Hemorrhagic stroke in the Stroke
Prevention by Aggressive Reduction in
L.B. Goldstein, MD
P. Amarenco, MD
M. Szarek, MS
A. Callahan III, MD
M. Hennerici, MD,
PhD
H. Sillesen, MD,
DMSc
J.A. Zivin, MD, PhD
K.M.A. Welch, MB,
ChB
On behalf of the
SPARCL
Investigators*
Address correspondence and
reprint requests to Larry B.
Goldstein, MD, Box 3651,
Duke University Medical
Center, Durham, NC 27710
golds004@mc.duke.edu
Supplemental data at
www.neurology.org
Editorial, page 2355
2364
Cholesterol Levels study
ABSTRACT
Background: In the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL)
study, atorvastatin 80 mg/day reduced the risk of stroke in patients with recent stroke or TIA.
Post hoc analysis found this overall benefit included an increase in the numbers of treated pa-
tients having hemorrhagic stroke (n ⫽ 55 for active treatment vs n ⫽ 33 for placebo).
Methods: We explored the relationships between hemorrhage risk and treatment, baseline patient
characteristics, most recent blood pressure, and most recent low-density lipoprotein (LDL) cho-
lesterol levels prior to the hemorrhage.
Results: Of 4,731 patients, 67% had ischemic strokes, 31% TIAs, and 2% hemorrhagic strokes
as entry events. In addition to atorvastatin treatment (HR 1.68, 95% CI 1.09 to 2.59, p ⫽ 0.02),
Cox multivariable regression including baseline variables significant in univariable analyses
showed that hemorrhagic stroke risk was higher in those having a hemorrhagic stroke as the entry
event (HR 5.65, 95% CI 2.82 to 11.30, p ⬍ 0.001), in men (HR 1.79, 95% CI 1.13 to 2.84, p ⫽
0.01), and with age (10y increments, HR 1.42, 95% CI 1.16 to 1.74, p ⫽ 0.001). There were no
statistical interactions between these factors and treatment. Multivariable analyses also found
that having Stage 2 (JNC-7) hypertension at the last study visit before a hemorrhagic stroke
increased risk (HR 6.19, 95% CI 1.47 to 26.11, p ⫽ 0.01), but there was no effect of most recent
LDL-cholesterol level in those treated with atorvastatin.
Conclusions: Hemorrhagic stroke was more frequent in those treated with atorvastatin, in those
with a hemorrhagic stroke as an entry event, in men, and increased with age. Those with Stage 2
hypertension at the last visit prior to the hemorrhagic stroke were also at increased risk. Treat-
ment did not disproportionately affect the hemorrhagic stroke risk associated with these other
factors. There were no relationships between hemorrhage risk and baseline low-density lipopro-
tein (LDL) cholesterol level or recent LDL cholesterol level in treated patients.
Neurology® 2008;70:2364–2370
GLOSSARY
DBP ⫽ diastolic blood pressure; LDL ⫽ low-density lipoprotein; SBP ⫽ systolic blood pressure; SPARCL ⫽ Stroke Prevention
by Aggressive Reduction in Cholesterol Levels.
The Stroke Prevention with Aggressive Reductions in Cholesterol Levels (SPARCL) trial
was a prospective, double-blind, randomized clinical trial which showed that treatment
e-Pub ahead of print on December 12, 2007, at www.neurology.org.
*SPARCL Investigators are listed in appendix e-1 on the Neurology® Web site at www.neurology.org.
From Duke University Medical Center (L.B.G.), Durham, NC; Denis Diderot University (P.A.), Paris, France; Pfizer (M.S.), New York, NY;
Neurologic Consultants (A.C.), Nashville, TN; University of Heidelberg (M.H.), Mannheim, Germany; University of Copenhagen (H.S.),
Denmark; University of California (J.A.Z.), San Diego; and Rosalind Franklin University of Medicine and Science (K.M.A.W.), North
Chicago, IL.
Disclosure: Larry Goldstein has received honoraria from Pfizer during the course of this study. The honoraria did not exceed $10,000/year.
Pierre Amarenco has received grants from Pfizer for other research or activities not reported in this research exceeding $10,000/year and
honoraria from Pfizer in excess of $10,000/year during the course of this study. Alfred Callahan has received honoraria from Pfizer in excess
