Ticagrelor in Remote Ischemic Preconditioning Study

Study Overview
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Brief Summary
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Remote ischemic preconditioning (RIPC) reduces periprocedural myocardial injury (PMI) after percutaneous coronary intervention (PCI) through various pathways, including an adenosine-triggered pathway. Ticagrelor inhibits adenosine uptake, thus may potentiate the effects of RIPC. This randomized trial tested the hypothesis that ticagrelor potentiates the effect of RIPC and reduces PMI, as assessed by post-procedural troponin release

Detailed Description
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Percutaneous coronary intervention (PCI) is often complicated by peri-procedural myocardial injury, with widespread adoption of sensitive cardiac biomarkers assays allowing detection of smaller amounts of myocardial necrosis (1, 2). Peri-procedural cardiac troponin elevation has been associated with new irreversible myocardial injury, detected by delayed-enhancement magnetic resonance imaging (3), and even though the prognostic significance of peri-procedural cardiac troponin elevation has been highly debated (4), several studies have reported that peri-procedural injury is associated with worse prognosis (5, 6). Peri-procedural myocardial injury attenuation is expected to improve cardiovascular outcomes following PCI, and this could be achieved through such cardioprotective interventions as ischemic preconditioning (IPC) (2). Converging experimental and clinical evidence suggests that the long-established therapeutic potential of remote IPC or ischemic perconditioning may find clinical use in the setting of elective PCI or ST-elevation myocardial infarction (MI)(7-9). Nevertheless, recent clinical trials suggest that the cardioprotective effect of remote IPC is moderate (10, 11), thus demonstrating the need to explore methods to augment it. The ischemic conditioning signal is considered a summation of signals derived from multiple disparate receptor-ligand interactions, which reaches a threshold once sufficient combined signals are generated (12, 13). Adenosine, with its plasma levels increasing after cellular stresses and ischemia, is a crucial trigger of the preconditioning cascade (14), however it is rapidly taken up by cells through sodium-independent equilibrative nucleoside transporters (ENT 1/2) and sodium-dependent concentrative nucleoside transporters (CNT 2/3) (15). Experimental data suggest that ticagrelor inhibits cellular reuptake of adenosine, thereby increasing systemic and tissue adenosine levels (15-17). Moreover, the antiplatelet effects of ticagrelor have been shown to be partly mediated by increased extracellular adenosine levels and ticagrelor enhances the hyperemic response to adenosine (16, 18). Clinical evidence suggests that in patients with acute coronary syndromes (ACS) ticagrelor treatment is associated with higher adenosine levels and an augmentation of coronary blood flow velocity in response to adenosine (19, 20). The investigators hypothesized that ticagrelor treatment would potentiate the effects of remote IPC and would thereby reduce peri-procedural myocardial injury and the incidence of post-PCI MI.

Official Title
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Ticagrelor in Remote Ischemic Preconditioning Study

Conditions
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Periprocedural Myocardial Infarction

Intervention / Treatment
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* Drug: Ticagrelor
* Procedure: Remote Ischemic Preconditioning
* Drug: Clopidogrel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of informed consent prior to any study specific procedures Patients (Female and male) ≥ 18 of age Patients with NSTE-ACS undergoing coronary angiography, eligible for PCI Exclusion Criteria: Women of childbearing potential Severe comorbidity (estimated life expectancy <6 months) Baseline cTnI before PCI that is not stable or falling or is > 5 ×99th percentile URL. End-stage renal disease(eGFR<15 ml/min/1.73 m2) CRUSADE Bleeding Score >50 Patients with an indication for oral anticoagulation On maintenance therapy with ticagrelor or those that have received clopidogrel for less than 3 days Use of nicorandil or glibenclamide Concomitant theophylline/aminophylline use Known contraindications to the use of ticagrelor Hypersensitivity to the active substance or to any of the excipients Active pathological bleeding History of intracranial haemorrhage Moderate to severe hepatic impairment Co-administration of ticagrelor with strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin, nefazodone, ritonavir, and atazanavir). Patients meeting criteria for immediate or early (<24h) invasive strategy based on the current relevant European Society of Cardiology guidelines

Ages Eligible for Study
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Minimum Age: 18 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: Factorial Assignment
Interventional Model Description: The TRIP study was a randomized, assessor-blind, active comparator-controlled, clinical trial using a 2×2 factorial design, with 1:1 patient allocation to ticagrelor or clopidogrel and within each treatment a 1:1 allocation to RIPC or control.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ticagrelor - Remote Ischemic Preconditioning<br>Ticagrelor 180mg loading dose, and 90mg b.i.d thereafter. 3 cycles of 5-minute ischemia/5-minute reperfusion using a BP cuff around the non-dominant arm | Drug: Ticagrelor<br>* Preprocedural ticagrelor loading and standard dose thereafter<br>Procedure: Remote Ischemic Preconditioning<br>* Preprocedural remote ischemic preconditioning on the non-dominant arm<br>|
| Other: Ticagrelor - Control<br>Ticagrelor 180mg loading dose, and 90mg b.i.d thereafter. BP-cuff uninflated around the non-dominant arm | Drug: Ticagrelor<br>* Preprocedural ticagrelor loading and standard dose thereafter<br>|
| Active Comparator: Clopidogrel - Remote Ischemic Preconditioning<br>Clopidogel 300mg loading dose, and 75mg q.d. thereafter. 3 cycles of 5-minute ischemia/5-minute reperfusion using a BP cuff around the non-dominant arm | Procedure: Remote Ischemic Preconditioning<br>* Preprocedural remote ischemic preconditioning on the non-dominant arm<br>Drug: Clopidogrel<br>* Preprocedural clopidogrel loading and standard dose thereafter<br>|
| Other: Clopidogrel - Control<br>Clopidogel 300mg loading dose, and 75mg q.d. thereafter. BP-cuff uninflated around the non-dominant arm | Drug: Clopidogrel<br>* Preprocedural clopidogrel loading and standard dose thereafter<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| deltaTnI | The primary outcome measure of the study was deltaTnI, defined as the difference between cardiac troponin I (cTnI) levels at 24 hours post-PCI and cTnI levels before the procedure. | At the time of PCI / 24 hours post-PCI | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peri-procedural MI (type 4a MI) | The prevalence of peri-procedural MI (type 4a MI) according to the third universal definition of MI (5xULN) was a secondary endpoint. | 24 hours post-PCI | 
| Chest pain during PCI: analog 10-point scale | Chest pain during PCI was assessed at the post-PCI clinical examination of the subject by an appropriately qualified person, who was unaware of patient's treatment allocation. An analog 10-point scale was used (0: no pain, 10: most severe discomfort ever experienced). | During the PCI procedure | 
| ST-segment deviation during PCI | ST-segment deviation during PCI was monitored by an appropriately qualified person, who was unaware of patient's treatment allocation. It was defined as the absolute value of ST-segment deviation at 60-80ms after the J-point in mm at the beginning of coronary angiography minus ST-segment deviation at 60-80ms after the J-point in mm during balloon occlusion. | During the PCI procedure |