Economic burden of stroke and the evaluation of new therapies

Public Health (1998) 112, 103±112 ß R.I.P.H.H. 1998

Economic burden of stroke and the evaluation of new therapies M Kaste1, R Fogelholm2 and A Rissanen2 1

Department of Clinical Neurosciences, Helsinki University Central Hospital, Haartmaninkatu 4, FIN-00290 Helsinki, Finland; and 2 Department of Neurology, Central Hospital of Central Finland, Jyvaskyla, Finland Stroke is a major health problem in all industrialised countries and evidence is mounting that this problem also affects the developing countries. In the industrialised countries, it is the third largest killer and, of the survivors, about one-half are left with a permanent handicap. Despite the huge burden of stroke on healthcare and social services (several USA studies estimate the annual cost of stroke to be between US $6.5 and 11.2 billion) the cost of strokes has aroused little attention. An absence of effective therapies may be one of the reasons for this lack of interest; the costs have been taken as inevitable. With the advent of new therapies for acute ischaemic stroke (thrombolytics and neuroprotectants) there is renewed interest in improving both the management and outcome for patients. Key to the evaluation (both clinical and economic) of new stroke therapies is the choice of evaluation scales/instruments. Increasingly, stroke investigators are using measures of functional outcome (for example the Barthel index) as a primary endpoint in stroke trials. This is pertinent, as functional outcome has been found to re¯ect reasonably well the degree to which a patient needs support after stroke, irrespective of whether this is provided by the family or society. Keywords: ischaemic stroke; epidemiology; outcome evaluation scales

Epidemiology of stroke Stroke is a major global health problem and, in most industrialised countries, is the third most common cause of death after heart disease and cancer. In addition to causing a huge number of deaths, stroke is the most important cause of physical disability in people over 60 y of age. According to the World Health Organization (WHO), stroke is de®ned as rapidly developing clinical signs of focal (or global) disturbance of cerebral function, lasting more than 24 h or leading to death, with no apparent cause other than vascular origin.1 In most cases (75±80%), stroke is caused by local ischaemic necrosis of the brain parenchyma, and the lesions are called brain (cerebral) infarctions. The underlying pathology is either local thrombosis in, or embolism to, precerebral or cerebral arteries. Emboli may either arise from atherosclerotic cervical arteries or the aorta, or they may be of cardiac origin. Platelet-®brin emboli may form on the atherosclerotic plaques of the arteries and aorta or, alternatively, necrotic atherosclerotic plaques may ulcerate and cause embolism to the peripheral cerebral arteries. Many types of heart disease are potential sources of cerebral (and systemic) embolism, the most important of which are atrial ®brillation combined with valvular lesions, and myocardial infarction. About 20±25% of all strokes are haemorrhagic, either primary intracerebral (15%) or subarachnoid (10%) haemorrhage. Primary intracerebral haemorrhage is usually caused by the rupture of an artery seated deep in the brain parenchyma which, as a rule, has been weakened by longstanding hypertension. Subarachnoid haemorrhage is most often due to a ruptured saccular aneurysm located at the bifurcation of a large super®cial cerebral artery. The ®rst epidemiological studies on stroke date back to the 1940s. In 1970, the WHO organised a meeting on

Correspondence: Prof M Kaste. Accepted 24 September 1997

cerebrovascular diseases, and this meeting marked the start of intensive epidemiological activity all over the world.2 Since then, a large number of reports from several countries have been published, and our knowledge on stroke epidemiology has increased immensely.

Stroke mortality Stroke mortality refers to a ratio of the total number of stroke deaths to the total population. It is usually given as the annual number of deaths per 100 000 population. The mortality data have, in general, been obtained from basic national statistics which are an important source of data, although different coding practices (related to tradition, culture and autopsy rates) make comparisons between countries dif®cult. In addition, only one-third of the world's population has a reliable death certi®cate system. Stroke mortality differs widely from country to country. An analysis of 27 countries with accurate population estimates, complete death registration, and comparable cause of death coding3 showed that, in 1985, the agestandardised stroke mortality rates for men aged 40±69 y showed up to a 6.6-fold difference between countries with the highest mortality rate compared with those with the lowest. For women, this difference was up to 7.4-fold (Figure 1). In all of these countries, stroke mortality for males was higher (median 52%, range 22±114%) than for females. In most industrialised countries, stroke mortality has declined by more than 50% since 1970.4 Exceptions are the former communist countries in eastern Europe where mortality has increased. Using age-standardised mortality ®gures from the 27 countries, Bonita et al 3 calculated that the percentage change per year during 1970±85 for men and women aged 40±69 y varied between ‡3.9% and 77.1% (Figure 2). The decline must result from either fewer stroke events (®rst or recurrent), or a declining case-fatality rate, or a combination of

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Economic burden of ischaemic stroke M Kaste et al

Figure 1 Age-standardised (European standard population) annual stroke mortality rates from 1985 of men and women aged 40±69 y (per 100 000 population) in 27 countries, by sex.

