Isolated and Borderline Isolated Systolic Hypertension Relative to Long-Term Risk and Type of Stroke

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1 Isolated and Borderline Isolated Systolic Hypertension Relative to Long-Term Risk and Type of Stroke A 20-Year Follow-Up of the National Health and Nutrition Survey Adnan I. Qureshi, MD; M. Fareed K. Suri, MD; Yousef Mohammad, MD; Lee R. Guterman, PhD, MD; L. Nelson Hopkins, MD Background and Purpose Although the short-term risks of stroke and types of stroke associated with isolated systolic hypertension (ISH) and borderline isolated systolic hypertension (BISH) have been described, the long-term effects of these hypertensive conditions, particularly in younger individuals, are unclear. We performed this study to evaluate the long-term risks of stroke, type of stroke, and predictors of stroke associated with ISH and BISH and how this risk compares with that for persons with diastolic hypertension and normotension. Methods We used the 20-year follow-up data for adults aged 25 to 74 years who participated in the First National Health and Nutrition Examination Survey Follow-Up Study to determine the aforementioned risks. Blood pressure (BP) measurements of the participants were obtained during baseline evaluation. ISH was defined as systolic BP 160 mm Hg and diastolic BP 90 mm Hg. BISH was defined as systolic BP between 140 and 159 mm Hg and diastolic BP 90 mm Hg. Diastolic hypertension was defined as a diastolic BP 90 mm Hg. Normotension was defined as systolic BP 140 mm Hg and diastolic BP 90 mm Hg. Incidence of stroke overall and incidence of ischemic stroke and intracerebral hemorrhage were determined from a review of hospital records and death certificates. Relative risk (RR) of stroke and stroke type in association with each hypertensive category was determined by Cox proportional hazards analysis after adjustment for potential confounding variables. Results Among the participants, hypertension was categorized as ISH (n 493), BISH (n 1241), and diastolic hypertension (n 3954). Normotension was observed in 6656 persons. After adjustment for differences in age, sex, education, serum cholesterol level, body mass index, diabetes mellitus, and cigarette smoking, a significantly higher RR for all strokes was observed in participants with ISH (RR, 2.7; 95% CI, 2.0 to 3.4) and BISH (RR, 1.4; 95% CI, 1.1 to 1.8) than those with normotension. The risk was significantly higher for ischemic stroke or intracerebral hemorrhage in persons with ISH and BISH. Among the 1734 persons with either ISH or BISH, the risk of stroke was independently associated with older age, diabetes mellitus, and systolic BP 180 mm Hg. Conclusions Increased risks for stroke, ischemic stroke, and intracerebral hemorrhage were observed in patients with BISH, similar to those associated with ISH and diastolic hypertension. Future clinical trials are required to evaluate the effect of antihypertensive treatment in younger patients with BISH and ISH. (Stroke. 2002;33: ) Key Words: hypertension intracerebral hemorrhage stroke stroke, ischemic Acommon belief among patients and some practitioners is that elevated diastolic pressure is more important than elevated systolic pressure. However, recent evidence suggests the importance of systolic blood pressure in determining the risks of myocardial infarction and stroke. 1 3 Two important categories of systolic hypertension have been recognized, which include isolated systolic hypertension (ISH) and borderline isolated systolic hypertension (BISH). ISH is characterized by reduced vascular compliance, often in combination with increased peripheral resistance. In absolute terms, ISH is defined as an elevated systolic blood pressure 160 mm Hg and a normal diastolic blood pressure ( 90 mm Hg). 2,3 BISH was introduced as a category of hypertension by the Joint National Committee in and further emphasized in and in reports on detection, evaluation, and treatment of high blood pressure. The entity was further stressed in the World Health Organization guidelines. 7 BISH is defined as systolic blood pressure between 140 and 159 mm Hg and normal diastolic blood pressure ( 90 mm Hg). 4 The prevalence of systolic hypertension varies, depending on the population screened. In the Hypertension Detection and Follow-Up Program, 8 blood pressures Received April 1, 2002; final revision received June 24, 2002; accepted July 10, From the Department of Neurosurgery, State University of New York at Buffalo (A.I.Q., M.F.K.S., L.R.G., L.N.H.), and Department of Neurology, Ohio State University, Columbus (Y.M.M.). Reprint requests to Adnan I. Qureshi, MD, Department of Neurosurgery, State University of New York at Buffalo, 3 Gates Circle, Buffalo, NY aiqureshi@hotmail.com 2002 American Heart Association, Inc. Stroke is available at DOI: /01.STR F 2781

