TIMES: Ticagrelor vs. Placebo/ Clopidogrel With Aspirin in Anterior STEMI Patients Treated With Primary PCI

Study Overview
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Brief Summary
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This is a single-centred, double blind randomized controlled trial comparing ticagrelor with placebo in clopidogrel and aspirin loaded patients.

Detailed Description
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The very early benefit of ticagrelor in STEMI is co-mediated by adenosine cardioprotection maintaining/ improving myocardial microcirculatory function, as well as via platelet inhibition or possibly other pleiotropic effects. Ticagrelor increases circulating adenosine by reducing cellular re-uptake. Adenosine is a cardioprotective agent that utilizes cellular survival kinase pathways that may have beneficial effects on the microcirculation and myocardium in patients presenting with STEMI. Adenosine is currently used as a treatment for no-reflow and improves MVO post-STEMI when administered during PPCI. A recent study of healthy volunteers has confirmed that non-invasive coronary flow is augmented by ticagrelor and that this is mediated by adenosine. The Investigators propose that the very early beneficial effects of Ticagrelor in ACS may be adenosine mediated cardioprotection, rather than only due to an antiplatelet effect. This important research is original and a natural progression of the ticagrelor story. It expands the adenosine hypothesis and mode of action of ticagrelor and addresses a novel cardioprotective/ microcirculatory mechanism of action.

Official Title
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A Randomised Mechanistic Study Comparing the Effects of Different Anti-platelet Combinations (Ticagrelor vs. Placebo/ Clopidogrel) With Aspirin in Patients Presenting With Anterior STEMI Treated With Primary PCI

Conditions
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ST Elevation Myocardial Infarction

Intervention / Treatment
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* Drug: Ticagrelor
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of informed verbal consent prior to any study specific procedures taking place with written consent confirmed prior to in-patient cardiac MRI. Male or female adult patient aged 18 - 90 years old Anterior STEMI (ST elevation ≥ 2mmHg in contiguous chest leads) with chest pain symptom onset < 12 hours Exclusion Criteria: Cardiogenic shock* Previous anterior myocardial infarction Unfavourable coronary anatomy for PCI: left main / surgical or distal coronary disease Already prescribed Ticagrelor at the time of admission Factors affecting study drug administration/ absorption: vomiting or allergy Concomitant use of potent CYP3A4 inhibitors/ inducers (e.g ketoconazole and rifampicin) or CYP3A4 substrates with a narrow therapeutic window (e.g. cisapride and ergot alkaloids) or simvastatin / lovostatin >40mg oral dose. Severe bleeding diathesis or current active bleeding* History of intracranial haemorrhage Moderate or Severe hepatic impairment Severe asthma or bradycardia/ complete heart block (contraindications to adenosine)* Severe co-morbidity with a life expectancy < 3 months. Women of child bearing potential (as determined by direct questioning of the patient to confirm and this will be documented in the medical notes). Patients that are found to have any excluding factor (e.g., unfavourable coronary anatomy for PCI) or develop any excluding factor (e.g., vomiting or cardiogenic shock) before the point of final IMR assessment will be discontinued from the study and followed up at discharge and by telephone at 3 and 12 months for adverse event monitoring purposes only.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ticagrelor<br>Patients will receive Ticagrelor 180mg (2 x 90mg tablets) | Drug: Ticagrelor<br>* 2 x 90mg Ticagrelor tablets<br>|
| Placebo Comparator: Placebo<br>Patients will receive Placebo (2 matching tablets) | Other: Placebo<br>* 2 x matching placebo tablets<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Index of Myocardial Resistance (IMR) | To compare final Index of Myocardial Resistance (IMR) at the end of the PPCI procedure between the two arms. | Baseline to end of PPCI procedure. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Baseline IMR and change in IMR during PPCI | To compare between the two arms. | Baseline to end of PPCI procedure. | 
| ACF and AMR pre/post PPCI | To compare between the two arms. | Baseline to end of PPCI procedure. | 
| TIMI flow and TMBG pre/post PPCI | To compare between the two arms. | Baseline to end of PPCI procedure. | 
| ST segment resolution | To compare between the two arms. | Baseline to end of PPCI procedure. | 
| OCT quantified clot volume pre/post PPCI | To compare between the two arms. | Baseline to end of PPCI procedure. | 
| Cardiac troponin - I and CKMB levels at 0, 12 and 24 hours | To compare between the two arms. | Baseline to 24 hours. | 
| Cardiac MRI microvascular obstruction between 24-48 hours and infarct size at 3 months | To compare between the two arms. | Baseline to 3 months. |