MEDICAL PRACTICE CME
Anticoagulation for stroke prevention in elderly patients with non-valvular atrial fibrillation: what are the obstacles?
CW Wong, FHKCP, FHKAM (Medicine)
Department of Medicine and Geriatrics, Caritas Medical Centre, Shamshuipo, Hong Kong
Corresponding author: Dr CW Wong (email@example.com)
The elderly with atrial fibrillation are more prone to stroke. Oral anticoagulants such as warfarin are effective in the prevention of atrial fibrillation–associated stroke and systemic embolism. The CHADS2 or CHA2DS2-VASc score and HAS-BLED score were developed to stratify stroke risk associated with atrial fibrillation and bleeding risk in a patient with atrial fibrillation, respectively, to facilitate the decision for and safe use of oral anticoagulant. Nonetheless, the decision for anticoagulation is not straightforward and the elderly with non-valvular atrial fibrillation are often precluded from anticoagulant prescription. Advanced age and disadvantages associated with the elderly such as fall, comorbidities, cognitive impairment, and polypharmacy contribute to the over-concern of physicians about bleeding risk. Various treatment options such as low-intensity warfarin and aspirin plus clopidogrel have been suggested but are inferior to dose-adjusted warfarin. Novel oral anticoagulants with promising efficacy and convenience hold great appeal. Optimal management of underlying medical conditions and modifiable stroke risk factors, together with intervention to improve the safe use of oral anticoagulants, are useful.
Atrial fibrillation (AF) is common in the elderly. The prevalence tends to increase with age with 1.7% in people aged 60-64 years increasing to 17.8% in those aged ≥85 years.1 A similar trend has been reported in the Chinese population despite a lower prevalence of 1.3% in the 60-69 years’ age-group and 7.5% in those aged 80-89 years.2
Atrial fibrillation is an independent risk factor for stroke.3 There is an almost five-fold increase in age-adjusted incidence of AF-associated stroke if no anticoagulation therapy is given. The attributable risk of stroke associated with other cardiovascular risk factors—such as hypertension, congestive heart failure, and ischaemic heart disease—decreases with age. In contrast, the attributable risk for stroke associated with AF increases with age, rising from 1.5% in people aged 50-59 years to 23.5% in those aged 80-89 years. In addition, consequent stroke tends to be more severe with significant disability, and mortality rate is double that of non-AF stroke, especially in people ≥75 years.4 Thus, older patients with AF are particularly prone to stroke and its adverse effects.
Antithrombotic therapy is effective in reducing AF stroke risk with oral anticoagulant (OAC) more efficacious than antiplatelet agents.5 Until recently and before the advent of novel OAC, the vitamin K antagonist, warfarin, was the only OAC available and it is still the most common OAC prescribed nowadays. Nonetheless, warfarin is inconvenient to use and its associated bleeding risk is particularly troublesome for the elderly. As a consequence, it is often underutilised in the elderly.
Stroke risk assessment
Stroke risk varies widely in AF patients and depends on the presence of stroke risk factors. There are several risk stratification schemes to facilitate the decision to commence antithrombotic therapy of which the CHADS2 or CHA2DS2-VASc score is the most common and easy to use with satisfactory reliability (Table 1).6 7 The CHA2DS2-VASc score is an extension of the CHADS2 (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, and prior stroke or transient ischaemic attack [TIA]) with the addition of other stroke risk factors (vascular disease in the form of prior myocardial infarction, plaque in aorta and peripheral artery disease, age 65-74 years, and female sex) that enable a more comprehensive stroke risk assessment. Prior stroke or TIA, and age ≥75 years are regarded as major risk factors and score 2 points each while other risk factors are regarded as non-major risk factors and score 1 point each. Recommendation for antithrombotic therapy is based on the presence or absence of risk factors.
