Challenges in managing atrial fibrillation among older adults with recurrent falls

Contributed by:

Karen Leung MD/MSc, CCFP(COE)
(Click for bio)

Case

Mrs. Green is a mildly frail, 85-year-old who had a ground-level fall. This is her second fall in 12 months. She reports her heart is racing. Her blood pressure is 135/70 without orthostatic changes. An ECG shows new atrial fibrillation (AF) with a heart rate of 120, and a beta-blocker is initiated for rate control. A Holter shows paroxysmal AF with the longest run lasting six hours.

Her medical history includes hypertension, diabetes, GERD, chronic kidney disease (creatinine of 135 mol/L), osteoporosis and mild cognitive impairment. There is no valvular heart disease or previous strokes. She takes perindopril 8 mg daily, metformin 500 mg twice daily, pantoprazole 40 mg daily and aspirin 81 mg daily for primary prevention. She takes naproxen 500 mg as needed for osteoarthritis.

Background

The prevalence of nonvalvular AF increases significantly with age, from 0.7% in adults under age 60 to 17.8% in those over 85.¹ Ischemic stroke and systemic embolism are the major adverse consequences.^1,2 Because the annual stroke risk increases up to 4.4% in those over age 75, starting therapy for stroke prevention is the standard of care.³ However, all anticoagulants and antiplatelet agents increase the bleed risk, with intracranial hemorrhages being most concerning.^1-3 Some studies have found that the bleed risk nearly doubles among adults with recurrent falls, although estimates vary depending on ground-level versus high-impact falls.^4,5 Understandably, some clinicians are hesitant to start anticoagulation in adults prone to falls.

According to the 2020 Canadian Cardiovascular Society guidelines, shared decision-making with patients about their stroke versus bleed risks and treatment preferences is essential.³ Oral anticoagulation is recommended for adults over age 65 or those with one or more CHADS2 risk factors: heart failure, hypertension, diabetes and previous stroke/systemic embolism.³ Previous randomized controlled trials (RCTs) of warfarin have found that the annual stroke risk would decrease from 2.1% to 0.7% while the major bleed risk would increase from 0.5% to 1% per year.³ Furthermore, Markov modeling estimates that a person would have to fall 295 times in one year to outweigh the benefits of stroke prevention.⁶

Unless contraindicated, direct oral anticoagulants (DOACs) are recommended over both warfarin and aspirin for stroke prevention.³ The guidelines acknowledge that while concerning, falls alone should not deter anticoagulation because of the net clinical benefits of stroke prevention.³ The European Society of Cardiology suggests that alternatives to anticoagulation may be considered in conditions that cause frequent falls such as uncontrolled epilepsy or multiple systems atrophy with severe retropulsion.⁷ Clinicians should explore strategies to reduce bleed and falls risks.

Issue

Upwards of 30% of Canadians with AF who would otherwise qualify for anticoagulation do not receive therapy due to concerns of frailty and falls.² What is some of the evidence regarding using anticoagulants among older adults with recurrent falls?

Evidence

Much of the research supporting the use of DOACs over warfarin comes from four large RCTs of apixaban (ARISTOTLE),⁸ dabigatran (RE-LY),⁹ edoxaban (ENGAGE-TIMI-48)¹⁰ and rivaroxaban (ROCKET-AF).¹¹ A systematic review of 117 RCTs and observational studies using ‘real-world’ data totaling over 3.9 million participants suggests that apixaban and dabigatran significantly reduced the risk of stroke or systemic embolism while edoxaban and rivaroxaban were non-inferior to warfarin.¹² This network meta-analysis suggests that apixaban and edoxaban significantly reduced major bleeds while rivaroxaban and dabigatran had similar rates of bleeds as warfarin.¹²