2 2782 Stroke December 2002 were measured in individuals from 14 communities throughout the United States during The measurements were obtained at the homes of these individuals. Of the total population screened, 2.4% had ISH (systolic blood pressure 160 mm Hg and diastolic blood pressure 90 mm Hg). ISH was present for 0.5% of those aged 30 to 39 years and 6.8% of those aged 60 to 69 years. The prevalence of ISH was greater in blacks and women than in both whites and men. The prevalence of ISH was 5.3% in white men, 6.4% in black men, 7.4% in white women, and 8.3% in black women. In an analysis of 30-year follow-up data from the Framingham Study, Wilking et al 9 reported that ISH occurred in 14% of men and 23% of women aged 65 years and accounted for 57% of all hypertensive conditions in men and 65% in women. Although the risk of stroke overall and according to type and subtype has been evaluated in some clinical trials involving participants with ISH, the long-term natural history of ISH and BISH has not been determined, particularly in younger age groups. We used 20-year follow-up data from the first National Health and Nutrition Examination Survey (NHANES I) Epidemiological Follow-Up Study (NHEFS) to determine the risks of stroke and types of stroke that are associated with ISH and BISH. For a comparative analysis, we estimated the risk of these outcomes in patients with diastolic hypertension and normotension. We also evaluated the factors that increase the risk of stroke in patients with these hypertensive conditions. Subjects and Methods NHANES I was conducted by the National Center for Health Statistics of the Centers for Disease Control and Prevention during to collect health-related information on a probability sample of the civilian, noninstitutionalized population in the United States A sample of approximately persons aged between 1 and 74 years was included. The NHANES I was designed so that certain population groups considered at high risk of malnutrition (such as the elderly, those living in poverty areas, and women of child-bearing age) were oversampled at preset rates. Adjusted sampling weights were computed within 60 age/sex/race categories to inflate the sample to closely reflect the US civilian noninstitutionalized population at the midpoint of the survey. A subset of NHANES I participants who were between the ages of 25 and 74 years (at the time of the baseline survey) received a more detailed health examination. The NHEFS comprised a series of studies to provide follow-up data on these NHANES I participants. The NHEFS included 4 periods of follow-up: , 1986, 1987, and The first wave of data collection was performed during It included tracing the cohort; conducting personal interviews with subject or proxy; measuring pulse rate, weight, and blood pressure of surviving participants; collecting hospital and nursing home records of overnight stay; and collecting death certificates of decedents. Subsequent follow-up of the NHEFS was conducted with the same design and data collection procedures except that a 30-minute computer-assisted telephone interview was administered in place of a personal interview and no physical measurements were made. Tracing and data collection in the NHEFS were very high, with 94% of the study population traced for each completed wave of follow-up. The interview rates ranged from 91% to 96% of the participants traced. By the end of the 1992 NHEFS survey period, 90% of the subjects not reported dead in previous surveys had been successfully traced. 