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.
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17 March 2017
An erratum to this article has been published.
References
Kishima H, Mine T, Kodani T, Masuyama T (2015) Prediction of left atrial thrombi in patients with atrial tachyarrhythmias during warfarin administration: retrospective study in Hyogo College of Medicine. Heart Vessels 30:331–337
Bügel S (2008) Vitamin K and bone health in adult humans. Vitam Horm 78:393–416
Fusaro M, D’Alessandro C, Noale M, Tripepi G, Plebani M, Veronese N, Iervasi G, Giannini S, Rossini M, Tarroni G, Lucatello S, Vianello A, Santinello I, Bonfante L, Fabris F, Sella S, Piccoli A, Naso A, Ciurlino D, Aghi A, Gallieni M, Cupisti A (2016) Low vitamin K1 intake in haemodialysis patients. Clin Nutr (Epub ahead of print)
Caluwe R, Pyfferoen L, De Boeck K, De Vriese AS (2016) The effects of vitamin K supplementation and vitamin K antagonists on progression of vascular calcification: ongoing randomized controlled trials. Clin Kidney J 9:273–279
Fusaro M, Crepaldi G, Maggi S, D’Angelo A, Calo L, Miozzo D, Fornasieri A, Gallieni M (2011) Bleeding, vertebral fractures and vascular calcifications in patients treated with warfarin: hope for lower risks with alternative therapies. Curr Vasc Pharmacol 9:763–769
Poterucha TJ, Goldhaber SZ (2016) Warfarin and vascular calcification. Am J Med 129:635.e631–635.e634
Gage BF, Birman-Deych E, Radford MJ, Nilasena DS, Binder EF (2006) Risk of osteoporotic fracture in elderly patients taking warfarin: results from the National Registry of Atrial Fibrillation 2. Arch Intern Med 166:241–246
Kovac JR, Gomez L, Smith RP, Coward RM, Gonzales MA, Khera M, Lamb DJ, Lipshultz LI (2014) Measurement of endothelial dysfunction via peripheral arterial tonometry predicts vasculogenic erectile dysfunction. Int J Impot Res 26:218–222
Nichols WW, Singh BM (2002) Augmentation index as a measure of peripheral vascular disease state. Curr Opin Cardiol 17:543–551
Namba S, Yamaoka-Tojo M, Hashikata T, Ikeda Y, Kitasato L, Hashimoto T, Shimohama T, Tojo T, Takahira N, Masud T, Ako J (2015) Long-term warfarin therapy and biomarkers for osteoporosis and atherosclerosis. BBA Clin 4: 76–80
Kasukawa Y, Miyakoshi N, Ebina T, Aizawa T, Hongo M, Nozaka K, Ishikawa Y, Saito H, Chida S, Shimada Y (2014) Effects of risedronate alone or combined with vitamin K2 on serum undercarboxylated osteocalcin and osteocalcin levels in postmenopausal osteoporosis. J Bone Miner Metab 32:290–297
Avbersek-Luznik I, Gmeiner Stopar T, Marc J (2007) Activity or mass concentration of bone-specific alkaline phosphatase as a marker of bone formation. Clin Chem Lab Med 45:1014–1018
Orito S, Kuroda T, Onoe Y, Sato Y, Ohta H (2009) Age-related distribution of bone and skeletal parameters in 1,322 Japanese young women. J Bone Miner Metab 27:698–704
Poole KE, Reeve J (2005) Parathyroid hormone - a bone anabolic and catabolic agent. Curr Opin Pharmacol 5:612–617
Murer H, Biber J (2010) Phosphate transport in the kidney. J Nephrol 23(Suppl 16):S145–S151
Kurata M, Okura T, Watanabe S, Fukuoka T, Higaki J (2006) Osteopontin and carotid atherosclerosis in patients with essential hypertension. Clin Sci (Lond) 111:319–324
Franzen A, Heinegard D (1985) Isolation and characterization of two sialoproteins present only in bone calcified matrix. Biochem J 232:715–724
Wolak T (2014) Osteopontin—a multi-modal marker and mediator in atherosclerotic vascular disease. Atherosclerosis 236:327–337
Chen J, Lu Y, Huang D, Luo X, Zhang Y (2014) Relationship of osteopontin and renal function with severity of coronary artery lesions. Int J Clin Exp Med 7:1122–1127
Kahles F, Findeisen HM, Bruemmer D (2014) Osteopontin: a novel regulator at the cross roads of inflammation, obesity and diabetes. Mol Metab 3: 384–393