Anticoagulant use in atrial fibrillation for stroke prevention
An anticoagulant that clears clotting factors from the circulation to prevent blood clot formation is considered the most effective AF stroke preventive therapy. The traditional anticoagulant, the vitamin K antagonist—warfarin—impairs the synthesis of clotting factors II, VII, IX, and X; novel OACs selectively inhibit only thrombin (dabigatran) or factor Xa (rivaroxaban, apixaban, and edoxaban).
Adjusted-dose warfarin (target international normalised ratio [INR], 2-3) has been shown to reduce stroke risk by 64% while antiplatelet agents to reduce the risk by 22%5; high-risk patients showed larger stroke risk reduction with warfarin. There was a small increase in major extracranial and intracranial haemorrhage (ICH) risk (0.2%-0.3% per year) associated with warfarin but overall mortality was significantly reduced (26%) by warfarin.
The European Society of Cardiology incorporated the CHADS2/CHA2DS2-VASc risk stratification scheme into guidelines to help clinicians decide the most appropriate antithrombotic therapy.8 It recommends no treatment rather than aspirin for patients with CHA2DS2-VASc score of 0 (including female <65 years) because aspirin may not be better than no treatment in the reduction of stroke risk and increases the bleeding risk6; OAC is recommended for those who score ≥1.
Underutilisation of oral anticoagulant in the elderly
The elderly with AF, especially those aged ≥75 years, are considered to have at least one major risk factor for stroke with a CHA2DS2-VASc score of 2, thus, OAC is certainly recommended. Nonetheless, it is underutilised in the clinical setting. Among older patients with known AF without contra-indications to OAC and admitted for ischaemic stroke, only 40% were prescribed warfarin prior to the stroke event.9 Prescription rate decreased with increasing age, from 75% in those <70 years to 24% in those aged ≥90 years.10
Overestimation of the bleeding risk and disadvantages associated with advanced age are barriers to prescription of OAC in the elderly. The most commonly cited reason not to anticoagulate is increased bleeding risk followed by fall risk.11 Advanced age, co-morbidities, and patient compliance have also been reported to influence physician decision on anticoagulation. The inconvenience of frequent monitoring with dose adjustment, and drug and food interactions further contribute to OAC underuse. A small survey in Hong Kong showed that both physician awareness and patient knowledge of anticoagulation for AF stroke prevention is insufficient, which is another barrier to OAC use.12
The Birmingham Atrial Fibrillation Treatment of the Aged Study recruited nearly 1000 patients aged ≥75 years with AF to receive either warfarin (INR, 2-3) or aspirin 75 mg daily with a mean follow-up of 2.7 years. It revealed a significant reduction in ischaemic stroke in the warfarin group compared with the aspirin group (relative risk=0.3; 95% confidence interval [CI], 0.13-0.63).13 The main benefit was seen in the reduction of severe or disabling non-fatal stroke. The efficacy of warfarin did not change with increasing age. There was no difference between the two groups in major bleeding rate.
Analysis of the Atrial Fibrillation Investigators database revealed that the relative benefit of OAC versus an antiplatelet agent and no antithrombotic therapy did not vary by age for ischaemic stroke prevention whilst the benefit of an antiplatelet agent decreased with age.14
Analysis of local registry data from 2339 non-valvular AF Chinese patients aged ≥80 years demonstrated a lower rate of ischaemic stroke and death in patients prescribed warfarin (hazard ratio=0.53; 95% CI, 0.48-0.58) but a higher ICH rate than in those without anti-thrombotic therapy after 2.2 years’ follow-up (1.1% per year vs 0.6% per year).15 Overall, net clinical benefits favoured warfarin for all elderly patients, particularly those at high stroke and ICH risk.
Therefore, age alone should not be a reason to exclude anticoagulation.
