Subscribe to RSS
Vitamin K Antagonists, Non–Vitamin K Antagonist Oral Anticoagulants, and Vascular Calcification in Patients with Atrial Fibrillation
09 April 2018
21 September 2018
10 November 2018 (online)
Background Vitamin K antagonists (VKAs) are associated with coronary artery calcification in low-risk populations, but their effect on calcification of large arteries remains uncertain. The effect of non–vitamin K antagonist oral anticoagulants (NOACs) on vascular calcification is unknown. We investigated the influence of use of VKA and NOAC on calcification of the aorta and aortic valve.
Methods In patients with atrial fibrillation without a history of major adverse cardiac or cerebrovascular events who underwent computed tomographic angiography, the presence of ascending aorta calcification (AsAC), descending aorta calcification (DAC), and aortic valve calcification (AVC) was determined. Confounders for VKA/NOAC treatment were identified and propensity score adjusted logistic regression explored the association between treatment and calcification (Agatston score > 0). AsAC, DAC, and AVC differences were assessed in propensity score–matched groups.
Results Of 236 patients (33% female, age: 58 ± 9 years), 71 (30%) used VKA (median duration: 122 weeks) and 79 (34%) used NOAC (median duration: 16 weeks). Propensity score–adjusted logistic regression revealed that use of VKA was significantly associated with AsAC (odds ratio [OR]: 2.31; 95% confidence interval [CI]: 1.16–4.59; p = 0.017) and DAC (OR: 2.38; 95% CI: 1.22–4.67; p = 0.012) and a trend in AVC (OR: 1.92; 95% CI: 0.98–3.80; p = 0.059) compared with non-anticoagulation. This association was absent in NOAC versus non-anticoagulant (AsAC OR: 0.51; 95% CI: 0.21–1.21; p = 0.127; DAC OR: 0.80; 95% CI: 0.36–1.76; p = 0.577; AVC OR: 0.62; 95% CI: 0.27–1.40; p = 0.248). A total of 178 patients were propensity score matched in three pairwise comparisons. Again, use of VKA was associated with DAC (p = 0.043) and a trend toward more AsAC (p = 0.059), while use of NOAC was not (AsAC p = 0.264; DAC p = 0.154; AVC p = 0.280).
Conclusion This cross-sectional study shows that use of VKA seems to contribute to vascular calcification. The calcification effect was not observed in NOAC users.
Keywordscardiac events - computed tomographic imaging - aortic and arterial diseases - atrial fibrillation - oral anticoagulant treatment
All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.
- 1 van Gorp RH, Schurgers LJ. New insights into the pros and cons of the clinical use of vitamin K antagonists (VKAs) versus direct oral anticoagulants (DOACs). Nutrients 2015; 7 (11) 9538-9557
- 2 Koos R, Mahnken AH, Mühlenbruch G. , et al. Relation of oral anticoagulation to cardiac valvular and coronary calcium assessed by multislice spiral computed tomography. Am J Cardiol 2005; 96 (06) 747-749
- 3 Lerner RG, Aronow WS, Sekhri A. , et al. Warfarin use and the risk of valvular calcification. J Thromb Haemost 2009; 7 (12) 2023-2027
- 4 Schurgers LJ, Aebert H, Vermeer C, Bültmann B, Janzen J. Oral anticoagulant treatment: friend or foe in cardiovascular disease?. Blood 2004; 104 (10) 3231-3232
- 5 Rennenberg RJ, Kessels AG, Schurgers LJ, van Engelshoven JM, de Leeuw PW, Kroon AA. Vascular calcifications as a marker of increased cardiovascular risk: a meta-analysis. Vasc Health Risk Manag 2009; 5 (01) 185-197
- 6 Kirchhof P, Benussi S, Kotecha D. , et al; ESC Scientific Document Group. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J 2016; 37 (38) 2893-2962
- 7 Sterne JA, Bodalia PN, Bryden PA. , et al. Oral anticoagulants for primary prevention, treatment and secondary prevention of venous thromboembolic disease, and for prevention of stroke in atrial fibrillation: systematic review, network meta-analysis and cost-effectiveness analysis. Health Technol Assess 2017; 21 (09) 1-386
- 8 Morishima Y, Kamisato C, Honda Y, Furugohri T, Shibano T. The effects of warfarin and edoxaban, an oral direct factor Xa inhibitor, on gammacarboxylated (Gla-osteocalcin) and undercarboxylated osteocalcin (uc-osteocalcin) in rats. Thromb Res 2013; 131 (01) 59-63
- 9 Weijs B, Blaauw Y, Rennenberg RJ. , et al. Patients using vitamin K antagonists show increased levels of coronary calcification: an observational study in low-risk atrial fibrillation patients. Eur Heart J 2011; 32 (20) 2555-2562
