Stroke 2013 Wang 1833 9

Cholesterol Levels and Risk of Hemorrhagic Stroke
A Systematic Review and Meta-Analysis

Xiang Wang, MD*; Yan Dong, MD*; Xiangqian Qi, MD*; Chengguang Huang, MD; Lijun Hou, MD
Downloaded from http://stroke.ahajournals.org/ by guest on September 9, 2016
Background and PurposeCholesterol levels are inconsistently associated with the risk of hemorrhagic stroke. The purpose
of this study is to assess their relationships using a meta-analytic approach.
MethodsWe searched PubMed and Embase for pertinent articles published in English. Only prospective studies that
reported effect estimates with 95% confidential intervals (CIs) of hemorrhagic stroke for 3 categories of cholesterol
levels, for high and low comparison, or for per 1 mmol/L increment of cholesterol concentrations were included. We used
the random-effects model to pool the study-specific results.
ResultsTwenty-three prospective studies were included, totaling 1430141 participants with 7960 (5.6%) hemorrhagic
strokes. In high versus low analysis, the summary relative risk of hemorrhagic stroke was 0.69 (95% CI, 0.590.81)
for total cholesterol, 0.98 (95% CI, 0.801.19) for high-density lipoprotein cholesterol, and 0.62 (95% CI, 0.410.92)
for low-density lipoprotein cholesterol. In doseresponse analysis, the summary relative risk of hemorrhagic stroke for
1 mmol/L increment of total cholesterol was 0.85 (95% CI, 0.800.91), for high-density lipoprotein cholesterol was 1.11
(95% CI, 0.991.25), and for low-density lipoprotein cholesterol was 0.90 (95% CI, 0.771.05). The pooled relative risk
for intracerebral hemorrhage was 1.17 (95% CI, 1.021.35) for high-density lipoprotein cholesterol.
ConclusionsTotal cholesterol level is inversely associated with risk of hemorrhagic stroke. Higher level of low-density
lipoprotein cholesterol seems to be associated with lower risk of hemorrhagic stroke. High-density lipoprotein cholesterol
level seems to be positively associated with risk of intracerebral hemorrhage.(Stroke. 2013;44:1833-1839.)
Key Words: hemorrhagic stroke high-density lipoprotein cholesterol intracerebral hemorrhage
low-density lipoprotein cholesterol meta-analysis subarachnoid hemorrhage total cholesterol
independent risk factor for hemorrhagic stroke.8 In the post

hoc analysis of Stroke Prevention by Aggressive Reduction
in Cholesterol Levels (SPARCL) trial, although hemorrhagic
stroke was more frequent in individuals treated with atorvastatin, its relations with concentrations of TC or low-density
lipoprotein cholesterol (LDL-C) were not detected.3
Recent meta-analyses suggested no evidence that statins
were associated with ICH.9,10 However, stratified cholesterol
levels were not explored. Hence, we undertook this metaanalysis, aiming to investigate the relationships between
different categories of cholesterol and risk of hemorrhagic
stroke.
ypercholesterolemia has been well documented as a

modifiable risk factor for ischemic stroke.1 Currently,
lipid-lowering therapy with statins is widely used for patients
with ischemic stroke.2 However, concerns have been raised
about the accompanied risk of hemorrhagic stroke, mainly
including intracerebral hemorrhage (ICH) and subarachnoid
hemorrhage (SAH), which may be attributed to decreasing
serum cholesterol concentrations.3,4
In the early Japanese studies, the inverse relationship
between serum cholesterol level and increased risk of hemorrhagic stroke was first revealed.5 Later, in the Multiple Risk
Factor Intervention Trial, the risk of fatal ICH was found to
be 3 higher in those with total serum cholesterol (TC) <4.13
mmol/L than in those with values higher than that.6 In the
collaborative analysis of 12 Asian cohorts, a 27% increase
in risk of hemorrhagic stroke was shown for a 0.6 mmol/L
decrease in cholesterol concentrations.7 However, conclusions
were not consistent between studies. In the Korea Medical
Insurance Corporation Study, low TC was not shown to be an
Methods
Search Strategy
Two investigators (X.W. and Y.D.) independently searched PubMed
and Embase for prospective studies examining the association between cholesterol and the risk of hemorrhagic stroke. Three main
categories of cholesterol, including TC, high-density lipoprotein
Received February 28, 2013; accepted April 9, 2013.

From the Department of Neurosurgery, Changzheng Hospital, Second Military Medical University, Shanghai, China.
*Drs Wang, Dong, and Qi contributed equally to the article.
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.
113.001326/-/DC1.
Correspondence to Lijun Hou, MD, Department of Neurosurgery, Changzheng Hospital, Second Military Medical University, 415 Fengyang Rd,
Shanghai, China (E-mail lj_hou@hotmail.com); or Chengguang Huang, MD, Department of Neurosurgery, Changzheng Hospital, Second Military Medical
University, 415 Fengyang Rd, Shanghai, China (E-mail huang64@163.com).
2013 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.113.001326
1833
1834StrokeJuly 2013
cholesterol (HDL-C), and LDL-C, were investigated, respectively.
Hemorrhagic stroke mainly included ICH and SAH. The search was
limited to studies published between 1980 and January 2013. The
language was restricted to English. The detailed search strategy is
given in Methods in the online-only Data Supplement.
Selection Criteria
To be included, studies had to have a prospective design (prospective cohort, or nested prospective case-control study), and investigate
the association between cholesterol (TC, HDL-C, or LDL-C) and the
risk of hemorrhagic stroke (ICH, SAH, or both). The authors should
report effect estimates (risk ratio [RR], hazard ratio, or odds ratio)
and 95% confidential intervals (CIs) for >3 categories of cholesterol
concentrations, for the comparison between low and high concentrations, or for per 1 mmol/L increment. The detailed search strategy is
provided in Methods in the online-only Data Supplement.
Data Extraction and Quality Assessment

Three authors (X.W.,Y.D., and X.Q.Q.) extracted the data in standardized data-collection forms, and 2 authors (X.W. and Y.D.) assessed
the study quality. Three degrees for adjustment of confounders were
defined. The NewcastleOttawa Scale was used to evaluate the methodological quality.11 Details are described in Methods in the onlineonly Data Supplement.
Statistical Analysis
The RRs and associated 95% CIs were considered as the effect sizes.
We first used the random-effects model to calculate summary RRs and
95% CIs for the high versus low levels of cholesterol. Then doseresponse analyses were conducted to estimate the RRs and 95% CIs for
per 1 mmol/L increment of cholesterol concentration. Heterogeneity
was mainly assessed by the I2 statistic.12 We considered low, moderate,
and high I2 values to be 25%, 50%, and 75%, respectively.12 Subgroup
analyses and sensitivity analyses were also performed. A potential
nonlinear relationship between cholesterol level and hemorrhagic risk
was explored.13 Inter-rater reliabilities were calculated by Cohen
statistics, with 5 levels of agreement, namely poor (=0.000.20), fair
(=0.210.40), moderate (=0.410.60), good (=0.610.80), and
very good (=0.811.00).14 The Egger test was used to assess publication bias.15 All statistical analyses were performed with the STATA
software (version 12.0; Stata Corporation, College Station, TX). A
threshold of P<0.1 was used to decide whether heterogeneity or publication bias was present.15,16 In other ways, P values were 2 sided, with
a significance level of 0.05. Detailed data are provided in Methods in
the online-only Data Supplement.
Results
Literature Search
The results of study-selection process were shown in Figure1.
The initial search produced 453 studies from PubMed and
665 articles from Embase. After exclusion of duplicates and
irrelevant studies, 97 potentially eligible studies were selected.
After detailed evaluations, 23 studies were selected for final
meta-analysis. A manual search of reference lists of these studies did not yield any new eligible study. Agreement on selection of studies between 2 assessors was very good (=0.87).
Study Characteristics
Twenty-three were included consisting of 19 prospective
cohort studies,8,1734 and 4 nested case-control studies,3538
involving 1430141 participants with 7960 (5.6%) hemorrhagic stroke events (Table I in the online-only Data
Supplement). Four studies were conducted in American populations,20,25,29,36 9 in European populations,18,19,21,23,24,26,3335

