Korean Circ J.  2018 Oct;48(10):873-889. 10.4070/kcj.2018.0261.

Anticoagulation for Stroke Prevention in Older Adults with Atrial Fibrillation and Comorbidity: Current Evidence and Treatment Challenges

• Sabbag A
• Yao X
• Siontis KC
• Noseworthy PA

• KMID: 2420640
• DOI: http://doi.org/10.4070/kcj.2018.0261

Abstract

The burden of atrial fibrillation (AF) is projected to increase substantially over the next decade in parallel with the aging of the population. The increasing age, level of comorbidity, and polypharmacy will complicate the treatment of older adults with AF. For instance, advanced age and chronic kidney disease have been shown to increase the risk of both thromboembolism and bleeding in patients with AF. Frailty, recurrent falls and polypharmacy, while very common among elderly patients with AF, are often overlooked in the clinical decision making despite their significant interaction with oral anticoagulant (OAC) and profound impact on the patient's clinical outcomes. Such factors should be recognized, evaluated and considered in a comprehensive decision-making process. The introduction of non-vitamin K oral anticoagulants has radically changed the management of AF allowing for a more individualized selection of OAC. An understanding of the available data regarding the performance of each of the available OAC in a variety of at risk patient populations is paramount for the safe and effective management of this patient population. The aim of this review is to appraise the current evidence, point out the gaps in knowledge, and provide recommendations regarding stroke prevention in older adults with AF and comorbid conditions.

Keyword

Frailty; Warfarin; NOAC; Stroke; Bleeding

MeSH Terms

Accidental Falls
Adult*
Aged
Aging
Anticoagulants
Atrial Fibrillation*
Clinical Decision-Making
Comorbidity*
Hemorrhage
Humans
Polypharmacy
Renal Insufficiency, Chronic
Stroke*
Thromboembolism
Warfarin
Anticoagulants
Warfarin

Reference

1. Chugh SS, Havmoeller R, Narayanan K, et al. Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 study. Circulation. 2014; 129:837–847.

2. Miyasaka Y, Barnes ME, Gersh BJ, et al. Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence. Circulation. 2006; 114:119–125.

3. Stroke Risk in Atrial Fibrillation Working Group. Independent predictors of stroke in patients with atrial fibrillation: a systematic review. Neurology. 2007; 69:546–554.

4. Lopes RD, Guimarães PO, Kolls BJ, et al. Intracranial hemorrhage in patients with atrial fibrillation receiving anticoagulation therapy. Blood. 2017; 129:2980–2987.

5. Kooiman J, van de Peppel WR, van der Meer FJ, Huisman MV. Incidence of chronic kidney disease in patients with atrial fibrillation and its relevance for prescribing new oral antithrombotic drugs. J Thromb Haemost. 2011; 9:1652–1653.

6. Hart RG, Eikelboom JW, Brimble KS, McMurtry MS, Ingram AJ. Stroke prevention in atrial fibrillation patients with chronic kidney disease. Can J Cardiol. 2013; 29:S71–8.

7. Soliman EZ, Prineas RJ, Go AS, et al. Chronic kidney disease and prevalent atrial fibrillation: the Chronic Renal Insufficiency Cohort (CRIC). Am Heart J. 2010; 159:1102–1107.

8. Jha V, Garcia-Garcia G, Iseki K, et al. Chronic kidney disease: global dimension and perspectives. Lancet. 2013; 382:260–272.

9. Kaufman DW, Kelly JP, Rosenberg L, Anderson TE, Mitchell AA. Recent patterns of medication use in the ambulatory adult population of the United States: the Slone survey. JAMA. 2002; 287:337–344.

10. Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest. 2010; 138:1093–1100.

11. Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation. Chest. 2010; 137:263–272.

12. Kato ET, Giugliano RP, Ruff CT, et al. Efficacy and safety of edoxaban in elderly patients with atrial fibrillation in the ENGAGE AF-TIMI 48 trial. J Am Heart Assoc. 2016; 5:e003432.

13. Mant J, Hobbs FD, Fletcher K, et al. Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomised controlled trial. Lancet. 2007; 370:493–503.

