(Stroke. 1995;26:1319-1324.)
© 1995 American Heart Association, Inc.
Articles |
Morbidity, Mortality, and Antihypertensive Treatment Effects by Extent of Atherosclerosis in Older Adults With Isolated Systolic Hypertension
From the Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh (Pa).
Correspondence to Kim Sutton-Tyrrell, DrPH, Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, 130 DeSoto St, Pittsburgh, PA 15261.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Background and Purpose The Systolic Hypertension in the Elderly Program (SHEP) demonstrated a significant reduction in stroke and coronary event rates among participants randomly assigned to active blood pressure treatment. Selected participants were evaluated for peripheral atherosclerosis and followed up for cardiovascular events beyond the end of the SHEP trial. Antihypertensive treatment effects were evaluated based on the presence or absence of clinical or subclinical atherosclerosis.
Methods As an ancillary study to SHEP, 190 participants at the Pittsburgh center were evaluated for peripheral atherosclerosis, defined as either an internal carotid stenosis (by duplex scan) or lower extremity arterial disease (identified by ankle blood pressure). Participants were subsequently followed up for cardiovascular events.
Results Estimates of 4-year mortality rates were 4.8% for participants with no atherosclerosis, 16.7% for those with subclinical atherosclerosis, and 23% among those with clinical evidence of atherosclerosis (P<.001). Fatal plus nonfatal cardiovascular event rates were 10.9%, 29.8%, and 58.3% for the three groups, respectively (P<.001). Differences remained significant after adjustment for age, sex, treatment assignment, smoking, and high-density lipoprotein cholesterol. Individuals assigned to placebo at the beginning of SHEP had higher cardiovascular event rates than individuals assigned to active treatment (P=.011), with the most striking difference 3 or more years after the end of the SHEP trial. When this analysis was stratified by the presence or absence of detectable atherosclerosis, the absolute treatment effect was largest among those with evidence of disease.
Conclusions Individuals with systolic hypertension and evidence of peripheral atherosclerosis are at high risk for cardiovascular events. Targeting this group for antihypertensive therapy would result in the prevention of a large number of cardiovascular events.
Key Words: atherosclerosis • carotid stenosis • clinical trials • hypertension
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The Systolic Hypertension in the Elderly Program (SHEP) was a randomized, placebo-controlled trial to test the efficacy of treating isolated systolic hypertension in adults older than 60 years.1 Results revealed a 36% reduction in stroke rates as well as a significant reduction in coronary events among participants assigned to active blood pressure treatment.2 In addition to observing treatment effects on the clinical sequelae of atherosclerosis, an ancillary study conducted at the University of Pittsburgh center has allowed the observation of treatment effects on the peripheral vessels with the use of ultrasound techniques. Participants assigned to active treatment were found to have lower progression rates of carotid atherosclerosis than those assigned to placebo.3
Ultrasound is a useful technique that allows investigators to observe peripheral atherosclerosis in its subclinical stages. Individuals with asymptomatic carotid atherosclerosis are at high risk for stroke,4 ischemic heart disease,5 6 7 and cardiovascular death.4 8 Similarly, persons with disease of the lower extremities are at high risk for cardiovascular events and death.9 10 11 Thus, many authors have suggested that peripheral disease marks the presence of generalized systemic atherosclerosis. Noninvasive evaluation of the peripheral vessels may identify individuals who should be targeted for risk factor modification.
SHEP participants at the University of Pittsburgh field center were evaluated for both carotid stenosis and lower extremity arterial disease and then subsequently followed up for cardiovascular events. The purpose of this report is to evaluate cardiovascular morbidity and mortality in these participants based on the extent of atherosclerosis at the time of this examination. In addition, antihypertensive treatment effects were evaluated based on the presence or absence of atherosclerotic disease.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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As an ancillary study to SHEP, participants at the University of Pittsburgh Center were invited to undergo an evaluation for subclinical peripheral atherosclerosis. Duplex scans of the carotid arteries were used to identify an internal carotid stenosis, and ankle blood pressures were used to identify lower extremity arterial disease.
