Correspondence
HEMORRHAGIC STROKE IN THE STROKE
PREVENTION BY AGGRESSIVE REDUCTION
IN CHOLESTEROL LEVELS STUDY
To the Editor: The investigators of the Stroke Pre-
vention by Aggressive Reduction in Cholesterol Lev-
els (SPARCL) study1 analyze the increased risk of
hemorrhagic stroke in patients with a history of cere-
brovascular disease treated with statins. Since statin
use is associated with an increased risk of hemor-
rhagic stroke in patients with a history of cerebrovas-
cular disease, this study is important because it
identifies at-risk subgroups of patients.2
The authors emphasize that hemorrhagic stroke as
an entry event is associated with hemorrhagic stroke
during follow-up. Since patients with hemorrhagic
stroke are usually not treated with statins for secondary
prevention, this observation is of minor clinical impor-
tance. Far more interesting is the increased risk of hem-
orrhagic stroke in patients with lacunar stroke, caused
by cerebral small vessel disease (hazard ratio [HR] 4.99,
95% confidence interval [CI] 1.71 to 14.61), treated
with statins. The authors discuss that increased hemor-
rhagic strokes in small vessel disease might lack validity,
because secondary outcomes in isolated subgroups have
a high risk of false-positive findings.
Although we agree with the authors from a statis-
tical point of view, we believe that future investiga-
tions should focus on whether statin treatment might
be contraindicated in patients with small vessel dis-
ease. Patients with cerebral small vessel disease often
have intracerebral microhemorrhages.3 These micro-
hemorrhages may change into macrohemorrhages if
patients are treated with statins. Statins exert pleio-
tropic effects on, for example, the coagulation cas-
cade and fibrinolytic system.
It is still unclear from the SPARCL study whether
statins in patients with small vessel disease prevent only
minor (lacunar) strokes and whether the risk of fatal
hemorrhagic stroke is increased in this group of pa-
tients. We would ask the SPARCL investigators to
present data on benefit vs complications in the sub-
group of patients with small vessel disease (lacunar
stroke).
Mervyn D.I. Vergouwen, M. Vermeulen,
Yvo B.W.E.M. Roos, Amsterdam, The Netherlands
Disclosure: The authors report no disclosures.
Reply from the Authors: Dr. Vergouwen and col-
leagues reiterate our caution that our report was
exploratory and that drawing conclusions based on
analyses of isolated subgroups is hazardous.1 We
further cautioned that baseline stroke subtype cat-
egorization in SPARCL was based on the clinical
impression of the investigator and was not other-
wise standardized or adjudicated.1
With these important caveats stated, we did find an
increased risk of outcome hemorrhagic strokes in sub-
jects with an investigator-designated small vessel stroke
at baseline. The validity of this post hoc observation is
worthy of further study. Dr. Vergouwen and colleagues
requested that we provide data reflecting the benefit vs
complications in the subgroup of patients with small vessel
disease. These data are given in the report (table 1).1
Subjects with a baseline small-vessel stroke who
were randomized to treatment with atorvastatin 80
mg per day had a benefit in the primary endpoint
(combined risk of any fatal or nonfatal stroke, HR
0.84, 95% CI 0.64 to 1.11)1 that was virtually iden-
tical to the benefit in the overall study population
(HR 0.84, 95% CI 0.71 to 0.99).4 There was no
overall treatment-related difference in the frequency
of fatal hemorrhages (17 in the active treatment and
18 in the placebo groups).4 There are too few sub-
jects and too many potential confounders to perform
any further meaningful analyses of these data.
We do not have data from SPARCL to address
their conjectures regarding the possible importance
of cerebral microhemorrhages or the pleiotropic ef-
fects of statins in this setting. As further discussed in
the editorial that accompanied our report, “The true
mechanism linking statins to brain hemorrhage (in
patients with a history of recent stroke or TIA) re-
mains a mystery.”5
Larry B. Goldstein, Durham, NC
Disclosure: Steering Committee for the SPARCL study, which
was supported by Pfizer, and a consultant for Pfizer.
Copyright © 2009 by AAN Enterprises, Inc.
1. Goldstein LB, Amarenco P, Szarek M, et al, on behalf of
the SPARCL Investigators. Hemorrhagic stroke in the
Stroke Prevention by Aggressive Reduction in Cholesterol
Levels study. Neurology 2008;70:2364 –2370.
2. Vergouwen MD, de Haan RJ, Vermeulen M, Roos YB.
Neurology 72 April 21, 2009 1447
 Statin treatment and the occurrence of hemorrhagic stroke
in patients with a history of cerebrovascular disease. Stroke
2008;39:497–502.
3. Kwa VI, Franke CL, Verbeeten B Jr, Stam J. Silent intrace-
rebral microhemorrhages in patients with ischemic stroke:
Amsterdam Vascular Medicine Group. Ann Neurol 1998;
44:372–377.
