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© The European Society of Cardiology 2005. All rights reserved. For Permissions, please e-mail: journals.permissions@oupjournals.org

Economic factors associated with antithrombotic treatments for stroke prevention in patients with atrial fibrillation

Paul S.J. Miller1,*, Michael F. Drummond2, Lars K. Langkilde3, John J.V. McMurray4 and Mats Ögren3

1AstraZeneca, HEOR/Medical Science, Parklands FE2 D/4, Alderley Park SK10 4TG, UK
2University of York, Heslington, UK
3AstraZeneca, Mölndal, Sweden
4Western Infirmary, Glasgow, UK

* Corresponding author. Tel: +44 1625 519944; fax: +44 1625 518537. E-mail address: paul.miller3{at}astrazeneca.com


   Abstract
Top
 Abstract
Introduction
 Key drivers for economic...
 Effect of stroke, VKA...
 Efficacy and safety in...
 Avoidable strokes and their...
 Conclusion
 Acknowledgements
 References
 
Our objective is to summarize the key components of a health economic evaluation of antithrombotic treatments for stroke prevention in patients with atrial fibrillation (AF). The key drivers are the changes in cost and quality of life associated with: thromboembolic events; the antithrombotic drug and its management; and bleeding events. Data on costs and utilities associated with all three components are presented. In clinical trials, vitamin K antagonists (VKAs, e.g. warfarin) substantially reduce the risk of stroke in patients with AF. However, the high cost of stroke makes clinical effectiveness a key element in the economic evaluation of stroke prevention interventions. Clinical effectiveness is lower than efficacy in clinical trials because of the variable anticoagulant effect and significant underuse of VKA therapy. The pure cost implication of reduced clinical effectiveness is illustrated using published data to extrapolate from clinical trials to clinical practice. If VKA effectiveness equivalent to that seen in trials could be achieved, 13.79 strokes per 100 patients over 5 years could be avoided compared with the typical current treatment pattern. If we take the lifetime cost of stroke to be {euro}126 797 (based on a USA estimate), preventing these additional strokes will trigger lifetime cost savings of {euro}1.75 million. Health economic decision-making must balance these gains against the cost of drug and management of VKA therapy.

Key Words: Anticoagulants • Arrhythmia • Stroke • Prevention • Health economic analysis


   Introduction
Top
 Abstract
 Introduction
Key drivers for economic...
 Effect of stroke, VKA...
 Efficacy and safety in...
 Avoidable strokes and their...
 Conclusion
 Acknowledgements
 References
 
The net socioeconomic burden of stroke is enormous; as well as 5.1 million deaths per year worldwide, 15 million non-fatal strokes occur each year, and >50 million individuals worldwide are alive having survived a stroke.1 Depending on the extent of disability, these individuals will have a high demand for health and social services in addition to the burden on themselves, their carers, and their families. Several studies have reported that stroke accounts for as much as 3–5% of all national health care expenditures in many countries.2,3 In the USA, direct costs of stroke were estimated to exceed US $28 billion in 1998 ({euro}28.3 billion) with a further US $15 billion ({euro}15.2 billion) of indirect costs.4 All currency conversions have been made from the original currency to the German Euro using Purchasing Power Parities for the year in which the cost was estimated.5

As many as 18% of all cerebrovascular events are associated with atrial fibrillation (AF).6 AF affects ~5% of all elderly people and increases the risk of stroke five-fold compared with patients in normal sinus rhythm.7,8 As both the incidence of AF and the stroke risk attributable to AF increase with age, AF and AF-related stroke will pose major societal costs over the coming decades.7,9–12 Importantly, the proportion of elderly in all developed countries is rapidly growing, and the estimate of 2.3 million adults in the US who currently have AF, is projected to grow ~2.5-fold to 5.6 million by 2050, substantially increasing the challenges of stroke prevention and the management of AF.12 Understandably, health economic data are of increasing importance for decisions on allocation of health care resources.13,14

