Abstract
Background
Prior estimates of lifetime risk (LTR) for cardiovascular disease (CVD) examined the impact of blood pressure at the index age and did not account for changes in blood pressure over time. We examined how changes in blood pressure during middle-age affect LTR for CVD, coronary heart disease (CHD) and stroke.
Methods and Results
Data from 7 diverse US cohort studies were pooled. Remaining LTR for CVD, CHD and stroke were estimated for White and Black men and women with death free of CVD as a competing event. LTR for CVD by blood pressure (BP) strata and by changes in BP over an average of 14 years were estimated. Starting at age 55, we followed 61,585 men and women for 700,000 person-years. LTR for CVD was 52.5% (95% CI 51.3–53.7) for men and 39.9% (38.7–41.0) for women. LTR for CVD was higher for Blacks and increased with increasing BP at index age. Individuals who maintained or decreased their BP to normal levels had the lowest remaining LTR for CVD, 22–41%, as compared to individuals who had or developed hypertension by the age of 55, 42–69%; suggesting a dose-response effect for the length of time at high BP levels
Conclusions
Individuals who experience increases or decreases in BP in middle age have associated higher and lower remaining LTR for CVD. Prevention efforts should continue to emphasize the importance of lowering BP and avoiding or delaying the incidence of hypertension in order to reduce the LTR for CVD.
Keywords: cardiovascular disease, coronary heart disease, stroke, hypertension, risk factors
Introduction
Cardiovascular disease (CVD) is responsible for over one third of all deaths in the United States.1 Although CVD mortality rates have decreased over the past four decades, it remains the leading cause of death and one of the top causes of functional disability.1 Given the burden of cardiovascular disease, further efforts are needed to improve cardiovascular disease prevention. Clinical practice guidelines focused on prevention have recommended developing lifetime risk estimates as a method for improved long-term prediction for individuals, better estimation of the burden in the population and more appropriate comparisons of risk between diseases.2–3 In addition, lifetime risk estimates appear to be particularly useful in education campaigns as they may be more easily understood than traditional epidemiologic measures.3–4
The lifetime risk for CVD among Caucasians has been estimated to be 1 in 2 for men and 1 in 3 for women.5 Data from a single cohort with a limited number of blacks suggest that black men and women have lifetime risks for CVD death at least as high as whites of the same sex.6 In addition, the lifetime risk for CVD increases with increasing risk factor burden.6–7 Blood pressure represents one of the most important modifiable risk factors for cardiovascular disease. The lifetime risk for CVD, particularly stroke, increases dramatically with increasing blood pressure for both Blacks and Whites such that the remaining lifetime risk for CVD was twice as high among individuals with stage 2 hypertension in middle age as compared to those with optimal blood pressure levels.7
Previous studies of the lifetime risk for CVD have been limited to single measures of blood pressure during middle-age.8 However, in order to be more useful for individualized risk prediction and communication, detailed, risk-factor-specific lifetime risk estimates must be developed.4 Systolic blood pressure generally increases linearly with age and individuals with higher systolic blood pressure experience the largest increases.9 However, little is known about how changes in blood pressure during middle-age may affect the lifetime risk for CVD. Accordingly, we examined the impact of blood pressure at specific ages, and blood pressure change over > 10 years, on the lifetime risk for all CVD as well as for fatal and non-fatal coronary heart disease and stroke among Black and White men and women in the Lifetime Risk Pooling Project.
Methods
Study Sample
Data for this study came from the Cardiovascular Lifetime Risk Pooling Project. Detailed methods for the Pooling Project have been previously published.7 In brief, data from 17 US epidemiologic cohort studies were pooled to create the Cardiovascular Lifetime Risk Pooling Project. All cohorts had to meet several criteria: 1) community- or population-based sampling or large volunteer cohort; 2) availability of at least one baseline examination at which participants provided demographic, personal and medical history information and underwent direct measurement of physiologic and/or anthropometric variables (e.g., blood pressure, weight); 3) longitudinal follow-up of at least 10 years with complete or near-complete ascertainment of vital status; and 4) availability of cause-specific or cardiovascular mortality data with or without ascertainment of non-fatal cardiovascular events. Because one of the chief aims of the Cardiovascular Lifetime Risk Pooling Project is to compare lifetime risks between different race/ethnic groups, we specifically sought to obtain data from cohort studies that included non-white race/ethnic groups. We did not include cohorts of individuals that participated in clinical trials, had only self-report of risk factors for important covariates without direct physical examination by study investigators, or had few deaths or events.
Datasets which included all cardiovascular outcomes including fatal and non-fatal stroke were included in this study. These cohorts include the Atherosclerosis Risk in Communities (ARIC) Study, Framingham Heart Study, Framingham Offspring Study, Honolulu Heart Program, Kaiser Permanente Study of the Oldest Old, Cardiovascular Health Study, and the Women’s Health Initiative Observational Study. Limited access datasets were obtained from the National Heart, Lung and Blood Institute for Atherosclerosis Risk in Communities (ARIC) Study,10 Framingham Heart Study (FHS),11 Framingham Offspring Study (FOS),12 and Honolulu Heart Program (HHP).13–14 Data from the Kaiser Permanente Study of the Oldest Old15 were obtained from the Inter-University Consortium for Political and Social Research at the University of Michigan [http://www.icpsr.umich.edu/ICPSR/index.html]. Complete datasets were obtained directly by agreement from the Cardiovascular Health Study (CHS)16 and Women’s Health Initiative Observational Study (WHI-OS)17 investigators. After obtaining all of the data, variables of interest from each dataset were cleaned and renamed using a standardized protocol to allow for ease of use in the pooling project analyses. Given that data were obtained from cohort studies spanning 6 decades from the 1940s to the 2000s, there were differences between studies in measurement techniques. Whenever possible, values obtained using the most similar techniques were used for analyses. All data were appropriately de-identified and all study protocols and procedures were approved by the IRB at Northwestern University.