Figure 2 Percentage change in age-standardised annual stroke mortality rates during 1970±1985 of men and women aged 40±69 y in 27 countries, by sex.

these. The causes of these possible changes, however, remain unknown.

criteria, complete case ascertainment, prospective design, inclusion of ®rst ever strokes only, and con®rmation of stroke subtype (brain infarction, primary intracerebral haemorrhage, subarachnoid haemorrhage) by early computed tomography (CT) or necropsy. Stroke mainly affects the elderly, with two-thirds of the victims being 65 y of age or older. Correspondingly, the incidence of stroke increases almost exponentially from the age of 25±34 y to 85‡ y. Figure 3 shows (on a logarithmic scale) the steep increase of ®rst stroke incidence, by age, in Oxfordshire (UK) between 1981±86,7 in Espoo-Kauniainen (Finland) between 1978±808 and in Perth (Australia) between 1989±90.9 If recurrent strokes are included, the ®gures will be 20±35% higher, especially in the older age groups. Of the stroke subtypes, ischaemic brain infarction and primary intracerebral haemorrhage exhibit this age-related pattern, which the incidence of subarachnoid haemorrhage shows a more gradual increase reaching a maximum incidence in the age group 50±60 y. Based on 37 studies, the standardised (USA population January 1, 1976 as standard) annual incidence per 100 000 population of ®rst stroke has ¯uctuated between 135 and 272 in the USA, 117 to 219 in Europe, and between 83 and 329 in Japan and China.10 The standardised incidence ratios varied correspondingly between 3.6 and 0.7, but in 31 of the studies it was between 2.0 and 0.75. It was concluded that the worldwide variation in age-sex adjusted stroke rate is relatively small. Long-term trends in stroke incidence have been estimated from surveys monitoring stroke incidence in a given population for several years, or from surveys which

Stroke incidence Incidence is the rate at which new events occur in a population. Usually it is given as the number of new cases per 100 000 population during 1 y. Strictly speaking, this de®nition does not include recurrences which must, however, be included when the impact of stroke on the community is estimated. A boom of stroke incidence studies occurred after the WHO meeting in 1970,2 and today we have at our disposal several studies from many countries across all continents. Unfortunately, variations in study design, differences in diagnostic criteria and case ®nding methods, the age ranges of patients included and the age structure of the target populations, and inclusion of either ®rst-ever or all stroke events make it dif®cult to compare the results from different studies reliably. In order to make the results reliable and to determine whether the incidence of stroke varies by time and place, the study design must be uniform. In the 1970s, the WHO made a ®rst attempt at designing a study which would enable results to be compared, and this WHO Collaborative Study was reported in 1980.1 After this, a second multinational prospective study to monitor trends in cardiovascular disease was introduced by the WHO in the beginning of the 1980s.5 In 1987, criteria for an `ideal' stroke incidence study were provided.6 Of the twelve prerequisites for an ideal study, the most important are standard diagnostic

Economic burden of ischaemic stroke M Kaste et al

after the stroke onset. If the improved survival is a true ®gure, the precise reason for it is still unclear. No effective new treatments for acute stroke were introduced during the years concerned, but management of the acutely ill patient aimed at preventing systemic complications and/or rehabilitation aimed at improving the patient's self-suf®ciency may have been more effective than before. Stroke severity may today be milder than before, or it may be that patients with different prognostic indicators (namely more favourable) compared to those of the earlier series, were included.29 On the other hand, the precise diagnosis of stroke and its subtypes has changed fundamentally since CT was introduced. Prevalence of stroke Figure 3 Age-speci®c annual incidence of stroke per 100 000 population in three selected studies: Oxfordshire (UK) 1981±86,7 Espoo-Kauniainen (Finland) 1978±80,8 Perth (Australia) 1989±90.9

were repeated with intervals of several years in the same population. The ®ndings of a number of such studies have, however, been con¯icting; the incidence has been found to be either falling,11,12 increasing,13,14 or increasing only after decades of decline,15 but often no change has been observed.16±19 Thus, currently, the picture of stroke incidence is at the very least con¯icting, and no de®nite trend can be identi®ed.6,20