and 10 studies in Asian populations.8,17,22,27,28,3032,37,38
Rodriguez et al25 separately investigated 2 cohorts, and the
Honululu Program had been reported earlier.17 However,
different aspects of the analysis raised concerns (Table
II in the online-only Data Supplement). Seven cohorts
only enrolled male participants,8,17,21,2427 1 study only
enrolled male smokers,21 and another only enrolled steelworkers.27 Most studies had a follow-up duration of more
than 10 years, and had a high degree of covariate adjustment, with 14 studies of +++,8,17,20,21,23,25,28,3034,36,38 5 of
++,19,22,27,35,37 and 4 of +.18,24,26,29 (Table II in the onlineonly Data Supplement) Cohorts and case-control studies
were assessed by NewcastleOttawa Scale (Tables III and
IV in the online-only Data Supplement). Most items had full
agreement, except for 2 items. For representativeness of
the exposed cohort, the agreement was 96% with a value
of 0.65. For comparability, the agreement was 92% with a
value of 0.75. Both items had good agreement.
Total Serum Cholesterol

High Versus Low
Seventeen studies compared the highest level with the lowest
level (or referent) categories of cholesterol.8,18,19,2124,2629,31,32,3437
Two studies compared the bottom level with a composite
higher level.17,20 Results of ICH and SAH were separately
reported in 5 studies,8,19,21,34,37 and those of different sexes were
separately assessed in 6 studies.1820,22,32,34 Only 1 study investigated the difference between 2 age groups.20 These separate
results were initially pooled in each study using a fixed-effects
model, which were further aggregated into the overall analysis, using a random-effects model. The summary RR was 0.69
(95% CI, 0.590.81; P<0.01; Figure2A), with evidence of
moderate heterogeneity (I2=57.6%; P<0.01). Publication bias
was detected by the Egger test (P=0.03).
DoseResponse Analysis
Seventeen studies reported RRs for categorized cholesterol
levels, or for per 1 mmol/L increment, including 14 prospective cohort studies,8,18,2129,31,32,34 and 3 nested case-control studies.3537 Four studies reported both RRs for categorical levels
and RRs for per 1 mmol/L increase,27,28,34,35 and 1 study only
reported RRs of per 1 mmol/L increase for 2 large cohorts.25
Thus, we included 17 articles with 18 data for doseresponse
analysis. The number of participants in each category was
not reported in 4 studies, and thus was calculated by estimation.18,21,26,28 The summary RR was 0.85 (95% CI, 0.80
0.91; P<0.01; Figure 2B), with high heterogeneity (I2=81%;
P<0.01). We detected a potentially nonlinear doseresponse
relationship (P<0.01; Figure3).
Sensitivity and Subgroup Analyses
The potential sources of heterogeneity were explored by
sensitivity and stratifying analyses. No significantly altered
result was shown when excluding studies 1 by 1. When
evaluating 1 confounding covariate, results stratified by it
were separately analyzed. Studies comparing high with low
levels, and studies assessing doseresponse associations
Wang et al Cholesterol Levels and Risk of Hemorrhagic Stroke 1835
Figure 1. The flow diagram for identifying eligible

studies. CI indicates confidence interval.
were explored, respectively. Overall, the inverse relationships

between cholesterol levels and risk of hemorrhagic stroke were
similarly significant in subgroups that were defined by sex,
sample size, and follow-up duration. However, in subgroups
of case-control design, SAH, + degree of adjustment,
and end point of hemorrhagic stroke mortality, the inverse

relationships were not statistically significant (Table V in the
online-only Data Supplement). Besides, in the dose-response
subgroup of European population, the inverse association was
not statistically significant.
Figure 2. Forest plots of total cholesterol levels and risk of hemorrhagic stroke. A, High vs low analysis. B, Per 1 mmol/L increment. CI
indicates confidence interval; and RR, risk ratio.
1836StrokeJuly 2013
results for different types of stroke or different sexes,21,34,35
which were aggregated using fixed-effect model for each
study. The summary RR was 1.05 (95% CI, 0.881.24;
P=0.60; Figure 4B), with low evidence of heterogeneity
(I2=35.1%; P=0.15). No potentially nonlinear doseresponse
relationship was detected (P=0.11; Figure5A).
Figure 3. Relative risk (solid line) with 95% CI (long dashed lines)
for the association of total cholesterol level with risk of hemorrhagic stroke in a restricted cubic spline random-effects model.
High-Density Lipoprotein Cholesterol

High Versus Low

Eight studies were available, including 5 prospective cohort
studies,21,29,31,33,34 and 3 nested case-control studies.35,36,38
Three studies reported separate results for different types
of hemorrhagic stroke, or different sexes,21,34,35 which were
aggregated together using a fixed-effects model for each
study. Overall, the summary RR was 0.98 (95% CI, 0.80
1.19; P=0.81; Figure4A), with little evidence of heterogeneity (I2=10.3%; P=0.35). Although the number of included
studies was small, publication bias was not revealed by the
Egger test (P=0.82).
Five prospective cohort studies,21,29,31,33,34 and 3 nested casecontrol studies were included. Three studies reported separate
Sensitivity and Subgroup Analyses

In sensitivity analyses, no significantly altered result was
shown when excluding studies 1 by 1. The stratified analyses were defined by study design, sex, stroke type, sample
size, study population, degree of adjustment, and follow-up
duration. Studies comparing high with low levels, and studies
assessing doseresponse associations were explored, respectively. In high versus low comparisons, the estimate was not
significant in any subgroup. In doseresponse analysis, positive relationships between HDL-C levels and risk of hemorrhagic stroke were significant in both subgroups of ICH and
SAH. A marginal significance was indicated by pooling 2
studies of American population (Table VI in the online-only
Data Supplement).
Low-Density Lipoprotein Cholesterol

High Versus Low
Four prospective cohort studies were included.2931,33 The summary RR was 0.62 (95% CI, 0.410.92; P=0.02; Figure 4C),
with some low evidence of heterogeneity (I2=43.3%; P=0.15).
In sensitivity analysis, when excluding the study by Imamura
et al,30 the result was more robust (RR=0.52; 95% CI, 0.37
0.72; P<0.01), with low level of heterogeneity (I2=11.1%;
P=0.33). Although the number of included studies was small,
publication bias was not detected by the Egger test (P=0.09).
Figure 4. Forest plots of high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) levels and risk of
hemorrhagic stroke. A, High vs low analysis of HDL-C. B, Per 1 mmol/L increment for HDL-C. C, High vs low analysis of LDL-C. D, Per 1
mmol/L increment for LDL-C. CI indicates confidence interval; and RR, risk ratio.
Figure 5. Relative risk (solid line) with 95% confidence interval (long dashed lines) for the associations of high-density lipoprotein cholesterol level (A) and low-density lipoprotein cholesterol level (B) with risk of hemorrhagic stroke in a restricted cubic spline random-effects
model.
Four prospective cohort studies were identified.2931,33 The
summary RR was 0.90 (95% CI, 0.771.05; P=0.18; Figure
4D), with moderate heterogeneity (I2=67%; P=0.03). In sensitivity analysis, when excluding the study by Noda et al,31
the summary RR was 0.93 of marginal significance (95% CI,
0.860.996; P=0.04) without evidence of heterogeneity (I2=0;
P<0.01). We did not detect a potentially nonlinear dose
response relationship (P=0.77; Figure 5B). Too few studies
precluded any meaningful subgroup analysis.
Discussion
Our findings showed a statistically significant inverse association between TC level and risk of hemorrhagic stroke. An
increment of 1 mmol/L in TC concentration was associated
with a 15% decreased risk of hemorrhagic stroke. Lower
LDL-C concentration was also associated with a higher risk
of hemorrhagic stroke. However, no significant association
between HDL-C and risk of hemorrhagic stroke was indicated.
In subgroup analyses of TC, the inverse relationship seemed
specifically robust for ICH but not for SAH, probably because
of their different pathological mechanisms.39 Statistically significant results were shown for prospective cohorts, but not
for nested case-control studies. The smaller number and less
strict design of case-control studies likely contributed to this
discrepancy. Results for studies with adjustment degree of
+ were not significant. Seemingly, the interaction between
multiple unadjusted confounders and TC leaded to weak conclusions. No significant association between TC and fatal
hemorrhagic stroke was detected either. For HDL-C, the risk
of ICH significantly increased for per 1 mmol/L increment.
Although significant inverse relation with risk of SAH was
indicated, its strength was limited by too few studies. In dose
response analysis of LDL-C, statistically significant inverse
association with hemorrhagic stroke was detected by excluding 1 study.31
Low cholesterol may play a role in promoting arterial medial
layer smooth muscle cell necrosis.36 The impaired endothelium
would be more susceptible to microaneurysms, which were
the chief pathological finding of ICH, thereby contributing
to the onset of hemorrhage.39 Another mechanism was speculated especially for the association between cholesterol levels
and mortality of hemorrhagic stroke.36 Cholesterol levels may

