescriptions for P2Y12 inhibitors within 30 days of discharge. Prasugrel and ticagrelor had higher patient costs and lower adherence in the year following PCI compared with clopidogrel. The introduction of newer, more expensive P2Y12 inhibitors was associated with lower adherence to these therapies.