Mohamadpour AH, Abdolrahmani L, Mirzaei H, Sahebkar A, Moohebati M, Ghorbani M, Ferns GA, Ghayour-Mobarhan M (2015) Serum osteopontin concentrations in relation to coronary artery disease. Arch Med Res 46:112–117
Lee CJ, Wang JH, Chen YC, Chen ML, Yang CF, Hsu BG (2014) Serum osteopontin level correlates with carotid-femoral pulse wave velocity in geriatric persons. Biomed Res Int 570698
Bazzichi L, Ghiadoni L, Rossi A, Bernardini M, Lanza M, De Feo F, Giacomelli C, Mencaroni I, Raimo K, Rossi M, Mazzone AM, Taddei S, Bombardieri S (2009) Osteopontin is associated with increased arterial stiffness in rheumatoid arthritis. Mol Med 15:402–406
Osako MK, Nakagami H, Shimamura M, Koriyama H, Nakagami F, Shimizu H, Miyake T, Yoshizumi M, Rakugi H, Morishita R (2013) Cross-talk of receptor activator of nuclear factor-kappaB ligand signaling with renin–angiotensin system in vascular calcification. Arterioscler Thromb Vasc Biol 33:1287–1296
Ndip A, Wilkinson FL, Jude EB, Boulton AJ, Alexander MY (2014) RANKL-OPG and RAGE modulation in vascular calcification and diabetes: novel targets for therapy. Diabetologia 57:2251–2260
Shimamura M, Nakagami H, Osako MK, Kurinami H, Koriyama H, Zhengda P, Tomioka H, Tenma A, Wakayama K, Morishita R (2014) OPG/RANKL/RANK axis is a critical inflammatory signaling system in ischemic brain in mice. Proc Natl Acad Sci USA 111:8191–8196
Hashikata T, Yamaoka-Tojo M, Namba S, Kitasato L, Kameda R, Murakami M, Niwano H, Shimohama T, Tojo T, Ako J (2015) Rivaroxaban inhibits angiotensin II-induced activation in cultured mouse cardiac fibroblasts through the modulation of NF-kappaB pathway. Int Heart J 56:544–550
Tomiyama H, Yamashina A (2010) Non-invasive vascular function tests: their pathophysiological background and clinical application. Circ J 74:24–33
Vermeer C, Theuwissen E (2011) Vitamin K, osteoporosis and degenerative diseases of ageing. Menopause Int 17:19–23
Betge S, Kretzschmar D, Figulla HR, Lichtenauer M, Jung C (2016) Predictive value of the augmentation index derived vascular age in patients with newly diagnosed atherosclerosis. Heart Vessels. doi:10.1007/s00380-016-0868-0
Schurgers LJ, Joosen IA, Laufer EM, Chatrou ML, Herfs M, Winkens MH, Westenfeld R, Veulemans V, Krueger T, Shanahan CM, Jahnen-Dechent W, Biessen E, Narula J, Vermeer C, Hofstra L, Reutelingsperger CP (2012) Vitamin K-antagonists accelerate atherosclerotic calcification and induce a vulnerable plaque phenotype. PLoS One 7:e43229
Hara T, Fukuda D, Tanaka K, Higashikuni Y, Hirata Y, Nishimoto S, Yagi S, Yamada H, Soeki T, Wakatsuki T, Shimabukuro M, Sata M (2015) Rivaroxaban, a novel oral anticoagulant, attenuates atherosclerotic plaque progression and destabilization in ApoE-deficient mice. Atherosclerosis 242:639–646
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Dr. Minako Yamaoka-Tojo was partly supported by grants from Bayer Pharma, Daiichi-Sankyo, and Boehringer Ingelheim. Dr. Junya Ako received speaking honorarium from Tanabe Mitsubishi, Daiichi-Sankyo, MSD K.K., Boehringer Ingelheim, Kowa, and Kyowa Hakko Kirin. Other authors have nothing to disclose regarding this manuscript.
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An erratum to this article is available at https://doi.org/10.1007/s00380-017-0966-7.
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Namba, S., Yamaoka-Tojo, M., Kakizaki, R. et al. Effects on bone metabolism markers and arterial stiffness by switching to rivaroxaban from warfarin in patients with atrial fibrillation. Heart Vessels 32, 977–982 (2017). https://doi.org/10.1007/s00380-017-0950-2
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DOI: https://doi.org/10.1007/s00380-017-0950-2