Favorable Outcome of Ischemic Stroke in Patients
Pretreated with Statins
Joan Martı́-Fàbregas, MD, PhD; Meritxell Gomis, MD; Adrià Arboix, MD, PhD; Aitziber Aleu, MD;
Javier Pagonabarraga, MD; Robert Belvı́s, MD; Dolores Cocho, MD; Jaume Roquer, MD, PhD;
Ana Rodrı́guez, MD; Marı́a Dolores Garcı́a, MD; Laura Molina-Porcel, MD;
Jordi Dı́az-Manera, MD; Josep-Lluis Martı́-Vilalta, MD, PhD
Downloaded from http://stroke.ahajournals.org/ by guest on July 12, 2017
Background and Purpose—Statins may be beneficial for patients with acute ischemic stroke. We tested the hypothesis that
patients pretreated with statins at the onset of stroke have less severe neurological effects and a better outcome.
Methods—We prospectively included consecutive patients with ischemic stroke of ⬍24-hour duration. We recorded
demographic data, vascular risk factors, Oxfordshire Classification, National Institutes of Health Stroke Scale (NIHSS)
score, admission blood glucose and body temperature, cause (Trial of Org 10172 in Acute Treatment [TOAST] criteria),
neurological progression at day 3, previous statin treatment, and outcome at 3 months. We analyzed the data using
univariate methods and a logistic regression with the dependent variable of good outcome (modified Rankin Scale
[mRS] 0 to 1, Barthel Index [BI] 95 to 100).
Results—We included 167 patients (mean age 70.7⫾12 years, 94 men). Thirty patients (18%) were using statins when
admitted. In the statin group, the median NIHSS score was not significantly lower and the risk of progression was not
significantly reduced. Favorable outcomes at 3 months were more frequent in the statin group (80% versus 61.3%,
P⫽0.059 with the mRS; 76.7% versus 51.8%, P⫽0.015 with the BI). Predictors of favorable outcome with the BI were:
NIHSS score at admission (OR: 0.72; CI: 0.65 to 0.80; P⬍0.0001), age (OR: 0.96; CI: 0.92 to 0.99; P⫽0.017), and statin
group (OR: 5.55; CI: 1.42 to 17.8; P⫽0.012).
Conclusions—Statins may provide benefits for the long-term functional outcome when administered before the onset of
cerebral ischemia. However, randomized controlled trials will be required to evaluate the validity of our results. (Stroke.
2004;35:1117-1123.)
Key Words: outcome 䡲 ischemia 䡲 statins
S
tatins belong to a group of drugs that lowers the level of
lipids. They have broad effects, some of which are
potentially beneficial for patients with ischemic stroke.1
There is evidence that statins have neuroprotective properties
for the acute ischemic brain.1– 8 Also, statins promote stabilization of atherosclerotic plaques. Furthermore, statins reduce the risk of stroke in patients with coronary artery
disease.9 –12 But there are potential drawbacks of statin
therapy, because high cholesterol levels have been associated
with lower mortality in acute ischemic stroke.13,14 To confuse
the issue further, lower cholesterol levels have been associated with a high risk of hemorrhagic stroke.9 Although there
are beneficial and negative effects, there is a need to evaluate
the early and long-term clinical benefits of statin therapy for
patients with acute cerebral ischemia. In a retrospective
study, Jonsson et al showed that the overall outcome tended
to be better in patients pretreated with statins than in matched
controls.15
We tested the hypothesis that pretreatment with statins
lessens the severity of stroke and improves the functional
outcome. We did a prospective study of consecutive patients
with acute ischemic stroke. We analyzed whether patients
who were already being treated with statins at the time of
stroke were affected less neurologically and had a better
long-term functional outcome than patients who were not
receiving statins.