15 Approximately 32% of the NHEFS cohort was known to be deceased, with a death certificate available for 98% of the 4604 NHEFS decedents. An analysis was performed to determine the effect of age at baseline evaluation on loss to follow-up. Age at baseline was categorized into five 10-year age groups. Rates of loss to follow-up were highest for participants aged 45 years (14%) and decreased for subsequent age categories (5% and 6% for participants aged 45 to 64 years and 65 years, respectively). Definitions of Stroke Events and Stroke Types Participants were considered to have experienced a stroke event if they were hospitalized or died during the 20-year follow-up period with primary diagnoses categorized by codes 431 to or 437 to according to the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). Our definition of stroke event included both ischemic and hemorrhagic events but not transient ischemic events (ICD-9-CM code 435). ICD-9-CM codes were assigned on the basis of the underlying cause of death listed on the participant s death certificate. Stroke events were further classified as intracerebral hemorrhage in participants with ICD-9-CM codes 431 to or as cerebral infarction in those with codes 433 to or 436 to Definitions of Hypertensive Conditions Blood pressure status was categorized on the basis of measurements obtained at physical examination during the NHANES I baseline clinical evaluation. One blood pressure measurement was obtained from all participants in a sitting position and was used for the present analysis. ISH was defined as systolic blood pressure 160 mm Hg and diastolic blood pressure 90 mm Hg. BISH was defined as systolic blood pressure 140 mm Hg and 160 mm Hg and diastolic blood pressure 90 mm Hg. Diastolic hypertension was defined as diastolic blood pressure 90 mm Hg. Normotension was defined as systolic blood pressure 140 mm Hg and diastolic blood pressure 90 mm Hg. A subset of persons (n 6844) evaluated in the NHANES I baseline survey had 3 consecutive blood pressure measurements performed. We determined the correlation between single blood pressure recordings with the average of 3 consecutive blood pressure recordings. Pearson product-moment coefficient was used to test this correlation with the use of JMP statistical software (SAS Institute Inc). A high correlation coefficient of 0.95 and 0.92 for systolic and diastolic blood pressure, respectively, was observed between single recording and average of multiple recordings. Study Variables Known cerebrovascular risk factors that were identified as potential confounding variables in our study of the association between hypertensive conditions and stroke events were age, sex, race/ ethnicity (black, white, other), educational attainment ( 12 years, 12 years), serum cholesterol level ( 200 mg/dl, 200 mg/dl), body mass index (calculated as weight in kilograms divided by the square of the height in meters), diabetes mellitus, and cigarette smoking (never, former, and current). All measurements were obtained prospectively during the NHANES I baseline interview. Information regarding the status of cigarette smoking was obtained from the 1982 follow-up. Socioeconomic data and smoking status were self-reported. Diabetes mellitus was determined from the patient s report of a physician s diagnosis. Trained examiners measured the height and weight of each participant during the NHANES I physical examination. Statistical Analyses Because the duration of follow-up varied among the participants, Cox proportional hazard analysis was used to estimate the relative risk (RR) for stroke and stroke types. We included all patients in the analysis and censored the data for patients who died from noncardiovascular deaths at the time of death. RR for stroke and stroke types for each type of hypertension was estimated after adjustment for the established cerebrovascular risk factors. The Cox proportional hazard model was adjusted for differences in age, sex, race/ethnicity, education, cigarette smoking, serum cholesterol level, diabetes mellitus, history of myocardial infarction, and body mass index. In the present model age was dichotomized at 60 or 60 years. The cutoff for dichotomization is based on the age definitions

