Commentary
The US Decline in Stroke Mortality: What Does Ecological Analysis Tell Us? David R Jacobs, Jr, PhD, Paul G. McGoven*, PhD, and Henry Blackburn, MD In this issue of the Journal, Casper et al.' use population data and ecological associations to shed doubt on the assumptions of many health professionals that improved treatment of hypertension is the primary determinant of the recent decline in US stroke deaths and that the National High Blood Pressure Education Program is principally responsible for the greater slope of this decline since the mid1970s.2-4 Casper et al. examined the association between hypertension prevalence and treatment and the decline in stroke mortality in 45- through 74-year-old men and women, Black and White, in the United States. Their analysis was based on death certificate data from 1962 to 1980 and successive National Center for Health Statistics surveys (National Health Examination Survey, National Health and Nutrition Examination Survey (NHANES) I and II) that took place between 1960 and 1980. Casper et al. explored ecological correlations between trends in (1) the average annual change in prevalence of either treated or controlled hypertension among those identified as hypertensive and (2) the average annual percentage change in stroke mortality for 1962 to 1972 and for 1973 to 1980. Averages were obtained for each of96 race, sex, age, region, and metropolitan groups. The authors considered the average prevalence of hypertension and a specific socioeconomic profile (percentage who completed high school, had a white collar job, and/or had an annual income equal to or greater than $10 000) as confounders and as predictors of percentage change in the annual stroke mortality rate. The authors made appropriate efforts to standardize the survey methods. Casper et al. 's regression analysis results suggest that the trends for hypertension treatment or control and for stroke
mortality rates were parallel over the entire period 1962 to 1980, but not within the shorter periods (1962 to 1972 and 1973 to 1980). Levels and change of socioeconomic status tended to relate to levels and change of stroke mortality. Increased hypertension prevalence was related to greater declines in stroke mortality, after adjustment for changes in prevalence of controlled or treated hypertension. Accepting a role for pharmacotherapy in the treatment of high blood pressure,5,6 Casper et al. nevertheless conclude that mass drug treatment of hypertension cannot bring about the "optimal decline" in stroke mortality. In essence, they pose a sociocultural hypothesis-which we share7-of the population causes of mass hypertension. This hypothesis is based on the fact that the largest fraction of population-attributable risk for stroke derives from the "high normal blood pressure and mild hypertensive" groups that benefit least from the hypertension detection-andmedication approach. Because life-style factors correlate more strongly with stroke mortality trends than does the drug treatment of hypertension, Casper et al. suggest that cultural change is more relevant than medical management to hypertension prevention. We address two issues. First, Casper et al. assume that population correlations are appropriate for studying the population effect of blood-pressure medication on stroke mortality rates. We discuss the The authors are with the Division of Epidemiology, School of Public Health, University of Minnesota, Minneapolis, Minn. Requests for reprints should be sent to David R. Jacobs, Jr, PhD, School of Public Health, University of Minnesota, 1300 S Second St, Suite 300, Minneapolis, MN 55454. Editor's Note. See related article by Casper et al. (p 1600) in this issue.
December 1992, Vol. 82, No. 12
Commentag
ecological method's potential ability to answer such questions. Second, we consider Casper et al.'s conclusion that the increased use of antihypertensive medication is not the basis for the current decline in stroke mortality. We suggest that other possible sources of this decline are the population-wide falls in levels of blood pressure, cigarette smoking, and coronary heart disease mortality and the improved treatment of stroke.
The Ecologia Method and the Effects of Medical Inteernions Ecological analysis is one method to answer questions about medical interventions' population-wide effects on disease8; modeling of results from clinical trials9 is another method. The ecological method can find associations such as those we posit here. For example, an association was found in Japan between the coverage of mass uterinecancer screening (Pap smear) and death rates from that cancer. Kuroishi et al.1O computed coverage rates for screenings conducted from 1969 to 1978 in 3278 Japanese municipalities; they then selected the 61 areas with 20% or greater coverage and with uterine-cancer death rates that, for 1969 to 1972, were at least 90% of the Japanese average rate. They matched these areas with 122 control areas on uterine-cancer death rate, population size, and coverage by National Health Insurance. Within the defined subset during the period 1973 to 1977, they found a statistically significant 50%o reduction in uterine-cancer death rates in the areas having high coverage (mean 25% screened) vs low coverage (mean 8% screened). They concluded that the ongoing screening coverage influenced the change in mortality between the earlier and later time periods. However, the ecological method has inherent weaknesses, and it is often hard to tell whether those weaknesses are present. The interpretation of ecological variables may be different from that of corresponding individual level variables. In general, the average stroke mortality rate is the end product of the population-wide effects of all factors, known and unknown, that influence the recording of stroke on a death certificate and its coding as the underlying cause of death. Stroke mortality rates may decline with no reduction in incidence if patients recover partially and eventually die of nonstroke causes. In a recovered person, stroke may not even be mentioned on the death certificate. In adDecember 1992, Vol. 82, No. 12
dition, there may be artifacts in stroke mortality rates since the advent of computerized tomography; for example, milder strokes may be diagnosed using computerized tomography and not only clinical grounds.1" Stroke diagnosis in hospitals may also be influenced by the diagnosis-related groups financial structure introduced in the mid-1980s, insofar as hospitals may systematically select the more remunerative diagnosis among equal choices. Similarly, the average rates of treatment or control with antihypertensive medication represent both the extent of a group's exposure to treatment and the degree of blood-pressure control achieved. In the population-ecological context, treatment may not have the same meaning as in the individual-c a-trial context: for example, population-wide drug treatment is likely to be less intensive and to use a broadervariety of drugs than a clinical trial. Thus, the question ofwhether optimal treatment affects the risk of stroke in a patient with elevated blood pressure is different from the question whether routine treatmentoveran entire population-one having a wide range of mild, moderate, and severe blood-pressure elevations-affects stroke rates. Furthermore, treatment and hypertension measures obtained in survey data are subject to biases from incomplete participant response to the survey, poor recall, poor understanding of survey questions, and variability in blood-pressure measurement.
