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(Stroke. 1998;29:1333-1340.)
© 1998 American Heart Association, Inc.

Original Contributions

Risk Factors for Stroke and Type of Stroke in Persons With Isolated Systolic Hypertension

Barry R. Davis, MD, PhD; Thomas Vogt, MD; Philip H. Frost, MD; Alfredo Burlando, MD; Jerome Cohen, MD; Alan Wilson, PhD; Lawrence M. Brass, MD; William Frishman, MD; Thomas Price, MD; Jeremiah Stamler, MD; for the Systolic Hypertension in the Elderly Program Cooperative Research Group

From the University of Texas School of Public Health, Houston (B.R.D.); Cancer Research Center of Hawaii, Honolulu (T.V.); University of California, San Francisco (P.H.F.); University of California, Davis (A.B.); St Louis University School of Medicine (Mo) (J.C.); Robert Wood Johnson Medical School, New Brunswick, NJ (A.W.); Yale University School of Medicine, New Haven, Conn (L.M.B.); Albert Einstein School of Medicine, Bronx, NY (W.F.); University of Maryland School of Medicine, Baltimore (T.P.); and Northwestern University Medical School, Chicago, Ill (J.S.).

Correspondence to Barry R. Davis, MD, PhD, University of Texas School of Public Health, 1200 Herman Pressler St, Houston, TX 77030. E-mail davis{at}utsph.sph.uth.tmc.edu

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose—We sought to determine risk factors for stroke and stroke type in persons with isolated systolic hypertension (ISH).

Methods—We performed proportional hazards analyses of data from the Systolic Hypertension in the Elderly Program, a double-blind, randomized, placebo-controlled trial of 4736 persons aged 60 years with ISH (systolic blood pressure, 160 to 219 mm Hg; diastolic blood pressure, <90 mm Hg). One treatment group received chlorthalidone (12.5 to 25 mg/d) with step-up to atenolol (25.0 to 50.0 mg/d) or reserpine (0.05 to 0.10 mg/d), if needed. The other treatment group received matching placebo. The main outcome measures were stroke, stroke or transient ischemic attack [TIA], and stroke types: ischemic (including lacunar, atherosclerotic, and embolic) and hemorrhagic.

Results—During an average follow-up of 4.5 years, 384 strokes or TIAs and 262 strokes (including 217 ischemic, 66 lacunar, 26 atherosclerotic, and 25 embolic strokes) were documented. In multivariate analyses, placebo treatment, older age, smoking, history of diabetes, higher systolic blood pressure, lower HDL cholesterol, and ECG abnormality were significantly associated (P<0.05) with increased incidence of stroke or TIA, stroke, or ischemic stroke. Greater lacunar stroke risk was significantly related to placebo treatment, older age, history of diabetes (relative risk [RR]=3.03; 95% confidence interval [CI], 1.70 to 5.40), and smoking (RR=3.04; 95% CI, 1.73 to 5.37). Greater atherosclerotic and embolic stroke risk were significantly related to presence of carotid bruit (RR=5.75; 95% CI, 2.50 to 13.24) and older age (RR=1.65 per 5 years; 95% CI, 1.25 to 2.18), respectively.

Conclusions—In older persons with ISH, history of diabetes and smoking are important risk factors for lacunar stroke, whereas carotid bruit and age are important risk factors for atherosclerotic and embolic stroke, respectively.

Key Words: clinical trials • hypertension • lacunar infarction • stroke, ischemic

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Risk factors for stroke have been derived from analyses of data collected during prospective and case-control studies of men and women.^{1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37} Reported predisposing factors are high blood pressure, older age, male sex, black race, history of coronary heart disease, stroke, TIA, diabetes mellitus, sickle cell disease, presence of carotid bruit, atrial fibrillation, cigarette smoking; alcohol consumption, elevated serum cholesterol, elevated hematocrit, LVH, higher BMI, and orthostatic hypotension.^{1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37} Few reports have assessed risk factors for stroke in older persons^{33 34 35 36 37} and in those with ISH, and few have had the power to examine how risk factors differ for varying types of strokes. This is one of very few opportunities to assess risk factors prospectively in a major cohort.