Although AF is the most common chronic cardiac arrhythmia, a well recognized cause of cardiovascular morbidity, and an increasingly common cause of hospital admission, the cost of AF to a health care system has only been quantified recently with the availability of large relevant datasets.10 Stewart et al.10 estimated that the direct cost of AF to the UK National Health Service, treating 534 000 people with AF (0.9% of the whole population and 5% of those ≥65 years) was £244 million in 1995 ({euro}403 million). The greatest component of this expenditure (50%) was for hospital admissions. However, the total figure was a conservative estimate based on hospitalizations where AF was the principal diagnosis at discharge. Costs for admission of patients with a primary diagnosis of heart failure or stroke attributable to AF amounted to an additional £221 million ({euro}365 million) and £228 million ({euro}376 million), respectively. Costs related to stroke rehabilitation, digoxin toxicity, and warfarin- and acetylsalicylic acid (ASA)-related haemorrhage were not considered in this analysis. The second greatest component of the overall cost (20%) was drug treatment. The total cost of pharmacological management of AF (excluding anticoagulant treatment and monitoring) was £22 million ({euro}36 million). If 30% of AF patients were prescribed warfarin, which reflects the substantial underuse of warfarin in current practice, the cost of coagulation monitoring in these patients was £26.9 million ({euro}44 million). However, sensitivity analyses showed that a modest 15% reduction in stroke-related AF admission would reduce the cost related to AF by £30 million ({euro}50 million) a year.10

By identifying and modifying risk factors in older people, there are clear opportunities to reduce the cost, morbidity, and mortality of stroke related to AF. In randomized controlled trial settings, anticoagulation with vitamin K antagonists (VKAs, e.g. warfarin) for patients with AF has been shown to produce a 68% relative risk reduction for stroke compared with placebo.15 In routine clinical practice, however, the narrow therapeutic window, variable pharmacokinetics, and interactions with food and other drugs make it difficult and often resource-intensive to maintain good anticoagulation control with VKAs.16 Coagulation monitoring and dose adjustment are required, aiming for a target international normalized ratio (INR) between 2.0 and 3.0, to ensure effective prevention of stroke and other systemic embolism without excessive risk of bleeding.17,18

The difficulties involved in achieving a consistent and optimal intensity of anticoagulation with VKAs result in suboptimal care for patients, but also lead to underutilization of VKAs.19,20 Hence, many avoidable strokes are occurring. Strategies have been devised to improve the management of VKA treatment, for example, using specialist anticoagulation clinics and patient self-monitoring devices.

Decision-makers need to know the likely cost and benefit implications of adopting different treatment strategies. The objectives of this paper are to outline the components of cost and benefit that go into an economic evaluation of antithrombotic treatments for the prevention of ischaemic stroke among patients with non-valvular AF. The data are also used to illustrate the number of avoidable strokes and the costs that could be saved if improvements in current, routine provision of anticoagulant therapy for stroke prevention tend towards achieving the greater effectiveness of VKA therapy that is shown in clinical trial settings.


   Key drivers for economic analysis of stroke prevention
Top
 Abstract
 Introduction
 Key drivers for economic...
Effect of stroke, VKA...
 Efficacy and safety in...
 Avoidable strokes and their...
 Conclusion
 Acknowledgements
 References
 
The key drivers for the economic analysis of antithrombotic therapy for the prevention of stroke in patients with AF are the cost of thromboembolic events that occur (i.e. are not prevented) while receiving anticoagulation, the cost of antithrombotic drug, the cost of managing this therapy, and the cost of bleeding events (including haemorrhagic stroke) related to antithrombotic therapy. These costs fall on the health care system, other social care agencies, and on the patient/family. Figure 1 summarizes the general components of the economic evaluation of a health care intervention.21



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  		Figure 1. Components of economic evaluation in health care. As an example, ‘costs’ could refer to the costs of stroke in patients with AF and the ‘health care programme’ would be the provision of anticoagulation. (Reproduced from Drummond et al.21 by permission of Oxford University Press.)

 
Cost of thromboembolic events
Most of the costs associated with antithrombotic therapy for the prevention of stroke are incurred from clinical events, namely, thromboembolic stroke and bleeding events. In particular, the monetary valuation placed on stroke events is a key component of the economic assessment of events that could be avoided by anticoagulation. Long-term cost estimates show that the cost of stroke is substantial in all countries22–31 and the average total lifetime cost of a stroke, including social service costs, has been estimated to be as high as US $130 450 ({euro}126 797) in 2004 costs (US $90 981 in 1990,22 adjusted for inflation using the Consumer Price Index32).

