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

Pistrosch, Frank; Matschke, Jan; Schipp, Dorothea; Schipp, Bernhard; Henkel, Elena; Weigmann, Ingo; Sradnick, Jan; Bornstein, Stefan R.; Birkenfeld, Andreas L.; Hanefeld, Markolf

doi:10.1007/s00125-021-05562-9

Cited by 14 publications

(7 citation statements)

References 41 publications

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“…Some preclinical evidence showed the anti-inflammatory effects of rivaroxaban in inducing atherosclerotic plaque stabilization, 2 reducing serum levels of proinflammatory molecules such as monocyte chemoattractant protein-1 (MCP-1), IL-6, and tumor necrosis factor-alpha (TNF-α) 3 and inhibiting FXa-mediated macrophage inflammasome activities in ApoE −/− mice. 4 Moreover, some clinical studies confirmed the decreased serum levels of inflammatory markers among patients with atrial fibrillation (AF) 5,6 or diabetes 7 on rivaroxaban therapy at standard (20/15 mg OD) or nonapproved reduced dose (5 mg TD). No data are available about the anti-inflammatory effects of rivaroxaban 2.5 TD and aspirin 100 mg among patients with CAD and/or PAD.…”

Section: Discussionmentioning

confidence: 97%

“…1 The underlying mechanisms explaining these latter CV benefits are not clearly understood; however, previous evidence suggested an anti-inflammatory effect of rivaroxaban in different clinical settings. [2][3][4][5][6][7] Particularly, interleukin-6 (IL-6) is a proinflammatory cytokine which plays a key role in the pathogenesis of atherosclerosis 8 ; its serum levels were associated with atherosclerotic CV events and mortality. 9 Our explorative observational study aimed to evaluate the effects of the association of rivaroxaban and aspirin on plasma inflammation and coagulation markers among real-world patients with CAD and/or PAD.…”

Section: Introductionmentioning

confidence: 99%

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Dual Pathway Inhibition with Rivaroxaban and Aspirin Reduces Inflammatory Biomarkers in Atherosclerosis

Russo

Fabiani

Leonardi

et al. 2023

Journal of Cardiovascular Pharmacology

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Dual pathway inhibition (DPI) with low-dose rivaroxaban and aspirin in patients with coronary artery disease (CAD) and/or peripheral artery disease (PAD) reduces the occurrence of cardiovascular (CV) events; however, the underlying mechanisms explaining these latter CV benefits are not clearly understood. Our explorative observational study aimed to evaluate the effect of dual pathway inhibition on plasma inflammation and coagulation markers among real-world patients with CAD and/or PAD. We prospectively included all consecutive patients with an established diagnosis of CAD and/or PAD treated with aspirin 100 mg once daily (OD) and rivaroxaban 2.5 mg twice daily (TD). Clinical evaluation and laboratory analyses, including hemoglobin, renal function (creatinine, urea, and cystatin-C), coagulation markers (INR and aPTT), inflammation markers (IL-6, CRP, lipoprotein-associated phospholipase A2, and copeptin), and growth differentiation factor-15 (GDF-15), were conducted at baseline, before starting treatment, and at 4 and 24 weeks after study drug administration. Fifty-four consecutive patients (mean age 66 6 7 years; male 83%) who completed the 6-month follow-up were included. At 24-week follow-up, a statistically significant reduction in IL-6 serum levels [4.6 (3.5-6.5) vs. 3.4 (2.4-4.3) pg/mL; P = 0.0001] and fibrinogen [336 (290-390) vs. 310 (275-364) mg/dL; P = 0.04] was shown; moreover, a significant increase in GDF-15 serum level [1309 (974-1961) vs. 1538 (1286-2913) pg/mL; P = 0.002] was observed. Hemoglobin, renal function, and cardiovascular homeostasis biomarkers remain stable over the time. The anti-Xa activity at both [0.005 (0-0.02) vs. 0.2 (0.1-0.34); P , 0.0001) significantly increased. The dual pathway inhibitions with low-dose rivaroxaban and aspirin in patients with CAD and/or PAD were associated with the reduction of inflammation biomarkers.

