Worldwide stroke incidence and early case fatality reported in 56 population-based studies: a systematic review

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1 Worldwide stroke incidence and early case fatality reported in 56 population-based studies: a systematic review Valery L Feigin, Carlene M M Lawes, Derrick A Bennett, Suzanne L Barker-Collo, Varsha Parag This systematic review of population-based studies of the incidence and early (21 days to 1 month) case fatality of stroke is based on studies published from 1970 to Stroke incidence (incident strokes only) and case fatality from 21 days to 1 month post-stroke were analysed by four decades of study, two country income groups (high-income countries and low to middle income countries, in accordance with the World Bank s country classification) and, when possible, by stroke pathological type: ischaemic stroke, primary intracerebral haemorrhage, and subarachnoid haemorrhage. This Review shows a divergent, statistically significant trend in stroke incidence rates over the past four decades, with a 42% decrease in stroke incidence in high-income countries and a greater than 100% increase in stroke incidence in low to middle income countries. In , the overall stroke incidence rates in low to middle income countries have, for the first time, exceeded the level of stroke incidence seen in high-income countries, by 20%. The time to decide whether or not stroke is an issue that should be on the governmental agenda in low to middle income countries has now passed. Now is the time for action. Introduction WHO estimates for 2001 indicate that death from stroke in low-income and middle-income countries accounted for 85 5% of stroke deaths worldwide, and the disabilityadjusted life years (DALYs) lost in these countries was almost seven times those lost in high-income countries. 1 Evidence from developed countries suggests that one in 20 adults (aged >14 years) is affected by stroke, including clinically covert strokes, 2,3 and the incidence of acute cerebrovascular events (stroke and transient ischaemic attack combined) currently exceeds the incidence of acute coronary heart disease. 4 Although rates of stroke mortality and burden vary greatly among countries, low-income countries are the most affected. Current measures of the prevalence of cardiovascular risk factors at the population level poorly predict overall stroke mortality and burden and do not explain the greater burden in low-income countries. 5 This worldwide stroke epidemic and the well recognised medicosocial consequences of stroke (including post-stroke dementia) justify the need for periodic reviews of the best available evidence of worldwide stroke epidemiology. This will advance our understanding of stroke frequency and determinants in various populations, enabling better health-care planning. The most reliable data on stroke incidence and case fatality come from population-based incidence studies. Our last systematic review of population-based stroke incidence and case fatality studies was published in Several new population-based stroke incidence studies have been published since, which suggests there is a need for more in-depth systematic analysis. In addition, this and other reviews 6,7 of population-based stroke incidence studies were limited: they did not include all previously published studies, they did not provide pooled estimates, and they did not systematically analyse stroke morbidity and early mortality in various populations. The aims of this systematic review are to update current knowledge of stroke morbidity and early case fatality with all available population-based stroke incidence studies and to review secular trends in stroke incidence and case fatality. Methods Search strategy and selection criteria We searched Medline, Scopus, PubMed, and ScienceDirect, from 1950 to May, 2008, with the words stroke, isch(a)emic stroke, intracerebral, intraparenchymal, subarachnoid, h(a)emorrhage, population-based, community-based, community, epidemiology, epidemiological, incidence, attack rates, survey, surveillance, mortality, morbidity, fatality, case fatality, or trends. Eligibility criteria were as follows: complete, populationbased case ascertainment based on multiple overlapping sources of information (hospitals, outpatient clinics, and death certificates); standard WHO definition of stroke; 7 incident stroke cases reported; data collection over whole years; no upper age limit for the population studied; availability of the raw numbers needed to calculate the rates in question (if all the raw numbers were not available in a publication that was otherwise eligible for inclusion, one of the corresponding authors was contacted for the missing data); and a prospective study design. Only papers published in English were reviewed. The literature search strategy and inclusion criteria for stroke 7 and stroke types were based on those used in our previous review 5 but with no restriction on study date. Population-based studies confined to only one pathological type of stroke were excluded from the analysis. Three authors (VLF, CMML, and SLB-C) independently graded the articles for eligibility criteria and any disagreement was resolved by discussion. Different subsets of studies were potentially eligible for different parts of this review. Our analysis of stroke incidence and case fatality was restricted to incident stroke cases. Stroke was defined according to WHO criteria as rapidly developed signs of focal (or global) disturbance Lancet Neurol 2009; 8: Published Online February 20, 2009 DOI: /S (09) See Reflection and Reaction page 306 See Articles page 345 National Research Centre for Stroke, Applied Neurosciences and Neurorehabilitation, School of Rehabilitation and Occupation Studies, School of Public Health and Psychosocial Studies, AUT University, Auckland, New Zealand (V L Feigin MD); Clinical Trials Research Unit, School of Population Health, University of Auckland, Auckland, New Zealand (C M M Lawes FAFPHM); Clinical Trials Service Unit and Epidemiological Studies, University of Oxford, Oxford UK (D A Bennett PhD); Department of Psychology, University of Auckland, Auckland, New Zealand (S Barker-Collo PhD); and Clinical Trials Research Unit, School of Population Health, University of Auckland, Auckland, New Zealand (V Parag MSc) Correspondence to Valery L Feigin, National Research Centre for Stroke, Applied Neurosciences and Neurorehabilitation, AUT University, North Shore Campus, AA254, 90 Akoranga Drive, Northcote 0627, Private Bag 92006, Auckland 1142, New Zealand valery.feigin@aut.ac.nz Vol 8 April

