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(Stroke. 1999;30:1312-1318.)
© 1999 American Heart Association, Inc.
Original Contributions |
Excess Stroke Among Hypertensive Men and Women Attributable to Undertreatment of Hypertension
From the Department of Pharmacoepidemiology and Pharmacotherapy, Faculty of Pharmacy, University of Utrecht (O.H.K., A.H.P.P., A.B., A. de B.); Department of Chronic Diseases and Environmental Epidemiology, National Institute of Public Health and Environmental Protection, Bilthoven (O.H.K., J.C.S.); and Department of Epidemiology and Biostatistics, Erasmus University Medical School, Rotterdam (O.H.K., B.H.C.S., Z.V., M.M.B.B.), Netherlands.
Correspondence to Olaf H. Klungel, PhD, Department of Pharmacoepidemiology and Pharmacotherapy, Faculty of Pharmacy, University of Utrecht, Sorbonnelaan 16, PO Box 80082, 3508 TB Utrecht, Netherlands. E-mail o.h.klungel{at}pharm.uu.nl
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Background and Purpose—Most population-based studies indicate that a considerable proportion of hypertensive subjects are undertreated and that undertreatment is more prevalent among hypertensive men than among hypertensive women. The aim of our study was to investigate the consequences of undertreatment of hypertension for women and men in terms of stroke occurrence.
Methods—Approximately 45 000 men and women aged 
20 years were
examined in 2 population-based studies in the Netherlands. A cohort of
2616 hypertensive subjects (pharmacologically treated hypertensives and
untreated hypertensives who needed pharmacological treatment according
to the severity of their hypertension and the coexistence of additional
cardiovascular risk factors) was selected for a
follow-up study. Follow-up (mean duration, 4.6 years) was complete for
2369 (91%) of the enrolled hypertensive subjects.
Results—Compared with treated and controlled hypertensives, the
relative risks of stroke for treated and uncontrolled hypertensives and
for untreated hypertensives who needed treatment were 1.30 (95% CI,
0.70 to 2.44) and 1.76 (95% CI, 1.05 to 2.94), respectively. These
relative risks and the prevalence of (undertreated) hypertension in the
total population of 45 000 subjects were used to estimate the number
of strokes in the Netherlands attributable to undertreatment. Among
hypertensive men and women aged 20 years in the Netherlands, the
proportions of strokes attributable to treated but uncontrolled blood
pressure were 3.1% (95% CI, -5.2% to 18.7%) and 4.1% (95% CI,
-7.2% to 20.7%), respectively. For untreated hypertensive men and
women who should have been treated, these proportions were 22.8% (95%
CI, 0.8% to 38.4%) and 25.4% (95% CI, 0.5% to 42.5%),
respectively.
Conclusions—Increasing the detection of hypertension and improving adherence to current guidelines might prevent a considerable proportion of the incident strokes among hypertensives. The potential impact of achieving control of blood pressure in patients already being treated on the reduction of strokes requires further investigation.
