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

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.

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.

Study Overview

• Status: Completed
• Conditions: Coronary Artery Disease
• Intervention / Treatment: Procedure: Coronary stenting; Drug: Ticagrelor; Drug: Clopidogrel; Drug: Prasugrel

• Study Type: Interventional
• Enrollment (Actual): 126
• Phase: Phase 4

Contacts and Locations

Study Locations

• Germany
  • Mainz, Germany, 55131
    • 2 Medical Clinic

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in FMD	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.	baseline and 1 month

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
FMD 2 hours after loading dose	Change in FMD 2 hours after the administration of the study drug	baseline and 2 hours after loading dose
L-FMC at 2 hours after the loading dose	change in L-FMC at two hours after the loading dose	baseline and 2 hours
L-FMC 1 month after loading dose	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	baseline and 1 day after stenting
Safety and tolerability	Number of patients with adverse events.	from baseline to 1 month after enrollment

Collaborators and Investigators

• Sponsor: Johannes Gutenberg University Mainz
• Investigators: Study Chair: Thomas Munzel, MD Prof., University Medical Center Mainz

Publications and helpful links

General Publications

• Schnorbus B, Jurk K, Lackner KJ, Welk C, Munzel T, Gori T. Effects of Clopidogrel, Prasugrel and Ticagrelor on Microvascular Function and Platelet Reactivity in Patients With Acute Coronary Syndrome Undergoing Coronary Artery Stenting. A Randomized, Blinded, Parallel Group Trial. Front Cardiovasc Med. 2021 Dec 13;8:780605. doi: 10.3389/fcvm.2021.780605. eCollection 2021.
• Schnorbus B, Daiber A, Jurk K, Warnke S, Konig 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.

Study record dates

Study Major Dates

• Study Start: August 1, 2012
• Primary Completion (Actual): July 1, 2016
• Study Completion (Actual): September 1, 2016

Study Registration Dates

• First Submitted: September 4, 2012
• First Submitted That Met QC Criteria: October 3, 2012
• First Posted (Estimate): October 4, 2012

Study Record Updates

• Last Update Posted (Estimate): September 7, 2016
• Last Update Submitted That Met QC Criteria: September 4, 2016
• Last Verified: September 1, 2016

More Information

Terms related to this study

• Keywords: Coronary artery disease; platelet aggregation; coronary stenting
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Purinergic P2 Receptor Antagonists; Purinergic Antagonists; Purinergic Agents; Ticagrelor; Clopidogrel; Prasugrel Hydrochloride
• Other Study ID Numbers: CTH-C1