Ticagrelor improves blood viscosity-dependent microcirculatory flow in patients with lower extremity arterial disease: the Hema-kinesis clinical trial

Background: Microvascular blood flow (MBF) impairment in patients with lower extremity arterial disease (LEAD) is associated with more severe major adverse limb events (MALE). The contribution of ticagrelor, a P2Y12 antagonist and an adenosine enhancer, on blood viscosity (BV) and BV-dependent MBF in LEAD is unknown. The aim of the trial is to investigate the effects of ticagrelor on BV, and explore the association of BV-dependent MBF in participants with LEAD and type 2 diabetes (T2DM). Methods: Randomized, double-blind, double-dummy, crossover trial design that compares treatment with aspirin 81mg/ticagrelor placebo, aspirin 81mg/ticagrelor 90mg twice daily and aspirin placebo/ticagrelor 90mg twice daily on high-shear (300 s(-1)) and low-shear (5 s(-1)) BV, and laser Doppler flowmetry (LDF) in the dorsum of the feet of participants with T2DM. Results: We randomized 70 (45% female) participants aged (mean +/- SD) 72 +/- 9years. The duration of LEAD was 12.3 +/- 10.3years, and 96.9% reported intermittent claudication symptoms. Use of statins was 93% (high-intensity 43%, moderate intensity 49%), renin-angiotensin-aldosterone system inhibitors (75%) and beta-blockers (61%). Treatment with ticagrelor with or without aspirin reduced high-shear BV by 5%, in both cases, while aspirin monotherapy increased high-shear BV by 3.4% (p<0.0001). Ticagrelor with or without aspirin reduced low-shear BV by 14.2% and 13.9% respectively, while aspirin monotherapy increased low-shear BV by 9.3% (p<0.0001). The combination of ticagrelor and aspirin increased MBF in the left foot compared to the other two treatments (p=0.02), but not in the right foot (p=0.25). Conclusions: Ticagrelor should be considered in the treatment of microvascular disease in patients with LEAD and T2DM.