Key Words: hypertension • population-based studies • stroke • treatment
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Hypertension is one of the most important risk factors for cardiovascular diseases in general and for cerebrovascular diseases in particular.1 Although the beneficial effect of pharmacological treatment of hypertension on the incidence of coronary heart diseases and cerebrovascular diseases has been demonstrated in several controlled clinical trials,2 most population-based studies indicate that a large proportion of treated hypertensive patients still have elevated blood pressure,3 and a considerable proportion of hypertensive patients are not treated with antihypertensive drugs.4 However, not all hypertensives need pharmacological treatment because, according to several guidelines on the management of hypertension, this depends on the severity of hypertension and in moderate hypertension may depend on the coexistence of additional cardiovascular risk factors.5 6 7 In a population-based study among men and women aged 20 to 59 years in the Netherlands, we demonstrated that approximately 42% and 29% of the pharmacologically treated men and women, respectively, still had elevated blood pressure levels. Of those hypertensive men and women not treated pharmacologically, 53% and 34%, respectively, should have been treated when additional cardiovascular risk factors and the severity of hypertension were taken into account.8
The consequences of undertreatment of hypertension in terms of cardiovascular disease occurrence have been studied in observational studies. However, these studies had several limitations. First, most studies were restricted to either uncontrolled blood pressure among treated hypertensives9 10 11 12 or to untreated hypertension.13 14 15 16 17 18 19 Second, in none of the studies was the coexistence of additional cardiovascular disease risk factors taken into account to assess the need for pharmacological treatment. Finally, in most of these studies, treated hypertensives were compared with the remainder of the population or normotensive controls9 13 14 15 16 17 18 19 20 or with untreated hypertensives irrespective of their need for treatment.13 14 Thus, the reference groups in these studies were not comparable with the treated hypertensives with respect to risk of cardiovascular disease, and this may have led to confounding by the indication for the treatment of hypertension.21
The aim of our study was to estimate the proportion of incident strokes attributable to undertreatment of hypertension in men and women, taking into account the shortcomings of previous studies.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Data
For the present study we used data from 2 population-based studies in the Netherlands. The first study, the Monitoring Project on Cardiovascular Risk Factors, was started in 1987 as a cross-sectional study in Amsterdam, Maastricht, and Doetinchem. In Doetinchem this study was continued as a prospective follow-up study by reexamining the subjects examined in 1987 again in 1993. The second study, the Rotterdam Study, was started in 1990 in Rotterdam as a population-based prospective follow-up study.
The Monitoring Project on Cardiovascular
Risk Factors
This study was conducted from 1987 to 1991. Each year a new
random sample of men and women aged 20 to 59 years in Amsterdam,
Maastricht, and Doetinchem was selected. The design of this study has
been described in detail elsewhere.22 The overall response
rate in Amsterdam, Maastricht, and Doetinchem was 45%, 58%, and 62%,
respectively. Several characteristics such as educational level,
smoking, alcohol use, height, and weight of nonrespondents and
respondents have been evaluated in previous studies.8 The
results of these studies suggested that no substantial selection had
taken place with respect to these characteristics.
The Rotterdam Study
This study on the occurrence and determinants of chronic
disabling diseases at older ages was started in 1990. All 10 275
residents of a suburb of Rotterdam aged 55 years were invited to
participate; 7983 (78%) subjects agreed to participate. The design of
this study has been described in detail elsewhere.23 The
baseline measurements took place until 1993.
Baseline Measurements
Information on demographic variables, current health status,
medical history, family history of diseases, smoking habits, and
current use of medication was obtained during a home interview in the
Rotterdam study, whereas self-administered questionnaires were used in
the Monitoring Project on Cardiovascular Risk
Factors. The self-administered questionnaires were checked at the study
center with the participant for completeness. In both studies the
physical examinations were performed by either trained technicians or
physicians according to a standardized protocol. Blood pressure,
weight, and height were measured, and blood was drawn for total
cholesterol and HDL cholesterol determination.
A random zero sphygmomanometer was used to measure blood pressure twice
with the subject in sitting position. Systolic blood pressure
(SBP) was recorded at the appearance of sounds (first-phase
Korotkoff), and diastolic blood pressure (DBP) was
recorded at the disappearance of sounds (fifth-phase Korotkoff).
For the analyses, we used the mean of 2 blood pressure
measurements.
Follow-Up
For this study, we selected subjects who were treated
pharmacologically for hypertension and subjects who were untreated but
in need of pharmacological treatment for hypertension (see Definitions)
at the baseline measurement in Rotterdam (1990–1993) and Doetinchem
(1987–1991). The follow-up period in both studies started at the
baseline examination and lasted until April 1, 1996, in Rotterdam, and
until January 1, 1996, in Doetinchem. Information on fatal and nonfatal
strokes was obtained through patient records of general
practitioners (GPs) and the GPs' archives of
specialists' reports.