Secondary analyses of ARISTOTLE and ENGAGE-TIMI-48 have examined falls risks. Among those with falls, apixaban compared to warfarin was associated with lower risks of intracranial hemorrhages (HR=0.19, 95%CI: 0.04–0.88) with no differences in strokes (HR=0.88, 95%CI: 0.40–1.93) and major bleeds (HR=0.81, 95%CI: 0.48–1.36).¹³ Similarly, no differences were observed in the efficacy or safety outcomes of edoxaban compared to warfarin.⁵ The authors of the analyses calculated that fewer than six persons with falls would need to be treated for 10 years with edoxaban to prevent either an intracranial hemorrhage or another secondary net clinical outcome including death, disabling stroke or life-threatening bleed.⁵

Aspirin is sometimes viewed as a safer compromise due to a lower perceived bleed risk while providing a 21% reduction in stroke risk.¹⁴ The AVERROES trial was a double-blinded RCT comparing apixaban to aspirin among 5,599 adults with AF and contraindications to warfarin use.¹⁵ The trial was terminated early in favor of apixaban, which showed a significant reduction in stroke or systemic embolism (HR=0.45, 95%CI: 0.32–0.62), a trend toward reduced mortality (HR=0.79, 95%CI: 0.62–1.02), and no difference in major bleeding including intracranial hemorrhages (HR=1.13, 95%CI: 0.74–1.75).¹⁵

In a subgroup analysis of AVERROES, these benefits extended to adults over 85. The absolute rate of stroke or systemic embolism was 1%/year among apixaban users and 7.5%/year among aspirin users (HR=0.14, 95%CI: 0.02–0.48).¹⁶ Similar risk of major bleeding was observed between apixaban and aspirin users (HR=0.96, 95%CI: 0.38–2.39) with a trend toward reduced intracranial hemorrhages among apixaban users (HR=0.17, 95%CI: 0.01–1.02).¹⁶

Back to the Case

Mrs. Green is tolerating the beta-blocker well. Her CHADS2 score is 3 (i.e., age, hypertension and diabetes) and HASBLED score is 2 (i.e., age and NSAID; no point for well-controlled hypertension). Her stroke risk is 5.9/100 patient-years with no treatment,¹⁷ and bleed risk is 1.88/100 patient-years.¹⁸ The bleed risk could be lowered further to 1.02/100 patient-years if she stops the NSAID.¹⁸ Mrs. Green is worried about strokes, as her older sister recently moved to a nursing home after a debilitating stroke.

A DOAC is recommended over warfarin because of the favorable stroke risk reduction, lower intracranial hemorrhage risk and ease of blister packing given her cognitive impairment. Based on AVERROES, apixaban is recommended over aspirin due to the superior stroke risk reduction and comparable bleed risk. Apixaban 2.5 mg twice daily is started because she meets two of the three criteria for reduced dosing (i.e., age over 80, creatinine over 133 mol/L or weight under 60 kg).⁸

To further reduce her bleeding risk, aspirin is discontinued.^7,19 Naproxen is replaced with acetaminophen. She will be monitored closely for bleeds. Finally, Mrs. Green is agreeable to starting a falls prevention program.

