Concerns about clinical efficacy and safety of warfarin in diabetic patients with atrial fibrillation
Cardiovascular Diabetology volume 18, Article number: 12 (2019)
Atrial fibrillation (AF) is one of the most common arrhythmias in elderly people. The risk of thromboembolic stroke is increased in AF patients, especially those with diabetes. Anticoagulant therapy, such as warfarin and non-vitamin K oral anticoagulants (NOACs), is recommended for diabetic patients with AF. However, recent guidelines do not preferentially recommend NOACs over warfarin for diabetic patients. Variability of glycemic control in diabetic patients could affect the pharmacokinetics and anticoagulant activity of warfarin, therefore, the risk–benefit balance of warfarin is prone to be compromised in diabetic patients with AF. Furthermore, since warfarin inhibits the vitamin K-dependent gamma-glutamyl carboxylation of proteins, including osteocalcin and matrix Gla protein, use of warfarin may increase the risk of osteoporotic bone fracture and vascular calcification, both of which are the leading causes of morbidity that diminish the quality of life in diabetic patients. Even though the cost of NOACs is high, NOACs may be preferable to warfarin for the treatment of diabetic patients with AF.
A number of papers have suggested that diabetes is one of the risk factors for development of atrial fibrillation (AF) [1,2,3]. The Framingham Heart Study showed that comorbidity-adjusted risk for developing AF was 1.4 and 1.6 in diabetic men and women, respectively . Meta-analysis of 7 prospective cohort and 4 case–control studies comprised of about 1,686,000 people revealed that hazard ratio for developing AF in type 2 diabetic patients was 1.39 compared with non-diabetic subjects . Furthermore, a recent prospective study comprised of about 35,000 type 1 diabetic patients and age-, sex-, and birthplace-matched 175,000 controls also showed that patients with type 1 diabetes had a significantly higher risk for developing AF compared with controls; hazard ratios for AF in type 1 diabetic patients versus controls were 1.13 in men and 1.50 in women . Since the excess risk for developing AF was larger in diabetic patients with poor glycemic control or a long disease duration, cumulative hyperglycemic exposure may partly contribute to new-onset AF in diabetic patients [1,2,3]. Oxidative stress and inflammation have also been shown to play a role in the pathogenesis of AF in diabetes [4, 5].
CHA2DS2-VASc score is used for stroke risk stratification for AF patients in current guidelines, which is calculated by awarding 1 point each for congestive heart failure, hypertension, diabetes, presence of vascular disease, age 65–74 years, and female, and assigning 2 points for age ≥ 75 years and presence of prior stroke or transient ischemic attack . Oral anticoagulant therapy, such as warfarin and non-vitamin K oral anticoagulants (NOACs) is recommend for AF patients with CHA2DS2-VASc score of 2 . Among the CHA2DS2-VASc score components, diabetes is one of the stronger risk factors for ischemic stroke in AF patients; hazard ratios for ischemic stroke are 2.66 in both diabetic men and women compared with non-diabetic individuals . Hyperglycemia is associated with enhanced thrombin formation in patients with diabetes or cardiovascular disease, which could increase the risk of thromboembolic events [8, 9]. Meta-analysis of four randomized clinical trials to compare the efficacy and safety of NOACs with warfarin revealed that NOACs significantly reduced stroke or systemic embolic events, intracranial hemorrhage, and all-cause mortality without the increased risk of bleeding except for gastrointestinal bleeding in a broad range of AF patients, including those with diabetes [10, 11]. However, recent guidelines do not preferentially recommend NOACs over warfarin for diabetic patients . Here I would like to raise clinical concerns about the use of warfarin for diabetic patients with AF (Fig. 1).
