Stroke Incidence and Mortality Rates 1987 to 2006 Related to Secular Trends of Cardiovascular Risk Factors in Gothenburg, Sweden

; Stroke Incidence and Mortality Rates 1987 to 2006 Related to Secular Trends of Cardiovascular Risk Factors in Gothenburg, Sweden Per Harmsen, MD; Lars Wilhelmsen, MD, PhD; Anders Jacobsson, BSc Background and Purpose Stroke incidence rates were unchanged whereas fatality rates declined during the period 1971 to 1987 in Gothenburg (Göteborg), Sweden. For the period 1987 to 2006, we now report on trends in stroke incidence and mortality with concurrent risk factor trends in the same population. Since 1976 the incidence of myocardial infarction decreased by 50%. Methods Through the National Hospital Discharge Register linked with the Cause of Death Register, 12 904 males and 15 250 females with first strokes were detected for the period 1987 to 2006. Cardiovascular risk factor data were available for random population samples of men and women aged 50 years from 1963 to 2003. Results Incidence and mortality rates for all-stroke were unchanged. Rates for subarachnoid hemorrhage declined for the age group 45 to 54 in men, but not significantly in any other age group of men or women. Mortality rates of intracerebral hemorrhage declined for women aged 65 to 74, with no significant changes in any other age group. Ischemic stroke incidence did not change, but mortality increased for men and women aged 75 and older, whereas mortality declined for the age group 20 to 44 for men. In the general population there were significant reductions in smoking, total cholesterol, and blood pressure levels in both men and women, whereas diabetes prevalence, body weight, and BMI increased among both sexes, and triglycerides increased in men. Conclusion Contrary to myocardial infarction, stroke incidence and mortality did not change. Monitoring of cardiovascular risk factors in the community is important. (Stroke. 2009;40:2691-2697.) Key Words: brain infarction epidemiology registry mortality rates myocardial infarction risk factors subarachnoid hemorrhage incidence rates time trends A decrease in stroke incidence and mortality in some high-income countries during the 1960s and 1970s leveled out during the 1980s. Since the 1990s mortality has continued to decrease, but several studies have reported either no change 1 or an increase in stroke incidence. 2,3 In a recent survey, data for Europe regarding stroke were considered to be very limited, 4 and such data are of great importance for health care planning. In contrast with a recent report from the United Kingdom of a 40% decrease in major stroke in Oxfordshire over the past 20 years, 5 studies from Sweden report on increasing stroke incidence in recent years 6 8 or no change. 9 In an earlier study from the stroke register in Gothenburg, we reported no change in stroke incidence but a decline in fatality rates during the period 1971 to 1987. 10 Continued stroke recordings for the years 1984 to 1994 from the MONICA center in Gothenburg showed no definite trends. 11 It was recently shown that coronary heart disease incidence as well as mortality decreased markedly in Gothenburg from 1975 to 1979 and 2000 to 2004. It was also shown that the level of risk factors for coronary heart disease declined correspondingly. 12 In recent years, national registers have been used for epidemiological descriptive purposes in Finland, 13 in England, 14 and in Canada. 