References

1. Heeringa J, van der Kuip DA, Hofman A, Kors JA, van Herpen G, Stricker BH, Stijnen T, Lip GY, Witteman JC. Prevalence, incidence and lifetime risk of atrial fibrillation: the Rotterdam study. European heart journal. 2006 Apr 1;27(8):949-53.
2. Lefebvre MC, St-Onge M, Glazer-Cavanagh M, Bell L, Nguyen JN, Nguyen PV, Tannenbaum C. The effect of bleeding risk and frailty status on anticoagulation patterns in octogenarians with atrial fibrillation: the FRAIL-AF study. Canadian Journal of Cardiology. 2016 Feb 1;32(2):169-76.
3. Andrade JG, Aguilar M, Atzema C, Bell A, Cairns JA, Cheung CC, Cox JL, Dorian P, Gladstone DJ, Healey JS, Khairy P. The 2020 Canadian Cardiovascular Society/Canadian Heart Rhythm Society Comprehensive Guidelines for the Management of Atrial Fibrillation. Canadian Journal of Cardiology. 2020 Dec 1;36(12):1847-948.
4. Brook R, Aswapanyawongse O, Tacey M, Kitipornchai T, Ho P, Lim HY. Real‐world direct oral anticoagulant experience in atrial fibrillation: falls risk and low dose anticoagulation are predictive of both bleeding and stroke risk. Internal medicine journal. 2020 Nov;50(11):1359-66.
5. Steffel J, Giugliano RP, Braunwald E, Murphy SA, Mercuri M, Choi Y, Aylward P, White H, Zamorano JL, Antman EM, Ruff CT. Edoxaban versus warfarin in atrial fibrillation patients at risk of falling: ENGAGE AF–TIMI 48 analysis. Journal of the American College of Cardiology. 2016 Sep 13;68(11):1169-78.
6. 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. Archives of internal medicine. 1999 Apr 12;159(7):677-85.
7. Kirchhof P, Benussi S, Kotecha D, Ahlsson A, Atar D, Casadei B, Castella M, Diener HC, Heidbuchel H, Hendriks J, Hindricks G. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. European journal of cardio-thoracic surgery. 2016 Nov 1;50(5):e1-88.
8. Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, Al-Khalidi HR, Ansell J, Atar D, Avezum A, Bahit MC. Apixaban versus warfarin in patients with atrial fibrillation. New England Journal of Medicine. 2011 Sep 15;365(11):981-92.
9. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S. Dabigatran versus warfarin in patients with atrial fibrillation. New England Journal of Medicine. 2009 Sep 17;361(12):1139-51.
10. Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, Waldo AL, Ezekowitz MD, Weitz JI, Špinar J, Ruzyllo W. Edoxaban versus warfarin in patients with atrial fibrillation. New England Journal of Medicine. 2013 Nov 28;369(22):2093-104.
11. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Piccini JP, Becker RC. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. New England Journal of Medicine. 2011 Sep 8;365(10):883-91.
12. Lowenstern A, Al-Khatib SM, Sharan L, Chatterjee R, Allen LaPointe NM, Shah B, Borre ED, Raitz G, Goode A, Yapa R, Davis JK. Interventions for preventing thromboembolic events in patients with atrial fibrillation: a systematic review. Annals of internal medicine. 2018 Dec 4;169(11):774-87.
13. Rao MP, Vinereanu D, Wojdyla DM, Alexander JH, Atar D, Hylek EM, Hanna M, Wallentin L, Lopes RD, Gersh BJ, Granger CB. Clinical outcomes and history of fall in patients with atrial fibrillation treated with oral anticoagulation: insights from the ARISTOTLE trial. The American journal of medicine. 2018 Mar 1;131(3):269-75.
14. Atrial Fibrillation Investigators. The efficacy of aspirin in patients with atrial fibrillation. Arch Intern Med. 1997;157:1237-40.
15. Connolly SJ, Eikelboom J, Joyner C, Diener HC, Hart R, Golitsyn S, Flaker G, Avezum A, Hohnloser SH, Diaz R, Talajic M. Apixaban in patients with atrial fibrillation. New England Journal of Medicine. 2011 Mar 3;364(9):806-17.
16. Ng KH, Shestakovska O, Connolly SJ, Eikelboom JW, Avezum A, Diaz R, Lanas F, Yusuf S, Hart RG. Efficacy and safety of apixaban compared with aspirin in the elderly: a subgroup analysis from the AVERROES trial. Age and ageing. 2016 Jan 1;45(1):77-83.
17. Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA. 2001 Jun 13;285(22):2864-70.
18. 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 Nov 1;138(5):1093-100.
19. Edward JA, Gopal RK. Anticoagulation and Antiplatelet Therapy in Atrial Fibrillation: A Teachable Moment. JAMA Internal Medicine. 2020 Sep 1;180(9):1246-7.