2 For more on the World Bank income groups see K2CKM78CC studies in database search 861 abstracts reviewed 104 manuscripts appraised by three reviewers 56 population-based studies were included Figure 1: Selection of studies 2190 did not meet inclusion criteria 757 were not applicable 48 manuscripts did not meet eligibility criteria of cerebral function lasting longer than 24 hours (unless interrupted by death), with no apparent nonvascular cause. 8 Stroke subtype-specific analyses were confined to population-based studies in which CT, MRI, or autopsy findings were available for about 70% or more of strokes. On the basis of these neuroimaging findings, strokes were classified into four main types: ischaemic stroke, primary intracerebral haemorrhage, subarachnoid haemorrhage, and undefined. Criteria that were acceptable for a diagnosis of subarachnoid haemorrhage also included a clinical picture that was supported by characteristic CSF or angiography findings. Patients who fulfilled the WHO criteria for stroke but for whom neither a CT, MRI, nor an autopsy (or cerebral angiography or CSF examination for patients with suspected subarachnoid haemorrhage) was done were classified as having undefined stroke. These criteria (except for undefined) are based on the standard definitions suggested by Sudlow and Warlow 7 to compare pathological stroke types. Ischaemic strokes were further categorised by four causal (large artery disease, cardioembolic, small artery disease [including lacunar strokes], and other) 9 or anatomical (total anterior circulation infarct, partial anterior circulation infarct, lacunar infarcts, and posterior circulation infarct) 10 classifications whenever a distinction could be made from the original publication. Statistical analysis Stroke incidence and early case fatality (21 days to 1 month) were analysed for four study periods ( , , , ), two country income groups (highincome countries and low to middle income countries [according to the World Bank s country classification]) and, when possible, by stroke pathological type (ischaemic stroke, primary intracerebral haem orrhage, subarachnoid haemorrhage, and undefined). Age-standardised rates per individuals were calculated by the direct method with the 1996 world population as the standard. 11 Crude incidence rates per population per year with corresponding 95% CIs were calculated by use of standard approaches Centres with more than one study in a decade were combined for the analyses and the closest years to the decade were taken if necessary. Only those studies that had complete data for important covariates (age, sex, and stroke type) were suitable for the pooled analyses, thus Figure 2: World map showing areas of population-based stroke incidence studies Studies or centres with no data on stroke incidence trends Studies or centres with data on stroke incidence trends High-income countries that are included in this analysis Low to middle income countries that are included in this analysis Vol 8 April 2009

3 Study duration (years) Personyears Age range (years) Total number incident strokes Crude incidence of total strokes (95% CI) Age-adjusted incidence (or range) of total strokes (95% CI) Hospital admission rate 1 month case fatality (or range) of total strokes (%) CT/MRI autopsy rate Timing of CT/MRI after stroke Data on stroke type(s) by age and sex Rochester, MN, USA All ( ) 91 (81 102) NR 15 24% 43% 3 months Total strokes All ( ) 88 (78 98) NR 17 21% 73% 3 months Total strokes, IS All ( ) 107 (96 118) NR 16 20% 88% 3 months Total strokes, IS All ( ) 102 (92 112) 85% % 92% 3 months Total strokes, IS Tartu, Estonia ( ) 170 ( ) 40% 49% NR NR Total strokes All ( ) 231 ( ) 80% 30% 19% NR Total strokes All ( ) 125 ( ) 88% 26% 90% NR Total strokes Copenhagen, Denmark All ( ) 80 (74 85) 89% NR NR NR Total strokes Dublin, Ireland All ( ) 118 ( ) 90% NR NR NR Total strokes North Karelia, Finland All ( ) 141 ( ) 91% NR NR NR Total strokes Ibadan, Nigeria All (13 17) 41 (36 45) 89% NR NR NR Total strokes Saku, Japan All ( ) 153 ( ) 49% NR NR NR Total strokes Ulan Bator, Mongolia All (46 54) 78 (71 84) 51% NR NR NR Total strokes Rohtak, India All (21 33) 48 (38 59) 55% NR NR NR Total strokes Colombo, Sri Lanka All (20 27) 41 (35 47) 98% NR NR NR Total strokes Frederiksberg, Denmark All ( ) 85 (79 92) NR NR NR NR Total strokes All ( ) 106 (89 123) 88% NR 75% NR Total strokes Espoo Kauniainen, Finland (86 130) 194 ( ) 89% 35% NR NR Total strokes (77 118) 145 ( ) 95% 29% 11% NR Total strokes ( ) 100 (91 110) 86% 23% 60% NR Total strokes Söderham, Sweden ( ) 254 ( ) 89% 23% 1% NR Total strokes ( ) 312 ( ) 95% 22% 38% NR Total strokes Shibata, Japan ( ) 223 ( ) NR NR NR NR Total strokes and SAH Tilburg, Netherlands All ( ) 100 (81 119) 85% 30% (21 days) NR NR Total strokes Auckland, NZ ( ) 137 ( ) 62% 33% 21% 30 days Total strokes * ( ) 141 ( ) 73% 24% 41% 30 days Total strokes ( ) 126 ( ) 91% 21% 91% 7 days Total IS, PICH, SAH, UND Turku, Finland ( ) 359 ( ) NR 30% (for the whole NR NR Total strokes period) ( ) 367 ( ) NR 30% (for the whole NR NR Total strokes period) ( ) 314 ( ) NR 30% (for the whole period) NR NR Total strokes (Continues on next page) Vol 8 April