Prevalence measures the number of people at any one time in the population (often given per 100 000) who have or have had a disease. Our knowledge about stroke prevalence is, despite its importance in measuring the total impact of stroke in the population, very limited compared with incidence data due to the dif®culty in obtaining data from a total population. The prevalence of stroke in persons over the age of 25 y, estimated on the basis of incidence and survival data, has been found to be 410±792/100 000 in Australia.30 In a cohort study, the prevalence of stroke among Finnish men and women aged over 20 y was 1030 and 580/100 000, respectively.31 The prevalence ®gures increased steeply from 160±2750 between the age of 20± 44 y and the age of 75‡ y in men, and women from 110± 3510/100 000, respectively.

Case fatality Case fatality gives the proportion of all cases which are fatal within a speci®ed time interval. Stroke is a serious disease and many of its victims die early after onset, though the case fatality pattern of ischaemic brain infarctions differs from that following haemorrhagic stroke. As a rule, haemorrhagic strokes kill within the ®rst few days or weeks, after which the prognosis is remarkably good. By contrast, patients with ischaemic brain infarctions, thrombotic or embolic, have better early survival, but the late survival (months after onset) is worse because of infectious and thromboembolic stroke complications, and because of cardiovascular deaths. Fifty per cent of patients with primary intracerebral, and 60% of those with subarachnoid haemorrhage are alive at 1 month after the stroke, and 40% and 50%, respectively, are alive 1 y after onset.21,22 The prognosis of ischaemic brain infarctions is much brighter; 82±90% survive the ®rst month, with 67±77% being alive 1 y after onset.23,24 Many factors other than stroke subtype have a bearing on the prognosis. Reduced consciousness after onset, a sign of severe stroke, and old age are both markers of a poor prognosis. In addition, the early case fatality rates have varied between different populations. The WHO MONICA Project has demonstrated, in 18 populations, that the 28 d case fatality rates varied between 15% and 49% in men, and between 18% and 57% in women.25 No clear explanation for this variation could be given. Time-trends for case fatality rates have been investigated, but the results have been, as in the case of stroke incidence, inconsistent. The case fatality rate has either remained stable,8,16 or an increased proportion of patients have survived the ®rst four weeks12,19,26,27 and are alive 2 y

Costs of strokes The scarcity of resources in healthcare, compared with people's expectations, has meant that the demand for economic ef®ciency has become increasingly important. This has led to the assessment of cost-effectiveness of treatment policies. Despite the magnitude of stroke as a burden on healthcare and social services, the costs of stroke have aroused little attention. Lack of effective therapies may be one of the reasons for this lack of interest; the costs have been taken as inevitable. With the advent of new therapies,32 the costs of stroke will inevitably be seen in a new light. Estimation of costs The costs of stroke can be subdivided into direct and indirect costs. Direct costs include direct medical costs (hospitalisation, rehabilitation, nursing home, home health care services) and direct non-medical costs (such as cost of home modi®cations, appliances, transportation, domestic aid). Indirect costs include the loss of production due to the stroke (lost time from work, movement into less productive job, time lost from homemaking activities). In several studies in the USA, the annual costs of stroke have been estimated as varying between US $6.5 and 11.2 billion.33±38 Berk et al 33 calculated the total costs of all diseases in the USA, and found that the costs of stroke were 2.6% of the total sum. In the UK, the proportion of the cost of stroke to the total cost of illness has been estimated to be around 2.5±3%,39 and in France in 1982 the corresponding ®gure was 2% of the total Social Security budget.40