Elderly patients are prone to anticoagulant-associated bleeding. The incidence of life-threatening or fatal bleeding has been shown to be significantly higher in elderly patients aged ≥80 years than in those aged <50 years (relative risk=4.6; 95% CI, 1.2-18.1) on warfarin.16 Major bleeding risk has been shown to rise with increasing age in AF patients regardless of anticoagulant use; patients ≥80 years on warfarin were at particularly high risk of ICH.17 Further, ICH as a consequence of warfarin intake was associated with poor outcome; 3-month mortality was double that of patients not taking warfarin.18 The Chinese population has a higher background haemorrhagic stroke rate that accounts for at least 30% of all strokes.19 Together with a four-fold higher warfarin-associated ICH risk in Asians compared with whites,20 concern about warfarin is even greater in Chinese elderly patients.
A simple bleeding risk score, HAS-BLED (hypertension, abnormal renal/liver disease, stroke history, bleeding history, liable INR, elderly >65 years, drugs/alcohol) [Table 2], has been derived to predict major bleeding risk in AF patients21 and incorporated into AF management guidelines as an indicator for bleeding risk.8 A score of 0-1 indicates ‘low risk’ with annual bleeding rate of <2%, a score of 2-3 indicates ‘moderate risk’ with annual bleeding rate of 2%-4%, and a score of ≥4 indicates ‘high risk’ with annual bleeding rate of >4%. It is particularly useful in predicting major bleeding risk in patients who are receiving an antiplatelet agent alone or no antithrombotic therapy prior to the initiation of OAC. Its use is not to exclude patients from OAC but to identify modifiable bleeding risk factors that can then be corrected to minimise bleeding risk. Assessment of both CHA2DS2-VASc and HAS-BLED can help balance the stroke risk and bleeding risk in AF patients, but details of how to incorporate the CHA2DS2-VASc score into the HAS-BLED score to guide the management of AF needs further study.
Table 2. Clinical characteristics of the HAS-BLED bleeding risk score21
Fall risk and fall-related head injury with ICH increase with age, which is another concern when considering anticoagulation.
Using pooled data from major AF trials, warfarin showed a net benefit of stroke protection in elderly patients with average stroke and fall risk over aspirin or no treatment in terms of higher quality-adjusted life-years.22 Regardless of patient age or baseline stroke risk, fall risk was not an important factor in determining optimal therapy: patients with average fall risk would need to fall 295 times in a year for warfarin not to be the optimal therapy.
Another database study of nearly 20 000 elderly AF patients (mean age, 80 years) found that patients at high fall and stroke (CHADS2 score ≥2) risk appeared to have a net benefit from OAC despite an increased baseline ICH risk, in which OAC use was associated with a 25% relative risk reduction in the composite outcome of stroke, any haemorrhage, myocardial infarction and death whilst there was an insignificant reduction in those at high risk for fall but with CHADS2 score of 0 or 1.23
A subsequent prospective study showed that among 515 AF patients discharged on OAC, there was no significant increase in major bleeding rate (including fatal haemorrhage and ICH) in patients at high fall risk compared with those at low fall risk at 12 months.24
These data suggest that in patients with valid indications for anticoagulation, the benefits outweigh the risk, and fall risk should not be a sole reason to withhold anticoagulation.
Narrow therapeutic range, co-morbidities, and polypharmacy
Maintaining INR at 2 to 3 for at least 60% of the time provides effective stroke prevention and minimises bleeding risk.8 Nonetheless, maintaining this optimal range is not easy as it is influenced by both internal and external factors.
Consistent dietary intake of vitamin K is important for stable anticoagulation. This is difficult for elderly patients with poor health, who get sick frequently, have a poor diet and fluctuating vitamin K intake, or for patients with cognitive impairment who cannot comply with a diet with constant vitamin K content.