4 Study duration (years) Personyears Age range (years) Total number incident strokes Crude incidence of total strokes (95% CI) Age-adjusted incidence (or range) of total strokes (95% CI) Hospital admission rate 1 month case fatality (or range) of total strokes (%) CT/MRI autopsy rate Timing of CT/MRI after stroke Data on stroke type(s) by age and sex (Continued from previous page) Novosibirsk, Russia All ( ) ( ) 30 60% 22 40% 48% 30 days Total strokes Dijon, France * ( ) 92 (78 106) 95% 21% 86% 7 days Total, IS, PICH, SAH, UND * All ( ) 67 (48 85) 89% 15% 97% NR Total, IS, PICH, SAH, UND * All ( ) 58 (53 63) 86% 8% 100% NR Total, IS, PICH, SAH, UND Umbria, Italy All ( ) 105 (92 118) 85% 20% 70% 30 days Total strokes Oyabe, Japan ( ) 375 ( ) 19% 22% NR NR Total strokes ( ) 269 ( ) 33% 20% NR NR Total strokes ( ) 260 ( ) 41% 19% NR NR Total strokes Krasnoyarsk, Russia All ( ) 233 ( ) 53% 38% 45% NR Total strokes Malmö, Sweden All ( ) 83 (74 91) 95% 15% 51% 7 days Total strokes Valley d Aosta, Italy All ( ) 116 ( ) 82% 31% 82% 3 days Total strokes All ( ) 82 (61 98) 88% 22% 94% 14 days Total, IS, PICH, SAH, UND Perth, Australia All ( ) 104 (84 124) 79% 23% 86% NR Total, IS, PICH, SAH, UND All 213* 156 ( ) 76 (65 87) 92% 23% 78% NR Total, IS, PICH, SAH, UND All ( ) 67 (56 79) 92% 20% 89% NR Total, IS, PICH, SAH, UND Belluno, Italy All ( ) 110 ( ) 92% 33% 90% 30 days Total, IS, PICH, SAH, UND Greater Cincinnati/Northern Kentucky, USA * * All ( )* 113 ( ) 98% 14 15% NR NR Total, IS, PICH, SAH, UND Arcadia, Greece ( ) 133 ( ) 90% 27% 82% 7 days Total, IS, PICH, SAH, UND L Aquila, Italy All ( ) 113 ( ) 92% 26% 89% 7 days Total, IS, PICH, SAH, UND East Lancashire, UK All ( ) 74 (67 80) 70% 34% 12% NR Total strokes Innherred, Norway ( ) 154 ( ) 87% 19% 88% 21 days Total, IS, PICH, SAH, UND Erlangen, Germany 54, All ( ) 85 (76 95) 95% 19% 96% 3 14 days Total, IS, PICH, SAH, UND South London, UK All ( ) 82 (80 84) 84% 27% 88% 30 days Total strokes Vibo Valentia, Italy All ( ) 87 (78 97) 98% 24% 96% 30 days Total, IS, PICH, SAH, UND Melbourne, Australia All ( ) 100 (95 105) NR 20% 91% 28 days Total, IS, PICH, SAH, UND Martinique, French West Indies All ( ) 102 (99 105) 94% 19% 93% 30 days Total, IS, PICH, SAH, UND Scottish Borders region, UK All ( [IS]) 47 (34 61 [PICH]) 155 ( [IS]) 18 (10 27 [PICH]) 91% 19% 92% 14 days Age-sex specific rates for IS and PICH only (Continues on next page) Vol 8 April 2009

5 Study duration (years) Personyears Age range (years) Total number incident strokes Crude incidence of total strokes (95% CI) Age-adjusted incidence (or range) of total strokes (95% CI) Hospital admission rate 1 month case fatality (or range) of total strokes (%) CT/MRI autopsy rate Timing of CT/MRI after stroke Data on stroke type(s) by age and sex (Continued from previous page) Porto, Portugal 61 (rural) All ( ) 261 ( ) 52% 15% 96% 2 days Total strokes Porto, Portugal 61 (urban) All ( ) 118 ( ) 58% 17% 97% 2 days Total strokes Uzhhorod, West Ukraine All ( ) 238 ( ) 66% 23% 41% NR Total strokes Örebro, Sweden All ( ) 126 ( ) 92% 19% 84% NR Total, IS, PICH, SAH, UND Tbilisi, Georgia All ( ) 103 (72 133) 66% 35% 67% NR Total, IS, PICH, SAH, UND Iquique, Chile All (65 82) 86 (76 95) 71% 23% 91% 3 days Total, IS, PICH, SAH, UND Barbados, USA All ( ) 88 (79 98) 69% 30% 96% NR Total, IS, PICH, SAH, UND Lund-Orup, Sweden ( ) 133 ( ) NR 14% NR NR Total strokes Oxfordshire, UK * All ( )* 102 (92 112) 54% 18% 82% NR Total strokes * All ( )* 73 (64 83) 56% 17% 98% NR Total strokes Matão, Brazil All (84 131) 130 ( ) 100% 19% 100% 2 days Total strokes, IS, PICH Mumbai, India > ( ) 151 ( ) 67% 30% 89% NR Total strokes IS=ischaemic stroke. PICH=primary intracerebral haemorrhage. SAH=subarachnoid haemorrhage. UND=undefined pathological stroke type. NR=not reported. *Additional data were provided by corresponding author of the publication. Confidence intervals calculated from published data. Approximated from the graph in the original publication. Those without CT/MRI scans were classified into pathological types with a high degree of certainty on the Guy s Hospital stroke diagnosis score (10% upper and lower scores). Subtypes determined by CT/MRI or autopsy (cerebral angiography or CSF for SAH). Table 1: Characteristics of population-based studies included in the analysis of stroke incidence per person-years and case fatality (%) reducing the risk of bias. Pooled overall and age-specific stroke incidence rates with corresponding 95% CIs adjusted for age by direct standardisation (1996 Segi s World population as the standard) 11 were calculated within each strata by use of a random effects model by the DerSimonian and Laird method. 15 A random effects model was chosen over a fixed effect model owing to the great heterogeneity among the individual study estimates, which could be due to genuine regional differences and the wide range of ages. This model attempts to incorporate the heterogeneity among studies into a pooled estimate. These pooled estimates were also used for time-trend analysis of stroke incidence stratified by country income (high-income countries and low to middle income countries). A χ² test for linear trend was calculated on the basis of the pooled estimates for each period. 16 We did not assess non-linearity because it was not possible to assess this reliably without individual participant data. Yearly percentage change in pooled age-standardised stroke incidence rates was calculated by dividing the overall change between the decades and by the number of years. Agespecific analyses of pooled estimates of time trends were done in patients in two age groups younger than 75 years and 75 years or older. The 75 year cut off point was used to facilitate the balance between the comparison groups. 5 A probability value of less than 0 05 was deemed statistically significant. Results We initially retrieved 3051 potentially relevant studies (figure 1). The titles of these were scanned for appropriateness for our review, and those that did not meet the inclusion criteria (eg, those for only specific age ranges or those for only hospitalisations) were removed (2190). The abstracts of the remaining 861 studies were retrieved and reviewed to eliminate any that were obviously inappropriate (757 removed). The remaining 104 manuscripts were appraised independently by three reviewers (VLF, CMML, SLB-C). This led to the exclusion of a further 48 manuscripts that did not meet our eligibility criteria. Thus, 56 eligible population-based studies from 47 centres in 28 countries ( person-years; incident strokes) were available for analysis (figure 2, table 1). Vol 8 April