14. Hart RG, Benavente O, McBride R, Pearce LA. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis. Ann Intern Med. 1999; 131:492–501.

15. Chao TF, Liu CJ, Lin YJ, et al. Oral anticoagulation in very elderly patients with atrial fibrillation: a nationwide cohort study. Circulation. 2018; 138:37–47.

16. Lauw MN, Eikelboom JW, Coppens M, et al. Effects of dabigatran according to age in atrial fibrillation. Heart. 2017; 103:1015–1023.

17. Romanelli RJ, Nolting L, Dolginsky M, Kym E, Orrico KB. Dabigatran versus warfarin for atrial fibrillation in real-world clinical practice: a systematic review and meta-analysis. Circ Cardiovasc Qual Outcomes. 2016; 9:126–134.

18. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011; 365:883–891.

19. Halperin JL, Hankey GJ, Wojdyla DM, et al. Efficacy and safety of rivaroxaban compared with warfarin among elderly patients with nonvalvular atrial fibrillation in the Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF). Circulation. 2014; 130:138–146.

20. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011; 365:981–992.

21. Halvorsen S, Atar D, Yang H, et al. Efficacy and safety of apixaban compared with warfarin according to age for stroke prevention in atrial fibrillation: observations from the ARISTOTLE trial. Eur Heart J. 2014; 35:1864–1872.

22. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013; 369:2093–2104.

23. Kanapuru B, Ershler WB. Inflammation, coagulation, and the pathway to frailty. Am J Med. 2009; 122:605–613.

24. Rockwood K, Song X, MacKnight C, et al. A global clinical measure of fitness and frailty in elderly people. CMAJ. 2005; 173:489–495.

25. Gale CR, Cooper C, Sayer AA. Prevalence of frailty and disability: findings from the English Longitudinal Study of Ageing. Age Ageing. 2015; 44:162–165.

26. Harttgen K, Kowal P, Strulik H, Chatterji S, Vollmer S. Patterns of frailty in older adults: comparing results from higher and lower income countries using the Survey of Health, Ageing and Retirement in Europe (SHARE) and the Study on Global AGEing and Adult Health (SAGE). PLoS One. 2013; 8:e75847.

27. Bandeen-Roche K, Seplaki CL, Huang J, et al. Frailty in older adults: a nationally representative profile in the United States. J Gerontol A Biol Sci Med Sci. 2015; 70:1427–1434.

28. Fried LP, Tangen CM, Walston J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci. 2001; 56:M146–57.

29. Rockwood K, Howlett SE, MacKnight C, et al. Prevalence, attributes, and outcomes of fitness and frailty in community-dwelling older adults: report from the Canadian study of health and aging. J Gerontol A Biol Sci Med Sci. 2004; 59:1310–1317.

30. Shamliyan T, Talley KM, Ramakrishnan R, Kane RL. Association of frailty with survival: a systematic literature review. Ageing Res Rev. 2013; 12:719–736.

31. Sourial N, Wolfson C, Bergman H, et al. A correspondence analysis revealed frailty deficits aggregate and are multidimensional. J Clin Epidemiol. 2010; 63:647–654.

32. Polidoro A, Stefanelli F, Ciacciarelli M, Pacelli A, Di Sanzo D, Alessandri C. Frailty in patients affected by atrial fibrillation. Arch Gerontol Geriatr. 2013; 57:325–327.

33. Kim SW, Yoon SJ, Choi JY, et al. Clinical implication of frailty assessment in older patients with atrial fibrillation. Arch Gerontol Geriatr. 2017; 70:1–7.

34. Lefebvre MC, St-Onge M, Glazer-Cavanagh M, et al. The effect of bleeding risk and frailty status on anticoagulation patterns in octogenarians with atrial fibrillation: the FRAIL-AF study. Can J Cardiol. 2016; 32:169–176.

35. Perera V, Bajorek BV, Matthews S, Hilmer SN. The impact of frailty on the utilisation of antithrombotic therapy in older patients with atrial fibrillation. Age Ageing. 2009; 38:156–162.

36. Martinez BK, Sood NA, Bunz TJ, Coleman CI. Effectiveness and safety of apixaban, dabigatran, and rivaroxaban versus warfarin in frail patients with nonvalvular atrial fibrillation. J Am Heart Assoc. 2018; 7:e008643.

