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

Robert S Rosenson, Qinzhong Chen, Sherwin D Najera, Prakash Krishnan, Martin L Lee, Daniel J Cho, Robert S Rosenson, Qinzhong Chen, Sherwin D Najera, Prakash Krishnan, Martin L Lee, Daniel J Cho

Abstract

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 81 mg/ticagrelor placebo, aspirin 81 mg/ticagrelor 90 mg twice daily and aspirin placebo/ticagrelor 90 mg 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 ± 9 years. The duration of LEAD was 12.3 ± 10.3 years, 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. Trial registration Registration number: NCT02325466, registration date: December 25, 2014.

Keywords: Blood viscosity; Lower extremity arterial disease; Microvascular disease; Ticagrelor; Type 2 diabetes.

Conflict of interest statement

Dr. Rosenson receives grant funding from Akcea, Amgen, AstraZeneca, Medicines Company and Regeneron. At the time of funding for this trial, he attended an Advisory Board for AstraZeneca. He receives consulting fees and honoraria from Amgen, C5, CVS Caremark and Kowa; royalties from UpToDate, Inc. and holds stock in MediMergent LLC. Dr. Chen and Mr. Najera report no relevant conflicts of interest. Dr. Krishnan receives consultanting fees Medtronic and Abbott. Dr. Lee and Mr. Cho receive consulting fees from Rheovector LLC.

Figures

Fig. 1
Fig. 1
Flow of patients throughout the trial
Fig. 2
Fig. 2
Mean levels of blood viscosity measured at low shear and high shear rate in patients treated with aspirin monotherapy, ticagrelor monotherapy and combined aspirin and ticagrelor therapy

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