Blood Pressure Measures
For all cohorts except the Kaiser Permanente Study blood pressure was recorded as the average of 2 or 3 seated measurements taken by trained study personnel on manual mercury sphygnomanometers (Supplemental Table 1). Blood pressure data for participants of the Kaiser Permanente Study of the Oldest Old were taken from clinical measurements recorded in the participants’ medical record. Participants were grouped according to their index blood pressure as measured within five years of each index age. For example, blood pressures measured between ages 40 and 50 were included in the analyses for index age 45. According to JNC VII18 criteria, the average of at least 2 blood pressure measurements was categorized as follows: normal - <120/<80 mm Hg untreated; prehypertension – untreated with medication systolic blood pressure 120 – 139 or diastolic blood pressure 80 – 89 mm Hg; stage 1 hypertension – untreated with medication systolic blood pressure 140 – 159 or diastolic blood pressure 90 – 99 mm Hg; and stage 2 or treated hypertension - systolic blood pressure ≥160 or diastolic blood pressure ≥100 mm Hg or treated with antihypertensive medication. The prevalence of hypertension treatment in this study is low due to the time period during which these cohorts were initiated. In addition, although the risk for CVD is reduced for hypertensive individuals who receive anti-hypertensive medication, their risk remains higher than individuals with untreated, ideal blood pressure levels.19 Therefore, in order to be conservative we included treated individuals in the highest risk group.
Blood pressure changes were examined among individuals who had at least two separate blood pressure measurements separated by 10 years or more. The baseline blood pressure measurement had to have been after the age of 20 and at least 10 years prior to the blood pressure measurement at the index age, as defined above. On average baseline blood pressure measurements were recorded 14 years prior to the index age, i.e. average age for baseline blood pressures were taken at age 41 for index age 55. In order to classify an individual’s change in blood pressure we collapsed blood pressure into three categories: normal - <120/<80 mm Hg untreated; prehypertension - untreated systolic blood pressure 120 – 139 or diastolic blood pressure 80 – 89 mm Hg; or hypertension - systolic blood pressure ≥140 or diastolic blood pressure ≥90 mm Hg or treated hypertension. Blood pressure change was categorized into 9 categories based on the change from first to second measurement.
Event Ascertainment and Definition
For all cohorts except the Kaiser Permanente Study of the Oldest Old cardiovascular disease was defined as fatal coronary heart disease, hospitalized myocardial infarction, non-hospitalized myocardial infarction, fatal and non-fatal stroke by trained physician adjudicators using all available medical records. For death events, many cohorts used linkage to the National Death Index for underlying cause of death from death certificate data, whereas others used adjudicated cause of death by study investigators after review of all available medical records and/or autopsy data. For the present analyses, deaths due to CVD (as adjudicated, or indicated by ICD-8 and ICD-9 codes 390 to 458 and ICD-10 codes I00-I99) or CHD (as adjudicated, or indicated by ICD-8 and ICD-9 codes 410 to 414 and ICD-10 codes I20-I25) were included. Non-fatal events of interest, including myocardial infarction and stroke, were obtained only from studies that adjudicated events with one exception (the Kaiser Permanente Study). Criteria for adjudication of myocardial infarction and stroke have been published for these cohorts: ARIC,10 CHS,16 FHS and FOS,20–21 HHP,22 and WHI.17. Diagnosis of myocardial infarction generally required at least two of the following criteria for diagnosis: typical chest discomfort, evolution of electrocardiographic abnormalities consistent with myocardial infarction, and serologic evidence of myocardial necrosis. For most cohorts, stroke was diagnosed as a persistent central neurologic deficit(s) lasting longer than 24 hours and unexplained by other causes, as adjudicated by trained physician adjudicators using standard criteria 10–17. In the Kaiser Permanente Study 15 incident stroke events were ascertained using hospitalization discharge codes. For this cohort, we only counted the first hospitalization for which stroke (ICD-8 and ICD-9 codes 430 to 438 and ICD-10 codes I60-I69) was the first-listed discharge diagnosis.
Statistical Analyses
Lifetime risk was calculated using a modified technique of survival analyses23–24 in which participants contribute information on the incidences of CVD, CHD and stroke for each age they attain during follow up. This approach has been used in numerous prior studies of lifetime risk.25–26 Each subject in the study was followed from study entry until the occurrence of a first CVD event, death, or attainment of age 95. Remaining lifetime risk estimates for CVD, CHD and stroke were stratified by blood pressure level and were calculated separately for Black and White men and women beginning at ages 45, 55, 65, and 75 years. Lifetime risk estimates for CVD, CHD and stroke were also stratified by change in blood pressure category for index age 55. Because of the limited number of Blacks and overall similar patterns of association with blood pressure, Blacks and Whites were combined in estimates of lifetime risk by change in blood pressure. Lifetime risks to age 85 by strata of change in blood pressure were estimated. Given the uncertainty associated with small numbers, lifetime risk estimates are only reported where adjusted person-time exceeded 100-person years at the extremes of age. All statistical analyses were performed using SAS statistical software, version 9.1 (SAS Institute, Inc., Cary, NC).
Results
Study Sample and Remaining Lifetime Risk For CVD, CHD and Stroke
A total of 61,585 men and women were followed from the age of 55 and contributed 695,394 person-years of follow-up. The number of participants, events and person years of follow-up for stroke, CHD and CVD at Index Ages 45, 55, 65 and 75 are shown in Supplemental Table 2. Given the large number of participants and years of follow-up at index age 55 and the relatively few events which occurred prior to this age, we focused our findings on the remaining lifetime risk starting at index age 55. Overall, starting at the age of 55 the remaining lifetime risk for CVD was 52.5% (95% Cl 51.3–53.7%) for men and 39.9% (38.7–41.0%) for women; for CHD was 30.9% (95% Cl 29.8–31.9%) for men and 17.5% (16.6–18.3%) for women; and for stroke was 11.2% (95% Cl 10.3–12.1%) for men and 14.7% (13.6–15.8%) for women.
Remaining Lifetime Risk by Blood Pressure at Index Age
When participants were categorized according to their blood pressure at index age 55 years, 25.7% of men and 40.8% of women had normal blood pressure; 49.4% of men and 47.5% of women had pre-hypertension, 18.1% of men and 9.6% of women had stage 1 hypertension and 6.8% of men and 2.2% of women had stage 2 or treated hypertension. The lifetime risk for CVD, CHD and stroke increased with increasing blood pressure category for both men and women (Tables 1–3; Figure 1; Supplemental Table 4). Lifetime risk for CVD by blood pressure was similar for index age 45 (Supplemental Figure 1). As shown in Table 4, the higher the blood pressure level, the younger the age at which participants reached a LTR for CVD, CHD and stroke of 8% (a measure of early burden and approximately half of the remaining lifetime risk to age 85). In general, Black women had the greatest age difference (9–21 yrs) between when the lowest and highest BP strata reached a LTR of 8%; the difference was largest for stroke. The age at which Blacks reached higher LTR was younger than for Whites at almost all blood pressure levels. These patterns were similar when cohorts were examined individually and when results were examined with and without the relatively large number of WHI participants (Supplemental Table 4).