A total of 222 SHEP participants were recruited at the Pittsburgh field center. Recruitment took place at retirement centers, churches, and other locations where predominantly healthy elderly adults could be found. Qualifications for entry included age older than 60 years, systolic blood pressure between 160 and 219 mm Hg, and diastolic blood pressure lower than 90 mm Hg. Exclusions included recent myocardial infarction, stroke with residual paresis, uncontrolled congestive heart failure, peripheral arterial disease with evidence of tissue injury or loss, transient ischemic attacks with associated carotid bruits, and contraindication to study medications. Complete screening techniques and exclusion criteria have been previously reported.1 12 After study entry, participants were assigned at random to either stepped-care blood pressure treatment or matching placebo medication by means of a double-blind design. Participants initially received 12.5 mg/d chlorthalidone or matching placebo. This dosage was doubled for participants who did not achieve their systolic blood pressure goal at follow-up visits. If the participant's blood pressure failed to respond to this maximum dose of chlorthalidone, 25 mg/d atenolol or matching placebo was added. When atenolol was contraindicated, 0.05 mg/d reserpine or matching placebo could be substituted.
Duplex scanning of the carotid arteries was performed at the Peripheral Vascular Diagnostic Laboratory located in Montefiore University Hospital, Pittsburgh, Pa. A Diasonics DRF 400 duplex scanner with a 10-MHz imaging probe and 4.5-MHz Doppler was used. Internal carotid artery stenosis was defined as a luminal diameter reduction of approximately 40% to 50% or greater, as evidenced by Doppler.13 Although this does not necessarily represent disease that would cause clinical concern, it represents the lowest level of disease that can be reliably detected by Doppler. Doppler measurements obtained by duplex scanning have shown good agreement with angiography in the identification of carotid stenosis.14 15 16 17 In addition, the measures used to determine stenosis were highly reproducible in participants who had duplicate scans on the same day.18
Atherosclerotic disease of the large vessels of the legs was detected by obtaining ankle blood pressures with the use of a standard blood pressure cuff and a Doppler probe. Ankle blood pressure measurement is a simple, inexpensive, and accurate method for detecting lower extremity arterial disease.19 20 21 The arm systolic blood pressure is divided by the ankle systolic blood pressure to obtain a ratio called the ankle/arm index. The ankle/arm index is normally 1.00 or above. As atherosclerosis in the vessels of the legs worsens, the ankle blood pressure becomes progressively lower. For this study lower extremity arterial disease was defined as an ankle/arm index of 0.90 or below.
Participants have been followed up prospectively for cardiovascular events for an average of 8.4 years starting from SHEP entry. The evaluation for peripheral disease was done on average 3.7 years after SHEP entry, resulting in an average follow-up time of 4.7 years after this evaluation. At the end of SHEP, all participants were counseled on the importance of antihypertensive therapy. Participants assigned to active treatment were given a 3-month supply of medication and told to see their primary care physician for continued treatment. Participants assigned to placebo were asked to see their physician within 3 months so that antihypertensive therapy could be initiated. One year after SHEP closeout, participants were interviewed to determine whether they were on antihypertensive therapy. Of those interviewed, 73% of individuals who had been assigned to active treatment were taking blood pressure medication and 63% of individuals who had been assigned to placebo were taking blood pressure medication. Further details of this 1-year interview are part of a separate report under preparation.
Participants have been followed up for cardiovascular events including stroke, transient ischemic attack, myocardial infarction, hospitalization for unstable angina, coronary revascularization, and congestive heart failure. Cause of death was categorized as cardiovascular or other. All events were verified by committee review of hospital records and death certificates according to the SHEP protocol.