6 These studies report on data collected from 1970 to 2008 (earlier data from Rochester, MN, USA, were not included because there were no other population-based data for that period for comparison). Population-based data on stroke incidence in high-income countries were available from 35 centres in 18 countries: Australia, 42 45,58 Barbados, 66 Denmark, 6,21,22 Estonia, 19,20 Finland, 21,23,24 France, 34,35 Germany, 54,55 Greece, 50 Italy, 36,39 41,46,51,57 Ireland, 21 Japan, 21,27,37 A Rochester, MN, USA Tartu, Estonia Copenhagen, Denmark Umbria, Italy North Karelia, Finland Frederiksberg, Denmark Espoo-Kauniainen, Finland Söderhamn, Sweden Shibata, Japan Oyabe, Japan Turku, Finland B Ibadan, Nigeria Ulan Bator, Mongolia Rohtak, India Colombo, Sri Lanka Oxfordshire, UK Copenhagen, Denmark Frederiksberg, Denmark Rochester, MN, USA Söderhamn, Sweden Oyabe, Japan Turku, Finland Auckland, New Zealand Dijon, France Dublin, Ireland Malmö, Sweden Valley d Aosta, Italy Perth, Australia Krasnoyarsk, Russia Novosibirsk, Russia Oxfordshire, UK Tartu, Estonia Turku, Finland Auckland, New Zealand Dijon, France Perth, Australia Belluno, Italy Greater Cincinnati, USA Arcadia, Greece L Aquila, Italy East Lancashire, UK Innherred, Norway Erlangen, Germany South London, UK Vibo Valentia, Italy Melbourne, Australia Scottish Borders region, UK Porto, Portugal (rural) Rochester, MN, USA Örebro, Sweden Novosibirsk, Russia Martinique, French West Indies Uzhhorod, West Ukraine Tartu, Estonia Dijon, France Valley d Aosta, Italy Perth, Australia Tbilisi, Georgia Iquique, Chile Matão, Brazil Mumbai, India Age-adjusted stroke incidence rates (per ) Age-adjusted stroke incidence rates (per ) Figure 3: Age-adjusted stroke incidence rates per person-years across the four study periods (A) High-income countries. (B) Low to middle income countries. Solid line is regression trend line. The regression line is based on a regression of average incidence on study period Vol 8 April 2009

7 UND PICH SAH IS High-income countries Low to middle income countries Rochester, MN, USA Frederiksberg, Denmark Perth, Australia Rochester, MN, USA Perth, Australia Belluno, Italy Arcadia, Greece L Aquila, Italy Innherred, Norway Erlangen, Germany Vibo Valentia, Italy Melbourne, Australia Scottish Borders region, UK Greater Cincinnati/Northern Kentucky, USA Auckland, NZ Dijon, France Valley d Aosta, Italy Barbados Tbilisi, Georgia Iquique, Chile Matão, Brazil Figure 4: Proportional frequency of stroke pathological types by country income level and study decade Norway, 53 New Zealand, Portugal, 61 Sweden, 25,26,38,63,67 Netherlands, 28 UK, 4,52,56,60,68 70 USA. 17,47 49 Population-based data on stroke incidence in low to middle income countries were available from 12 centres in ten countries: Brazil, 71 Chile, 65 French West Indies, 59 Georgia, 64 India, 21,72 Nigeria, 21 Mongolia, 21 Sri Lanka, 21 Russia, 32,33 and the Ukraine incident strokes were available for analysis from high-income countries and 7045 incident strokes from low to middle income countries. During the four periods studied, eligible data were available for analysis from 12 high-income and four low to middle income countries in (7199 and 1198 strokes, respectively). In , data were available from 12 high-income and two low to middle income countries (6860 and 2884 strokes, respectively); in , from 18 high-income and three low to middle income countries (12187 and 1901 strokes, respectively); and in , from eight high-income and four low to middle income countries (4172 and 1062 strokes, respectively). Age-specific data on well documented main pathological types of stroke were available from 18 centres, 4,17,30,41,43,46,50,51,53,55 59,63 66 including only three centres from low to middle income countries. 64,65,71 Only four centres (Auckland, New Zealand; 30 Perth, Australia; Erlangen, Germany; 54,55 and Dijon, France 73 ) provided data on the causes of the ischaemic strokes, and only two centres (Barbados 66 and Iquique, Chile 65 ) provided data on anatomical types of ischaemic stroke. Data on early case fatality were available from 22 high-income countries or centres 4,17,19,20,23,24,28 31,34 46,50,51, 53 55,57,58,61,63,66,68 70 in all four study periods, but only nine of these reported case fatality by some or all stroke pathological types. 17,29 31,34,35,42 46,50,53 55,63 Only one study, from Tilburg, Netherlands, 28 reported stroke case fatality at 21 days, and all other relevant studies that were included in the analysis reported case fatality at 28 days or 1 month (30 days). In low to middle income countries, data on early case fatality were available from ten centres 32,33,59,62,64,65,71,72 but for only and High-income countries Ischaemic stroke NA 9 16% 10 32% (10 20%) Intracerebral haemorrhage NA 38 66% 20 58% (35 55%) Subarachnoid haemorrhage NA 22 40% 20 50% (30 50%) All strokes combined 29 49% (30 35%) Low to middle income countries 14 31% (20 30%) 12 33% (18 26%) 13 23% 25 35% 25 35% 17 30% (20 30%) Ischaemic stroke NA NA NA 13 19% Intracerebral haemorrhage NA NA NA 30 48% Subarachnoid haemorrhage NA NA NA 40 48% All strokes combined NA 28 39% 23% 18 35% (23 35%) Range in brackets is the range that most studies in this category fall into, and is given if it is narrower than the total range. NA=not available. Table 2: Range in early (21-day to 1-month) case fatality in high-income countries and low to middle income countries across the four study periods Vol 8 April

8 High-income countries (n=11 by age, n=12 for total) (n=10 by age, n=12 for total) (n=18) (n=8) p for trend Low to middle income countries (n=3 by age, n=4 for total) (n=2) (n=3) (n=4) <75 years REM 118 (95 140) 103 (78 128) 91 (77 104) 66 (51 81) < (26 66) 151 ( ) 133 (80 187) 94 (70 118) FEM 78 (75 81) 85 (82 88) 72 (70 74) 63 (60 66) < (42 48) 132 ( ) 107 ( ) 88 (81 94) < years REM 2044 ( ) 1761 ( ) 1752 ( ) 1216 ( ) < ( ) 2421 ( ) 1596 ( ) Cannot be < calculated FEM 1520 ( ) 1673 ( ) 1544 ( ) 1151 ( ) < ( ) 1916 ( ) 1473 ( ) 1030 ( ) < Total REM 163 (98 227) 157 ( ) 121 ( ) 94 (72 116) (33 71) 197 ( ) 164 ( ) 117 (79 156) < FEM 150 ( ) 192 ( ) 95 (93 96) 85 (82 88) < (48 54) 167 ( ) 108 ( ) 108 ( ) < Data are mean (95% CI). n=number of studies. *Pooled estimates using a random effects model (REM) and fixed effects model (FEM). Table 3: Averaged age-adjusted annual incidence of stroke* by age groups per population per year of total strokes