of $10,000 during the course of this study. Michael Hennerici has received grants from Pfizer for other research or activities not reported in
this research/article and honoraria from Pfizer during the course of the study. Neither the grants nor the honoraria exceeded $10,000/year.
Henrik Sillesen has received grants from Pfizer for other research or activities not reported in this research/article in excess of $10,000/year
and honoraria exceeding $10,000/year during the course of this study. Michael Szarek was a former employee of Pfizer and had an equity or
ownership interest in the sponsor of the study. K. Michael Welch has received honoraria from Pfizer during the course of the study in excess
of $10,000/year. Justin Zivin has received honoraria from Pfizer during the course of this study. The honoraria did not exceed $10,000/year.
The SPARCL trial was funded by Pfizer. Employees of Pfizer contributed to the design and conduct of the study, the collection, management,
analysis, and interpretation of the data, and reviewed the manuscript.
Copyright © 2008 by AAN Enterprises, Inc.
with a HMG-CoA reductase inhibitor
(atorvastatin 80 mg per day) resulted in a
16% reduction in the combined risk of fatal
and nonfatal stroke in patients with a recent
(within 1 to 6 months) stroke or TIA and no
known coronary heart disease (11.2% vs
13.1% over 4.9 years; HR 0.84, 95% CI 0.71
to 0.99, p ⫽ 0.03).1 A post hoc analysis found
the overall benefit of treatment included an
increase in the numbers of patients having
hemorrhagic stroke (n ⫽ 55 for active treat-
ment vs n ⫽ 33 for placebo; unadjusted HR
1.68, 95% CI 1.09 to 2.59) with no difference
in the incidence of fatal hemorrhagic stroke
between the groups (17 in the atorvastatin
and 18 in the placebo group).
A variety of clinical factors are associated
with an increased risk of hemorrhagic stroke
including advancing age, hypertension, ciga-
rette smoking, use of antithrombotic medica-
tions, lower blood glucose, and having a
prior hemorrhagic stroke.2-4 Although meta-
analysis of previous statin trials carried out
predominately in patients with coronary
heart disease found no relationship between
statin treatment and hemorrhagic stroke
risk,5,6 epidemiologic studies show a relation-
ship between low cholesterol levels and hem-
orrhagic stroke.7-10 In SPARCL, atorvastatin
treatment was associated with a mean post-
randomization low-density lipoprotein
(LDL) cholesterol of 72.9 ⫾ 0.5 mg per decili-
ter (1.88 ⫾ 0.01 mmol per liter) vs 128.5 ⫾
0.5 mg per deciliter (3.32 ⫾ 0.01 mmol per
liter) with placebo treatment (p ⬍ 0.001).1
This analysis explores the relationships be-
tween baseline patient characteristics, ator-
vastatin treatment, most recent blood
pressure, and LDL cholesterol levels and the
risk of hemorrhagic stroke in patients en-
rolled in the SPARCL trial.
METHODS The methods of the SPARCL study have been
described in detail previously.1,11 The local research ethics
committee or institutional review board at each participat-
ing study center approved the study protocol (15 of 205 cen-
ters excluded otherwise suitable patients with an LDL
cholesterol level above 160 mg per deciliter [4.1 mmol per
liter], as required by their institutional review boards), and
all patients gave written informed consent. The primary hy-
pothesis of the SPARCL trial was that treatment with 80 mg
of atorvastatin per day would reduce the combined risk of
fatal and nonfatal stroke among patients with a history of
stroke or TIA. Eligible patients were men and women over
18 years of age who had had an ischemic or hemorrhagic
stroke or a TIA (diagnosed by a neurologist within 30 days
after the event) 1 to 6 months before randomization. Stroke
was defined by focal clinical signs of CNS dysfunction of
vascular origin that lasted for at least 24 hours; TIA was
defined by the loss of cerebral or ocular function for less than
24 hours. Patients had to be ambulatory, with a modified