The institutional review board for the University of Pittsburgh approved the SHEP trial as well as the ancillary study. Participants signed separate informed consent forms for SHEP participation, ultrasound evaluation of peripheral atherosclerosis, and continued follow-up after the end of SHEP.
Participants were divided into three groups defined by extent of atherosclerosis. Group 1 had no detectable atherosclerotic disease, group 2 had subclinical peripheral atherosclerosis but no history of clinical events, and group 3 had a history of a clinical cardiovascular event. Kaplan-Meier life table methods were used to estimate mortality and fatal plus nonfatal cardiovascular event rates for these three groups. Analysis of mortality included all deaths regardless of the cause. A composite end point was used to evaluate all fatal and nonfatal cardiovascular events. In this analysis, participants who died from noncardiovascular causes were censored at the time of death. For these analyses, time zero was the date of the evaluation for peripheral disease. The Mantel-Cox statistic was used to determine whether the survival curves differed, with a value of P<.05 considered statistically significant. It should be noted that nominal probability values are reported without adjustments for multiple comparisons. The primary hypothesis a priori was that extent of atherosclerosis at baseline would be associated with higher event rates. The relationship between extent of atherosclerosis and outcome was adjusted for baseline risk factors with the use of a Cox proportional hazards model. The proportionality assumption was evaluated by plotting the logarithm of the cumulative hazard function.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Data sufficient to establish extent of atherosclerosis were available on 190 of the 222 SHEP participants recruited in Pittsburgh. Of the remaining 32, 4 died, 16 were lost to follow-up before the vascular evaluation could be completed, and 12 participants refused to return to the clinic for follow-up. Data on lower extremity disease were available for 189 subjects, data on carotid stenosis were available for 186 subjects, and both measures were available for 173 participants. Baseline characteristics were compared between these participants and the entire SHEP cohort. The subgroup presented here is slightly older (mean age of 75 years for the subgroup and 72 years for the entire SHEP cohort), and participants were less likely to have ever smoked (38% for the subgroup and 50% for the entire SHEP cohort). All other baseline factors were similar between the two groups.
At the time of evaluation, 38 participants (20%) had a history of
clinical atherosclerosis, with the predominant
conditions being angina or congestive heart failure (Table 1
). The prevalence of peripheral
atherosclerosis was high. Internal carotid
stenosis was found in 25% and lower extremity
arterial disease in 29%, and either one or the other
condition was present in 43%.
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During follow-up, 40 participants (21.1%) experienced one or more
cardiovascular events (Table 2). The
most common event was a cardiac death (7.3%). To determine the
predictive value of peripheral
atherosclerosis without concomitant clinical disease,
participants with clinical disease were excluded from this
analysis. Table 3 presents estimates of
4-year mortality and fatal plus nonfatal cardiovascular
event rates for participants with and without carotid stenosis,
with and without lower extremity arterial disease, and with
and without either condition. In all cases, event rates were higher
among participants with evidence of peripheral disease
(Table 3).
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Next, participants with and without peripheral disease were
compared with the group with clinical disease. Four-year
cardiovascular event rates were 10.9% among those with
no disease, 29.8% among those with subclinical disease, and 58.3%
among those with clinical disease (Table 4, Fig 1,
P<.001). After adjustment for
age, sex, smoking, high-density lipoprotein cholesterol,
and treatment assignment, degree of atherosclerosis
remained significantly associated with both total mortality
(P=.007) and cardiovascular events
(P=.008). Subclinical disease was associated with a 3.9-fold
increase in mortality and a 1.4-fold increase in
cardiovascular events compared with the group with no
disease. Clinical disease was associated with a 5.8-fold increase in
mortality and a 2.6-fold increase in cardiovascular
events compared with the group with no disease.
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The effect of treatment assignment was evaluated for the group as a
whole. Fig 2 presents fatal plus nonfatal
cardiovascular event rates for the entire follow-up
experience of the Pittsburgh cohort, from SHEP entry to September 1994.
In this figure, SHEP closeout occurred between years 3 and 5.
