NEUROLOGY 2007;68:719–720 Editorial

Low LDL cholesterol, statins, and

brain hemorrhage
Should we worry?
Larry B. Goldstein, MD, FAAN, FAHA

In a retrospective observational study, Bang et al. transformation of ischemic infarctions, primary

report that low low-density lipoprotein (LDL) choles-
terol levels are independently associated with an in-
creased risk of hemorrhagic transformation after
recanalization therapy for acute ischemic stroke.1
What are the implications of this study for clinical
practice?
As Bang et al. point out, it is important to recog-
nize the limitations of their study design. Analyses of
even large observational studies can be misleading.
For example, epidemiologic studies of postmeno-
pausal hormone therapy found their use was associ-
ated with a reduction in cardiovascular events,2 but
randomized trials found no effect or harm.3-5 An ob-
servational study can be useful for identifying poten-
tial risk factors, especially when the finding is
supported by other studies. Whether risk factor mod-
ification alters outcomes can only be established
through properly controlled, prospective studies.
Are there data from other studies to support a
relationship between low LDL cholesterol and the
risk of hemorrhagic infarction? Epidemiologic stud-
ies generally find that lower cholesterol levels are
associated with an increased risk of brain hemor-
rhage, even without recanalization therapy. For ex-
ample, the Asia-Pacific Cohort study showed a 20%
(95% CI: 8 to 30%) decreased risk of hemorrhagic
stroke per 4.5 mg/dL increase in cholesterol levels.6
Bang et al.’s findings would be consistent with the
epidemiologic observations if the bleeding in these
studies was primarily due to hemorrhagic infarction
(i.e., the pathophysiology of the hemorrhages would
be similar and related to reperfusion of ischemic
brain). It is not possible, however, to determine
whether the effect reported from epidemiologic
studies is related to an increase in hemorrhagic
hemorrhages, or both. Unless sequential brain
scans are available, differentiating the two types
of parenchymal hemorrhages can be difficult. If
the findings of Bang et al. are verified in other
studies, understanding the mechanism by which
low cholesterol (and low LDL cholesterol) increases
the risk of hemorrhagic infarction might lead to
treatments to reduce this complication.
How much does low LDL cholesterol contribute to
the risk of symptomatic hemorrhagic transforma-
tion? Bang et al. found the greatest risk of bleeding
after recanalization therapy was independently re-
lated to current cigarette smoking followed by in-
creasing stroke severity and lower LDL cholesterol.
No threshold level below which risk increases was
reported with the impact of LDL cholesterol being
related to the magnitude of the reduction (a 3.2%
decrease in risk was found for every 1 mg/dL in-
crease in LDL cholesterol). The amount of variance
in bleeding risk explained by the model is not given
(i.e., the effect of the factors included in logistical
regression equation on total risk is not provided), so
the relative impact of unmeasured factors is
uncertain.
An important question for current clinical practice
is whether lowering LDL cholesterol is associated
with undue risk of brain hemorrhage. Meta-analysis
of over 90,000 subjects, predominately with coronary
heart disease, enrolled in statin trials found a 19%
proportional reduction (RR 0.81, 99% CI 0.74 to 0.89;
p ⫽ 0.0001) in ischemic strokes per mmol/L LDL
cholesterol reduction with no difference in hemor-
rhagic stroke (RR 1.05, 99% CI 0.78 to 1.41; p ⫽
0.7).7 Similarly, the Treating to New Targets (TNT)
study found no increase in brain hemorrhages de-

See also page 737

From the Department of Medicine (Neurology), Center for Cerebrovascular Disease, Center for Clinical Health Policy Research, Duke University and
Durham VA Medical Center, Durham, NC.
Disclosure: Steering Committee for the Stroke Prevention with Aggressive Reduction in Cholesterol (SPARCL) study supported by Pfizer and a consult for
Pfizer.
Address correspondence and reprint requests to Dr. Larry B. Goldstein, Box 3651, Duke University Medical Center, Durham, NC 27710; e-mail:
golds004@mc.duke.edu

Copyright © 2007 by AAN Enterprises, Inc. 719

spite profound lowering of cholesterol levels in pa-
tients with stable coronary heart disease.8 The
benefits of statin therapy outweigh the risks in these
populations.
Does lowering cholesterol levels with statins in-
crease the risk of hemorrhagic infarction in persons
with prior stroke? Bang et al. found that the effect of
statin therapy was not significant after controlling
for the level of LDL cholesterol. This lack of effect of
statins in the multivariate model may have been due
to statistical colinearity (i.e., the use of statins was
strongly related to lower LDL cholesterol levels). The
Heart Protection Study (HPS) comparing simvasta-
tin 40 mg per day vs placebo in patients at high
vascular risk included a subgroup of subjects with
prior stroke.9 An unplanned, post hoc analysis found
the effect of statin treatment on bleeding risk dif-
fered between those with and without a history of
prior cerebrovascular disease. The small increase in
hemorrhages in those treated with the statin (n ⫽
21, 1.3% vs n ⫽ 11, 0.7%) was not significant. Hem-
orrhage subtype was not given. Although Bang et al.
correctly indicate that the Stroke Prevention with
Aggressive Reductions in Cholesterol Levels
(SPARCL) trial found high dose statin therapy (ator-
vastatin 80 mg per day) in patients with recent
stroke or TIA and no known coronary heart disease
was associated with an increase in brain hemor-
rhage, this too was based on a post hoc analysis.10
The pathophysiologic subtypes of brain hemorrhage
(i.e., primary parenchymal hemorrhage vs hemor-
rhagic infarction) were not reported. Therefore, there
remain no data showing that statin treatment in-
creases the risk of hemorrhagic infarction.
Should clinicians worry about increasing the risk
of hemorrhagic infarction or primary brain hemor-
rhages by reducing LDL cholesterol with statins in
patients with prior stroke, and should recanalization
therapy be withheld in those with low LDL choles-
terol level? Although HPS found no reduction in re-
current stroke with statin therapy, treatment was
720 NEUROLOGY 68 March 6, 2007
associated with major reductions in other vascular
events in patients with prior cerebrovascular disease
regardless of baseline cholesterol levels. In SPARCL,
there was not only a significant 16% reduction in the
combined risk of nonfatal and fatal stroke with treat-
ment, but also profound reductions in other major
vascular events. Therefore, the available data sup-
port the use of statins in patients with a history of
cerebrovascular disease.
Whether low LDL cholesterol levels increase the
risk of hemorrhagic infarction in patients undergo-
ing recanalization therapy requires verification.
Even if true, the increased chances of bleeding asso-
ciated with this and other identified contributors to
risk such as current cigarette smoking would need to
be balanced against the benefits of restoring circula-
tion to ischemic brain.
References
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