Peripheral Endothelial Function Assessment of Patients on Ticagrelor vs. Clopidogrel Who Have Undergone PCI

• ClinicalTrials.gov Identifier: NCT02469740
• Recruitment Status: Completed
• First Posted: June 11, 2015
• Last Update Posted: March 11, 2016
• Sponsor: University Hospital of Limerick
• Information provided by (Responsible Party): Ronstan Lobo, University Hospital of Limerick

Tracking Information

• First Submitted Date: June 9, 2015
• First Posted Date: June 11, 2015
• Last Update Posted Date: March 11, 2016
• Study Start Date: July 2015
• Actual Primary Completion Date: January 2016 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: June 10, 2015): The number of patients with endothelial dysfunction (Reactive Hyperemia index of < 1.67 using the non-invasive Endo-PAT 2000 device) on ticagrelor versus clopidogrel. [ Time Frame: 9 weeks ]
• Original Primary Outcome Measures: Same as current
• Change History: Complete list of historical versions of study NCT02469740 on ClinicalTrials.gov Archive Site
• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Peripheral Endothelial Function Assessment of Patients on Ticagrelor vs. Clopidogrel Who Have Undergone PCI
• Official Title: Peripheral Endothelial Function Assessment of Patients on Ticagrelor vs. Clopidogrel Who Have Undergone Percutaneous Coronary Intervention - a Randomised, Crossover Study.

Brief Summary

Usage of antiplatelet agents and cardiac procedures such as coronary angioplasty has dramatically improved the morbidity and mortality associated with coronary artery disease. In patients with a coronary stent, dual antiplatelet therapy is recommended. Aspirin is the main antiplatelet agent used. For many years, clopidogrel was the second antiplatelet of choice. Recent studies have revealed new antiplatelet drugs that can substitute clopidogrel, one of which is ticagrelor. The degree to which ticagrelor reduced the overall mortality compared to clopidogrel in the PLATO trial suggested that ticagrelor possibly has a pleiotropic effect and that the reduction in mortality is not simply due to its antiplatelet effects. The ticagrelor molecule resembles adenosine. Adenosine has been shown to be cardioprotective.

The aim of this project is to study the effects of ticagrelor on the arterial system using a noninvasive method. The study will employ the measurement of peripheral endothelial function of patients who undergo percutaneous coronary intervention who are on ticagrelor vs. clopidogrel using a cross over trial design.

Detailed Description

Cardiovascular disease remains the most common cause of death in Ireland. Usage of antiplatelet agents and cardiac procedures such as coronary angioplasty has dramatically improved the morbidity and mortality associated with coronary artery disease. In patients with a coronary stent, dual antiplatelet therapy is recommended. Aspirin is the main antiplatelet agent used. For many years, clopidogrel was the second antiplatelet of choice. Recent studies have revealed new antiplatelet drugs that can substitute clopidogrel, one of which is ticagrelor. Ticagrelor received approval from regulatory authorities such as the Food and Drug Administration and the European Medicines Agency based on the PLATO trial which demonstrated a reduction in overall mortality and thrombotic cardiovascular events when compared to clopidogrel. Ticagrelor is approved in Europe and specifically in Ireland for use in patients with ACS and in patients undergoing coronary angioplasty. The degree to which ticagrelor reduced the overall mortality compared to clopidogrel in the PLATO trial suggested that ticagrelor possibly has a pleiotropic effect and that the reduction in mortality is not simply due to its antiplatelet effects. The ticagrelor molecule resembles adenosine. It has been shown that ticagrelor increases adenosine concentration, by interfering with its red blood cells' uptake and by inducing the release of ATP which is then converted to adenosine. Adenosine has been shown to be cardioprotective.

Peripheral Arterial Tonometry (EndoPAT 2000 system (Itamar Medical, Caesarea, Israel) is a method for evaluating endothelial dysfunction. The device has received a CE mark (approved for use in Europe). It uses a non-invasive assessment called fingertip pulse amplitude tonometry.