105

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In the USA, the direct costs accounted for 47%, and the indirect costs for 53% of the total cost of stroke.36 In Sweden this distribution was quite different: 76% were due to direct and 24% to indirect costs.41 Differences in the age structure were thought to be partly responsible for this discrepancy. The expenditure per stroke patient was US $23 000 in Massachusetts 197534 and US $20 640 in Sweden 1977.42 The comparison of data on the costs of stroke from different countries is often dif®cult because of medicosocial differences, varying validity of background data, and different rates of in¯ation. However, because the healthcare and social ward systems are similar in Finland and Sweden, we have been able to justify a comparison of the costs of stroke in these countries. Scandinavian studies The costs of stroke in Finland have been calculated on the basis of an epidemiological study performed in the JyvaÈskylaÈ Region, Central Finland.24 The costs during the ®rst years after stroke were calculated from the incidence study, which included all acute strokes occurring between 1st September 1985 and 31st August 1986 in the population of 114 600 living in the JyvaÈskylaÈ Region. A total of 271 patients had an acute stroke, for 219 it was their ®rst ever, which gives an annual incidence of 317 (95% con®dence interval 274±360) per 100 000 (age-adjusted for standard European population aged 25 y43). The costs after the ®rst year of stroke were calculated from the prevalence study of the same population.24 All patients who had had a stroke and who, on the prevalence day (28th February 1989), were either in hospital, an old people's home or sheltered housing, as well as those who lived at home, but needed outside help, were traced. Patients who had had their ®rst stroke within 1 y of the prevalence day were excluded, and the remaining 406 patients whose dependency was assessed to be exclusively or mostly due to the previous stroke provided the basis for cost calculations of stroke after the ®rst year. Of these patients, 206 were permanently institutionalised, and the other 200 were living at home and receiving outside help. In calculating the direct costs, we included the costs of hospital treatment, of a stay in an old people's home and sheltered housing, the costs of rehabilitation and help devices, and the costs of outside help given by nurses and home help workers to the patients living at home. For the hospital treatment, the different levels of healthcare were taken into account; University Hospital (neurosurgery), Central Hospital (neurology, medicine, vascular surgery), and Health Centre (long-term treatment, permanent institutionalisation, day hospital and social holiday periods). We did not include the costs of household modi®cations or out-patient visits to a physician in the calculations, which accounted for 2±3% of the direct costs in Sweden,41 nor did we include transportation services or medicines. From the results in the JyvaÈskylaÈ Region, the costs of stroke were extrapolated to the total population of Finland (5.1 million) with an age structure very similar to the study population. In order to allow comparison with the costs of stroke in Sweden,41 our data were extrapolated down to represent the year 1991. A discount rate of 5% and an increase of productivity by 1.5% were used in the calculations of indirect costs. The calculations were performed according to the method presented by Drum-

mond.44 The mean currency rate in 1991 was used to convert Finnish marks into US dollars (1 US $ ˆ 4.05 FIM). Unit costs of healthcare and social services in the JyvaÈskylaÈ Region in 1987 are presented in Table 1. The direct annual costs of the ®rst year after stroke in Finland were US $131.1 million, and after the ®rst year US $441.4 million, totalling US $572.5 million (Table 2), equivalent to US $114 per inhabitant. In the study area, the total direct costs of the ®rst year and the later years calculated on the basis 219 incident and the 506 prevalent cases amount to US $14.9 million per year. Calculated from these ®gures the total lifetime direct costs of one new stroke patient in Finland was US $59 789 using a 5% discount rate. The indirect costs were calculated from the incidence study. Altogether 2500 people years were lost due to retirement before the age of 65 y. A total of 5200 working years were lost through death. When the mean industrial wages45 combined with the social costs paid by the employers were used as the measure of loss of production, the total indirect costs were US $243.6 million (Table 3). Thus, the combined annual direct and indirect costs of stroke in Finland are US $816.1 million. When three different approaches were used in Sweden, there was a 1.6-fold difference between the highest (US $2413 million) and the lowest (US $1534 million) estimates of the total costs of stroke.41 The lowest estimate was selected for the ®nal calculation in Sweden, but our ®gures, after taking the difference in population (5.1 vs 8.7 million) into account, are slightly lower than this Swedish estimate. Methodological differences can, at least partly, explain this difference; for example we did not include the costs of hospital treatment after stroke if this was due to causes other than stroke. In Sweden, after deduction of prestroke costs that had occurred in the preceding year, the lifetime costs of stroke were reduced to less than half, from US $73 333 to US $33 000.41 This is considerably lower than the US $55 525 which is our estimate of direct strokerelated lifetime costs in Finland. We deducted from the total direct costs the pre-stroke permanent institutional treatment, and the pre-stroke home nurse visits and home help. In the Swedish study, all medical costs from all causes (surgical treatment being a major component) as well as out-patient visits were deducted. Thus, the Swedish ®gures may underestimate, and ours may overestimate the strokerelated costs (Table 4). Table 1 Unitary costs of healthcare and social services needed in the treatment of stroke patients in the JyvaÈskylaÈ Region, Central Finland, 1987. Neurosurgery is provided by the Kuopio University Hospital serving Central Finland and the eastern regions of the country Cost (US $) Inpatient care per day Neurology Neurosurgery Health centre Nursing home Care at home Nurse visit Home help visit Rehabilitation Physiotherapy per session Speech therapy per session Rehabilitation institution per day