Table 1.
Ten, Twenty, Thirty and Forty Year Cumulative Risk for CVD Adjusted for Competing Risk Starting At Index Age 55 by Gender and Race
| Cumulative Adjusted Risk (95% CI) through Specified Follow-Up Starting at Index Age 55
|
||||||||
|---|---|---|---|---|---|---|---|---|
| Men | Women | |||||||
| Whites | Through Age 65 | Through Age 75 | Through Age 85 | Through Age 95 | Through Age 65 | Through Age 75 | Through Age 85 | Through Age 95 |
| Normal Blood Pressure | 8.7 (7.6–9.8) | 21.3 (18.9–23.6) | 39.8 (35.9–43.6) | -- | 2.3 (2.1–2.6) | 9.2 (7.9–10.5) | 27.8 (24.9–30.7) | 46.1 (4.3–50.8) |
| Pre-hypertension | 9.6 (8.8–10.4) | 27.7 (26.4–29.0) | 50.8 (49.1–52.5) | 61.8 (59.7–64.0) | 3.3 (3.0–3.6) | 13.9 (13.0–14.8) | 38.1 (36.4–39.6) | 56.2 (53.9–58.6) |
| Stage 1 Hypertension | 12.4 (11.0–13.8) | 32.7 (30.7–34.7) | 57.1 (54.7–59.4) | -- | 5.2 (4.4–6.0) | 19.6 (17.9–21.3) | 45.9 (43.4–48.3) | 64.7 (61.3–68.1) |
| Stage 2 Hypertension | 15.5 (13.0–18.0) | 38.8 (35.4–42.2) | 59.3 (55.6–62.9) | -- | 9.8 (7.7–11.9) | 30.5 (27.1–33.9) | 53.7 (49.6–57.8) | -- |
| Blacks | Through Age 65 | Through Age 75 | Through Age 85 | Through Age 95 | Through Age 65 | Through Age 75 | Through Age 85 | Through Age 95 |
| Normal Blood Pressure | 11.7 (7.5–15.8) | 23.5 (15.2–31.8) | -- | -- | 5.2 (3.8–6.5) | 19.0 (11.3–26.6) | -- | -- |
| Pre-hypertension | 14.3 (11.6–16.9) | 29.9 (24.9–34.8) | 49.3 (39.8–58.8) | -- | 8.3 (7.1–9.5) | 15.2 (12.5–18.0) | 35.3 (25.8–44.8) | -- |
| Stage 1 Hypertension | 16.1 (11.5–20.7) | 38.4 (31.0–45.7) | 53.3 (44.1–62.6) | -- | 16.1 (13.0–19.2) | 34.8 (26.5–43.0) | -- | -- |
| Stage 2 Hypertension | 20.8 (13.8–27.8) | 41.2 (31.9–50.4) | -- | -- | 20.6 (15.0–26.2) | 37.1 (28.1–46.1) | -- | -- |
-- denotes limited person-years of follow-up, precluding stable estimate.
Table 3.
Ten, Twenty, Thirty and Forty Year Cumulative Risk for Stroke Adjusted for Competing Risk Starting At Index Age 55 by Gender and Race
| Cumulative Adjusted Risk (95% CI) through Specified Follow-Up Starting at Index Age 55
|
||||||||
|---|---|---|---|---|---|---|---|---|
| Men | Women | |||||||
| Whites | Through Age 65 | Through Age 75 | Through Age 85 | Through Age 95 | Through Age 65 | Through Age 75 | Through Age 85 | Through Age 95 |
| Normal Blood Pressure | 1.2 (0.8–1.7) | 3.4 (2.4–4.4) | 7.7 (5.7–9.7) | 10.8 (7.8–13.8) | 0.5 (0.4–0.7) | 2.4 (1.6–3.1) | 7.3 (5.6–8.9) | 12.8 (9.8–15.7) |
| Pre-hypertension | 1.7 (1.4–2.1) | 5.3 (4.6–6.0) | 9.7 (8.8–10.7) | 11.4 (10.2–12.6) | 0.8 (0.7–1.0) | 3.1 (2.6–3.5) | 8.3 (7.4–9.2) | 14.1 (12.6–15.7) |
| Stage 1 Hypertension | 2.4 (1.7–3.1) | 5.4 (4.4–6.4) | 9.6 (8.2–10.9) | 11.5 (9.6–13.4) | 1.7 (1.2–2.2) | 5.5 (4.5–6.5) | 11.1 (9.1–12.5) | 16.7 (14.4–19.0) |
| Stage 2 Hypertension | 3.5 (2.2–4.9) | 6.8 (5.0–8.6) | 9.1 (7.0–11.2) | -- | 4.1 (2.7–5.6) | 9.9 (7.6–9.1) | 15.8 (12.9–18.7) | -- |
| Blacks | Through Age 65 | Through Age 75 | Through Age 85 | Through Age 95 | Through Age 65 | Through Age 75 | Through Age 85 | Through Age 95 |
| Normal Blood Pressure | 3.7 (0.9–6.4) | -- | -- | -- | 1.5 (0.7–2.3) | 7.7 (1.4–14.1) | -- | -- |
| Pre-hypertension | 5.8 (3.6–7.9) | 8.2 (5.4–10.9) | 8.2 (5.4–10.9) | -- | 2.8 (2.0–3.5) | 4.5 (3.2–5.8) | 9.0 (3.8–14.2) | -- |
| Stage 1 Hypertension | 8.3 (4.4–12.3) | 13.8 (8.2–19.3) | 15.0 (9.1–21.0) | -- | 5.7 (3.6–7.9) | 7.3 (4.7–10.0) | -- | -- |
| Stage 2 Hypertension | 8.5 (2.8–14.1) | 12.1 (5.4–18.9) | -- | -- | 9.1 (4.1–14.1) | 13.2 (6.5–20.0) | -- | -- |
-- denotes limited person-years of follow-up, precluding stable estimate.
Figure 1.