3 Qureshi et al ISH and BISH and Stroke Risk 2783 TABLE 1. Baseline Characteristics of Participants According to Blood Pressure Status Characteristics Diastolic Hypertension (n 3954) Isolated Systolic Hypertension (n 493) Borderline Isolated Systolic Hypertension (n 1241) Normotension (n 6656) Age, y * * * Sex Men 1924 (49) 179 (36) 535 (43) 2425 (36) Women 2030 (51)* 314 (64) 706 (67)* 4231 (64) Race/ethnicity White 3151 (80) 401 (81) 1079 (87) 5909 (89) Black 770 (19)* 88 (17)* 149 (12) 683 (10) Other 33 (1) 4 (2) 13 (1) 64 (1) Diabetes mellitus Yes 157 (40)* 51 (10)* 74 (6)* 110 (2) Data unavailable 866 (22) 49 (10)* 183 (15)* 1550 (23) No 2931 (38) 393 (80) 984 (79) 4996 (75) Smoking status Current 633 (16)* 32 (6)* 161 (13)* 1755 (26) Former 1211 (31) 136 (28)* 402 (32) 1780 (27) Never 2110 (63) 325 (66) 678 (55) 3121 (47) Education 12 years 1833 (46) 172 (35) 530 (43) 4430 (67) 12 years 2121 (54)* 321 (65)* 711 (57)* 2226 (33) Mean body mass index, kg/m * * * Alcohol Use Frequent 597 (15) 61 (12)* 174 (14)* 754 (11) Infrequent 1601 (40)* 128 (26)* 425 (34)* 3445 (52) None 1756 (45) 304 (62) 642 (52) 2457 (37) Mean cholesterol, mg/dl * * * Values are frequency (percentage) for categorical variables and mean SD for continuous variables. *P value 0.05 using chi-square method or ANOVA. used by previous clinical trials evaluating the effect of treated and untreated hypertension on cardiovascular diseases The data regarding diabetic status were unavailable for a large proportion of participants. The exact relationship between this category of diabetes and stroke is undefined and probably not comparable to participants either with or without documented diabetes mellitus. Therefore, we entered the variable of diabetes mellitus as absent, present, or unknown. A second logistic regression analysis was performed without including serum cholesterol levels in the model. This analysis was performed because serum cholesterol levels may be associated with ischemic stroke but not with intracerebral hemorrhage. 19 Furthermore, an inverse association has been suggested between serum cholesterol levels and intracerebral hemorrhage. 20 Because the exclusion of serum cholesterol levels from the model did not affect the results, the results of the analysis including serum cholesterol levels are presented. All the variables were entered in the model simultaneously to adjust for the potential confounding effect of each variable. A separate Cox proportional hazards analysis was performed to evaluate the effect of the following variables: age, sex, absolute measurement value of systolic and diastolic blood pressure, diabetes mellitus, smoking, serum cholesterol, body mass index, and use of antihypertensive medication on risk of stroke in participants with ISH or BISH. A subset analysis was performed in patients with diastolic hypertension to determine the effect of systolic blood pressure on the risk of stroke compared with normotensive persons. The multivariate-adjusted risk of stroke was analyzed for different levels of systolic blood pressure ( 120, 121 to 150, 151 to 180, and 180 mm Hg). A probability value of 0.05 was considered significant. All analyses were performed with the use of SPSS. Results A total of persons aged 25 to 74 years underwent an interview and examination during the NHANES I baseline survey. A total of 1697 persons were lost to follow-up. Another 366 participants were excluded from the present analysis because of history of stroke or intracerebral hemorrhage (n 299) or unavailability of blood pressure readings (n 67). Those who died from causes other than stroke (n 2738) were censored at the time of death and included in the analysis. Among the total participants included in the analysis (n ), hypertension was categorized as ISH (n 493), BISH (n 1241), and diastolic hypertension (n 3954). Normotension was observed in 6656 persons. During the 20-year follow-up period, stroke events occurred in 825 participants (7%). The rates of ischemic stroke and intracerebral hemorrhage were 745 (6%) and 198 (2%), respectively (118 participants had experienced both types of stroke events). Baseline characteristics of the participants according to blood pressure status are provided in Table 1. Participants with normotension were more likely to be younger and to have attained higher levels of education ( 12