37. Segal JB, Chang HY, Du Y, Walston JD, Carlson MC, Varadhan R. Development of a claims-based frailty indicator anchored to a well-established frailty phenotype. Med Care. 2017; 55:716–722.

38. Andrassy KM. Comments on ‘KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease’. Kidney Int. 2013; 84:622–623.

39. Yagmur E, Frank RD, Neulen J, Floege J, Mühlfeld AS. Platelet Hyperaggregability is highly prevalent in patients with chronic kidney disease: an underestimated risk indicator of thromboembolic events. Clin Appl Thromb Hemost. 2015; 21:132–138.

40. Nelson SE, Shroff GR, Li S, Herzog CA. Impact of chronic kidney disease on risk of incident atrial fibrillation and subsequent survival in Medicare patients. J Am Heart Assoc. 2012; 1:e002097.

41. Hwang HS, Park MW, Yoon HE, et al. Clinical significance of chronic kidney disease and atrial fibrillation on morbidity and mortality in patients with acute myocardial infarction. Am J Nephrol. 2014; 40:345–352.

42. Watanabe H, Watanabe T, Sasaki S, Nagai K, Roden DM, Aizawa Y. Close bidirectional relationship between chronic kidney disease and atrial fibrillation: the Niigata preventive medicine study. Am Heart J. 2009; 158:629–636.

43. Bansal N, Fan D, Hsu CY, Ordonez JD, Marcus GM, Go AS. Incident atrial fibrillation and risk of end-stage renal disease in adults with chronic kidney disease. Circulation. 2013; 127:569–574.

44. Olesen JB, Lip GY, Kamper AL, et al. Stroke and bleeding in atrial fibrillation with chronic kidney disease. N Engl J Med. 2012; 367:625–635.

45. Molshatzki N, Orion D, Tsabari R, et al. Chronic kidney disease in patients with acute intracerebral hemorrhage: association with large hematoma volume and poor outcome. Cerebrovasc Dis. 2011; 31:271–277.

46. Lee JG, Lee KB, Jang IM, et al. Low glomerular filtration rate increases hemorrhagic transformation in acute ischemic stroke. Cerebrovasc Dis. 2013; 35:53–59.

47. Sohal AS, Gangji AS, Crowther MA, Treleaven D. Uremic bleeding: pathophysiology and clinical risk factors. Thromb Res. 2006; 118:417–422.

48. Benigni A, Boccardo P, Galbusera M, et al. Reversible activation defect of the platelet glycoprotein IIb–IIIa complex in patients with uremia. Am J Kidney Dis. 1993; 22:668–676.

49. Ng KP, Edwards NC, Lip GY, Townend JN, Ferro CJ. Atrial fibrillation in CKD: balancing the risks and benefits of anticoagulation. Am J Kidney Dis. 2013; 62:615–632.

50. Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J. 2016; 37:2893–2962.

51. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2014; 64:e1–76.

52. Piccini JP, Stevens SR, Chang Y, et al. Renal dysfunction as a predictor of stroke and systemic embolism in patients with nonvalvular atrial fibrillation: validation of the R₂CHADS₂ index in the ROCKET AF (Rivaroxaban Once-daily, oral, direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation) and ATRIA (AnTicoagulation and Risk factors In Atrial fibrillation) study cohorts. Circulation. 2013; 127:224–232.

53. Roldán V, Marín F, Manzano-Fernandez S, et al. Does chronic kidney disease improve the predictive value of the CHADS₂ and CHA₂DS₂-VASc stroke stratification risk scores for atrial fibrillation? Thromb Haemost. 2013; 109:956–960.

54. Lau YC, Proietti M, Guiducci E, Blann AD, Lip GY. Atrial fibrillation and thromboembolism in patients with chronic kidney disease. J Am Coll Cardiol. 2016; 68:1452–1464.

55. Lip GY, Skjoth F, Nielsen PB, Kjaeldgaard JN, Larsen TB. The HAS-BLED, ATRIA, and ORBIT bleeding scores in atrial fibrillation patients using non-vitamin K antagonist oral anticoagulants. Am J Med. 2018; 131:574.e13–574.e27.