The reactive hyperaemia response as detected by the reactive hyperaemia index (RHI) has been shown to be related to multiple traditional and metabolic risk factors. It has also been found to positively correlate with flow mediated dilatation (FMD) and coronary vasoreactivity as assessed by intracoronary acetylcholine. A significant advantage of the endoPAT device is the reproducibility of results when compared to FMD in assessment of peripheral endothelial function. Smaller studies have shown positive effects of ticagrelor on endothelial function assessment compared with clopidogrel or prasugrel but no randomised study has been done to date.

The aim of this project is to study the effects of ticagrelor on the arterial system using a noninvasive method. The study will employ the measurement of peripheral endothelial function of patients who undergo percutaneous coronary intervention who are on ticagrelor vs. clopidogrel using a cross over trial design.

• Study Type: Interventional
• Study Phase: Phase 4
• Study Design: Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: None (Open Label); Primary Purpose: Basic Science

Condition

• Myocardial Ischemia
• Coronary Artery Disease
• Endothelial Dysfunction

Intervention

• Drug: Ticagrelor
  Patients that are randomly selected to receive ticagrelor during the first phase of the study will receive the dose of 90 mg BD orally. This will be continued for 4 weeks before the endothelial function test will be performed. If the patients are assigned in the 2nd phase of the study, they will receive 90 mg BD orally for 5 weeks (4 weeks plus a 1 week washout period).
  Other Name: Brilique
• Drug: Clopidogrel
  Patients that are randomly selected to receive ticagrelor during the first phase of the study will receive the dose of 75 mg OD orally. This will be continued for 4 weeks before the endothelial function test will be performed. If the patients are assigned in the 2nd phase of the study, they will receive 75 mg OD orally for 5 weeks (4 weeks plus a 1 week washout period).
  Other Name: Plavix, Clodel

Study Arms

• Experimental: Ticagrelor
  Patients in this group will be prescribed ticagrelor 90 mg BD for 4 weeks.
  Intervention: Drug: Ticagrelor
• Active Comparator: Clopidogrel
  Patients in this group will be prescribed clopidogrel 75 mg OD for 4 weeks
  Intervention: Drug: Clopidogrel

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: June 10, 2015): 61
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: January 2016
• Actual Primary Completion Date: January 2016 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Subjects must be able and willing to give written informed consent and to comply with the requirements of this study protocol
• Subjects must be male or female, aged 18 years or above at baseline
• Diagnosed with coronary artery disease and undergone PCI
• Female subjects of child bearing potential must be willing to ensure that they or their partner use effective contraception during the study and for 12 months (as per guidelines on patients undergoing PCI who are on antiplatelet therapy).
• Female subjects' urine pregnancy test performed at the baseline visit must be negative (which is required by local hospital policy in order to undergo PCI).

Exclusion Criteria:

• Allergy/hypersensitivity to study medications or their ingredients

• Contraindications to either clopidogrel or ticagrelor:

  • Ticagrelor contraindications - active bleeding, history of intracranial haemorrhage, moderate to severe hepatic impairment, dialysis, uric acid nephropathy, co-administration of a strong CYP3A4 inhibitor (e.g. ketoconazole, clarithromycin, nefazodone, ritonavir and atazanavir), history of sick sinus syndrome or high degree AV block without pacemaker protection
  • Clopidogrel contraindications - severe hepatic impairment, active bleeding
• On treatment with oral anticoagulant (vitamin K antagonist, dabigatran, rivaroxaban, apixaban)
• Unable to follow up in research centre (for example, due to logistic difficulties)
• Female subjects who are pregnant or breast-feeding, or considering becoming pregnant during the study.
• Subjects who have participated in another study and received any other investigational agent within the previous 12 months
• Subjects unable to provide written informed consent within 24 hours of PCI (for example, intubated patients)
• Subjects who have a history of drug or alcohol use that, in the opinion of the investigator, would interfere with adherence to study requirements.
• Use of both left and right radial access for PCI

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Ireland

Administrative Information

• NCT Number: NCT02469740
• Other Study ID Numbers: RON004; 2015-000334-30 ( EudraCT Number )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Ronstan Lobo, University Hospital of Limerick
• Study Sponsor: University Hospital of Limerick
• Collaborators: Not Provided

Investigators

• Study Chair: Thomas J Kiernan; University Hospital of Limerick

• PRS Account: University Hospital of Limerick
• Verification Date: March 2016