Global perspectives from the
cutting edge of stroke prevention
in atrial fribillation


Professor Raffaele De Caterina
Chair of Cardiology, University of Pisa
Chief, Cardiology Division, Pisa University Hospital


Professor Paul Dorian
Professor of Medicine, Division of Cardiology and Division of Clinical Pharmacology, University of Toronto
Staff Cardiac Electrophysiologist
St. Michael’s Hospital, Canada

Click here to watch a summary video
by Professor Raffaele De Caterina

The management of atrial fibrillation in the frail and elderly

Elderly patients with AF represent a population at high risk for both thromboembolic and bleeding events. Despite the benefits of treatment, concern over warfarin-related bleeding has led to suboptimal anticoagulation in this population. Patients treated with warfarin also require frequent monitoring and dose adjustment. These inconveniences have led to the development of NOACs, which generally have shown at least similar outcomes to warfarin in terms of reduced risk for stroke or systemic embolism and bleeding in patients aged 75 years or older (Figure 1).1

Based on individual trial data, however, not all NOACs are deemed the same. Although the efficacy and safety of all NOACs are largely preserved in older patients, some NOACs are associated with a higher potential for bleeding. For instance, the rates of gastrointestinal bleeding appear to be increased in patients treated with dabigatran, rivaroxaban or edoxaban compared with warfarin.3 This is typically attributed to the presence of comorbid diseases (ie, impaired renal function) or the coadministration of other medications (ie, platelet inhibitors).3,4

Figure 1. Efficacy and safety of NOACs versus warfarin in patients ≥75 years of age 1,2

Adapted from Capranzano P, et al. Expert Rev Cardiovasc Ther 2013;11:959-973 and Kato ET, et al.J Am Heart Assoc 2016;5:e003432.
*Reduced to 15 mg if CrCl 30–49 mL/min; **Reduced to 2.5 mg BID if at least two of the following criteria were present: age ≥80 years; body weight ≤60 kg; and serum creatinine ≥1.5 mg/dL; †p<0.001 vs warfarin. ‡Reduced dose as per the SmPC.
There are no head-to-head RCTs comparing the NOACs. Comparisons cannot be made between individual NOACs based on these data.
BID, twice daily; CrCl, creatinine clearance; ICH, intracranial haemorrhage; NOAC, non-vitamin K oral anticoagulant; QD, once daily; RCT, randomized clinical trial; SmPC, summary of product characteristics.

Apixaban in the elderly, frail patient with multiple comorbidities

Data from ARISTOTLE, a randomized, double-blind trial comparing apixaban 5 mg twice daily with warfarin, show that apixaban treatment numerically reduced the rates of stroke, death and major bleeding in elderly patients regardless of renal function status.5 The relative benefits for stroke and major bleeding appear to be greater in patients with lower estimated glomerular filtration rate (eGFR) treated with apixaban relative to warfarin (Figure 2).5,6

Figure 2. Apixaban efficacy and safety data in the elderly (≥75 years) in relation ro renal function 5

Interaction p values are based on categorical eGFR; eGFRs according to Cockcroft-Gault method.
The use of apixaban is not recommended in patients with a CrCl of <15 mL/min. Patients with severe renal impairment (CrCl of 15–29 mL/min) should receive the lower dose of apixaban, 2.5 mg BID (Apixaban SmPC).
BID, twice daily; CI, confidence interval; CrCl, creatinine clearance; eGFR, estimated glomerular filtration rate; HR, hazard ratio; SmPC, summary of product characteristics.
Adpated from Halvorsen S, et al. Eur Heart J 2014;35:1864-1872

In patients of advanced age (≥80 years), the superiority of apixaban was also documented, making this NOAC
an attractive alternative to warfarin.5 Additionally, the comparative retrospective study, ARISTOPHANES, showed that frail patients with AF treated with apixaban had a lower risk of stroke and systemic embolism than patients

treated with warfarin, as well as a lower risk of major bleeding compared with those taking other NOACs (ie, dabigatran, rivaroxaban).7*
The benefits of apixaban over warfarin have also been demonstrated in patients with AF and a history of falling.
These patients had a higher risk of major bleeding, including intracranial bleeding, and death, but similar rates of stroke or systemic embolism and haemorrhagic stroke compared with patients without a history of falling. Benefits of apixaban over warfarin were preserved, with an 80% reduction in intracranial bleeding; thus, apixaban appears to be a better anticoagulant option than warfarin for patients with a history of falls.8

Apixaban in other high-risk populations

The benefits of apixaban have also been shown in patients with a high bleeding risk.9 Apixaban is associated with less total bleeding and fewer deaths than warfarin in AF patients with heart failure.10 Lastly, apixaban’s benefits for reducing stroke, mortality and intracranial bleeding rates are similar to those of warfarin in patients with and without diabetes. 11


Elderly patients are at exceptionally high risk of AF and stroke. As warfarin has serious limitations in the elderly,
NOACs have become the treatment of choice in frail and high-risk patients (ie, renal disease, heart failure, fall
history) for their efficacy in stroke prevention and low risk of major bleeding. Studies have shown that, of the
NOACs, apixaban appears to have advantages in terms of its associated bleeding risk.

1. Capranzano P, et al. Expert Rev Cardiovasc Ther 2013;11:959-973. 2. Kato ET, et al. J Am Heart Assoc 2016;5:e003432. 3. Schäfer A, et al. Cardiovasc Drugs Ther 2020;34:555-568. 4. Karamichalakis N, et al. J Geriatr Cardiol 2016;13:718-723. 5. Halvorsen S, et al. Eur Heart J 2014;35:1864-1872. 6. Granger CB, et al. N Engl J Med 2011;365:981-992. 7. Lip GYH, et al. J Intern Med 2021;289:42-52. 8. Rao MP, et al. Am J Med 2018;131:269-275.e2. 9. Lopes RD, et al. Lancet 2012;380:1749-1758. 10. Jackevicius CA, et al. Circ Cardiovasc Qual Outcomes 2021;14:e007230. 11. Ezekowitz JA, et al. Eur Heart Journal Cardiovasc Pharmacother 2015;1:86-94.

*There are no head-to-head RCTs comparing the NOACs

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