Poor control of warfarin therapy, particularly in the elderly, is a common cause of adverse drug reactions (ADRs) in Australia. Recent data shows that anticoagulants are one of the major causes of ADRs, and the rate of anticoagulation-related ADRs
has increased dramatically in recent years.75 Optimal control of warfarin therapy is
extremely important. It has been estimated that maintaining a high levels of INR control would prevent 1750 episodes of bleeding and 700 ischaemic strokes each year in Australia,76 and could avoid one in every four haemorrhagic events, and one
in every ten thromboembolic events experienced in elderly anticoagulated patients.76
It has been conclusively demonstrated in the literature that optimal anticoagulation therapy with warfarin can reduce the annual risk of stroke by approximately 68% in patients with non-valvular AF, making warfarin three times more effective than aspirin for stroke prevention in this population.7, 77-84 However, much of this
potential remains unfulfilled because of under and suboptimal use.85 In elderly
patients, who often possess multiple risk factors and are at higher baseline risk for stroke, the potential benefits of warfarin may be even greater.86
The presence of AF has been found to more than quadruple a person’s risk of stroke87, 88 and accounts for approximately 14% of all strokes in patients greater
than 60 years old,89 and 25% of strokes in those aged over 80 years.86 Ischaemic
strokes associated with AF are typically more severe than those which occur in the absence of AF, and this increased severity is independent of increasing age and other risk factors for stroke.90 AF also significantly increases the risk of stroke recurrence
after one year and increases post-stroke mortality at both 30 days and one year.90, 91
Unsurprisingly, the increase in mortality and morbidity associated with AF translates to a significant cost to the healthcare system and the economy as a whole. In a report commissioned by the National Stroke Foundation, the Australian health system expenditure associated with strokes in the presence of AF in the 2008-2009 financial year was estimated to be $874 million, while the total cost to the Australian economy of these events was estimated to be at least $1.25 billion.92
Despite the demonstrated benefits of anticoagulation therapy in significantly reducing thromboembolic complications associated with AF, and the enormous cost savings that would result from optimal anticoagulant use, they remain underused.93
A number of risk stratification tools exist for assigning a level of stroke risk to a person based on their medical history and conditions. One of these is the CHADS2
risk assessment method, which awards one point each for congestive heart failure, hypertension, age >75 years, and diabetes mellitus.94 Two points are given to a
patient with prior stroke or TIA.94 A patient at low risk for stroke would have a
CHADS2 score of 0 to 1, a patient at moderate risk would have a score of 2, and a
patient at high risk would have a score of ≥3 Table 2).
Table 2: CHADS2 risk stratification (adapted from Goldstein et al. 2006)95 CHADS2
score Risk level
Stroke rate (%/year)
Treatment recommendations based on risk stratification
0 Low 1.0 Aspirin*
1 Low-moderate 1.5 Warfarin** or aspirin*
2 Moderate 2.5 Warfarin**
3 High 5.0 Warfarin**
≥4 Very high >7.0 Warfarin**
* 75-325mg per day
** INR 2.0-3.0; consider patient preferences, bleeding risk, and access to INR monitoring
A recent systematic review found that most of the included studies reported underuse of oral anticoagulants for high-risk AF patients.93 They found that most
studies based on the CHADS2 score reported treatment levels of eligible patients
classified at high risk (score of ≥3) of between 39% and 70%.93 Data from the UK
suggests that 50% of patients with AF who should be taking warfarin are not receiving it,96 while data from the US suggests that only about one third of general
While the structure of healthcare systems and funding models differs from country to country, it has been proposed that the reasons for underuse are widely applicable and include low levels of therapy initiation, the narrow therapeutic margin of available anticoagulants and the associated inconvenience of monitoring, patient compliance, and physicians’ fear of bleeding events.98-100