Definitions
Hypertension was defined as DBP 95 mm Hg and/or SBP
160 mm Hg and/or use of antihypertensive drugs for
hypertension. Subjects who said that they used blood pressure–lowering
drugs and mentioned at least 1 drug with an approved indication for the
treatment of hypertension were considered pharmacologically treated for
hypertension. With regard to cardiovascular drug use,
it was previously demonstrated that concordance between medication use
according to patient interview and pharmacy records is very
high.24 25 Three categories of hypertensives were
distinguished according to the Dutch guidelines for the management of
hypertension.5 First, the reference group was defined as
pharmacologically treated hypertensives whose blood pressure was below
the treatment goal of the Dutch guidelines (DBP 
90 mm Hg and
SBP 160 mm Hg). The second group included pharmacologically
treated hypertensives whose blood pressure was above this treatment
goal (DBP >90 mm Hg or SBP >160 mm Hg). The third group
consisted of untreated hypertensives who need pharmacological treatment
when the coexistence of additional cardiovascular risk
factors was taken into account. According to the Dutch guidelines,
hypertension should be treated pharmacologically when the DBP is
between 100 and 105 mm Hg and 1 or more
cardiovascular risk factors are present, or when
the SBP is between 160 and 180 mm Hg and 1 or more
cardiovascular risk factors are present, or when
DBP or SBP are >105 mm Hg or >180 mm Hg, respectively.
The following additional cardiovascular risk factors
should be evaluated according to these guidelines: sex (male), current
smoking, hypercholesterolemia (total
cholesterol 6.5 mmol/L), diabetes, target organ
disease, age 60 years, and cardiovascular disease
among parents or sisters or brothers aged <60 years.
Strokes that could be confirmed by specialists' letters to the GPs and strokes that were certain according to the GP were included for the analysis, whereas events that were probable according to the GP were excluded. The end point of interest was a first or recurrent fatal or nonfatal stroke (International Classification of Diseases, Tenth Revision codes I60 to I69), excluding transient ischemic attacks (TIA) during follow-up.
History of cardiovascular disease was defined as a self-reported history of any cardiovascular disease or written information from the GPs that indicated presence of any cardiovascular disease, excluding cerebrovascular diseases. History of cerebrovascular disease was defined as a self-reported history of stroke or TIA, confirmed by written information from the GPs.
Analyses
Estimation of Risk of Stroke Attributed to Undertreatment of
Hypertension
To study the association between undertreatment and incidence of
stroke, the Cox proportional hazards model was used, and
multivariately adjusted relative risks (RRs) and their
95% CIs26 were calculated. Analyses were
initially performed separately for the Doetinchem study and the
Rotterdam study to evaluate effect-modification due to differences in
study design. The RRs of undertreatment of hypertension for the
occurrence of stroke were virtually the same in the Doetinchem study
and the Rotterdam study. Therefore, the results from the combined
analysis are presented.
In addition to the evaluation of all subjects
simultaneously, subgroup analyses were performed
after exclusion of patients without a history of cerebrovascular
disease and after exclusion of patients with any history of
cardiovascular disease. Furthermore, men and women and
subjects aged <80 and 80 years (the efficacy of
antihypertensive treatment at 80 years is unknown2 ) were
analyzed separately.
All RR estimates were adjusted for age, history of diabetes, total cholesterol, body mass index, smoking, and history of cardiovascular disease. When men and women were analyzed together, adjustments were also made for sex, and in the analysis of all subjects irrespective of a history of cerebrovascular disease, adjustments were also made for a history of stroke or TIA. For the adjustment of RRs, smoking was categorized into never, former, or current smoking.
Estimation of Prevalences of Undertreatment of
Hypertension
Age- and sex-specific prevalences of hypertension, treated and
controlled hypertension, treated but uncontrolled hypertension, and
untreated hypertension that should be treated were estimated among all
subjects who were examined in all 4 cities in both population studies.
These prevalence estimates were used to compute the number of subjects
within these categories of hypertensives in the whole Dutch
population.