Many concurrent diseases can also influence INR control. It is particularly troublesome during the exacerbation of disease or if the disease course is fluctuating. Hepatic dysfunction impairs synthesis of clotting factors and thus potentiates the anticoagulation effects. Hepatic congestion as a result of congestive heart failure can inhibit warfarin metabolism and lead to accumulation of warfarin and over-anticoagulation. Hypermetabolic states such as febrile illness or thyrotoxicosis may increase catabolism of vitamin K–dependent clotting factors and may increase INR level.25 On the contrary, hypothyroidism that decreases the catabolism of vitamin K–dependent clotting factors may decrease INR. Patients with AF with concomitant acute coronary disease and percutaneous coronary intervention require aspirin-clopidogrel dual therapy in addition to warfarin, and this further increases bleeding risk. Patients with severe chronic kidney disease (estimated glomerular filtration rate, <30 mL/min/1.73 kg/m2) who are prescribed warfarin are at higher risk of over-anticoagulation, which is associated with more than double the risk for major bleeding compared with patients with mild or moderate chronic kidney disease.26 Patients with cognitive impairment have difficulty in managing their warfarin intake, coping with dosage adjustment, and being aware of drug and food interactions; all of which may result in over- or under-anticoagulation.
Warfarin can interact with many drugs and herbal products. This has clinical implications because polypharmacy and adjustment of medications due to an acute illness is frequent in the elderly. Polypharmacy is an independent risk factor for warfarin-related major bleeding and there is a 12% increase in risk for each additional drug taken.24 It is relatively easier to manage drugs in chronic use than those prescribed for a short period of time or when necessary. Warfarin-drug interaction is through the influence of pharmacokinetics that reduce gastrointestinal absorption or disrupts metabolic clearance and pharmacodynamics that alter the haemostatic response.25 The Box lists the common drugs and food that interact with warfarin.27 It should be noted that the majority of the data are from case series or reports because of the scarcity of randomised controlled trials. Thus, the rate of harm and its generalisation to all warfarin users needs continuous review. Nonetheless, physicians should proceed with caution and frequently monitor INR when prescribing potential offending drugs. There is a group of drugs that potentiate bleeding on their own without alteration of INR that includes antiplatelet drugs, heparin, non-steroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase-2 (COX-2) inhibitors, and selective serotonin reuptake inhibitors.
Box. Common drug and food interactions with warfarin27
Pain syndrome and analgesic use are common in the elderly. Among analgesics, paracetamol is preferred for occasional use when taking warfarin.28 A dose that exceeds 2 g daily for more than a few days may raise INR and increase the bleeding risk, however. The NSAIDs, including COX-2 selective NSAIDs, should be avoided. Non-pharmacological methods of pain relief to minimise the use of analgesics are encouraged.
Undiagnosed/occult atrial fibrillation
It is not uncommon for a patient to have AF first diagnosed when ischaemic stroke occurs. Very often, AF is undiagnosed as it is usually asymptomatic; 10% to 40% of AF cases are asymptomatic.29 A population-based study revealed that 20.1% of AF in patients aged >60 years was undiagnosed.30 Paroxysmal AF, which bears a similar stroke risk and benefit from anticoagulation to sustained AF,31 also easily evades ordinary electrocardiography (ECG) screening. Paroxysmal AF is common (up to 16%) in cryptogenic stroke32 that constitutes 25% of ischaemic stroke.33
Alternatives to warfarin
Intensity of anticoagulation correlates directly with incidence of haemorrhage,34 thus low-intensity warfarin with a subtherapeutic range of INR, such as INR of <2, is suggested for the elderly to lower bleeding risk while still effectively preventing stroke. The Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators found that low-dose warfarin (target INR, 1.5-2.7) was more effective than placebo in stroke prevention.35 There is a racial difference in response to warfarin—a lower INR target of 1.8 to 2.4 appears to be sufficient in lowering both major bleeding and thromboembolic events in Chinese.36 Japanese studies and their registry data also support the lower INR target and have recommended INR of 1.6 to 2.6 for AF patients of ≥70 years in their AF management guideline.37
Aspirin plus clopidogrel
Aspirin (75-100 mg daily)–clopidogrel (75 mg daily) dual therapy has been shown to be better than aspirin alone in stroke prevention in AF patients, reducing stroke risk by 28% compared with aspirin alone.38 Nonetheless, it is inferior to OAC in AF patients with at least one risk factor for stroke; OAC reduced stroke risk by 42% compared with dual therapy.39 Both dual therapy and OAC were associated with similar but higher bleeding risk than aspirin. Therefore, dual therapy may only be considered for patients in whom OAC is unsuitable or for patient preference.8