reflect the nutritional status of patients with ICH. Low cholesterol level may be a surrogate for nutritional deficiencies, a
harbinger of low-serum albumin, or a sign of debilitating diseases,20 thus being predisposed to increased stroke mortality.40
Recent meta-analyses showed no evidence that statin therapy was associated with increased ICH.9,10,41 However, other
than reducing cholesterol levels, statins may also decrease
platelet aggregation and hence thrombogenesis, which might
increase the risk of bleeding and thus obscure the results.10,42
Additionally, the follow-up durations in statin trials were usually no longer than 5 years.43,44 Longer exposure to low cholesterol levels might be necessary to alter the integrity of cerebral
vessels. Although another large meta-analysis has shown that
hemorrhagic stroke mortality was likely related to lower TC
levels in a few stroke subgroups,4 it was limited by including considerable studies published before the 1980s, and thus
failed in verifying the stroke type by reliable imaging method.
In comparison, our study had strengths in conducting longer follow-up, including newer studies with reliable imaging examinations, and performing quantitative analyses.
Additionally, most included studies have large sample sizes
involving different general populations throughout the world.
On the whole, sufficient adjustment of potential risk factors
for hemorrhagic stroke was performed, and the methodological qualities were satisfying. As we included mainly prospective studies, the likelihood of selection bias and recall bias in
retrospective studies was greatly reduced.
However, we were aware of several potential limitations.
First, studies with significant results may be more likely to
be published, and are preferentially published in English
journals.15 We included only studies written in English and
hence, may have missed relevant articles in non-English
journals. Notably, publication bias was detected in studies
of TC, which might overestimate the inverse relationship,
as harmful association was more likely to be published.
Second, hemorrhagic stroke is a mixed term, including ICH,
SAH, subdural or epidural hemorrhages, or hemorrhagic
transformation after ischemic stroke.10 Several studies
only reported this composite outcome and precluded the
distinction between hemorrhage subtypes.23,2628,32,35,36 In fact,
TC studies showed a more convincing result for ICH than
1838StrokeJuly 2013
SAH. Third, although adjusted estimates were reported in

general, the observational design had its inherent weakness
that any association may be because of the presence of
inadequately measured or unmeasured residual confounding
variables. For instance, the prescription of statins was not
described largely,31,33,34,36,38 and the socioeconomic status
was rarely investigated. Another major concern was that our
results might be confounded by comorbidity at baseline.
Because patients who died from other diseases at earlier ages
could not contribute to a later risk of ICH, a survival bias
possibly existed. No study excluded the first 5 or 10 years of
follow-up, and still showed an association for hemorrhagic
stroke. This bias may explain the protection conferred
by high TC against hemorrhagic stroke, by progressively
decreasing the proportion of patients with atherothrombotic
disease and subsequently increasing the proportion of other
cerebral vessel diseases or conditions in the elderly, which
cause hemorrhagic stroke with unknown relations with
cholesterols. Also, other emerging imaging confounders,
including signs of leukoaraiosis, cerebral microbleeds,
and multilacunes,41 were seldom mentioned. Furthermore,
the number of studies was limited for HDL-C and LDLC, and thus might be insufficient for drawing definite
conclusions. Last, several studies only had the baseline data
on cholesterols and no data on possible changes in serum
levels during follow-up.34,37,38
Despite these limitations, this study has notable clinical
and public health implications. Our findings should never
be interpreted against the well-established statin regimen, in
which the potential hazards are far outweighed by the definite
absolute benefits for preventing occlusive vascular disease.43,44
Nevertheless, we highlighted that low TC and LDL-C levels
seemed to be risk factors of hemorrhagic stroke, especially
ICH. Our results remind clinicians to take this caution during
intensive lipid-lowering therapy. Further studies are needed
to investigate the underlying pathogenesis better, and identify
subjects who would benefit most from lowering cholesterol
without risk of hemorrhagic stroke.
Disclosures
None.
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Cholesterol Levels and Risk of Hemorrhagic Stroke: A Systematic Review and

Meta-Analysis
Xiang Wang, Yan Dong, Xiangqian Qi, Chengguang Huang and Lijun Hou
Stroke. 2013;44:1833-1839; originally published online May 23, 2013;

doi: 10.1161/STROKEAHA.113.001326
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright 2013 American Heart Association, Inc. All rights reserved.
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SUPPLEMETNAL MATERIAL
Cholesterol Levels and Risk of Hemorrhagic Stroke: A Systematic Review and Meta-Analysis
Xiang Wang, MD; Yan Dong, MD; Xiangqian Qi, MD; Chengguang Huang, MD; Lijun Hou, MD
Supplemental Methods
Search Strategy
Our meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and
Meta-analysis (PRISMA) statement.1 Two investigators (X.W. and Y.D.) independently searched Pubmed and
Embase for prospective studies examining the association between cholesterol and the risk of hemorrhagic stroke.
Three main categories of cholesterol, including total cholesterol (TC), high density lipoprotein cholesterol
(HDL-C), and low density lipoprotein (LDL-C), were investigated, respectively. Hemorrhagic stroke mainly
included ICH and SAH. The search was limited to studies published between 1980 and January 2013. The
language was restricted to English. The search terms were (cerebral hemorrhage[Mesh] OR subarachnoid
hemorrhage[Mesh]
OR
hemorrhagic
stroke[Title/Abstract])
AND
(cholesterol[Mesh]
OR
hypercholesterolemia[Mesh] OR dyslipidemia[Mesh]) for Pubmed, and (cerebral hemorrhageexp OR
cerebral hemorrhage OR subarachnoid hemorrhage/exp OR subarachnoid hemorrhage OR hemorrhagic
stroke/exp OR hemorrhagic stroke) AND (cholesterol/exp OR cholesterol OR dyslipidemia/exp OR
dyslipidemia OR hypercholesterolemia/exp OR hypercholesterolemia) for Embase. We further conducted the
manual search of references of selected studies.
Selection Criteria
To be included studies had to have a prospective design (prospective cohort, or nested prospective case-control
study), and investigate the association between cholesterol (TC, HDL-C, or LDL-C) and the risk of hemorrhagic
stroke (ICH, SAH, or both). The authors should report effect estimates (risk ratio [RR], hazard ratio [HR], or odds
ratio [OR]) and 95% confidential intervals (CIs) for more than 3 categories of cholesterol concentration, for the
comparison between low and high concentration, or for per 1mmol/L increase in concentration. We excluded
cross-sectional studies and retrospective studies, and studies with participants of pre-existing stroke (hemorrhagic
or ischemic). Studies with pediatric or pregnant participants, and those of only irrelevant exposures (e.g.
triglyceride) and diseases (e.g. ischemic stroke) were also excluded. For study populations that were reported more
than once, duplicated results were combined, whereas data of different statistical methods were separately
extracted. For instance, when the high versus low analysis and dose-response analysis were conducted in two
papers with the same cohort, their results were pooled into different aspects of our meta-analysis.
Data Extraction and Quality Assessment

