The Comparative Effects of Ticagrelor and Clopidogrel on Arterial Injury and In-Stent Restenosis and Thrombosis of Carotid Artery in Atherosclerotic Rabbits

Abstract

Introduction - Carotid artery angioplasty and stenting (CAS) is expanding as a method to treat carotid artery disease worldwide. Until now a combination of aspirin and clopidogrel has been used pre and post CAS. Ticagrelor, a P2Y (12) inhibitor, has an important role in coronary artery angioplasty. There is lack of evidence about the impact of ticagrelor on carotid artery disease and CAS. Our aim was the comparative evaluation of ticagrelor and clopidogrel on carotid balloon-injury and in-stent restenosis (ISR) and thrombosis in rabbits. Methods - After a pharmacokinetic study to standardise the appropriate dose of ticagrelor, we enrolled 48 New Zealand White rabbits. They were fed a high-cholesterol diet for 8 weeks prior to and up to 4 weeks following interventions in the right carotid artery (RCA). Aspirin was administered orally (10mg/kg/day) to all rabbits, beginning 7 days before the procedures and continued until euthanasia (4 weeks later). At 8th week of age, all rabbits were randomly assigned into the following equivalent (N=12) groups: A1) Balloon injury and clopidogrel (30 mg/kg/day), A2) Balloon injury and ticagrelor (21mg/kg bd), B3) Balloon injury and CAS and clopidogrel (30 mg/kg/day), B4) Balloon injury and CAS and ticagrelor (21mg/kg bd). During CAS a balloon expandable 2,25x8 mm bare metal stent was implanted in the RCA. Before euthanasia optical coherence tomography (OCT) and angiography were carried out to evaluate the patency of both carotid arteries. Blood samples to measure platelet aggregation and lipid profile were obtainedas well. Rabbits were then immediately euthanized and both carotid arteries (right-RCA and left-LCA) were excised for histological analysis. Results - Among groups, no significant differences were seen regarding balloon injury, stent implantation success rates and platelet aggregation measurements (p>0.05). All groups had similar lipid levels (total cholesterol, triglycerides) and weight by the end of the study. Notably, 3 rabbits in the B3 group appeared with thrombotic total occlusion of the carotid stents and were excluded from morphometric analysis. None such episode was observed after CAS in ticagrelor-treated rabbits. In balloon injury rabbits, the OCT-calculated neointimal areas in RCAs were: A1: 4.20±0.96mm2, A2: 3.78±1.31mm2, p=0.781, while the mid-stent neointimal areas were: B1: 1.74±0.51mm2 and B2: 1.45±0.62mm2, p=0.654. The histological findings in balloon-injured rabbits were in agreement with those from OCT analysis, since the percentage of intima/(media + intima)(%) in RCA did not differ between groups: A1 (68.48±12.31%) vs A2 (64.22±13.22%) (p=0.812). Importantly the atherosclerotic lesions in non-injured LCAs did not differ between all groups (p>0.1). Conclusion - In atherosclerotic rabbits undergoing carotid artery balloon injury with or without stent implantation, clopidogrel and ticagrelor seemed to be equally effective in terms of neointimal formation and ISR prevention. . Importantly, ticagrelor treatment prevented thrombotic stent occlusions compared to clopidogrel treatment. Further studies are needed to clarify the impact of P2Y(12) inhibitors on carotid in-stent restenosis and thrombosis in humans.