Rivaroxaban compared with low-dose aspirin in individuals with type 2 diabetes and high cardiovascular risk: a randomised trial to assess effects on endothelial function, platelet activation and vascular biomarkers,Diabetologia

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Rivaroxaban compared with low-dose aspirin in individuals with type 2 diabetes and high cardiovascular risk: a randomised trial to assess effects on endothelial function, platelet activation and vascular biomarkers
Diabetologia ( IF 8.4 ) Pub Date : 2021-09-08 , DOI: 10.1007/s00125-021-05562-9
Frank Pistrosch ₁ , Jan B Matschke ₁ , Dorothea Schipp ₂ , Bernhard Schipp ₃ , Elena Henkel ₄ , Ingo Weigmann ₁ , Jan Sradnick ₁ , Stefan R Bornstein ₁ , Andreas L Birkenfeld _{5,

6} , Markolf Hanefeld ₁

Affiliation

Aims/hypothesis

Individuals with type 2 diabetes mellitus and subclinical inflammation have stimulated coagulation, activated platelets and endothelial dysfunction. Recent studies with the direct factor Xa inhibitor rivaroxaban in combination with low-dose aspirin demonstrated a significant reduction of major cardiovascular events, especially in individuals with type 2 diabetes and proven cardiovascular disease. Therefore, we asked the question of whether treatment with rivaroxaban could influence endothelial function, arterial stiffness and platelet activation.

Methods

We conducted a multi-centre, prospective, randomised, open-label trial in 179 participants with type 2 diabetes (duration 2–20 years), subclinical inflammation (high-sensitivity C-reactive protein 2–10 mg/l) and at least two traits of the metabolic syndrome to compare the effects of the direct factor Xa inhibitor rivaroxaban (5 mg twice daily) vs aspirin (100 mg every day) on endothelial function (assessed by forearm occlusion plethysmography), skin blood flow (assessed by laser-Doppler fluxmetry), arterial stiffness (assessed by pulse wave velocity) and serum biomarkers of endothelial function and inflammation. Furthermore, we investigated phosphorylation of vasodilator-stimulated phosphoprotein (VASP) in platelets, the concentration of platelet-derived microparticles (PMPs) and the effects of isolated PMPs on HUVEC proliferation in vitro.

Results

Rivaroxaban treatment for 20 weeks (n = 89) resulted in a significant improvement of post-ischaemic forearm blood flow (3.6 ± 4.7 vs 1.0 ± 5.2 ml/100 ml, p = 0.004), a numerically increased skin blood flow and reduced soluble P-Selectin plasma level vs aspirin. We did not find significant differences of arterial stiffness or further biomarkers. Neither rivaroxaban nor aspirin influenced VASP phosphorylation of platelets. The number of PMPs increased significantly with both rivaroxaban (365.2 ± 372.1 vs 237.4 ± 157.1 μl⁻¹, p = 0.005) and aspirin (266.0 ± 212.7 vs 201.7 ± 162.7 μl⁻¹, p = 0.021). PMPs of rivaroxaban-treated participants stimulated HUVEC proliferation in vitro compared with aspirin. Rivaroxaban was associated with a higher number of bleeding events.

Conclusions/interpretation

Our findings indicate that the direct factor Xa inhibitor rivaroxaban improved endothelial function in participants with type 2 diabetes and subclinical inflammation but also increased the risk of bleeding.

Trial registration:

ClinicalTrials.gov NCT02164578.

Funding

The study was supported by a research grant from Bayer Vital AG, Germany.

Graphical abstract

中文翻译：

利伐沙班与低剂量阿司匹林对 2 型糖尿病和高心血管风险个体的比较：一项评估对内皮功能、血小板活化和血管生物标志物影响的随机试验

目标/假设

患有 2 型糖尿病和亚临床炎症的个体会刺激凝血、活化血小板和内皮功能障碍。最近的 Xa 因子直接抑制剂利伐沙班联合低剂量阿司匹林的研究表明，主要心血管事件显着减少，尤其是在患有 2 型糖尿病和已证实有心血管疾病的个体中。因此，我们提出了利伐沙班治疗是否会影响内皮功能、动脉僵硬度和血小板活化的问题。

方法

我们对 179 名患有 2 型糖尿病（持续 2-20 年）、亚临床炎症（高敏 C 反应蛋白 2-10 mg/l）和至少代谢综合征的两个特征，比较直接因子 Xa 抑制剂利伐沙班（5 mg，每天两次）与阿司匹林（100 mg，每天）对内皮功能（通过前臂闭塞体积描记法评估）、皮肤血流量（通过激光-多普勒通量测定）、动脉僵硬度（通过脉搏波速度评估）和内皮功能和炎症的血清生物标志物。此外，我们研究了血小板中血管扩张剂刺激的磷蛋白 (VASP) 的磷酸化、血小板衍生微粒 (PMP) 的浓度以及分离的 PMP 对体外 HUVEC 增殖的影响。

结果

利伐沙班治疗 20 周 ( n = 89) 显着改善缺血后前臂血流量 (3.6 ± 4.7 vs 1.0 ± 5.2 ml/100 ml, p = 0.004)，皮肤血流量增加，可溶性 P 减少-选择素血浆水平与阿司匹林。我们没有发现动脉僵硬度或其他生物标志物的显着差异。利伐沙班和阿司匹林均不影响血小板的 VASP 磷酸化。^{利伐沙班（365.2 ± 372.1 vs 237.4 ± 157.1 μl -1}，p = 0.005）和阿司匹林（266.0 ± 212.7 vs 201.7 ± 162.7 μl ^-1，p ）的 PMP 数量显着增加 = 0.021)。与阿司匹林相比，利伐沙班治疗的参与者的 PMP 在体外刺激 HUVEC 增殖。利伐沙班与更多的出血事件相关。