Rankin score of no more than 3 (scores can range from 0 to
5, with higher scores indicating more severe disability), and
to have an LDL cholesterol level of at least 100 mg per deci-
liter (2.6 mmol per liter) and no more than 190 mg per decili-
ter (4.9 mmol per liter). Patients who were taking lipid-
altering drugs had to stop these medications 30 days before
the screening phase of the study and these drugs were pro-
hibited during the course of the trial. Excluded patients in-
cluded those with atrial fibrillation, mechanical prosthetic
heart valves, or subarachnoid hemorrhage. The investigators
categorized stroke subtype as ischemic (large vessel athero-
thromboembolic, cardioembolic, small vessel, other etiol-
ogy, or unknown cause), hemorrhagic, other, or unable to be
determined based on their clinical judgment (diagnostic cri-
teria were not provided and stroke subtype was not adjudi-
cated). Patients with hemorrhagic stroke (2% of the study
population) could be included if they were deemed by the
investigator to be at risk for ischemic stroke or coronary
heart disease. Subjects were enrolled between September
1998 and March 2001.
The primary outcome was the time from randomization
to a first nonfatal or fatal stroke. An independent endpoint
committee adjudicated all potential endpoints without
knowledge of the patients’ treatment status or cholesterol
levels. In a post hoc analysis, strokes occurring after ran-
domization were categorized as being ischemic, hemor-
rhagic, or unclassified based on standard clinical and
radiographic criteria.
The SPARCL steering committee developed the study
protocol with the sponsor and takes responsibility for the
data and data analyses. Medpace (Cincinnati) managed all
data. Medpace, Charles River Laboratories Clinical Services
(Brussels), and the sponsor provided site monitoring
throughout the study. A data and safety monitoring board
with independent statistical support performed interim mon-
itoring analyses for safety and efficacy.
For the current secondary analyses, we first explored re-
lationships between individual baseline factors and time to
hemorrhagic stroke in separate Cox regression models with
adjustment for treatment. Interactions between the factors
and treatment assignment were assessed. A factor for treat-
ment and individual baseline factors significant at the ⬍0.10
level were subsequently entered into a single multivariable
model and backward elimination removed factors from the
model that did not remain significant (p ⬎ 0.10).
The effects of two post-randomization variables on the
risk of hemorrhagic stroke were then assessed with adjust-
ment for significant variables from the multivariable base-
line risk factor model. The association between blood
pressure during follow-up and the risk of hemorrhagic
stroke was evaluated using the Joint National Committee–7
(JNC-7) classification categories (normal, systolic blood
pressure [SBP] ⬍120 mm Hg and diastolic blood pressure
[DBP] ⬍80 mm Hg; pre-hypertension, SBP 120 to 139 mm
Hg or DBP 80 to 89 mm Hg; stage 1 hypertension, SBP 140 to
159 mm Hg or DBP 90 to 99 mm Hg; stage 2 hypertension,
Neurology 70 June 10, 2008 (Part 2 of 2) 2365
 SBP ⱖ160 mm Hg or DBP ⱖ100 mm Hg)12 as a time-varying
covariate in a Cox regression model. The value of the time- Figure Kaplan-Meier curves (with unadjusted
hazard ratios) for the occurrence of all
varying covariate for each subject was updated each time a
fatal and nonfatal stroke, fatal stroke,
subject’s blood pressure was measured prior to a hemor-
and nonfatal stroke
rhagic stroke or prior to the end of follow-up for hemor-
rhagic stroke. The interaction between the time-varying
covariate and treatment group was also evaluated. A multi-
variable analysis including LDL-cholesterol levels during
follow-up in the atorvastatin group was also performed with
LDL cholesterol as the time-varying covariate.

