Endothelium, Stenting, and Antiplatelet Therapy: Clopidogrel, Prasugrel, Ticagrelor Study

Study Questions:

What is the impact of clopidogrel, prasugrel, or ticagrelor on peripheral endothelial function in patients undergoing stenting for an acute coronary syndrome (ACS)?


The investigators conducted a randomized, parallel, blinded study. The primary endpoint of the trial was the change in flow-mediated dilation (FMD) at 1 day, 1 week, and 1 month after percutaneous coronary intervention (PCI) across patients randomized to be treated with clopidogrel, prasugrel, or ticagrelor. Secondary objectives were to test the impact of the three study medications on parameters of endothelial function after an acute loading dose of the three study drugs and to investigate the changes in low-flow-induced vasoconstriction (L-FMC), as well as markers of platelet activation and inflammation/oxidative stress in the three groups. Furthermore, the safety and tolerability of clopidogrel, prasugrel, and ticagrelor were investigated. For the primary analysis, FMDs in the prasugrel and ticagrelor groups were tested separately in two independent mixed models in which an unstructured covariance matrix incorporated the dependency between the three repeated measurements after stenting.


A total of 90 patients (ages 62 ± 9 years, 81 males, 22 diabetics, 49 non–ST-segment elevation myocardial infarctions [NSTEMI]) were enrolled. There were no significant differences among groups in any clinical parameter. Acutely before stenting, all three drugs improved FMD without differences between groups (p = 0.73). Stenting blunted FMD in the clopidogrel and ticagrelor groups (both p < 0.01), but not in the prasugrel group. During follow-up, prasugrel was superior to clopidogrel (mean difference, 2.13; 95% confidence interval [CI], 0.68-3.58; p = 0.0047) and ticagrelor (mean difference, 1.57; 95% CI, 0.31-2.83; p = 0.0155), but this difference was limited to patients who received the study therapy 2 hours before stenting. Ticagrelor was not significantly superior to clopidogrel (mean difference, 0.55; 95% CI, -0.73 to 1.82; p = 0.39). No significant differences were seen among groups for low-flow-mediated dilation. Plasma interleukin (IL)-6 (p = 0.02 and p = 0.01, respectively) and platelet aggregation reactivity in response to adenosine diphosphate (p = 0.002 and p = 0.035) were lower in the prasugrel compared to clopidogrel and ticagrelor group.


The authors concluded that as compared to ticagrelor and clopidogrel, therapy with prasugrel in patients undergoing stenting for an ACS is associated with improved endothelial function, stronger platelet inhibition, and reduced IL-6 levels.


This study reports that on day 1 after PCI and during subsequent follow-up, prasugrel prevented the endothelial dysfunction associated with stenting and was a more potent inhibitor of platelet aggregation. However, this protective effect of prasugrel disappeared when the drugs were administered immediately after PCI. Furthermore, the more potent antiplatelet effect of prasugrel was more evident in NSTEMI patients as compared to patients with unstable angina. Collectively, these data appear to support the link between inflammation, platelet activation, and endothelial dysfunction in ACS, and prasugrel might be a more potent inhibitor of this cascade in the acute ACS/PCI phase. While the recently reported ISAR-REACT 5 trial would support such a hypothesis, additional prospective randomized head-to-head comparative clinical trials are needed to assess the superiority of prasugrel over ticagrelor in ACS patients undergoing PCI.

Clinical Topics: Acute Coronary Syndromes, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Prevention, ACS and Cardiac Biomarkers, Heart Failure and Cardiac Biomarkers, Interventions and ACS, Stress

Keywords: Acute Coronary Syndrome, Angina, Unstable, Diabetes Mellitus, Dilatation, Inflammation, Interleukin-6, Myocardial Infarction, Oxidative Stress, Percutaneous Coronary Intervention, Platelet Activation, Platelet Aggregation, Platelet Aggregation Inhibitors, Secondary Prevention, Vasoconstriction

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