4 2784 Stroke December 2002 TABLE 2. Age-Adjusted and Multivariate-Adjusted Relative Risks of Stroke, Ischemic Stroke, and Intracerebral Hemorrhage Participants Sample Size No. of Strokes Stroke Rate per 100 Age-Adjusted RR (95% CI) Multivariate-Adjusted RR (95% CI) All strokes Normotension Reference Reference Diastolic hypertension ( ) 1.9 ( ) ISH ( ) 2.7 ( ) BISH ( ) 1.4 ( ) Ischemic stroke Normotension Reference Reference Diastolic hypertension ( ) 1.9 ( ) ISH ( ) 2.7 ( ) BISH ( ) 1.4 ( ) Intracerebral hemorrhage Normotension Reference Reference Diastolic hypertension ( ) 2.4 ( ) ISH ( ) 3.1 ( ) BISH ( ) 2.1 ( ) Multivariate-adjusted for age, sex, race, body mass index, smoking, alcohol use, cholesterol level, education, history of myocardial infarction, and diabetes mellitus. RR indicates relative risk; ISH, isolated systolic hypertension; BISH, borderline isolated systolic hypertension. years) than those with ISH, BISH, or diastolic hypertension. Moreover, the mean body mass index and mean serum cholesterol levels were lower in the normotensive cohort than in participants with ISH, BISH, or diastolic hypertension. Diabetes mellitus was more frequent in patients with diastolic hypertension. Table 2 provides the stroke rates and age- and multivariate-adjusted RRs of all strokes, ischemic stroke, and intracerebral hemorrhage according to blood pressure status. Participants with ISH, BISH, or diastolic hypertension were 3 to 6 times more likely to have strokes than those with normotension. The stroke rate was 2 times higher in persons with ISH than in those with either BISH or diastolic hypertension. A significantly higher RR for all strokes was observed in participants with ISH (RR, 2.7; 95% CI, 2.0 to 3.4) and BISH (RR, 1.4; 95% CI, 1.1 to 1.8) compared with normotensive persons after adjustment for confounding factors through multivariate analysis. An increased RR for both ischemic stroke and intracerebral hemorrhage was found in persons with ISH, BISH, and diastolic hypertension compared with those with normotension. Table 3 demonstrates the factors that contributed to increased risk for all strokes among participants with ISH or BISH (n 1734). The risk of stroke was higher in persons aged 45 to 64 years and those aged 65 years than in those aged 45 years. Other independent variables associated with risk of stroke were diabetes mellitus (RR, 2.1; 95% CI, 1.4 to 3.3) and systolic blood pressure 180 mm Hg (RR, 2.4; 95% CI, 1.5 to 4.0). Regular or occasional use of antihypertensive medication was not associated with the risk of stroke. In the subset analysis including patients with diastolic hypertension, there was a stepwise increase in the risk for stroke with higher systolic blood pressure. Compared with normotensive patients, the multivariate-adjusted risk of stroke for each category of systolic blood pressure was as follows: 120 mm Hg: RR, 1.0 (95% CI, 0.5 to 2.3); 121 to 150 mm Hg: RR, 1.5 (95% CI, 1.2 to 1.9); 151 to 180 mm Hg: RR, 2.2 (95% CI, 1.8 to 2.7); and 180 mm Hg: RR, 3.1 (95% CI, 2.4 to 4.0). Discussion Our analysis showed that each category of hypertension represented in this study confers an increased risk for stroke, including both ischemic stroke and intracerebral hemorrhage. ISH appeared to pose the highest risk for both types of stroke events. The stroke risk for persons with BISH appears to approximate that for persons with diastolic hypertension. Our analysis also identified characteristics in persons with ISH or BISH that are associated with an increased risk of stroke. ISH as a Risk Factor for Stroke Kannel et al 21 reported prospective data from the Framingham Study relating systolic and diastolic blood pressure, pulse-wave configuration, and patient age to future stroke incidents. Subjects with ISH experienced 2 to 4 times as many strokes as did normotensive persons. Although diastolic blood pressure was related to stroke in subjects with systolic hypertension, the diastolic component added little to the risk assessment in men and was unrelated to the overall incidence of stroke. Systolic pressure seemed to be the more potent contributor of stroke. The Copenhagen City Heart Study, 22 a prospective population survey, evaluated the prevalence of ISH and associated risk of major cardiovascular events. The risk of stroke and myocardial infarction in association with ISH was assessed in 6621 subjects aged 50 years who were not receiving antihypertensive or cardiac medicine and had no history of stroke or myocardial infarction. The prevalence of ISH showed an age-related increase from 3% in 55-year-