In addition to the incidence of stroke, the severity, mortality, and recurrence rate of stroke in patients with AF are relevant to lifetime costs. It has been clearly demonstrated that strokes in patients with AF are more severe than strokes in patients without AF, irrespective of the measure used. In addition to being more severe, strokes in patients with AF are also more often fatal, have a higher recurrence rate, are associated with longer hospital stay, leave patients more impaired and more dependent, and decrease the likelihood of discharge to the subject's own home.6,33–37a Therefore, costs associated with stroke in AF patients are expected to be higher than the cost of strokes in patients without AF and higher than the cost of an average stroke. It is generally health care costs that will be higher, but the proportion of costs that are the responsibility of the patient's family will depend on the local model of health care provision.

Although we were unable to find published cost data specific to strokes occurring in a population of patients with AF, there is evidence for a positive correlation between severity of stroke and longer term stroke costs.38 Studies reporting the cost of thromboembolic events according to their level of severity are summarized in Table 1.24,30,39 In studies estimating the cost-effectiveness of anticoagulation in AF patients, severe stroke has been considered to cost 2.8-fold40 or 3.5-fold41,42 the cost of mild stroke. A large proportion of the total cost of stroke derives from long-term care. For example, a USA study estimated that 93% of the total cost of a disabling stroke [US $131 547 in 1995 ({euro}135 493)] was taken up by subsequent care costs.43 A UK economic model of stroke found that >80% of total stroke costs arose from long-term care. Thus, while the average acute cost in 1996 was £8326 ({euro}13 258), the long-term care cost of a major stroke was £75 985 ({euro}122 205) and of a minor stroke was £27 995 ({euro}45 024).30


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  		Table 1 Long-term cost-of-stroke estimates for stroke of different severities
 
Greater mortality among AF stroke patients results in fewer survivors incurring long-term costs compared with the population having non-AF-related stroke. However, in an economic evaluation the reduction in mortality is an important category of benefit. The value of more premature deaths avoided (years of life gained) by stroke prevention among AF patients must be realistically incorporated into cost-effectiveness estimates.44 The increased recurrence rate associated with AF stroke also has to be accurately represented in economic analyses in terms of additional costs and years of life lost, because recurrent strokes tend to be more severe and more often fatal than first strokes.45 Furthermore, stroke severity is a significant predictor of length of initial hospital stay.46

Additional costs further contribute to the burden of stroke. In countries with structures in place for patient rehabilitation after stroke (e.g. Switzerland), the cost of follow-up care falls on the healthcare system;47 in countries that do not provide state-funded, long-term care for stroke patients (e.g. Portugal, Italy), the responsibility of care falls to the patient's family. Although the cost of follow-up care to the government is low in these countries,47 it does not reflect the true cost of long-term care. As an example of the additional care required by patients who have had a stroke, a North American study reported that stroke can increase the daily cost of nursing-home care by as much as 11% compared with residents who have not had a stroke.48

Clearly, for an accurate economic evaluation of anticoagulation for the prevention of stroke, the cost of thromboembolic events specifically in patients with AF should be used in economic models, because the costs that could be avoided by preventing an AF-related stroke will be greater on average than those associated with a stroke event in a patient without AF.

Cost of drug and management of therapy
The cost of drug and of anticoagulation monitoring account for up to 25% of the total costs of VKA therapy (which includes the cost of drug and monitoring, plus the cost of managing thromboembolic events that occur even if warfarin is used, and that of managing bleeding complications).43 This has been estimated for patients with AF43 as well for patients who have had myocardial infarction, or for the patients receiving VKAs in general (which would include AF, prosthetic heart valves, venous thrombosis, pulmonary embolism, etc.).49–51 Several systems are in use to provide anticoagulation monitoring, and the national patterns vary. In the USA, most patients receive monitoring through their usual care physician,52 whereas specialized anticoagulation clinics are common in The Netherlands53 and UK.54 In Germany, patient self-monitoring is undertaken by some patients on long-term anticoagulation.50 As with all health care service costs, the costs involved in anticoagulation monitoring vary with health care system and country (Table 2).49–51,53,55–63 Nevertheless, patient self-testing tends to be the most expensive option, followed by anticoagulation clinics and physician monitoring. As patient self-management requires frequent INR tests, the yearly monitoring costs can exceed those incurred in primary care or anticoagulation clinics (Table 2).50,51,57–59 Additional costs are incurred from patient self-monitoring, as training is required for patients and for health care professionals who train the patients.64 Apart from the running of anticoagulation clinics, investment in establishing new clinics is costly.65,66 In the UK, monitoring costs in hospital clinics were lower than in primary care clinics (Table 2).55,56