Three reviewers (X.W.,Y.D., and X.Q.Q.) extracted the data in standardized data-collection forms, and two authors
and two authors (X.W. and Y.D.) assessed the study quality. The following data were abstracted: author;
publication year; study design; population (categorized as American, Asian [including Japanese populations in
Hawaii], and European); sample size; participants characteristics (age and sex); exposure; type of hemorrhagic
stroke (ICH, SAH, or both); follow-up duration; covariates in fully adjusted model; degree of adjustment for
confounders (categorized as + for age and/or sex only; ++ for these further adjusted for fewer than five
standard vascular risk factors (i.e., blood pressure, smoking status, alcohol consumption, and BMI); +++ for
these plus five or more risk factors, including unconventional factors or markers of socioeconomic status (i.e., use
of statin medications, pre-existing coronary heart disease, and education); comparison categories and
corresponding relative risks (RRs), hazard ratios (HRs), or odds ratios (ORs) with 95% CIs. For studies that
2
reported several multivariable-adjusted RRs, we used the effect estimate that was most fully adjusted. The
NewcastleOttawa Scale (NOS) was used to evaluate the methodological quality, which scored studies by the
selection of the study groups, the comparability of the groups, and the ascertainment of the outcome of interest.2
Statistical Analysis
The RRs and their associated 95% CIs were considered as the effect size for all studies. HR was regarded
equivalent to RR in cohort studies. Because of the low incidence of hemorrhagic stroke in general population, ORs
could be assumed to be accurate estimates of RRs. Studies often used mmol/L or mg/dl in the measurement units of
cholesterol. We preferred to mmol/L as it was more frequently reported. The dose conversion factor for serum
concentration of cholesterol data as mg/dL to mmol/L was 0.0259. For studies that reported results for men and
women separately, for ICH and SAH separately, or for different age subgroups separately, we combined the
estimates using a fixed effects model to obtain an overall estimate for hemorrhagic stroke, both genders, or all age
categories combined. We firstly utilized the random effects models to calculate summary RRs and 95% CIs for the
high versus low levels of cholesterol. For RRs and 95% CIs that were expressed as lowest level versus highest
level, they were converted to their reciprocals. In dose-response analysis, we assigned the mean or median level of
cholesterol in each category to the corresponding RR. If these values were unavailable, we estimated the midpoint
in each category for studies that reported the serum concentration of cholesterol by ranges. For studies with an
open-ended highest or lowest cholesterol category, we assumed that the amplitudes were the same as the closest
adjacent category. In population with mixed genders, when the cut-off values were separately fixed for men and
women, we calculated the estimated average values. The generalized least squares (GLST) regression model was
used to calculate the study-specific linear trends and 95% CI from the natural logs of the RRs and CIs across
categories of cholesterol concentrations.3, 4 This model requires that the distribution of cases, person years or
non-cases, and the RRs with the variance estimates are known for each category of cholesterol levels. For studies
that did not report the distribution of person years or cases whereas reported the total number of person years or
cases, the distribution of person years or cases were estimated. For example, the total number of cases was divided
by 4 when data were reported by quartiles to derive the number of cases in each fourth. Considering the
heterogeneity among results from different studies, random effects models were used to pool the respective results.
The dose-response results in the forest plots are presented for a 1mmol/L increment for cholesterol. To examine a
potential nonlinear relationship between cholesterol level and hemorrhagic risk, the model of restricted cubic
splines was utilized. In the pooled values of cholesterol concentrations, 3 knots were fixed at percentiles 10%, 50%,
and 90% of the distribution.5 A probability value for nonlinearity was calculated by testing the null hypothesis that
the coefficient of the second spline is equal to zero.
Statistical heterogeneity among studies was mainly assessed by the I2 statistic.6 For the I2 metric, we considered
low, moderate and high I2 values to be 25%, 50%, and 75%, respectively.2 Subgroup analyses were conducted
based on the potential sources of heterogeneity inferred a priori, including study design, populations, genders,
hemorrhagic types, sample sizes, follow-up duration, degrees of covariates adjustment, and endpoint outcomes.
Sensitivity analysis was conducted by excluding one study at a time to explore whether the results were driven by
one large study or by a study with an extreme result.
Inter-rater reliabilities on selection of studies and quality assessment were calculated by Cohen statistics, with
3
five levels of agreement, namely poor (=0.000.20), fair (=0.210.40), moderate (=0.410.60), good
(=0.610.80), and very good (=0.811.00).1, 4, 5 The Eggers test was used to quantitatively assess publication
bias.6 All statistical analyses were performed with the STATA software (version 12.0; Stata Corporation, College
Station, Texas). A threshold of P<0.1 was used to decide whether heterogeneity or publication bias was present. 1, 6
In other ways, P values were two sided with a significance level of 0.05.
Supplemental Table S1. Characteristics of prospective studies of cholesterol levels and risk of hemorrhagic stroke.
Study
Study design
Study population
No of
participants
%
men
Age (mean
or range)
(years)
Exposure
Endpoints (No of
cases)
Degree of
covariables
adjustment
Duration of
follow-up (years)
Yano 1989
Prospective cohort
Asian
(Japanese-American)
7850
100
45-68
TC
ICH (77), SAH (39)
+; +++
18 (mean)
Knekt8 1991
Prospective cohort
European (Finnish)
42862
54
20-69
TC
SAH (187)
12
Gatchev 1993
Prospective cohort
European (Swedish)
54385
49
25-74
TC
Fatal SAH (87); fatal

ICH (347)
++
20.5
Iribarren10 1996
Prospective cohort
American
61756
46
54
TC
ICH (386)
+++
15
Prospective cohort
European (Finnish)
28519
100
50-69
TC, HDL-C
ICH (112), SAH (85)
+++
Prospective cohort
Asian (Japanese)
38053
47
33-93
TC
ICH (111); SAH (19)
+; ++
Prospective cohort
European (British)
15267
46
45-64
TC
HS (90)
+; +++
20
Prospective cohort
Asian (Korean)
114793
100
35-59
TC
ICH (372), SAH (98)
+++
Prospective cohort
European (Swedish)
6193
100
28-61
TC
ICH (29); SAH (9)
23
Prospective cohort
Asian
(Japanese-American)
7589
100
54
TC
HS (112)
+; +++
20
Prospective cohort
American
1216
100
56
TC
HS (18)
+; +++
20
Nested
case-control
European (4 nations)
1251
66
62
TC; HDL-C
HS (346)
++
4*
Jood18 2004
Prospective cohort
European (Swedish)
7402
100
47-55
TC
HS (144)
28
19
Prospective cohort
Asian (Chinese)
5092
100
18-74
TC
HS (48)
++
13.5 (mean)
Tirschwell 2004
Nested
case-control
American
8010
44
66
TC; HDL-C
HS (313); ICH (217);

SAH (96)
++; +++
11
Ebrahim21 2006
Prospective cohort
Asian (Korean)
787442
84
30-64
TC
HS (3345)
+; +++
11
Cui 2007
Nested
case-control
Asian (Japanese)
38158
35
40-79
TC
Fatal ICH (76); fatal