Materials and Methods
We studied consecutive patients with acute ischemic stroke who
were admitted to the neurology departments of 3 different tertiary
hospitals located in Barcelona, Spain. The inclusion criteria were: (1)
clinical symptoms and signs attributable to cerebral ischemia of
⬍24-hour duration (onset of symptoms was defined as the last time
the patient was free of any symptoms); (2) acute or subacute cerebral
computed tomography (CT) or magnetic resonance (MR) with
changes typical of acute cerebral infarction; (3) previous modified
Rankin scale (mRS) score of 0; and (4) no previous symptomatic
Received October 14, 2003; final revision received January 15, 2005; accepted January 22, 2004.
From Departments of Neurology, Hospital de la Santa Creu i Sant Pau (J.M.-F., A.A., J.P., R.B., D.C., M.D.G., L.M.-P., J.D.-M., J.-L.M.-V.), Hospital
Nostra Senyora del Mar (M.G., J.R., A.R.), and Hospital del Sagrat Cor (A.A.), Barcelona, Spain.
Correspondence to Dr Joan Martı́-Fàbregas, Servei de Neurologia, Hospital de la Santa Creu i Sant Pau, Avda Sant Antoni Maria Claret 167, 08025
Barcelona, Spain. E-mail [email protected]
© 2004 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org
DOI: 10.1161/01.STR.0000125863.93921.3f
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May 2004
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cerebral infarction or intracerebral hemorrhage. Patients were excluded if recombinant tissue plasminogen activator (rt-PA) was
administered, or if the patient was included in any therapeutic trial.
For each patient, we recorded the following data: (1) demographics (age, sex); (2) vascular risk factors (ie, presence or absence of
high blood pressure, diabetes mellitus, ischemic heart disease, atrial
fibrillation, peripheral artery disease, smoking habit, alcohol abuse,
previous transient ischemic attack, hypercholesterolemia, and hypertriglyceridemia); (3) clinical presentation that was classified according to the Oxfordshire Community Stroke Project;16 (4) severity of
the neurological deficit at admission as measured by the National
Institutes of Health Stroke Scale (NIHSS) score at admission; (5)
blood pressure, body temperature, and blood glucose at admission;
(6) neurologic progression at day 3, defined by an increase in ⬎3
points in the NIHSS score in comparison with the baseline NIHSS
score; and (7) whether the patient was currently receiving statins.
The type and dose was recorded. Additionally, the compliance was
evaluated by asking the patient and relatives about the date and time
that the patient took the statin for the last time, and: (8) cholesterol
and triglyceride levels during the acute phase (within 1 week after
admission, normal values at our center ⬍6.2 mmol/L for cholesterol
and ⬍2.23 mmol/L for triglyceride); (9) cause of the cerebral
infarction was considered after the completion of the appropriate
complementary tests and was classified according to the Trial of Org
10172 in Acute Treatment (TOAST) investigators;17 and (11) functional outcome as measured with the mRS and the Barthel Index (BI)
at 3 months. Patients who died scored 6 in the mRS and 0 in the BI.
A mRS of 0 to 1, or a BI score of 95 to 100 was considered as a
favorable outcome.
Although there were no predefined guidelines for therapy during
the acute, subacute, and chronic stages, all hospital centers had
standard protocols.
Statistical Analyses
To evaluate the severity of the stroke, we compared the median of
NIHSS in both groups (statin and nonstatin) with the Mann–Whitney
U test. The proportions of patients with and without neurological
deterioration and the functional status at 3 months in each group
were compared with contingency tables and the ␹2 test. We performed a forward logistic regression analysis with favorable outcome
at 3 months as the dependent variable (separately for mRS and BI).
Variables in this analysis were selected from univariate analysis
(Student t test, contingency tables, and Mann–Whitney U test) when
they reached a significance ⱕ0.10. The variables analyzed included
age, sex, risk factors, Oxfordshire subtype, baseline NIHSS score,
neurological progression, blood pressure, body temperature and
blood glucose at admission, pretreatment with statin, lipid levels
after admission, and the TOAST etiologic subtype. For all the
statistical analyses, the results were considered significant when
P⬍0.05. All statistical analyses were performed with the SPSS
software (v.11.0).