in high-income and low to middle income countries across the four study periods p for trend (three of these centres 64,65,71 reported case fatality by some or all stroke pathological types). Table 1 and figure 3 show that for the whole study period ( ), there was noticeable variation in crude and age-adjusted stroke incidence rates among countries or centres. During the four decades, total crude stroke incidence rates (per person-years) among high-income countries ranged from 125 (Rochester, MN, USA) to 460 (Oyabe, Japan) in ; from 156 (Rochester, MN, USA) to 466 (Turku, Finland) in ; from 131 (south London, UK) to 451 (Turku, Finland) in ; and from 112 (Dijon, France) to 223 (Tartu, Estonia, and Valley d Aosta, Italy) in In , the highest crude incidence rates of ischaemic stroke were reported in Vibo Valentia, Italy (264 of ), of primary intracerebral haemorrhage in Arcadia, Greece (48 per ), and of subarachnoid haemorrhage in Arcadia, Greece; Innherred, Norway; and Melbourne, Australia (9 per ). The lowest rates of these pathological types of stroke were reported in Erlangen, Germany (ischaemic stroke 137 per and primary intracerebral haemorrhage 24 per ), and Dijon, France (subarachnoid haemorrhage 4 per ). In , the highest crude stroke typespecific incidence rates were reported in Valley d Aosta, Italy (ischaemic stroke 174 per and primary intracerebral haemorrhage 23 per ) and Auckland (subarachnoid haemorrhage 10 per ). The lowest rate was in Dijon, France (ischaemic stroke 101 per , primary intracerebral haemorrhage 10 per , and subarachnoid haemorrhage 2 per ). Among low to middle income countries, crude rates of stroke incidence ranged from 15 per (Ibadan, Nigeria) to 50 per (Ulan Bator, Mongolia) in ; from 202 per (Novosibirsk, Russia) to 217 per (Krasnoyarsk, Russia) in ; from 167 per (Martinique, French West Indies) to 281 per (Uhhgorod, West Ukraine) in ; and from 73 per (Iquique, Chile) to 165 per (Tbilisi, Georgia) in Reliable data on stroke pathological types were not available in low to middle income countries until after During , the highest rates of ischaemic stroke, primary intracerebral haemorrhage, and subarachnoid haemorrhage were reported in Matão, Brazil (ischaemic stroke 92 per ) and Tbilisi, Georgia (primary intracerebral haemorrhage 44 per and subarachnoid haemorrhage 16 per ). The lowest rates were reported in Iquique, Chile (ischaemic stroke 47 per , primary intracerebral haemorrhage 17 per , and subarachnoid haemorrhage 4 per ). Figure 4 shows the proportional frequency of stroke pathological types in 18 centres (14 countries, strokes) by study period and country income level. Of the studies included in the analysis, no accurate data on stroke types were available until after 2000 in low to middle income countries. Among high-income countries, in such data were only reported in Rochester, MN, USA (ischaemic stroke 82%, primary intracerebral haemorrhage 9%, and subarachnoid haemorrhage 95%). In , 70 85% of strokes were classified as ischaemic stroke (highest in Rochester, MN, USA; lowest in Perth, Australia), 6 12% as primary intracerebral haemorrhage (highest in Perth, Australia; lowest in Frederiksberg, Denmark), 5 10% as subarachnoid haemorrhage (highest in Perth, Australia; lowest in Frederiksberg, Denmark). In , the frequency of ischaemic stroke ranged from 67% in Belluno, Italy, to 84% in greater Cincinnati/Northern Kentucky, USA; primary intracerebral haemorrhage from 8% in the Scottish Borders region, UK, to 20% in Belluno, Italy; subarachnoid haemorrhage from 10% in Belluno, Italy to 2% in Melbourne, Australia, and greater Cincinnati/ Northern Kentucky, USA. In , the lowest Vol 8 April 2009

9 proportion of ischaemic stroke (73%) was recorded in Auckland, New Zealand, and the highest (90%) in Dijon, France; the proportion of primary intracerebral haemorrhage ranged from 9% in Dijon, France, to 13% in Barbados and the proportion of subarachnoid haemorrhage ranged from 1% in Dijon, France, to 6% in Auckland, New Zealand. Among low to middle income countries in , the proportional frequency of ischaemic stroke ranged from 54% in Tbilisi, Georgia, to 85% in Matão, Brazil; primary intracerebral haemorrhage ranged from 14% in Matão, Brazil, to 27% in Tbilisi, Georgia; and subarachnoid haemorrhage ranged from 5% in Iquique, Chile, to 10% in Tbilisi, Georgia. The proportional frequency of ischaemic stroke causal and anatomical subtypes among six of the centres included in the analysis 30,42-45,54,55,65,66 varied substantially, largely owing to the variations in the completeness of diagnostic work-ups between the centres. The proportion of large arterial disease ranged from 6% in Auckland, New Zealand, 30 to 71% in Perth, Australia; cardioembolic ranged from 19% to 55% at different times in Perth, Australia; small artery disease from 10% in Perth, Australia, to 23% in Erlangen, Germany. 54,55 In Barbados 66 and Iquique, Chile, 65 the proportions of anatomical subtypes of ischaemic stroke were reported respectively as 18% and 17% for total anterior circulation infarct, 31% and 27% for partial anterior circulation infarct, 6% and 43% for lacunar infarcts, and 60% and 7% for posterior circulation infarcts. The variations in crude stroke incidence rates across all countries narrowed considerably when age-adjusted rates within each of the four study periods were compared separately in high-income countries (2 fold to 4 fold difference, with reduced between-country variations over time) and low to middle income countries ( fold difference; figure 3). Early stroke case fatality (total and by pathological types) varied substantially among countries and study periods (table 2). In high-income countries, the lowest early stroke case fatality was reported in Dijon, France, in (8%) and the highest in Tartu, Estonia, in (49 2%). In low to middle income counties, the lowest early stroke case fatality was reported in Matão, Brazil, in (18 5%) and the highest was reported in Krasnoyarsk, Russia, in (37 6%). Variations in stroke case fatality were less noticeable if compared by study decades. Over the four decades, age-adjusted stroke incidence rates in high-income countries decreased by 42% (from 163 per person-years in