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  		Table 2 Cost estimates of INR monitoring
 
Monitoring costs are higher for particular subgroups of patients. For example, in recent studies 12–40% of patients received domiciliary care,53,55,60 and a home visit increased the cost of anticoagulation monitoring by 25–50% (Table 2).55,60 Patients with unstable INR values and those at higher risk of complications (bleeding or thromboembolic events) may require more frequent monitoring in order to control closely the intensity of anticoagulation.16,67–69

Certain additional costs are associated with VKA therapy, such as the management of asymptomatic over-anticoagulation by stopping the VKA, by giving vitamin K, or by infusing fresh frozen plasma or prothrombin concentrate. In the UK, instances of INR >8.0 were found to incur an average cost of £251 ({euro}385, assuming 2003 costs).70

Anticoagulation monitoring can also be expensive for patients (Table 3). These costs include travel and lost working/leisure time for the patient and, if present, their caregiver. In some cases, the costs borne by patients can be as great as those incurred by the provider. In the UK, yearly costs incurred per patient (in 1999) were £102 ({euro}158) when monitored at a hospital, compared with £69 ({euro}107) incurred by the provider, and £68 ({euro}105) at a primary care clinic, compared with £97 ({euro}151) incurred by the provider.56 In the USA, patients were estimated to incur annual costs of US $520 ({euro}525) in 1997 for monitoring at an anticoagulation clinic compared with an estimated cost to the provider of US $233 ({euro}235).51,57 Most evaluations of costs include only the payer perspective, but including patient costs can significantly alter the cost analysis.


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  		Table 3 Summary of studies documenting costs of INR monitoring to patients and carers
 
Cost of bleeding events
The total cost of haemorrhagic complications in patients with prior stroke receiving VKA therapy in Sweden (approximately 45 000 patients or 5.3/1000 of the population being on continuous VKA treatment in 1995) was SEK 34 million ({euro}3.7 million), according to an analysis of published data.71 A recent study, based on patients with AF, estimated an annual national cost of £48 million ({euro}74 million; assuming 2003 prices) in the UK for treating all bleeding events and managing patients with asymptomatic excessive INRs.70 The seriousness and outcome of a bleeding event determine the cost of treatment. Bleeds range in severity from minor events, which may require minimal intervention, to intracranial haemorrhages requiring an intensive level of care. Hence, the cost of treatment spans as wide a range as the severity of the events in patients with AF and in mixed groups of patients undergoing anticoagulation with VKAs.29,43,51,57,70 According to a meta-analysis of clinical trials, the rate of intracranial haemorrhage in patients with AF during anticoagulation with warfarin averaged 0.3% compared with 0.1% in patients receiving placebo.15 However, the risk of intracranial haemorrhage increases dramatically if the INR exceeds 4.0.72 Examples of cost estimates for bleeding events in patients receiving VKA therapy are given in Table 4.


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  		Table 4 Summary of studies documenting the cost of bleeding events while patients receive VKAs
 
To estimate the average cost of a bleeding event in patients undergoing anticoagulation, the cost of an event of each severity must be weighted by the relative frequency of the various events and consequences. The estimated 10 year cost of an average bleeding event in patients with AF is £2064 ({euro}3341) estimated in 1997.29 However, long-term care costs add considerably to acute costs for serious bleeding events (Table 4).29,43,51,57,70 For example, the direct medical costs of a disabling intracranial haemorrhage in the USA in 1995 have been estimated to total US $138 876 ({euro}143 042), of which $122 844 ({euro}122 844) or 88% is spent on subsequent care.43 Although minor bleeds are less costly to manage than major bleeds, they are relatively frequent, and a UK study has shown that minor bleeds and asymptomatic high INRs account for 40% of the cost of treating bleeding complications associated with VKA therapy.70


   Effect of stroke, VKA therapy and bleeding events on quality of life
Top
 Abstract
 Introduction
 Key drivers for economic...
 Effect of stroke, VKA...
Efficacy and safety in...
 Avoidable strokes and their...
 Conclusion
 Acknowledgements
 References
 
The impairment associated with stroke can have a substantial negative impact on patients' quality of life, which provides a major impetus for avoiding strokes (or, at the very least, reducing their severity). A bleeding event, while receiving anticoagulant therapy also affects quality of life. In addition, anticoagulant therapy with a VKA places restrictions on lifestyle and diet, and, while providing protection from stroke, also imposes an increased risk of bleeding. Health economic analyses of antithrombotic therapy should account for benefits and preferences in terms of improvements in patients' health state and/or willingness to pay for these improvements.