RESULTS The figure gives the Kaplan-Meier

curves and unadjusted hazard ratios for the oc-
currence of all fatal and nonfatal (top panel), fatal
(middle panel), and nonfatal (bottom panel) isch-
emic and hemorrhagic strokes based on the inten-
tion to treat subjects with atorvastatin or placebo
(the net difference in statin use because of drop-
ins and drop-outs between groups was 78%1),
regardless of the type (i.e., ischemic or hemor-
rhagic) of entry event. The median follow-up was
4.9 years. A 21% reduction in fatal and nonfatal
ischemic stroke (unadjusted HR 0.79, 95% CI
0.66 to 0.95) is partially attenuated by an in-
creased risk of hemorrhage (unadjusted HR 1.68,
95% CI 1.09 to 2.59) resulting in the previously
reported, treatment-related 16% overall reduc-
tion in the risk of fatal and nonfatal stroke (ad-
justed hazard ratio ⫽ 0.84; 95% CI 0.71 to 0.99,
p ⫽ 0.03; unadjusted p ⫽ 0.05).1 The figure shows
that the risk of ischemic stroke was higher than
hemorrhagic stroke in both treatment groups
early after randomization and remained so
throughout follow-up. Of those randomized to
atorvastatin, 2.3% had a hemorrhagic stroke as
compared to 1.4% of those randomized to pla-
cebo. Subgroup analyses showed a treatment-
associated reduction in the risk of fatal ischemic Kaplan-Meier curves (with unadjusted hazard ratios) for the
occurrence of all fatal and nonfatal stroke (top panel), fatal
stroke with no difference in the rate of fatal hem-
stroke (middle panel), and nonfatal stroke (bottom panel) for
orrhagic strokes. patients randomized to atorvastatin 80 mg per day or pla-
Table e-1 on the Neurology® Web site at cebo within 1 to 6 months after a nondisabling stroke or TIA,
www.neurology.org gives baseline characteristics regardless of the type (i.e., ischemic or hemorrhagic) of entry
event.
of subjects who later did or did not have a post-
randomization hemorrhagic stroke with the asso-
ciated unadjusted univariable hazard ratios based LDL or total cholesterol, smoking status, or the
on Cox regression models (a table providing com- use of antiplatelet agents or anticoagulants did
parisons of the baseline characteristics of patients not affect the risk of hemorrhagic stroke.
randomized to atorvastatin or placebo has been Table 1 gives the numbers of patients having
published1). In addition to randomization to ator- an outcome ischemic, hemorrhagic, or any stroke
vastatin treatment, the risk of hemorrhagic stroke and associated unadjusted hazard ratios based on
was higher in those with hemorrhage as the entry the type of entry event as designated by the inves-
event, was increased in men, increased with age, tigators. Those having a hemorrhagic stroke as an
and tended to be higher in those with a history of entry event had an overall higher risk of an out-
hypertension. There were no statistical interac- come stroke with treatment (HR 2.82, 95% CI
tions between any of the significant baseline fac- 0.89 to 9.01).
tors and atorvastatin treatment for the risk of Cox multivariable regression including base-
hemorrhage. Time since entry event, baseline line variables significant in the univariable analy-

2366 Neurology 70 June 10, 2008 (Part 2 of 2)

 sis showed that having a hemorrhagic stroke as the

0.69 (0.48, 0.99)

0.87 (0.60, 1.24)

0.84 (0.64, 1.11)

0.89 (0.62, 1.27)

2.82 (0.89, 9.01)

0.85 (0.72, 1.00)

entry event (HR 5.65, 95% CI 2.82 to 11.30, p ⬍
0.001), male sex (HR 1.79, 95% CI 1.13 to 2.84, p ⫽

HR (95% CI)
0.01), atorvastatin treatment (HR 1.68, 95% CI 1.09
to 2.59, p ⫽ 0.02), age (10 y increments, HR 1.42,
95% CI 1.16 to 1.74, p ⫽ 0.001), but not a history of

72/401 (18.0)

109/701 (15.6)

60/463 (13.0)

311/2366 (13.1)
hypertension (HR 1.41, 95% CI 0.88 to 2.25, p ⫽

Placebo, n/N (%)

66/752 (8.8)

4/48 (8.3)
0.15) were independently associated with the risk of
hemorrhagic stroke. The overall model explained
1% of the risk of hemorrhagic stroke suggesting
most of the risk is related to unmeasured factors

Atorvastatin, n/N (%)

(model R2 ⫽ 0.009). Clinical factors aside from ran-

50/396 (12.6)

93/708 (13.1)

58/506 (11.5)

10/45 (22.2)

265/2365 (11.2)
54/708 (7.6)
domization to treatment with atorvastatin were as-
Any stroke*

sociated with 86% of the variance explained by the

model.
Table 2 gives the Cox multivariable regres-
sion analysis evaluating the effects of post-
4.99 (1.71, 14.61)

4.06 (0.84, 19.57)

1.16 (0.42, 3.19)

1.07 (0.48, 2.37)

0.91 (0.34, 2.44)

1.68 (1.09, 2.59)

randomization time-varying blood pressure,
HR (95% CI)

adjusting for significant variables from the multi-

variable baseline risk factor model (four factor
model excluding a history of hypertension).
Blood pressure categorization was based on
Placebo, n/N (%)