The sample size and range of the independent variable may also influence the outcome of ecological analysis. For correct inferences, there must be a sufficient number of ecological units with precisely measured outcome and exposure variables. Composite ecological measures (as opposed to Susser's8 integral features, such as the availability of trained health professionals in a city) are less variable than the corresponding measures in individuals. (The variance of the ecological measure is [&I/n]- [1 + pn], where &2 is the variance, n is the number per unit, and p is the intraclass correlation.) Casper et al.'s sample size of 96 is large among ecological analyses, and their stroke mortality rates are based on large numbers for each subgroup. However, those survey measures (blood pressures, prevalences) that are defined by relatively few individuals may be imprecise when used in some ecological units. Specifically, the National Health and Exmination Survey had an average of 27.6 persons per unit, and many of Casper et al.'s units must be
smaller. Furthermore, the sample base for the percentage of hypertensives treated or controlled is usually about one third as large as the base for other characteristics, depending on the prevalence of hypertension. For example, given the relatively small number of units, an outlying value for percentage controlled hypertensives may unduly influence the overall findings. The Stein estimator used by Casper et al. may help by reducing the influence of unstable data points, although at the expense of analyzing less than full information from each point. When the range of the independent variable is small, existing relationships may not be reflected in regression. In the study of Casper et al., the range from the 10th to 90th decile of the average annual change in controlled hypertension is limited within the shorter time periods (-1.9% to 1.1% during the 1962 to 1972 period and -0.1% to 5.3% during 1973 to 1980). Another concern in the analysis of Casper et al. is that their inclusion of the prevalence ofhypertension in their regression models may represent overadjustment and may be masking a small effect of blood-pressure control on stroke mortality decline. "Prevalence of hypertension" is generally defined as a composite of the proportion of the population above a blood-pressure cutpoint and the proportion under treatment (irrespective of measured blood pressure). Because average population blood-pressure levels are decreasing,12,13 higher prevalences of hypertension may be taken as a reflection of wider antihypertensive treatment. Therefore, the small but statistically significant inverse relationship between the prevalence of hypertension and a decline in stroke mortality may reflect some contribution of treatment. Given Casper et al.'s (1) slope estimate of a -0.03 to -0.06% decline in stroke mortality per year per percent of prevalent hypertension and (2) range of about 20%o for hypertension prevalence across units, we estimate that treatment's contribution is an approximate 0.5% to 1% decline in the stroke mortality rate per year.