5 Qureshi et al ISH and BISH and Stroke Risk 2785 TABLE 3. Predictors of Stroke in Isolated and Borderline Isolated Systolic Hypertension Variables No. of Participants (%) Multivariate-Adjusted RR (95% CI) P Value Age (12) Reference (27) 4.7 ( ) (61) 15.1 (4.7 48) Sex (men) 714 (41) 1.2 ( ) 0.2 Race White 1480 (85) Reference Black 237 (14) 1.2 ( ) 0.4 Other 17 (1) Smoking Current 193 (11) 0.9 ( ) 0.8 Former 538 (31) 1.3 ( ) 0.08 Diabetes mellitus Present 125 (7) 2.1 ( ) 0.01 Unknown 232 (13) Antihypertensive medication use Regular 272 (16) 1.3 ( ) 0.2 Occasional 32 (2) 1.9 ( ) 0.1 Unknown 234 (13) Serum cholesterol ( 200 mg/dl) 1340 (77) 1.2 ( ) 0.3 Body mass index ( 30 kg/m 2 ) 305 (18) 1.2 ( ) 0.3 Education ( 12 years) 1032 (60) 1.2 ( ) 0.3 Systolic BP (80) Reference (16) 1.3 ( ) (4) 2.4 ( ) Diastolic BP (88) Reference (10) 1.4 ( ) (2) 1.8 ( ) 0.4 RR, relative risk; BP, blood pressure. old subjects to 13% in 72-year-old subjects. The RR of stroke after adjustment for other risk factors was 3.0 (95% CI, 1.6 to 5.3) for women and 2.7 (95% CI, 1.8 to 4.3) for men. This was the highest RR among all hypertensive groups. The population-attributable risk for stroke associated with ISH was estimated as 30%. The risk of death from coronary heart disease, stroke, all cardiovascular disease, and all-cause mortality associated with ISH among the middle-aged population was determined in men and women aged 25 to 64 years without history of myocardial infarction or stroke over a 15-year follow-up period. 23 Coronary heart disease, stroke, cardiovascular disease, and mortality from all causes among men and women aged 45 to 64 years increased with increasing levels of systolic blood pressure. Among women aged 45 to 64 years, ISH increased the RR of these fatal events. Among men aged 45 to 64 years, only deaths related to coronary heart disease were significantly associated with ISH. Petrovitch et al 24 examined the prevalence of ISH in a population of 8006 Japanese-American men aged 45 to 68 years and compared rates of stroke among those with ISH, isolated diastolic hypertension, combined systolic-diastolic hypertension, and normotension. Men with ISH had the highest rates of stroke, followed by men with systolic-diastolic hypertension. Men with isolated diastolic hypertension had rates only slightly higher than those of men in the normotension group. RR adjusted for other risk factors varied by age group. For men aged 45 to 54 years, RRs of stroke for subjects with ISH, isolated diastolic hypertension, and systolic-diastolic hypertension (compared with normotensive subjects) were 4.8, 1.4, and 4.3, respectively. For men aged 55 to 68 years, the same RRs were 1.2, 1.8, and 1.7. Borderline Isolated Systolic Hypertension In a follow-up analysis of the Framingham Study, Sagie et al 25 reported on 2667 subjects. During 34 years of monitor-

6 2786 Stroke December 2002 ing, cardiovascular disease events occurred in 1010 subjects, congestive heart failure in 228, and death in After adjustment for age, sex, and cardiovascular risk factors, subjects with BISH (according to blood pressure measurements at baseline examination) had an excess risk of cardiovascular disease (hazard ratio, 1.47; 95% CI, 1.24 to 1.74) and death from cardiovascular disease (hazard ratio, 1.57; 95% CI, 1.24 to 2.00) compared with normotensive subjects. They were also at significantly higher risk for coronary artery disease (hazard ratio, 1.44), stroke and transient ischemic attacks (hazard ratio, 1.42), and congestive heart failure (hazard ratio, 1.60). Impact of Antihypertensive Treatment Recent clinical trials demonstrate the importance of treatment of ISH and risk reduction for stroke and other cardiovascular diseases in the elderly. 16,17 Staessen et al 26 performed a quantitative overview of 8 clinical trials to evaluate the risk associated with systolic blood pressure in treated and untreated elderly patients ( 60 years) with ISH. In these trials, participants with ISH were followed up for 3 to 8 years. Various antihypertensive medications were used to treat ISH. These included thiazides, calcium channel blockers, a combination of thiazide and triamterene, -blockers, and thiazide in combination with either amiloride or a -blocker. Among 7757 placebo-treated patients, major cardiovascular complications occurred in 835 (10.8%) and death occurred in 734 (9.5%) persons. Among 7936 patients who received pharmacological treatment, major complications occurred in 647 (8.1%) and death occurred in 