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High-Dose Statin for Every StrokeThe Good, the Bad, and the
Unknown
Magdy H. Selim, MD, PhD; Carlos A. Molina, MD, PhD
S tatins exert neuroprotective, microvascular, and
anti-inflammatory beneficial effects in animal stroke
models,independent of their lipid-lowering capabilities. These
are
seen at the highest doses with a doseresponse effect.
Observational studies show that statin use is associated
with
improved outcome in patients with ischemic stroke, presum-
ably a result of the pleiotropic effects suggested in animal
studies. This prompted an ongoing debate as to whether
statins should be used in every patient with ischemic stroke
regardless of the stroke mechanism and whether maximum
doses should be used on initiation of therapy. Our experts
firmly hold opposing and widely divergent views.
So, let us address the following questions. Is there suffi-
cient evidence that statins have neuroprotective effects in
patients with stroke? First, we point out that interpretation
of
clinical studies linking statins to improved stroke outcome,
which were mostly retrospective, is difficult due to
variability
in patient population and follow-up periods and insufficient
power to fully adjust for confounding variables. Few random-
ized trials of statins in acute stroke have been performed
with
inconclusive results. The Stroke Prevention by Aggressive
Reduction in Cholesterol Levels (SPARCL) trial, while it
demonstrated the benefit of high-dose atorvastatin for
secondary stroke prevention, it did not provide evidence
ofneuroprotective benefits. However, patients in SPARCL
began their treatment within 30 to 60 days after the stroke.
In another pilot study, randomization to simvastatin at 40
mg/day within 12 hours and for 72 hours after stroke onset
was associated with improvement in neurological function
by Day 3 compared with placebo, but this did not persist at
Day 90.2
Should all patients with stroke be started on high-dose
statins? Is there an association between dose and response?
The answers are presently unknown. The SPARCL study
reliably showed that high-dose atorvastatin at 80 mg/day
reduces the risk of recurrent stroke and other
cardiovascular
events in patients with stroke without known coronary dis-ease,
classified as having large-vessel disease, small-vessel
disease, or stroke of unknown cause. It is, however, unclear
in
the absence of randomized comparisons in patients with
stroke if lower doses of atorvastatin are equally or less
effective than the high-dose regimen. Although the Medical
Research Council/British Heart Foundation Heart Protection
Study (HPS) showed no obvious reduction in stroke recur-
rence among those with a history of stroke with simvastatin
at
40 mg/day, these results do not necessarily imply that
atorvastatin in doses 80 mg/day would have been less
effective in SPARCL given the differences in medical comor-
bidities between HPS and SPARCL participants. The dose
response analyses in the North Dublin Population Stroke
Study were exploratory, and the observed association be-
tween atorvastatins dose and outcome was largely driven by
worse outcome in atorvastatin-untreated patients.
There is randomized evidence that atorvastatin at 80
mg/day provides significant reductions in the risks of
cardio-
vascular events and stroke beyond that afforded by a 10-mg
dose in patients with coronary disease.1 In the Treating to
New Targets (TNT) trial, high-dose atorvastatin
significantly
reduced total cholesterol and triglycerides levels compared
with the 10-mg dose. However, the high-dose regimen was
associated with significantly more frequent adverse events
(8.1% versus 5.8%), higher rate of discontinuation of treat-
ment due to treatment-related adverse events (7.2% versus5.3%),
and greater incidence of persistent elevations in liver
enzymes (1.2% versus 0.2%). As Dr Furie points out, the
benefit of high-dose atorvastatin in SPARCL occurred with a
greater incidence in cerebral hemorrhage (2.3% versus 1.4%
in placebo-treated patients); and the treatment was
associated
with elevations in liver enzymes and creatine kinase levels
(2.2% versus 1.4%) and a discontinuation rate of 15.4%.