Fawtors Influencig Stoke
Modality Raes Because treatment with blood-pressure medication reduces the risk of stroke in individuals with high blood pressure, stroke mortality decline in the population should reflect such medication if the treat-
American Joumal of Public Health 1597
COMMMW7 ment reduces risk in a sufficient number of people. Casper et al.'s findings imply that many people with moderate elevations in stroke risk are untreated, and that something in addition to treatment is driving down stroke risk. We consider the evidence overwhelming that average bloodpressure reduction is playing an important role in the decline of stroke mortality. McMahon et al.14 conclude from their metaanalysis of observational studies that a 5 mm Hg average decline in diastolic blood pressure is associated with a 34% reduction in the incidence of stroke (corrected for regression dilution bias). Shimamoto et al.1516 find concordance between reductions in stroke incidence in Japan (primarily intracranial hemorrhage) and population blood-pressure levels and their correlates. Moreover, the total potential of antihypertensive treatment may not have been reached yet, as approximately 3 of 10 hypertensive people remain undetected12 and we suppose that the lag between the first diagnosis of hypertension and the inception of effective treatment might still be shortened. We have recently published findings on changes in stroke mortality and its ecological correlates.12 Stroke mortality rates in Minnesota declined more than 50% during the period 1960 to 1990, while mean blood pressure fell and antihypertensive treatment increased between 1973 and 1987. To estimate which part of the observed decline in mean population bloodpressure could be explained by pharmacotherapy, we exanmined datal2 on trends in average blood pressure in our community and on the prevalence of antihypertensive treatment. We computed mean diastolic blood-pressure levels, assuming that the levels among treated hypertensives had been 10 mm Hg higher before treatment. (The exact reduction in mean diastolic blood pressure under routine treatment in a community is not known; for modeling purposeswe took 10mmHg, which is likely an overestimate of treatment effect.17) The proportion of the mean blood-pressure decline attributable to medication was equal to or less than 40% in all period-age-sex cases, except between 1973 and 1981 forwomen aged SOto 59 years (Table 1). Minnesota Heart Survey data tend to support findingsl2 of a small effect of medication on the stroke mortality decline, because antihypertensive treatment explains only part of the average population bloodpressure decline. Our findings differ somewhat from the results of Casper et al., which appear to indicate that antihyper1598 American Journal of Public Health
tensive treatment has no effect on population-wide stroke mortality rates. Declines in the average and distributions of blood pressure in the population are consistent with the observed declines in stroke mortality. The causes of these population-wide reductions (apart from the wider use of antihypertensive medication) remain to be elucidated. Changes in physical activity18 and body weight12 may be relevant. We reported increased levels of leisure-time physical activity between 1957 and 1987.18-20 In light of concurrent increases in population levels of body mass index,'2 we suppose that physical activity at work, in transportation, and in the home declined during this period. Changes in alcohol intake and other dietary factors such as sodium intake deserve further study. The Minnesota Heart Survey has also found that smoking prevalence has declined in recentyears12 and has been on the decline since the 1964 Surgeon General's report.21 Smoking is significantly related to stroke
mortality in cohort studies,2224 and the decline in smoldng may therefore have had a directinfluence on the decline in stroke mortality. Given the greatly increased preva-
lence of cgarette smoldng at lower levels of education,25 smoking may be an important factor in the relation of socioeconomic status with stroke mortality. In addition, declines in average population serum total cholesteroll2 occurred between 1973 and 1987. Small reductions in rates of thromboembolic stroke and small increases in rates of intracranial hemorrhage26 conceivably may have resulted from these cholesterol trends. Finally, we note that declines in stroke mortality rates are not necessarily the same as declines in stroke incidence. Our recent report12 showed that stroke as a hospital discharge diagnosis fell about 40% between 1970 and 1985, but hospital stroke discharge rates validated by standard criteria did not change. The true change in the stroke discharge rate was probably intermediate, because the use of December 1992, Vol. 82, No. 12
Commentary computerized tomography in later years improved the sensitivity of the validated stroke diagnosis. Both short- and longterm case-fatality rates fell between 1970 and 1985, perhaps due to the improved treatment of the cardiac and respiratory sequelae of stroke and, to a lesser extent, to the inclusion of milder hemorrhagic strokes in the data of later years.27 There has also been a reduction in coronaryheart-disease mortality in recent years, which may have contnbuted to the decline in stroke mortality. (Atrial fibrillation,28 29 myocardial infarction, or poor left-ventricular function may enhance cardiac thrombus formation, resulting in an embolic stroke.) We conclude that (1) the stroke mortality rate changes in the United States since 1960 have followed population blood-pressure changes, influenced to some extent by the expanded use of antihypertensive medication, and (2) the full potential of this use in the population may notyet have been reached. Other life-style factors have probably influenced the decline of stroke deaths, both directly (e.g., the decreasing prevalence of cigarette smoking) and indirectly (e.g., the effects ofdecreased sodium and alcohol intake on blood pressure). Improved treatment after stroke and medical-care changes that have influenced the course of coronary heart disease may also have played a role in the reduced stroke mortality rate. O
Acknowledgment The authors thank Dr. Jack Whlisnant for his review of this paper.
References 1. Casper M, Wing S, Strogatz D, Davis CE, Tyroler HA. Antihypertensive treatment and US trends in stroke mortality, 1962 to 1980. Am J Psblic Health. 1992;82:16001606. 2. WhisnantJP. The decline of stroke. Stroke.
1984;15:160-168.
3. Gillum RF, Gomez-Marin 0, Kottke TE, Jacobs DR, Prineas RJ, Folsom AR, Luepker RV, Blackburn H. Acute stroke in a metropolitan area, 1970 and 1980: the Minnesota Heart Survey. J Chronic Dis. 1985; 38:8911-8918.