Cumulative Lifetime Risk (%) of CVD, CHD and Stroke Adjusted for Competing Risk of Non-CVD Death by Blood Pressure Category for Men and Women
Table 4.
Age at Which Cumulative Lifetime Risk for CVD, CHD, and Stroke Exceeds 8% by Blood Pressure Category at Index Age 55
| Blood Pressure Category
|
||||
|---|---|---|---|---|
| Normal | Pre-hypertension | Stage 1 Hypertension | Stage 2 Hypertension | |
| Cardiovascular Disease (CVD) | ||||
| 8% LTR | ||||
| White Men | 63 | 63 | 62 | 60 |
| Black Men | 63 | 60 | 59 | 59 |
| White Women | 73 | 71 | 67 | 63 |
| Black Women | 67 | 64 | 60 | 58 |
| Coronary Heart Disease (CHD) | ||||
| 8% LTR | ||||
| White Men | 68 | 66 | 63 | 62 |
| Black Men | 68 | 66 | 65 | 65 |
| White Women | 80 | 76 | 73 | 69 |
| Black Women | -- | 81 | 72 | 63 |
| Stroke | ||||
| 8% LTR | ||||
| White Men | 86 | 82 | 82 | 79 |
| Black Men | -- | 69 | 65 | 64 |
| White Women | 87 | 85 | 80 | 71 |
| Black Women | -- | 85 | -- | 64 |
-- denotes limited person-years of follow-up, precluding stable estimate.
Blood Pressure Changes During Middle Age
Over half of all men and women remained in consistent blood pressure strata from ages 41 through 55 (Supplemental Table 3). Almost 20% of men experienced decreases in their blood pressure and 30% experienced increases prior to age 55. In contrast, almost 40% of women experienced an increase in blood pressure and only 10% experienced a decrease prior to age 55. At baseline, men tended to have higher systolic blood pressures, however, by index age 55 systolic blood pressures were higher among women due to larger increases in blood pressure observed among women during middle age. Individuals who became hypertensive during middle age experienced the largest increases in systolic blood pressure with an increase of 32 mm Hg. Women had lower diastolic blood pressures in all categories. Changes in diastolic blood pressure over middle age were similar for both men and women. Participants who experienced decreases in blood pressure during middle age had smaller increases in total cholesterol and BMI as compared to participants who maintained their BP or experienced increasing blood pressure.
Change in Blood Pressure and Remaining Lifetime Risk for Stroke
Men and women who consistently had blood pressures <120/<80 mmHg and those whose blood pressure decreased to <120/<80 mmHg over time tended to have the lowest remaining lifetime risk for CVD, CHD and stroke (Table 5). The remaining lifetime risks were similar for individuals who were consistently <120/<80 mmHg and those whose blood pressure decreased to this level. Individuals whose blood pressure increased over time prior to age 55 had higher lifetime risks compared with those whose blood pressure remained stable or decreased prior to age 55. Although findings were similar for men and women, men who had hypertension throughout middle-life experienced the highest remaining lifetime risk for stroke, while men whose blood pressure increased to hypertensive levels had the highest lifetime risks for CVD and CHD. In contrast, women whose blood pressure increased to hypertensive levels by 55 had the highest lifetime risk for stroke, but those who consistently had hypertensive levels prior to age 55 had the highest lifetime risks for CVD and CHD.
Table 5.
Cumulative Lifetime Risk for Fatal/Non-Fatal Stroke, CHD and CVD (95% CI) by Blood Pressure Categories at Baseline and Index Ages
| BP Category at Baseline (≥10 years prior to index age) | BP Category at Index Age | Remaining Lifetime Risk (95% CI) through Age 85
|
||
|---|---|---|---|---|
| Stroke | CHD | CVD | ||
| MEN | ||||
| <120/<80 | <120/<80 | 12.5 (6.4–18.6) | 24.8 (16.9–32.7) | 41.0 (31.9–50.2) |
| 120–139/80–89 | 19.8 (11.3–28.3) | 33.6 (24.2–42.9) | 52.2 (41.3–63.1) | |
| >140/>90/Rx | 23.5 (8.0–39.0) | 30.5 (16.3–44.7) | 69.0 (47.5–90.6) | |
| 120–139/80–89 | <120/<80 | 10.1 (5.1–15.2) | 24.6 (17.4–31.8) | 34.5 (26.3–42.6) |
| 120–139/80–89 | 18.4 (14.1–22.7) | 34.7 (25.3–35.3) | 50.7 (44.9–56.5) | |
| >140/>90/Rx | 19.2 (14.1–24.4) | 45.0 (38.3–51.7) | 65.3 (58.4–72.3) | |
| >140/>90/Rx | <120/<80 | -- | -- | -- |
| 120–139/80–89 | 22.6 (15.1–30.0) | 32.3 (23.9–40.8) | 59.4 (49.9–69.0) | |
| >140/>90/Rx | 23.6 (19.2–27.9) | 43.3 (38.1–48.5) | 65.3 (59.9–70.6) | |
| WOMEN | ||||
| <120/<80 | <120/<80 | 10.8 (7.0–14.7) | 5.8 (3.1–8.5) | 21.8 (16.9–26.8) |
| 120–139/80–89 | 13.6 (9.1–18.1) | 14.6 (10.1–19.1) | 34.1 (27.8–40.5) | |
| >140/>90/Rx | 26.0 (16.7–35.4) | 13.5 (6.9–20.0) | 42.2 (30.0–54.4) | |
| 120–139/80–89 | <120/<80 | 10.2 (5.3–15.1) | 12.2 (7.1–17.3) | 24.7 (17.8–31.6) |
| 120–139/80–89 | 17.6 (13.5–21.6) | 16.6 (12.7–20.5) | 38.9 (33.6–44.2) | |
| >140/>90/Rx | 22.4 (17.2–27.6) | 21.7 (16.8–26.7) | 47.2 (40.8–53.6) | |
| >140/>90/Rx | <120/<80 | -- | -- | -- |
| 120–139/80–89 | 17.8 (9.6–26.0) | 15.8 (8.3–23.3) | 36.5 (26.2–46.7) | |
| >140/>90/Rx | 19.4 (15.1–23.7) | 24.9 (20.3–29.5) | 49.4 (43.8–62.6) | |
-- denotes limited person-years of follow-up, precluding stable estimate.