7/401 (1.8)

12/752 (1.6)

4/701 (0.6)

8/463 (1.7)

2/48 (4.2)

33/2366 (1.4)

59,547 measurements (mean of 12.6 measure-

ments per subject); 9% were in the normal, 37%
in the pre-hypertension, 36% in the stage 1 hyper-
tension, and 18% in the stage 2 hypertension
range. Increasing blood pressure was indepen-
Atorvastatin, n/N (%)
Hemorrhagic stroke

dently associated with an increased risk of hemor-

7/45 (15.6)
8/396 (2.0)

12/708 (1.7)

20/708 (2.8)

8/506 (1.6)

55/2365 (2.3)
Outcome ischemic, hemorrhagic, and total strokes by entry event and treatment group

rhagic stroke (four-category time-varying blood

pressure, p ⫽ 0.01) with those having a blood
pressure in the stage 2 hypertension range at high-
est risk.
0.64 (0.43, 0.94)

0.85 (0.57, 1.26)

0.76 (0.57, 1.02)

0.92 (0.62, 1.35)

1.64 (0.27, 9.82)

0.79 (0.66, 0.95)

Table 3 gives the Cox multivariable regres-

sion analysis evaluating the effects of post-
HR (95% CI)

randomization time-varying LDL-cholesterol

level (divided in quartiles) in the atorvastatin-
randomized patients (based on 27,649 values in
64/401 (16.0)

102/701 (14.6)

51/463 (11.0)

274/2366 (11.6)

2,365 patients), adjusting for significant variables

Placebo, n/N (%)

55/752 (7.3)

2/48 (4.2)

from the multivariable baseline risk factor model.

The median LDL cholesterol was 66 mg per deci-
liter (1.7 mmol per liter) with few values ⬎100 mg
per deciliter (2.6 mmol per liter). There was no
Atorvastatin, n/N (%)

relationship between LDL-cholesterol level and

41/396 (10.4)

79/708 (11.2)

51/506 (10.1)
44/708 (6.2)

3/45 (6.7)

218/2365 (9.2)
Ischemic stroke

the risk of hemorrhagic stroke. Very low LDL-

cholesterol levels (less than 40 mg per deciliter
[1.0 mmol per liter]) were not associated with in-
*Includes stroke of unverified type.

creased risk, and we found no threshold below

HR ⫽ unadjusted hazard ratio.

which the risk was increased.

Large vessel atheroembolic

Other or unknown cause*

Small vessel (lacunar)

