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Ticagrelor in Remote Ischemic Preconditioning Study (TRIP)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04174261
Recruitment Status : Completed
First Posted : November 22, 2019
Last Update Posted : November 22, 2019
Sponsor:
Information provided by (Responsible Party):
Hellenic Society of Interventional Cardiology

Brief Summary:

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


Condition or disease Intervention/treatment Phase
Periprocedural Myocardial Infarction Drug: Ticagrelor Procedure: Remote Ischemic Preconditioning Drug: Clopidogrel Phase 4

Detailed Description:

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 245 participants
Allocation: Randomized
Intervention Model: Factorial Assignment
Intervention 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 (Outcomes Assessor)
Masking Description: Patient randomization in the ticagrelor and the clopidogrel group took place using sealed, opaque envelopes containing a computer-generated randomization scheme. Using a similar procedure, patients were then randomly assigned to RIPC or no RIPC within 1 hour before the procedure.
Primary Purpose: Treatment
Official Title: Ticagrelor in Remote Ischemic Preconditioning Study
Actual Study Start Date : January 29, 2017
Actual Primary Completion Date : December 18, 2017
Actual Study Completion Date : January 17, 2018

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Ticagrelor - Remote Ischemic Preconditioning
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
Preprocedural ticagrelor loading and standard dose thereafter

Procedure: Remote Ischemic Preconditioning
Preprocedural remote ischemic preconditioning on the non-dominant arm

Ticagrelor - Control
Ticagrelor 180mg loading dose, and 90mg b.i.d thereafter. BP-cuff uninflated around the non-dominant arm
Drug: Ticagrelor
Preprocedural ticagrelor loading and standard dose thereafter

Active Comparator: Clopidogrel - Remote Ischemic Preconditioning
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
Preprocedural remote ischemic preconditioning on the non-dominant arm

Drug: Clopidogrel
Preprocedural clopidogrel loading and standard dose thereafter

Clopidogrel - Control
Clopidogel 300mg loading dose, and 75mg q.d. thereafter. BP-cuff uninflated around the non-dominant arm
Drug: Clopidogrel
Preprocedural clopidogrel loading and standard dose thereafter




Primary Outcome Measures :
  1. deltaTnI [ Time Frame: At the time of PCI / 24 hours post-PCI ]
    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.


Secondary Outcome Measures :
  1. Peri-procedural MI (type 4a MI) [ Time Frame: 24 hours post-PCI ]
    The prevalence of peri-procedural MI (type 4a MI) according to the third universal definition of MI (5xULN) was a secondary endpoint.

  2. Chest pain during PCI: analog 10-point scale [ Time Frame: During the PCI procedure ]
    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).

  3. ST-segment deviation during PCI [ Time Frame: During the PCI procedure ]
    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.


Other Outcome Measures:
  1. Bleeding [ Time Frame: At the time of PCI / 24 hours post-PCI ]
    Bleeding, according to the Thrombolysis In Myocardial Infarction (TIMI) criteria, was considered as a safety outcome.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04174261


Locations
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Greece
Athens Red Cross Hospital
Athens, Attica, Greece, 11526
Sponsors and Collaborators
Hellenic Society of Interventional Cardiology
Investigators
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Principal Investigator: Apostolos Katsivas Head Cardiology Department, Athens Red Cross Hospital
  Study Documents (Full-Text)

Documents provided by Hellenic Society of Interventional Cardiology:
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Responsible Party: Hellenic Society of Interventional Cardiology
ClinicalTrials.gov Identifier: NCT04174261    
Other Study ID Numbers: ESR-14-10310
First Posted: November 22, 2019    Key Record Dates
Last Update Posted: November 22, 2019
Last Verified: November 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Myocardial Infarction
Infarction
Ischemia
Pathologic Processes
Necrosis
Myocardial Ischemia
Heart Diseases
Cardiovascular Diseases
Vascular Diseases
Clopidogrel
Ticagrelor
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