Results
A total of 167 consecutive patients were prospectively evaluated. As shown in Table 1, they were divided into a statin
group (n⫽30) and a nonstatin group (n⫽137). The mean age
was ⬇70 in both groups and the sex distribution was 53%
men in the statin group and 56% in the nonstatin group. None
of these differences was statistically significant. Thirty patients (18%) were undergoing statin therapy when admitted to
the emergency room. Four of them were using atorvastatin
(10 to 20 mg/d), 14 simvastatin (20 to 40 mg/d), 7 pravastatin
(20 to 40 mg/d), 4 lovastatin (20 mg/d), and 1 fluvastatin
(dose unknown). All of the patients in the statin group, except
2, took the last dose of statin ⬍24 hours before the onset of
symptoms. The remaining 2 patients took the last dose of
statin 48 to 72 hours before the onset of stroke. All patients
TABLE 1. Demographic Data and Distribution of Vascular
Risk Factors
Statin
Group n (%)
Totals
30 (18)
Age
Nonstatin
Group n (%)
P
137 (82)
70.6⫾11.1
70.8⫾12.3
53.3
56.2
0.84
High blood pressure
21 (72)
83 (60)
0.21
Diabetes mellitus
14 (47)
30 (22)
0.01
Sex distribution (% men)
0.93
Ischemic heart disease
5 (17)
9 (6.5)
0.14
Atrial fibrillation
7 (24)
45 (33)
0.67
Peripheral artery disease
4 (14)
Smoking habit
9 (31)
38 (27.5)
7 (5)
0.82
0.11
Alcohol abuse
2 (7)
11 (8)
0.99
Transient ischemic attack
7 (24)
9 (6.5)
Hypercholesterolemia
28 (93)
18 (13)
⬍0.0001
Hypertriglyceridemia
7 (24)
10 (7)
0.01
0.01
who were receiving statins at admission, except 8 of them,
were discharged while still using statin therapy. Nineteen of
the 137 patients who were not receiving statins at admission
were put on statin therapy after admission and at discharge
(usually because of high lipid levels). Therefore, 27 patients
(16%) were moved from 1 treatment group (statin or nonstatin) to the other, either during admission or at discharge.
Patients in the statin group were included later than patients
not taking statins, although the difference was not statistically
significant (13.1⫾13.1 versus 8.4⫾6.7 hours, P⫽0.06).
As shown in Table 1, most of the vascular risk factors were
not significantly different in both groups, except for a
significantly higher frequency of diabetes mellitus, transient
ischemic attacks, hypercholesterolemia, and hypertriglyceridemia in the statin group.
Table 2 shows that the 4 clinical classifications did not
show significant differences between the 2 groups. However,
as depicted in Table 3, the stroke causes were not equivalent
in both groups: lacunar cause was significantly more frequent
(40% versus 25%) and undetermined cause was less frequent
(0% versus 17%) in the statin group (P⫽0.04). Median
NIHSS scores at admission was lower in the statin group, but
this difference was not statistically significant (5 versus 6,
P⫽0.76). Other prognostic factors such as age, blood pressure, body temperature, blood glucose, and cholesterol levels
also showed no significant difference between both groups.
TABLE 2.
Distribution of Clinical Stroke Syndromes
Clinical Classification
Totals
Statin
Group n (%)
Nonstatin
Group n (%)
30 (18)
137 (82)
Total anterior cerebral syndrome
5 (17)
25 (18)
Partial anterior cerebral syndrome
9 (30)
49 (36)
Lacunar cerebral syndrome
14 (47)
39 (28.5)
Posterior cerebral syndrome
2 (6)
24 (17.5)
Global P⫽0.21
Martı́-Fàbregas et al
TABLE 3.