15,16 In this article we present data for Gothenburg on stroke incidence and mortality based on the Swedish Hospital Discharge Register linked and matched with the Swedish Cause of Death Register covering the period 1987 to 2006. Further, we relate to concurrent time trends for cardiovascular risk factors in the Gothenburg population. Subjects and Methods Data on stroke for the Gothenburg population were collected from the Hospital Discharge Register, which has operated on a nationwide base since 1987 and is kept by the Swedish National Board of Health and Welfare. The coverage of the register was at least 98% for somatic short-term care; 17 this includes care of stroke patients in the acute phase, during which rehabilitation also is initiated. The city of Received February 23, 2009; final revision received April 3, 2009; accepted May 1, 2009. From Institute of Clinical Neuroscience (P.H.), Department of Internal Medicine (L.W.), Sahlgrenska University Hospital, Gothenburg, Sweden; Sahlgren s Academy (A.J.), University of Gothenburg, Gothenburg, Sweden, and Centre for Epidemiology, the National Board of Health and Welfare, Stockholm, Sweden. Correspondence to Professor Lars Wilhelmsen, Fregattgatan 16, SE-42674 V Frölunda, Sweden. E-mail lars.wilhelmsen@gu.se 2009 American Heart Association, Inc. Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.109.550814 2691

2692 Stroke August 2009 Table 1. Person-Years at Risk and Age-Specific All-Stroke, Intracerebral Hemorrhage, and Ischemic Stroke Incidence Rates Per 100 000 Persons 1987 2006 in Gothenburg 1987 1989 1990 1994 1995 1999 N at Risk Incidence Rate N at Risk Incidence Rate N at Risk Incidence Rate AS IH Isc AS IH Isc AS IH Isc 20 44 258 843 21 8 8 430 717 22 5 13 455 405 23 7 12 45 54 69 126 146 27 94 133 083 152 23 108 148 673 126 31 84 55 64 64 546 392 85 282 97 402 423 75 318 100 786 433 80 337 65 74 60 162 936 126 785 95 710 1061 170 866 84 044 1071 150 901 75 37 101 2189 288 1889 65 880 2376 260 2090 71 158 2587 285 2284 20 44 25 2852 16 5 6 419 638 21 4 10 441 213 23 5 12 45 54 66 763 79 9 43 127 415 76 9 47 144 984 93 21 50 55 64 69 780 183 36 119 104 502 172 33 118 103 605 241 40 174 65 74 76 640 594 86 478 120 536 661 93 534 104 774 681 81 572 75 70 881 2010 191 1789 124 705 2176 186 1958 130 958 2174 225 1923 AS indicates all-stroke; IH, intracerebral hemorrhage; Isc, ischemic stroke; NS, not significant. ICD 10 I60 I64, I61 I62, and I63 I64, respectively. Gothenburg has 1 university hospital located in 3 sites with identical procedures for acute care of stroke patients. Traditionally, every acute stroke patient is taken to hospital, and during recent years this practice has been further strengthened with the introduction of modern therapy and by the guiding principles laid out by the National Board of Health and Welfare. The Swedish Cause of Death Register has been operating since 1961 and has been found to miss only single events. An ongoing validation study of population coverage of stroke incidence derived from the Hospital Discharge Register and the Cause of Death Register finds that positive predicted value and sensitivity of the 2 are close to 90%, (unpublished data 2009). 18 In the present study, the records of the 2 registers were linked based on personal identification codes. For any person, only the first episode of hospitalization since 1987 for stroke was Table 2. Person-Years At Risk and Age-Specific All-Stroke, Intracerebral Hemorrhage, and Ischemic Stroke, Mortality Rates Per 100 000 Persons 1987 2006 in Gothenburg N at Risk 1987 1989 1990 1994 Mortality Rate Mortality Rate AS IH Isc N at Risk AS IH Isc 20 44 258 843 3 1 1 430 717 5 1 3 45 54 69 126 27 10 10 133 083 29 9 14 55 64 64 546 77 37 36 97 402 67 27 35 65 74 60 162 258 62 186 95 710 258 84 163 75 37 101 906 167 728 65 880 905 161 727 20 44 252 852 3 1 1 419 638 4 1 2 45 54 66 763 16 6 4 127 415 17 6 5 55 64 69 780 44 13 19 104 502 31 12 11 65 74 76 640 161 57 87 120 536 159 45 99 75 70 881 841 151 667 124 705 865 107 737 ICD 10 I60 I64, I61 I62, and I63 I64 respectively.

