Effects of Cangrelor on MIcRovAscular Disfunction During Elective Percutaneous CORonary Intervention

Background and state of the art Dual antiplatelet therapy (DAPT) is the main therapy for patients presenting with chronic coronary syndrome (CCS) undergoing elective percutaneous coronary interventions (PCI). It is mainly represented by acetylsalicylic acid (ASA) and Adenosine-diphosphate (ADP) receptor antagonists, such as Clopidogrel, Prasugrel and Ticagrelor. However, pretreatment with DAPT in patients undergoing elective PCI is only considered optional, thereby a large proportion of these patients is not adequately treated at the moment of PCI.1, 2 Manipulations of the coronary arteries during PCI, particularly when complex procedures are performed, might favor platelets aggregation and small thrombus formations with distal embolization.3, 4 In addition, the higher platelet reactivity in this context is associated with endothelial dysfunction which might favour the higher incidence of microvascular damage during PCI.5-9 This latter might be responsible of persistence of angina symptoms even after successfull PCI.10-12 In the setting of CCS and elective PCI, ASA is mainly associated with Clopidogrel. This latter is an oral pro-drug which needs to be converted by the liver in an active metabolite which is able to inhibit the ADP receptor in few hours after the loading dose. However, some patients might be resistent to Clopidogrel with inadeguate platelets inhibition and higher risk of ischemic events.1, 2 Normally, in naïve patients, Clopidogrel is administered at the end of the procedure with an oral loading dose of 600mg, followed by 75mg per day, while ASA can be administered as soon as possible by endovenous bolus (250mg).

Cangrelor is an analogous of the ADP which inhibits platelets aggregation in few minutes after endovenous administration, thereby it can be administered at the moment of PCI potentially reducing the risk of microvascular damage as compared with regular practice.13 This drug is currently recommended by the European guidelines for coronary revascularization in CCS patients, not on treatment with other ADP receptor antagonists.

Objectives The main purpose of the present randomised and open-label study will be the comparison between Cangrelor and regular practice with Clopidogrel in terms of incidence of microvascular damage in CCS patients undergoing elective PCI. The assessment of microvascular damage will be performed by measuring the index of microvascular resistance (IMR) before and after PCI. Even though recommended by the current European guidelines, cangrelor has never been evaluated with the purpose to protect microcirculation during PCI and this study might highlight the potential benefit of Cangrelor, as compared with regural practice, in the context of elective PCI. In addition, as secondary objectives, the occurrence of peri-procedural myocardial infarction (MI) will be evaluated and platelets reactivity will be also assessed with the aim to correlate platelets reactivity with IMR values, supporting the correlation between platelets reactivity and endothelial dysfunction.

At 30 and 90 days of follow-up, patients will report on the persistence of angina symptoms by completing a specific questionary (SAQ7). This point is also of interest, since coronary microvascular dysfunction (IMR>25) might be responsible of angina symptoms regardless of the presence of epicardial stenosis. Microvascular dysfuction can be detected either before PCI or after PCI as result of microvascular damage. Although with poor prognostic value, microvascular damage might be responsible of persistence of typical symptoms and ischemic signs at non-invasive tests despite a successful PCI, leading patients towards the esecution of several and useless non-invasive and invasive tests. Thereby, the protection of the coronary microcirculation during elective PCI might significantly reduce the persistence of typical symptoms in post-PCI patients and finally provide a significant savings for the heath care system.

Methodology and work plan This will be a randomised and open-label study, including all consecutive patients presenting with chronic coronary syndromes not on treatment with any of the ADP receptor antagonists, and undergoing elective PCI of functionally significant intermediate de-novo coronary artery stenoses. Patients presenting with ACS or heart failure (left ventricle ejection fraction < 30%) will be excluded as well as patients with a subtotal occlusion of a major coronary artery not requiring FFR evaluation.

• Pre-procedural assessment. All patients will be screened before the procedure and will be asked to answer the specific angina questionary (Seattle Angina Questionnaire SAQ-7), for the assessment of the severity of the angina symptoms.
• Coronary angiography and functional assessment of intermediate coronary artery stenoses. Coronary angiography will be performed as per regular practice through the radial or femoral access in order to evaluate the presence of any epicardial stenoses in a major vessel. In this case, the ischemic potential of each stenosis will be assessed with the Fractional Flow Reserve (FFR), as also recommended by the current European guidelines.14, 16 Briefly, a pressure/temperature guidewire will be advanced beyond the stenosis and during i.v. adenosine induced maximal hyperemia the ratio between distal (Pd) and proximal (Pa) pressures will be calculated. A FFR value ≤ 0.80 will identify a functionally significant coronary stenosis with indication to perform PCI. With the same guidewire, and the same setting, it will be also possible to measure both the Coronary Flow Reserve (CFR) and the Index of Microcirculatory Resistance (IMR).17-19
• Randomization and PCI procedure. After the evaluation of both inclusions and exclusions criteria, patients will be randomised in a 1:1 allocation ratio in two groups: 1) Experimental Group 2) Control Group. RedCap software will be used to randomise and to manage patients data. In the Experimental group, before performing PCI, all patients will be treated with Cangrelor (Kangrexal) with an i.v. loading bolus (30mg/Kg) followed by i.v. infusion (4mg/Kg/min) for 2 hours. At the end of the infusion, as per current clinical practice, a loading dose of Clopidogrel (600mg) will be administered. A manteinance daily dose of 75mg will be associated with oral ASA (100mg). In the Control group, either before or after PCI a loading dose of Clopidogrel will be administered and a manteinance daily dose of 75mg will be associated with oral ASA (100mg). PCI procedure will be performed as per current cinical practice, according clinical guidelines and at operator discretion.14
• Assessment of Platelets reactivity (PR). Blood samples for platelet function analysis will be collected in the catheterization laboratory through the arterial sheath. PR will be measured with the VeryfyNow system in three different time points, without interfering with the regular PCI procedure:
• Time 0: Before PCI and Cangrelor/Clopidogrel administration;
• Time 1: At the end of the PCI procedure and within 1 hour from the administration of Cangrelor/Clopidogrel.
• Time 2: At 4-6 hours from PCI procedure.
• Post PCI assessment. Both FFR and CFR/IMR will be assessed at the end of the PCI with the purpose to evaluate 1) the completeness of the revascularization from a functional standpoint and 2) the occurrence of microvascular damage. This latter will be diagnosed in case of Post-PCI IMR values > 25 if Pre-PCI IMR values are normal (<25) or, in case of abnormal Pre-PCI IMR values, if Post-PCI values will be 20% higher.
• Non-invasive Post-PCI assessment. Blood samples will be collected at 12 and 24 hours with the aim to evaluate the occurrence of peri-procedural MI defined as follow:
• The finding of high sensitive Troponine I (hsTrop-I) values higher than 5X the ULN, in patients with normal hsTrop-I before PCI;
• The finding of hsTrop-I values higher than 20% the baseline values, in patients with abnormal hsTrop-I before PCI;

In addition, the following criteria should also be fulfilled:

• ECG ischemic modification after PCI
• The findings of new Q waves at ECG
• The findings at the angiography of some modifications consistent with the hdTrop-I increase (i.e. side branch occlusion/dissection, distal embolization).
• Follow-up. Patients will be followed up at 30 and 90 days. Besides clinical assessment, patients will be asked to complete SAQ7 questionary in order to evaluate the severity of residual symptoms, if any. In addition, at 90 days only, all patienst will perform a single photon emission computed tomography (SPECT) in order to evaluate the presence of ipoperfused areas downstream to the treated vessel.