Atrial fibrillation and increasing age are both risk factors for stroke
Atrial fibrillation (AF) is associated with increased morbidity and mortality from stroke, thromboembolism and heart
failure. AF increases the risk of ischaemic stoke approximately five-fold and the prevalence of AF increases with age.
It is estimated that 5% of people aged over 65 years and 10% of people aged 80 years and older have AF.1
Stroke risk doubles every ten years after age 55, with over 50% of strokes occurring in people aged over 75 years.2 Approximately
one-third of strokes in patients aged 80–89 years are related to AF.3 Evidence also shows that people with
AF related strokes have a poorer prognosis when compared with people who have non-AF strokes, with larger neurological
deficits, increased medical complications and higher inpatient mortality.4 In people with non-valvular AF,
anticoagulation with warfarin is more effective at reducing stroke than the antiplatelet agent aspirin.5
Older people with AF are at the highest risk of stroke, so they stand to benefit the most from treatment. Providing
bleeding risks can be managed, the most effective treatment, i.e. warfarin, should be offered. Evidence suggests however,
that warfarin is under utilised in elderly people, both in primary care and hospital practice.6 The dilemma
in older patients with AF is that the same factors indicating a need for anticoagulation with warfarin, e.g. hypertension,
older age, previous stroke, are also the risk factors for intracranial haemorrhage.
Warfarin or aspirin?
Both warfarin and aspirin increase the risk of bleeding via different mechanisms. Warfarin requires careful monitoring
and is susceptible to drug interactions which increases the hazards associated with its use compared with aspirin. However,
bleeding rates in comparative clinical trials between aspirin and warfarin for AF are generally very similar, which may
partly reflect close monitoring in the study situation. Until recently, clinical trials for stroke prevention in AF did
not include, or were under-represented by, older people. Trials such as the Birmingham Atrial Fibrillation Treatment
of the Aged Study (BAFTA) and recent review articles indicate that warfarin has significant net beneficial effects compared
with aspirin, in people with AF aged 75 years and older, who are at the highest risk of stroke.7,8 In the
BAFTA trial, which included people with AF aged over 75 years, the risk of a primary endpoint (stroke, intracranial haemorrhage
or arterial embolism) was significantly lower with warfarin (1.8%) compared with aspirin (3.8%), and there was no evidence
that warfarin caused more bleeding complications than aspirin.7
The use of warfarin in older people
The decision to use warfarin in an older person requires consideration of the following:
- Risk factors for bleeding
- Tools to evaluate baseline stroke risk
- Individual assessment of the patient with regard to co-morbidities, medications and ability to comply with monitoring
Warfarin-related bleeding
The risk of bleeding while on warfarin is greatest in patients who have not previously received warfarin, and in the
first 90 days of treatment.9 A lower starting dose is recommended in older people as they are more sensitive
to the effects of warfarin. Lower maintenance doses are also often required, e.g. 2–4 mg.10 The potential for
bleeding complications in older people is also increased by pathological changes that accompany ageing.
Most bleeding related to the use of warfarin occurs in the gastrointestinal tract, urinary tract, soft tissues and oropharynx
with gastrointestinal haemorrhage being the most severe.10 Patients who have an extracranial haemorrhage while
on warfarin are less likely to die from the initial event or in the first month after discharge and also less likely to
have long term functional deficits, than those who have intracranial haemorrhage.11
Although the absolute risk is relatively low at 0.2% per year, intracranial haemorrhage is the most serious complication
of anticoagulation-related bleeding with a mortality rate reported of up to 50%.5,10,11 Intracranial haemorrhage
includes bleeding that is intracerebral (approximately 70%), subdural or subarachnoid and is the cause of approximately
90% of the deaths from warfarin associated bleeding.11 Patients who initially survive an intracranial haemorrhage
are likely to be discharged with significant functional deficits or to die within the first 30 days after discharge.11
There is good evidence that older age (>75 years), elevated INR level (>3.0), uncontrolled hypertension (e.g. systolic
blood pressure > 160 mmHg) and a history of ischaemic stroke increase the likelihood of an intracranial haemorrhage. However,
a previous stroke, hypertension and older age are also risk factors for ischaemic stroke.10,12,13 Risk factors
for warfarin associated intracranial haemorrhage also overlap with risk factors for spontaneous intracranial haemorrhage
(see sidebar). However, for older people on warfarin the beneficial reduction in the risk of stroke is greater than the
small increase in the risk of serious haemorrhage.14
Many other risk factors for warfarin associated bleeding have been investigated, however, there is conflicting evidence
and often a lack of consistency in the proposed risk factors. There is some evidence to support a higher risk of bleeding
complications in people with the following risk factors:8,12,13
- Concomitant use of aspirin, other antiplatelet medicines or NSAIDs
- Polypharmacy - seven or more medications
- Other co-morbidities e.g. diabetes, anaemia, alcohol or drug misuse, smoking, falls risk
- Patient factors e.g. Insufficient education on the use of warfarin, poor compliance, confusion
Spontaneous intracranial haemorrhage13
The rate of spontaneous intracranial haemorrhage in people aged over 70 years is approximately 0.15% per year. Risk
factors for spontaneous intracranial haemorrhage include; uncontrolled hypertension, increasing age, an underlying pathological
condition e.g. tumour, infection, vascular malformation, ethnicity (increased risk in people of Asian descent), and illicit
drug use e.g. cocaine, amphetamine.