Consistent with the full SHEP trial, individuals assigned to
placebo had higher cardiovascular event rates than
individuals assigned to active treatment (P=.011).
Interestingly, the treatment effect becomes more apparent the longer
the participants are followed up, with the most striking difference 3
or more years after the end of the SHEP trial. Kaplan-Meier estimates
of 8-year cardiovascular event rates were 17% for the
active treatment group and 37% for the placebo group.
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Analysis of the treatment effect was stratified by the presence
or absence of clinical or subclinical atherosclerosis
(Table 5). Evidence of a treatment effect on
cardiovascular event rates is present for both
groups. However, the absolute treatment effect is larger for the group
with clinical or subclinical disease. Among the group with no disease,
the cardiovascular event rate was 9.3 percentage points
higher for participants assigned to placebo compared with those
assigned to active treatment. Among the group with clinical or
subclinical disease, the cardiovascular event rate was
29.3 percentage points higher among those assigned to placebo compared
with those assigned to active treatment. The treatment effect was
statistically significant only among the group with evidence of either
clinical or subclinical atherosclerosis. While the
absolute treatment effect was larger among the group with evidence of
atherosclerosis at baseline, the relative treatment
effect was similar regardless of the presence of baseline disease. The
relative risk of a cardiovascular event in the placebo
group versus the active treatment group was 2.4 (16.0/6.7) for those
with no disease at baseline and 2.2 (53.0/23.7) for those with disease
at baseline. Thus, an interaction or synergistic relationship between
evidence of disease and treatment does not appear to exist. To test
this, a treatment by disease interaction term was added to the
multivariate model. As expected, this term was not
statistically significant.
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When looking at total mortality rates (Table 5
), more of a difference
in relative treatment effects is seen. The relative risk of mortality
for those assigned to placebo versus active treatment was 1.1 (5.1/4.5)
for those with no disease at baseline and 2.1 (27.2/12.8) for those
with disease at baseline. However, when tested, a treatment by disease
interaction term was not significant.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The presence of subclinical peripheral atherosclerosis is clearly associated with increased cardiovascular risk in individuals with isolated systolic hypertension. Risk associated with presence of peripheral disease exists even in the absence of a history of cardiovascular disease at baseline. This is consistent with other studies that have shown that evidence of lower extremity disease is associated with subsequent mortality.9 10 11 22 23 Other authors have also demonstrated that evidence of carotid atherosclerosis is predictive of subsequent cardiovascular events.6 7 In the present study the risk associated with carotid stenosis was stronger than that for lower extremity arterial disease. This may be due to the strong association between carotid atherosclerosis and systolic hypertension. This may also be due to small numbers in our sample. A larger sample of the SHEP cohort has demonstrated a significant relationship between lower extremity disease and mortality.23 To compare the value of lower extremity arterial disease versus carotid stenosis in predicting events, one would have to compare patients with carotid stenosis alone to those with lower extremity arterial disease alone. The high correlation between these two conditions results in relatively few patients in these two categories. Thus, such a comparison is beyond the scope of this study.
The high cardiovascular morbidity and mortality associated with peripheral atherosclerosis suggests that these individuals should be targeted for aggressive risk factor modification. This raises the question of the benefit of risk factor modification in this subgroup. This study indicates that for individuals with isolated systolic hypertension, antihypertensive therapy is particularly important among individuals with evidence of clinical or subclinical atherosclerosis. This is primarily because the rate of cardiovascular events is much higher among those with either clinical or subclinical disease and the number of events that can potentially be prevented with antihypertensive therapy is higher. Even though the absolute treatment differences observed in this study were striking, the relative risks were similar regardless of the presence or absence of disease at baseline. This underscores the benefit of treatment of isolated systolic hypertension in all individuals. While a significant interaction between preexisting atherosclerosis and treatment was not found, this may have been due to a lack of power. Several thousand participants would be required to completely rule out the existence of such an interaction.