DISCUSSION In addition to treatment with ator-

Hemorrhagic stroke

vastatin, this exploratory analysis found that hav-

or cardioembolic

ing hemorrhagic stroke as an entry event, male

Entry event

All subjects
Table 1

sex, and advancing age at baseline accounted for

86% of the increased risk of hemorrhagic stroke
TIA

explained by the Cox regression model, with the

Neurology 70 June 10, 2008 (Part 2 of 2) 2367

 were permitted to randomize patients with a hem-
Table 2 Multivariable Cox regression model evaluating the effect of post-
randomization time-varying blood pressure on the risk of
orrhagic stroke if they were deemed to be at risk
hemorrhagic stroke, adjusting for significant baseline for ischemic stroke or coronary heart disease. A
characteristics prior study found that the rate of recurrent hemor-
Hazard ratio (95% CI) p Value
rhagic stroke and ischemic events were similar.2 Al-
though the numbers were small and the CIs were
Atorvastatin treatment 1.69 (1.10, 2.60) 0.02
wide, there were excess numbers of treatment-
Male gender 1.77 (1.11, 2.81) 0.02
associated outcome ischemic and hemorrhagic
Age, 10 y increment 1.37 (1.12, 1.69) 0.003
strokes among patients with an entry hemorrhage
Entry event ⫽ hemorrhagic stroke 5.81 (2.91, 11.60) ⬍0.001
whereas those with entry ischemic strokes, regard-
Blood pressure — 0.01 less of investigator-designated subtype, benefited
Normotension (SBP ⬍120 and DBP ⬍80 mm Hg)* — — (table 1). As shown in table 1, there was an increase
Pre-hypertension (SBP 120–139 or DBP 80–89 mm Hg) 3.18 (0.76, 13.34) 0.11 in outcome hemorrhagic strokes in subjects with an
Stage 1 hypertension (SBP 140–159 or DBP 90–99 3.49 (0.83, 14.61) 0.09 investigator-designated small-vessel distribution
mm Hg)
stroke at entry (possibly contributing to some of the
Stage 2 hypertension (SBP ⱖ160 or ⱖ100 mm Hg) 6.19 (1.47, 26.11) 0.01
unexplained variance in hemorrhage risk). Because
p Value for treatment ⫻ entry event interaction ⫽ 0.20. p Value for treatment ⫻ hypertension
of the high risk of false-positive findings, conclu-
interactions ⫽ 0.25. sions regarding treatment effects on secondary out-
*Referent category. comes in isolated subgroups may lack validity.
SBP ⫽ systolic blood pressure; DBP ⫽ diastolic blood pressure.
Those with an entry small-vessel distribution stroke
also had a reduction in outcome ischemic strokes
largest risk being associated with having a hemor- resulting in a total benefit similar to the overall
rhagic stroke as the qualifying event at baseline. study cohort (table 1).
Although each of these factors and treatment as- A cohort study of patients with prior stroke or
signment were related to the risk of having such TIA found that increasing age, lower blood glu-
an event during follow-up, they explained a rela- cose, systolic blood pressure, and the use of anti-
tively small proportion of the overall risk (about hypertensive medications were associated with an
1%). The impact of baseline characteristics on increased risk of hemorrhagic stroke.4 A history
hemorrhagic stroke risk was similar in those ran- of hypertension at baseline tended to be associ-
domized to atorvastatin vs placebo (i.e., these fac-
ated with increased risk of hemorrhagic stroke
tors, including hemorrhagic stroke as the entry
based on univariable analyses, a trend lost after
event, did not disproportionately increase risk in
accounting for other factors. An independent re-
atorvastatin-treated patients).
lationship between blood pressure recorded at the
The risk of recurrent hemorrhagic stroke is es-
last assessment prior to a hemorrhagic stroke and
timated at 2.5% per year.2,13 It is, therefore, not
bleeding risk was found with the largest risk be-
surprising that having a hemorrhagic stroke as an
ing in those with stage 2 hypertension. These data
entry event was associated with having an out-
support the need for aggressive management of
come hemorrhage. In SPARCL, investigators
hypertension to reduce the risk of hemorrhagic
stroke.14,15 We do not have data on blood glucose
Table 3 Multivariable Cox regression model evaluating the effect of post- at the time of hemorrhagic stroke and cannot ad-
randomization time-varying LDL cholesterol on the risk of dress the possible role of lower levels of blood
hemorrhagic stroke, adjusting for significant baseline characteristics
glucose on this risk.
Hazard ratio (95% CI) p Value Epidemiologic studies have found an association
Male gender 2.21 (1.20, 4.09) 0.01
between low cholesterol levels and an increased risk
Age, 10 y increment 1.40 (1.08, 1.81) 0.01
of hemorrhagic stroke,7-10 a relationship not found
in more recent clinical trials of statins given for
Entry event ⫽ hemorrhagic stroke 8.38 (3.78, 18.56) ⬍0.001
coronary heart disease, including in those patients
LDL cholesterol (quartiles, atorvastatin group) — 0.77
with major reductions in LDL cholesterol.5,6,16
LDL cholesterol ⬍52 mg/dL (1st quartile, 12 events)* — —
Consistent with these observations, we found no
LDL cholesterol 52 to 65 mg/dL (2nd quartile, 18 events) 1.26 (0.60, 2.64) 0.54
relationships between the baseline levels of either
LDL cholesterol 66 to 92 mg/dL (3rd quartile, 13 events) 0.97 (0.44, 2.17) 0.94 total or LDL cholesterol and the risk of hemor-
LDL cholesterol ⱖ93 mg/dL (4th quartile, 45 events) 1.37 (0.63, 2.98) 0.43 rhagic stroke, no disproportionate increase in the
risk of bleeding associated with treatment based
To convert mg/dL to mmol/L multiply by 0.02586.
*Referent category. on baseline cholesterol levels, and no independent
LDL ⫽ low-density lipoprotein. effect of LDL-cholesterol levels at the last mea-