SAH (66)
+; ++
10
Sturgeon23 2007
Prospective cohort
American
21680
44
59
TC;
HDL-C;
ICH (135)
15
11
Leppala 1999
12
Okumura 1999
13
Hart 2000
14
Suh 2001
15
Engstrom 2002
16
Rodriguez
a
2002
Rodriguez16
b
2002
Bots17 2002
Zhang 2004
20
22
LDL-C
24
Imamura 2009
Prospective cohort
Asian (Japanese)
2351
42
57
LDL-C
HS (80)
+++
19
25
Noda 2009
Prospective cohort
Asian (Japanese)
91219
34
40-79
TC;
HDL-C;
LDL-C
ICH (264)
+++
10
Nago26 2011
Prospective cohort
Asian (Japanese)
12241
39
40-69
TC
Fatal HS (55)
+++
13
Wieberdink 2011
Prospective cohort
European (Dutch)
5773
67
67
HDL-C;
LDL-C
ICH (85)
+++
15
Zhang28 2012
Prospective cohort
European (Finnish)
58235
48
25-74
TC; HDL-C
ICH (497), SAH

(332)
+; ++; +++
30
Chei29 2013
Nested
case-control
Asian (Japanese)
12804
41
40-85
HDL-C
HS (86); ICH (64)
+++
14
27
HDL-C, high-density lipoprotein cholesterol; HS, hemorrhagic stroke; ICH, intracranial hemorrhage; LDL-C, low-density lipoprotein cholesterol; SAH,
subarachnoid hemorrhage; TC, total cholesterol.
duplicated studies relating to Honolulu Heart Program, with different aspects of statistical results.
Supplemental Table S2. Categorization, relative risks, and covariates of included studies.
Study
Effect
estimate
Exposure
Study
outcome
Gender
Comparison categories and corresponding effect

estimates (95% CI)
Covariates in fully adjusted model
Yano7 1989
RR
TC
HS
Male
Lowest quintile (1.32-4.87 mmol/L) vs higher quintiles

(>4.87 mmol/L): 2.13 (1.43 to 3.17)
Age, diastolic blood pressure, serum uric acid,

cigarettes/d, and alcohol consumption
Yano7 1989
RR
TC
ICH
Male

(>4.87 mmol/L): 2.55 (1.58 to 4.12)

Yano7 1989
RR
TC
SAH
Male

(>4.87 mmol/L): 1.49 (0.72 to 3.11)

Knekt8 1991
RR
TC
SAH
Male
5.96 mmol/L: 1.0 (reference); 5.98-6.99 mmol/L:

0.8 (0.5 to 1.3); >6.99 mmol/L: 0.9 (0.6 to 1.5)
Age
Knekt8 1991
RR
TC
SAH
Female
5.96 mmol/L: 1.0 (reference); 5.98-6.99 mmol/L:

1.0 (0.6 to 1.9); >6.99 mmol/L: 1.0 (0.6 to 1.8)
Age
Gatchev9 1993
RR
TC
ICH
mortality
Male
Lowest quartile (no range available) vs highest quartile

(no range available): 1.10 (0.76 to 1.61)
Age, follow-up period, and diastolic blood pressure
Gatchev9 1993
RR
TC
ICH
mortality
Female

Gatchev9 1993
RR
TC
SAH
mortality
Male

Gatchev9 1993
RR
TC
SAH
mortality
Female

Iribarren10
1996
RR
TC
ICH
Male
Levels below 10th percentile vs higher levels: 40-64y:

0.71 (0.33 to 1.54); 65-89y: 2.72 (1.46 to 5.02)
Iribarren10
1996
RR
TC
ICH
Female
Levels below 10th percentile vs higher levels: 40-64y:

1.04 (0.45 to 2.40); 65-89y: 2.23 (0.90 to 5.54)
Male
4.9 mmol/L: 1 (reference); 5.0-5.9 mmol/L: 0.77

(0.47 to 1.26); 6.0-6.9 mmol/L: 0.46 (0.27 to 0.78);
7.0 mmol/L: 0.20 (0.10 to 0.42)
Leppala11 1999
RR
TC
ICH
Age, race, education level, body mass index, systolic

blood pressure, smoking status, alcohol consumption,
blood glucose, and prevalent medical conditions
Age, body mass index, systolic blood pressure, serum
HDL cholesterol, smoking, alcohol consumption,
diabetes, heart disease, education, physical activity, and
tocopherol and carotene supplementation
7
Leppala11 1999
Leppala11 1999
Leppala11 1999
RR
RR
RR
TC
TC
TC
SAH
ICH
SAH
Male

(0.62 to 2.32); 6.0-6.9 mmol/L: 0.60 (0.29 to 1.24);
7.0 mmol/L: 0.78 (0.38 to 1.62)

HDL cholesterol, smoking, alcohol consumption,
diabetes, heart disease, education, physical activity, and
tocopherol and carotene supplementation
Male

(0.64 to 2.41); 1.15-1.44 mmol/L: 1.05 (0.52 to 2.15);
1.45 mmol/L: 1.33 (0.62 to 2.85)

total cholesterol, smoking, alcohol consumption, diabetes,
heart disease, education, physical activity, and tocopherol
and carotene supplementation
Male

(0.26 to 0.95); 1.15-1.44 mmol/L: 0.69 (0.36 to 1.33);
1.45 mmol/L: 0.26 (0.11 to 0.62)
Okumura12
1999
Okumura12
1999
Hart13 2000
Suh14 2001
Suh14 2001
OR
OR
TC
TC
ICH
ICH
Men
Female

(0.38 to 1.30); 4.97-5.62 mmol/L: 0.77 (0.55 to 1.08);
5.65 mmol/L: 0.73 (0.56 to 0.96)
(0.43 to 3.13); 4.97-5.62 mmol/L:1.26 (0.79 to 1.99);

total cholesterol, smoking, alcohol consumption, diabetes,
heart disease, education, physical activity, and tocopherol
and carotene supplementation
Sex, age, systolic blood pressure, proteinuria
Sex, age, systolic blood pressure, proteinuria
5.65 mmol/L: 0.84 (0.70 to 1.19)
RR
RR
RR
TC
TC
TC
HS
ICH
SAH
Both
genders

(0.51 to 1.65); 5.85-6.35 mmol/L: 0.71 (0.38 to 1.34);
6.36-6.98 mmol/L: 0.92 (0.52 to 1.65); 6.99
mmol/L: 0.22 (0.08 to 0.57)
Age, sex, diastolic blood pressure, height, smoking, and

pre-existing coronary heart disease
Male
<4.31 mmol/L: 1.22 (0.88 to 1.69); 4.31-4.74 mmol/L:

0.86 (0.60 to 1.21); 4.74-5.16: 1.08 (0.78 to 1.48);
5.16-5.69 mmol/L: 1.03 (0.75 to 1.41); 5.69
mmol/L: 1 (reference)
Age, smoking, alcohol consumption, blood pressure,

body mass index and blood glucose while fasting
Male
<4.31 mmol/L: 1.44 (0.76 to 2.73); 4.31-4.74 mmol/L:

1.13 (0.59 to 2.20); 4.74-5.16: 1.21 (0.64 to 2.29);
5.16-5.69 mmol/L: 1.12 (0.59 to 2.14); 5.69
mmol/L: 1 (reference)
Age, smoking, alcohol consumption, blood pressure,

body mass index and blood glucose while fasting
<4.5 mmol/L: 1 (reference); 4.5-5.49 mmol/L: 0.48
Engstrom15
2002
RR
TC
ICH
Male
Rodriguez16
2002
RR
TC
HS
Male
HS
Both
genders
17
Bots 2002
Bots17 2002
17
Bots 2002
18
Jood 2004
Zhang19 2004
Tirschwell
2004
OR
OR
OR
HR
RR
TC
HDL-C
HDL-C
TC
TC
TC
Age
Per 1 mmol/L increase: Honolulu study: 0.70 (0.60 to