Harmsen et al Stroke Incidence and Mortality Rates 2693 Table 1. Continued 2000 2004 2005 2006 N at Risk Incidence Rate N at Risk Incidence Rate P for Trend AS IH Isc AS IH Isc AS IH Isc 481 315 21 7 10 200 002 12 5 5 NS NS NS 148 624 127 30 87 59 062 125 41 76 NS 0.07 NS 122 219 398 69 312 54 119 384 76 298 NS NS NS 75 907 933 129 784 30 863 846 123 706 0.06 0.19 NS 72 498 2226 270 1930 28 524 2047 319 1697 NS 0.09: 0.003 465 054 17 3 11 192 512 16 2 10 NS NS NS 148 229 103 20 59 58 653 89 17 43 NS NS NS 122 243 218 35 153 54 566 203 27 154 NS NS NS 91 721 647 67 553 35 468 550 62 454 NS 0.14 NS 128 811 2062 207 1824 49 634 1995 200 1771 NS NS NS included to obtain first incidence rates. An event (nonfatal or fatal) that occurred within 28 days was considered to be the same event and was counted as 1 event. In 1987 the International Classification of Diseases (ICD) was changed from the 8 th to the 9 th revision, and in 1997 there was a change to ICD-10. For the present analyses the following principal or contributory diagnoses at hospitalization or death were used: stroke, nonfatal and fatal, Table 2. N at Risk Continued 1995 1999 2000 2004 2005 2006 ICD-9 codes 430-434, 436, and ICD-10 codes I60, I61, I62, I63, and I64. Risk Factor Analyses Cardiovascular risk factors in the population of Gothenburg were analyzed in representative population samples of 50-year-old men examined every tenth year from 1963 to 2003, 12 in 45- to 54-year-old Mortality Rate Mortality Rate Mortality Rate P for Trend AS IH Isc N at Risk AS IH Isc N at Risk AS IH Isc AS IH Isc 455 405 3 1 2 481 315 2 1 0 200 002 3 2 1 NS NS 0.047 148 673 13 6 5 148 624 15 7 7 59 062 12 3 8 NS 0.14 0.14 100 786 62 32 27 122 219 64 24 38 54 119 50 22 28 NS 0.072 NS 84 044 262 73 182 75 907 246 62 181 30 863 201 39 149 NS NS NS 71 158 1259 155 1103 72 498 1101 146 944 28 524 1101 182 912 NS NS 0.0000 441 213 4 1 1 465 054 2 1 1 192 512 2 0 2 NS NS NS 144 984 14 6 3 148 229 16 4 4 58 653 10 2 7 NS NS NS 103 605 42 13 26 122 243 34 16 11 54 566 33 9 18 NS NS NS 104 774 152 50 95 91 721 153 34 108 35 468 110 14 76 NS 0.007 NS 130 958 1082 157 906 128 811 1137 121 995 49 634 1088 105 971 NS NS 0.0000

2694 Stroke August 2009 Table 3. Incidence of All-Stroke (I60 I64) by Sex and 5-Year Time Groups, Adjusted to the European Population Year N N at Risk Crude Adjust 95% CI 1987 1989 1783 489 777 364 319 304 334 1990 1994 3289 822 791 400 347 334 359 1995 1999 3469 860 064 403 357 344 369 2000 2004 3097 900 562 344 315 304 327 2005 2006 1151 372 570 309 286 269 303 1987 1989 2101 536 916 391 220 209 230 1990 1994 3875 896 795 432 233 224 241 1995 9199 4046 925 533 437 248 240 257 2000 2004 3747 956 056 392 232 224 241 2005 2006 1379 390 832 353 216 203 229 Table 4. Mortality of All-Stroke (I60 I64) by Sex and 5-Year Time Groups, Adjusted to the European Population Year N N at Risk Crude Adjust 95% CI 1987 1989 569 489 777 569 98 89 106 1990 1994 966 822 791 966 96 89 102 1995 1999 1213 860 064 1 213 114 107 121 2000 2004 1097 900 562 1 097 101 94 107 2005 2006 416 372 570 416 91 81 100 1987 1989 769 536 916 143 73 67 79 1990 1994 1340 896 795 149 72 67 76 1995 9199 1656 925 533 179 81 76 86 2000 2004 1681 956 056 176 80 76 85 2005 2006 607 390 832 155 70 63 77 women in 1968 to 1969, and in 50-year-old women in 2003. 19,20 Data on smoking and treatment for hypertension were assessed via questionnaires, diabetes at examination, and through blood analyses, body variables, and blood pressure measured at examination; all laboratory tests were performed at the same accredited hospital laboratory. Statistical Methods Incidence and mortality rates were calculated with the mid-year Gothenburg population in the respective age groups as denominator. Ages were categorized in 10-year age groups. Differences over time in incidence and mortality were tested with the 2 trend test (EpiInfo). Differences between discrete variables and differences between continuous variables were tested with 2 analyses and the t test, respectively. Two-sided tests with P 0.05 were considered significant. Stroke incidence and mortality were age-adjusted to the standard European population. 