The purpose of this article is to use data from the Systolic Hypertension in the Elderly Program (SHEP) to assess risk factors for the following cerebrovascular disease outcomes—stroke, stroke plus TIA, ischemic stroke, hemorrhagic stroke, lacunar stroke, atherosclerotic stroke, and embolic stroke—among older persons with ISH.

SHEP was a double-blind, randomized, placebo-controlled trial of treatment for ISH in persons aged 60 years and older. Its primary objective was to determine whether antihypertensive drug treatment reduced risk of total stroke (nonfatal or fatal) in a multiethnic cohort of men and women aged 60 years and older with ISH.^{38 39 40} Secondary goals were to determine whether treatment of ISH would reduce coronary and cardiovascular disease incidence as well as cause-specific and all-cause mortality.

The trial showed a 36% reduction in incidence of stroke (P<0.001), a 27% reduction in coronary heart disease (P=0.015), and a 33% reduction in combined incidence of stroke or coronary heart disease (P<0.001). There was also a 25% reduction in the incidence of TIA (P=0.089).⁴⁰

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
SHEP design and methods have been reported in detail.^{38 39 40} The study recruited 4736 participants aged 60 years or older with ISH, defined as mean SBP of 160 to 219 mm Hg and DBP <90 mm Hg. Persons were excluded if they had a history and/or signs of specified major cardiovascular diseases, other major diseases, or medical management problems. The study was approved by a review board at each institution, and participants gave informed consent for screening and later study participation.

Participants were randomized in a double-blind manner. One treatment group received chlorthalidone (12.5 to 25 mg/d) with step-up to atenolol (25.0 to 50.0 mg/d) or reserpine (0.05 to 0.10 mg/d), if needed. The other treatment group received matching placebo. Baseline SBP was used to establish a goal blood pressure for each participant. For individuals with SBP 180 mm Hg, goal was a reduction to <160 mm Hg. For those at 160 to 179 mm Hg, goal was a reduction of 20 mm Hg. Blood pressure above escape criteria, despite maximal stepped-care therapy, was an indication for prescribing open label active therapy.

The average follow-up of SHEP participants was 4.5 years. They were seen monthly until their SBP reached goal level or until the maximum level of stepped-care treatment was reached. All participants had quarterly visits from date of randomization. An ECG was also done at entry and at the second and final annual visits.

Blood Sampling, Laboratory Methods, and ECG Readings
Baseline blood samples were obtained at the second baseline visit, immediately before randomization. Sixty-four percent of all blood samples were collected with the patients in a fasting state. Lipids determined included TC, HDL-C, and triglycerides. Non–HDL-C, the difference between TC and HDL-C, was calculated for all participants with these measures at baseline. LDL-C was estimated in those individuals fasting at baseline and with triglycerides <4.50 mmol/L.⁴¹ Methods of analysis and external laboratory surveillance have been described.⁴²

An ECG abnormality was defined as one or more of the following Minnesota codes: 1.1 to 1.3 (Q/QS), 3.1 to 3.4 (high R waves), 4.1 to 4.4 (ST depression), 5.1 to 5.4 (T-wave changes), 6.1 to 6.8 (atrioventricular conduction defects), 7.1 to 7.8 (ventricular conduction defects), 8.1 to 8.6 (arrhythmias), and 9.1 to 9.3 and 9.5 (miscellaneous items).^{43 44} ECG abnormalities were classified further as either ischemia (codes 1.1 to 1.3, 3.1 to 3.4, 4.1 to 4.4, and 5.1 to 5.4) or arrhythmia or conduction defect (codes 6.1 to 6.8, 7.1 to 7.8, 8.1 to 8.6, 9.1 to 9.3, and 9.5).

End Point Ascertainment
Total stroke was the primary end point. Stroke was defined as rapid onset of a new neurological deficit attributed to obstruction or rupture in the cerebral arterial system.^{38 39} The defined deficit had to persist for at least 24 hours unless death supervened and had to include specific localizing findings confirmed by neurological examination and by CT or MRI scan, if available, with lack of evidence of an underlying nonvascular cause. Fatal stroke determination was based on either autopsy or death certificate diagnosis plus data on preterminal hospitalization with definite diagnosis of stroke.

TIA was defined as rapid onset of focal neurological deficit lasting more than 30 seconds and less than 24 hours, presumed to be due to cerebral ischemia and without evidence of underlying nonvascular cause.

