Correspondence
Letter by Goldstein Regarding Article, “Statins
and Intracerebral Hemorrhage”
An exploratory SPARCL analysis found no relationship between the
degree of lipid lowering in statin-treated subjects and hemorrhage, a
statin risk that remained after adjustment for other variables.5 A
meta-analysis of trials of subjects randomly assigned to statins found
no overall relationship between low-density lipoprotein-cholesterol
levels and bleeding.3
SPARCL showed the unequivocal benefit of a statin begun within
1 to 6 months after transient ischemic attack or stroke, an effect
partially attenuated by an increased risk of hemorrhagic stroke.5
Although the result of the present meta-analysis is reassuring, it
cannot be used to completely discount the possible statin-associated
risk of brain hemorrhage in SPARCL-type patients.
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To the Editor:
The Stroke Prevention by Aggressive Reduction in Cholesterol
Levels (SPARCL) trial enrolled subjects with recent (within 1– 6
months) transient ischemic attack or stroke, reporting more frequent
brain hemorrhages among those randomly assigned to a statin
(hazard ratio⫽1.66; 95% CI, 1.08 –2.55).1 Hackam et al2 write that
this finding has “led to some uncertainty regarding the balance of
benefits and risks of statins, particularly in patients with a history of
cerebrovascular disease.” Notwithstanding their exhaustive metaanalysis, the reason for this concern is not clear.
The SPARCL trial, the only randomized trial designed to evaluate
a statin in a cerebrovascular population, found a treatment-related
reduction in all strokes (hazard ratio⫽0.84; 95% CI, 0.71– 0.99), a
result that included brain hemorrhages.1 SPARCL, therefore, raised
no uncertainty regarding the balance of risks and benefits of statins
in this group of patients; there was a clear treatment benefit. Previous
meta-analyses found an overall reduction in stroke and no significant
increased bleeding among subjects with coronary heart disease or
other high-risk conditions randomly assigned to statins.3 Whether
statin treatment increases brain hemorrhage in patients with a recent
cerebrovascular event is a separate question.
Hackam et al2 report that, “among 11 studies (including SPARCL)
exclusively enrolling patients with cerebrovascular disease, [there
was] no evidence that statins selectively increased the risk of
intracerebral hemorrhage.” Of these studies, 10 were considered
observational (7 cohort studies, 2 case-control studies, 1 crossover
study); only 1, SPARCL, was a prospective, double-blind, randomized trial. As pointed out by Hackam et al,2 observational studies are
subject to a variety of potential biases. Although the SPARCL
outcome stroke subtype analysis was not preplanned, the study had
a rigorous design with independent end point adjudication.1 It is
difficult to use observational data to completely discount the
SPARCL observation. This is especially true because a Heart
Protection Study exploratory analysis found heterogeneity in the
effect of randomization to statin therapy on the risk of brain
hemorrhage based on whether subjects had a history of cerebrovascular disease.4
Hackam et al also write that, “Although concerns regarding the
association of low cholesterol and brain hemorrhage were first
recorded several decades ago, the recent SPARCL trial was the first
major signal of risk linking statin therapy with this complication,”
implying that the statin-associated bleeding risk in SPARCL might
have been due to the drug’s lipid-lowering effect. There are no data
from SPARCL or other statin trials suggesting this might be the case.
Disclosures
Dr Goldstein is a member of the SPARCL steering committee, has
been a consultant for Pfizer, the study sponsor, and has spoken at
meetings sponsored by Pfizer.
Larry B. Goldstein, MD, FAAN, FAHA
Department of Medicine (Neurology)
Duke Stroke Center
Duke University
Durham VA Medical Center
Durham, NC
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. Hackam DG, Woodward M, Newby LK, Bhatt DL, Shao M, Smith EE,
Donner A, Mamdani M, Douketis JD, Arima H, Chalmers J, MacMahon
S, Tirschwell DL, Psaty BM, Bushnell CD, Aguilar MI, Capampangan
DJ, Werring DJ, De Rango P, Viswanathan A, Danchin N, Cheng C-L,
Yang Y-HK, Verdel BM, Lai M-S, Kennedy J, Uchiyama S, Yamaguchi T,
Ikeda Y, Mrkobrada M. Statins and intracerebral hemorrhage. Circulation.
2011;124:2233–2242.
3. Cholesterol Treatment Trialists Collaboration. Efficacy and safety of
more intensive lowering of LDL cholesterol: a meta-analysis of data from
170 000 participants in 26 randomised trials. The Lancet. 2010;376:
1670 –1681.
4. Heart Protection Study Collaborative Group. Effects of cholesterollowering with simvastatin on stroke and other major vascular events in
20 536 people with cerebrovascular disease or other high-risk conditions.
Lancet. 2004;363:757–767.
5. Goldstein LB. Hemorrhagic stroke in the stroke prevention by aggressive
reduction in cholesterol levels study. Neurology. 2009;72:1447–1448.
(Circulation. 2012;125:e1015.)
© 2012 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org
DOI: 10.1161/CIRCULATIONAHA.111.076802
e1015
Letter by Goldstein Regarding Article, ''Statins and Intracerebral Hemorrhage''
Larry B. Goldstein
Circulation. 2012;125:e1015
doi: 10.1161/CIRCULATIONAHA.111.076802
Downloaded from http://circ.ahajournals.org/ by guest on July 28, 2017
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