21 Results The number of patients aged 20 years and older who were hospitalized for a first stroke in 1987 to 2006 were 12 904 men and 15 250 women in a population of 187 286 men and 196 116 women aged 20 years and older in 2006. Incidence and mortality rates per 100 000 of the population for all strokes (ICD-10, I60 I64), with intracerebral hemorrhage (I61 I62), and ischemic stroke (I63 I63) are shown in Tables 1 and 2. There were no significant trends over time for any age group of men or women. The incidence rates and mortality rates for subarachnoid hemorrhage declined for the age group 45 to 54 among men, whereas declining trends in some other age groups were not statistically significant, and are not shown in the Tables. The incidence and mortality rates of intracerebral hemorrhage did not change over time, except for women aged 65 to 74, among whom mortality decreased significantly. Incidence and mortality rates for ischemic stroke increased for men aged 75 and older, whereas mortality declined in the age group 20 to 44, and mortality declined in the oldest age group of women. The 28-day fatality rate among hospitalized cases for all-stroke (I60 I64) as well as for ischemic stroke decreased significantly for the age groups 65 to 74 and 75 and older for both men and women (data not shown). Stroke incidence and mortality rates age-standardized to the European population for all-stroke (I60 I64) are shown in Tables 3 and 4. It should be emphasized that rates also include stroke as a secondary diagnosis in people cared for under other primary diagnoses. We have previously reported on stroke risk factors in the Gothenburg population 22 and have documented some differences in risk factors between stroke and myocardial infarction. 23 The secular changes in cardiovascular risk factors were investigated in successive cross-sectional population samples of 50-year-old men every 10 years in Gothenburg from 1963 to 2003, 12 and in 50-year-old women from 1968 to 1969 until 2003, 19,20 as shown in Table 5. It appears that important risk factors decreased (smoking, blood pressure, and total serum cholesterol), others did not change (physical activity, mental stress, and triglycerides in women), and some increased (diabetes prevalence, body weight, BMI, as well as serum triglycerides in men). Discussion The incidence of stroke, with few exceptions such as subarachnoid hemorrhage and ischemic stroke among the oldest men, did not decrease significantly during the period 1987 to 2006. Stroke mortality was also rather stable, with the exception of a single age group of women aged 65 to 74 years with intracerebral hemorrhage. Mortality increased for the oldest age group of both men and women with ischemic stroke, perhaps because a larger proportion of persons of older age made up this rather broad age group (75 years and older). In general, the incidence is influenced by the level of risk factors and preventive treatment of especially high blood pressure, whereas fatality rates among hospitalized stroke patients depend on the severity of the stroke and treatment in hospital. The primary aim of this report is to analyze incidence rates. In our previous report covering the period 1971 to 1987, stroke incidence rates were unchanged, whereas fatality rates decreased. Data were based on the Gothenburg Stroke Register, which was continued until 1993. The rates in that report were slightly lower than those of the present series. These

Harmsen et al Stroke Incidence and Mortality Rates 2695 Table 5. Cardiovascular Risk Factor Changes Among 50-Year-Old During the Years 1963 and 2003 12 and Among From 1968 1969 and 2003 19,20 SD SD P for Trend Year of examination 1963 2003 N examined 855 595 Never and ex-smokers, % 43.9 78.5 Smokers, % 56.1 21.5 0.0001 Diabetes % 3.6 6.6 0.005 BMI, kg/m 2 24.8 3.2 26.6 3.7 0.00001 Waist circumference, cm 87.0 9.6 94.5 9.9 0.00001 Systolic blood pressure, mm Hg 138.2 20.9 134.7 17.6 0.00001 Diastolic blood pressure, mm Hg 90.6 12.5 84.9 10.4 0.00001 Drugs for hypertension, % 1.6 7.1 0.00001 Serum cholesterol, mmol/l 6.42 1.12 5.50 1.01 0.0001 Serum triglycerides, mmol/l 1.26 0.82 1.71 1.18 0.0001 SD SD P for Trend Year of examination 1968 1969 2003 N examined 398 667 Never and ex-smokers, % 62.8 73.9 Smokers, % 37.2 26.1 0.0001 Diabetes % 1.3 6.2 0.00001 BMI, kg/m 2 24.5 4.3 25.6 4.5 0.0001 Systolic blood pressure, mm Hg 138.0 21.8 130.7 18.6 0.00001 Diastolic blood pressure, mm Hg 86.0 10.6 80.8 10.2 0.00001 Drugs for hypertension, % 4.5 9.6 0.0027 Serum cholesterol mmol/l 7.14 1.08 5.44 0.93 0.0001 Serum triglycerides, mmol/l 1.26 0.58 1.24 1.14 NS differences are slight and probably do not indicate any true increase. In the present series there was some decrease in fatality rates for ischemic stroke in the older age groups (65 to 74 years and 75 years and older) for both men and women, but this did not correspond to significant decreases in total stroke mortality for the same groups, or for any other group. Mortality did not decline during this period. Use of the national registers might incur more uncertain identification of stroke cases than the use of stroke registration, as we encountered previously with a community-based, prospective registry. 