One of the most recent models that attempts to establish the risk of bleeding in older people on warfarin is the HAS-BLED
Bleeding Risk Score (Table 1).15 This model would be ideal for use in general practice. It aims to provide
a rapid, simple method to predict bleeding risk. A score of three or more indicates a patient who may be at high risk
of bleeding complications and who therefore may benefit from more regular review of warfarin therapy.15
Table 1: HAS-BLED Bleeding Risk Score (adapted from Pisters et al, 201015)
| Letter |
Clinical Characteristic |
Points |
| H |
Hypertension (systolic blood pressure > 160 mm Hg) |
1 |
| A |
Abnormal renal and liver function |
1 point each |
| S |
Stroke (past history) |
1 |
| B |
Bleeding (previous history of bleeding or predisposition to bleeding) |
1 |
| L |
Labile INRs (unstable, high or insufficient time within therapeutic range) |
1 |
| E |
Elderly (> 65 years) |
1 |
| D |
Drugs or alcohol (including concomitant use of aspirin, other antiplatelet agents
and NSAIDs) |
1 point each |
| |
|
Max 9 points |
The clinical characteristics that may predict a high risk of bleeding are often thought of as contraindications to warfarin
use in older people, however, the majority of these may be considered relative contraindications and will depend on individual
patient characteristics and the clinical situation. In many cases the overall benefit of warfarin may still outweigh the
potential risk of treatment. For patients in such clinical situations, for whom embolic risk is deemed to be high, consultation
with a stroke specialist should be considered to discuss the possibility of treatment with warfarin or the use of other
alternatives.
Clinical situations that may be a contraindication to warfarin use include:16,17
- Actual or potential haemorrhagic conditions e.g. peptic ulceration (or history of within the previous six months)
- Uncontrolled or severe hypertension (blood pressure consistently above 160/90 mmHg)
- Severe renal or liver disease
- Recurrent unexplained syncope or recurrent falls
- Planned surgery
- Unsupervised dementia
Tools to evaluate baseline stroke risk
Stroke assessment tools for patients with AF6,18
The updated stroke assessment tool CHA2DS2-VAS puts greater emphasis on increasing age ( ≥ 75
years) and also incorporates additional risk factors for stroke – female gender, age group 65 – 75 years and a history
of vascular disease e.g. myocardial infarction, peripheral arterial disease. Scores for each tool are calculated as follows:
| CHADS2 |
Score |
| Congestive heart failure |
1 |
| Hypertension |
1 |
| Age 75 years or older |
1 |
| Diabetes mellitus |
1 |
| Previous Stroke or TIA |
2 |
| Maximum score |
6 |
| CHA2DS2-VAS |
Score |
| Congestive heart failure/LV dysfunction |
1 |
| Hypertension |
1 |
| Age ≥ 75 years |
2 |
| Diabetes mellitus |
1 |
| Stroke/TIA |
2 |
| Vascular disease (prior MI, peripheral vascular disease) |
1 |
| Age 65–75 years |
1 |
| Sex category (i.e. female gender) |
1 |
| Maximum score |
9 |
The risk of stroke can be evaluated using a risk stratification tool such as CHADS2 or the updated version,
CHA2DS2-VAS, which now includes additional stroke risk factors (see sidebar).6,18 CHADS2 is
a simpler tool for use in general practice. These tools can be used to help decide whether to use warfarin in patients
with non-valvular AF. However, they do not take into account bleeding risks, monitoring requirements and other factors
that may make warfarin less suitable or potentially hazardous in a particular patient.