In many instances, physicians appear to initiate anticoagulation and antithrombotic therapies based solely on their attitudes to therapy rather than the appropriate guidelines.101, 102 One study found that anticoagulation is often initiated primarily on
the classification of AF, rather than the calculated risk of stroke (Figure 4).101 Glazer
et al. found approximately three quarters of patients with newly detected AF received antithrombotic therapy (warfarin or aspirin) during the first six months of follow-up. However, 41% of patients at high risk of stroke did not receive warfarin despite guidelines recommending anticoagulation for such patients.101 They found
that AF classification was the strongest predictor of warfarin use (compared with transitory AF, the RR for intermittent AF was 2.8 [95% CI, 2.2-3.6], and the RR for sustained AF was 2.9 [95% CI, 2.2-3.7]), with none of the other stroke risk factors or warfarin contraindications being significantly associated with warfarin use.101
Figure 4: Use of antithrombotic therapy by AF classification and American College of Chest Physicians (ACCP) stroke risk (taken from Glazer et al.101)
A systematic review by Pugh et al.102 found that physicians are reluctant to
recommend warfarin for elderly patients in AF, despite evidence supporting an increased benefit of warfarin in elderly patients compared with younger patients. Advancing age was found to be the most important barrier to the prescription of warfarin.102 Bleeding risk and falls risk were also found to be disproportionate
barriers to initiating warfarin therapy.102
Clearly, improvements are needed in the assessment of stroke and bleeding risk factors to enable warfarin to be prescribed safely and appropriately to all patients in whom it is indicated. A number of tools for stratifying both bleeding and stroke risk exist.95, 103-107 However, the widespread application of these tools has been
hampered by complex calculating methods, a lack of consensus and varying predictive values of some of the scores.108
The CHADS2 scheme for categorising stroke risk for patients with AF (described
above), recommends ‘oral anticoagulation or aspirin’ for people categorised at low- moderate risk (CHADS2 score = 1).95 However, recent data suggests that in patients
with a CHADS2 score of one, oral anticoagulation is superior to aspirin for stroke and
mortality prevention.109 The CHADS
2 score has many limitations and does not
include some known risk factors for thromboembolism; as such it has recently evolved to a more refined risk stratification tool.108 This tool is the CHA2DS2-VASc
score (Table 3) which identifies low risk AF patients as those with a score of zero.109
All other patients (CHA2DS2-VASc score ≥ 1) can be considered for antithrombotic
therapy.109 This consideration of whether to utilise antithrombotic therapy could be
guided by the use of a bleeding risk stratification tool, rather than simply relying on the physician’s perception of bleeding risk.109 The HAS-BLED bleeding risk score
(Table 3) is one such simple tool which assigns points for bleeding risk factors and has the potential to support clinical decision making in patients with AF.103 A HAS-
BLED score of 0-2 would suggest the patient is at a low bleeding risk, while a score of ≥3 would suggest a risk of bleeding that would warrant consideration.108
Table 3: Risk stratification with CHA2DS2-VASc and HAS-BLED scoring schemes (based on data from Lip et al.109 and Pisters et al.103)
CHA2DS2-VASc Acronym Score HAS-BLED Acronym Score
Congestive heart failure/left ventricular dysfunction
1 Hypertension 1
Hypertension 1 Abnormal renal and liver
function (1 point each)
1 or 2
Aged ≥ 75 years 2 Stroke 1
Diabetes mellitus 1 Bleeding 1
Stroke/TIA/TE 2 Labile INRs* 1
Vascular disease (prior MI, PAD, or aortic plaque)
1 Elderly 1
Aged 64-75 years 1 Drugs or alcohol (1 point each) 1 or 2 Sex (female category) 1
Maximum score 10 Maximum score 9 * Labile INRs refers to unstable/high INRs or poor TTR
When comparing the two risk stratification tools it becomes clear that there are a number of risk factors for stroke which are also risk factors for bleeding (shown in bold in Table 3).110 This becomes particularly important when the use of
anticoagulants in the elderly is considered, and the overlap of potential risk versus benefit in this population.