December 1992, Vol. 82, No. 12
4. Garroway WM, Whisnant JP. The changing pattern of hypertension and the declining incidence of. stroke. JAMA. 1987;258: 214-217. 5. MacMahon S, CutlerJ, FurbergCD, Payne GH. The effects of drug treatment for hypertension on morbidity and mortality from cardiovascular disease: a review of randomized controlled trials. Pg Cardiovasc Dis. 1986;29(suppl 1):99-118. 6. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. JAMA. 1991;265: 3255-3264. 7. Blackburn H, Prineas R. Diet and hypertension: anthropology, epidemiology, and public health implications. Prog Biochem PharmacoL 1983;19:31-79. 8. Susser M. The logic of ecologic. 1992; unpublished manuscript. 9. Bonita R, Beaglehole R. Increased treatment of hypertension does not explain the decline in stroke in the United States, 19701980. Hypertension. 1989;13(suppl I):I-691-73. 10. Kuroishi T, Hirose K, Tominaga S. Evaluation of the efficacy of mass screening for uterine cancer in Japan. JpnJ Cancer Res. 1986;77:399-405. 11. Iso H, Jacobs DR, Goldman L. Accuracy of death certificate diagnosis of intracranial hemorrhage and nonhemorrhagic stroke. The Minnesota Heart Survey. Am J EpidemioL 1990;132:993-998. 12. McGovern P, Burke GL, Sprafka JM, Xue S, Folsom AR, Blackburn H. Trends in mortality, morbidity and risk factor levels for stroke from 1960 to 1990: the Minnesota Heart Survey. JAMA 1992;268:753-759. 13. Blood pressure levels in persons 18-74 years of age in 1976-1980, and trends in blood pressure from 1960 to 1980 in the United States. Vital Health Stat [11]. 1986; no. 234. DHHS publication PHS 86-1684. 14. MacMahon S, Peto R, Cutler J, Collins R, Sorlie P, Neaton J, Abbott R, Godwin J, Dyer A, Stamler J. Blood pressure, stroke, and coronary heart disease. Part 1, prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet. 1990;335:765-774. 15. Shimamoto T, Komachi Y, Inada H, Doi M, Iso H, Sato S, Kitamura A, Iida M, Konishi M, Nakanishi N, Terao A, Naito Y, Kojima S. Trends for coronaxy heart disease and stroke and their risk factors in Japan. Ciculation. 1989;79:503-515. 16. Blackburn H, Jacobs D. The ongoing natural experiment of cardiovascular disease in Japan. Circulation. 1989;79:718-720. 17. Hebert PR, Fiebach NH, Eberlein KA,
18.
19.
20.
21.
22.
23.
24. 25.
26.
27.
28. 29.
Taylor JO, Hennekens CH. The community-based randomized trials of pharmacologic treatment of mild-to-moderate hypertension. Am J EpidemioL 1988;127:581590. Jacobs DR, Hahn LP, FolsomAR, Hannan PJ, Sprafka JM, Burke GL. Time trends in leisure-time physical activity in the Upper Midwest 1957-1987: University of Minnesota studies. Epidemiology. 1991;2:8-15. Yeager KK, Macera CA, Eaker E, Merritt RK Time trends in leisure-time physical activity: another perspective. Epidemiology. 1991;2:313-314. Letter. Jacobs DR, Folsom AR, Hannan PJ, Sprafka JM, McGovern PG, Salem N. The authors reply. Epidemiology. 1991;2:315316. Letter. SmoldAng and Health. Report of theAdvisory Committee to the Surgeon General of the Public Health Service. Atlanta, Ga: US Public Health Service, Centers for Disease Control; 1964. PHS publication 1103. Wolf PA, Kannel WB, Cupples LA, D'Agostino RB. Risk factor interaction in cardiovascular and cerebrovascular disease. In: Furlan AJ, ed. The Heart and
Stroke: ExplornngMutual Cerebrovascular and Cardiovascular Issues. New York, NY: Springer Verlag; 1987:331-355. Bonita R, Scragg R, Stewart A, Jackson R, Beaglehole R. Cigarette smoking and risk of premature stroke in men and women. Br Med.J. 1986;293:6-8. Abbott RD, Yin Yin MA, Reed DM, Yano K. Risk of stroke in male cigarette smokers. N Engl J Med. 1986;315:717-720. Wagenknecht LE, Perkins LL, Cutter GR, Sidney S, Burke GL, Manolio TA, Jacobs DR, Liu K, Friedman GD, Hughes GH, Hulley SB. Cigarette smoking behavior is strongly related to educational status: the CARDIA study. Pn-v Med 1990;19:158169. Iso H, Jacobs DR, Wentworth D, Neaton JD, Cohen JD. Serum cholesterol levels and six-year mortality from stroke in 350,977 men screened for the Multiple Risk Factor Intervention Trial. N Engl J Met 1989;320:904-910. Broderick JP, Phillips SP, Whisnant JP, O'Fallon WM, Bergstralh EJ. Incidence rates of stroke in the eighties: the end of the decline in stroke? Stroke. 1989;20:577-582. Wolf PA. An overview ofthe epidemiology of stroke. Stroke. 1990;21(suppl II):II4II-6. Benjamin EJ, Plehn JF, D'Agostino RB, Belanger AJ, Comai K, Fuller DL, Wolf PA, Levy D. Mitral annular calcification and the risk of stroke in an elderly cohort. N Engl J MedL 1992;327:374-379.