For suspected stroke or TIA, a standardized neurological evaluation was performed by a SHEP neurologist. This evaluation and notes from the attending neurologist, scans, other studies of the brain, and any additional information were forwarded to the coordinating center. Death certificates and autopsy reports were obtained for decedents. For hospitalizations and nursing home admissions, discharge or admission papers were obtained.

CT or MRI films were read independently according to specified criteria by two neuroradiologists. Discrepancies between the two readings were adjudicated by a SHEP neurologist. The adjudicated reading was used by the three coding physicians, two of whom were neurologists, in confirming possible neurological events. These physicians were blinded to randomization allocation.

The method of determining stroke type (hemorrhagic, ischemic, or unknown) was similar to that used in the Stroke Data Bank.⁴⁵ Hemorrhagic stroke was diagnosed if intracranial bleeding was found by CT scan, MRI, lumbar puncture, or at autopsy and there was no evidence on the brain image of bleeding late into an ischemic infarction. Ischemic stroke was diagnosed when a focal deficit was present and no blood was observed in the brain image or was found by lumbar puncture. Stroke type unknown was diagnosed when the definition of stroke was satisfied but there was insufficient evidence to determine whether the stroke was hemorrhagic or ischemic. Hemorrhagic strokes were classified as due to subarachnoid hemorrhage if the blood was seen in the subarachnoid space and as intraparenchymal if the blood was seen within the brain substance itself.

Ischemic strokes were subdivided into lacunar, embolic, atherosclerotic, or other/unknown subtypes on the basis of clinical information and the brain image. The algorithm for deciding in which of the categories the ischemic stroke would be placed is delineated in Table 1.

View this table: [in this window] [in a new window]   Table 1. Definitions for Subtypes of Ischemic Strokes

Statistical Methods
Descriptive statistics were determined for baseline characteristics. The outcomes were time to first event (eg, stroke, stroke or TIA, ischemic stroke). For strokes and strokes plus TIA, an individual was censored at the time of nonstroke death, loss to follow-up (10 individuals), or the completion of the study. For stroke subtypes, an individual was censored at the time of nonstroke death, loss to follow-up (10 individuals), the completion of the study for those who did not have a stroke, or the time of stroke for those who had a different subtype of stroke. For example, for the outcome of lacunar stroke, individuals were (1) censored at the time of loss to follow-up if they were lost to follow-up without having had a lacunar stroke, (2) censored at the time of death if they died from a cause that was not classified as lacunar stroke, (3) censored at the time of stroke if the stroke was not classified as lacunar, (4) censored at the end of the study if they completed the study without having had a lacunar stroke, or (5) counted as an event at the time of a lacunar stroke if they experienced one.

Cumulative event rates were calculated by life-table methods. RRs and percent changes were calculated by proportional hazards regression⁴⁶ based on the entire duration of follow-up. Univariate regression analyses were done to explore potential risk factors. Multivariate regression analyses were also done to examine risk factors adjusted for potential confounding covariates. The number of factors included in the multivariate models was limited to approximately 10% of the total number of events under consideration.^{47 48} These factors included randomization group, age, sex, SBP, pulse, presence of carotid bruits, current smoking, history of diabetes, history of stroke, intermittent claudication, alcohol use, education, HDL-C, uric acid, hematocrit, ECG abnormalities, and BMI (and its square term).

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Baseline Findings
Previous reports have presented detailed data on baseline findings for SHEP participants overall and for subgroups.⁴⁰ Table 2 presents data on the baseline variables used in this report.

View this table: [in this window] [in a new window]   Table 2. Baseline Characteristics

The mean age of participants was 72 years; 57% were women; ethnicities were 82% white, 14% black, 2.5% Asian, 1% Hispanic, and 0.5% others. Of all participants, 1.4% reported a history of stroke, and 4.9% reported a history of myocardial infarction. Stroke with apparent residual effects and myocardial infarction within 6 months of randomization were exclusion criteria. On physical examination, 7% had carotid bruits. Mean SBP was 170.3 mm Hg; mean DBP was 76.6 mm Hg. Approximately 60% had an ECG abnormality.