414 678 133 101 51 45 43 57 185

Economic burden of ischaemic stroke M Kaste et al

Table 2 Direct annual costs (in US $ million) of stroke in Finland. The costs of the ®rst year after stroke are calculated on the basis of incidence data from 1985±86, and the costs after the ®rst year on the basis of the prevalence data from 1989, JyvaÈskylaÈ Region, Central Finland (Rissanen24) Costs of the ®rst year

Costs after the ®rst year

75.9 4.2 23.1 11.9 Ð

19.4 Ð 202.4 135.9 9.2

2.6 6.5

11.3 44.0

0.8 0.3 2.6 1.5 129.4

3.9 0.5 13.1 1.7 441.4

In-patient care Department of neurology Department of neurosurgery Health care Nursing home Day hospital (social causes) Care at home Nurse visits Home help Rehabilitation Physiotherapy Speech therapy Rehabilitation institution Aids and appliances Total Table 3 Indirect costs of stroke in Finland calculated on basis of the incidence data, from the JyvaÈskylaÈ Region, Central Finland, 1985±86 (Rissanen24) Costs (US $ million)

Survival Fewer than 20% of patients should die within the ®rst month after stroke.

101.5 141.2 0.9 243.6

Dependency More than 70% of the surviving patients should be independent 3 months after stroke.

Early retirement Early death Sickness bene®t Total

Table 4 Comparison of costs of stroke between Finland and Sweden in US $, discounted to the 1991 level Finland Costs per inhabitant Direct costs Indirect costs Total Lifetime costs of a stroke patient Of these, stroke-related costs

Table 5 Management of acute stroke, WHOs goals for 2005

Sweden

114 49 163

154 48 202

59789 55525

73333 30000

Pitfalls of pharmacoeconomic analyses Calculation of the costs of a disease is very complicated. For example, it is impossible to know exactly what the costs for a person without a stroke would be. Could a person who is bedridden because of stroke otherwise live an independent life at home, or would he/she need treatment in a nursing home or bed ward because of other diseases? Calculating the indirect costs is even more dif®cult than calculating the direct ones. Production losses are usually calculated by assuming full-time employment, a situation which is almost never the case in industrialised countries today. Therefore, the production loss caused by early retirement or death will differ depending on the employment situation. There are many consequences of stroke which cannot be evaluated purely in monetary terms, such as the psychosocial suffering, life satisfaction and quality of life, and effects on caregivers. These factors also need to be taken into consideration when decisions in healthcare are made.33,44

Assessment of new drugs for acute stroke treatment What properties will a new therapy need to have in order to be justi®ed? There is no consensus as to what properties a new therapy will have to have in order to be justi®ed in the treatment of patients with acute stroke. The Helsingborg Declaration on Stroke Management in Europe46 highlights a few simple goals for the management of acute stroke (Table 5). Both increased survival and an increased proportion of survivors who are independent in everyday activities are good goals for the year 2005, but hard to achieve. In a Phase II study, the neuroprotectant, Prosynap1 (lubeluzole), was found to produce a signi®cant bene®cial effect on case fatality and a trend towards improved functional outcome on the Barthel Index.47 If the Phase III data con®rm the Phase II results, lubeluzole may prove to be the ®rst neuroprotectant therapy available for acute ischaemic stroke. Thrombolysis with intravenous recombinant tissue plasminogen activator (rtPA) within 3 hours of stroke onset improved the functional and neurological outcome in a large NIH-sponsored study.48 Well-organised management of acute stroke at the Helsinki University Central Hospital, without recourse to new therapies, improved stroke outcome in a way that led to radical changes in local stroke services in the City of Helsinki.49 In this randomised trial of elderly patients (aged 65 y) with acute stroke, the in-hospital stay was shortened signi®cantly, patients were signi®cantly more often able to return to their homes, and were signi®cantly more often independent in their daily lives at one year (Table 6). The study convinced the healthcare administrators that all acute stroke patients in Helsinki should be treated at the

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Table 6 Results of a randomised study comparing `routine' and `well-organised' degrees of stroke care on stroke outcome in elderly patients (Kaste et al 49)  Patients treated by well-organised management were able to leave hospital, on average, 16 d earlier compared with those treated routinely.  Out of each 100 patients treated by well-organised management, 13 more were able to return to their home at hospital discharge.  Out of each 100 patients, 17 more were totally independent in their daily life at 1y follow-up, if treated by well-organised management.

