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.