In quality-of-life estimates known as utilities, a value of 1.0 represents a health state as good as current health and death has a value of 0. However, even within a subset of stroke severities (moderate, severe, etc.), the range of utility values obtained is wide, according to a review of published studies (not confined to stroke in patients with AF).73 A few studies have obtained utilities for stroke, bleeding, and anticoagulation therapy from patients with AF; those reporting mean values are presented in Table 5. While the utility of a mild stroke may be relatively high, a moderate stroke has a substantially larger impact and a major stroke leading to functional dependence may have a utility close to 0.40,41


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  		Table 5 Mean utilities for stroke, anticoagulation therapy, and bleeding events in patients with AF receiving a VKA
 
Possible reasons for variability in utility values include variability in the disease (stroke) and level of disability, variability in baseline characteristics of respondents (e.g. age), variability in methods used to elicit utilities, and variability in individuals' responses and adaptation to the stroke and acceptance of the stroke. Similar factors apply to bleeding and treatment utilities.

The mean utility assigned to a major bleeding event in patients with AF receiving warfarin was 0.84, whereas a major upper gastrointestinal (GI) bleed had a mean utility of 0.39 (Table 5).40,74 However, it should be noted that individual bleeding events, such as intracranial haemorrhage, may be devastating to the patient, while a minor bleed may have little effect on utilities.

A number of investigations of the attitudes of patients with AF to warfarin therapy have been conducted, finding mean utilities for warfarin treatment >0.9 (Table 5).40,41 The utility for ASA is close to 1.0,41 presumably because ASA treatment does not impose lifestyle restrictions, unlike the management of VKA therapy which requires patients to attend for regular coagulation monitoring and dose adjustment, to maintain consistent dietary vitamin K intake, and to avoid potentially interacting drugs and alcohol to ensure safe and effective treatment. Furthermore, ASA is associated with a lower risk of (and hence, less fear of) bleeding complications than VKAs.

Results suggest that patients on average would accept warfarin therapy for a relatively small benefit in terms of stroke risk reduction.75–77 Only 7% of patients in one survey agreed that warfarin restricted their lifestyle.78 These patients did not report a significantly worse health status, assessed by the SF-36, in comparison with control patients who received no anticoagulation or ASA, unless they had experienced a major or a minor bleeding episode on warfarin. A difficulty in interpreting patients' attitudes to therapy is that patients may accept inconveniences of therapy in the knowledge that it is beneficial to their health. In fact, fear of stroke has been identified as a major factor influencing patients' decisions to take warfarin.77 Patients assessing the maximum bleeding risk and the minimum reduction in stroke risk associated with antithrombotic therapy placed more value on the avoidance of stroke and less value on the avoidance of bleeding than did physicians who treat patients with AF.75

An important feature of the majority of the above studies of stroke, treatment, and bleeding utilities is the large interpatient variability in responses. This serves to highlight the relevance of incorporating individual patient preferences when choosing stroke prophylaxis.40,79,80


   Efficacy and safety in trials and clinical practice
Top
 Abstract
 Introduction
 Key drivers for economic...
 Effect of stroke, VKA...
 Efficacy and safety in...
Avoidable strokes and their...
 Conclusion
 Acknowledgements
 References
 
Accurate estimation of the health economic impact of antithrombotic therapy requires reliable data on the clinical effects of therapy. In this section, we summarize data on the risk of stroke in patients in the absence of antithrombotic therapy and with antithrombotic therapy managed according to different scenarios. The variability in quality of anticoagulation control (e.g. time in therapeutic INR range) between current treatment strategies, and the general underuse of anticoagulant therapy in practice, contribute to variable effectiveness. In addition to these factors, the characteristics of patient populations in clinical practice are likely to differ from those in clinical trials that have evaluated the efficacy of antithrombotic therapy.

Figure 2 illustrates the estimated number of strokes per 100 patients with AF over 5 years across the range of Framingham Heart Study stroke risk scores in patients not receiving antithrombotic therapy.81 Superimposed on this are the estimated rates of stroke with the provision of different antithrombotic treatment strategies, as discussed subsequently.