Discussion
Among the cohorts included in the Lifetime Risk Pooling Project, the remaining lifetime risk for CVD was 52.5% in men and 39.9% in women. The lifetime risk for CVD was higher among Blacks compared with Whites of the same sex, and increased with increasing blood pressure at the index age. Changes in blood pressure during middle age appear to have a substantial impact on the lifetime risk for stroke. Almost 70% of all men who develop hypertension in middle age will experience a CVD event by the age of 85. Among women, those who have hypertension from ages 41 through 55 have the greatest lifetime risk for CVD, at 49.4%. Individuals who are able to maintain normal or decrease their blood pressure to normal levels during middle age have significantly lower lifetime risks for CVD, at approximately 35–40% and 22–25% for men and women, respectively.
Among the White participants of the Framingham Heart Study (ages 40–59) previous estimates for the lifetime risk of CVD were similar, at 51.7% for men and 39.2% for women, as compared to 52.5% and 39.9% in this study, respectively.27 Lifetime risk estimates for CHD were lower in this study as compared to previous estimates from Framingham, 30.9% versus 40.8% for men and 17.5% versus 24.6% in women.5 Similarly, lifetime risk estimates for stroke were slightly lower in this study as compared to previous estimates from Framingham, 11.2% versus 14.5% for men and 14.7% versus 18.1% in women; although participants in Framingham were followed up to age 106 as compared to 95 in this study.8 Birth-cohort effects may explain the lower lifetime risks for stroke observed in this study as Framingham participants were recruited into the original Framingham cohort in 1948, compared to some of the more contemporary cohorts included in the Lifetime Risk Pooling Project. Significant declines in blood pressure levels have occurred over the past 50 years due to improvements in population levels of untreated blood pressure and increased treatment and control of hypertension.28–30 Even within Framingham, Carandang et al. found a trend towards decreased lifetime risk of stroke from 1950–2004.31 Although decreasing population blood pressure levels may have resulted in slightly lower overall lifetime risk estimates than those previously published by Framingham, analyses within the Lifetime Risk Pooling Project have demonstrated that regardless of changes in prevalence, within strata the association between blood pressure and lifetime risk for cardiovascular disease remains the same over time.7
Prior estimates for the lifetime risk for CVD have been based on single blood pressure measurements taken at or near the index age. However, individuals are exposed to different blood pressure levels throughout their life, and thus a more detailed examination of the effect of blood pressure exposure is warranted. Systolic blood pressure tends to increase linearly throughout middle-age, although there is variability in the slope of the increase.9 Individuals with the highest levels of systolic blood pressure at baseline appear to have the largest age-related linear increases in systolic blood pressure.9 Above and beyond current blood pressure, antecedent blood pressure has also been found to be an important determinant in risk for CVD.32 Specifically examining stroke risk, studies done among Japanese populations have found that in addition to current blood pressure, blood pressure increases over the prior 20 years represent an independent risk factor for stroke.33 Individuals who were found to have hypertension at multiple time points had the greatest risk for stroke.34 The current study is the first to examine how changes in blood pressure throughout middle age (average change from age 41 to age 55) affect subsequent lifetime risks for CVD, CHD and stroke among a large, diverse, US population. We found that individuals who maintained or reduced their blood pressure to normal levels by the age of 55 had the lowest lifetime risks. Decreases in blood pressure may have been due to lifestyle changes as suggested by the changes in BMI and total cholesterol, although it is possible that differences were due to random variation or regression to the mean. The highest lifetime risk for CVD among men was among those who developed hypertension during middle age. In contrast, among women, individuals who had hypertension from ages 41 through 55 had the highest lifetime risk for CVD. Although it was not consistently evident that longer duration of high blood pressure was associated with increased lifetime risks, it is possible that a greater duration of hypertension is associated with increased competing risk from non-CVD mortality.
Our findings suggest the hypothesis that there may be a dose-response effect for the length of time at higher blood pressures. Buck et al.35 found that the cardiovascular risk for hypertensive patients was highest for those who developed hypertension at younger ages and declined as age of onset increased from 40–69 years of age. Similarly, patterns in our findings suggest that women who had developed hypertension by early middle-age (mean age of 41 years) had a higher lifetime risk for CVD and CHD compared to those who had developed hypertension later in middle age, age 55. A similar pattern was seen among men when examining the remaining lifetime risk of stroke.
This study has several strengths. First, we examined the lifetime risk for CVD among a large, diverse sample of population-based cohorts. These analyses included almost 700,000 person years of follow-up. Many of the cohorts included in the Lifetime Risk Pooling Project are more contemporary than those used to derive prior estimates of the lifetime risk for stroke, thereby providing more current lifetime risk estimates. Importantly longitudinal blood pressure measurements were available allowing us to examine how blood pressure changes over an average of 14 years during middle age affect the lifetime risk for cardiovascular disease. However, some individuals may not have had a second blood pressure available due to death or more likely due to the cohort structure and timing of visits. These individuals therefore would not have been included in our analyses of blood pressure change. Despite pooling there was limited follow-up for Blacks; therefore, we had to combine races in our analyses on change in blood pressure and were unable to determine racial differences in the association between blood pressure changes and lifetime risk for CVD. By examining stratified estimates we have adjusted for any confounding by age, race, gender and blood pressure; however, the methods used to determine lifetime risk do not allow for adjustment and therefore there may be potential confounding by other factors such as socioeconomic status, body mass index, and other behavioral factors which could not be included in the model. In addition, we pooled multiple population-based cohorts and there is a potential for heterogeneity due to birth-cohort effects and/or secular trends in the lifetime risk estimates. Although there have been secular trends in the CVD event rates and treatment patterns31, most of the follow-up we have is prior to widespread use of antihypertensives and lipid-lowering therapies. In the Lifetime Pooling Project the prevalence of risk factors has changed over birth cohorts, however, the relatiohships between risk factors and outcomes has remained remarkably consistent across cohorts and birth cohorts in the Lifetime Pooling Project. In addition, changes in an individual’s treatment status during follow-up may have thus affected their remaining lifetime risk for CVD. However, the data we used to estimate lifetime risks for stroke are similar to what would be available to patients and clinicians at a given index age, without knowing subsequent changes in treatment strategy. Given the limited follow-up duration, it is not possible to estimate lifetime risks using only data from cohorts recruited in the last decade, when antihypertensive use has become prevalent.