Stroke and Stroke Plus TIA Incidence, Active Treatment, and Placebo Groups
By life-table analyses, 5-year cumulative stroke rates were 5.1/100 for the active treatment group and 7.9/100 for the placebo group. On the basis of proportional hazards regression analysis, RR was 0.64 (95% CI, 0.50 to 0.82). Absolute reduction in 5-year risk of stroke was 30/1000. Corresponding data for coronary heart disease were RR of 0.75 (95% CI, 0.60 to 0.94) and absolute reduction in 5-year risk of 15/1000; for incidence of all major cardiovascular diseases, RR was 0.67 (95% CI, 0.55 to 0.82), and absolute reduction in 5-year risk was 34/1000.

Relation of Baseline Variables to Incidence of Stroke, Stroke Plus TIA, and Stroke by Type: Univariate Analyses
Stroke
For stroke and all other outcomes, only factors that showed statistical significance are displayed in Table 3. Assignment to placebo treatment, older age, higher SBP, higher pulse, current smoking, history of diabetes, lower HDL-C, history of stroke, presence of ECG abnormality, higher serum glucose, and carotid bruit were significantly (P<0.05) related to increased stroke risk (Table 3). With classification of ECG abnormality into ischemic and conduction/arrhythmic, only ischemic abnormality was significantly related to stroke. Race, sex, prior antihypertensive drug use, hematocrit, ECG LVH, DBP, orthostatic hypotension, and alcohol consumption were not significantly related to stroke incidence.

View this table: [in this window] [in a new window]   Table 3. Univariate Cox Regressions

Stroke Plus TIA
Results for the broader cerebrovascular disease end point of stroke plus TIA were similar to the foregoing with a few differences. Additional statistically significant factors included DBP, history of cardiovascular disease, intermittent claudication, and ECG LVH (Table 3).

Major Stroke Types: Ischemic and Hemorrhagic
There were 217 ischemic strokes, 28 hemorrhagic strokes, and 17 strokes that could not be classified into either of these categories. Assignment to placebo treatment, older age, black race, higher SBP, current smoking, history of diabetes, history of myocardial infarction, carotid bruit, ECG abnormality, lower HDL-C, higher hematocrit, higher serum glucose, and higher TC to HDL-C and non–HDL-C to HDL-C ratios were significantly (P<0.05) related to increased incidence of ischemic stroke (Table 3). With classification of ECG abnormality into ischemic and conduction/arrhythmic, only ischemic abnormality was significantly related to ischemic stroke.

Since there were fewer hemorrhagic strokes than ischemic strokes, the power to delineate factors significantly associated with this outcome is low. BMI had a significant quadratic relationship with hemorrhagic stroke. Those with low and high BMIs had an increased risk. History of stroke, lower serum uric acid, and estrogen use in women were associated with increased hemorrhagic stroke risk.

Ischemic Stroke Subtypes: Lacunar, Atherosclerotic, and Embolic
There were 66 lacunar, 26 atherosclerotic, 25 embolic, and 100 unknown type ischemic strokes. Assignment to placebo treatment, older age, higher SBP, current smoking, history of diabetes, higher serum glucose, and higher TC to HDL-C and non–HDL-C to HDL-C ratios were significantly (P<0.05) related to increased incidence of lacunar stroke (Table 2). Carotid bruit and higher LDL-C to HDL-C ratio were significantly (P<0.05) related to increased incidence of atherosclerotic stroke, although the latter factor could only be evaluated in a subset of participants with fasting blood specimens (Table 3). Older age, lower DBP, and ECG abnormality were significantly (P<0.05) related to increased incidence of embolic stroke (Table 3). With classification of ECG abnormality into ischemic and conduction/arrhythmic, only ischemic abnormality was significantly related to embolic stroke risk.

Relation of Baseline Variables to Incidence of Stroke, Stroke Plus TIA, and Stroke by Type: Multivariate Analyses
Stroke and Stroke Plus TIA
In multivariate analyses, several baseline traits remained significantly related (P<0.05) to increased risk of stroke and stroke plus TIA (Table 4), including placebo treatment assignment, older age, current smoking, history of diabetes, higher SBP, lower HDL-C, and ECG abnormalities. Higher pulse was significantly related to increased stroke risk. Similar results were obtained within each treatment group (active and placebo).

View this table: [in this window] [in a new window]   Table 4. Multivariate Cox Regressions*

Major Stroke Types: Ischemic and Hemorrhagic
Placebo treatment assignment, older age, current smoking, history of diabetes, higher SBP, lower HDL-C, and ECG abnormalities were significantly related to increased ischemic stroke risk in the multivariate analysis (Table 4).