656 (8.3%) persons. Pharmacological treatment of ISH reduced total mortality by 13%, cardiovascular mortality by 18%, all cardiovascular complications by 26%, stroke by 30%, and coronary events by 33%. We observed that in patients with BISH or ISH, antihypertensive treatment did not affect the risk for stroke. This finding may be secondary to treated hypertensives having had years of uncontrolled hypertension. Giles et al, 27 in an analysis of the NHANES I cohort, observed that among persons with a blood pressure 140/ 90 mm Hg, persons who were receiving medication had a mean blood pressure of 164/94 mm Hg, while persons who reported not taking medication had a mean blood pressure of 152/92 mm Hg. The lack of beneficial effect of antihypertensive medication is probably attributable to the presence of more severe hypertension in treated patients. Stroke Types and Subtypes and ISH We observed that the risk of either ischemic stroke or intracerebral hemorrhage is higher in persons with ISH and BISH. In a subgroup analysis in the Systolic Hypertension in the Elderly Program (SHEP), Perry et al 28 evaluated the incidence of stroke types and subtypes in 4736 men and women aged 60 years with ISH from 16 clinical centers in the United States. Participants were randomly assigned to receive treatment with either chlorthalidone (12 mg daily), chlorthalidone (same dose) with atenolol (25 mg daily) or reserpine (0.05 mg daily), or a placebo. They were followed for an average period of 4.5 years. A total of 85 and 132 participants in the active treatment and placebo groups, respectively, had ischemic stroke; 9 and 19 participants, respectively, had hemorrhagic strokes. A significant reduction was observed in the risk for ischemic and hemorrhagic stroke in the active treatment group. No significant difference was observed in the risk for stroke of unknown type. Among patients with ischemic stroke, a significant reduction was observed in the RR for ischemic strokes classified as lacunar and undetermined. The RR was not significantly different for embolic and atherosclerotic ischemic stroke. ISH appeared to have a stronger association with both ischemic stroke and intracerebral hemorrhage compared with BISH and diastolic hypertension (Table 2). No clear evidence exists to support a differential effect of ISH and diastolic hypertension in predisposing to ischemic or hemorrhagic stroke. Davis et al 29 determined the risk factors for stroke and stroke subtype in the SHEP trial. In the multivariate analysis, higher systolic blood pressure was associated with an increased risk for stroke and ischemic stroke. No definite relationship could be demonstrated between systolic blood pressure and hemorrhagic stroke, atherosclerotic ischemic stroke, lacunar ischemic stroke, or embolic stroke. However, the analysis was limited because of the small number of patients in each of the outcome categories. A report of a combined analysis of 13 cohorts from eastern Asia reported the effect of baseline diastolic pressure on risk of ischemic and hemorrhagic stroke in participants with person-years of observation. 19 Logistic regression analyses demonstrated a somewhat stronger association between diastolic blood pressure and hemorrhagic stroke in comparison with ischemic stroke. Persons With ISH and BISH at Risk for Stroke We found a higher risk of stroke among participants with ISH or BISH aged 45 years. Other persons at higher risk included diabetics, and those with systolic blood pressures 180 mm Hg. Previous studies have recognized the prognostic importance of age and diabetes mellitus for determining the risk of stroke among patients with ISH. Davis et al 29 performed proportional hazards analyses of data from the SHEP to determine risk factors for stroke and stroke type in persons with ISH. During an average follow-up of 4.5 years, 384 strokes or transient ischemic attacks and 262 strokes (including 217 ischemic, 66 lacunar, 26 atherosclerotic, and 25 embolic strokes) were documented. The authors concluded that in older persons with ISH, history of diabetes and smoking are important risk factors for lacunar stroke, whereas carotid bruit and age are important risk factors for atherosclerotic and embolic stroke, respectively. In the SHEP pilot project, Siegel et al 30 examined the effect of known cardiovascular risk factors in younger persons to see whether they were applicable in an elderly population. They prospectively followed up 551 men and women aged 60 years and who had pretreatment systolic blood pressures 160 mm Hg and diastolic blood pressures 90 mm Hg. After adjustment for confounding variables, age, level of education, history of cardiovascular event, and smoking remained significant predictors of a first-time cardiovascular event. We did not find a relationship between diastolic blood pressure and risk of stroke. In a subgroup analysis of the 4736 participants in