Novel oral anticoagulants
Novel OACs (dabigatran, rivaroxaban, apixaban, and edoxaban) have been approved by the US Food and Drug Administration (FDA) for AF stroke prevention. They have undergone large clinical trials in AF patients (mean age ≥70 years) with at least one additional stroke risk factor. Rivaroxaban, dabigatran 110 mg, and edoxaban were non-inferior whilst both apixaban and dabigatran 150 mg were superior to warfarin in stroke or systemic embolism prevention; overall they significantly reduced the risk by 19% compared with warfarin, mainly due to a large reduction in haemorrhagic stroke.40 All-cause mortality was also significantly reduced by 10%. The newer anticoagulants appear to be safer with at least a similar major bleeding rate and consistently lower ICH rate (>50% fewer) compared with warfarin. The exception is gastrointestinal bleeding risk in dabigatran 150 mg, rivaroxaban and edoxaban 60 mg, occurrence of which was 25% more than with warfarin. The favourable result was sustained across a wide stratum of patients at high risk of both ischaemic and bleeding events. The efficacy and safety of novel OACs are consistent among Asian patients including Chinese41 42 43 as well as Chinese elderly aged ≥80 years.44 Because of the favourable efficacy and safety profile, current guidelines have recommended novel OACs as an alternative to warfarin in primary and secondary stroke prevention in patients with non-valvular AF.8
In addition, novel OACs are convenient because of their predictable and reliable anticoagulation properties, with far fewer drug interactions and no food interactions or dietary restrictions. They can be administered at a fixed dose and monitoring of coagulation is unnecessary.
Nonetheless, their use is not without drawbacks. They are eliminated renally, thus dose adjustment based on renal function is required and they are not recommended for patients with severely impaired renal function (creatinine-clearance, <15 mL/min). Although drug interactions are fewer than those for warfarin, there is potential interaction with P-glycoprotein and CY3A4 inhibitors or inducers, which include common cardiovascular drugs such as amiodarone, dronedarone and diltiazem (all are combined P-glycoprotein inhibitors and weak/moderate CYP3A4 inhibitors), and anti-infectives such as rifampicin (strong CYP3A4 inducers), clarithromycin and ketoconazole (strong dual inhibitors of P-glycoprotein and CYP3A4), thus caution is required. Because they do not affect INR and there is no readily available measure to monitor their anticoagulation, it is difficult to confirm if patients are compliant with therapy. Thus, good drug compliance is as important as taking warfarin. Besides, the cost of novel OAC is more expensive and long-term evidence is not complete. For those patients already on warfarin who have satisfactory anticoagulation control, whether there is extra benefit in switching to novel OAC needs to be explored.
Left atrial appendage closure
Since >90% non-valvular AF stroke inducing thromboemboli are from the left atrial appendage (LAA), LAA closure is considered an alternative to OAC.45 Percutaneous occlusion by placing the WATCHMAN device in the LAA was approved by the US FDA for the prevention of LAA thromboembolism in patients in whom OAC was contra-indicated or in whom management with an OAC was difficult. The WATCHMAN device was shown to be non-inferior to OAC in the composite endpoint of stroke, cardiovascular death, and systemic embolism.46 Main adverse effects are procedure-related, eg pericardial effusion, incomplete LAA closure, dislodgement of device, and blood clot formation on the device that requires prolonged OAC.
Decision-making and strategies to improve
The aim of prescribing OAC to AF patients is to prevent stroke or systemic embolism such that patients’ health and functional state can be maintained. The decision to prescribe an OAC in the elderly is complicated, however. It requires not only balancing the stroke risk and bleeding risk from OAC, but also needs to consider the patient’s general health, functional and cognitive ability, availability of a caregiver, and patient’s attitude and preference towards anticoagulation. Elderly patients with AF who are in good health or have few co-morbidities and a good functional state will definitely benefit from OAC; for patients in poor health with multiple co-morbidities who are functionally dependent, OAC is not likely to provide additional benefit and there is a high risk of bleeding. Apart from that, decision making for other clinical scenarios is not easy. Careful assessment and discussion with patients and/or caregivers is essential when deciding whether to prescribe OAC.