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Dual Pathway Inhibition with Rivaroxaban and Aspirin Reduces Inflammatory Biomarkers in Atherosclerosis

Russo

Fabiani

Leonardi

et al. 2023

Journal of Cardiovascular Pharmacology

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“…We, therefore, chose a dose of 10 mg/kg/day, at which improvement in vascular remodeling provided data to support the benefits of low-dose aspirin. Although aspirin has been comprehensively used in populations, comparatively, its clinical reports about arterial stiffness are not too many [ 19 , 61 , 62 ], and none of them involve mechanism explanation. It is taken for granted anti-platelet effect duo to direct correlation of platelet activation with arterial stiffness [ 63 , 64 , 65 ].…”

Section: Discussionmentioning

confidence: 99%

Effects of Long-Term Intervention with Losartan, Aspirin and Atorvastatin on Vascular Remodeling in Juvenile Spontaneously Hypertensive Rats

et al. 2023

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Hypertension in adolescents is associated with adverse cardiac and vascular events. In addition to lowering blood pressure, it is not clear whether pharmacological therapy in early life can improve vascular remodeling. This study aimed to evaluate the effects of long-term administration of losartan, aspirin, and atorvastatin on vascular remodeling in juvenile spontaneously hypertensive rats (SHRs). Losartan, aspirin, and atorvastatin were administered via gavage at doses of 20, 10, and 10 mg/kg/day, respectively, on SHRs aged 6–22 weeks. Paraffin sections of the blood vessels were stained with hematoxylin-eosin (H&E) and Sirius Red to evaluate the changes in the vascular structure and the accumulation of different types of collagen. The plasma levels of renin, angiotensin II (Ang II), aldosterone (ALD), endothelin-1 (ET-1), interleukin-6 (IL-6), and neutrophil elastase (NE) were determined using ELISA kits. After the 16-week treatment with losartan, aspirin, and atorvastatin, the wall thickness of the thoracic aorta and carotid artery decreased. The integrity of the elastic fibers in the tunica media was maintained in an orderly manner, and collagen deposition in the adventitia was retarded. The plasma levels of renin, ALD, ET-1, IL-6, and NE in the SHRs also decreased. These findings suggest that losartan, aspirin, and atorvastatin could improve vascular remodeling beyond their antihypertensive, anti-inflammatory, and lipid-lowering effects. Many aspects of the protection provided by pharmacological therapy are important for the prevention of cardiovascular diseases in adults and older adults.

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“…Thus, rivaroxaban prevented replicative senescence in HUVECs and aortic endothelial cells, restored endothelial function and prevented the progression of atherosclerosis [ 97 ]. A clinical study with type 2 diabetes mellitus and subclinical inflammation showed that rivaroxaban compared to Aspirin could improve endothelial function based different measures such as post-ischaemic forearm blood flow during reactive hyperaemia, skin blood flow, sP-Selectin or platelet-derived microparticles which stimulate endothelial repair [ 98 ].…”

Section: Methodsmentioning

confidence: 99%

The effect of rivaroxaban on biomarkers in blood and plasma: a review of preclinical and clinical evidence

Schiffer

Schwers

Heitmeier

2023

J Thromb Thrombolysis

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Rivaroxaban is a direct, oral factor Xa inhibitor that is used for the prevention and treatment of various thromboembolic disorders. Several preclinical and clinical studies have utilized specific molecules as biomarkers to investigate the potential role of rivaroxaban beyond its anticoagulant activity and across a range of biological processes. The aim of this review is to summarize the existing evidence regarding the use of blood-based biomarkers to characterize the effects of rivaroxaban on coagulation and other pathways, including platelet activation, inflammation and endothelial effects. After a literature search using PubMed, almost 100 preclinical and clinical studies were identified that investigated the effects of rivaroxaban using molecular biomarkers. In agreement with the preclinical data, clinical studies reported a trend for reduction in the blood concentrations of D-dimers, thrombin–antithrombin complex and prothrombin fragment 1 + 2 following treatment with rivaroxaban in both healthy individuals and those with various chronic conditions. Preclinical and also some clinical studies have also reported a potential impact of rivaroxaban on the concentrations of platelet activation biomarkers (von Willebrand factor, P-selectin and thrombomodulin), endothelial activation biomarkers (matrix metalloproteinase-9, intercellular adhesion molecule-1 and vascular cell adhesion molecule-1) and inflammation biomarkers (interleukin-6, tumor necrosis factor-α and monocyte chemoattractant protein-1). Based on the results of biomarker studies, molecular biomarkers can be used in addition to traditional coagulation assays to increase the understanding of the anticoagulation effects of rivaroxaban. Moreover, there is preliminary evidence to suggest that rivaroxaban may have an impact on the biological pathways of platelet activation, endothelial activation and inflammation; however, owing to paucity of clinical data to investigate the trends reported in preclinical studies, further investigation is required to clarify these observations.

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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

Cited by 14 publications

References 41 publications

Dual Pathway Inhibition with Rivaroxaban and Aspirin Reduces Inflammatory Biomarkers in Atherosclerosis

Dual Pathway Inhibition with Rivaroxaban and Aspirin Reduces Inflammatory Biomarkers in Atherosclerosis

Effects of Long-Term Intervention with Losartan, Aspirin and Atorvastatin on Vascular Remodeling in Juvenile Spontaneously Hypertensive Rats

The effect of rivaroxaban on biomarkers in blood and plasma: a review of preclinical and clinical evidence

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