University Central Hospital in order to improve stroke outcome and to save tax payers' money. What are the bene®ts of new therapies? Only one large stroke trial, so far, has demonstrated that rtPA is an effective therapy for acute ischaemic stroke.48 The tools used to evaluate the effectiveness of the therapy were the NIH Stroke Scale,50 the Barthel Index,51 the Modi®ed Rankin Scale,52,53 and the Glasgow Outcome Scale.54 At 3 months follow-up, all these parameters were found to be signi®cantly better in actively-treated patients compared with patients treated with placebo. The 3-month case fatality was non-signi®cantly lower in the rt-PA treated group. In the European Cooperative Acute Stroke Study (ECASS), the other large multicentre trial of rt-PA in acute ischaemic stroke, the functional parameters (the Modi®ed Rankin Scale and the Barthel Index) and neurological scales (including the Scandinavian Stroke Scale55 and NIH Stroke Scale) revealed a signi®cantly better outcome in per protocol but not in intention-to-treat patients at 3 months.56 Although the 1-month case fatality did not differ signi®cantly between the rt-PA- and placebo-treated groups, at 3 months there was a signi®cant difference in the intentionto-treat analysis disfavouring the rt-PA therapy. If a new stroke therapy is able to improve neurological and functional outcome using combinations of validated assessment instruments, and if this can be achieved without increasing the case fatality, then the new therapy would appear to be justi®ed. This view is supported by the fact that the Food and Drug Administration (FDA) recently approved, on the basis of the results of the National Institute of Neurological Disorders (NINDS) Study,48 thrombolysis with rt-PA for the treatment of ischaemic stroke. This is also re¯ected by a statement from a Special Writing Group of the Stroke Council of the American Heart Association which recommends the use of rt-PA within 3 h from stroke onset in selected stroke patients.57 European Health Authorities have not approved ischaemic stroke as an indication for rt-PA therapy, probably because of the increased case fatality in the ECASS trial in spite of the improved outcome of patients at whom it was aimed.56 How should new stroke therapies be evaluated? This question will be addressed by all investigators who wish to study a new drug in acute stroke trials. Because human stroke is heterogeneous and, in many ways, much

more complicated than experimental research in laboratories with standardised stroke models, the clinical stroke trial must ful®l even more rigorous scienti®c criteria than experimental studies. Otherwise, the chances of detecting any effects of a study drug may be lost. The multitude of problems which investigators face in clinical trials is overwhelming. The aetiology of stroke is diverse and so is the natural outcome of different stroke subtypes. A cardiogenic stroke often has a poor outcome,58 while the outcome of lacunar stroke is often quite fair.59 If, by chance, more cardioembolic patients end up in the active treatment group, and more lacunar ones in the placebo group, this may abolish the investigators' chances of ®nding any positive effects on outcome of the study drug. The same holds true if the severity of stroke, the most important prognostic factor, is imbalanced between the study groups. Fortunately, the randomisation process is able to balance these and many unrevealed prognostic factors in large trials. Both animal experiments and clinical trials have demonstrated the crucial importance of the time window from stroke onset to the beginning of the therapy. In a post hoc analysis of the ECASS data, patients treated within 3 h made a better, although non-signi®cant, functional recovery than those treated after 3 h.60 In most trials with the calcium blocker nimodipine, the patients have been randomised up to as late as 48 h after onset and, as a result, a fair chance for the drug to show its effectiveness in acute stroke treatment may not have been provided.61 The inclusion and exclusion criteria are of vital importance for a clinical drug trial. By selecting these appropriately, the investigators try to enrol as homogenous and representative patient groups as possible. If only patients with very severe strokes with a large brain infarction and poor prognosis are included, it will be very hard to prove any substantial bene®ts of a treatment. On the other hand, in such severe cases it is easy to justify even high risks associated with the drug. If, on the other hand, one includes only very mild strokes often recovering spontaneously, there is little place for an improvement caused by an investigational therapy. In such cases, it is also harder to justify the possible risks of a new study drug. Both the very severe and very mild strokes increase the `statistical noise' in a drug trial and weaken the likelihood of a statistically signi®cant difference between the treatment groups. Major protocol violations when patients are enrolled in a study may also reduce or even abolish the chance to show bene®ts in an intention-to-treat analysis. This happened in ECASS when 52 out of 620 patients with large cerebral infarction on the admission CT were mistakenly enrolled in the study.56 If the ®rst trial of a new drug turns out to be promising, and the drug is likely to be approved by healthcare agencies, then the ensuing trials of the agent may try to specify the indications and/or the time window. The forthcoming trial of intravenous rt-PA in the United States will examine the possibility of extending the time window from 3±5 h. To underline different views on how to evaluate the outcome of stroke in patients treated with an investigational drug, two examples of opposite views are outlined below: (1) A trial might only count `cof®ns and wheelchairs' against all other outcomes or, as is the case in the International Stroke Trial,62,63 the evaluation could use a more sophisticated instrument with a 4-way split as follows:

Economic burden of ischaemic stroke M Kaste et al

Ð dead Ð alive but not independent in activities of daily life (ADL) Ðtotally independent in ADL but not completely recovered from stroke Ðcomplete recovery (2) A trial may specify the primary endpoint as precisely as possible. The ongoing enlimomab stroke trial serves as an example. The protocol assesses the primary outcome by the combined measures of ADL and neurological impairment. At each value of the Barthel Index (BI), the Scandinavian Stroke Scale (SSS) is used to account for a clinically meaningful difference in a neurological de®cit. When the difference in the SSS score between active treatment and placebo with the same BI score is 4 points, the patient with the larger SSS score will be considered to have the superior outcome.

Table 7 The role of neurological stroke scales in acute stroke trials

The ®rst approach gives information on what is important for stroke patients.63 The second outcome instrument mentioned is so complicated, even for the stroke specialist, that the FDA asked the investigators and the sponsor to replace it with a better known outcome scale. Because the stroke population is heterogeneous in terms of stroke severity, comorbidity, and other prognostic factors, and the effects of an intervention may, although worthwhile, be moderate, we need to rely on both sensitive and reliable methods to interpret the impact of a new therapy. Sophisticated instruments are not necessarily better than crude measures of outcome, and there is no consensus on the best evaluation method to be used. In the next section we discuss the different tools that can be used to measure outcome. Although the process of randomisation should ensure that the different treatment groups are balanced for prognostic factors, the outcome results should be adjusted for all baseline differences between the groups. In addition, it may not be suf®cient to aim for effectiveness in terms of achieving the best possible outcomes for the patients and their carers, but also there is a need to demonstrate the cost-effectivensss of a new treatment.

There are a great number of neurological scales, many of which are widely used. Most of these scales include similar core items (consciousness, speech, motor function), and they are highly related to each other.67 A common weakness to them all is that they ignore or provide only minimal assessment of cognitive function. Assessment of stroke severity has speci®c value in stroke trials (Table 7). All stroke scales should be validated before they are used in trials. The NIH Stroke Scale,68 the Canadian Stroke Scale,69 the Scandinavian Stroke Scale,70 and the Middle Cerebral Artery Neurological Scale71 have been validated, and they all are well known. One should use one of these scales instead of inventing a non-validated scale of one's own. There is, however, no consensus about which, if any, of these scales should be used.63,72 Although the value of neurological scales as an endpoint in stroke trials has been downplayed by some stroke neurologists,63,73 others strongly favour their use.74 The present-day investigators generally choose functional outcome scales or scales which also give an impression of the handicap, in favour of pure neurological scales as a primary endpoint.48,56 The health authorities also seem to share this view.

Should new drugs be evaluated in community hospitals, in stroke units, or in stroke centres? The answer to this question depends primarily on what kind of drug the investigators would like to study. If they have to study a new drug which may be bene®cial but which may also turn out to have serious side effects, as is the case with thrombolytic and many tissue protecting agents, it is obvious that the drug should be studied in a highly specialised centre capable of complying with the selection criteria, execution of the treatment, and monitoring of side effects. Many recent stroke trials have been terminated prematurely because of severe side-effects or because minimal, or lack of therapeutic effects, have not justi®ed extension of the enrolment.64±66 It is clear that such trials should not be performed in community hospitals. On the other hand, if the study drug has been approved for general use and has been widely-used, then large trials can be executed at the community hospital level. The International Stroke Trial62 is an example of such a study. An advantage of such a trial is the possibility of collecting data from a large patient series, which can be widely applied, but the outcome evaluation of which, on the other hand, cannot be very sophisticated.