Better preparation of eligible patients for anticoagulation by optimising their medical condition to reduce the risk of stroke and bleeding, together with education of patients and caregiver to enhance compliance, are also useful. The following are recommendations to improve the safety and optimal effect of OAC:
- Co-morbidities: optimise underlying medical conditions, increase frequency of anticoagulation monitoring if medical condition changes or during acute illness
- Cardiovascular risk factors: screening for and proper control of modifiable cardiovascular risk factors
- Cognitive impairment: encourage involvement of caregiver to ensure compliance
- Polypharmacy: review and simplify drug regimen; discontinue unnecessary medications, avoid drugs that interact with OAC or use alternative drugs with less potential for interaction; frequent INR monitoring if offending drugs are prescribed or discontinued
- Bleeding: avoid concomitant medications associated with bleeding such as antiplatelet agent, NSAIDs and alcohol; better control of hypertension to lower ICH risk47; add proton pump inhibitor to lower upper gastrointestinal bleeding risk, especially those at increased risk48
- Fall prevention: fall risk assessment followed by intervention such as exercises for gait, balance, and strength training; education to increase safety awareness, prescription of appropriate walking aids, correction of vision if necessary, environmental modifications, and minimise or avoid offending medications
- Undiagnosed AF: liberal recording of ECGs in the elderly, especially those with cardiovascular risk factors, to capture AF49; for those with cryptogenic stroke, vigorously look for occult AF by prolonged ECG monitoring32
- Regular assessment of patient compliance with OAC, and review of stroke and bleeding risk and adjust the management plan accordingly
- Continued education for physicians about AF and OAC management
- Setting up of a warfarin clinic in Hong Kong with a multidisciplinary approach (physicians, pharmacists, and nurses) to provide patient education, regular INR monitoring with warfarin dosage adjustment, monitoring of drug and food interactions, and signs of bleeding have been shown to improve drug compliance, minimise bleeding risk, and maintain INR within the therapeutic range50
The elderly with AF are more prone to stroke than younger patients, especially those aged ≥75 years. Anticoagulation is effective in the prevention of stroke in the elderly despite the increased bleeding risk. Age alone should not exclude anticoagulation. Novel OAC is convenient with comparable efficacy to warfarin and a lower risk for ICH. This may improve the prescription, however, long-term evidence is awaited. The best management of the elderly with AF depends on careful estimation of thromboembolic and bleeding risk, patient’s ability to cope with anticoagulation, and patient preference. Optimal control of other potential risk factors for stroke and bleeding is also important.