Distribution of Stroke Causes
Stroke Cause
Statins and Outcome of Ischemic Stroke
TABLE 5.
Statin
Group n (%)
Nonstatin
Group n (%)
1119
Results of the Logistic Regression Analysis
Variable
Regression
Coefficient
Odds Ratio
95% CI
P
30 (18)
137 (82)
Age
⫺0.040
0.96
0.92–0.99
0.034
Large-artery atheromatosis
8 (27)
33 (24)
NIHSS at admission
⫺0.32
0.72
0.65–0.80
⬍0.0001
Cardioembolism
9 (30)
45 (33)
Statin therapy
1.61
5.55
1.42–17.8
0.012
Totals
Small-vessel disease
12 (40)
34 (25)
Unusual
1 (3)
2 (1)
Undetermined
0 (0)
23 (17)
Dependent variable: Barthel Index of 95 to 100 at 3 months.
Global P⫽0.04
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Neurological progression was seen in only 1 (3.3%) patient
in the statin group compared with 11 (8.1%) in the nonstatin
group, but this difference was not statistically significant. Ten
patients (6%) died, 1 (3.4%) in the statin group and 9 (6.6%)
in the nonstatin group (nonsignificant difference).
The percentage of patients who were living without significant disability as measured by the BI was significantly
higher in the group pretreated with statins (76.7% versus
51.8%, P⫽0.015) and of borderline significance when measured with the mRS (80% versus 61.3%, P⫽0.059).
The univariate analyses of variables associated with the
functional outcome are shown in Table 4. The results of the
logistic regression analyses were analyzed separately for
mRS and the BI. As shown in Table 5, the independent
TABLE 4.
predictive variables for a BI score of 95 to 100 were: NIHSS
score at admission (OR: 0.72), age (OR: 0.96), and statin
group (OR: 5.55). The only independent predictive variable
for a mRS score of 0 to 1 was the NIHSS at admission (OR:
0.76; CI: 0.70 to 0.82; P⬍0.0001). The functional outcome
for patients who received statin at any time (pretreated,
during hospital admission, or at discharge) showed borderline
significance with the BI (P⫽0.057) and a nonsignificant
difference with the mRS scale (P⫽0.10).
Discussion
Our study suggests that if a patient is being treated with
statins and has a stroke, the long-term functional outcome is
better than that of a patient who was not receiving statins at
the onset of stroke. However, there was no significant benefit
in the short-term of statin therapy before admission. There
was an absolute difference of 25% (by the BI, P⫽0.015) or
Variables Related to Functional Outcome at 3 Months in Univariate Analyses
Rankin Score
0 to1 (n⫽108)
Age
Sex (% men)
69.7⫾11.6
63
Rankin Score
⬎1 (n⫽59)
P
72.6⫾12.6
0.15
42.4
0.01
Barthel Index
95 to 100 (n⫽94)
68.7⫾12
Barthel Index
0 to 90 (n⫽73)
P
73.3⫾11.7
0.02
66
42.5
0.003
Body temperature (admission)
36.1⫾0.4
36.3⫾0.6
0.05
36.1⫾0.4
36.3⫾0.6
0.03
Blood glucose (admission)
6.87⫾3.37
7.02⫾3.36
0.79
7.02⫾3.37
6.80⫾3.36
0.67
Systolic blood pressure (admission)
157⫾27.4
156.7⫾28.9
0.95
158.7⫾26.4
154.3⫾29.7
0.39
Diastolic blood pressure (admission)
86.6⫾14.5
88⫾14.7
0.62
87.6⫾15
86.3⫾13.9
0.62
12.2⫾7.3
⬍0.0001
11.7
0.99
NIHSS (admission)
4.1⫾3.4
Hypercholesterolemia (% after admission)
12
13.4⫾7.3
⬍0.0001
10.2
0.80
3.6⫾2.7
11
Hypertriglyceridemia (% after admission)
10.2
5.8
0.57
6.8
10.6
0.43
High blood pressure (%)
62
62.7
0.99
62.8
61.6
0.99
Diabetes mellitus (%)
27.8
23.7
0.71
28.7
23.3
0.48
7.4
10.2
0.56
6.4
11
0.40
23.1
45.8
0.03
22.3
42.5
0.007
7.4
5.1
0.74
7.4
5.5
0.75
Smoking habit (%)
29.6
25.4
0.59
30.9
24.7
0.39
Alcohol abuse (%)
7.4
8.5
0.77
8.5
6.8
0.77
5.5
0.12
Acute myocardial infarction (%)
Atrial fibrillation (%)
Peripheral artery disease (%)
Transient ischemic attack (%)
12
6.8
0.42
13.8
Previous hypercholesterolemia (%)