History of stroke and BMI were significantly related to increased hemorrhagic stroke risk (Table 4). BMI had a significant quadratic relationship with hemorrhagic stroke. Those with low and high BMIs had an increased risk.

In further multivariate analyses, aspirin use at baseline was not significantly associated with ischemic or hemorrhagic stroke risk. However, in an analysis among women, estrogen use at baseline was associated with a significant increase in hemorrhagic stroke risk (RR=4.87; 95% CI, 1.49 to 15.90).

Ischemic Stroke Subtypes: Lacunar, Atherosclerotic, and Embolic
Placebo treatment assignment, older age, history of diabetes (RR=3.03; 95% CI, 1.70 to 5.40), and smoking (RR=3.04, 95% CI, 1.73 to 5.37) were significantly related to increased lacunar stroke risk in the multivariate analysis (Table 4). Carotid bruit (RR=5.75; 95% CI, 2.50 to 13.24) and older age (RR=1.65 per 5 years; 95% CI, 1.25 to 2.18) were significantly related to increased atherosclerotic and embolic stroke risk, respectively, in the multivariate analysis (Table 4). Increased alcohol intake (RR=0.31 for 1 drink per week) and ECG abnormality (RR=2.07) were of borderline significance (P0.055) for decreased atherosclerotic and increased embolic stroke risk, respectively,

The multivariate models were run separately for all of the above outcomes within each treatment group. The results were essentially similar.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
In persons aged 60 years and older with ISH, risk factors for stroke or stroke and TIA as a combined end point, in multivariate analyses, were no antihypertensive treatment, older age, higher SBP and heart rate, lower HDL-C, cigarette smoking, history of diabetes mellitus, history of stroke, and presence of ECG abnormality. With the exception of ECG abnormality, which has only been previously reported as significantly related to stroke incidence in Manolio et al,³³ our data confirm those reported in previous studies. There are reports that ECG signs of ventricular hypertrophy are associated with increase in stroke risk.^{2 3 19} In SHEP, the major ECG abnormality that contributes to stroke risk is the ischemic component.

SHEP data contribute to understanding causes of and potential for reduction of stroke. The primary risk factors identified in SHEP are those often identified as contributors to atherosclerosis or markers of established atherosclerotic disease, and benefit resulted from antihypertensive treatment. SHEP active antihypertensive therapy was associated with a 36% reduction in incidence of stroke. The reduction in stroke rate at 5 years was estimated at 30/1000. This large effect occurred even though 35% of those assigned to placebo took known antihypertensive medication during the trial. This reduction was seen in varying degrees across types of stroke.

Within the large category of ischemic stroke, lacunar stroke risk appears to be associated particularly with smoking and history of diabetes, whereas atherosclerotic and embolic stroke risk appears to be related especially to signs of established cardiovascular disease, eg, carotid bruit and ECG abnormality (although of borderline significance). Carotid bruit may indicate some degree of carotid stenosis, which is known to be significantly associated with stroke incidence.^{32 33} Although atherosclerotic stroke includes presence of a carotid bruit in its definition, other stroke subtypes occurred in individuals with carotid bruits. In SHEP, of the 16 people with bruits who had a classifiable stroke, 8 (50%) were atherosclerotic. In addition, embolic stroke includes the presence of atrial fibrillation or recent myocardial infarction in its definition, either of which might have been noted on the baseline ECG. Of the 99 people with baseline ECG abnormalities who had a classifiable stroke, 21 (21%) had embolic stroke. Among these 21 individuals, none had atrial fibrillation, and only three had some evidence of old infarction. These three participants had no clinical history of a prior MI, and they experienced their strokes between 20 and 27 months after entry into the trial.

Risk factors for lacunar stroke found in past studies include diabetes, smoking, hypertension, and physical inactivity.^{11 26} In SHEP, diabetes and smoking were significantly related to lacunar stroke risk. All subjects in SHEP had systolic hypertension; those randomized to active treatment experienced reduction in their risk of lacunar stroke. Physical activity was not measured in SHEP, but those with higher baseline heart rate did have higher risk.

