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Received December 29, 1997; final revision received April 9, 1998; accepted April 9, 1998.
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.).
Complete listings of the Systolic Hypertension in the Elderly Program were published (JAMA. 1991;265:32553264).
Correspondence to Barry R. Davis, MD, PhD, University of Texas School of Public Health, 1200 Herman Pressler St, Houston, TX 77030. E-mail
davis@utsph.sph.uth.tmc.edu
1998 American Heart Association, Inc.
1333
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1334
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
Davis et al
TABLE 1.
TABLE 2.
July 1998
1335
Baseline Characteristics
Mean
(SD) or %
Variable
Randomization, % active treatment
4736
50.0%
Age, y
4736
71.6 (6.7)
4736
86.1%
Sex, % men
4736
43.2%
SBP, mm Hg
4736
170.3 (9.4)
DBP, mm Hg
4736
76.6 (9.7)
Orthostatic hypotension, %
4732
12.1%
Pulse, bpm
4736
70.8 (10.6)
4736
33.3%
BMI, kg/m
4678
27.5 (5.0)
Education $12 y, %
4723
30.8%
Current smoking, %
4730
12.7%
History of diabetes, %
4734
10.1%
4736
29.8%
C. Atherosclerotic stroke: 1 or 2
History of MI, %
4736
4.9%
4736
5.4%
History of stroke, %
4736
1.4%
4736
7.1%
4736
7.1%
4734
2.3%
Intermittent claudication, %
4730
2.3%
4710
5.5%
ECG abnormality, %
4680
61.0%
1. All cases not classified by the above rules for lacunar, embolic, or
atherosclerotic infarction
4672
7.4%
4680
40.9%
2. All cases that could be classified in more than one of the above
categories
4680
29.1%
4736
17.6%
2690
7.6%
4571
6.02 (1.86)
4476
315.2 (83.2)
Hematocrit, %
4173
42.2 (4.6)
TC, mmol/L
4428
6.11 (1.15)
HDL-C, mmol/L
4432
1.39 (0.38)
Baseline Findings
NonHDL-C, mmol/L
4393
4.72 (1.14)
TC/HDL-C ratio
4393
4.69 (1.43)
NonHDL-C/HDL-C ratio
4393
3.69 (1.43)
2853
1.62 (1.00)
LDL-C, mmol/L
2740
3.98 (1.04)
LDL-C/HDL-C ratio
2740
3.02 (1.10)
Results
Fasting
Triglycerides, mmol/L
Fasting and triglycerides ,4.50 mmol/L
bpm indicates beats per minute; MI, myocardial infarction; CHD, coronary
heart disease; CABG, coronary artery bypass graft; PTCA, percutaneous
transluminal coronary angioplasty; and CVD, cardiovascular disease.
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
1336
Discussion
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
Davis et al
TABLE 3.
July 1998
1337
Variable
Randomization (active vs placebo)
Age (per 5 y higher)
Race (nonblack vs black)
Sex (men vs women)
DBP (per 10 mm Hg higher)
SBP (per 10 mm Hg higher)
Pulse (per 10 bpm higher)
BMI (per kg/m2 higher)
Education ($12 y vs ,12 y)
Smoking (current vs otherwise)
History of diabetes (yes vs no)
Alcohol use ($1 vs ,1 drink per week)
History of MI (yes vs no)
History of stroke (yes vs no)
Presence of carotid bruits (yes vs no)
History of CVD (CHD/stroke/TIA endarterectomy
(yes vs no)
Intermittent claudication (yes vs no)
ECG abnormalities (yes vs no)
Presence of LVH (yes vs no)
Estrogen use [women only] (yes vs no)
Serum glucose (per 1.67 mmol/L higher)
Serum uric acid (per 59.5 mmol/L higher)
Hematocrit (per 5% higher)
HDL-C (per 0.39 mmol/L higher)
TC/HDL-C ratio (per unit higher)
NonHDL-C/HDL-C ratio (per unit higher)
Fasting and triglycerides ,4.50 mmol/L
LDL-C/HDL-C ratio (per unit higher)