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  		Figure 2. Estimated number of strokes in AF patients according to Framingham Heart Study stroke risk score81 and treatment strategy.

 
No treatment
Baseline risk of stroke data are available from studies of AF patients randomized to placebo or control arms in clinical trials. Meta-analyses of these trials demonstrate an annual rate of stroke of ~4.5% in the absence of anticoagulation.15,82,83 This risk varies from 1% in patients younger than 65 years with no additional risk factors for stroke to 8.1% in patients older than 85 years who had one or more additional risk factors. Risk stratification schemes based on follow-up of trial cohorts have been developed,17,18,82,84,85 but clinical trial populations may not reflect population epidemiology. Several population-based studies have provided estimates of the risk of stroke between ~1 and 4.5%, but did not adjust for prior stroke,86 were not AF-specific,87 or were based on hospitalized patients only.88 The Framingham Heart Study risk score for predicting stroke in patients with AF in the community provides a comprehensive summary of baseline stroke risk across all patient groups. The crude annual rate of stroke among the patients with AF not taking warfarin was 2.9%.81

ASA or VKA therapy in clinical trials
ASA offers only modest protection against stroke, with an average relative risk reduction for stroke of 22% compared with placebo or no treatment, according to a meta-analysis of six clinical trials.15 However, warfarin therapy is highly efficacious as primary stroke prevention. Meta-analyses of trials have reported aggregated relative risk reductions of 62,15 66,83 and 68%82 compared with placebo or no treatment. The relative risk reduction for secondary stroke prevention is similar (68%).89 Annual rates of major bleeding obtained from meta-analyses of clinical trials were ~1.0% without antithrombotic treatment, 1.0% for ASA, and 1.3% for warfarin.15,82,83

van Walraven et al.85 conducted an individual patient meta-analysis, based on 4052 patients from six trials randomly assigned to receive therapeutic doses of warfarin or ASA with or without low-dose anticoagulants. Patients in the warfarin group had 2.4 strokes per 100 patient-years, whereas those receiving ASA had 4.5 strokes per 100 patient-years, a hazard ratio of 0.55. However, patients treated with warfarin were more likely to experience major bleeding than those receiving ASA (2.2 vs. 1.3 events per 100 patient-years; hazard ratio 1.71).

Impact of INR control on efficacy and safety of VKA therapy
Control of anticoagulant intensity within the target therapeutic INR range is critical to the success of VKA anticoagulation therapy. An INR between 2.0 and 3.0 is optimal for stroke prevention in patients with non-valvular AF. Below 2.0 the risk of thromboembolic events increases, and above 3.0 the risk of bleeding increases.16,17,72 Furthermore, a review of published studies demonstrated a strong relationship between time in target therapeutic range and clinical outcomes of thromboembolic events and major bleeding in patients undergoing VKA therapy.90

It has also been shown that anticoagulation that results in an INR <2.0 independently increases the severity of ischaemic stroke and the risk of death, when a stroke does occur. A large cohort study of patients with AF and ischaemic stroke showed that the 30 day mortality rate was 6% among patients who were taking warfarin and had INR ≥2.0 at the time of the stroke. This compared with 16% among those taking warfarin whose INR was <2.0, 15% among those taking ASA, and 24% among those taking neither ASA nor warfarin.91 Furthermore, even moderately low INR values of 1.5–1.9 resulted in stroke mortality rates similar to those in patients with INR <1.5. The rate of intracranial haemorrhage was approximately 0.5 per 100 patient-years at INR values up to 3.9, but 2.7 and 9.4 per 100 patient-years at INR 4.0–4.5 and INR >4.5, respectively.

Effectiveness and safety of VKA therapy in practice
The quality of anticoagulation control in clinical practice tends to be worse than in clinical trials, and this may be reflected in a greater number of thromboembolic and haemorrhagic events. Per cent of time in target INR range was 66% in an analysis of pooled trial data82 and as high as 83%,92 and 71%84 in individual trials. However, randomized trials are subject to selection bias, and health care driven by protocols is likely to differ from routine health care. For example, AF patients in routine care had a higher prevalence of comorbidities, were older,30,93 and had a less frequent INR monitoring than those in clinical trials.93 In clinical practice, adherence to complex dosing instructions or concomitant drug and dietary restrictions, poorer compliance, and medical need to stop and restart VKA therapy during long-term use may also result in INR values outside the therapeutic range.16

Studies of ‘usual care’ VKA anticoagulation have consistently reported less time in target range (e.g. 37–61%)93–100 than in clinical trials. Patients are more likely to have subtherapeutic than supratherapeutic INR values (perhaps due to cautious dosing to avoid iatrogenic bleeding),98,101 which exposes patients to increased risk of thromboembolism.