Estimation of the Number of Incident Strokes Attributable to
Undertreatment of Hypertension
Age- and sex-specific incidence rates of stroke among all
hypertensives, treated and controlled hypertensives, treated but
uncontrolled hypertensives, and untreated hypertensives who should be
treated were computed (PYRS version 1.2) to estimate the number of
incident strokes in these categories of hypertensives in the
Netherlands in 1994. This was done by multiplying the age- and
sex-specific estimated numbers of subjects within the different
categories of hypertensives in the Netherlands in 1994 by the
corresponding age- and sex-specific incidence rates. Subsequently, we
estimated the proportions of incident strokes attributable to treated
but uncontrolled blood pressure and untreated hypertension that should
be treated within each of these categories of undertreatment as the
ratio (RR-1)/RR. The adjusted RRs of exposed persons (treated but
uncontrolled hypertensives or untreated hypertensives who should be
treated) compared with unexposed persons (treated and controlled
hypertensives) were used for the RR. These proportions were used to
estimate the absolute number of incident strokes attributable to both
types of undertreatment. Finally, these attributable numbers of
incident strokes were expressed as percentages of the total number of
incident strokes among all hypertensive subjects. We estimated 95% CIs
of the attributable number of incident strokes according to the method
of Rothman and Greenland.27
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Study Population
A total of 44 571 subjects (12 448 in Doetinchem, 11 488 in Amsterdam, 12 652 in Maastricht, and 7983 in Rotterdam) were examined in both population studies. After exclusion of pregnant women (n=306) and subjects with missing data (n=1665), 42 600 subjects remained available for the estimation of prevalences of hypertension and undertreatment of hypertension.
Hypertension was prevalent among 2072 subjects (28.9%) of the Rotterdam study and among 1096 subjects (9.4%) in Doetinchem. Subjects who did not need antihypertensive drug treatment according to the guidelines (n=552) were excluded from the analysis. Therefore, our study population comprised 2616 subjects pharmacologically treated for hypertension or untreated for hypertension but in need of pharmacological treatment. Follow-up was complete for 2369 subjects (90.6%).
The differences in baseline characteristics between those lost to follow-up and those for whom follow-up was complete were negligible (data not shown).
The number of hypertensives who were treated pharmacologically and had
DBP <90 mm Hg and SBP <160 mm Hg was 879, whereas 482
subjects were treated pharmacologically but had DBP >90 mm Hg or
SBP >160 mm Hg, and 1008 subjects were inappropriately not
treated pharmacologically for hypertension. Baseline characteristics of
all 2369 hypertensive men and women stratified by these 3 categories
are listed in Table 1
. Most risk
factors were evenly distributed across these categories. One important
difference was a higher prevalence of past
cardiovascular disease (excluding cerebrovascular
disease) among pharmacologically treated hypertensives compared with
untreated hypertensives who should have been treated. This difference
was more pronounced for men than for women (data not shown). Prevalence
of past cerebrovascular disease was also slightly higher for
pharmacologically treated hypertensives.
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Undertreatment of Hypertension and Risk of Stroke
During the follow-up period (mean duration, 4.6 years), 40 men and
68 women experienced a first or recurrent stroke. The number of fatal
stroke events was 2 for men and 15 for women.
The crude incidence rates of stroke among treated hypertensives with
controlled blood pressure levels, treated hypertensives with
uncontrolled blood pressure levels, and untreated hypertensives who
should have been treated were 6.7, 8.2, and 14.0 per 1000 person-years,
respectively (Table 2).
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Compared with treated hypertensives who had controlled blood pressure
and after adjustment for potential confounding factors, treated
hypertensives who had uncontrolled blood pressure levels had a
1.30-fold increased risk of stroke (not statistically significant),
whereas untreated hypertensives who should have been treated had a
1.76-fold increased risk of stroke (Table 2
). These RRs were
similar for men and women. Exclusion of subjects with a history of
cerebrovascular disease resulted in slightly increased RRs of treated
but uncontrolled blood pressure and untreated hypertension that should
be treated compared with treated and controlled blood pressure (1.47
[95% CI, 0.73 to 2.95] and 1.86 [95% CI, 1.04 to 3.33],
respectively).