2368 Neurology 70 June 10, 2008 (Part 2 of 2)

surement prior to a hemorrhagic stroke in those
treated with atorvastatin. Moreover, we found no
threshold of LDL cholesterol below which the
risk of hemorrhagic stroke was increased.
Anticoagulants and some antiplatelet regimens
may be associated with increased risk of post-
stroke brain hemorrhage.17,18 We, however, found
no overall effect of antiplatelet drugs or antico-
agulants on the risk of brain hemorrhage in
SPARCL. Despite statins having antithrombotic
properties,19-22 we also found no statistical inter-
action between treatment and the use of any indi-
vidual or combination of antithrombotic drugs
(table e-1). An increase in the risk of hemorrhagic
stroke related to a statin’s antithrombotic proper-
ties cannot be excluded.
Post hoc analysis of data from patients with
prior cerebrovascular disease enrolled in the
Heart Protection Study found a non-significant
increase in hemorrhagic stroke in those treated
with simvastatin 40 mg per day vs placebo (n ⫽
21, 1.3% vs n ⫽ 11, 0.7%).23 The overall number
of strokes was small, and the Heart Protection
Study was not powered to detect these differ-
ences. Treatment-associated hemorrhagic stroke
in SPARCL remained after accounting for the
other factors included in this exploratory analysis
(table 2). Although meta-analysis of over 90,000
subjects in statin trials of patients with coronary
heart disease found no increase in the risk of hem-
orrhagic stroke associated with statin treat-
ment,5,6 it is possible that patients with a prior
stroke or TIA are at greater risk of statin-related
bleeding. Nevertheless, it remains uncertain
whether there is a difference in the risk of bleed-
ing in statin-treated patients with prior stroke
compared to those with coronary heart disease,
given the small numbers of patients with hemor-
rhagic stroke in these trials and the post hoc na-
ture of the analyses.
No baseline (including having a hemorrhagic
stroke as an entry event) or post-randomization
factors were identified that disproportionately in-
creased bleeding in treated compared with pla-
cebo patients, but treatment-associated risk
remained after adjustment for other significant
factors. Although not significant, the numbers of
patients with an entry hemorrhagic stroke having
an outcome ischemic or hemorrhagic stroke was
greater in treated vs placebo patients. Therefore,
unlike those having an entry ischemic stroke,
there is no evidence that those having a hemor-
rhagic stroke at baseline benefited from treat-
ment. It is, however, important to re-emphasize
the exploratory nature of these analyses that are
useful for hypothesis generation, but cannot be
conclusive. Outcome hemorrhagic strokes oc-
curred in less than 2% of the study population,
the observation was found in a post hoc analysis,
and the exploratory statistical models account for
only a small proportion of bleeding. In making
therapeutic decisions, the increase in the risk of
hemorrhagic stroke found in SPARCL, if not due
to chance, must be balanced against the benefit of
treatment with atorvastatin 80 mg per day in re-
ducing the overall risk of stroke, as well as other
cardiovascular events found in the study’s pre-
specified, intention-to-treat analysis.
Received July 2, 2007. Accepted in final form September 21,
2007.
REFERENCES
1. The Stroke Prevention by Aggressive Reduction in
Cholesterol Levels (SPARCL) Investigators. High-dose
atorvastatin after stroke or transient ischemic attack.
N Engl J Med 2006;355:549–559.
2. Hill MD, Silver FL, Austin PC, Tu JV. Rate of stroke
recurrence in patients with primary intracerebral hem-
orrhage. Stroke 2000;31:123–127.
3. Ariesen MJ, Claus SP, Rinkel GJ, Algra A. Risk factors
for intracerebral hemorrhage in the general popula-
tion: a systematic review. Stroke 2003;34:2060–2065.
4. Ariesen MJ, Algra A, Warlow CP, Rothwell PM. Predic-
tors of risk of intracerebral haemorrhage in patients with