7 Qureshi et al ISH and BISH and Stroke Risk 2787 SHEP, Somes et al 31 found, for persons with ISH, that a decrease of 5 mm Hg in diastolic BP increased the risk for stroke (RR, 1.14), coronary heart disease (RR, 1.08), and cardiovascular disease (RR, 1.11). Issues Related to Data Interpretation We used the blood pressure recording from baseline evaluation to define various forms of hypertension. Blood pressure is not static but rather a continuous variable that changes from minute to minute. 32 Therefore, casual blood pressure readings represent a minute part of the entire 24-hour circadian blood pressure pattern. In addition, some patients may manifest a transient stress response when blood pressure is measured in the presence of a medical professional (white coat hypertension). Perloff et al 33 evaluated 1076 persons with both office and ambulatory blood pressure measurements. The ambulatory measurements were obtained with a semiautomatic patient-activated portable device (10 to 40 measurements per patient over 1 to 2 days). The ambulatory blood pressure measurements were lower than office measurements in 78% of the patients. The effect of this overestimation by office blood pressure measurement was most prominent in women and persons with borderline hypertension. The relationship between the measurements generated by these 2 methods correlated in a linear manner. Our use of a single blood pressure measurement to define various forms of hypertension may have led to inclusion of nonhypertensive patients in the BISH category. Because of the presence of normotensive persons, the actual risk of stroke in persons with BISH may be higher than that determined in our study. We used International Classification of Diseases, Ninth Revision (ICD-9) codes from discharge abstracts and death certificates to identify incident cases of stroke and stroke subtypes. Broderick et al 34 determined the accuracy and yield of ICD-9-CM codes for cases of stroke and transient ischemic attack in a population-based study. The ICD-9 diagnoses were compared with the diagnoses made by the study neurologist after review of clinical and radiographic information for each potential case. When primary discharge diagnoses of ICD-9-CM codes 430 to 436 were used, the true positive rate was 83% and the yield of cases of stroke and transient ischemic attack was 84%. The validity of death certificate diagnosis of stroke and its type as the underlying cause of death was investigated in a sample of in-hospital deaths of possible stroke cases from the Minnesota Heart Survey. 35 Relative to a standardized physician diagnosis, positive predictive values for the death certificate diagnosis were 100% for all types of stroke, 82% for intracranial hemorrhage, and 97% for nonhemorrhagic stroke. On the basis of results of previous population-based studies, we think that hospital discharge or death certificate diagnoses are sufficiently accurate to justify their use in epidemiologic studies. Probably most important, the validity of ICD-9 diagnoses does not differ by strata defined by blood pressure. The follow-up rates differed by age, with the lowest tracing rate observed in participants aged 45 years. Because the majority of strokes occur among older adults, participants lost to follow-up could not have substantially biased the results presented in this report. Conclusions We observed that BISH is a category of hypertension that is associated with an increased risk of stroke, ischemic stroke, and intracerebral hemorrhage, which is similar to that associated with ISH and diastolic hypertension. The increased risk of stroke was also observed in the younger group of participants (aged 45 to 64 years) who had systolic hypertension. 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