Biological effects of ticagrelor over clopidogrel in patients with stable coronary artery disease and chronic obstructive pulmonary disease

Gianluca Campo, Francesco Vieceli Dalla Sega, Rita Pavasini, Giorgio Aquila, Francesco Gallo, Francesca Fortini, Elisabetta Tonet, Paolo Cimaglia, Annamaria Del Franco, Gabriele Pestelli, Alessandro Pecoraro, Marco Contoli, Cristina Balla, Simone Biscaglia, Paola Rizzo, Roberto Ferrari, Gianluca Campo, Francesco Vieceli Dalla Sega, Rita Pavasini, Giorgio Aquila, Francesco Gallo, Francesca Fortini, Elisabetta Tonet, Paolo Cimaglia, Annamaria Del Franco, Gabriele Pestelli, Alessandro Pecoraro, Marco Contoli, Cristina Balla, Simone Biscaglia, Paola Rizzo, Roberto Ferrari

Abstract

Patients with SCAD and concomitant COPD are at high risk of cardiovascular adverse events, due to chronic inflammation, responsible of endothelial dysfunction, oxidative stress and heightened platelet reactivity (PR). The objective of this randomised clinical trial was to test if ticagrelor is superior to clopidogrel in improving endothelial function in patients with stable coronary artery disease (SCAD) and concomitant chronic obstructive pulmonary disease (COPD). Forty-six patients with SCAD and COPD undergoing percutaneous coronary intervention (PCI) were randomly assigned to receive clopidogrel (n=23) or ticagrelor (n=23) on top of standard therapy with aspirin. The following parameters were assessed at baseline and after 1 month: i) rate of apoptosis and ii) nitric oxide (NO) levels in human umbilical vein endothelial cells (HUVECs), iii) levels of reactive oxygen species (ROS) in peripheral blood mononuclear cell, iv) 29 cytokines/chemokines, v) on-treatment PR. The primary endpoint of the study was the 1-month rate of HUVECs apoptosis. The rate of apoptosis after 1 month was significantly lower in patients treated with ticagrelor (7.4 ± 1.3 % vs 9.3 ± 1.5 %, p<0.001), satisfying the pre-specified primary endpoint. In the ticagrelor arm, levels of NO were higher (10.1 ± 2.2 AU vs 8.5 ± 2.6 AU, p=0.03) while those of ROS (4 ± 1.8 AU vs 5.7 ± 2.8 AU, p=0.02) and P2Y12 reactivity units (52 ± 70 PRU vs 155 ± 62 PRU, p<0.001) were lower. There were no differences in cytokines/chemokines levels and aspirin reactivity units between groups. In patients with SCAD and COPD undergoing PCI, ticagrelor, as compared to clopidogrel is superior in improving surrogate markers of endothelial function and on-treatment PR (ClinicalTrials.gov, NCT02519608).

Keywords: Ticagrelor; chronic obstructive pulmonary disease; clopidogrel; endothelial function; stable coronary artery disease.

Conflict of interest statement

Conflicts of Interest Gianluca Campo has received honoraria for lectures from Astrazeneca, Menarini, Abbott Vascular, Boston Scientific. Roberto Ferrari has received honoraria for lectures from Servier. The other Authors did not report disclosures.

Figures

Figure 1: Study flow diagram
Figure 1: Study flow diagram
. CAA: coronary artery angiography. NSTEACS: not ST-segment elevation acute coronary syndrome. STEMI: ST-segment elevation myocardial infarction. SCAD: stable coronary artery disease. COPD: chronic obstructive pulmonary disease. AVK: antagonist vitamin K. AF: atrial fibrillation.
Figure 2: Schematic representation of endothelial function…
Figure 2: Schematic representation of endothelial function assays in two patients
. We reported the endothelial function assays of patient #4 (randomised to clopidogrel) and of patient #23 (randomised to ticagrelor) both at baseline and after 1 month. A and D) Rate of apoptosis. B and E) ROS generation. C and F) NO levels. Of note, in Figures B, C, E and F baseline sample is pink, 1-month sample is green and the overlap zone is brown. PI: propidium iodide. DCF: 2’,7’dichlorofluorescin diacetate. DAF-FM: 4-amino-5-methylamino-2’,7’ difluorofluorescein diacetate.
Figure 3: Apoptosis rate
Figure 3: Apoptosis rate
. Apoptosis is expressed as percentage of Annexin V positive cells on the total number of cells. Black circle: patient randomised to clopidogrel. White square: patient randomised to ticagrelor.
Figure 4: P2Y 12 reaction units
Figure 4: P2Y 12 reaction units
. Black circle: patient randomised to clopidogrel. White square: patient randomised to ticagrelor.

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Source: PubMed

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