56. Olesen JB, Lip GY, Lindhardsen J, et al. Risks of thromboembolism and bleeding with thromboprophylaxis in patients with atrial fibrillation: a net clinical benefit analysis using a ‘real world’ nationwide cohort study. Thromb Haemost. 2011; 106:739–749.

57. Providência R, Marijon E, Boveda S, et al. Meta-analysis of the influence of chronic kidney disease on the risk of thromboembolism among patients with nonvalvular atrial fibrillation. Am J Cardiol. 2014; 114:646–653.

58. Bonde AN, Lip GY, Kamper AL, et al. Net clinical benefit of antithrombotic therapy in patients with atrial fibrillation and chronic kidney disease: a nationwide observational cohort study. J Am Coll Cardiol. 2014; 64:2471–2482.

59. Friberg L, Rosenqvist M, Lip GY. Evaluation of risk stratification schemes for ischaemic stroke and bleeding in 182,678 patients with atrial fibrillation: the Swedish Atrial Fibrillation cohort study. Eur Heart J. 2012; 33:1500–1510.

60. Yang F, Hellyer JA, Than C, et al. Warfarin utilisation and anticoagulation control in patients with atrial fibrillation and chronic kidney disease. Heart. 2017; 103:818–826.

61. Bohula EA, Giugliano RP, Ruff CT, et al. Impact of renal function on outcomes with edoxaban in the ENGAGE AF-TIMI 48 trial. Circulation. 2016; 134:24–36.

62. Fox KA, Piccini JP, Wojdyla D, et al. Prevention of stroke and systemic embolism with rivaroxaban compared with warfarin in patients with non-valvular atrial fibrillation and moderate renal impairment. Eur Heart J. 2011; 32:2387–2394.

63. Hijazi Z, Hohnloser SH, Oldgren J, et al. Efficacy and safety of dabigatran compared with warfarin in relation to baseline renal function in patients with atrial fibrillation: a RE-LY (Randomized Evaluation of Long-term Anticoagulation Therapy) trial analysis. Circulation. 2014; 129:961–970.

64. Hohnloser SH, Hijazi Z, Thomas L, et al. Efficacy of apixaban when compared with warfarin in relation to renal function in patients with atrial fibrillation: insights from the ARISTOTLE trial. Eur Heart J. 2012; 33:2821–2830.

65. Kimachi M, Furukawa TA, Kimachi K, Goto Y, Fukuma S, Fukuhara S. Direct oral anticoagulants versus warfarin for preventing stroke and systemic embolic events among atrial fibrillation patients with chronic kidney disease. Cochrane Database Syst Rev. 2017; CD011373.

66. Seliger SL, Gillen DL, Tirschwell D, Wasse H, Kestenbaum BR, Stehman-Breen CO. Risk factors for incident stroke among patients with end-stage renal disease. J Am Soc Nephrol. 2003; 14:2623–2631.

67. Zimmerman D, Sood MM, Rigatto C, Holden RM, Hiremath S, Clase CM. Systematic review and meta-analysis of incidence, prevalence and outcomes of atrial fibrillation in patients on dialysis. Nephrol Dial Transplant. 2012; 27:3816–3822.

68. Poli D, Antonucci E, Zanazzi M, et al. Impact of glomerular filtration estimate on bleeding risk in very old patients treated with vitamin K antagonists. Results of EPICA study on the behalf of FCSA (Italian Federation of Anticoagulation Clinics). Thromb Haemost. 2012; 107:1100–1106.

69. Shah M, Avgil Tsadok M, Jackevicius CA, et al. Warfarin use and the risk for stroke and bleeding in patients with atrial fibrillation undergoing dialysis. Circulation. 2014; 129:1196–1203.

70. Galloway PA, El-Damanawi R, Bardsley V, et al. Vitamin K antagonists predispose to calciphylaxis in patients with end-stage renal disease. Nephron. 2015; 129:197–201.

71. Lomashvili KA, Wang X, Wallin R, O'Neill WC. Matrix Gla protein metabolism in vascular smooth muscle and role in uremic vascular calcification. J Biol Chem. 2011; 286:28715–28722.