American Joumal of Public Health 1599
The US Decline in Stroke Mortality: What Does Ecological Analysis Tell Us? David R Jacobs, Jr, PhD, Paul G. McGoven*, PhD, and Henry Blackburn, MD In this issue of the Journal, Casper et al.' use population data and ecological associations to shed doubt on the assumptions of many health professionals that improved treatment of hypertension is the primary determinant of the recent decline in US stroke deaths and that the National High Blood Pressure Education Program is principally responsible for the greater slope of this decline since the mid1970s.2-4 Casper et al. examined the association between hypertension prevalence and treatment and the decline in stroke mortality in 45- through 74-year-old men and women, Black and White, in the United States. Their analysis was based on death certificate data from 1962 to 1980 and successive National Center for Health Statistics surveys (National Health Examination Survey, National Health and Nutrition Examination Survey (NHANES) I and II) that took place between 1960 and 1980. Casper et al. explored ecological correlations between trends in (1) the average annual change in prevalence of either treated or controlled hypertension among those identified as hypertensive and (2) the average annual percentage change in stroke mortality for 1962 to 1972 and for 1973 to 1980. Averages were obtained for each of96 race, sex, age, region, and metropolitan groups. The authors considered the average prevalence of hypertension and a specific socioeconomic profile (percentage who completed high school, had a white collar job, and/or had an annual income equal to or greater than $10 000) as confounders and as predictors of percentage change in the annual stroke mortality rate. The authors made appropriate efforts to standardize the survey methods. Casper et al. 's regression analysis results suggest that the trends for hypertension treatment or control and for stroke
mortality rates were parallel over the entire period 1962 to 1980, but not within the shorter periods (1962 to 1972 and 1973 to 1980). Levels and change of socioeconomic status tended to relate to levels and change of stroke mortality. Increased hypertension prevalence was related to greater declines in stroke mortality, after adjustment for changes in prevalence of controlled or treated hypertension. Accepting a role for pharmacotherapy in the treatment of high blood pressure,5,6 Casper et al. nevertheless conclude that mass drug treatment of hypertension cannot bring about the "optimal decline" in stroke mortality. In essence, they pose a sociocultural hypothesis-which we share7-of the population causes of mass hypertension. This hypothesis is based on the fact that the largest fraction of population-attributable risk for stroke derives from the "high normal blood pressure and mild hypertensive" groups that benefit least from the hypertension detection-andmedication approach. Because life-style factors correlate more strongly with stroke mortality trends than does the drug treatment of hypertension, Casper et al. suggest that cultural change is more relevant than medical management to hypertension prevention. We address two issues. First, Casper et al. assume that population correlations are appropriate for studying the population effect of blood-pressure medication on stroke mortality rates. We discuss the The authors are with the Division of Epidemiology, School of Public Health, University of Minnesota, Minneapolis, Minn. Requests for reprints should be sent to David R. Jacobs, Jr, PhD, School of Public Health, University of Minnesota, 1300 S Second St, Suite 300, Minneapolis, MN 55454. Editor's Note. See related article by Casper et al. (p 1600) in this issue.
December 1992, Vol. 82, No. 12
Commentag
ecological method's potential ability to answer such questions. Second, we consider Casper et al.'s conclusion that the increased use of antihypertensive medication is not the basis for the current decline in stroke mortality. We suggest that other possible sources of this decline are the population-wide falls in levels of blood pressure, cigarette smoking, and coronary heart disease mortality and the improved treatment of stroke.
The Ecologia Method and the Effects of Medical Inteernions Ecological analysis is one method to answer questions about medical interventions' population-wide effects on disease8; modeling of results from clinical trials9 is another method. The ecological method can find associations such as those we posit here. For example, an association was found in Japan between the coverage of mass uterinecancer screening (Pap smear) and death rates from that cancer. Kuroishi et al.1O computed coverage rates for screenings conducted from 1969 to 1978 in 3278 Japanese municipalities; they then selected the 61 areas with 20% or greater coverage and with uterine-cancer death rates that, for 1969 to 1972, were at least 90% of the Japanese average rate. They matched these areas with 122 control areas on uterine-cancer death rate, population size, and coverage by National Health Insurance. Within the defined subset during the period 1973 to 1977, they found a statistically significant 50%o reduction in uterine-cancer death rates in the areas having high coverage (mean 25% screened) vs low coverage (mean 8% screened). They concluded that the ongoing screening coverage influenced the change in mortality between the earlier and later time periods. However, the ecological method has inherent weaknesses, and it is often hard to tell whether those weaknesses are present. The interpretation of ecological variables may be different from that of corresponding individual level variables. In general, the average stroke mortality rate is the end product of the population-wide effects of all factors, known and unknown, that influence the recording of stroke on a death certificate and its coding as the underlying cause of death. Stroke mortality rates may decline with no reduction in incidence if patients recover partially and eventually die of nonstroke causes. In a recovered person, stroke may not even be mentioned on the death certificate. In adDecember 1992, Vol. 82, No. 12
dition, there may be artifacts in stroke mortality rates since the advent of computerized tomography; for example, milder strokes may be diagnosed using computerized tomography and not only clinical grounds.1" Stroke diagnosis in hospitals may also be influenced by the diagnosis-related groups financial structure introduced in the mid-1980s, insofar as hospitals may systematically select the more remunerative diagnosis among equal choices. Similarly, the average rates of treatment or control with antihypertensive medication represent both the extent of a group's exposure to treatment and the degree of blood-pressure control achieved. In the population-ecological context, treatment may not have the same meaning as in the individual-c a-trial context: for example, population-wide drug treatment is likely to be less intensive and to use a broadervariety of drugs than a clinical trial. Thus, the question ofwhether optimal treatment affects the risk of stroke in a patient with elevated blood pressure is different from the question whether routine treatmentoveran entire population-one having a wide range of mild, moderate, and severe blood-pressure elevations-affects stroke rates. Furthermore, treatment and hypertension measures obtained in survey data are subject to biases from incomplete participant response to the survey, poor recall, poor understanding of survey questions, and variability in blood-pressure measurement.