Non-enzymatic glycation of amino groups of proteins has progressed under hyperglycemic conditions, which could alter the structure and function of various circulating and tissue matrix proteins, thus being involved in diabetes-associated complications, such as atherosclerotic cardiovascular disease and osteoporosis . Compared with control albumin, glycated albumin or albumin purified from diabetic patients had the decreased binding affinity to warfarin with higher free fraction of this anticoagulant . Therefore, variability of glycated albumin, a marker of short-term (2–3 weeks) glycemic control, may affect the pharmacokinetics of warfarin and its anticoagulant activity in diabetic patients. Indeed, when patients were stratified by quartile of international normalized ratio (INR) values out of range, presence of diabetes was independently associated with worst INR control in warfarin-treated AF patients . The efficacy and safety of warfarin are totally dependent on the time in therapeutic range (TTR) of INR; 10% decrease in TTR is associated with about 10% rise in ischemic stroke and thromboembolic events . Risk of major bleeding was significantly higher in AF patients receiving warfarin with TTR < 66% than those treated by NOACs . These findings suggest that risk–benefit balance of warfarin is prone to be compromised in AF patients with diabetes.
Warfarin exerts anticoagulant effects by inhibiting the vitamin K-dependent gamma-glutamyl carboxylation of clotting factors II, VII, IX, and X [16, 17]. However, this type of posttranslational modification is also essential for the proper functioning of other gamma-carboxyglutamic acid (Gla) proteins, such as osteocalcin (bone Gla protein) and matrix Gla protein (MGP) [16, 17]. Osteocalcin-deficient mice have been shown to develop hyperostosis, whereas gamma-carboxylation confers a greater Ca-binding capacity to osteocalcin, playing a crucial role in normal bone mineralization [16, 17]. Therefore, warfarin may have deleterious effects on bone health. Circulating vitamin K levels were decreased in women with osteoporotic hip fracture and inversely correlated with incidence of vertebral fracture [16, 17]. High levels of undercarboxylated osteocalcin, a marker of low vitamin K status, were associated with the reduced lumber bone mineral density and predicted the increased risk of hip fracture in healthy women [16, 17]. Moreover, intake of vitamin K-rich food is restricted in AF patients receiving warfarin. In consistent with these findings, the risk of osteoporotic bone fracture was reported to be significantly increased in elderly patients with AF receiving long-term warfarin therapy compared with untreated subjects . Meta-analysis revealed that the risk of bone fracture was significantly lower in AF patients receiving NOACs compared with warfarin . As is the case with AF, osteoporotic bone fracture is increased in both type 1 and type 2 diabetic patients, especially in those with a long-term disease history . Given the potential adverse effects of warfarin on osteoporotic bone fracture, NOACs may be safer than warfarin for the treatment of diabetic patients with AF.
MGP is a Ca-binding extracellular matrix protein with inhibitory effects on soft tissue calcification, which is mainly produced by chondrocytes and vascular smooth muscle cells [20,21,22,23,24]. While MGP-knockout mice displayed massive arterial calcification, warfarin, but not rivaroxaban induced vascular calcification in apolipoprotein E-deficient mice [21, 22]. Undercarboxylated and nonphosphorylated MGP levels predicted the risk of all-cause mortality and cardiovascular death in a general population . Use of vitamin K antagonists (VKAs), such as warfarin, was associated with the increased risk for coronary artery calcification in patients irrespective of the presence or absence of AF; mean coronary calcification scores were significantly increased with the duration of VKA use [22, 23]. Moreover, supplementation of vitamin K was reported to significantly inhibit the progression of coronary artery calcification in elderly patients . Since coronary artery calcification is more prevalent in diabetes and predicts future cardiovascular events and death , NOACs would seem preferable to warfarin for prevention of atherosclerotic cardiovascular disease. Further randomized controlled trials of NOACs vs. warfarin in diabetic patients with AF are warranted to address these clinical concerns about warfarin use.