72. Nigwekar SU, Zhao S, Wenger J, et al. A nationally representative study of calcific uremic arteriolopathy risk factors. J Am Soc Nephrol. 2016; 27:3421–3429.

73. Chan KE, Edelman ER, Wenger JB, Thadhani RI, Maddux FW. Dabigatran and rivaroxaban use in atrial fibrillation patients on hemodialysis. Circulation. 2015; 131:972–979.

74. Stangier J, Rathgen K, Stähle H, Mazur D. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-centre study. Clin Pharmacokinet. 2010; 49:259–268.

75. Kubitza D, Becka M, Mueck W, et al. Effects of renal impairment on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban, an oral, direct factor Xa inhibitor. Br J Clin Pharmacol. 2010; 70:703–712.

76. Wang X, Tirucherai G, Marbury TC, et al. Pharmacokinetics, pharmacodynamics, and safety of apixaban in subjects with end-stage renal disease on hemodialysis. J Clin Pharmacol. 2016; 56:628–636.

77. Mavrakanas TA, Samer CF, Nessim SJ, Frisch G, Lipman ML. Apixaban pharmacokinetics at steady state in hemodialysis patients. J Am Soc Nephrol. 2017; 28:2241–2248.

78. Chokesuwattanaskul R, Thongprayoon C, Tanawuttiwat T, Kaewput W, Pachariyanon P, Cheungpasitporn W. Safety and efficacy of apixaban versus warfarin in patients with end-stage renal disease: meta-analysis. Pacing Clin Electrophysiol. 2018; 41:627–634.

79. Siontis KC, Zhang X, Eckard A, et al. Outcomes associated with apixaban use in end-stage kidney disease patients with atrial fibrillation in the United States. Circulation. 2018.

80. Koretsune Y, Yamashita T, Kimura T, Fukuzawa M, Abe K, Yasaka M. Short-term safety and plasma concentrations of edoxaban in Japanese patients with non-valvular atrial fibrillation and severe renal impairment. Circ J. 2015; 79:1486–1495.

81. De Vriese AS, Caluwé R, Bailleul E, et al. Dose-finding study of rivaroxaban in hemodialysis patients. Am J Kidney Dis. 2015; 66:91–98.

82. Steffel J, Verhamme P, Potpara TS, et al. The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Eur Heart J. 2018; 39:1330–1393.

83. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. Circulation. 2014; 130:e199–267.

84. Brodsky SV, Collins M, Park E, et al. Warfarin therapy that results in an international normalization ratio above the therapeutic range is associated with accelerated progression of chronic kidney disease. Nephron Clin Pract. 2010; 115:c142–6.

85. Brodsky SV, Nadasdy T, Rovin BH, et al. Warfarin-related nephropathy occurs in patients with and without chronic kidney disease and is associated with an increased mortality rate. Kidney Int. 2011; 80:181–189.

86. Brodsky SV, Satoskar A, Chen J, et al. Acute kidney injury during warfarin therapy associated with obstructive tubular red blood cell casts: a report of 9 cases. Am J Kidney Dis. 2009; 54:1121–1126.

87. Ware K, Brodsky P, Satoskar AA, et al. Warfarin-related nephropathy modeled by nephron reduction and excessive anticoagulation. J Am Soc Nephrol. 2011; 22:1856–1862.

88. Böhm M, Ezekowitz MD, Connolly SJ, et al. Changes in renal function in patients with atrial fibrillation: an analysis from the RE-LY trial. J Am Coll Cardiol. 2015; 65:2481–2493.

89. Hijazi Z, Hohnloser SH, Andersson U, et al. Efficacy and safety of apixaban compared with warfarin in patients with atrial fibrillation in relation to renal function over time: Insights from the aristotle randomized clinical trial. JAMA Cardiol. 2016; 1:451–460.

90. Chan YH, Yeh YH, Hsieh MY, et al. The risk of acute kidney injury in Asians treated with apixaban, rivaroxaban, dabigatran, or warfarin for non-valvular atrial fibrillation: a nationwide cohort study in Taiwan. Int J Cardiol. 2018; 265:83–89.