31.5
20.3
0.14
34
Previous hypertriglyceridemia (%)
13.9
3.4
0.03
Oxfordshire classification*
49.2
0.9
TOAST classification†
25
Progression at day 3
0
Statin at admission
22.2
19.2
0.04
14.9
4.1
0.03
⬍0.0001
39.7
1.1
⬍0.0001
45.8
0.004
23.4
43.8
⬍0.0001
20.3
⬍0.0001
0
16.4
⬍0.0001
10.2
0.059
24.5
9.6
0.015
*Percentage relates to total anterior cerebral syndrome, because this subtype was associated to worsen the outcome.
†Percentage relates to cardiac embolism, because this cause was associated with a worse outcome.
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19% (by the mRS, P⫽0.059) favoring the statin group in the
proportion of patients who ultimately achieved independence.
Moreover, by logistic regression analyses, patients receiving
statin before the onset of stroke were more likely to have a
good functional outcome. This was true when the BI was
measured, but not when the mRS was measured. Although
both the BI and the mRS are valid measures of disability, they
are not identical and the results obtained from both scales can
differ slightly.18 However, we emphasize that the absolute
benefit of statin therapy was impressive irrespective of the
method of measurement. It is likely that a larger sample
would provide more reliable results.
The mechanisms by which statins provide benefit to
patients with acute ischemic stroke remain speculative and
are likely multifactorial. Several studies indicate that statins
have multiple effects beyond lowering the cholesterol
level.5– 8,19 Some of these effects could be neuroprotective.1 Statins interfere with platelet aggregation and have
antiinflammatory, antioxidative, and antiapoptotic properties. Statins improve blood flow to the ischemic brain.1,7 In
experimental animal models of stroke, statins showed a
reduction in infarct size,3,4 improved neurological function,2– 4 and increased cerebral blood flow.3,4 These results
were seen when the statin was started either before3,4 or
after2 the stroke.
The delay from symptom onset to the administration of a
neuroprotective drug can mask the beneficial effects because
of an irreversible neuronal injury by the time the drug reaches
the injured tissue.20 Patients already receiving statins are at an
advantage because of the immediate effect of the drug.
Our hypothesis was that pretreatment with statins lessens
the severity of stroke and improves the functional outcome at
3 months. However, we found that the differences in NIHSS
scores at admission and in the proportion of neurological
progression between treated and nontreated patients were not
statistically significant. The lower NIHSS scores at admission
in the statin group could be attributed to a higher proportion
of patients with lacunar infarction; however, in the multivariate analysis, the stroke cause was not prognostic. Although it
is possible that statins do not provide appreciable neuroprotection or do not completely prevent neurological worsening
in acute ischemic stroke, it may be that the effects of statins
are too mild to be detected, or that our sample was not large
enough to detect a beneficial effect or that the benefits of
statins may be delayed to some extent. Finally, it is likely that
not all of the pathophysiological mechanisms involved in
neurological deterioration can be prevented by statins.
We observed that an increase in the proportion of patients
who live functionally independent at 3 months is a long-term
benefit. This is the most important finding of our study. In
addition to the aforementioned effects, there are other effects
of statin therapy that can be beneficial in the long-term.