- 10 Assmann G, Cullen P, Schulte H. Simple scoring scheme for calculating the risk of acute coronary events based on the 10-year follow-up of the prospective cardiovascular Münster (PROCAM) study. Circulation 2002; 105 (03) 310-315
- 11 Agatston AS, Janowitz WR, Hildner FJ, Zusmer NR, Viamonte Jr M, Detrano R. Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol 1990; 15 (04) 827-832
- 12 Evangelista A, Flachskampf F, Lancellotti P. , et al; European Association of Echocardiography. European Association of Echocardiography recommendations for standardization of performance, digital storage and reporting of echocardiographic studies. Eur J Echocardiogr 2008; 9 (04) 438-448
- 13 Rassen JA, Shelat AA, Franklin JM, Glynn RJ, Solomon DH, Schneeweiss S. Matching by propensity score in cohort studies with three treatment groups. Epidemiology 2013; 24 (03) 401-409
- 14 Blackstone EH. Comparing apples and oranges. J Thorac Cardiovasc Surg 2002; 123 (01) 8-15
- 15 Rennenberg RJ, van Varik BJ, Schurgers LJ. , et al. Chronic coumarin treatment is associated with increased extracoronary arterial calcification in humans. Blood 2010; 115 (24) 5121-5123
- 16 Holden RM, Sanfilippo AS, Hopman WM, Zimmerman D, Garland JS, Morton AR. Warfarin and aortic valve calcification in hemodialysis patients. J Nephrol 2007; 20 (04) 417-422
- 17 Schurgers LJ, Uitto J, Reutelingsperger CP. Vitamin K-dependent carboxylation of matrix Gla-protein: a crucial switch to control ectopic mineralization. Trends Mol Med 2013; 19 (04) 217-226
- 18 Luo G, Ducy P, McKee MD. , et al. Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein. Nature 1997; 386 (6620): 78-81
- 19 Price PA, Faus SA, Williamson MK. Warfarin causes rapid calcification of the elastic lamellae in rat arteries and heart valves. Arterioscler Thromb Vasc Biol 1998; 18 (09) 1400-1407
- 20 Dowd P, Hershline R, Ham SW, Naganathan S. Vitamin K and energy transduction: a base strength amplification mechanism. Science 1995; 269 (5231): 1684-1691
- 21 Schurgers LJ, Spronk HM, Skepper JN. , et al. Post-translational modifications regulate matrix Gla protein function: importance for inhibition of vascular smooth muscle cell calcification. J Thromb Haemost 2007; 5 (12) 2503-2511
- 22 Beulens JW, Bots ML, Atsma F. , et al. High dietary menaquinone intake is associated with reduced coronary calcification. Atherosclerosis 2009; 203 (02) 489-493
- 23 Gast GC, de Roos NM, Sluijs I. , et al. A high menaquinone intake reduces the incidence of coronary heart disease. Nutr Metab Cardiovasc Dis 2009; 19 (07) 504-510
- 24 Cranenburg EC, Koos R, Schurgers LJ. , et al. Characterisation and potential diagnostic value of circulating matrix Gla protein (MGP) species. Thromb Haemost 2010; 104 (04) 811-822
- 25 Kälsch H, Lehmann N, Möhlenkamp S. , et al; Investigator Group of the Heinz Nixdorf Recall Study. Prevalence of thoracic aortic calcification and its relationship to cardiovascular risk factors and coronary calcification in an unselected population-based cohort: the Heinz Nixdorf Recall Study. Int J Cardiovasc Imaging 2013; 29 (01) 207-216
- 26 Kälsch H, Lehmann N, Berg MH. , et al. Coronary artery calcification outperforms thoracic aortic calcification for the prediction of myocardial infarction and all-cause mortality: the Heinz Nixdorf Recall Study. Eur J Prev Cardiol 2014; 21 (09) 1163-1170
- 27 Kälsch H, Lehmann N, Moebus S. , et al. Aortic calcification onset and progression: association with the development of coronary atherosclerosis. J Am Heart Assoc 2017; 6 (04) e005093
- 28 Caluwé R, Pyfferoen L, De Boeck K, De Vriese AS. The effects of vitamin K supplementation and vitamin K antagonists on progression of vascular calcification: ongoing randomized controlled trials. Clin Kidney J 2016; 9 (02) 273-279
- 29 Kadoglou NP, Moustardas P, Katsimpoulas M. , et al. The beneficial effects of a direct thrombin inhibitor, dabigatran etexilate, on the development and stability of atherosclerotic lesions in apolipoprotein E-deficient mice: dabigatran etexilate and atherosclerosis. Cardiovasc Drugs Ther 2012; 26 (05) 367-374
- 30 Eikelboom JW, Connolly SJ, Bosch J. , et al; COMPASS Investigators. Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med 2017; 377 (14) 1319-1330