Our results suggest that there may be a dose-response effect for the number of years with high blood pressure on the lifetime risk of cardiovascular disease, coronary heart disease and stroke. Individuals who are able to maintain or decrease their blood pressure to normal blood pressure levels during middle age have the lowest lifetime risk for CVD. In contrast, individuals who experience an increase in blood pressure have higher lifetime risks for CVD. Taking blood pressure changes into account can provide more accurate estimates for lifetime risk for cardiovascular disease and represent a step forward in developing individualized risk prediction strategies. Therefore, avoiding hypertension before middle age and delaying the onset of the development of hypertension both appear to have a significant impact on an individual’s remaining lifetime risk for CVD.
Supplementary Material
Table 2.
Ten, Twenty, Thirty and Forty Year Cumulative Risk for CHD Adjusted for Competing Risk Starting At Index Age 55 by Gender and Race
| Cumulative Adjusted Risk (95% CI) through Specified Follow-Up Starting at Index Age 55
|
||||||||
|---|---|---|---|---|---|---|---|---|
| Men | Women | |||||||
| Whites | Through Age 65 | Through Age 75 | Through Age 85 | Through Age 95 | Through Age 65 | Through Age 75 | Through Age 85 | Through Age 95 |
| Normal Blood Pressure | 5.9 (4.9–6.8) | 13.6 (11.7–15.5) | 22.9 (19.9–26.0) | 29.0 (24.8–33.1) | 1.1 (0.9–1.3) | 4.3 (3.4–5.2) | 11.0 (9.2–12.9) | 18.3 (15.0–21.6) |
| Pre-hypertension | 7.0 (6.3–7.6) | 18.0 (16.9–19.1) | 30.1 (28.6–31.5) | 35.4 (33.6–37.2) | 1.7 (1.5–1.9) | 6.8 (6.2–7.5) | 16.3 (15.1–17.4) | 23.4 (21.7–25.1) |
| Stage 1 Hypertension | 9.0 (7.8–10.2) | 21.2 (19.5–23.0) | 34.8 (32.7–37.0) | 39.60 (37.0–42.2) | 2.7 (2.2–3.3) | 9.7 (8.4–10.9) | 22.1 (20.2–24.1) | 28.8 (26.4–31.3) |
| Stage 2 Hypertension | 10.6 (8.5–12.7) | 25.4 (22.2–28.1) | 37.5 (34.1–41.0) | -- | 4.2 (2.8–5.6) | 14.7 (12.2–17.3) | 26.6 (23.2–30.1) | -- |
| Blacks | Through Age 65 | Through Age 75 | Through Age 85 | Through Age 95 | Through Age 65 | Through Age 75 | Through Age 85 | Through Age 95 |
| Normal Blood Pressure | 5.9 (2.9–8.9) | 10.9 (4.6–17.3) | -- | -- | 1.8 (1.0–2.6) | 4.8 (0.5–9.0) | -- | -- |
| Pre-hypertension | 6.7 (4.8–8.6) | 13.0 (9.6–16.4) | 25.7 (17.5–34.0) | -- | 2.9 (2.2–3.7) | 4.9 (3.4–6.4) | 14.8 (8.1–21.5) | -- |
| Stage 1 Hypertension | 7.3 (4.2–10.5) | 17.3 (11.9–22.8) | 25.4 (18.0–32.9) | -- | 5.4 (3.6–7.3) | 12.2 (6.8–17.7) | -- | -- |
| Stage 2 Hypertension | 7.6 (3.0–12.3) | 18.0 (11.0–25.0) | -- | -- | 8.8 (5.0–12.6) | 13.3 (7.6–19.0) | -- | -- |
-- denotes limited person-years of follow-up, precluding stable estimate.
Clinical Summary.
Prior estimates of lifetime risk for cardiovascular disease (CVD) examined the impact of blood pressure at the index age and did not account for changes in blood pressure over time. Using pooled data from 7 diverse US cohort studies, we examined how changes in blood pressure during middle-age affect the lifetime risk for CVD, coronary heart disease (CHD) and stroke. Remaining lifetime risk from age 55 for CVD, CHD and stroke wasestimated for 61,585 White and Black men and women by blood pressure (BP) strata and by changes in BP over an average of 14 years. LTR for CVD was 52.5% (95% CI 51.3–53.7) for men and 39.9% (38.7–41.0) for women. Lifetime risk for CVD was higher for Blacks and increased with increasing BP at index age. Individuals who maintainedor decreased their BP to normal levels had the lowest remaining lifetime risk for CVD, 21–41%, as compared to individuals who had or developed hypertension by the age of 55, 49.4–69.0%. Individuals who experience increases or decreases in BP in middle age have associated higher and lower remaining lifetime risk for CVD, and there may be a dose-response effect for the length of time at high BP levels. Prevention efforts should continue to emphasize the importance of lowering BP and avoiding or delaying the incidence of hypertension in order to reduce the lifetime risk for CVD.
Acknowledgments
The investigators of the Cardiovascular Lifetime Risk Pooling Project wish to extend their deepest gratitude to the investigators of all of the included cohort studies for their hard work and dedication in collecting the underlying data; and especially to the participants in the cohorts, whose dedication and commitment have formed the basis of profound observations regarding health and disease that have contributed to improved health, longevity, and quality of life for millions of individuals.
Funding Sources: Dr. Lloyd-Jones had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Dr. Lloyd-Jones and this work are supported in part by grant R21 HL085375 from the National Heart, Lung, and Blood Institute. As part of his research training, Dr. Allen has received support from a Ruth Kirschstein NRSA/ NHLBI fellowship at Northwestern University Feinberg School of Medicine (T32 HL 069771-07). The Atherosclerosis Risk in Communities Study, Framingham Heart Study, Framingham Offspring Study, and Honolulu Heart Program are conducted and supported by the National Heart, Lung, and Blood Institute in collaboration with the study investigators. This manuscript was prepared using limited access datasets obtained from the NHLBI for these studies, and does not necessarily reflect the opinions or views of the study investigators or the NHLBI. The research reported in this article from the CHS was supported by contract numbers N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, grant number U01 HL080295 from the National Heart, Lung, and Blood Institute, with additional contribution from the National Institute of Neurological Disorders and Stroke. A full list of principal CHS investigators and institutions can be found at http://www.chs-nhlbi.org/pi.htm. The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221. The authors thank the WHI investigators and staff for their dedication, and the study participants for making the program possible. A full listing of WHI investigators can be found at: http://www.whiscience.org/publications/WHI_investigators_shortlist.pdf.
