Switching from Warfarin to rivaroxaban induces sufficiency of vitamin K and reduction of arterial stiffness in patients with atrial fibrillation

Ikari, Yuji; Saito, Fumie; Kiyooka, Takahiko; Nagaoka, Masakazu; Kimura, Manabu; Furuki, Takayuki; Tanaka, Shigemitsu

doi:10.1007/s00380-020-01651-8

Cited by 7 publications

(8 citation statements)

References 23 publications

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“…Therefore, we can assume that 20 weeks of rivaroxaban treatment did not significantly improve stiffness of large conductance arteries. In contrast to our findings, a short-term investigation over 3 months demonstrated an improvement of arterial stiffness with rivaroxaban treatment compared with warfarin in individuals with non-valvular atrial fibrillation; however, this study mainly represented a worsening of arterial stiffness with warfarin rather than an improvement with rivaroxaban [ 12 ].…”

Section: Discussioncontrasting

confidence: 99%

“…Animal and cell culture studies established a clear effect of factor Xa on platelet activation and endothelial cell dysfunction via the protease-activated receptors (PAR) [ 10 ]. Furthermore, there is some evidence from small clinical trials that beyond the anti-coagulatory action, inhibition of factor Xa could have additional anti-inflammatory actions that might evolve some beneficial effects in the microcirculation [ 11 ] or improve arterial stiffness, as observed in individuals with atrial fibrillation [ 12 ]. However, effects on endothelial function in individuals receiving direct factor Xa inhibition have never been measured before.…”

Section: Introductionmentioning

confidence: 99%

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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

et al. 2021

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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

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Section: Discussioncontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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“…Despite improvements in dp-ucMGP levels in both the rivaroxaban and rivaroxaban plus vitamin K2 arms, no differences were noted in vascular stiffness, coronary artery calcification or aortic calcification scores compared to the control group at 18 months. This contrasts with results from a trial of 80 patients with atrial fibrillation reported from Japan [58]; short-term substitution of warfarin with rivaroxaban produced a small but statistically significant improvement in brachial-ankle pulse wave velocity at 3 months (1.4% improvement in the rivaroxaban group; 3.5% worsening in warfarin group). Vascular calcification was not measured in this trial.…”

Section: Recent Intervention Studies Using Vitamin K To Prevent or Re...contrasting

confidence: 98%

Vitamin K and vascular calcification

Lees

Mark

Witham

2021

Current Opinion in Nephrology &Amp; Hypertension

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Purpose of reviewVascular calcification is a common and important cardiovascular risk factor in patients with chronic kidney disease (CKD). Recent advances in the understanding of the biology of vascular calcification implicate vitamin K-dependent proteins as important regulators in this process. This review highlights recent key advances in vascular biology, epidemiology, and clinical trials in this rapidly evolving field.Recent findingsVitamin K deficiency is associated with increasing severity of vascular calcification among patients with CKD, but the relationship with cardiovascular disease and mortality is inconsistent. Vitamin K may reduce calcification propensity by improving the activity of vitamin K-dependent calcification inhibitors or by down-regulating components of the innate immune system to reduce inflammation. However, recent randomized controlled trials in patients with diabetes, CKD, renal transplant, and on hemodialysis have failed to demonstrate improvement in vascular calcification or stiffness after vitamin K treatment.SummaryCurrent evidence does not support a clinically useful role for vitamin K supplementation to prevent or reverse vascular calcification in patients with CKD. Knowledge gaps remain, particularly whether higher doses of vitamin K, longer duration of supplementations, or use a vitamin K as a part of a package of measures to counteract vascular calcification might be effective.

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“…This was associated with a significant reduction in arterial stiffness via brachial–ankle PWV. 30 The role of active MGP seems to extend beyond protection from calcification and is implicated in reduced elastin degradation and collagen formation in the arterial wall, both of which can potentially improve arterial stiffness. 31 …”

Section: Vitamin K-dependent Proteins and Cardiovascular Healthmentioning

confidence: 99%

Vitamin K₂—a neglected player in cardiovascular health: a narrative review

et al. 2021

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Vitamin K2 serves an important role in cardiovascular health through regulation of calcium homeostasis. Its effects on the cardiovascular system are mediated through activation of the anti-calcific protein known as matrix Gla protein. In its inactive form, this protein is associated with various markers of cardiovascular disease including increased arterial stiffness, vascular and valvular calcification, insulin resistance and heart failure indices which ultimately increase cardiovascular mortality. Supplementation of vitamin K2 has been strongly associated with improved cardiovascular outcomes through its modification of systemic calcification and arterial stiffness. Although its direct effects on delaying the progression of vascular and valvular calcification is currently the subject of multiple randomised clinical trials, prior reports suggest potential improved survival among cardiac patients with vitamin K2 supplementation. Strengthened by its affordability and Food and Drug Adminstration (FDA)-proven safety, vitamin K2 supplementation is a viable and promising option to improve cardiovascular outcomes.

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Switching from Warfarin to rivaroxaban induces sufficiency of vitamin K and reduction of arterial stiffness in patients with atrial fibrillation

Cited by 7 publications

References 23 publications

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

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

Vitamin K and vascular calcification

Vitamin K₂—a neglected player in cardiovascular health: a narrative review

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Switching from Warfarin to rivaroxaban induces sufficiency of vitamin K and reduction of arterial stiffness in patients with atrial fibrillation

Cited by 7 publications

References 23 publications

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

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

Vitamin K and vascular calcification

Vitamin K2—a neglected player in cardiovascular health: a narrative review

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Vitamin K₂—a neglected player in cardiovascular health: a narrative review