Statins reduce the risk of stroke in patients with coronary
artery disease by 30%,9,12 regardless of the level of cholesterol. But there are no reports of a reduction in the frequency
of stroke in patients treated with statins after a transient
ischemic attack or after a cerebral infarction. Statins may
reduce the incidence of cardioembolic stroke, retard the
progression of extracranial carotid atherosclerosis,21,22 and
also stabilize plaques, not only in extracranial arteries but also
in intracranial arteries and in the aortic arch.1,5,6,11,23,24 In our
study, the higher proportion of patients with a previous
transient ischemic attack in the statin group could have
triggered ischemic tolerance.
Biological basis of neurological recovery after cerebral
infarction is poorly understood. Besides reorganization of
neuronal circuits and the effects of diaschisis, it must be
emphasized that the mammalian adult brain has exhibited
neurogenesis.25 A recent study demonstrated a statinmediated amplification of neurogenesis, angiogenesis and
synaptogenesis in a rat stroke model.2
Jonsson et al compared the findings in 125 stroke patients
pretreated with statins with those of 250 matched stroke
controls.15 The overall outcome tended to be better in the
statin group, although statin therapy was not an independent
predictor of a good outcome. Their study was retrospective
and the control group was not matched for severity of the
neurological deficit. They also included patients with intracerebral hemorrhage. Taking into account these differences, it
is noteworthy that their study and ours agreed that statins
positively influence the functional outcome of patients with
acute cerebral infarction.
The beneficial effects of statin therapy in acute ischemic
stroke must be weighed against 2 potential risks. Low
cholesterol may be associated with hemorrhagic stroke;9
however, in trials of patients with coronary artery disease, no
increased risk of hemorrhagic stroke was noted among
statin-treated patients.9,11,26 However, statin therapy may
interfere with some neuroprotective effect of cholesterol.13,14
We recognize that our study has several limitations. The
assessment was not blind. The number of patients on statins
was rather small; therefore, the statistical power of our results
is limited. The low mortality and the low proportion of
patients with neurological progression could be secondary to
a selection bias because of the admission of younger patients
and those with less severe symptoms, especially those who
survived the first hours after their strokes. We cannot be sure
of the doses and lengths of statin treatment, and it is possible
that the beneficial effect depends on the length of treatment
before stroke.4,27 These data are pertinent because some of the
variable effects of statins appear early after the initiation of
the therapy28 and such improvement can be observed over a
period of weeks.5 It can also be argued that there are
differences among statins in their potential benefits in acute
ischemic stroke.29 The 16% of patients that were moved from
1 treatment group (statin or nonstatin) to the other makes the
interpretation of our results difficult. Finally, to compare our
studies to others, we used an arbitrary cut-off for mRS and BI,
even though it is possible that different cut-off values may
lead to different results.30,31
In conclusion, we found that the use of statin before an
acute ischemic stroke may improve the long-term outcome of
patients. Definitive recommendations for the use of statins in
stroke patients must await further experimental and clinical
data. Our study suggests that for maximum benefit, statin
therapy should be initiated within the first few hours of an
ischemic stroke.
Martı́-Fàbregas et al
Acknowledgments
We are grateful to Professor William Stone for his helpful comments
on the manuscript.
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population-based primary preventive trial of the effect of LDL lowering
on atherosclerotic progression in carotid and femoral arteries. Circulation. 1995;92:1758 –1764.
23. Crouse JR. Effects of statins on carotid disease and stroke. Curr Opin
Lipidol. 1999;10:535–541.
24. Vaughan CJ, Gotto Jr AM, Basson CT. The evolving role of statins in the
management of atherosclerosis. J Am Coll Cardiol. 2000;35:1–10.
25. Nadareishvili Z, Hallenbeck J. Neuronal regeneration after stroke. N Engl
J Med. 2003;348:2355–2356.
