ticagrelor and Aortic-Aneurysm--Abdominal

To evaluate if ticagrelor, an effective platelet inhibitor without known non-responders, could inhibit growth of small abdominal aortic aneurysms (AAAs).. In this multi-centre randomized controlled trial, double-blinded for ticagrelor and placebo, acetylic salicylic acid naïve patients with AAA and with a maximum aortic diameter 35-49 mm were included. The primary outcome was mean reduction in log-transformed AAA volume growth rate (%) measured with magnetic resonance imaging (MRI) at 12 months compared with baseline. Secondary outcomes include AAA-diameter growth rate and intraluminal thrombus (ILT) volume enlargement rate. A total of 144 patients from eight Swedish centres were randomized (72 in each group). MRI AAA volume increase was 9.1% for the ticagrelor group and 7.5% for the placebo group (P = 0.205) based on intention-to-treat analysis, and 8.5% vs. 7.4% in a per-protocol analysis (P = 0.372). MRI diameter change was 2.5 mm vs. 1.8 mm (P = 0.113), US diameter change 2.3 mm vs. 2.2 mm (P = 0.778), and ILT volume change 12.9% vs. 10.4% (P = 0.590).. In this RCT, platelet inhibition with ticagrelor did not reduce growth of small AAAs. Whether the ILT has an important pathophysiological role for AAA growth cannot be determined based on this study due to the observed lack of thrombus modulating effect of ticagrelor.. The TicAAA trial is registered at the US National Institutes of Health (ClinicalTrials.gov) #NCT02070653.

Topics: Aged; Aged, 80 and over; Aortic Aneurysm, Abdominal; Disease Progression; Double-Blind Method; Female; Hemorrhage; Humans; Magnetic Resonance Angiography; Male; Middle Aged; Platelet Aggregation Inhibitors; Sweden; Thrombosis; Ticagrelor; Time Factors; Treatment Outcome

Platelet activation and thrombus renewal are keys to intraluminal thrombus formation and progression of abdominal aortic aneurysms (AAA). This study explored the ability of AZD6140, a P2Y(12) receptor antagonist, to inhibit platelet activation and prevent aneurysm development in a rat experimental model of AAA.. Aortic aneurysms were induced by implanting a segment of sodium dodecyl sulfate-decellularized guinea pig aorta in rat aortas. One day later, rats were randomized to AZD6140 (10 mg/kg twice daily by mouth) or diluent (n = 23 per group) for either 10 (n = 18) or 42 days (n = 28). Adenosine diphosphate (ADP)-mediated platelet aggregation, aneurysm expansion, intraluminal thrombus formation, inflammatory infiltration, matrix metalloproteinase-9 (MMP-9) expression, and smooth muscle cell colonization were measured.. AZD6140 inhibited ADP-induced platelet aggregation in vivo for 12 hours, justifying twice-daily administration in rats. The spontaneous increase in aortic diameter shown in the aneurysmal model (2.22 +/- 0.56 mm at day 10 vs 5.21 +/- 1.22 mm at day 42) was reduced with AZD6140 (3.61 +/- 1.46 mm at day 42, P < .01). This beneficial effect was associated with a significant reduction of thrombus development, platelet CD41 expression (P < .05), and leukocyte infiltration of the mural thrombus at days 10 and 42 (P < .01). MMP-9 expression correlated with mural thrombus area and was significantly reduced by AZD6140 (P < .05). AZD6140 limited elastic fiber degradation (P < .05) and enhanced progressive colonization of the thrombus by smooth muscle cells at day 42 (P < .01).. These data suggest that inhibition of platelet activation limits intraluminal thrombus biologic activities, thereby impairing aneurysm development.

Topics: Adenosine; Adenosine Diphosphate; Animals; Aorta; Aortic Aneurysm, Abdominal; Blood Platelets; Disease Models, Animal; Disease Progression; Elastic Tissue; Guinea Pigs; Inflammation; Male; Matrix Metalloproteinase 9; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Platelet Aggregation; Platelet Aggregation Inhibitors; Purinergic P2 Receptor Antagonists; Rats; Rats, Inbred Lew; Receptors, Purinergic P2; Receptors, Purinergic P2Y12; Thrombosis; Ticagrelor; Time Factors; Transplantation, Heterologous