According to the lacunar hypothesis, hypertensive small-vessel disease is the most important cause of lacunar stroke as opposed to the causes of atherosclerosis and embolism.²⁶ In addition, diabetes mellitus may cause microatheroma in small vessels, and such changes may be present in lacunar infarction.²⁶⁷ In SHEP, lacunar strokes accounted for 56% (66/117) of the classifiable ischemic strokes and the largest reduction in type of ischemic strokes between treatment groups.

Stroke and ischemic stroke risk factors found in other studies were in general agreement with those found in SHEP. A recent review article²⁷ listed ranges of RRs for modifiable ischemic stroke risk factors that were similar to those of SHEP: RRs of 1.5 to 3.0 (2.3 in SHEP) for diabetes; 1.5 to 2.9 (1.8 in SHEP) for cigarette smoking; and 2.0 to 4.0 for cardiac disease (1.4 in SHEP for ECG abnormality). A recent case-control study showed that TIAs, diabetes, smoking, and ischemic heart disease were risk factors for ischemic stroke.²⁸ HDL-C was inversely associated with ischemic stroke mortality in one study by a magnitude similar to that found for ischemic stroke risk in SHEP.³¹ In addition, the other factors in that study associated with ischemic stroke mortality—age, SBP, diabetes, and smoking—were significant risk factors for ischemic stroke in SHEP. Among Japanese-American men in the Honolulu Heart Program, older age, elevated SBP, increased glucose, smoking, LVH by ECG, and history of CHD were significantly associated with increased thromboembolic stroke risk.²⁴ Elevated blood pressure, cigarette smoking, diabetes, elevated serum cholesterol, and history of myocardial infarction were associated with increased nonhemorrhagic ischemic stroke death risk in long-term follow-up of those screened in the Multiple Risk Factor Intervention Trial.²³ In a case-control study to evaluate the effect of alcohol, Palomaki and Kaste²¹ showed that light to moderate alcohol intake has an inverse association with the risk of ischemic stroke. For atherosclerotic strokes in SHEP, there appeared to be an association (69% lowered risk) with moderate alcohol intake (P=0.055). In a prospective study of a large cohort of men in England, elevated hematocrit was an independent risk factor for all stroke, and this was most apparent in those with hypertension.²⁵ In SHEP, there was a 12% lowered risk associated with a 5% higher hematocrit (P=0.06).

In a case-control study from the Melbourne Risk Factor Study, hypertension was the most important risk factor for intracerebral hemorrhagic risk.²⁹ Low serum cholesterol and high BMI were also associated with an increased risk. Aspirin-like drugs were not associated with an increased risk. The results of studies examining the association between estrogen replacement therapy and stroke have been inconsistent.⁴⁹ The greater than 3.5-fold increase in hemorrhagic stroke risk seen in women in SHEP needs further clarification from other studies of stroke in women, especially hypertensive women.

Combining SHEP data with confirmed stroke risk factors from other studies indicates that patients with ISH plus one or more of the following traits are at considerably greater risk of stroke: high SBP and/or DBP without adequate therapeutic control, diabetes mellitus, low HDL-C, cigarette smoking, and history of stroke. These patients are also at greater risk of coronary heart disease.⁵⁰ Patients with hypertension who also have one or more of the other risk factors should be followed and treated comprehensively with particular care.

	Selected Abbreviations and Acronyms

 

BMI = body mass index CI = confidence interval DBP = diastolic blood pressure HDL-C = high-density lipoprotein cholesterol ISH = isolated systolic hypertension LDL-C = low-density lipoprotein cholesterol LVH = left ventricular hypertrophy RR = relative risk SBP = systolic blood pressure SHEP = Systolic Hypertension in the Elderly Program TC = total cholesterol TIA = transient ischemic attack

	Acknowledgments

 
The SHEP trial was supported by contracts from the National, Heart, Lung, and Blood Institute and the National Institute on Aging. Drugs were supplied by the Lemmon Company, Sellersville, Pa; Wyeth Laboratories and AH Robins Company, Richmond, Va; and Stuart Pharmaceutical, Wilmington, Del. It is a pleasure to acknowledge the contribution of the investigators and staff at the 16 clinical centers and coordination and service centers of the SHEP Cooperative Research Group.

	Footnotes

 
Complete listings of the Systolic Hypertension in the Elderly Program were published (JAMA. 1991;265:3255–3264).

Received December 29, 1997; revision received April 9, 1998; accepted April 9, 1998.

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