Major Risk Factors for Intracerebral Hemorrhage in the
Young Are Modifiable
Edward Feldmann, MD; Joseph P. Broderick, MD; Walter N. Kernan, MD; Catherine M. Viscoli, PhD;
Lawrence M. Brass, MD; Thomas Brott, MD; Lewis B. Morgenstern, MD;
Janet Lee Wilterdink, MD; Ralph I. Horwitz, MD
Downloaded from http://stroke.ahajournals.org/ by guest on June 14, 2017
Background and Purpose—To identify risk factors for intracerebral hemorrhage (ICH), we examined data from the
Hemorrhagic Stroke Project (HSP), a case-control study of hemorrhagic stroke among men and women aged 18 to
49 years.
Methods—Case subjects for the HSP were recruited from 44 hospitals in the United States. Eligibility criteria included an
ICH within 30 days preceding enrollment, no history of stroke or known brain lesion. For this report, we focused on
patients with primary ICH, defined as not associated with an aneurysm, arteriovenous malformation or other structural
lesion. Two control subjects were sought for each case subject. A multivariate regression analysis was performed to
determine risk factors for primary ICH.
Results—A total of 1714 patients with hemorrhagic stroke were identified for participation in the HSP. Of these, 217 cases
met the criteria for primary ICH. Cases with primary ICH were matched to 419 controls. Independent risk factors for
ICH included hypertension (adjusted odds ratio [OR], 5.71; 95% CI, 3.61 to 9.05), diabetes (adjusted OR, 2.40; 95%
CI, 1.15 to 5.01), menopause (adjusted OR, 2.50; 95% CI, 1.06 to 5.88), current cigarette smoking (adjusted OR, 1.58;
95% CI, 1.02 to 2.44), alcoholic drinksⱖ2/day (adjusted OR, 2.23; 95% CI, 1.16 to 4.32), caffeinated drinksⱖ5/day
(adjusted OR, 1.73; 95% CI, 1.08 to 2.79), and caffeine in drugs (adjusted OR, 3.55; 95% CI, 1.24 to 10.20).
Conclusions—Among young men and women, the major risk factors for primary ICH can be modified, suggesting that this
type of stroke may be preventable. Our findings for caffeine and menopause warrant further study. (Stroke. 2005;36:
1881-1885.)
Key Words: cerebral hemorrhage 䡲 risk factors
I
ntracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH) occur in 55 000 to 60 000 people in the
United States every year.1 The mortality of hemorrhagic
stroke is 40% to 50%.1 Therefore, prevention of hemorrhagic
stroke remains the most important means of reducing its
morbidity and mortality. Effective prevention requires understanding the factors underlying the occurrence of ICH and the
population subgroups at greatest risk. We have previously
reported on the risk factors for aneurysmal SAH in the
young.2
Only 20% of ICHs have a clear cause of arterial rupture
identified on brain imaging or cerebral angiography.1,3 Most
ICHs result from rupture of a small penetrating artery or
arteriole within the brain. ICHs in the deep subcortical
regions, cerebellum, and brain stem are the most common
locations for ICH and are thought to follow damage of small
penetrating arteries from sustained hypertension.1,4
In contrast, only 50% to 60% of cases with a lobar or
cortical hemorrhage have a history of hypertension.1,5 A small
percentage of lobar hemorrhages are attributable to identified
structural abnormalities such as vascular malformations or
tumors. The identification of amyloid deposition in cortical
arterial blood vessels in the 1970s identified amyloid angiopathy as associated with lobar hemorrhages in the elderly
(aged ⬎70 years).6 Amyloid deposition in leptomeningeal
blood vessels before the age of 60 years is rare in autopsy
studies.6
The Hemorrhagic Stroke Project (HSP) was a collaboration
between investigators of 4 clinical stroke centers and their
surrounding hospitals, the Food and Drug Administration,
and manufacturers of products containing phenylpropanalamine (PPA). The main purpose of the project was to
examine the association of PPA to risk of hemorrhagic stroke
in persons aged 18 to 49 years. Primary results of the HSP
Received February 9, 2005; final revision received April 5, 2005; accepted April 28, 2005.