10 However, the procedure of reporting to the national register is well-established, and a population coverage of 90% is being validated by Koster and Stegmayr. 18 With increasing awareness of early, prompt hospitalization of patients with stroke, the number not admitted will be negligible. Our comparisons are kept within the period 1987 to 2006, using identical methodology. The increasing incidence rates reported from the southern parts of Sweden 6,7,24 were followed by a report that incidence rates had leveled out since the turn of the century in southern Sweden. 25 The rates seem to be of the same order of magnitude as our rates from Gothenburg in western Sweden. The decline in incidence or mortality reported from England, 5,14 Finland, 13 and from the north of Sweden 26 are at variance with our results. Smoking rates and total cholesterol values decreased significantly during the period 1963 to 2003. Blood pressure decreased during these years, partly because slightly more people were being treated with drugs, but there was also a decline that could not be explained by more intensive drug treatment. 12 According to a multivariable risk function based on the 3 risk factors, high blood pressure, smoking, and total serum cholesterol, the risk of myocardial infarction was estimated to have decreased to 45% of its value in men in 1963. The incidence of myocardial infarction decreased by almost 50% in men and decreased somewhat less in women. We have previously reported 23 that there were differences in risk factors for stroke and myocardial infarction, with serum total cholesterol being a strong risk factor for myocardial infarction but not for stroke, whereas blood pressure and BMI were stronger risk factors for stroke. Diabetes was of equal strength. Even though the mean blood pressure levels declined (only partly because of increased antihypertensive treatment), there was still a considerable number of both men and women who had blood pressures above the

2696 Stroke August 2009 recommended limits 140/90 mm Hg (46% of 50-year-old men and 36% of the women). 20 This is probably the main reason for the unchanged stroke incidence and mortality. The increased diabetes prevalence and higher BMI and serum triglycerides (in men), despite declining smoking habits, may be additional reasons. We have previously found that diabetes is a strong risk factor for stroke. 22 It has also been shown that high serum triglycerides is a risk factor for stroke in both sexes, 27 29 and high BMI has been shown to be a risk factor in men 30 and in women. 31 34 Fibrinogen levels 35 (not assessed during all of the study period) might also have contributed to the unchanged stroke incidence. The declining incidence rate of myocardial infarction was, however, unaffected. Stroke mortality also remained unchanged despite the improved knowledge of stroke care. The city of Gothenburg had insufficient coverage of specialized stroke units during part of the period studied. Contrary to these findings, there was a marked decline in mortality rate after a myocardial infarction. 11 In this study we included cases of stroke as a secondary diagnosis. This may be 1 reason for the high rates recorded here compared to the recent study from 6 European countries. 36 In other studies, premorbid risk factor prevalence is often given for the stroke patients; we emphasize that we present risk factor prevalence in the general population here. We are aware of no population studies (since the MONICA study 37 ) of trends in cardiovascular risk factor prevalence covering the same population as the reporting of stroke incidence other than the Gothenburg population studies presented here. In conclusion, there has been no change in stroke incidence and mortality over the past 20 years in Gothenburg. 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