Footnotes
Conflict of Interest Disclosures: None
References
- 1.Roger VL, Go AS, Lloyd-Jones DM, Adams RJ, Berry JD, Brown TM, Carnethon MR, Dai S, de Simone G, Ford ES, Fox CS, Fullerton HJ, Gillespie C, Greenlund KJ, Hailpern SM, Heit JA, Ho PM, Howard VJ, Kissela BM, Kittner SJ, Lackland DT, Lichtman JH, Lisabeth LD, Makuc DM, Marcus GM, Marelli A, Matchar DB, McDermott MM, Meigs JB, Moy CS, Mozaffarian D, Mussolino ME, Nichol G, Paynter NP, Rosamond WD, Sorlie PD, Stafford RS, Turan TN, Turner MB, Wong ND, Wylie-Rosett J. Heart Disease and Stroke Statistics--2011 Update: A Report From the American Heart Association. Circulation. 2011;123:e18–e209. doi: 10.1161/CIR.0b013e3182009701. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Mosca L, Banka CL, Benjamin EJ, Berra K, Bushnell C, Dolor RJ, Ganiats TG, Gomes AS, Gornik HL, Gracia C, Gulati M, Haan CK, Judelson DR, Keenan N, Kelepouris E, Michos ED, Newby LK, Oparil S, Ouyang P, Oz MC, Petitti D, Pinn VW, Redberg RF, Scott R, Sherif K, Smith SC, Jr, Sopko G, Steinhorn RH, Stone NJ, Taubert KA, Todd BA, Urbina E, Wenger NK. Evidence-based guidelines for cardiovascular disease prevention in women: 2007 update. Circulation. 2007;115:1481–1501. doi: 10.1161/CIRCULATIONAHA.107.181546. [DOI] [PubMed] [Google Scholar]
- 3.Wilkins J, Lloyd-Jones D. Short-term Versus Lifetime Risk Assessment for Cardiovascular Disease: Pros, Cons, and Clinical Implications. Current Cardiovascular Risk Reports. 2009;3:144–149. [Google Scholar]
- 4.Seshadri S, Wolf PA. Lifetime risk of stroke and dementia: current concepts, and estimates from the Framingham Study. Lancet Neurol. 2007;6:1106–1114. doi: 10.1016/S1474-4422(07)70291-0. [DOI] [PubMed] [Google Scholar]
- 5.Lloyd-Jones DM, Larson MG, Beiser A, Levy D. Lifetime risk of developing coronary heart disease. Lancet. 1999;353:89–92. doi: 10.1016/S0140-6736(98)10279-9. [DOI] [PubMed] [Google Scholar]
- 6.Lloyd-Jones DM, Dyer AR, Wang R, Daviglus ML, Greenland P. Risk factor burden in middle age and lifetime risks for cardiovascular and non-cardiovascular death (Chicago Heart Association Detection Project in Industry) Am J Cardiol. 2007;99:535–540. doi: 10.1016/j.amjcard.2006.09.099. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Lloyd-Jones D, Berry J, Thomas A, Garside D, Cai X, Horn LV, Tracy R, Dyer A. Remaining Lifetime Risks After Age 45 for Fatal and Non-Fatal Cardiovascular Events in Different Race/Ethnic Groups: The Cardiovascular Lifetime Risk Pooling Project. NEJM. 2011 In Press. [Google Scholar]
- 8.Seshadri S, Beiser A, Kelly-Hayes M, Kase CS, Au R, Kannel WB, Wolf PA. The lifetime risk of stroke: estimates from the Framingham Study. Stroke. 2006;37:345–350. doi: 10.1161/01.STR.0000199613.38911.b2. [DOI] [PubMed] [Google Scholar]
- 9.Franklin SS, Gustin Wt, Wong ND, Larson MG, Weber MA, Kannel WB, Levy D. Hemodynamic patterns of age-related changes in blood pressure. The Framingham Heart Study. Circulation. 1997;96:308–315. doi: 10.1161/01.cir.96.1.308. [DOI] [PubMed] [Google Scholar]
- 10.The ARIC Investigators. The Atherosclerosis risk in communities (ARIC) study: design and objectives. Am J Epidemiol. 1989;129:687–702. [PubMed] [Google Scholar]
- 11.Dawber TR, Kannel WB, Lyell LP. An approach to longitudinal studies in a community: the Framingham Study. Ann N Y Acad Sci. 1963;107:539–556. doi: 10.1111/j.1749-6632.1963.tb13299.x. [DOI] [PubMed] [Google Scholar]
- 12.Kannel WB, Manning F, McNamara P, RJG, Castelli WP. An investigation of coronary heart disease in families. The Framingham Offspring Study. Am J Epidemiol. 1979;110:281–290. doi: 10.1093/oxfordjournals.aje.a112813. [DOI] [PubMed] [Google Scholar]
- 13.Kagan A, Harris BR, Winkelstein W, Jr, Johnson KG, Kato H, Syme SL, Rhoads GG, Gay ML, Nichaman MZ, Hamilton HB, Tillotson J. Epidemiologic studies of coronary heart disease and stroke in Japanese men living in Japan, Hawaii and California: demographic, physical, dietary and biochemical characteristics. J Chronic Dis. 1974;27:345–364. doi: 10.1016/0021-9681(74)90014-9. [DOI] [PubMed] [Google Scholar]
- 14.Worth RM, Kagan A. Ascertainment of men of Japanese ancestry in Hawaii through World War II Selective Service registration. J Chronic Dis. 1970;23:389–397. doi: 10.1016/0021-9681(70)90022-6. [DOI] [PubMed] [Google Scholar]
- 15.Haan MN, Selby JV, Rice DP, Quesenberry CP, Jr, Schofield KA, Liu J, Fireman BH. Trends in cardiovascular disease incidence and survival in the elderly. Ann Epidemiol. 1996;6:348–356. doi: 10.1016/s1047-2797(96)00054-3. [DOI] [PubMed] [Google Scholar]
- 16.Fried LP, Borhani NO, Enright P, Furberg CD, Gardin JM, Kronmal RA, Kuller LH, Manolio TA, Mittelmark MB, Newman A, et al. The Cardiovascular Health Study: design and rationale. Ann Epidemiol. 1991;1:263–276. doi: 10.1016/1047-2797(91)90005-w. [DOI] [PubMed] [Google Scholar]