91. Yao X, Tangri N, Gersh BJ, et al. Renal outcomes in anticoagulated patients with atrial fibrillation. J Am Coll Cardiol. 2017; 70:2621–2632.

92. Banerjee A, Clementy N, Haguenoer K, Fauchier L, Lip GY. Prior history of falls and risk of outcomes in atrial fibrillation: the Loire Valley Atrial Fibrillation Project. Am J Med. 2014; 127:972–978.

93. Man-Son-Hing M, Nichol G, Lau A, Laupacis A. Choosing antithrombotic therapy for elderly patients with atrial fibrillation who are at risk for falls. Arch Intern Med. 1999; 159:677–685.

94. Gage BF, Birman-Deych E, Kerzner R, Radford MJ, Nilasena DS, Rich MW. Incidence of intracranial hemorrhage in patients with atrial fibrillation who are prone to fall. Am J Med. 2005; 118:612–617.

95. Garwood CL, Corbett TL. Use of anticoagulation in elderly patients with atrial fibrillation who are at risk for falls. Ann Pharmacother. 2008; 42:523–532.

96. Donzé J, Clair C, Hug B, et al. Risk of falls and major bleeds in patients on oral anticoagulation therapy. Am J Med. 2012; 125:773–778.

97. Steffel J, Giugliano RP, Braunwald E, et al. Edoxaban versus warfarin in atrial fibrillation patients at risk of falling: ENGAGE AF-TIMI 48 analysis. J Am Coll Cardiol. 2016; 68:1169–1178.

98. Rao MP, Vinereanu D, Wojdyla DM, et al. Clinical outcomes and history of fall in patients with atrial fibrillation treated with oral anticoagulation: insights from the ARISTOTLE trial. Am J Med. 2018; 131:269–275.e2.

99. Bushardt RL, Massey EB, Simpson TW, Ariail JC, Simpson KN. Polypharmacy: misleading, but manageable. Clin Interv Aging. 2008; 3:383–389.

100. Proietti M, Raparelli V, Olshansky B, Lip GY. Polypharmacy and major adverse events in atrial fibrillation: observations from the AFFIRM trial. Clin Res Cardiol. 2016; 105:412–420.

101. Wang Y, Singh S, Bajorek B. Old age, high risk medication, polypharmacy: a ‘trilogy’ of risks in older patients with atrial fibrillation. Pharm Pract (Granada). 2016; 14:706.

102. Gómez C, Vega-Quiroga S, Bermejo-Pareja F, Medrano MJ, Louis ED, Benito-León J. Polypharmacy in the elderly: a marker of increased risk of mortality in a population-based prospective study (NEDICES). Gerontology. 2015; 61:301–309.

103. Maher RL, Hanlon J, Hajjar ER. Clinical consequences of polypharmacy in elderly. Expert Opin Drug Saf. 2014; 13:57–65.

104. Lim LM, McStea M, Chung WW, et al. Prevalence, risk factors and health outcomes associated with polypharmacy among urban community-dwelling older adults in multi-ethnic Malaysia. PLoS One. 2017; 12:e0173466.

105. Jaspers Focks J, Brouwer MA, Wojdyla DM, et al. Polypharmacy and effects of apixaban versus warfarin in patients with atrial fibrillation: post hoc analysis of the ARISTOTLE trial. BMJ. 2016; 353:i2868.

106. Holbrook A, Schulman S, Witt DM, et al. Evidence-based management of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012; 141:e152S–e184S.

107. Battistella M, Mamdami MM, Juurlink DN, Rabeneck L, Laupacis A. Risk of upper gastrointestinal hemorrhage in warfarin users treated with nonselective NSAIDs or COX-2 inhibitors. Arch Intern Med. 2005; 165:189–192.

108. Chang SH, Chou IJ, Yeh YH, et al. Association between use of non-vitamin K oral anticoagulants with and without concurrent medications and risk of major bleeding in nonvalvular atrial fibrillation. JAMA. 2017; 318:1250–1259.

109. Piccini JP, Hellkamp AS, Washam JB, et al. Polypharmacy and the efficacy and safety of rivaroxaban versus warfarin in the prevention of stroke in patients with nonvalvular atrial fibrillation. Circulation. 2016; 133:352–360.