BackgroundTicagrelor is a P2Y12 receptor inhibitor used in acute coronary syndromes to reduce platelet activity and to decrease thrombus formation. Ticagrelor is associated with a reduction in mortality incremental to that observed with clopidogrel, potentially related to its non–antiplatelet effects. Evidence from animal models indicates that ticagrelor potentiates adenosine‐induced myocardial blood flow (MBF) increases. We investigated MBF at rest and during adenosine‐induced hyperemia in patients with stable coronary artery disease treated with ticagrelor versus clopidogrel.Methods and ResultsThis randomized double‐blinded crossover study included 22 patients who received therapeutic interventions of ticagrelor 90 mg orally twice a day for 10 days and clopidogrel 75 mg orally once a day for 10 days, with a washout period of at least 10 days between the treatments. Global and regional MBF and myocardial flow reserve were measured using rubidium 82 positron emission tomography/computed tomography at baseline and during intermediate‐ and high‐dose adenosine. Global MBF was significantly greater with ticagrelor versus clopidogrel (1.28±0.55 versus 1.13±0.47 mL/min per gram, P=0.002) at intermediate‐dose adenosine and not different at baseline (0.65±0.19 versus 0.60±0.15 mL/min per gram, P=0.084) and at high‐dose adenosine (1.64±0.40 versus 1.61±0.19 mL/min per gram, P=0.53). In regions with impaired myocardial flow reserve (<2.5), MBF was greater with ticagrelor compared with clopidogrel during intermediate and high doses of adenosine (P<0.0001), whereas the differences were not significant at baseline.ConclusionsTicagrelor potentiates global and regional adenosine‐induced MBF increases in patients with stable coronary artery disease. This effect may contribute to the incremental mortality benefit compared with clopidogrel.Clinical Trial RegistrationURL: http://www.clinicaltrials.gov. Unique identifier: NCT01894789.