- 17.The Women’s Health Initiative Study Group. Design of the Women’s Health Inititiatve clinical trial and observational study. Control Clin Trials. 1998;19:61–109. doi: 10.1016/s0197-2456(97)00078-0. [DOI] [PubMed] [Google Scholar]
- 18.Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL, Jr, Jones DW, Materson BJ, Oparil S, Wright JT, Jr, Roccella EJ. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289:2560–2572. doi: 10.1001/jama.289.19.2560. [DOI] [PubMed] [Google Scholar]
- 19.Lloyd-Jones DM, Evans JC, Levy D. Hypertension in adults across the age spectrum: current outcomes and control in the community. JAMA. 2005;294:466–472. doi: 10.1001/jama.294.4.466. [DOI] [PubMed] [Google Scholar]
- 20.Lloyd-Jones DM, Larson MG, Beiser A, Levy D. Lifetime risk of developing coronary heart disease. Lancet. 1999;353:89–92. doi: 10.1016/S0140-6736(98)10279-9. [DOI] [PubMed] [Google Scholar]
- 21.Seshadri S, Beiser A, Kelly-Hayes M, Kase CS, Au R, Kannel WB, Wolf PA. The Lifetime Risk of Stroke: Estimates From the Framingham Study. Stroke. 2006;37:345–350. doi: 10.1161/01.STR.0000199613.38911.b2. [DOI] [PubMed] [Google Scholar]
- 22.Yano K, Grove JS, Reed DM, Chun HM. Determinants of the prognosis after a first myocardial infarction in a migrant Japanese population. The Honolulu Heart Program. Circulation. 1993;88:2582–2595. doi: 10.1161/01.cir.88.6.2582. [DOI] [PubMed] [Google Scholar]
- 23.Beiser A, D’Agostino RB, Sr, Seshadri S, Sullivan LM, Wolf PA. Computing estimates of incidence, including lifetime risk: Alzheimer’s disease in the Framingham Study. The Practical Incidence Estimators (PIE) macro. Stat Med. 2000;19:1495–1522. doi: 10.1002/(sici)1097-0258(20000615/30)19:11/12<1495::aid-sim441>3.0.co;2-e. [DOI] [PubMed] [Google Scholar]
- 24.Gaynor J, Feuer E, Tan C, Wu D, Little C, Straus D, Clarkson B, Brennan M. On the use of cause-specific failure and conditional failure probabilities. J Am Stat Assoc. 1993;88:402–409. [Google Scholar]
- 25.Berry JD, Garside DB, Cai X, Dyer AR, Lloyd-Jones DM. Abstract 3666: Remaining Lifetime Risks for Cardiovascular Disease Death by Risk Factor Burden at Selected Ages in Black and White Men and Women. Circulation. 2007;116:II_832a. [Google Scholar]
- 26.Lloyd-Jones DM, Larson MG, Leip EP, Beiser A, D’Agostino RB, Kannel WB, Murabito JM, Vasan RS, Benjamin EJ, Levy D. Lifetime risk for developing congestive heart failure: the Framingham Heart Study. Circulation. 2002;106:3068–3072. doi: 10.1161/01.cir.0000039105.49749.6f. [DOI] [PubMed] [Google Scholar]
- 27.Lloyd-Jones DM, Leip EP, Larson MG, D’Agostino RB, Beiser A, Wilson PW, Wolf PA, Levy D. Prediction of lifetime risk for cardiovascular disease by risk factor burden at 50 years of age. Circulation. 2006;113:791–798. doi: 10.1161/CIRCULATIONAHA.105.548206. [DOI] [PubMed] [Google Scholar]
- 28.Luepker RV, Arnett DK, Jacobs DR, Jr, Duval SJ, Folsom AR, Armstrong C, Blackburn H. Trends in blood pressure, hypertension control, and stroke mortality: The Minnesota Heart Survey. Am J Med. 2006;119:42–49. doi: 10.1016/j.amjmed.2005.08.051. [DOI] [PubMed] [Google Scholar]
- 29.Hajjar I, Kotchen TA. Trends in prevalence, awareness, treatment, and control of hypertension in the United States, 1988–2000. JAMA. 2003;290:199–206. doi: 10.1001/jama.290.2.199. [DOI] [PubMed] [Google Scholar]
- 30.Kumanyika SK, Landis JR, Matthews-Cook YL, Almy SL, Boehmer SJ. Systolic blood pressure trends in US adults between 1960 and 1980: influence of antihypertensive drug therapy. Am J Epidemiol. 1998;148:528–538. doi: 10.1093/oxfordjournals.aje.a009678. [DOI] [PubMed] [Google Scholar]
- 31.Carandang R, Seshadri S, Beiser A, Kelly-Hayes M, Kase CS, Kannel WB, Wolf PA. Trends in incidence, lifetime risk, severity, and 30-day mortality of stroke over the past 50 years. JAMA. 2006;296:2939–2946. doi: 10.1001/jama.296.24.2939. [DOI] [PubMed] [Google Scholar]
- 32.Vasan RS, Massaro JM, Wilson PW, Seshadri S, Wolf PA, Levy D, D’Agostino RB. Antecedent blood pressure and risk of cardiovascular disease: the Framingham Heart Study. Circulation. 2002;105:48–53. doi: 10.1161/hc0102.101774. [DOI] [PubMed] [Google Scholar]
- 33.Shimizu Y, Kato H, Lin CH, Kodama K, Peterson AV, Prentice RL. Relationship between longitudinal changes in blood pressure and stroke incidence. Stroke. 1984;15:839–846. doi: 10.1161/01.str.15.5.839. [DOI] [PubMed] [Google Scholar]
- 34.Kikumura T, Omae T, Ueda K, Takeshita M, Hirota Y. Long-term changes in blood pressure prior to the development of cerebral infarction--the Hisayama study. J Chronic Dis. 1981;34:239–248. doi: 10.1016/0021-9681(81)90029-1. [DOI] [PubMed] [Google Scholar]
- 35.Buck C, Baker P, Bass M, Donner A. The prognosis of hypertension according to age at onset. Hypertension. 1987;9:204–208. doi: 10.1161/01.hyp.9.2.204. [DOI] [PubMed] [Google Scholar]
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