Given the instability of anticoagulant activity of warfarin and its potential deleterious effects on bone and vasculature, NOACs may be preferable to warfarin for the treatment of diabetic patients with AF.
non-vitamin K oral anticoagulants
international normalized ratio
time in therapeutic range
matrix Gla protein
vitamin K antagonists
Benjamin EJ, Levy D, Vaziri SM, D'Agostino RB, Belanger AJ, Wolf PA. Independent risk factors for atrial fibrillation in a population-based cohort. The Framingham Heart Study. JAMA. 1994;271:840–4.
Huxley RR, Filion KB, Konety S, Alonso A. Meta-analysis of cohort and case-control studies of type 2 diabetes mellitus and risk of atrial fibrillation. Am J Cardiol. 2011;108:56–62.
Dahlqvist S, Rosengren A, Gudbjörnsdottir S, Pivodic A, Wedel H, Kosiborod M, Svensson AM, Lind M. Risk of atrial fibrillation in people with type 1 diabetes compared with matched controls from the general population: a prospective case-control study. Lancet Diabetes Endocrinol. 2017;5:799–807.
Karam BS, Chavez-Moreno A, Koh W, Akar JG, Akar FG. Oxidative stress and inflammation as central mediators of atrial fibrillation in obesity and diabetes. Cardiovasc Diabetol. 2017;16:120.
Ziolo MT, Mohler PJ. Defining the role of oxidative stress in atrial fibrillation and diabetes. J Cardiovasc Electrophysiol. 2015;26:223–5.
Plitt A, McGuire DK, Giugliano RP. Atrial Fibrillation, Type 2 Diabetes, and Non-Vitamin K Antagonist Oral Anticoagulants: A Review. JAMA Cardiol. 2017;2:442–8.
Chao TF, Liu CJ, Wang KL, Lin YJ, Chang SL, Lo LW, Hu YF, Tuan TC, Chen TJ, Lip GY, Chen SA. Should atrial fibrillation patients with 1 additional risk factor of the CHA2DS2-VASc score (beyond sex) receive oral anticoagulation? J Am Coll Cardiol. 2015;65:635–42.
Ceriello A, Giacomello R, Stel G, Motz E, Taboga C, Tonutti L, Pirisi M, Falleti E, Bartoli E. Hyperglycemia-induced thrombin formation in diabetes. The possible role of oxidative stress. Diabetes. 1995;44:924–8.
Lee S, Ay C, Kopp CW, Panzer S, Gremmel T. Impaired glucose metabolism is associated with increased thrombin generation potential in patients undergoing angioplasty and stenting. Cardiovasc Diabetol. 2018;17:131.
Ruff CT, Giugliano RP, Braunwald E, Hoffman EB, Deenadayalu N, Ezekowitz MD, Camm AJ, Weitz JI, Lewis BS, Parkhomenko A, Yamashita T, Antman EM. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet. 2014;383:955–62.
Ezekowitz JA, Lewis BS, Lopes RD, Wojdyla DM, McMurray JJ, Hanna M, Atar D, Cecilia Bahit M, Keltai M, Lopez-Sendon JL, Pais P, Ruzyllo W, Wallentin L, Granger CB, Alexander JH. Clinical outcomes of patients with diabetes and atrial fibrillation treated with apixaban: results from the ARISTOTLE trial. Eur Heart J Cardiovasc Pharmacother. 2015;1:86–94.
Yamagishi S. Potential clinical utility of advanced glycation end product cross-link breakers in age- and diabetes-associated disorders. Rejuvenation Res. 2012;15:564–72.
Baraka-Vidot J, Guerin-Dubourg A, Bourdon E, Rondeau P. Impaired drug-binding capacities of in vitro and in vivo glycated albumin. Biochimie. 2012;94:1960–7.
Nelson WW, Desai S, Damaraju CV, Lu L, Fields LE, Wildgoose P, Schein JR. International normalized ratio stability in warfarin-experienced patients with nonvalvular atrial fibrillation. Am J Cardiovasc Drugs. 2015;15:205–11.