Recently, the Food and Drug Administration issued a warning
regarding increased risk of myopathy in patients taking
simvastatin at 80 mg/day, especially if taken concomitantly
with calcium channel blockers, which are not uncommonly
used by patients with stroke. Needless to say, most
insurance
companies in the United States and primary care physiciansin
Europe substitute atorvastatin with generic simvastatin.
Here rests the conundrum! Interestingly, the recent American
Received January 13, 2012; accepted January 18, 2012.The
opinions expressed in this article are not necessarily those of the
editors or of the American Heart Association. This article is Part
3 of a 3-part
article. Parts 1 and 2 appear on pages 1992 and 1994,
respectively.
From Beth Israel Deaconess Medical Center (M.H.S.), Stroke
Division, Boston, MA; and Hospital Universitari Vall dHebron
(C.A.M.), Barcelona, Spain.This paper was presented in part at the
International Stroke Conference 2012.
Correspondence to Magdy H. Selim, MD, PhD, Beth Israel Deaconess
Medical Center, Stroke Division, 330 Brookline Avenue, Palmer 127,
Boston,MA 02215 (E-mail [email protected]); or Carlos A.
Molina, MD, PhD, Stroke Unit, Department of Neurology, Hospital
Vall dHebron-Barcelona, Passeig Vall dHebron 119-129, 08035,
Barcelona, Spain (E-mail [email protected]).
(Stroke. 2012;43:1996-1997.)
2012 American Heart Association, Inc.Stroke is available at
http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.111.648832
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Heart Association/American Stroke Association guidelines
for prevention of stroke in patients with stroke or
transient
ischemic attack cleverly state Statin-therapy with intensive
lipid-lowering effects is recommended without specifically
advocating a high-dose regimen.
Although the SPARCL results support the use of high-dose
atorvastatin for secondary stroke prevention, it is unclear
whether the highest currently approved doses of statins are
able elicit neuroprotective effects in patients. The Phase
1B
dose-escalation Neuroprotection with Statin Therapy for
Acute Recovery Trial (NeuSTART) investigated 4 doses of
lovastatin; 1 mg/kg, 3 mg/kg, 6 mg/kg, and 8 mg/kg (found to
be the maximum tolerated dose) daily for 3 days initiated
within 24 hours of stroke onset followed by 20 mg/day
for 27 days. There was no effect on C-reactive protein,
interleukin-6, or tumor necrosis factor levels within the
30-day
study period at any of the tested doses.3 Therefore, we
advise
caution. We need further reassurance that the benefit out-
weighs the risks before advocating routine use of high-dose
statins to all patients with stroke.The premise of statins
potential neuroprotective effects in
animals and observational studies should be considered
hypothesis-generating prompting further clinical studies and
not the basis to render therapy that may not only be not
indicated, but also costly and potentially harmful, prema-
turely. There are several other issues that require further
investigations. What is the optimal neuroprotective dose?
What is the optimal duration of treatment for neuroprotec-
tion? What is the optimal timing to initiate treatment?
There are known knowns; these are things we know we
know. We also know there are known unknowns; that is to
say we know there are some things we do not know, but there
are also unknown unknownsthese are things we do not
know we dont know.
DisclosuresNone.
References1. LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P,
Fruchart JC, et al.
Treating to New Targets (TNT) Investigators. Intensive lipid
lowering with
atorvastatin in patients with stable coronary disease. N Engl J
Med. 2005;
352:14251435.
2. Montaner J, Chacon P, Krupinski J, Rubio F, Millan M, Molina
CA, et al.
Simvastatin in the acute phase of ischemic stroke: a safety and
efficacy
pilot trial. Eur J Neurol. 2008;15:8290.
3. Elkind MS, Sacco RL, Macarthur RB, Peerschke E, Neils G,
Andrews H,
et al. High-dose lovastatin for acute ischemic stroke: results
of the phase-I
dose escalation neuroprotection with statin therapy for acute
recovery trial
(NeuSTART).Cerebrovasc Dis. 2009;28:266275.
KEY WORDS: neuroprotectants statins
Selim and Molina High-Dose Statin for Every Stroke 1997
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