Stroke
(n5262)
Stroke or TIA
(n5384)
Ischemic
Stroke
(n5217)
Hemorrhagic
Stroke
(n528)
Lacunar
Stroke
(n566)
Atherosclerotic
Stroke
(n526)
Embolic
Stroke
(n525)
0.64
(0.50.82)
1.25
(1.151.37)
0.77
(0.551.06)
1.17
(0.911.49)
0.95
(0.851.07)
1.22
(1.091.37)
1.08
(0.971.21)
0.99
(0.971.02)
0.76
(0.571.00)
1.49
(1.082.06)
2.14
(1.562.93)
0.91
(0.641.28)
0.79
(0.421.49)
2.70
(1.395.25)
1.62
(1.102.40)
1.13
(0.721.78)
1.73
(0.923.26)
1.57
(1.202.05)
1.42
(0.952.14)
1.24
(0.702.19)
1.20
(1.111.29)
1.01
(0.921.11)
0.88
(0.781.00)
0.78
(0.690.91)
1.10
(1.021.20)
1.10
(1.021.20)
1.10
(0.951.28)
0.67
(0.550.83)
1.19
(1.101.28)
0.97
(0.731.29)
1.21
(0.991.47)
0.90
(0.820.98)
1.16
(1.051.27)
1.06
(0.961.16)
0.98
(0.961.00)
0.87
(0.701.09)
1.43
(1.091.87)
2.07
(1.592.69)
1.01
(0.771.37)
1.05
(0.861.66)
2.97
(1.745.06)
1.84
(1.352.52)
1.44
(1.022.03)
2.07
(1.283.38)
1.36
(1.101.69)
1.56
(1.132.16)
1.18
(0.731.91)
1.16
(1.081.24)
1.04
(0.971.13)
0.87
(0.671.12)
0.81
(0.720.91)
1.11
(1.041.19)
1.11
(1.041.19)
1.16
(1.031.31)
0.63
(0.480.83)
1.27
(1.151.39)
0.71
(0.501.00)*
1.07
(0.811.38)
0.91
(0.811.02)
1.22
(1.071.38)
1.17
(0.991.38)
1.00
(0.971.02)
0.80
(0.591.08)
1.60
(1.122.23)
2.29
(1.633.21)
0.88
(0.651.19)
0.76
(0.380.54)
1.79
(0.744.35)
1.76
(2.162.68)
0.87
(0.501.53)
1.67
(0.823.39)
1.53
(1.142.04)
1.53
(0.992.35)
0.98
(0.501.93)
1.17
(1.081.28)
1.06
(0.961.17)
0.86
(0.750.99)
0.78
(0.670.91)
1.13
(1.041.24)
1.13
(1.041.24)
1.11
(0.651.19)
0.47
(0.211.04)
1.11
(0.851.46)
1.33
(0.404.41)
1.19
(0.562.49)
1.39
(0.852.21)
1.06
(0.721.56)
1.15
(0.821.62)
0.97
(0.901.05)
0.61
(0.251.51)
1.51
(0.594.10)
0.35
(0.052.59)
0.79
(0.331.84)
z z z\
zzz
5.77
(1.3724.30)
1.04
(0.204.39)
1.67
(0.495.41)
1.81
(0.2211.82)
1.46
(0.633.10)
0.50
(0.073.65)
4.50
(1.4314.14)
1.11
(0.851.41)
0.73
(0.540.99)
1.12
(0.731.70)
1.02
(0.691.44)
0.85
(0.631.14)
0.85
(0.631.14)
0.85
(0.531.36)
0.53
(0.320.88)
1.27
(1.071.51)
0.65
(0.351.19)
1.01
(0.621.64)
1.03
(0.801.34)
1.24
(0.991.55)
1.20
(0.971.50)
1.00
(0.951.04)
0.55
(0.301.01)
2.48
(1.424.31)
2.78
(1.564.94)
1.10
(0.651.84)
0.62
(0.152.53)
1.16
(0.168.36)
0.87
(0.322.39)
0.65
(0.202.06)
1.35
(0.335.53)
0.96
(0.591.56)
1.77
(0.853.71)
1.05
(0.323.42)
1.28
(1.141.45)
1.01
(0.841.21)
0.87
(0.671.12)
0.81
(0.621.07)
1.21
(1.051.40)
1.21
(1.051.40)
1.06
(0.791.44)
0.99
(0.462.13)
1.26
(0.961.66)
4.01
(0.5429.57)
1.17
(0.542.53)
0.80
(0.611.04)
1.31
(0.921.86)
1.05
(0.731.50)
0.95
(0.871.03)
0.41
(0.141.19)
1.30
(0.453.78)
1.72
(0.594.98)
0.31
(0.091.03)
0.80
(0.115.88)
3.01
(0.4122.21)
6.03
(2.6313.87)
1.14
(0.274.81)
3.63
(0.8615.36)
2.21
(0.895.51)
0.52
(0.073.81)
z z z\
zzz
0.99
(0.691.43)
0.90
(0.671.21)
1.06
(0.681.67)
0.90
(0.591.37)
1.07
(0.821.39)
1.07
(0.821.39)
1.54
(1.022.33)
0.55
(0.241.25)
1.72
(1.302.27)
0.64
(0.241.71)
0.79
(0.351.78)
0.77
(0.600.99)
1.30
(0.911.87)
1.24
(0.871.76)
1.03
(0.961.11)
1.07
(0.462.47)
0.30
(0.042.24)
1.83
(0.635.32)
0.59
(0.221.59)
1.74
(0.417.37)
3.19
(0.4323.60)
1.18
(0.285.07)
1.20
(0.285.07)
1.84
(0.2513.61)
3.53
(1.2110.28)
2.46
(0.847.16)
0.83
(0.116.25)
1.07
0.771.48)
1.05
(0.781.41)
0.89
(0.601.31)
0.76
(0.471.21)
1.12
(0.861.46)
1.12
(0.86.46)
1.04
(0.661.63)
P,0.05.