0.90); Framingham study: 1 (0.60 to 1.60)
Age, hypertension, diabetes, body mass index,

cigarettes/d, and alcohol intake

(0.37 to 1.79); 6.10-6.91 mmol/L: 1.28 (0.60 to 2.75);
Age, sex, and body mass index
6.91 mmol/L: 0.29 (0.09 to 0.92)
Male

(0.29 to 2.47); 1.16-1.37 mmol/L: 0.67 (0.19 to 2.37);
1.37 mmol/L: 1.35 (0.51 to 3.57)
Female
1.12 mmol/L: 1 (reference); 1.12-1.35 mmol/L: no

cases; 1.35-1.60 mmol/L: 1.97 (0.38 to 10.1); 1.60
mmol/L: 1.18 (0.24 to 5.85)
Male
<5 mmol/L: 1 (reference); 5-6.3 mmol/L: 1.03 (0.58 to

1.83); 6.4-7.4 mmol/L: 1.00 (0.54 to 1.85); >7.4
mmol/L: 1.10 (0.57 to 2.13)
Age
Male
<4.5 mmol/L: 1 (reference); 4.5-5.0 mmol/L: 0.6 (0.3

to 1.3); .5.0-5.5 mmol/L: 0.7 (0.3 to 1.5); 5.5-6.0
mmol/L: 0.10 (0.02 to 0.9); >6.0 mmol/L: 0.5 (0.2 to
1.3)
Age, blood pressure, body mass index, and smoking
HS
Both
genders
Mean 4.45 mmol/L: 1 (reference); mean 5.31 mmol/L:

0.6 (0.4 to 0.9); mean 5.83 mmol/L: 0.7 (0.5 to 1.0);
mean 6.40 mmol/L: 0.7 (0.5 to 1.0); mean 7.51
mmol/L: 0.8 (0.6 to 1.1)
Age, sex, race, treated hypertension, index year, and time

to cholesterol measurement, systolic and diastolic blood
pressure, coronary heart disease, diabetes, tobacco use,
atrial fibrillation, and the use of statin medications

0.5 (0.3 to 0.8); mean 5.83 mmol/L: 0.7 (0.4 to 1.0);
mmol/L: 0.6 (0.4 to 1.0)

HS
HS
HS
HS
20
OR
(0.2 to 1.3); 5.5-6.49 mmol/L: 0.48 (0.2 to 1.3); 6.5

mmol/L: 0.15 (0.03 to 0.75)
Tirschwell20
2004
OR
TC
ICH
Both
genders
Tirschwell20
OR
TC
SAH
Both
2004
Tirschwell
2004
genders
20
21
Ebrahim 2006
22
Cui 2007
Cui22 2007
Sturgeon23
2007
OR
HR
OR
OR
RR
TC
TC
TC
TC
TC
HS
ICH
ICH
mortality
SAH
mortality
1.1 (0.6 to 2.1); mean 5.83 mmol/L: 0.8 (0.4 to 1.6);

mmol/L: 1.3 (0.7 to 2.4)

Both
genders

0.9 (0.6 to 1.4); mean 1.27 mmol/L: 1.1 (0.7 to 1.7);
mmol/L: 1.1 (0.7 to 1.7)

Both
genders

(0.51 to 1.14); 4.14-5.17 mmol/L: 0.61 (0.41 to 0.91);
5.17-6.21 mmol/L: 0.55 (0.37 to 0.83); 6.21-6.98
mmol/L: 0.52 (0.34 to 0.79); 6.98 mmol/L: 0.80
(0.50 to 1.26)
Age, sex, body mass index, height, serum glucose,

hypertension, ethanol consumption, smoking, physical
activity, monthly pay, and area of residence
Both
genders

(0.02 to 0.44); 4.65-5.16 mmol/L: 0.35 (0.10 to 1.26);
5.17-5.68 mmol/L: 0.21 (0.05 to 0.90); 5.69-6.20
mmol/L: 0.20 (0.04 to 0.92); 6.21-6.71 mmol/L: 0.12
(0.02 to 0.80); 7.22 mmol/L: 0.12 (0.02 to 0.88)
Systolic blood pressure, HDL-cholesterol, ethanol intake,

smoking status, and diabetes, with age, sex, and
community matched
Both
genders

(0.43 to 8.41); 4.65-5.16 mmol/L: 1.08 (0.21 to 5.48);
5.17-5.68 mmol/L: 0.40 (0.07 to 2.16); 5.69-6.20
mmol/L: 1.53 (0.27 to 8.61); 6.21-6.71 mmol/L: 0.30
(0.02 to 3.96); 7.22 mmol/L: 0.60 (0.08 to 4.73)
1.24-4.81 mmol/L: 1 (reference); 4.82-5.46 mmol/L:
0.77 (0.48 to 1.23); 5.49-6.16 mmol/L: 0.82 (0.52 to
1.30); 6.18-15.38 mmol/L: 0.67 (0.41 to 1.10)
Systolic blood pressure, HDL-cholesterol, ethanol intake,

smoking status, and diabetes, with age, sex, and
community matched
ICH
Both
genders

0.88 (0.56 to 1.39); 3.44-4.11 mmol/L: 0.85 (0.53,
1.35); 4.11-13.07 mmol/L: 0.50 (0.29 to 0.87)
Age

0.81 (0.47 to 1.39); 1.30-1.60 mmol/L: 0.99 (0.60 to
Age
Sturgeon23
2007
RR
LDL-C
ICH
Both
genders
Sturgeon23
2007
RR
HDL-C
ICH
Both
genders
Age
10
1.66); 1.61-4.22 mmol/L: 1.39 (0.86 to 2.25)

Imamura24
2009
Noda25 2009
Noda25 2009
Noda25 2009
HR
HR
HR
HR
LDL-C
TC
LDL-C
HDL-C
HS
ICH
Both
genders
Both
genders
ICH
Both
genders
ICH
Both
genders
Men
Nago26 2011
HR
TC
HR
HDL-C
Wieberdink27
2011
HR
LDL-C
3.89 mmol/L: 1.01 (0.50 to 2.05)
Age, sex, HDL cholesterol, triglycerides, systolic blood

pressure, ECG abnormalities, fasting blood glucose, body
mass index, current drinking, current smoking, and
regular exercise

(0.65 to 1.46); 4.65-5.16 mmol/L: 0.63 (0.42 to 0.96);
5.17-5.67 mmol/L: 0.62 (0.40 to 0.95); 5.68-6.19
mmol/L: 0.59 (0.37 to 0.95)
Age, sex, blood pressure categories, antihypertensive

medication use, diabetes mellitus, lipid medication use,
body mass index, glutamyl transferase, smoking status,
alcohol consumption, and kindney dysfunction

(0.44 to 0.96); 2.58-3.09 mmol/L: 0.48 (0.32 to 0.71);

3.10-3.61 mmol/L: 0.50 (0.33 to 0.75); 3.62

mmol/L: 0.45 (0.30 to 0.69)
(0.47 to 1.06); 1.29-1.54 mmol/L: 0.68 (0.46 to 1.03);
1.55-1.80 mmol/L: 0.99 (0.65 to 1.51); 1.81
mmol/L: 0.98 (0.62 to 1.53)

<4.14 mmol/L: 1.96 (0.80 to 4.79); 4.14-5.16 mmol/L:

1 (reference); 5.17-6.21 mmol/L: 0.68 (0.21 to 2.16);
6.21 mmol/L: 1.76 (0.38 to 8.09)
HS
mortality
Women
Wieberdink27
2011

(0.35 to 1.47); 3.25-3.88 mmol/L: 1.41 (0.75 to 2.65);
<4.14 mmol/L: 3.86 (1.18 to 12.68); 4.14-5.16

mmol/L: 1 (reference); 5.17-6.21 mmol/L:1.94 (0.77 to
4.89); 6.21 mmol/L: 2.15 (0.68 to 6.77)
Age, systolic blood pressure, HDL cholesterol, smoking,

drinking, and body mass index
ICH
Both
genders
0.4-1.1 mmol/L: 1 (reference); 1.1-1.3 mmol/L: 0.76

