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

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.

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

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.