Although some studies30,93,94 report only a minor difference in clinical event rates between usual clinical practice and clinical trials (despite a lower proportion of time in therapeutic INR range),93,94 this may reflect small sample sizes or anticoagulation services having above-average quality of anticoagulation control. Annual rates of minor bleeding in usual care were reported to be 13.6% in routine care in a Health Management Organization in the USA, compared with 7.8–8.4% in two clinical trials with good anticoagulation control, but were similar to the rates seen in two trials with poorer control of anticoagulant intensity.93

In two studies in which decision-analytic models have been used to assess anticoagulation management in clinical practice and map these data on INR control to clinical endpoints, time in the therapeutic range was estimated at 5051 and 48%.102 When compared with the rate of thromboembolism among placebo or control patients from clinical trials,82 results from these models suggest that ‘usual care’ VKA provides a relative risk reduction of 4051 or 55%,102 when compared with the 68% relative risk reduction reported in clinical trials. Note that Samsa et al. acknowledge that their ‘usual care’ estimate is based on raw data from clinical trials, hence it is likely to overestimate effectiveness.

There are also differences in anticoagulation control and clinical event rates between usual care and specialist anticoagulation clinics. More frequent testing of INR and VKA dose adjustment is associated with increased time in therapeutic range.103 Specialist anticoagulation clinics, with more frequent testing and with point-of-care INR results and dose adjustment, have been established in an attempt to improve the quality of VKA treatment. Usual-care VKA has been estimated to entail 14 tests per year93 whereas specialist anticoagulation clinics entail 23 tests per year.104 Individual studies have shown similar105 or lower rates100,101 of thromboembolic and bleeding events in anticoagulation clinics compared with usual care. The resulting relative risk reduction from specialist VKA clinics compared with clinical trial controls82 is estimated at 4851 and 51%.102

One further technology that is available to assist in maintaining control of VKA treatment is patient self-testing devices for home monitoring. These can be used to monitor INR on a weekly basis and generate greater clinical effectiveness in terms of stroke prevention. Patient self-monitoring can achieve a similar59 or higher106,107 proportion of time in the therapeutic range in comparison with usual care and the relative risk reduction from patient self-testing compared with clinical trial controls82 is estimated at 65%.51

Underutilization of anticoagulant therapy
In practice, anticoagulant therapy is substantially underused in patients with AF, particularly in older patients. Around 50% of AF patients with additional stroke risk factors and without contraindications do not receive VKAs.19,20,108 Some receive no treatment and some receive ASA. This contributes to a significant tally of avoidable strokes. Among patients discharged from a Swedish hospital with a diagnosis of AF and without a contraindication to warfarin, 40% were receiving VKA therapy, 42% were receiving ASA, and 18% no antithrombotic therapy. Among the subset of these patients who were at moderate to high risk of stroke and had no warfarin contraindication, 40% were receiving no antithrombotic therapy.109 In a recent review108 of studies published from January 1998 to June 2003 reporting VKA use in patients with AF, 49 eligible publications were identified. Most studies only reported treatment rates for AF patients irrespective of stroke risk. However, in AF patients at high or high/medium risk of stroke and without VKA contraindications (13 studies), VKA treatment rates ranged from 23 to 66%, with all but one study reporting rates of ≤55%. Treatment rates were 14–50% in medium-risk patients without contraindications (3 studies). The proportion of patients considered to have VKA contraindications varied considerably (8–49%), but some studies included only specific bleeding risk factors as contraindications, where as others included factors such as patient preference, monitoring difficulties, and mental/cognitive state.108


   Avoidable strokes and their cost
Top
 Abstract
 Introduction
 Key drivers for economic...
 Effect of stroke, VKA...
 Efficacy and safety in...
 Avoidable strokes and their...
Conclusion
 Acknowledgements
 References
 
From a forward-looking perspective, it is most relevant to clinical decision-making to consider ‘avoidable’ strokes as those that might be avoided by optimizing the provision of antithrombotic therapy—for example providing VKA therapy with effectiveness equivalent to that achieved in clinical trials—in comparison with the number of strokes that currently occur in AF patients in routine clinical practice. The cost savings (through stroke avoidance) as antithrombotic treatment in routine clinical practice move towards the performance of clinical trial VKA therapy can be estimated by combining the data on current patterns of anticoagulation provision, the stroke risks associated with the current antithrombotic treatment mix and the hypothetical optimal (clinical trial standard) antithrombotic therapy, and the cost of stroke.