From the Department of Clinical Neurosciences (E.F., J.L.W.), Brown Medical School, Providence, RI; Department of Neurology (J.P.B.), University
of Cincinnati, Ohio; Departments of Internal Medicine (W.N.K., C.M.V., L.M.B.), Neurology (L.M.B.), and Epidemiology and Public Health (L.M.B.),
Yale University School of Medicine, New Haven, Conn; Stroke Program (L.B.M.), University of Michigan, Ann Arbor; Mayo Medical School (T.B.),
Rochester, Minn; and Case Western Reserve University School of Medicine (R.I.H.), Cleveland, Ohio.
Correspondence to Edward Feldmann, MD, Brown Medical School, 110 Lockwood St, Suite 324, Providence, RI 02903. E-mail
[email protected]
© 2005 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org
DOI: 10.1161/01.STR.0000177480.62341.6b
1881
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September 2005
have been reported elsewhere.7 The goal of this analysis was
to study the risk factors for “primary ICH without a documented structural cause.”
Methods
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Between December 1994 and July 1999, we identified patients with
symptomatic subarachnoid or ICH from 44 hospitals in Connecticut,
Massachusetts, Ohio, Kentucky, Rhode Island, and Texas.7 Eligibility criteria for cases included: age 18 to 49 years, ability to
communicate and complete the interview within 30 days of stroke
event, no previously diagnosed brain lesion predisposing to hemorrhage (ie, arteriovenous malformation, tumor, aneurysm), and no
previous stroke. Cases were recruited in-person or by telephone as
soon as they were identified, provided their personal
physician approved.
An ICH was diagnosed by appropriate symptoms plus a CT or
MRI showing blood in the brain parenchyma. For the present
analysis, we focused on cases of primary ICH, including only those
cases without documented structural cause, such as an aneurysm or
arteriovenous malformations. The primary analysis for this report
includes patients with either negative angiograms or, if an angiogram
was not performed, a CT scan showing no evidence for an underlying lesion. The HSP did not direct physicians in their diagnostic
evaluation of these patients.
We attempted to identify 2 matched controls for each case using
random digit dialing. Matching criteria included telephone exchange,
gender, ethnic group (black versus nonblack), and age. All control
subject interviews had to be completed within 30 days of the stroke
of the case subject event to minimize seasonal differences in
exposures.
Trained researchers used a structured questionnaire to obtain
demographic, risk factor, behavioral, and pharmaceutical information from all subjects. Interviews were conducted in-person unless
the subject refused or a meeting could not be arranged within 30 days
of the focal time of the case subject.7 These interviews were essential
to the design of the HSP. Thus, prospective ascertainment of risk
factors studied in this analysis represents a prespecified secondary
aim of the HSP.
We computed the odds ratio (OR) and associated probability value
for the association between ICH and a subject characteristic or
exposure using exact conditional logistic modeling for matched sets.
To identify independent risk factors, dichotomous features with
P⬍0.10 for the bivariate association with ICH were considered for
inclusion in a multivariate logistic model using a forward selection
algorithm, with criterion for entry set at P⫽0.05. The multivariate
model was performed using asymptotic methods. Exact logistic
models were estimated by the LogXact Program, version 2.1 (Cytel
Software Corporation). Adjusted models were estimated using SAS
Version 8.0 (SAS Corporation).
Results
Between 1994 and 1999, 1714 patients with hemorrhagic
stroke were identified (Table 1). Of the 277 cases of ICH, 217
cases met the criteria for primary ICH. Two control subjects
were enrolled for 202 case subjects (93%) and 1 control
subject for 15 case subjects (7%). All control subjects were
matched to their case subjects on gender and telephone
exchange. Age matching was successful for 414 controls
(99%), and ethnicity matching was achieved for 404 controls
(96%).