26. Byington RP, Davis BR, Plehn JF, White HD, Baker J, Cobbe SM,
Shepherd J, for the PPP investigators. Reduction of stroke events with
pravastatin. The prospective pravastatin pooling (PPP) project. Circulation. 2001;103:387–392.
27. Hsu CY, Nassief A. Editorial comment. Stroke. 2001;32:985–986.
28. John S, Delles C, Jacobi J, Schlaich MP, Schneider M, Schmitz G. Rapid
improvement of nitric oxide bioavailability after lipid-lowering therapy
with cerivastatin within two weeks. J Am Coll Cardiol. 2001;37:
1351–1358.
29. Chong PH, Seeger JD, Franklin C. Clinically relevant differences
between the statins: implications for therapeutic selection. Am J Med.
2001;111:390 – 400.
30. Sulter G, Steen C, De Keyser J. Use of the Barthel Index and modified
Rankin Scale in acute stroke trials. Stroke. 1999;30:1538 –1541.
31. Roberts L, Counsell C. Assessment of clinical outcomes in acute ischemic
stroke. Stroke. 1998;29:986 –991.
Editorial Comment
Statins, Stroke Outcome, and Stroke Prevention: When Should We
Start Treatment?
Statins or 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase inhibitors are a group of potent hypocholesterolemic agents that are widely used throughout the world.
Many long-term clinical studies have demonstrated that statin
therapy is associated with a reduced risk of vascular events—
mainly coronary— even in so-called normocholesterolemic
patients. Accordingly, guidelines for cholesterol treatment
have been and are being modified, particularly for patients
with ischemic heart disease (IHD). The magnitude of the
effects is large. A recent meta-analysis1 has demonstrated that
a decrease in low-density lipoprotein cholesterol levels by
1.8 mmol/L reduces the risk of IHD by 61% and the risk of
stroke by 17%, preventing thromboembolic but not hemorrhagic strokes. The benefit of statins treatment has also been
shown for patients with hypertension,2 diabetes mellitus,3
severe aortic arch plaques,4 and for high-risk patients in
general.5 For secondary stroke prevention, however, the data
are still somewhat circumstantial6 and a specific study is
underway.7 In many of the studies, the beneficial effects of
the statins were not directly related to their lipid-lowering
properties, and data on many other effects of statins is
accumulating.8,9 On the vascular wall, statins exert vasodilatation and plaque stabilizing effects by many ways, such as
upregulation of endothelial nitric oxide synthase (eNOS),
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suppression of heightened macrophage activity with subsequent reduced production of several matrix metalloproteins
and proinflammatory cytokines TNF␣, IL-6, CRP, and reduction of vascular expression of adhesion molecules. Because
all these factors enhance the thrombogenic potential of the
atherosclerotic plaque, statins have a role in ameliorating this
risk. Antiatherogenic properties of statins were demonstrated
in retarding intimal medial thickening of the carotid wall,
coronary plaque volume, and aortic atherosclerosis.9 A more
rapid clinical effect was recently reported in patients with
acute coronary syndrome: early statin administration was
associated with reduced ischemic events within the first
month of treatment.10 This effect was explained, at least in
part, by a reduction in local inflammation.11
For stroke, statin therapy is believed to be effective even
earlier, leading to a better functional recovery; animal studies
have recently shown the effects of statins on enhanced
functional outcome and induction of brain plasticity when
administered after stroke, probably by induction of angiogenesis, neurogenesis, and synaptogenesis.12 Lesion volumes
have decreased regardless of cholesterol blood levels. Stroke
protection is lost, however, within 2 to 4 days after withdrawal of statins treatment.13 These acute pleiotropic effects
induce neuroprotection throughout several mechanisms including eNOS modulation (by augmenting regional cerebral
blood flow), by inhibition of platelet aggregation, and by
antiinflammatory effects.9,12
Are these effects also applicable to human beings? A pilot
case-referent study14 has shown a trend for a favorable
outcome (earlier discharge to home) in patients pretreated
with statins, and a pilot randomized study on the acute effects
of simvastatin in ischemic stroke (MISTICS trial) has demonstrated beneficial effects.15
In this issue, Marti-Fabregas et al16 present their experience
with statin treatment and stroke outcome in 167 acute stroke
patients, of which 18% were pretreated with statins. This was
an open study in which patients were included prospectively
and followed-up for 3 months.