We provide an example for a patient with AF with a Framingham Heart Study risk score for stroke of 20 (from a possible range of 0–31) in the absence of VKA therapy. This risk score represents a 5 year risk of stroke of 34%81 (Figure 2), or an average annual rate of 6.8%. As described in the preceding section, the effectiveness increases in the order: ASA, usual care VKA, anticoagulation clinic VKA, patient self-test VKA, clinical trial VKA (Figure 2). The typical current mix of antithrombotic treatment strategies for patients without contraindications to VKA therapy is assumed (as an illustrative example) to be 40% receiving VKA managed in usual care, 10% receiving VKA managed in an anticoagulation clinic VKA, 30% receiving ASA, and 20% no treatment. This ‘current treatment mix’ achieves a level of effectiveness less than that of VKA therapy provided in a usual care setting.

At a risk score of 20, the typical current mix of treatment for patients without contraindications to VKA therapy results in a 24.67% 5 year risk of stroke, whereas VKA therapy with clinical trial effectiveness would result in a 10.88% 5 year stroke risk. Therefore, the current treatment mix avoids 9.33 strokes per 100 patients over 5 years compared with no treatment. However, if VKA effectiveness equivalent to that seen in clinical trials could be achieved routinely, a further 13.79 strokes per 100 patients over 5 years could be avoided. If we take the lifetime cost of stroke to be {euro}126 797 (based on US $90 981 in 199022 inflated to US $130 450 in 2004), preventing these additional 13.79 strokes per 100 patients over 5 years will trigger lifetime cost savings of {euro}1.75 million (13.79x{euro}126 797).


   Conclusion
Top
 Abstract
 Introduction
 Key drivers for economic...
 Effect of stroke, VKA...
 Efficacy and safety in...
 Avoidable strokes and their...
 Conclusion
Acknowledgements
 References
 
The information summarized in this paper suggests an opportunity to reduce the substantial socioeconomic burden of stroke, first by ensuring that patients with AF who can benefit from anticoagulant therapy are actually receiving appropriate therapy and, secondly, by efforts to improve antithrombotic therapy further to achieve a level of efficacy seen in randomized controlled clinical trials of VKAs. Bushnell and Matchar state that of the several strategies for managing anticoagulation with warfarin for the prevention of stroke in AF, one of the principal means of controlling costs is to avoid out-of-range INR values.110 Of the key components of the economic analysis of antithrombotic therapy for stroke prevention, the avoidance of stroke is expected to have the greatest impact on costs and quality of life. In fact, effective antithrombotic treatment strategies, achieving a consistent therapeutic anticoagulant effect, are likely to reduce the burden of bleeding complications as well as stroke. Health economic decision-making must balance these gains against the cost of drug and management of VKA therapy.


   Acknowledgements
Top
 Abstract
 Introduction
 Key drivers for economic...
 Effect of stroke, VKA...
 Efficacy and safety in...
 Avoidable strokes and their...
 Conclusion
 Acknowledgements
References
 
Thrombosis Quorum is supported by an educational grant from AstraZeneca. This Supplement has been developed as part of the Thrombosis Quorum initiative, under the direction of the Thrombosis Quorum Steering Group [G. Agnelli (Chairman), P. Bath, J. Emmerich, B. Gersh, M. Ögren, S. Schulman, and J. Weitz].

Conflicts of interest
P. Miller and L. Langkilde are employed by AstraZeneca. J. McMurray has received research grants, consulting fees, and honoraria from AstraZeneca. M. Ögren is Associate Professor in Surgery at Uppsala University, Sweden, and is employed by AstraZeneca.


   References
Top
 Abstract
 Introduction
 Key drivers for economic...
 Effect of stroke, VKA...
 Efficacy and safety in...
 Avoidable strokes and their...
 Conclusion
 Acknowledgements
 References
 

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