Additional analyses of subjects without any history of cardiovascular disease resulted in even higher RRs of treated but uncontrolled blood pressure and untreated hypertension that should be treated compared with treated and controlled blood pressure (2.0 [95% CI, 0.8 to 4.6] and 2.3 [95% CI, 1.1 to 4.8], respectively).
For subjects aged <80 years, the adjusted RRs of stroke of treated but
uncontrolled blood pressure and untreated hypertension that should be
treated were 1.4 (95% CI, 0.7 to 2.8) and 1.7 (95% CI, 0.9 to 3.0),
respectively. For subjects aged 80 years, these RRs were 1.2 (95%
CI, 0.2 to 5.6) and 2.6 (95% CI, 0.8 to 9.2), respectively. However,
because of the small numbers we could not further investigate these
associations by age.
Number of Incident Strokes Attributable to Undertreatment of
Hypertension
The incidence rates of stroke after
stratification for age, sex, and categories of hypertension (treated
and controlled, treated but uncontrolled, untreated but should be
treated) as derived from the 2 population studies are presented
in Table 3. In both sexes the incidence rates increased with
age. Furthermore, rates were highest in the untreated hypertensives who
should be treated. The respective age-adjusted prevalences of
hypertension (per 100 population), treated and controlled hypertension
(per 100 hypertensives), treated but uncontrolled hypertension (per 100
hypertensives), and untreated hypertension that should be treated (per
100 hypertensives) were 11.2, 28.2, 15.5, and 39.7 for men, whereas for
women these prevalences were 12.9, 39.4, 18.8, and 32.1. Age- and
sex-specific prevalences were used to calculate the number of subjects
in each of the categories of hypertension for the whole Dutch
population in 1994 (data not shown). These numbers were subsequently
multiplied by the corresponding incidence rates to estimate the
absolute number of strokes in these categories of hypertensive (Table 3). The number of strokes in women was more than twice the
number of strokes in men.
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The age-adjusted proportions of strokes among hypertensive men and
women attributable to treated but uncontrolled blood pressure were
3.1% (95% CI, -5.2% to 18.7%) and 4.1% (95% CI, -7.2% to
20.7%), respectively (Table 4). For untreated hypertensive men
and women who should have been treated, these proportions were 22.8%
(95% CI, 0.8 to 38.4%) and 25.4% (95% CI, 0.5 to 42.5%),
respectively. Among hypertensive subjects aged 20 years in the
Netherlands in 1994, 
26% (1230) of all incident strokes among
hypertensive men and 29% (1975) of all incident strokes among
hypertensive women were attributable to undertreatment of
hypertension.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In a previous study we showed that during the last decade in the Netherlands, a considerable proportion of hypertensive men and women aged 20 to 59 years were undertreated for hypertension.8 In the present study we investigated the consequences of undertreatment of hypertension among men and women aged
20 years with
respect to the occurrence of stroke. We demonstrated that untreated
hypertensives who needed treatment according to the severity of their
hypertension and the presence of additional
cardiovascular risk factors had an increased risk of
stroke compared with pharmacologically treated hypertensives whose
blood pressure level was controlled. Among hypertensive men and women
aged 20 years in the Netherlands, 1083 and 1702 incident
strokes per year, respectively (23% and 25% of all incident strokes
among hypertensive men and women, respectively) might be due to
untreated hypertension that should have been treated. According to an
average of several general practice registrations in the
Netherlands,28 13 026 and 15 119 incident strokes
occurred among men and women, respectively, in the whole Dutch
population aged 20 years in 1994. On the basis of these figures,
8.3% and 11.3% of all incident strokes among men and women aged
20 years in the Netherlands were attributable to untreated
hypertension that should have been treated. This is probably an
underestimation since the definition of stroke was more strict in our
study than in these general practice registrations. Because of the
imprecise RR estimate of treated but uncontrolled blood pressure, we
could not reliably estimate the number of strokes attributable to this
type of undertreatment. However, the attributable fraction due to
treated but uncontrolled blood pressure appears to be much lower than
that due to untreated hypertension that should be treated. Estimations of the proportion of a disease attributable to exposure are only valid when risk estimates and prevalence estimates on which these attributable proportions are based are unbiased. Therefore, it is important to discuss several limitations of our study that could potentially have biased our estimated proportion of strokes attributable to undertreatment of hypertension.