In general, warfarin is recommended in people at high risk of stroke (CHADS2 score ≥2 or CHA2DS2-VAS
score >1). The updated tool attempts to simplify the decision of which agent to use for anticoagulation by also recommending
warfarin for patients who have a CHA2DS2-VAS score = 1.18 Aspirin is still included as
an option for those who score 1 but a clear preference is stated for anticoagulation with warfarin. Patients who score
0 are now considered truly low risk and although may still be prescribed aspirin, choosing not to use antithrombotic therapy
may be preferred.8 Most older people will be in a higher risk group where warfarin is the most beneficial treatment.
If warfarin is contraindicated, not indicated or is declined by the patient, aspirin may be prescribed, as it reduces
the risk of stroke compared to no treatment.
The importance of INR monitoring
Appropriately monitored and dose adjusted warfarin is effective and relatively safe in elderly patients. However, warfarin
may be unsuitable or hazardous in some people if they are unable to manage the treatment and its monitoring.
Monitoring of INR is important in the context of both safety and effectiveness. Interactions, diet changes and unintentional
overdosing can all increase INR and bleeding risk. The ability of the patient to commit to ongoing monitoring for the
duration of warfarin therapy needs to be assessed. Older people may be at higher risk of bleeding for many reasons including
poor monitoring of INR.
For warfarin to be effective in preventing stroke it has been estimated that the INR should be in the target range of
2.0 to 3.0 ≥ 65% of the time.8 There is no lower threshold of INR that does not accentuate the risk of intracranial
haemorrhage therefore targeting a lower INR range, e.g. 1.5 to 2.0, does not reduce the risk of bleeding and is less likely
to prevent stroke.13,19
A target INR of 2.5 within a therapeutic range of 2.0–3.0 is widely recommended for older patients. The rate of intracranial
haemorrhage increases markedly in older people if the INR is >3.5 and to a lesser extent if the INR is above 3.0.8,12 The
difficulty is that although an INR above 3.0 increases the risk of intracranial haemorrhage, the majority of people on
warfarin who have warfarin associated intracranial haemorrhage have been found to have an INR within the therapeutic range
e.g. 2.0–3.0.13 Minimising the risk of intracranial haemorrhage therefore requires not only good control of
anticoagulation but also effective management of other modifiable risk factors, particularly hypertension.13
Individual patient assessment is essential
An individual assessment of the patient with regard to co-morbidities, medications and the ability to comply with monitoring
is essential for the safe use of warfarin.
Co-morbidities may be risk factors for bleeding and they may also increase the potential for falls.
A review of medicines is recommended to avoid concomitant use of those that may increase the risk of bleeding e.g. aspirin,
NSAIDs, Cox-2 inhibitors, dipyridamole. In addition bleeding risk should be reassessed when new medicines, including those
used for short periods such as quinolone or macrolide antibiotics, are introduced.
Before initiating warfarin the possibility of non-adherence and monitoring should be considered. Factors to take into
account may include any cognitive impairment, mental illness or an inability to access services.
Warfarin interacts with multiple other prescriptions medicines, as well as nutritional supplements, over-the-counter
medicines and some foods e.g. foods that contain high levels of vitamin K such as broccoli, spinach and cabbage. Discuss
the possibility of these interactions with patients and encourage them to consult about any major dietary changes they
are planning to make. Also inform patients that their general wellbeing may also affect their warfarin therapy, e.g. a
new illness such as fever or diarrhoea or a condition such as congestive heart failure. Poor quality patient education
has been found to be a significant risk factor for both ineffective anticoagulation and warfarin associated bleeding in
older patients.12
Bottom-line
Increasing age alone should not prevent the use of warfarin. The decision to use warfarin involves identification and
assessment of those patients who are at high risk of ischaemic stroke without warfarin and weighing this against the risk
of intracranial haemorrhage with warfarin treatment.11 Further research that includes older participants and
the ongoing development of risk assessment tools are first steps toward solving this problem.
Once the decision to use warfarin is made on an individual basis, prevention of bleeding complications relies on maintaining
an INR between 2.0 and 3.0, appropriately monitoring and adjusting doses as required, providing quality patient education
and effectively managing any modifiable risk factors.
Acknowledgement
Thank you to Dr Anna Ranta, Lead Stroke Physician, Consultant Neurologist and Head of Department,
Department of Neurology and Acute Stroke Services, Midcentral DHB, Palmerston North and Associate Dean of Undergraduate
Studies, University of Otago, Wellington for expert guidance in developing this article.