The sample size and range of the independent variable may also influence the outcome of ecological analysis. For correct inferences, there must be a sufficient number of ecological units with precisely measured outcome and exposure variables. Composite ecological measures (as opposed to Susser's8 integral features, such as the availability of trained health professionals in a city) are less variable than the corresponding measures in individuals. (The variance of the ecological measure is [&I/n]- [1 + pn], where &2 is the variance, n is the number per unit, and p is the intraclass correlation.) Casper et al.'s sample size of 96 is large among ecological analyses, and their stroke mortality rates are based on large numbers for each subgroup. However, those survey measures (blood pressures, prevalences) that are defined by relatively few individuals may be imprecise when used in some ecological units. Specifically, the National Health and Exmination Survey had an average of 27.6 persons per unit, and many of Casper et al.'s units must be
smaller. Furthermore, the sample base for the percentage of hypertensives treated or controlled is usually about one third as large as the base for other characteristics, depending on the prevalence of hypertension. For example, given the relatively small number of units, an outlying value for percentage controlled hypertensives may unduly influence the overall findings. The Stein estimator used by Casper et al. may help by reducing the influence of unstable data points, although at the expense of analyzing less than full information from each point. When the range of the independent variable is small, existing relationships may not be reflected in regression. In the study of Casper et al., the range from the 10th to 90th decile of the average annual change in controlled hypertension is limited within the shorter time periods (-1.9% to 1.1% during the 1962 to 1972 period and -0.1% to 5.3% during 1973 to 1980). Another concern in the analysis of Casper et al. is that their inclusion of the prevalence ofhypertension in their regression models may represent overadjustment and may be masking a small effect of blood-pressure control on stroke mortality decline. "Prevalence of hypertension" is generally defined as a composite of the proportion of the population above a blood-pressure cutpoint and the proportion under treatment (irrespective of measured blood pressure). Because average population blood-pressure levels are decreasing,12,13 higher prevalences of hypertension may be taken as a reflection of wider antihypertensive treatment. Therefore, the small but statistically significant inverse relationship between the prevalence of hypertension and a decline in stroke mortality may reflect some contribution of treatment. Given Casper et al.'s (1) slope estimate of a -0.03 to -0.06% decline in stroke mortality per year per percent of prevalent hypertension and (2) range of about 20%o for hypertension prevalence across units, we estimate that treatment's contribution is an approximate 0.5% to 1% decline in the stroke mortality rate per year.