Smith DE, Xuereb CB, Pattison HM, Lip GY, Lane DA. TRial of an Educational intervention on patients' knowledge of Atrial fibrillation and anticoagulant therapy, INR control, and outcome of Treatment with warfarin (TREAT). BMC Cardiovasc Disord. 2010;10:21.
Gundberg CM, Nieman SD, Abrams S, Rosen H. Vitamin K status and bone health: an analysis of methods for determination of undercarboxylated osteocalcin. J Clin Endocrinol Metab. 1998;83:3258–66.
Yamauchi M, Yamaguchi T, Nawata K, Takaoka S, Sugimoto T. Relationships between undercarboxylated osteocalcin and vitamin K intakes, bone turnover, and bone mineral density in healthy women. Clin Nutr. 2010;29:761–5.
Gage BF, Birman-Deych E, Radford MJ, NIlasena DS, Binder EF. Risk of osteoporotic fracture in elderly patients taking warfarin: results from the National Registry of Atrial Fibrillation 2. Arch Intern Med. 2006;166:241–6.
Gu ZC, Zhou LY, Shen L, Zhang C, Pu J, Lin HW, Liu XY. Non-vitamin K Antagonist Oral anticoagulants vs. warfarin at risk of fractures: a systematic review and meta-analysis of randomized controlled trials. Front Pharmacol. 2018;9:348.
Liu YP, Gu YM, Thijs L, Knapen MH, Salvi E, Citterio L, Petit T, Carpini SD, Zhang Z, Jacobs L, Jin Y, Barlassina C, Manunta P, Kuznetsova T, Verhamme P, Struijker-Boudier HA, Cusi D, Vermeer C, Staessen JA. Inactive matrix Gla protein is causally related to adverse health outcomes: a Mendelian randomization study in a Flemish population. Hypertension. 2015;65:463–70.
Rattazzi M, Faggin E, Bertacco E, Nardin C, Pagliani L, Plebani M, Cinetto F, Guidolin D, Puato M, Pauletto P. Warfarin, but not rivaroxaban, promotes the calcification of the aortic valve in ApoE-/- mice. Cardiovasc Ther. 2018;36:e12438.
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. Vitamin K-antagonists accelerate atherosclerotic calcification and induce a vulnerable plaque phenotype. PLoS ONE. 2012;7:e43229.
Weijs B, Blaauw Y, Rennenberg RJ, Schurgers LJ, Timmermans CC, Pison L, Nieuwlaat R, Hofstra L, Kroon AA, Wildberger J, Crijns HJ. Patients using vitamin K antagonists show increased levels of coronary calcification: an observational study in low-risk atrial fibrillation patients. Eur Heart J. 2011;32:2555–622.
Bell DSH, Goncalves E. Should we still be utilizing warfarin in the type 2 diabetic patient? Diabetes Obes Metab. 2018;20:2327–9.
Shea MK, O'Donnell CJ, Hoffmann U, Dallal GE, Dawson-Hughes B, Ordovas JM, Price PA, Williamson MK, Booth SL. Vitamin K supplementation and progression of coronary artery calcium in older men and women. Am J Clin Nutr. 2009;89:1799–807.
Kramer CK, Zinman B, Gross JL, Canani LH, Rodrigues TC, Azevedo MJ, Retnakaran R. Coronary artery calcium score prediction of all cause mortality and cardiovascular events in people with type 2 diabetes: systematic review and meta-analysis. BMJ. 2013;346:f1654.
SY conceptualized and designed the study, acquired, analyzed, and interpreted data, and drafted the manuscript, and took responsibility for the integrity of the data and the accuracy of the data analysis. The author read and approved the final manuscript.
There is no conflict of interest in this paper.
Availability of data and materials
All data generated or analyzed during this study are included in this published article.
Consent for publication
Ethics approval and consent to participate
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Yamagishi, Si. Concerns about clinical efficacy and safety of warfarin in diabetic patients with atrial fibrillation. Cardiovasc Diabetol 18, 12 (2019). https://doi.org/10.1186/s12933-019-0818-0