ComparisoN of ticAgrelor vs. Clopidogrel in endoTHeliAl Function of COPD patieNts

• Epidemiology Ischemic heart disease (IHD) and chronic obstructive pulmonary disease (COPD) are respectively the first and fourth cause of death in industrialized countries accounting for 10-15% of total disability adjusted life year (DALY). COPD is common in IHD patients, ranging from 5% to 18%, with a high prevalence of under diagnosis (until 87%). At the same time, one third of COPD patients' deaths are attributable to IHD and for every 10% decrease in forced expiratory volume in one second (FEV1), cardiovascular (CV) mortality rises by 28%.
• Prognostic implication of IHD-COPD comorbidity Presence of concomitant COPD and IHD has a negative impact on quality of life, disease progression and short and long-term outcome. After coronary revascularization patients with COPD are at higher risk of recurrent myocardial infarction (MI), heart failure (HF) and bleeding complications if compared to patients without COPD. Consequently, COPD is an independent predictor of mortality in MI patients (HR 1.4; 95%CI 1.2-1.6). In a retrospective study, including patients undergoing percutaneous coronary intervention (PCI) with a 4-years follow-up, COPD was an independent risk factor for all-cause mortality (odds ratio [OR], 1.79; 95%CI, 1.63-1.96), cardiac mortality (OR 1.57; 95%CI, 1.35-1.81), and occurrence of MI (OR 1.3; 95%CI, 1.14-1.47). Another prospective study on 5000 consecutive patients with coronary artery disease (CAD) evaluated the in-hospital period after PCI. Patients with COPD experienced a significantly higher incidence of angina (p<0.001), arrhythmias (p<0.001), composite major adverse cardiac events (p<0.001) and longer hospital stay (p<0.001) than patients without COPD. The analysis of Charlson index for stable CAD patients confirmed that the presence of COPD was strongly related with long-term survival.
• Inflammation, hypoxia and endothelial dysfunction COPD is characterized by a state of chronic inflammation of airways and vessels. Interleukin-6, C-reactive protein (CRP) and fibrinogen are often elevated in COPD and they facilitate both endothelial dysfunction and atherosclerosis progression. Fibrinogen induces plaque growing, stimulates platelets and white blood cells adhesion to vessels wall and promotes muscle cell proliferation and migration. Higher plasma levels of fibrinogen are directly related to a higher risk of acute coronary syndrome (ACS). CRP facilitates the production of interleukins and promotes the inflammatory state. Chronic hypoxia, contributing to endothelial dysfunction and increasing arterial stiffness, triggers, in vulnerable subjects, the growth and destabilization of atherosclerotic plaques.
• Platelet reactivity Heightened on-treatment PR is a well-known determinant of poor prognosis in PCI patients and it is significantly higher in COPD patients. In COPD patients, platelets' count tents to be higher, and thrombocytosis is associated with increased 1-year mortality (OR 1.53; 95% CI 1.03 to 2.29, p=0.03).
• Ticagrelor Ticagrelor is a direct-acting reversely binding inhibitor of P2Y12 platelets' receptor. Dual antiplatelet therapy (DAPT) with aspirin plus ticagrelor, as compared to aspirin plus clopidogrel, significantly reduces the rate of CV death, myocardial infarction, and/or stroke. Accordingly, DAPT with ticagrelor is guideline's recommended treatment (class I) in patients with ACS. On the contrary, DAPT with ticagrelor in stable CAD patients is not recommended. Dyspnea is a well-established ticagrelor potential side effect and it could be related to circulating increased adenosine levels after ticagrelor administration. A recent study by Alexopoulos et al. reported that COPD is a major determinant of poor/absent prescription of ticagrelor. Of note, Butler et al. demonstrated that ticagrelor administration does not alter pulmonary function at rest and during exercise in patients with COPD. Furthermore, ticagrelor-induced higher adenosine concentrations are considered the main mechanism of its "pleiotropic" effects (such as prevention of ADP-induced contraction of vascular smooth muscle cells, improvement of peripheral endothelial function and increase of endothelial nitric oxide synthase phosphorylation, reduction of pro-inflammatory thrombin-induced cytokines and chemokine's production during inflammation and coagulation activation).
• Research hypothesis and Rationale for conducting this study:

Many studies show that patients with COPD undergoing PCI and stent implantation are at higher risk of adverse events (death, MI and stent thrombosis, ST). This is true both for patients with ACS and stable coronary artery disease (SCAD). Many factors may explain this finding. First, COPD patients have a higher on-treatment (both aspirin and clopidogrel) platelet reactivity (PR). Second, inflammation profile is significantly enhanced in COPD, contributing to higher PR and endothelial dysfunction. Third, endothelial dysfunction due to hypoxia, abnormal shear stress and inflammation is common in COPD and may explain the increase of acute events after stent implantation. Patients receiving PCI and stent implantation must be treated with DAPT to minimize the risk of ST and recurrent MI. According current guidelines, DAPT should be started as soon as possible in patients with ACS and at the timing of PCI in patients with SCAD. Current guidelines recommended the association of aspirin and newer P2Y12 inhibitors (ticagrelor or prasugrel) for ACS patients, whereas aspirin and clopidogrel for SCAD patients. No data supports a different strategy and/or approach in COPD patients undergoing PCI. Ticagrelor, a new P2Y12 inhibitor, showed a significantly higher platelet inhibition as compared to clopidogrel. Recently, ticagrelor administration has been associated with a positive effect on endothelial function and a modulation of proinflammatory signalling. These actions are mediated by a significant influence of adenosine uptake. These findings support a possible positive effect of ticagrelor in COPD patients undergoing PCI for SCAD. Due to their comorbidity, COPD patients undergoing PCI for SCAD may be considered similar to ACS patients (higher platelet reactivity, chronic inflammatory response, heightened endothelial dysfunction). Accordingly, COPD patients undergoing PCI for SCAD may obtain a stronger benefit by ticagrelor when compared to clopidogrel. The aim of this study is to evaluate whether ticagrelor is superior to clopidogrel in reducing endothelial dysfunction, PR and inflammation profile of patients with stable CAD and COPD.

Type of Patients Subjects either male or female eligible for PCI and undergoing drug eluting stent implantation who have meet all inclusion criteria and did not meet any of the exclusion criteria.

Inclusion criteria

For inclusion in the study subjects should fulfill the following criteria:

• Age ≥18 years;
• Ability to provide informed written consent and to participate in the 6-months follow-up period;
• Diagnosis of SCAD requiring coronary artery angiography
• COPD diagnosis confirmed by spirometry in stable phase and after medical treatment from at least 3 months.

Exclusion criteria

Subjects should not enter the study if any of the following exclusion criteria are fulfilled:

• Patients hospitalized with diagnosis of acute coronary syndrome
• Previous chronic use of P2Y12 inhibitors
• Known intolerance to aspirin and/or P2Y12 inhibitors
• Absence of significant variation in guideline driven medical treatment in the last 15 days
• History of intracranial haemorrhage
• Known intake of a strong CYP3A4 inhibitor (e.g. ketoconazole, clarithromycin, nefazodone, ritonavir, and atazanavir),
• Known pregnancy, breast-feeding, or intend to become pregnant during the study period
• Planned surgery, including CABG as a staged procedure (hybrid) within 6 months;
• Known moderate to severe hepatic impairment (alanine-aminotransferase ≥ 3 x ULN);
• Need for chronic oral anti-coagulation therapy;
• Active major bleeding or major surgery within the last 30 days;
• Known stroke (any type) within the last 30 days;
• Currently participating in another trial before reaching primary endpoint;
• Thrombocytopenia;
• Increased risk of bradycardia;
• Known other inflammatory chronic disorders;
• Known or suspected malignancy
• Other concomitant pulmonary diseases