Median National Institutes of Health Stroke Scale (NIHSS)
scores at admission were lower in the statin group (5 versus
6) and neurological deterioration was less frequent in this
group (3.3% versus 8.1% in the nonstatin group); yet, maybe
because of the small sample size, these differences were not
significant. At 3 months, statin treatment was found to be
independently associated with a favorable outcome. The
authors conclude that statins may provide long-term beneficial effects when given before the onset of acute stroke. They
state that for maximum benefit, therapy should start within
the first few hours of an acute stroke and declare that a
randomized controlled study is needed to clarify the importance of statins on stroke outcome.
This article is important in strengthening previous observations; however, because of its nature (observational, unmatched), it still leaves some uncertainties. Apart from the
limitations acknowledged by the authors in their discussion,
there is also another concern, ie, the lack of information on
concomitant treatment. It is possible that other medications
confer neuroprotective properties, as has just recently been
presented for angiotensin-converting enzyme (ACE) inhibi-
tors.17 Also, the possibility that patients using statins are those
that get, or can afford, better medical care was not ruled out.
Why were only 18% of the patients using statins? Given
our current knowledge and the list of risk factors in the
“control” group, this percent should have been higher. Alternatively, the fact that only 18% of the whole group were
using statins suggests that a priori such patients are somewhat
protected from stroke. Additionally, the higher rate of lacunar
stroke in the treated group may imply that patients with large
artery atherothrombosis are more protected because of the
pleiotropic and plaque-stabilizing effects of statins.
This study provides information relating to the long-term
beneficial effects of statins on stroke outcome, including,
perhaps, an additional benefit at the subacute stage; however,
this does not clarify the acute effects of statins and the
importance of its administration in the hyperacute stage.
Thus, the exact timing of statin administration in acute stroke
remains open.
In the near future, however, with the completion of the
SPARCL study,7 it may be possible to answer 2 major
questions: (1) are statins beneficial in the secondary prevention of stroke in all patients regardless of their premorbid
conditions; and (2) are stroke outcomes in the statin-treated
group milder and/or associated with a better outcome once
they have occurred? We will also be able to learn which
subtypes of strokes are mostly influenced by statins.
Within a few years, it seems that most high-risk patients
will be treated with statins (the introduction of a “polypill”
including a statin has been recently suggested18 for those
patients), and thus only for a minority of the stroke patients
will we be facing the dilemma of when to start treatment.
Nonetheless, the importance of the pleiotropic effects of
statins in acute stroke should be investigated in a prospective
randomized study.
Jonathan Y. Streifler, MD
Neurology Department
Rabin Medical Center
Petach Tikva and Tel Aviv University
Israel
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Favorable Outcome of Ischemic Stroke in Patients Pretreated with Statins
Joan Martí-Fàbregas, Meritxell Gomis, Adrià Arboix, Aitziber Aleu, Javier Pagonabarraga,
Robert Belvís, Dolores Cocho, Jaume Roquer, Ana Rodríguez, María Dolores García, Laura
Molina-Porcel, Jordi Díaz-Manera and Josep-Lluis Martí-Vilalta
Downloaded from http://stroke.ahajournals.org/ by guest on July 12, 2017
Stroke. 2004;35:1117-1121; originally published online April 8, 2004;
doi: 10.1161/01.STR.0000125863.93921.3f
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2004 American Heart Association, Inc. All rights reserved.
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