(0.28 to 2.01); 1.3-1.6 mmol/L: 0.74 (0.27 to 2.03);
1.6-5.5 mmol/L: 1.29 (0.48 to 3.45)
Age, sex, lipid-lowering medication use, systolic blood

pressure, blood pressure-lowering medication use,
diabetes mellitus, serum glucose level, serum insulin
level, LDL, triglyceride, current cigarette smoking, body
mass index, antithrombotic use, and alcohol intake
ICH
Both
genders
0.1-3.2 mmol/L: 1 (reference); 3.2-3.7 mmol/L: 1.03

(0.44 to 2.41); 3.7-4.3 mmol/L: 1.47 (0.65 to 3.33);
Age, sex, lipid-lowering medication use, systolic blood

pressure, blood pressure-lowering medication use,
11
4.3-7.9 mmol/L: 0.98 (0.39 to 2.50)
Zhang28 2012
Zhang28 2012
Zhang28 2012
Zhang28 2012
HR
HR
HR
HR
TC
TC
TC
TC
SAH
SAH
ICH
ICH
Male

1.63); 6-6.9 mmol/L: 1.45 (0.83 to 2.52); 7.0
mmol/L: 1.79 (1.00 to 3.19)
Age, study year, education, physical activity, smoking,

alcohol consumption, family history of stroke, body mass
index, systolic blood pressure, history of diabetes, using
of cholesterol-lowering agent
Female

2.22); 6-6.9 mmol/L: 1.41 (0.84 to 2.37); 7.0
mmol/L: 1.25 (0.71 to 2.20)

Male

2.02); 6-6.9 mmol/L: 1.15 (0.74 to 1.81); 7.0
mmol/L: 1.06 (0.66 to 1.70)

Female

0.96); 6-6.9 mmol/L: 0.66 (0.43 to 1.02); 7.0
mmol/L: 0.55 (0.34 to 0.87)

<1 mmol/L: 1 (reference); 1.0-1.19 mmol/L: 0.54 (0.26

Zhang28 2012
HR
HDL-C
SAH
Male
to 1.13); 1.2-1.39 mmol/L: 0.65 (0.32 to 1.32); 1.4

mmol/L: 0.59 (0.29 to 1.19)
Zhang28 2012
28
Zhang 2012
HR
HR
HDL-C
HDL-C
SAH
ICH
diabetes mellitus, serum glucose level, serum insulin

level, LDL, triglyceride, current cigarette smoking, body
mass index, antithrombotic use, and alcohol intake
Female
Male
to 2.05); 1.2-1.39 mmol/L: 0.74 (0.36 to 1.51); 1.4

mmol/L: 0.65 (0.33 to 1.28)
to 1.76); 1.2-1.39 mmol/L: 1.30 (0.74 to 2.28); 1.4
mmol/L: 1.18 (0.67 to 2.08)

12
Zhang28 2012
29
Chei 2013
29
Chei 2013
HR
OR
OR
HDL-C
HDL-C
HDL-C
ICH
HS
ICH
Female
Both
genders
Both
genders

to 2.15); 1.2-1.39 mmol/L: 0.84 (0.45 to 1.60); 1.4
mmol/L: .1.01 (0.56 to 1.80)


0.46 (0.13 to 1.64); 1.17-1.39 mmol/L: 0.44
(0.12-1.62); 1.40-2.27 mmol/L: 0.35 (0.09 to 1.35)
Hypertension status BMI, current alcohol intake, cigarette

smoking status, cholesterol-lowering medication,
log-transformed triglyceride levels,
serum glucose category, and matching for sex, age,
community, year of serum stored, and fasting status

0.80 (0.13 to 4.95); 1.17-1.39 mmol/L: 0.52
(0.07-3.89); 1.40-2.27 mmol/L: 0.32 (0.05 to 2.16)
Hypertension status BMI, current alcohol intake, cigarette

smoking status, cholesterol-lowering medication,
log-transformed triglyceride levels,
serum glucose category, and matching for sex, age,
community, year of serum stored, and fasting status
HDL-C, high-density lipoprotein cholesterol; HR, hazard ratio; HS, hemorrhagic stroke; ICH, intracranial hemorrhage; LDL-C, low-density lipoprotein
cholesterol; OR, odds ratio; RR, relative risk; SAH, subarachnoid hemorrhage; TC, total cholesterol.
13
Supplemental Table S3. Quality scores of prospective cohort studies using Newcastle- Ottawa Scale (maximum score of 9)
Cohort studies
Selection
Comparability
Outcome
Reference
Representativeness
of the exposed
cohort
Selection of
the non
exposed
cohort
Ascertainment
of serum
cholesterol
Demonstration
that
hemorrhagic
stroke was not
present at start
of study
Comparability
on the basis of
the design or
analysis
Assessment
of outcome
Adequate
follow-up duration
(> 10 years)
Adequate
follow-up rate
(> 80%)
Overall
quality
Yano7 1989
Knekt 1991
10
11
Okumura 1999
Hart, 2000
Gatchev 1993
Iribarren 1996
Leppala 1999
12
14
Suh 2001
Engstrom15 2002
Rodriguez16 2002a
Rodriguez 2002
18
Jood 2004
19
16
Zhang 2004
21
23
24
Imamura 2009
25
Noda 2009
26
Wieberdink 2011
28
Ebrahim 2006
Sturgeon 2007
Nago 2011
27
Zhang 2012
0=No, Unable to determine or Not available.