Fawtors Influencig Stoke
Modality Raes Because treatment with blood-pressure medication reduces the risk of stroke in individuals with high blood pressure, stroke mortality decline in the population should reflect such medication if the treat-
American Joumal of Public Health 1597
COMMMW7 ment reduces risk in a sufficient number of people. Casper et al.'s findings imply that many people with moderate elevations in stroke risk are untreated, and that something in addition to treatment is driving down stroke risk. We consider the evidence overwhelming that average bloodpressure reduction is playing an important role in the decline of stroke mortality. McMahon et al.14 conclude from their metaanalysis of observational studies that a 5 mm Hg average decline in diastolic blood pressure is associated with a 34% reduction in the incidence of stroke (corrected for regression dilution bias). Shimamoto et al.1516 find concordance between reductions in stroke incidence in Japan (primarily intracranial hemorrhage) and population blood-pressure levels and their correlates. Moreover, the total potential of antihypertensive treatment may not have been reached yet, as approximately 3 of 10 hypertensive people remain undetected12 and we suppose that the lag between the first diagnosis of hypertension and the inception of effective treatment might still be shortened. We have recently published findings on changes in stroke mortality and its ecological correlates.12 Stroke mortality rates in Minnesota declined more than 50% during the period 1960 to 1990, while mean blood pressure fell and antihypertensive treatment increased between 1973 and 1987. To estimate which part of the observed decline in mean population bloodpressure could be explained by pharmacotherapy, we exanmined datal2 on trends in average blood pressure in our community and on the prevalence of antihypertensive treatment. We computed mean diastolic blood-pressure levels, assuming that the levels among treated hypertensives had been 10 mm Hg higher before treatment. (The exact reduction in mean diastolic blood pressure under routine treatment in a community is not known; for modeling purposeswe took 10mmHg, which is likely an overestimate of treatment effect.17) The proportion of the mean blood-pressure decline attributable to medication was equal to or less than 40% in all period-age-sex cases, except between 1973 and 1981 forwomen aged SOto 59 years (Table 1). Minnesota Heart Survey data tend to support findingsl2 of a small effect of medication on the stroke mortality decline, because antihypertensive treatment explains only part of the average population bloodpressure decline. Our findings differ somewhat from the results of Casper et al., which appear to indicate that antihyper1598 American Journal of Public Health
tensive treatment has no effect on population-wide stroke mortality rates. Declines in the average and distributions of blood pressure in the population are consistent with the observed declines in stroke mortality. The causes of these population-wide reductions (apart from the wider use of antihypertensive medication) remain to be elucidated. Changes in physical activity18 and body weight12 may be relevant. We reported increased levels of leisure-time physical activity between 1957 and 1987.18-20 In light of concurrent increases in population levels of body mass index,'2 we suppose that physical activity at work, in transportation, and in the home declined during this period. Changes in alcohol intake and other dietary factors such as sodium intake deserve further study. The Minnesota Heart Survey has also found that smoking prevalence has declined in recentyears12 and has been on the decline since the 1964 Surgeon General's report.21 Smoking is significantly related to stroke
mortality in cohort studies,2224 and the decline in smoldng may therefore have had a directinfluence on the decline in stroke mortality. Given the greatly increased preva-
lence of cgarette smoldng at lower levels of education,25 smoking may be an important factor in the relation of socioeconomic status with stroke mortality. In addition, declines in average population serum total cholesteroll2 occurred between 1973 and 1987. Small reductions in rates of thromboembolic stroke and small increases in rates of intracranial hemorrhage26 conceivably may have resulted from these cholesterol trends. Finally, we note that declines in stroke mortality rates are not necessarily the same as declines in stroke incidence. Our recent report12 showed that stroke as a hospital discharge diagnosis fell about 40% between 1970 and 1985, but hospital stroke discharge rates validated by standard criteria did not change. The true change in the stroke discharge rate was probably intermediate, because the use of December 1992, Vol. 82, No. 12
Commentary computerized tomography in later years improved the sensitivity of the validated stroke diagnosis. Both short- and longterm case-fatality rates fell between 1970 and 1985, perhaps due to the improved treatment of the cardiac and respiratory sequelae of stroke and, to a lesser extent, to the inclusion of milder hemorrhagic strokes in the data of later years.27 There has also been a reduction in coronaryheart-disease mortality in recent years, which may have contnbuted to the decline in stroke mortality. (Atrial fibrillation,28 29 myocardial infarction, or poor left-ventricular function may enhance cardiac thrombus formation, resulting in an embolic stroke.) We conclude that (1) the stroke mortality rate changes in the United States since 1960 have followed population blood-pressure changes, influenced to some extent by the expanded use of antihypertensive medication, and (2) the full potential of this use in the population may notyet have been reached. Other life-style factors have probably influenced the decline of stroke deaths, both directly (e.g., the decreasing prevalence of cigarette smoking) and indirectly (e.g., the effects ofdecreased sodium and alcohol intake on blood pressure). Improved treatment after stroke and medical-care changes that have influenced the course of coronary heart disease may also have played a role in the reduced stroke mortality rate. O
Acknowledgment The authors thank Dr. Jack Whlisnant for his review of this paper.
References 1. Casper M, Wing S, Strogatz D, Davis CE, Tyroler HA. Antihypertensive treatment and US trends in stroke mortality, 1962 to 1980. Am J Psblic Health. 1992;82:16001606. 2. WhisnantJP. The decline of stroke. Stroke.
1984;15:160-168.
3. Gillum RF, Gomez-Marin 0, Kottke TE, Jacobs DR, Prineas RJ, Folsom AR, Luepker RV, Blackburn H. Acute stroke in a metropolitan area, 1970 and 1980: the Minnesota Heart Survey. J Chronic Dis. 1985; 38:8911-8918.