to 94 per person-years in ; p=0 0004), whereas in low to middle income countries the stroke incidence rates more than doubled (52 per and 117 per person-years, respectively; p<0 0001) and exceeded the rate observed in high-income countries in the last decade (table 3). Yearly percentage change in pooled age-standardised stroke incidence rates during Pooled overall age-adjusted incidence rate (per person-years) High-income countries was 1 0% in high-income countries and 5 6% in low to middle income countries. In high-income countries, a significant decrease in incidence rates was seen in people younger than 75 years (44% reduction; p<0 0001) and aged 75 years or older (41% reduction; p<0 0001). Conversely, in low to middle income countries there was a significant two fold increase in the incidence rates in the younger (<75 years) age group of the population (p=0 001) and an almost four fold increase in the older ( 75 years) group of the population (p<0 0001). Figure 5 shows that from 1980 to 2008, the pooled ageadjusted incidence rates of ischaemic stroke in highincome countries fell by 11% (p for trend 0 53) and there was no change in the incidence of primary intracerebral IS PICH SAH UND Low to middle income countries Figure 5: Pooled overall age-adjusted stroke incidence rates of stroke pathological types and total strokes in high-income countries and low to middle income countries across different periods Only studies where a CT/MRI or autopsy was done in no less than about 70% of patients were included in the analyses of stroke subtypes. All stroke subtype analyses were based on cases classified by either CT/MRI or autopsy findings for ischaemic stroke (IS) and primary intracerebral haemorrhage (PICH), or CSF examination and/or cerebral angiography for subarachnoid haemorrhage (SAH). IS=ischaemic stroke. PICH=posterior intracerebral haemorrhage. SAH=subarachnoid haemorrhage. UND=undefined pathological type of stroke. Proportional frequency (%) of stroke pathological type High-income countries IS PICH SAH UND Low to middle income countries Figure 6: Proportional frequency of stroke pathological types in high-income countries and low to middle income countries across different study periods (pooled estimates) IS=ischaemic stroke. PICH=posterior intracerebral haemorrhage. SAH=subarachnoid haemorrhage. UND=undefined pathological type of stroke. Vol 8 April

10 1 month case fatality (%) 1 month case fatality (%) A B haemorrhage (p for trend 0 45) and subarachnoid haemorrhage (p for trend 0 41). In , there was no difference in the pooled age-adjusted incidence rates of ischaemic stroke between high-income (70 per ) and low to middle income countries (67 per ), but the rates of primary intracerebral haemorrhage and subarachnoid haemorrhage in low to middle income countries were almost twice the rates in high-income countries (primary intracerebral haemorrhage 22 per vs 10 per and subarachnoid haemorrhage seven per vs four per , respectively). Figure 6 shows that among high-income countries over three decades, the pooled proportional frequency of ischaemic stroke was 74% in , 77% in , and 82% in , and the frequencies of primary intracerebral haemorrhage were 9%, 13%, and 11%, respectively. The proportional frequency of subarachnoid haemorrhage was increased slightly (1 5%, 3%, and 3%, respectively; p=0 04). The pooled proportional frequency of ischaemic stroke in was lower in low to middle income countries than in high-income countries (67% and 82%, respectively), but the frequencies of primary intracerebral haemorrhage (22% and 11%, respectively) and subarachnoid haemorrhage (7% and 3%, respectively) were twice the frequencies in high-income countries for the same decade. The results Year Figure 7: Early (21-day to 1 month) stroke case fatality by study year (A) High-income countries. (B) Low to middle income countries. Solid line is a linear regression line were not altered when pooled estimates were calculated by a fixed effects method, but the significance of changes in the pooled estimates were enhanced (table 3). In high-income countries, the mean total stroke case fatalities in , , , and were 35 9%, 21 5%, 22 2% and 19 8%, respectively. Mean case fatality figures for ischaemic stroke, primary intracerebral haemorrhage, and subarachnoid haemorrhage were 15 2%, 45 5%, and 31 6%, respectively, in ; 17 5%, 35 2%, and 35 7% in , respectively; and 14 3%, 41 0%, and 30 0% in , respectively. In low to middle income countries, mean total stroke case fatalities were 35 2% in , 23 0% in , and 26 6% in In these low to middle income countries, the mean case fatalities for ischaemic stroke, primary intracerebral haemorrhage, and subarachnoid haemorrhage were 16 7%, 38 7%, and 43 9% in Overall, during the four decades studied, there was a non-significant reduction in early stroke case fatality in high-income and low to middle income counties (figure 7). In high-income countries, the yearly averaged percentage change in stroke case fatality during was 1 1%. In low to middle income countries, the yearly averaged percentage change in stroke case fatality during was 0 6%. Discussion To the best of our knowledge, this study reviews all the available data from population-based stroke incidence studies and documents stroke incidence rates over the past four decades: there has been a 42% decrease in stroke incidence in high-income countries and more than 100% increase in low to middle income countries. A summary of key findings is shown in the panel. From 1970 to 2008, the yearly percentage change in pooled age-standardised stroke incidence rates was reduced by 1 1% in highincome countries and increased by 5 3% in low to middle income countries. This divergence means that the overall stroke incidence rates in low to middle income countries have, for the first time, exceeded the level of stroke incidence currently seen in high-income countries a difference of 20% (117 per and 94 per , respectively). With the more than two fold increase in the incidence rates of stroke in low to middle income countries from 1970 to 2008, the incidence of stroke in low to middle income countries has reached an epidemic level. These divergent trends were evident in younger (<75 years) and older ( 75 years) individuals, although more pronounced in the older group. Another important finding of this study was the greater, although non-significant, reductions in the incidence of primary intracerebral haemorrhage than of ischaemic stroke in high-income countries over the past four decades, but virtually no change in the incidence of subarachnoid haemorrhage in high-income countries over the same period. Our data on the decline in stroke incidence and early case fatality in high-income countries but an increase in Vol 8 April 2009