1. Assessment of stroke severity Ð to include only patients with a certain stroke severity Ð to ensure that treatment groups are comparable Ð to stratify patients according to stroke severity 2. Assessment of neurological recovery Ð to detect stroke progression Ð to register stroke recovery at a speci®c point of time Ð to detect recurrent stroke 3. For the outcome evaluation at the ®nal follow-up

Tools for measurement of outcome Neurological stroke scales

Functional outcome scales As an endpoint measure, functional outcome scales are preferred over neurological stroke scales because they measure disability, which from the patient's, the relatives', and the community's point of view is much more relevant than anything that neurological stroke scales are able to assess. Outcome scales, for example the Barthel Index, measure the ability of a stroke patient to take care of their daily life independently and re¯ect the need of help that either the family or the society has to provide. Their weakness is, however, that a patient who has a score equivalent to `no disability' in a functional scale, often still has a marked handicap. Functional scales are not able to describe the overall life situation of a patient recovering from stroke. The most demanding item of the Barthel Index is whether the patient is able to take a bath on his/her own. It is obvious that life involves more than this.63 Handicap scales What counts for a patient after stroke is what he/she can do in life compared with what he/she wants to do, or was able to do before the stroke.63 The restrictions of lifestyle, that is

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the handicap, is dif®cult to measure in spite of its high relevance as an outcome measure in acute stroke trials. So far, the Modi®ed Rankin Scale, the Oxford Handicap Scale, and the Glasgow Outcome Scale provide the most practical instruments for outcome evaluation. Because the Glasgow Outcome Scale was originally aimed at patients with severe brain injuries, and included the vegetative state which does not usually occur in stroke, it is less suitable for evaluation of stroke outcome than the two others. The validated Modi®ed Rankin Scale score75 is a reasonable alternative as a primary endpoint in stroke trials, and is being used increasingly. The Oxford Handicap Scale, which is derived from the former, is also suitable for grading stroke handicap and has also been validated.53

stroke irrespective of whether it is provided by the family or society.

Quality-of-life scales

Acknowledgements

The interest in quality of life after stroke is increasing. It is the most subjective measure of outcome, and accordingly, hard to measure objectively. From the patient's point of view, however, it is the most relevant outcome instrument. There are at least ten quality-of-life scales in use,76 although none has gained wide use in stroke treatment trials. Only the Frenchay Activities Index77 is aimed at assessment of stroke patients; the other are targeted at general geriatric populations. Quality-of-life scales depend on more numerous factors than do the disability and handicap scales. They also re¯ect the patient's subjective feelings more, and not the doctor's own ideas, about how much stroke interferes with what is normal for that individual.73 So far, it has not been possible to reach a consensus about which one of the stroke scales, functional outcome scales, or handicap scales should be preferred in stroke trials.72 Accordingly, it will also be hard to achieve a consensus as to which one of the quality-of-life scales should be applied in stroke trials.

The authors would like to acknowledge the educational grant that has been provided by Janssen Pharmaceutica, Beerse, Belgium.

Is there a relationship between the need for social support and the functional outcome? De Haan and co-workers compared stroke scales with disability, handicap, and quality-of-life scales.76 The NIH and the SSS correlated strongly with each other, but less so with functional outcome scales, and even less with the handicap assessed by the Modi®ed Rankin Scale. They bore the weakest correlation with the quality of life as assessed by the Sickness Impact Pro®le.78 Objective data about the relationship between functional outcome after stroke and the need for social support is scant. Certain cut off points on the Barthel Index are often considered to re¯ect the need for support in daily life from other people. Patients scoring 40 points in the Barthel Index almost always need institutional care. Those scoring 41±60 points are able to live at home only when maximal support is provided by the family or society. Patients scoring 60 points are able to stay at home, but they need help in the ADL. Patients scoring 85 points are considered to be independent in their daily life, but many of them need help in shopping, cooking, and cleaning their homes. It is good to keep in mind that the need for social support depends not only on the functional outcome score of a patient but also his/her age, concomitant diseases, personality, and cognitive capacity. However, the functional outcome re¯ects reasonably well the degree to which a patient needs support after

Conclusion Although stroke is clearly a huge burden on healthcare and social services, the advent of new acute therapies is likely to revolutionise the way this condition is managed. However, in order to ensure the ef®cacy and costeffectiveness of a new treatment, there must be reliable measures of outcome. Based on a review of the evaluation scales currently used, the authors emphasise the need to reach a consensus on those which are most appropriate for trials of new therapies.

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