Effects on bone metabolism markers and arterial stiffness by switching to rivaroxaban from warfarin in patients with atrial fibrillation

Abstract

In recent years, direct oral anticoagulants (DOACs) of dabigatran, rivaroxaban, apixaban, edoxaban, which are all alternatives to warfarin, have been released. The use of DOACs is becoming more widespread in the clinical management of thrombotic stroke risk in patients with atrial fibrillation (AF). In large-scale clinical trials of each drug, DOACs were reported to inhibit intracranial hemorrhage, stroke, and death compared to warfarin. Warfarin is an endogenous vitamin K antagonist; therefore, patients who are taking warfarin must be prohibited from taking vitamin K. Vitamin K is an essential cofactor required for the ɤ-carboxylation of vitamin K-dependent proteins including coagulation factors, osteocalcin (OC), matrix Gla protein (MGP), and the growth arrest-specific 6 (GAS6). OC is a key factor for bone matrix formation. MGP is a local inhibitor of soft tissue calcification in the vessel wall. GAS6 prevents the apoptosis of vascular smooth muscle cells. Therefore, decrease of blood vitamin K levels may cause osteoporosis, vascular calcification, and the inhibition of vessels angiogenesis. This study aimed to evaluate the effects of changing from warfarin to rivaroxaban on bone mineral metabolism, vascular calcification, and vascular endothelial dysfunction. We studied 21 consecutive patients with persistent or chronic AF, who were treated with warfarin at least for 12 months. Warfarin administration was changed to rivaroxaban (10 or 15 mg/day) in all patients. Osteopontin (OPN), bone alkaline phosphatase (BAP), and under-carboxylated osteocalcin (ucOC) were measured. Pulse wave velocity (PWV) and augmentation index (AI) were also measured as atherosclerosis assessments. All measurements were done before and six months after the rivaroxaban treatment. There was a significant increase in serum level of BAP compared to baseline (12.5 ± 4.6 to 13.4 ± 4.1 U/L, P < 0.01). In contrast, there was a significant decrease in the serum level of ucOC (9.5 ± 5.0 to 2.7 ± 1.3 ng/ml, P < 0.01). Also, in the ucOC levels, there was a significant negative correlation between baseline values and baseline to 6-months changes in high ucOC group (r = -0.97, P < 0.01). The atherosclerosis- and osteoporosis-related biomarker, serum level of OPN were significantly decreased compared to baseline (268.3 ± 46.8 to 253.4 ± 47.1 ng/ml, P < 0.01). AI and PWV were significantly decreased after 6 months of treatment with rivaroxaban (33.9 ± 18.4 to 24.7 ± 18.4%, P = 0.04; 1638.8 ± 223.0 to 1613.0 ± 250.1 m/s, P = 0.03, respectively). Switching to rivaroxaban from warfarin in patients with atrial fibrillation was associated with an increase of bone formation markers and a decrease of bone resorption markers, and also improvements of PWV and AI.

New Anticoagulant Agents: Incidence of Adverse Drug Reactions and New Signals Thereof

“…37 Certain studies corroborate the fact that replacing VKAs with NOACs would improve the bone markers. 38 Likewise, our data support the notion that the continuous use of acenocoumarol increases osteoporosis risk as an adverse reaction. Some publications have focused on the possible usefulness of modifying the anticoagulant treatment in patients at risk for osteoporosis.…”

Osteocalcin, Vascular Calcification, and Atherosclerosis: A Systematic Review and Meta-analysis

“…An interesting study by Namba et al (75) examined the effect on bone metabolism markers and atherosclerosis measures in patients with atrial fibrillation when switching from warfarin (a vitamin K antagonist) to rivaroxaban (75). This study found ucOC concentrations to decrease after 6 months of rivaroxaban treatment as vitamin K was no longer prohibited.…”

Constitutive interpretation of arterial stiffness in clinical studies: a methodological review

“…Of those, the vast majority of papers (52 of 63 papers) described crosssectional associations of sub-ECM level factors with PWV (Tables 1, 2, 3, and 4). A small number of intervention studies (11 of 63 studies) addressed changes in arterial stiffness through modulation of ECM integrity (1,61,68,94,143) or smooth muscle tone (4,7,10,41,116,136). Only a handful (3 of 63 studies) used a modeling approach to quantitatively interpret these changes at the level of elastin, collagen, and ECM (42,64,125).…”