a history of TIA or minor ischaemic stroke. J Neurol
Neurosurg Psychiatry 2006;77:92–94.
5. Amarenco P, Labreuche J, Lavallee P, Touboul PJ.
Statins in stroke prevention and carotid atherosclero-
sis. Systematic review and up-to-date meta-analysis.
Stroke 2004;35:2902–2909.
6. Cholesterol Treatment Trialists’ (CTT) Collaborators.
Efficacy and safety of cholesterol-lowering treatment:
prospective meta-analysis of data from 90 056 partici-
pants in 14 randomised trials of statins. Lancet 2005;
366:1267–1278.
7. Iso H, Jacobs DRJ, Wentworth D, Neaton JD, Cohen
JD. Serum cholesterol levels and six-year mortality
from stroke in 350,977 men screened for the multiple
risk factor intervention trial. N Engl J Med 1989;320:
904–910.
8. Yano K, Reed DM, MacLean CJ. Serum cholesterol
and hemorrhagic stroke in the Honolulu heart pro-
gram. Stroke 1989;20:1460–1465.
9. Ebrahim S, Sung J, Song YM, Ferrer RL, Lawlor DA,
Davey Smith G. Serum cholesterol, haemorrhagic
stroke, ischaemic stroke, and myocardial infarction:
Korean national health system prospective cohort
study. BMJ 2006;333:22–28.
10. Leppala JM, Virtamo J, Fogelholm R, Albanes D,
Heinonen OP. Different risk factors for different stroke
subtypes: association of blood pressure, cholesterol,
and antioxidants. Stroke 1999;30:2535–2540.
11. The SPARCL Investigators . Design and baseline charac-
teristics of the stroke prevention by aggressive reduction
in cholesterol levels (SPARCL) study. Cerebrovascular
Diseases 2003;16:389–395.
Neurology 70 June 10, 2008 (Part 2 of 2) 2369
 12. Chobanian AV, Bakris GL, Black HR, et al. The sev-
enth report of the joint national committee on preven-
tion, detection, evaluation, and treatment of high
blood pressure: The JNC 7 report. JAMA 2003;289:
2560–2571.
13. Bae H-G, Jeong D-S, Doh J-W, Lee K-S, Yun I-G, Byun
B-J. Recurrence of bleeding in patients with hyperten-
sive intracerebral hemorrhage. Cerebrovascular Dis-
eases 1999;9:102–108.
14. Arakawa S, Saku Y, Ibayashi S, Nagao T, Fujishima
M. Blood pressure control and recurrence of hyperten-
sive brain hemorrhage. Stroke 1998;29:1806–1809.
15. PROGRESS Collaborative Group. Randomised trial of
a perindopril-based blood-pressure-lowering regimen
among 6105 individuals with previous stroke or tran-
sient ischaemic attack. Lancet 2001;358:1033–1041.
16. LaRosa JC, Grundy SM, Waters DD, et al. Intensive
lipid lowering with atorvastatin in patients with stable
coronary disease. N Engl J Med 2005;352:1425–1435.
17. Franke CL, de Jonge J, van Swieten JC, Op de Coul
AA, Van Gijn J. Intracerebral hemorrhage during anti-
coagulant treatment. Stroke 1990;21:726–730.
18. Diener H-C, Bogousslavsky J, Brass LM, et al. Aspirin
and clopidogrel compared with clopidogrel alone after
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recent ischaemic stroke or transient ischaemic attack in
high-risk patients (match): randomised, double-blind,
placebo-controlled trial. Lancet 2004;364:331–337.
19. Yokoyama S, Ikeda H, Haramaki N, Yasukawa H,
Katoh A, Imaizumi T. HMG CoA reductase inhibitor
protects against in vivo arterial thrombosis by aug-
menting platelet-derived nitric oxide release in rats.
J Cardiovasc Pharmacol 2005;45:375–381.
20. Ray KK, Cannon CP. Pathological changes in acute
coronary syndromes: the role of statin therapy in the
modulation of inflammation, endothelial function and
coagulation. J Thromb Thrombolysis 2004;18:89–101.
21. Libby P, Aikawa M. Effects of statins in reducing
thrombotic risk and modulating plaque vulnerability.
Clin Cardiol 2003;26.
22. Gaddam V, Li DY, Mehta JL. Anti-thrombotic effects
of atorvastatin: an effect unrelated to lipid lowering.
J Cardiovasc Pharmacol Therapeutics 2002;7:247–253.
23. Heart Protection Study Collaborative Group. Effects
of cholesterol-lowering with simvastatin on stroke and
other major vascular events in 20,536 people with cere-
brovascular disease or other high-risk conditions. Lan-
cet 2004;363:757–767.