14
Supplemental Table S4. Quality scores of case-control studies using Newcastle- Ottawa Scale (maximum score of 9)
Case-control studies
Selection
Comparability
Outcome
Reference
Adequate
definition of cases
Representativeness
of cases
Selection
of controls
Definition of
controls
Comparability
on the basis of
the design or
analysis
Assessment
of exposure
Same method of
ascertainment for
cases and controls
Non-response
rate (<20%)
Overall
quality
Bots17 2002
Cui 2007
29
20
Tirschwell 2004
22
Chei 2013
0=No, Unable to determine or Not available.
15
Supplemental Table S5. Subgroup analyses of total cholesterol level and risk of hemorrhagic stroke, high versus low and dose-response analyses,
respectively.
High versus low analyses
Dose-response analyses
No. of
studies
Relative risk (95% CI)
I (%)
P for
heterogeneity
P for test
No. of
studies
I2
(%)
P for
heterogeneity
P for test
Prospective cohort
16
0.71 (0.60 to 0.83)
59.9
<0.01
<0.01
15
0.90 (0.85 to 0.95)
66.4
<0.01
<0.01
Case-control
0.47 (0.20 to 1.10)
59.8
0.08
0.08
0.68 (0.44 to 1.06)
94
<0.01
0.09
Male
0.72 (0.54 to 0.97)
64
<0.01
0.03
0.83 (0.71 to 0.98)
77.6
<0.01
0.03
Female
0.78 (0.66 to 0.93)
0.55
0.02
0.92 (0.85 to 0.99)
0.92
0.04
ICH
11
0.60 (0.48 to 0.75)
65.1
<0.01
<0.01
0.80 (0.69 to 0.91)
89.1
<0.01
<0.01
SAH
0.92 (0.70 to 1.21)
24.3
0.24
0.56
0.97 (0.83 to 1.13)
57.9
0.05
0.67
<20000
0.58 (0.37 to 0.91)
69.1
<0.01
0.02
0.85 (0.78 to 0.93)
27.3
0.20
<0.01
>20000
11
0.74 (0.64 to 0.86)
43.7
0.06
<0.01
0.86 (0.78 to 0.94)
89.3
<0.01
<0.01
European
0.64 (0.45 to 0.90)
73.4
<0.01
0.01
0.89 (0.78 to 1.02)
76.3
<0.01
0.09
American
0.72 (0.58 to 0.89)
0.63
<0.01
0.79 (0.70 to 0.89)
13.2
0.32
0.03
Asian
0.69 (0.55 to 0.87)
51.4
0.04
<0.01
0.93 (0.88 to 0.99)
85.9
<0.01
<0.01
Subgroups
Study design
Gender
Stroke type
Sample size
Study population
Degree of adjustment
+
0.78 (0.51 to 1.21)
51.9
0.10
0.97 (0.91 to 1.02)
0.89
0.71 (0.56 to 0.90)
31.8
0.21
0.26
0.01
++
0.69 (0.49 to 0.97)
91.4
<0.01
0.22
0.03
+++
10
0.67 (0.53 to 0.86)
69.5
<0.01
<0.01
10
0.87 (0.81 to 0.94)
74.7
<0.01
<0.01
<10 years
0.63 (0.45 to 0.88)
67.5
0.03
0.01
0.84 (0.75 to 0.93)
57.3
0.07
<0.01
10 years
Endpoint
15
0.71 (0.59 to 0.86)
57.6
<0.01
<0.01
14
0.86 (0.79 to 0.93)
83
<0.01
<0.01
HS incidence
16
0.68 (0.57 to 0.80)
57.8
<0.01
<0.01
16
0.89 (0.85 to 0.94)
65.7
<0.01
<0.01
Follow-up duration
16
HS mortality
0.83 (0.35 to 1.93)
69.1
0.04
0.66
0.63 (0.32 to 1.21)
93.7
<0.01
0.16
17
Supplemental Table S6. Subgroup analyses of HDL-C level and risk of hemorrhagic stroke, high versus low analysis and dose-response analysis,
respectively.
High versus low analyses
Dose-response analyses
No. of
studies
I (%)
P for
heterogeneity
P for test
No. of
studies
I2
(%)
P for
heterogeneity
P for test
Prospective cohort
0.96 (0.76 to 1.21)
29.2
0.24
0.73
1.08 (0.91 to 1.28)
28.3
0.23
0.37
Case-control
0.99 (0.59 to 1.68)
16.8
0.31
0.99
0.85 (0.44 to 1.67)
58.7
0.09
0.64
Male
0.85 (0.61 to 1.17)
0.41
0.32
0.82 (0.59 to 1.16)
0.50
0.27
Female
0.86 (0.56 to 1.31)
0.69
0.49
0.87 (0.57 to 1.31)
0.67
0.50
ICH
1.15 (0.91 to 1.46)
0.86
0.23
1.17 (1.02 to 1.35)
0.79
0.03
SAH
0.43 (0.19 to 1.00)
66
0.09
0.05
0.49 (0.26 to 0.91)
45.2
0.18
0.02
<20000
1.07 (0.75 to 1.52)
0.39
0.70
1.01 (0.72 to 1.43)
43.1
0.15
0.94
>20000
0.94 (0.72 to 1.23)
32.3
0.22
0.67
1.04 (0.83 to 1.30)
45.3
0.14
0.72
European
0.87 (0.68 to 1.13)
0.47
0.30
0.98 (0.78 to 1.23)
11.5
0.34
0.83
American
1.22 (0.88 to 1.70)
0.48
0.22
1.18 (1.00 to 1.40)
0.64
0.05
Asian
0.72 (0.29 to 1.81)
50
0.16
0.49
0.71 (0.22 to 2.31)
80.6
0.02
0.57
Subgroups
Study design
Gender
Stroke type
Sample size
Study population
Degree of adjustment
+
1.39 (0.86 to 2.25)
0.18
1.21 (1.00 to 1.47)
0.05
++
1.30 (0.57 to 2.98)
0.54
1.26 (0.48 to 3.31)
0.64
+++
0.90 (0.73 to 1.10)
0.47
0.30
0.97 (0.78 to 1.22)
42.3
0.12
0.81
<10 years
0.92 (0.56 to 1.50)
20.8
0.28
0.73
0.98 (0.66 to 1.46)
36.1
0.21
0.93
10 years
1.00 (0.79 to 1.27)
20.5
0.28
1.00
14
1.06 (0.85 to 1.31)
46.2
0.12
0.61
Follow-up duration
18
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20

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Cholesterol Levels and Risk of Hemorrhagic Stroke

A Systematic Review and Meta-Analysis

Downloaded from http://stroke.ahajournals.org/ by guest on September 9, 2016

independent risk factor for hemorrhagic stroke.8 In the post

ypercholesterolemia has been well documented as a

Received February 28, 2013; accepted April 9, 2013.

Data Extraction and Quality Assessment

Supplement). Four studies were conducted in American populations,20,25,29,36 9 in European populations,18,19,21,23,24,26,3335

Total Serum Cholesterol

Wang et al Cholesterol Levels and Risk of Hemorrhagic Stroke 1835

Figure 1. The flow diagram for identifying eligible

were explored, respectively. Overall, the inverse relationships

and end point of hemorrhagic stroke mortality, the inverse

High-Density Lipoprotein Cholesterol

High Versus Low

Sensitivity and Subgroup Analyses

Low-Density Lipoprotein Cholesterol

Wang et al Cholesterol Levels and Risk of Hemorrhagic Stroke 1837

Downloaded from http://stroke.ahajournals.org/ by guest on September 9, 2016

and mortality of hemorrhagic stroke.36 Cholesterol levels may

Downloaded from http://stroke.ahajournals.org/ by guest on September 9, 2016

SAH. Third, although adjusted estimates were reported in

4. Lewington S, Whitlock G, Clarke R, Sherliker P, Emberson J, Halsey

Wang et al Cholesterol Levels and Risk of Hemorrhagic Stroke 1839

Downloaded from http://stroke.ahajournals.org/ by guest on September 9, 2016

37. Cui R, Iso H, Toyoshima H, Date C, Yamamoto A, Kikuchi S, et al;

Cholesterol Levels and Risk of Hemorrhagic Stroke: A Systematic Review and

Stroke. 2013;44:1833-1839; originally published online May 23, 2013;

Data Supplement (unedited) at:

Data Extraction and Quality Assessment

ICH (77), SAH (39)

Fatal SAH (87); fatal

ICH (112), SAH (85)

ICH (111); SAH (19)

ICH (372), SAH (98)

ICH (29); SAH (9)

HS (313); ICH (217);

Fatal ICH (76); fatal

ICH (497), SAH

HS (86); ICH (64)

Comparison categories and corresponding effect

Covariates in fully adjusted model

Lowest quintile (1.32-4.87 mmol/L) vs higher quintiles

Age, diastolic blood pressure, serum uric acid,

Lowest quintile (1.32-4.87 mmol/L) vs higher quintiles

Age, diastolic blood pressure, serum uric acid,

Lowest quintile (1.32-4.87 mmol/L) vs higher quintiles

Age, diastolic blood pressure, serum uric acid,

5.96 mmol/L: 1.0 (reference); 5.98-6.99 mmol/L:

5.96 mmol/L: 1.0 (reference); 5.98-6.99 mmol/L:

Lowest quartile (no range available) vs highest quartile

Age, follow-up period, and diastolic blood pressure

Lowest quartile (no range available) vs highest quartile

Age, follow-up period, and diastolic blood pressure

Lowest quartile (no range available) vs highest quartile

Age, follow-up period, and diastolic blood pressure

Lowest quartile (no range available) vs highest quartile

Age, follow-up period, and diastolic blood pressure

Levels below 10th percentile vs higher levels: 40-64y:

Levels below 10th percentile vs higher levels: 40-64y:

4.9 mmol/L: 1 (reference); 5.0-5.9 mmol/L: 0.77

Age, race, education level, body mass index, systolic

4.9 mmol/L: 1 (reference); 5.0-5.9 mmol/L: 1.20