4. The Stroke Prevention by Aggressive Reduction in Choles-
terol Levels (SPARCL) Investigators. High-dose atorvasta-
tin after stroke or transient ischemic attack. N Engl J Med
2006;355:549 –559.
5. Jacobs BS, Greenberg SM. Statins, low cholesterol, and
hemorrhagic stroke: an uncertain triangle. Neurology
2008;70:2355–2356.
To the Editor: The SPARCL Study Investigators1
further analyze the risk versus benefit of high-dose
atorvastatin. This is important since there has been a
push to use high-dose statin therapy in wide seg-
ments of the population in order to achieve aggres-
sive cholesterol-lowering goals.2
The new SPARCL analysis suggests that individu-
als free of coronary heart disease with a history of
hemorrhagic stroke, or any history of stroke and
stage 2 hypertension, should not be treated with high
dose atorvastatin therapy because of a sixfold risk of
subsequent hemorrhagic stroke. Additionally, the
risk appears to be magnified with advancing age. Fur-
thermore, there is no mortality benefit of high-dose
atorvastatin therapy among individuals free of coro-
nary heart disease, despite having a prior stroke.3
Although statin treatment may be effective in the
prevention of stroke in patients with known coro-
nary heart disease but without a history of cerebro-
vascular disease, some concerns remain when
considering high doses of statins in certain segments
of the population. High-dose compared to low-dose
atorvastatin therapy in women with stable coronary
heart disease increased all-cause mortality, fueled by a
large and significant increase in cancer mortality.4
Similarly, high-dose compared to low-dose atorva-
statin therapy in elderly subjects with stable coronary
heart disease is associated with a trend towards increased
all-cause mortality, mainly from increased cancer mor-
tality.5 We believe that high-dose atorvastatin therapy
should be not be used in elderly women, individuals
with prior hemorrhagic stroke, or those with stage 2
hypertension and any prior stroke.
Mark R. Goldstein, MD, FACP, Bonita Springs, FL;
Luca Mascitelli, MD, Udine, Italy; Francesca
Pezzetta, MD, Tolmezzo, Italy
Disclosure: The authors report no disclosures.
Reply from the Authors: Dr. Goldstein et al. assert
that our report suggests “individuals with a history of
hemorrhagic stroke, or any history of stroke and
stage 2 hypertension, should not be treated with high
1448 Neurology 72 April 21, 2009
dose atorvastatin therapy because of a sixfold risk of
subsequent hemorrhagic stroke.” It is first important
to reiterate that our report was exploratory and that
drawing firm conclusions based on unplanned, post
hoc analyses is hazardous.
Furthermore, there were no statistical interactions
between any of the identified factors—including having
a hemorrhagic stroke at baseline—and the risk of an
outcome hemorrhagic stroke. The risk of hemorrhage
was not disproportionately increased by treatment.1
However, we did point out that there was no evi-
dence that those with a baseline hemorrhagic stroke
benefited from treatment.1 The increased risk of
hemorrhagic stroke associated with stage 2 hyperten-
sion was independent of treatment. Rather than be-
ing an indication for avoiding statins, these data
reinforce the need to aggressively treat hypertension
as part of secondary stroke prevention management.6
The SPARCL trial was neither designed nor powered
to detect a difference in all cause mortality.3
We have also conducted a secondary analysis of
SPARCL data comparing the relative effects of treat-
ment on stroke and cardiovascular events in men and
women.7 Women constituted 40% of the SPARCL
population. There were no sex by treatment interac-
tions for the SPARCL primary endpoint (combined
risk of nonfatal and fatal stroke; interaction p ⫽
0.99) or for the occurrence of any of the SPARCL
secondary endpoints (major cardiac events, p ⫽ 0.45;
major cardiovascular events, p ⫽ 0.63; revasculariza-
tion procedures, p ⫽ 0.17; any coronary heart event,
p ⫽ 0.40). There was a statistically marginal ( p ⫽
0.06) sex by treatment interaction for all cause mor-
tality, suggesting a possible benefit in women.
In another analysis, we reported no statistical het-
erogeneity in the benefits associated with treatment
between younger and older SPARCL subjects.8 The
cited TNT trial analysis revealed no statistically sig-
nificant age by treatment interaction for all cause
mortality.5 This included a small difference in cancer
deaths between the two groups (2.8% for high dose
vs 2.1% for low dose).
As always, physicians need to weigh the benefits
against the risks of treatment in individual patients.
Our exploratory analysis suggests this is particularly
true for the use of statins in patients with a recent
brain hemorrhage. The data, however, do not sup-
port the view that high-dose atorvastatin therapy
should not be used in the elderly, in women, or in
those with stage 2 hypertension and any prior stroke.
Larry B. Goldstein, Durham, NC
Disclosure: Steering Committee for the SPARCL study, which
was supported by Pfizer, and a consultant for Pfizer.
Copyright © 2009 by AAN Enterprises, Inc.