BMI plus BMI2 was not significant, P.0.05.
BMI plus BMI2 was significant, P,0.05.
P.0.05.
\Not calculable because of lack of convergence in Cox regression.
1338
TABLE 4.
Stroke
(n5262)
Ischemic
Stroke
(n5217)
Hemorrhagic
Stroke
(n528)
Lacunar
Stroke
(n566)
Atherosclerotic
Stroke
(n526)
Embolic
Stroke
(n525)
0.70
0.60
0.66
0.49
0.53
zzz
0.53
(0.570.86)
(0.450.79)
(0.500.87)
(0.221.08)
(0.320.88)
zzz
(0.241.21)
0.21
1.24
1.32
zzz
1.40
zzz
1.65
(1.121.31)
(1.121.38)
(1.191.47)
zzz
(1.171.66)
zzz
(1.252.18)
zzz
1.28
zzz
zzz
zzz
zzz
zzz
(0.951.73)
zzz
zzz
zzz
1.15
zzz
1.17
zzz
zzz
1.12
zzz
zzz
zzz
zzz
(1.011.24)
(1.011.32)
(1.021.33)
zzz
zzz
1.15
1.14
zzz
zzz
1.19
zzz
1.08
zzz
zzz
zzz
5.75
zzz
zzz
Variable
Randomization (active vs placebo)
Age (per 5 y higher)
(0.981.20)
(1.011.30)
(1.011.30)
zzz
(0.951.48)
zzz
zzz
zzz
zzz
zzz
zzz
1.56
zzz
1.63
zzz
1.81
zzz
zzz
zzz
3.04
(2.5013.24)
zzz
zzz
(1.172.08)
(1.142.34)
(1.252.62)
zzz
(1.735.37)
zzz
zzz
zzz
3.03
zzz
zzz
zzz
zzz
2.03
1.80
2.29
(1.542.67)
(1.262.57)
(1.603.29)
2.41
2.13
zzz
zzz
5.86
(1.705.40)
zzz
zzz
zzz
(1.374.23)
(1.004.56)
zzz
(1.3924.80)
zzz
zzz
zzz
1.51
zzz
zzz
zzz
zzz
zzz
zzz
(0.902.52)
zzz
zzz
zzz
zzz
zzz
zzz
zzz
zzz
zzz
zzz
0.31
zzz
zzz
zzz
0.78
zzz
zzz
zzz
(0.091.03)
zzz
zzz
zzz
zzz
zzz
zzz
zzz
zzz
zzz
zzz
zzz
zzz
zzz
zzz
zzz
zzz
zzz
zzz
0.82
(0.571.06)
0.82
zzz
0.81
(0.730.93)
(0.700.96)
(0.690.95)
zzz
zzz
zzz
zzz
zzz
zzz
1.08
zzz
zzz
zzz
zzz
zzz
zzz
0.88
(0.971.20)
zzz
zzz
zzz
zzz
zzz
zzz
zzz
zzz
zzz
zzz
zzz
zzz
zzz
zzz
2.07
zzz
2.91
zzz
(0.835.16)
(0.998.56)
zzz
(0.771.01)
zzz
1.27
1.47
zzz
1.39
(1.011.59)
(1.091.99)
(1.021.90)
zzz
zzz
zzz
zzz
0.60
zzz
zzz
zzz
zzz
zzz
zzz
(0.430.82)
zzz
zzz
zzz
zzz
zzz
zzz
1.01
zzz
zzz
zzz
zzz
(1.001.01)
zzz
zzz
zzz
zzz
zzz
Ellipses indicate that variable was not included in the multivariate analysis.
P#0.05.
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.
Davis et al
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 smallvessel 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 mortalityage,
SBP, diabetes, and smokingwere 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 nonhemor-
July 1998
1339
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.
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Risk Factors for Stroke and Type of Stroke in Persons With Isolated Systolic Hypertension
Barry R. Davis, Thomas Vogt, Philip H. Frost, Alfredo Burlando, Jerome Cohen, Alan Wilson,
Lawrence M. Brass, William Frishman, Thomas Price and Jeremiah Stamler
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Stroke. 1998;29:1333-1340
doi: 10.1161/01.STR.29.7.1333
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