Endothelium, Stenting, and Antiplatelet Therapy (EST) - Clopidogrel, Prasugrel, Ticagrelor Study

Endothelial dysfunction is an important predictor - and a determinant - of adverse clinical outcome. Endothelial function is impaired by coronary artery stenting, a stud from our group has shown that it can be improved by platelet inhibition using clopidogrel. However, clopidogrel unresponsiveness is a known problem, and it has been show that the endothelial effects of clopidogrel tend to wane upon prolonged treatment. Whether a more effective anti-platelet therapy is able to prevent/improve not only thrombotic events but also endothelial dysfunction, with potential positive impact on clinical outcome in patients undergoing coronary artery stenting, is an important hypothesis that needs to be further investigated. To date, evidence regarding "ancillary" (non-platelet-dependent) effects of antiaggregant drugs is very limited. For instance, while their antiplatelet effects, and their beneficial effects in patients with acute coronary syndromes, have been clearly demonstrated in multicentric trials, it remains to be shown whether these drugs also protect endothelial function. Interestingly, some authors suggest that the mortality benefit observed in the PLATO study is at least in part independent of direct antiplatelet effects. No study, to date, has tested the effects of prasugrel and/or ticagrelor on endothelial function. With the present trial, the investigators plan to test the effect of clopidogrel, prasugrel and ticagrelor on endothelial function before and up to 4 weeks after coronary artery stenting. This study will provide important pathophysiologic insight on the relationship between platelet aggregation and endothelial function, two parameters that have been shown to influence patients' prognosis.


Eligibility Criteria:
Inclusion Criteria:

* - 18-75 years old consecutive patients undergoing coronary angiography and stenting at the University Medical Centre Mainz
* A coronary lesion (and patient) amenable to treatment with drug eluting stent
* Ability of subject to understand character and individual consequences of clinical trial
* Signed and dated informed consent of the subject must be available before start of any specific trial procedures.
* Negative pregnancy test of women with childbearing potential

Exclusion Criteria:

* Subjects presenting 1 or more of the following criteria will not be enrolled in the trial:
* Patients with elevated (\> 5 times upper normal limit) C-reactive protein level prior to stenting
* Patients in whom therapy with long-acting nitrates cannot be suspended prior to endothelial function measurements
* An acute coronary syndrome treated with coronary stenting within the last 4 weeks
* Patients with known inflammatory/infective diseases
* Patients with severe extracardiac diseases limiting life expectancy
* Known heart failure (LV-EF ≤ 40% AND NYHA III-IV)
* PCI or coronary By-Pass surgery within the last 4 weeks, pre-existing ongoing treatment with any of the study treatments.
* History of cerebrovascular events (stroke)
* Known renal dysfunction (serum creatinine ≥ 1.8mg/dl in women, ≥ 2.0mg/dl in men)
* Serum potassium \> 5.5mmol/l
* Known hepatic impairment (AST, ALT \> 3 times upper limit of normal)
* Changes in the ß-blocker, statin or ACE or angiotensin-receptor blocker inhibitor treatment within the past 2 weeks
* Pregnancy and lactation, inadequate contraception
* Body weight \< 60kg
* Active bleeding
* Therapy with CYP3A4 inhibitors (ketoconazole, protease inhibitors, macrolide antibiotics)
* Therapy with anticoagulants: phenprocoumone, warfarin, dabigatran, rivaroxaban
* History of hypersensitivity to any of the investigational medicinal products or to any drug with similar chemical structure or to any excipient present in the pharmaceutical form of the investigational medicinal product.
* Ongoing participation in other clinical trials or within the last 3 months, or ongoing therapy with one of the study medications.
* Medical or psychological condition that would not permit completion of the trial or signing of informed consent.
* Patients with acute ST-elevation myocardial infarction