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Rivaroxaban compared with low-dose aspirin in individuals with type 2 diabetes and high cardiovascular risk: a
Frank Pistrosch1, Jan B Matschke2, Dorothea Schipp3
1Medical Clinic III, Universitätsklinikum 'Carl Gustav Carus', Dresden, Germany. frank.pistrosch@uniklinikum-dresden.de.
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.
Insights
Rivaroxaban improved endothelial function in type 2 diabetes patients with inflammation, but increased bleeding risk. Aspirin did not show these effects.
Area of Science:
- Cardiovascular Medicine
- Pharmacology
- Endocrinology
Background:
- Type 2 diabetes mellitus (T2DM) with subclinical inflammation is linked to stimulated coagulation, platelet activation, and endothelial dysfunction.
- Rivaroxaban, a direct factor Xa inhibitor, combined with aspirin, has shown cardiovascular benefits in T2DM patients with established cardiovascular disease.
Purpose of the Study:
- To investigate the effects of rivaroxaban versus aspirin on endothelial function, arterial stiffness, and platelet activation in individuals with T2DM and subclinical inflammation.
Main Methods:
- A multi-center, prospective, randomized trial involving 179 participants with T2DM and subclinical inflammation.
- Comparison of rivaroxaban (5 mg twice daily) versus aspirin (100 mg daily) for 20 weeks.
- Assessment of endothelial function, skin blood flow, arterial stiffness, inflammatory biomarkers, and platelet-derived microparticles (PMPs).
Main Results:
- Rivaroxaban significantly improved post-ischaemic forearm blood flow and numerically increased skin blood flow compared to aspirin.
- Rivaroxaban treatment led to a reduced soluble P-Selectin plasma level.
- Both rivaroxaban and aspirin increased PMPs, with rivaroxaban-associated PMPs stimulating HUVEC proliferation in vitro. Rivaroxaban was linked to more bleeding events.
Conclusions:
- Rivaroxaban demonstrates a beneficial effect on endothelial function in T2DM patients with subclinical inflammation.
- The pro-proliferative effect of rivaroxaban-associated PMPs warrants further investigation.
- Increased bleeding risk is a significant consideration with rivaroxaban treatment in this population.
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