11 stroke incidence in low to middle income countries correspond to the reported divergence in stroke mortality in these groups and the difference observed in the WHO MONICA project However, the causes of these changes in stroke mortality are not fully understood. For example, recent data from the WHO MONICA project 80 suggested that changes in stroke mortality are largely attributable to changes in early case fatality rather than due to changes in stroke incidence. However, the WHO MONICA project only looked at 14 centres in nine countries and only at individuals aged years; thus, about three-quarters of patients will not have been included in the analysis. Our systematic review was based on population-based stroke incidence data from 47 centres in 28 countries, included all patients, and was not restricted by an upper age limit. Although our overview cannot provide direct evidence of the associations between changes in stroke incidence and mortality rates, the pattern of changes in stroke incidence rates in highincome and low to middle income countries and the data from studies of international mortality might imply that changes in stroke mortality rate are most probably due to the corresponding changes in stroke incidence rates. Our results also imply that the significant decrease in stroke incidence in high-income countries was largely due to a reduction in the incidence of ischaemic stroke and primary intracerebral haemorrhage over the past four decades (the observed rise in the incidence of primary intracerebral haemorrhage and subarachnoid haemorrhage in is likely to be accounted for by a wider worldwide introduction of CT or MRI brain scanning into clinical practice at around this time). Recent data from Oxfordshire 68 and London, 81 UK, and from Beijing, Shanghai, and Changsha, China, 82 suggest that the implementation of preventive treatments and reductions in risk factors at the population level contribute to the significant reduction of stroke incidence. The high and increasing incidence of stroke in low to middle income countries over the past four decades is probably due to health and demographic transitions in these countries. 83 This fits Omran s theory of the epidemiology of population change, 84 and suggests that countries included in this Review have entered the health transition. Although possible improvements in health-care systems and clinical diagnosis that might have contributed to the apparent increases in stroke incidence rates in these countries over the four study decades were not available for our analysis, the effect of these improvements on total stroke incidence rates is likely to be low because only stroke incidence studies that were truly population-based and methodologically comparable were included in the analysis across all study periods. The increases in the rates of mortality and morbidity from coronary heart disease in developing countries over the past few decades are in line with our findings. As exposure to cardiovascular risk factors (particularly smoking, raised blood pressure and blood glucose concentrations, westernised diets that are low in fruit and vegetables but high in fat and salt, and physical inactivity) and as the average age in low to middle income countries increases, 85,88,89 the burden of stroke in these countries will increase unless measures to control cardiovascular risk factors are urgently introduced. The discrepancy in the time trends of major pathological types of stroke (decreasing incidence rates of ischaemic stroke and primary intracerebral haemorrhage and relatively stable incidence rates of subarachnoid haemorrhage) adds to the evidence that the causes of subarachnoid haemorrhage are substantially different to Panel: Key findings There are trends in stroke incidence among high-income and low to middle income countries over the past four decades, with a 42% decrease in stroke incidence in high-income countries and greater than 100% increase in low to middle income countries. Corresponding trends in stroke incidence are observed in younger (<75 years) and older ( 75 years) age groups, although the differences are far more pronounced in the older group. In , stroke incidence rates in low to middle income countries have, for the first time, exceeded those in high-income countries. In high-income countries, there was a greater albeit non-significant reduction in the incidence of primary intracerebral haemorrhage than of ischaemic stroke, whereas the incidence of subarachnoid haemorrhage has remained relatively stable over the past four decades. The incidence and proportional frequency of intracerebral haemorrhage and subarachnoid haemorrhage in low to middle income countries are significantly greater than the incidence and frequency in high-income countries. The pattern of changes in stroke incidence rates in high-income and low to middle income countries corresponds to those reported in studies of international mortality trends, suggesting that changes in stroke mortality rates are most likely to be attributable to the corresponding changes in stroke incidence rates. In , early (21 days to 1 month) case fatality ranged from 17% to 30% (13 23% for ischaemic stroke, 25 35% for primary intracerebral haemorrhage, and 25 35% for subarachnoid haemorrhage) in high-income countries and from 18 to 35% in low to middle income countries (13 19% for ischaemic stroke, 30 48% for primary intracerebral haemorrhage, and 40 48% for subarachnoid haemorrhage). Early stroke case fatality is decreasing in both high-income and low to middle income countries but, overall, early stroke case fatality in low to middle income countries in the past decade is 25% higher than early stroke case fatality in high-income countries. Vol 8 April