First, blood pressure was measured only twice on 1 occasion. Because of within-person variability in blood pressure, the group of untreated hypertensives who should be treated will also comprise normotensive subjects.8 29 Misclassification of normotensives as hypertensive has probably caused an underestimation of our RR estimates.
A second limitation of this study could be that the results in part may be caused by confounding by the indication for the treatment of hypertension. However, we compared a high-risk group of untreated hypertensives with additional cardiovascular risk factors with treated and controlled hypertensives, and the differences between untreated hypertensives who should be treated and treated hypertensives were only marginal with respect to the traditional cardiovascular risk factors at baseline. Furthermore, all RR estimates were adjusted for the potential confounding influence of other cardiovascular disease risk factors.
Third, it cannot be excluded that treated hypertensives with controlled blood pressure had lower pretreatment blood pressure levels than treated but uncontrolled hypertensives. We could not adjust for this in the analysis. Nonetheless, the excess risk of treated but uncontrolled blood pressure compared with treated and controlled blood pressure suggests that lowering blood pressure in hypertensives with uncontrolled blood pressure would reduce the risk of stroke among these hypertensive patients.
Fourth, we measured the status of undertreatment only at baseline, whereas during the follow-up period treatment could have been started in untreated hypertensives and control of blood pressure could have been achieved among treated hypertensives who were uncontrolled at the baseline measurements. Assuming that it is more likely that untreated hypertensives are going to be treated during follow-up than that treatment is stopped in treated hypertensives, the RR of untreated hypertension that should be treated was probably underestimated.
Finally, because of the small numbers, some reservation with regard to the precision of the estimated number of attributable strokes must be taken into account. The RR of treated but uncontrolled blood pressure and the number of strokes attributable to this type of undertreatment were not statistically significant. However, several other studies also found an increased risk of stroke among treated hypertensives with uncontrolled blood pressure compared with those with controlled blood pressure.9 10 12 20 Furthermore, the increased risk of treated but uncontrolled blood pressure was consistent across the subgroups that we studied. Nonetheless, the number of strokes attributable to treated but uncontrolled blood pressure should be interpreted with caution.
Although the prevalence of undertreatment of hypertension was higher for hypertensive men than for hypertensive women, the proportion of incident strokes due to undertreatment was slightly smaller for men than for women. The absolute number of incident strokes attributable to undertreatment was also higher for hypertensive women than it was for hypertensive men. This can probably be explained by the higher number of elderly women, in particular at ages >70 years. Above this age the incidence rate of stroke was very high. Another explanation could be that the mortality from coronary heart disease is much higher among men than among women.30 31 32 This could have resulted in a selective depletion of the pool of men who are at high risk for stroke, resulting in more women than men at high risk for experiencing a stroke event.33
This study provides one of the first estimates of the risk of stroke in the population in relation to the quality of treatment of hypertension. Our findings suggest that improvement of the detection of hypertension and adherence to the current guidelines on the management of hypertension might prevent a considerable proportion of incident strokes among hypertensive men and women. The potential impact of achieving control of blood pressure among those already treated on the reduction of stroke incidence remains uncertain.
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Acknowledgments |
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This study was supported by a grant from the Stichting Maatschappelijke Aandachtsgebieden of the University of Utrecht.
Received February 22, 1999; revision received April 15, 1999; accepted April 16, 1999.
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