In bivariate analyses (Table 2), compared with controls,
cases of primary ICH were more likely to have lower
educational achievement, have a history of hypertension,
diabetes, menopause, and hypothyroidism, to smoke and use
alcohol regularly, and to consume caffeine in beverages and
drugs.
TABLE 1.
Assembly of Cohort
No.
Hemorrhagic Strokes
1714
Ineligible
784
Died within 30 days
389
Not able to communicate within 30 days
194
Prior stroke
120
Prior brain tumor or AVM
48
In hospital⬎72 hours before stroke
33
Eligible
930
Not enrolled
222
Not contacted within 30 days
182
Refused
37
No doctor approval
3
Enrolled
708 (425 SAH; 277 ICH)
Spontaneous ICH subjects for present analyses
217
In the multivariate model of risk for primary ICH, the
highest OR for the association with ICH was observed for
hypertension (OR, 5.71; 95% CI, 3.61 to 9.05) (Table 3).
Other significant independent risk factors included diabetes,
menopause, current smoking, consumption of ⬎2 alcohol
beverages daily, and consumption of caffeine in beverages or
drugs. A separate multivariate model considering packs/day
(ⱖ1/day versus none or ⬍1/day) in model selection suggested a dose response for smoking ⱖ1 pack/day as a risk
factor (OR, 2.52; 95% CI, 1.47 to 4.32).
When a stratified, adjusted analysis was performed for the
variables displayed in Table 3, the ORs for men and women
were of similar magnitude for diabetes, cigarette use, caffeine
in drugs, and caffeine in drinks. The ORs were higher among
men compared with women for hypertension (8.42 versus
3.44) and alcohol use (2.69 versus 1.64).
Discussion
Hypertension is the dominant risk factor for ICH among men
and women aged 18 to 49 years in our study, although
diabetes, menopause, current smoking, heavy alcohol use,
and caffeine in beverages and drugs may also play a role.
Because hypertension, smoking, and regular alcohol consumption are modifiable and common in the young, some of
the severe morbidity and mortality associated with ICH in
persons aged 18 to 49 years is preventable.
In previous population-based case-control studies, ICH has
been consistently associated with advancing age, race (black
and Asian populations), hypertension, anticoagulant use, and
heavy alcohol use.1,8 –12 Hypertension is the most important
modifiable risk factor in these reports. Risk factors that have
been variably related to ICH include prior ischemic stroke,
diabetes, and prior aspirin use.12–14 More recently, smoking
has been clearly associated with risk for ICH in men15 and
women.16 Our data confirm the importance of hypertension
and the additional contributions of diabetes, smoking, and
regular alcohol use as risk factors for ICH in the young and
middle-aged population. Because alcohol use, in moderation,
Feldmann et al
TABLE 2.