1. Heeringa J, van der Kuip DA, Hofman A, et al. Prevalence, incidence and lifetime risk of atrial fibrillation: the Rotterdam study. Eur Heart J 2006;27:949-53. CrossRef
2. Zhou Z, Hu D. An epidemiological study on the prevalence of atrial fibrillation in the Chinese population of mainland China. J Epidemiol 2008;18:209-16. CrossRef
3. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991;22:983-8. CrossRef
4. Lin HJ, Wolf PA, Kelly-Hayes M, et al. Stroke severity in atrial fibrillation. The Framingham Study. Stroke 1996;27:1760-4. CrossRef
5. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007;146:857-67. CrossRef
6. 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;285:2864-70. CrossRef
7. 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;137:263-72. CrossRef
8. Camm AJ, Lip GY, De Caterina R, et al. 2012 Focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur Heart J 2012;33:2719-47. CrossRef
9. Gladstone DJ, Bui E, Fang J, et al. Potentially preventable strokes in high-risk patients with atrial fibrillation who are not adequately anticoagulated. Stroke 2009;40:235-40. CrossRef
10. Hylek EM, D’Antonio J, Evans-Molina C, Shea C, Henault LE, Regan S. Translating the results of randomized trials into clinical practice: the challenge of warfarin candidacy among hospitalized elderly patients with atrial fibrillation. Stroke 2006;37:1075-80. CrossRef
11. Pugh D, Pugh J, Mead GE. Attitudes of physicians regarding anticoagulation for atrial fibrillation: a systematic review. Age Ageing 2011;40:675-83. CrossRef
12. Lee VW, Tam CS, Yan BP, Yu CM, Lam YY. Barriers to warfarin use for stroke prevention in patients with atrial fibrillation in Hong Kong. Clin Cardiol 2013;36:166-71. CrossRef
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. CrossRef
14. van Walraven C, Hart RG, Connolly S, et al. Effect of age on stroke prevention therapy in patients with atrial fibrillation: the Atrial Fibrillation Investigators. Stroke 2009;40:1410-6. CrossRef
15. Siu CW, Tse HF. Net clinical benefit of warfarin therapy in elderly Chinese patients with atrial fibrillation. Circ Arrhythm Electrophysiol 2014;7:300-6. CrossRef
16. Fihn SD, Callahan CM, Martin DC, McDonell MB, Henikoff JG, White RH. The risk for and severity of bleeding complications in elderly patients treated with warfarin. The National Consortium of Anticoagulation Clinics. Ann Intern Med 1996;124:970-9. CrossRef
17. Fang MC, Go AS, Hylek EM, et al. Age and the risk of warfarin-associated hemorrhage: the anticoagulation and risk factors in atrial fibrillation study. J Am Geriatr Soc 2006;54:1231-6. CrossRef
18. Rosand J, Eckman MH, Knudsen KA, Singer DE, Greenberg SM. The effect of warfarin and intensity of anticoagulation on outcome of intracerebral hemorrhage. Arch Intern Med 2004;164:880-4. CrossRef
19. Zhang LF, Yang J, Hong Z, et al. Proportion of different subtypes of stroke in China. Stroke 2003;34:2091-6. CrossRef
20. Shen AY, Yao JF, Brar SS, Jorgensen MB, Chen W. Racial/ethnic differences in the risk of intracranial hemorrhage among patients with atrial fibrillation. J Am Coll Cardiol 2007;50:309-15. CrossRef
21. 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;138:1093-100. CrossRef
22. 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;159:677-85. CrossRef
23. 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;118:612-7. CrossRef
24. Donzé J, Clair C, Hug B, et al. Risk of falls and major bleeds in patients on oral anticoagulation therapy. Am J Med 2012;125:773-8. CrossRef
25. Hirsh J, Fuster V, Ansell J, Halperin JL; American Heart Association/American College of Cardiology Foundation. American Heart Association/American College of Cardiology Foundation guide to warfarin therapy. Circulation 2003;107:1692-711. CrossRef
26. Limdi NA, Beasley TM, Baird MF, et al. Kidney function influences warfarin responsiveness and hemorrhagic complications. J Am Soc Nephrol 2009;20:912-21. CrossRef
27. Holbrook AM, Pereira JA, Labiris R, et al. Systematic overview of warfarin and its drug and food interactions. Arch Intern Med 2005;165:1095-106. CrossRef
28. NHS choices. Can I take paracetamol if I’m on warfarin? Available from: http://www.nhs.uk/chq/pages/858.aspx?categoryid=73&subcategoryid=103. Accessed Oct 2016.