December 1992, Vol. 82, No. 12
4. Garroway WM, Whisnant JP. The changing pattern of hypertension and the declining incidence of. stroke. JAMA. 1987;258: 214-217. 5. MacMahon S, CutlerJ, FurbergCD, Payne GH. The effects of drug treatment for hypertension on morbidity and mortality from cardiovascular disease: a review of randomized controlled trials. Pg Cardiovasc Dis. 1986;29(suppl 1):99-118. 6. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. JAMA. 1991;265: 3255-3264. 7. Blackburn H, Prineas R. Diet and hypertension: anthropology, epidemiology, and public health implications. Prog Biochem PharmacoL 1983;19:31-79. 8. Susser M. The logic of ecologic. 1992; unpublished manuscript. 9. Bonita R, Beaglehole R. Increased treatment of hypertension does not explain the decline in stroke in the United States, 19701980. Hypertension. 1989;13(suppl I):I-691-73. 10. Kuroishi T, Hirose K, Tominaga S. Evaluation of the efficacy of mass screening for uterine cancer in Japan. JpnJ Cancer Res. 1986;77:399-405. 11. Iso H, Jacobs DR, Goldman L. Accuracy of death certificate diagnosis of intracranial hemorrhage and nonhemorrhagic stroke. The Minnesota Heart Survey. Am J EpidemioL 1990;132:993-998. 12. McGovern P, Burke GL, Sprafka JM, Xue S, Folsom AR, Blackburn H. Trends in mortality, morbidity and risk factor levels for stroke from 1960 to 1990: the Minnesota Heart Survey. JAMA 1992;268:753-759. 13. Blood pressure levels in persons 18-74 years of age in 1976-1980, and trends in blood pressure from 1960 to 1980 in the United States. Vital Health Stat [11]. 1986; no. 234. DHHS publication PHS 86-1684. 14. MacMahon S, Peto R, Cutler J, Collins R, Sorlie P, Neaton J, Abbott R, Godwin J, Dyer A, Stamler J. Blood pressure, stroke, and coronary heart disease. Part 1, prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet. 1990;335:765-774. 15. Shimamoto T, Komachi Y, Inada H, Doi M, Iso H, Sato S, Kitamura A, Iida M, Konishi M, Nakanishi N, Terao A, Naito Y, Kojima S. Trends for coronaxy heart disease and stroke and their risk factors in Japan. Ciculation. 1989;79:503-515. 16. Blackburn H, Jacobs D. The ongoing natural experiment of cardiovascular disease in Japan. Circulation. 1989;79:718-720. 17. Hebert PR, Fiebach NH, Eberlein KA,
18.
19.
20.
21.
22.
23.
24. 25.
26.
27.
28. 29.
Taylor JO, Hennekens CH. The community-based randomized trials of pharmacologic treatment of mild-to-moderate hypertension. Am J EpidemioL 1988;127:581590. Jacobs DR, Hahn LP, FolsomAR, Hannan PJ, Sprafka JM, Burke GL. Time trends in leisure-time physical activity in the Upper Midwest 1957-1987: University of Minnesota studies. Epidemiology. 1991;2:8-15. Yeager KK, Macera CA, Eaker E, Merritt RK Time trends in leisure-time physical activity: another perspective. Epidemiology. 1991;2:313-314. Letter. Jacobs DR, Folsom AR, Hannan PJ, Sprafka JM, McGovern PG, Salem N. The authors reply. Epidemiology. 1991;2:315316. Letter. SmoldAng and Health. Report of theAdvisory Committee to the Surgeon General of the Public Health Service. Atlanta, Ga: US Public Health Service, Centers for Disease Control; 1964. PHS publication 1103. Wolf PA, Kannel WB, Cupples LA, D'Agostino RB. Risk factor interaction in cardiovascular and cerebrovascular disease. In: Furlan AJ, ed. The Heart and
Stroke: ExplornngMutual Cerebrovascular and Cardiovascular Issues. New York, NY: Springer Verlag; 1987:331-355. Bonita R, Scragg R, Stewart A, Jackson R, Beaglehole R. Cigarette smoking and risk of premature stroke in men and women. Br Med.J. 1986;293:6-8. Abbott RD, Yin Yin MA, Reed DM, Yano K. Risk of stroke in male cigarette smokers. N Engl J Med. 1986;315:717-720. Wagenknecht LE, Perkins LL, Cutter GR, Sidney S, Burke GL, Manolio TA, Jacobs DR, Liu K, Friedman GD, Hughes GH, Hulley SB. Cigarette smoking behavior is strongly related to educational status: the CARDIA study. Pn-v Med 1990;19:158169. Iso H, Jacobs DR, Wentworth D, Neaton JD, Cohen JD. Serum cholesterol levels and six-year mortality from stroke in 350,977 men screened for the Multiple Risk Factor Intervention Trial. N Engl J Met 1989;320:904-910. Broderick JP, Phillips SP, Whisnant JP, O'Fallon WM, Bergstralh EJ. Incidence rates of stroke in the eighties: the end of the decline in stroke? Stroke. 1989;20:577-582. Wolf PA. An overview ofthe epidemiology of stroke. Stroke. 1990;21(suppl II):II4II-6. Benjamin EJ, Plehn JF, D'Agostino RB, Belanger AJ, Comai K, Fuller DL, Wolf PA, Levy D. Mitral annular calcification and the risk of stroke in an elderly cohort. N Engl J MedL 1992;327:374-379.
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