Modifiable ICH in the Young
Subject Features and Risk of ICH
Cases
(n⫽217),
No. (%)
Controls
(n⫽419),
No. (%)
Female
95 (44)
180 (43)
Black
59 (27)
89 (21)
Age, y
Matched
OR
P
4 (2)
10 (2)
20–29
21 (10)
42 (10)
30–39
48 (22)
99 (24)
40–49
144 (66)
268 (64)
40 (19)
45 (11)
2.06
0.006
122 (56)
87 (21)
5.50
⬍0.0001
Education: ⬍12th grade
Hypertension
Diabetes
24 (11)
21 (5)
2.34
0.01
10 Family history
15 (7)
29 (7)
0.98
1.00
Body mass index⬍23 kg/m2
34 (16)
88 (21)
0.67
Polycystic kidney
0 (0)
1 (⬍1)
0.11
1.00
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Elevated cholesterol
31 (14)
70 (17)
0.83
0.51
Postmenopausal (% female)
24 (25)
20 (11)
2.84
0.006
Thyroid underactive
8 (4)
3 (1)
5.06
0.02
Thyroid overactive
2 (1)
2 (⬍1)
1.41
1.00
Tobacco
Never
86 (40)
181 (43)
Reference
Former
51 (23)
119 (28)
0.76
0.34
Current
80 (37)
119 (28)
1.51
0.07
139 (64)
302 (72)
Reference
⬍1pack/day
28 (13)
55 (13)
1.15
0.69
⬎1 pack/day
50 (23)
62 (15)
1.74
0.03
ETOH drinks⬎2/day*
33 (15)
42 (10)
1.76
0.05
Caffeinated drinks⬎5/day* (average)
65 (31)
102 (24)
1.42
0.09
Current tobacco*
None
Exposures in 3-day period
Cocaine†
4 (2)
6.61
0.16
Marijuana
14 (6)
22 (5)
2 (⬍1)
1.20
0.75
Aspirin
19 (9)
36 (9)
1.01
1.00
NSAIDS
0.15
36 (17)
91 (22)
0.71
Dextromethorphan hydrobromide
6 (3)
13 (3)
0.92
1.00
PPA
8 (4)
8 (2)
2.17
0.25
Other sympathomimetic (non-PPA)
Oral‡
17 (8)
37 (9)
0.86
0.74
Inhaled
2 (1)
14 (3)
0.29
0.12
Nasal
2 (1)
4 (1)
1.00
1.00
1 (⬍1)
2 (⬍1)
1.00
1.00
1.00
Stimulant (non-PPA)
Warfarin
Caffeine (in drugs)§
1 (⬍1)
13 (6)
3 (1)
0.67
10 (2)
2.32
0.07
0 (0)
2.00
0.67
Nicotine (in drugs)§
1 (⬍1)
Oral contraceptive use (% females)
7 (7)
17 (9)
0.73
0.66
Hormone replacement (% females)
2 (2)
10 (6)
0.30
0.24
*Average daily use in preceding 6 months; †2 case subjects and 2 control subjects used cocaine
and marijuana in 3-day period; ‡pseudoephedrine hydrochloride, phenylephrine, ephedrine, and
epinephrine contained in medications; §as an ingredient in pharmaceuticals. ETOH indicates alcohol.
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September 2005
TABLE 3.
Adjusted ORs for Risk of ICH
Adjusted OR
95% CI
Hypertension
5.71
(3.61–9.05)
Diabetes
2.40
(1.15–5.01)
Postmenopausal
2.50
(1.06–5.88)
Current cigarette smoking
1.58
(1.02–2.44)
ETOH drinks ⬎2/day
2.23
(1.16–4.32)
Caffeinated drinks ⬎5/day
1.73
(1.08–2.79)
Caffeine (in drugs)
3.55
(1.24–10.20)
ETOH indicates alcohol.
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may be protective for ischemic stroke, our data suggest that
heavy alcohol use should be reduced, not eliminated. Unfortunately, the location of ICH in the HSP was not determined;
therefore, we could not confirm whether the majority of these
primary ICHs were in a deep location, classically associated
with ICHs attributable to hypertensive arteriolar vasculopathy
at autopsy.
We also could not confirm an association between ICH and
use of warfarin, as compared with other studies,12,17 probably
because of the younger age of our study population as
compared with studies that include ICH cases of all ages. The
prevalence of coumadin use in persons aged 18 to 49 years is
very low: only 4 subjects were exposed to coumadin in our
study. In addition, because the HSP excluded cases of ICH
and SAH who had any prior stroke, we are unable to address
the association between prior ischemic stroke and ICH.
Other studies have reported a higher risk of ICH among
persons with hypocholesteremia18 or a lower risk with hypercholesteremia.19 We could not examine this association. The
mechanism underlying this relationship is unknown.