There is no question that this study would have been stronger if measures of peripheral atherosclerosis had been obtained when participants entered the SHEP trial instead of 3 to 4 years later. Crossover of treatment groups after SHEP closeout served to minimize our chances of finding a treatment effect. Because of this, the reported treatment effects are likely to be underestimates of what would have been found if measures of peripheral disease could have been done at the SHEP baseline.
The SHEP trial reported the beneficial effects of antihypertensive therapy in the prevention of stroke and other cardiovascular events, and these results have been confirmed by other studies.24 25 The data presented here demonstrate a treatment effect on cardiovascular events long after the end of the SHEP trial, when most of the placebo group had initiated therapy. This speaks to the chronic nature of atherosclerosis. The mechanism by which antihypertensive therapy reduces cardiovascular event rates is not completely understood. We have found in SHEP that progression rates of carotid atherosclerosis were lower among those receiving active treatment.3 Assuming that disease in the carotid arteries is a marker for what is ongoing in the coronary and intracerebral circulations, a slowing of atherosclerosis progression is likely to be at least part of the reason for the beneficial effects of antihypertensive therapy demonstrated by SHEP. A slowing of the progression of disease among the active treatment group during the SHEP trial would result in reduced event rates beyond the end of the trial, as observed here.
The cardiovascular event rate was very low among the group with no evidence of disease who were assigned to the active treatment group. One can conclude that these individuals had not yet responded to the hypertensive insult with the development of detectable disease. It is possible that if systolic hypertension is treated early enough, the associated cardiovascular risk may be negated. Individuals with systolic hypertension have more clinical events26 as well as more subclinical disease as measured by noninvasive techniques.27 28 29 Research has indicated that the adverse effects of hypertension are linear and begin with relatively low levels of systolic blood pressure.26 A follow-up study of the 361 662 men screened for the Multiple Risk Factor Intervention Trial (MRFIT) and followed up for 11 years revealed that most of the excess deaths occurred in those whose systolic blood pressures were in the 140 to 159 mm Hg range. Systolic blood pressures in this range are now referred to as stage I hypertension.30 In the Cardiovascular Health Study, stage I hypertension was found to be strongly related to subclinical disease,27 including left ventricular hypertrophy, silent myocardial infarction, and increased intima-media thickness of the carotid artery.
It is thus clear that in some individuals the atherosclerotic process develops in association with lower levels of systolic blood pressure. Because individuals exhibit varying degrees of susceptibility to specific risk factors, observing the atherosclerotic process through noninvasive means might provide us with an indication of an individual's vascular response to the hypertensive insult. This might be useful in making treatment decisions, as it has been suggested that blood pressure treatment should be prescribed based on patient risk rather than the absolute level of a patient's blood pressure.31 Clinical trials have shown the benefits of treating systolic hypertension of 160 mm Hg or greater. However, individuals with systolic blood pressures in the 140 to 159 mm Hg range and accompanying evidence of subclinical atherosclerosis are also likely to benefit from antihypertensive therapy. Clinical trials evaluating this are an important next step in hypertension research.
In summary, individuals with systolic hypertension and evidence of either clinical or subclinical atherosclerosis are at high risk for subsequent cardiovascular events. While there is evidence of an antihypertensive treatment effect for all participants, targeting the group with evidence of either clinical or subclinical disease has the potential to prevent the largest number of cardiovascular events. The antihypertensive treatment effect has persisted well beyond the end of the SHEP trial, underscoring the importance of treatment. Individuals with no detectable disease who were assigned to active blood pressure treatment had the lowest event rates, suggesting that early treatment for systolic hypertension might negate most of the associated cardiovascular risk.
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Acknowledgments |
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This study was supported by National Institutes of Health grant HL-39871. This study was done during the tenure of an established investigatorship from the American Heart Association.
Received March 8, 1995; revision received April 28, 1995; accepted May 5, 1995.
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References |
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