12 the causes of ischaemic stroke and primary intracerebral haemorrhage. Our finding of no significant change in the incidence of subarachnoid haemorrhage corresponds with that observed in the recent review of subarachnoid haemorrhage epidemiology from 1960 to 1994 by Linn and co-workers. 90 The stable incidence of subarachnoid haemorrhage, rather than other pathological types of stroke, re-emphasises the differences in the causes of subarachnoid haemorrhage compared with ischaemic stroke and primary intracerebral haemorrhage and indicates the need to implement more effective and targeted preventive measures for subarachnoid haemorrhage. We hypothesise that the differences between ischaemic stroke/primary intracerebral haemorrhage and subarachnoid haemorrhage over time reflects the differences in the lag time between initiation of programmes geared towards reducing stroke risk factors and the effect of such programmes on different stroke types. For example, the effect of strategies to reduce smoking one of the most significant risk factors for subarachnoid haemorrhage might be more delayed in reducing subarachnoid haemorrhage incidence when compared with interventions that target raised blood pressure. For those with intracerebral haemorrhage and ischaemic stroke, interventions to reduce raised blood pressure are expected to have a much more immediate effect than is smoking cessation. 91,92 In addition, we cannot exclude the possibility that the effect of preventive interventions at different times of life might influence the risk of stroke differently and, therefore, the incidence of different stroke types. Unlike the rather moderate differences in the incidence of ischaemic stroke between high-income (70 per ) and low to middle income countries (67 per ) during the last decade, the incidence of primary intracerebral haemorrhage and subarachnoid haemorrhage in low to middle income countries (22 per and 7 per , respectively) is currently almost twice the incidence in high-income countries (10 per and 4 per , respectively). During , the proportional frequency of ischaemic stroke among low to middle income countries is 20% lower than that in high-income countries, but the proportional frequency of primary intracerebral haemorrhage and subarachnoid haemorrhage are about double those currently reported in high-income countries (67%, 22%, and 7%, respectively, vs 82%, 11%, and 3%, respectively). These noticeable differences in the risk and proportions of patients with ischaemic and haemorrhagic strokes between highincome and low to middle income countries probably indicate differences in the exposure to environmental risk factors for stroke, particularly raised blood pressure and smoking Our analysis of ischaemic stroke subtypes was limited to only the six centres that reported relevant data, and this analysis was further complicated by substantial variations in the proportions of these subtypes, owing to differences in the completeness of diagnostic investigations in these centres; therefore, these data should be interpreted with caution. Our findings show a decrease in early (21 days to 1 month) stroke case fatality in high-income and low to middle income countries. This decrease was greatest in high-income countries, but the ranges for case fatality overlapped between high-income and low to middle income countries. Although the overall early stroke case fatality in low to middle income countries in the past decade was 25% higher than in high-income countries (26 6% vs 19 8%), there was not much difference between high-income and low to middle income countries in terms of early case fatality of ischaemic stroke and primary intracerebral haemorrhage. The only pathological type of stroke case fatality that was different between the two groups of countries was subarachnoid haemorrhage: case fatality of subarachnoid haemorrhage in low to middle income countries was 31 7% higher than it was in highincome countries (43 9% vs 30 0%). This difference is likely to be explained by poorer management of subarachnoid haemorrhage in low to middle income countries compared with the management in high-income countries. 96 The absence of differences in early case fatality for ischaemic stroke and primary intracerebral haemorrhage during can be explained by the fact that the most effective management strategies of acute stroke were not widely available until after 1995 (eg, availability of alteplase and organised multidisciplinary stroke units) and their wider implementation into practice is still in progress. 97,98 In light of these findings, the decline in early stroke case fatality in high-income and low to middle income countries is probably due to changes in the natural history of stroke (eg, a shift to less severe strokes), which has been suggested in some reports. These changes have been linked with better management of pre-stroke risk factors, particularly the use of ACE inhibitors 99,100 and aspirin, 101,102 the wider use of pre-stroke statins, 103,104 and improved stroke care 105 over the past decades. The main strengths of this study are four fold. First, this overview was based on all population-based stroke incidence studies that met the criteria for an ideal stroke incidence study, 18 which ensured the data were comprehensive and comparable and provided the most accurate estimates of stroke incidence rates and early case fatality. Second, this study included 56 eligible populationbased stroke incidence studies from 47 centres in 28 countries on all continents, totalling personyears of observation of people of all ages and incident strokes, thus ensuring the precision and robustness of the main estimates. Third, the study period comprised the past four decades, enabling estimates of stroke incidence and case fatality over a long period. Fourth, in addition to descriptive analysis, this overview used meta-analytic techniques, providing pooled estimates of stroke incidence rates and early case fatality by different study periods, age groups of the populations, and country income levels. However, even for such a large database, Vol 8 April 2009