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

• ClinicalTrials.gov Identifier: NCT01700322
• Recruitment Status: Completed
• First Posted: October 4, 2012
• Last Update Posted: September 7, 2016
• Sponsor: Johannes Gutenberg University Mainz
• Information provided by (Responsible Party): Tommaso Gori, Johannes Gutenberg University Mainz

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Coronary Artery Disease	Procedure: Coronary stenting; Drug: Ticagrelor; Drug: Clopidogrel; Drug: Prasugrel	Phase 4

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 126 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Investigator)
• Primary Purpose: Basic Science
• Official Title: Effects of Clopidogrel vs Prasugel vs Ticagrelor on Endothelial Function, Inflammatory and Oxidative Stress Parameters and Platelet Function in Patients Undergoing Coronary Artery Stenting. A Randomised, Prospective Study.
• Study Start Date: August 2012
• Actual Primary Completion Date: July 2016
• Actual Study Completion Date: September 2016

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Ticagrelor; Ticagrelor 180mg oral loading dose and 90mg b.i.d for 30 days following coronary artery stenting	Procedure: Coronary stenting; All patients will receive a drug eluting stent as clinically indicated.; Drug: Ticagrelor; Ticagrelor 180mg oral loading dose and 90mg b.i.d for 30 days following coronary artery stenting
Active Comparator: Clopidogrel; Clopidogrel 600mg loading dose + 75 mg once a day for 30 days following coronary artery stenting.	Procedure: Coronary stenting; All patients will receive a drug eluting stent as clinically indicated.; Drug: Clopidogrel; Clopidogrel 600mg loading dose + 75 mg once a day for 30 days following coronary artery stenting.
Active Comparator: Prasugrel; Prasugrel 60mg oral loading dose followed by 10mg once a day for 30 days following coronary artery stenting	Procedure: Coronary stenting; All patients will receive a drug eluting stent as clinically indicated.; Drug: Prasugrel; Prasugrel 60mg oral loading dose followed by 10mg once a day for 30 days following coronary artery stenting

Outcome Measures

Primary Outcome Measures :

1. Change in FMD [ Time Frame: baseline and 1 month ]
   The primary endpoint is the change in flow-mediated dilation (FMD) (comparison before treatment versus after treatment and stenting) in the three study groups. The mean FMD across the three measurements (1 day, 1 week, 1 month) performed after coronary artery stenting will be compared to the FMD value before drug administration and stenting.

Secondary Outcome Measures :

1. FMD 2 hours after loading dose [ Time Frame: baseline and 2 hours after loading dose ]
   Change in FMD 2 hours after the administration of the study drug
2. L-FMC at 2 hours after the loading dose [ Time Frame: baseline and 2 hours ]
   change in L-FMC at two hours after the loading dose
3. L-FMC 1 month after loading dose [ Time Frame: baseline and 1 day after stenting ]
   change in flow-mediated constriction (L-FMC) (comparison before treatment versus after treatment and stenting) in the three study groups. The mean L-FMC across the three measurements (1 day, 1 week, 1 month) performed after coronary artery stenting will be compared to the value before drug administration and stenting
4. Safety and tolerability [ Time Frame: from baseline to 1 month after enrollment ]
   Number of patients with adverse events.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

Germany

2 Medical Clinic

Mainz, Germany, 55131

Sponsors and Collaborators

Johannes Gutenberg University Mainz

Investigators

• Study Chair: Thomas Munzel, MD Prof.; University Medical Center Mainz

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Schnorbus B, Daiber A, Jurk K, Warnke S, König J, Krahn U, Lackner K, Munzel T, Gori T. Effects of clopidogrel, prasugrel and ticagrelor on endothelial function, inflammatory and oxidative stress parameters and platelet function in patients undergoing coronary artery stenting for an acute coronary syndrome. A randomised, prospective, controlled study. BMJ Open. 2014 May 6;4(5):e005268. doi: 10.1136/bmjopen-2014-005268.

• Responsible Party: Tommaso Gori, Professor, Johannes Gutenberg University Mainz
• ClinicalTrials.gov Identifier: NCT01700322
• Other Study ID Numbers: CTH-C1
• First Posted: October 4, 2012
• Last Update Posted: September 7, 2016
• Last Verified: September 2016

Keywords provided by Tommaso Gori, Johannes Gutenberg University Mainz:

Coronary artery disease; coronary stenting; platelet aggregation

Additional relevant MeSH terms:

Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Heart Diseases; Cardiovascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases; Clopidogrel; Ticagrelor; Prasugrel Hydrochloride; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Purinergic P2 Receptor Antagonists; Purinergic Antagonists; Purinergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Physiological Effects of Drugs