Two very recent studies reported familial aggregation of
spontaneous ICH in cases of ICH as compared with controls
among stroke patients.12,20 We suspect that the lack of
familial aggregation in our patients may be attributable to the
relatively young age of our population. For example, in
elderly patients with lobar ICH, apolipoprotein E4 and E2
alleles have been associated with lobar ICH secondary to
presumed or documented amyloid angiopathy of cortical
blood vessels.12 Yet, amyloid deposition in cortical blood
vessels before the age of 50 years is extremely rare.6 Thus,
our population would be unlikely to demonstrate any familial
aggregation of ICH related to the genetics of amyloid
angiopathy.
Our study demonstrates an association between menopause
and primary ICH. There are sparse data on the risk of ICH
and menopause outside of trials studying hormone replacement therapy (HRT). Menopausal women have been reported
to have an increased risk of hemorrhagic stroke during the
first 6 months of HRT21 but not with HRT after an acute
myocardial infarction.22 More potent estrogens and the estrogen/progestin combination have been associated with a reduced risk of fatal ICH.23 In the Women’s Health Initiative,
estrogen/progestin was not associated with ICH in women
aged 50 to 79 years.24 The relationship between menopause
itself and ICH is not well understood and warrants further
study, particularly because treatment of menopausal symp-
toms may increase the risk of ischemic stroke. Also, this
subgroup is small and may be affected by the young age of
our cohort.
Our data also reveal an association of consumption of
caffeine in beverages and pharmaceuticals with primary ICH.
Our previous report of risk factors for aneurysmal SAH in the
HSP reported an association between caffeine in pharmaceuticals and aneurysmal SAH, which we regarded as suggestive.2 Case reports have described stroke associated with
pharmaceutical doses of caffeine in combination with PPA25
and studies involving hypertensive animals suggest that high
doses of caffeine in combination with PPA may result in
ICH.26 To our knowledge, this is the first report of ICH in
humans associated with caffeine in beverages or pharmaceutical agents. Our finding is based on a secondary analysis of
the HSP. Although suggestive, this should only be regarded
as hypothesis generating.
Biases that might have affected this analysis of the HSP
include selection bias and recall bias. Selection bias could be
related to our exclusion of dead and noncommunicative case
subjects. We excluded 34% of screened subjects because of
death or inability to participate in the interview. It is possible
that risk factors are different for ICH leading to death and
impaired communication compared with less severe ICH.
Another case-control study of risk factors for ICH is examining subjects with all degrees of severity.12,27 Information on
risk factor exposure is being obtained from medical records
and, when available, in-person structured interviews. Preliminary reports indicate that the distribution of risk factors
among fatal cases of ICH are similar to that among nonfatal
cases.12,27 These findings suggest that selection bias related to
eligibility criteria may not be a substantial weakness of our
study.
Recall bias refers to the tendency of case subjects, compared with controls, to have more or less accurate recall of
exposures. Although recall bias is discussed, efforts to demonstrate that it has an important effect on measured associations have commonly failed.28 In the HSP, we adopted several
safeguards against recall bias, including a highly structured
interview. In addition, to overcome greater stimulation for
recall among case subjects, we used a shorter interval
between the focal time and interview dates for control
subjects.
In summary, hypertension, smoking, and regular heavy
alcohol use are important, modifiable risk factors for ICH in
the young and middle-aged and present an opportunity for
prevention of this devastating type of stroke. Our data should
encourage physician identification and treatment of hypertension, smoking, and heavy alcohol use. The association of ICH
with menopause and caffeine consumption deserve further
investigation.
Acknowledgments
Supported by Novartis Consumer Health Inc, Thompson Medical
Company Inc, and Chattem Inc.
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Major Risk Factors for Intracerebral Hemorrhage in the Young Are Modifiable
Edward Feldmann, Joseph P. Broderick, Walter N. Kernan, Catherine M. Viscoli, Lawrence M.
Brass, Thomas Brott, Lewis B. Morgenstern, Janet Lee Wilterdink and Ralph I. Horwitz
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Stroke. 2005;36:1881-1885; originally published online August 4, 2005;
doi: 10.1161/01.STR.0000177480.62341.6b
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2005 American Heart Association, Inc. All rights reserved.
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