29. Rho RW, Page RL. Asymptomatic atrial fibrillation. Prog Cardiovasc Dis 2005;48:79-87. CrossRef
30. Clua-Espuny JL, Lechuga-Duran I, Bosch-Princep R, et al. Prevalence of undiagnosed atrial fibrillation and of that not being treated with anticoagulant drugs: the AFABE study. Rev Esp Cardiol (Engl Ed) 2013;66:545-52. CrossRef
31. Hohnloser SH, Pajitnev D, Pogue J, et al. Incidence of stroke in paroxysmal versus sustained atrial fibrillation in patients taking oral anticoagulation or combined antiplatelet therapy: an ACTIVE W Substudy. J Am Coll Cardiol 2007;50:2156-61. CrossRef
32. Gladstone DJ, Spring M, Dorian P, et al. Atrial fibrillation in patients with cryptogenic stroke. N Engl J Med 2014;370:2467-77. CrossRef
33. Hart RG, Diener HC, Coutts SB, et al. Embolic strokes of undetermined source: the case for a new clinical construct. Lancet Neurol 2014;13:429-38. CrossRef
34. Levine MN, Hirsh J, Landefeld S, Raskob G. Hemorrhagic complications of anticoagulant treatment. Chest 1992;102(4 Suppl):352S-363S. CrossRef
35. The effect of low-dose warfarin on the risk of stroke in patients with nonrheumatic atrial fibrillation. The Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators. N Engl J Med 1990;323:1505-11. CrossRef
36. You JH, Chan FW, Wong RS, Cheng G. Is INR between 2.0 and 3.0 the optimal level for Chinese patients on warfarin therapy for moderate-intensity anticoagulation? Br J Clin Pharmacol 2005;59:582-7. CrossRef
37. JCS Joint Working Group. Guidelines for pharmacotherapy of atrial fibrillation (JCS 2008): digest version. Circ J 2010;74:2479-500. CrossRef
38. ACTIVE Investigators, Connolly SJ, Pogue J, et al. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med 2009;360:2066-78. CrossRef
39. ACTIVE Writing Group of the ACTIVE Investigators, Connolly S, Pogue J, et al. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet 2006;367:1903-12. CrossRef
40. Ruff CT, Giugliano RP, Braunwald E, et al. 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. CrossRef
41. Hori M, Connolly SJ, Zhu J, et al. Dabigatran versus warfarin: effects on ischemic and hemorrhagic strokes and bleeding in Asians and non-Asians with atrial fibrillation. Stroke 2013;44:1891-6. CrossRef
42. Wong KS, Hu DY, Oomman A, et al. Rivaroxaban for stroke prevention in East Asian patients from the ROCKET AF Trial. Stroke 2014;45:1739-47. CrossRef
43. Goto S, Zhu J, Liu L, et al. Efficacy and safety of apixaban compared with warfarin for stroke prevention in patients with atrial fibrillation from East Asia: a subanalysis of the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) Trial. Am Heart J 2014;168:303-9. CrossRef
44. Chan PH, Huang D, Hai JJ, et al. Stroke prevention using dabigatran in elderly Chinese patients with atrial fibrillation. Heart Rhythm 2016;13:366-73. CrossRef
45. Blackshear JL, Odell JA. Appendage obliteration to reduce stroke in cardiac surgical patients with atrial fibrillation. Ann Thorac Surg 1996;61:755-9. CrossRef
46. Holmes DR, Reddy VY, Turi ZG, et al. Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: a randomised non-inferiority trial. Lancet 2009;374:534-42. CrossRef
47. Hart RG, Tonarelli SB, Pearce LA. Avoiding central nervous system bleeding during antithrombotic therapy: recent data and ideas. Stroke 2005;36:1588-93. CrossRef
48. Lin KJ, Hernández-Díaz S, García Rodríguez LA. Acid suppressants reduce risk of gastrointestinal bleeding in patients on antithrombotic or anti-inflammatory therapy. Gastroenterology 2011;141:71-9. CrossRef
49. Samol A, Masin M, Gellner R, et al. Prevalence of unknown atrial fibrillation in patients with risk factors. Europace 2013;15:657-62. CrossRef
50. Outcome evaluation of warfarin clinic: safe and feasible care delivery model in primary care setting. Hong Kong Hospital Authority Convention 2008. Available from: http://www3.ha.org.hk/haconvention/hac2008/proceedings/pdf/Free%20Paper/SPP6-1.pdf. Accessed Oct 2016.