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DOI:10.1161/01.STR.0000165920.67784.58
published online May 5, 2005; Stroke
Majaz Moonis, Kevin Kane, Ute Schwiderski, Bobby W. Sandage and Marc Fisher
HMG-CoA Reductase Inhibitors Improve Acute Ischemic Stroke Outcome
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HMG-CoA Reductase Inhibitors Improve Acute Ischemic
Stroke Outcome
Majaz Moonis, MD, MRCP(I), DM; Kevin Kane, MA; Ute Schwiderski, PhD;
Bobby W. Sandage, PhD; Marc Fisher, MD
Background and PurposeStatins reduce the risk of stroke recurrence, but the benefits of statins in improving outcome
of acute stroke patients have not been well explored.
MethodsWe assessed potential effects of statins initiated before or within 4 weeks of stroke on 90-day outcome.
Favorable outcomes were National Institutes of Health Stroke Scale (NIHSS) score 2 at 12 weeks and modified
Rankin Scale (mRS) 2.
ResultsBefore stroke, 129 patients were receiving statins, 123 initiated statins within 4 weeks, and 600 patients were not
on statins. Multivariate logistic regression analysis demonstrated that poststroke statins were associated with a
significant probability of a favorable outcome at 12 weeks [NIHSS (P0.002; OR, 1.92; CI, 1.27 to 2.91) and mRS
(P0.033; OR, 1.57; CI, 1.04 to 2.38)], whereas prestroke statins demonstrated a trend toward significance.
ConclusionsThese preliminary results suggest that statin use may improve outcome of acute ischemic stroke. (Stroke.
2005;36:000-000.)
Key Words: ischemia

stroke

stroke outcome
P
rospective studies have demonstrated that HMG-CoA
reductase inhibitors (statins) reduce stroke recurrence by
20% to 25%.
1,2
As suggested by animal studies, statins may
also improve stroke outcome.
3
Materials and Methods
The medication records and the National Institutes of Health Stroke
Scale (NIHSS) and modified Rankin Scale (mRS) data were col-
lected from case report forms from the phase 3 citicoline trial and
patients were divided into 3 groups: using statins before stroke,
started statin after stroke onset, and patients not treated with statins
at anytime.
Outcome Measures
Primary favorable outcome was defined as 2 on the NIHSS at week
12 after stroke and mRS score 2 at 12 weeks.
Statistical Analysis
Univariate statistical analyses (
2
test for all variables except
continuous age variable in which t test was performed) to study the
associations of the demographic and medical and risk factors on
NIHSS at week 12 (Table 1). Significant univariate predictors
(P0.05) were included in multivariate stepwise binary logistic
regression analysis (Tables 2 and 3).
Results
Baseline NIHSS in the prestroke statin, poststroke statin, and
the group never exposed to statin were 13.13.8, 12.94.1,
and 13.13.7, respectively, and were not significantly differ-
ent. Patients on citicoline were equally distributed in the 3
groups (Table 1).
There was a significant difference in outcome between
statin groups (
2
9.90; P0.007), with statins after stroke
having a better outcome than the other 2 groups (
2
9.28,
P0.002). Prestroke statin group demonstrated a positive
trend. Other significant differences in the univariate analysis
were between stroke types (
2
4.46; P0.049), with patients
with all other stroke subtypes having a better outcome than
cardioembolic stroke (
2
4.46; P0.035). Diabetes
(P0.003), cardiac disease (P0.007), peripheral vascular
disease (P0.031), previous stroke or transient ischemic
attack (P0.008), and antihypertensive medication use
(P0.001) were predictors of a poor outcome. Citicoline was
not predictive of outcome. In multivariate analysis, statins
were significant predictors of good outcome (P0.008).
Statins after stroke (P0.002; OR, 1.92; CI, 1.27 to 2.91)
were associated with favorable outcome, whereas prestroke
statins demonstrated a trend toward good outcome (P0.07;
OR, 1.07; CI, 0.69 to 1.66). Other independent predictors of
outcome are presented in Table 2.
The results of mRS 2 as the outcome measure were
similar to the results of the outcomes of NIHSS 2. In the
univariate analysis, poststroke statins were strong predictor of
outcome compared with the other 2 groups (
2
9.47;
P0.002). Stroke subtypes besides cardioembolic stroke
Received January 6, 2005; accepted January 31, 2005.
From the Department of Neurology (M.M., K.K., M.F.), University of Massachusetts Medical School, Worcester, Mass; Indevus Pharmaceuticals, Inc
(U.S., B.W.S.), Lexington, Mass.
Correspondence to Majaz Moonis, Department of Neurology, University of Massachusetts Memorial Health Care, Worcester, MA 01655. E-mail
moonism@ummhc.org
2005 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org DOI: 10.1161/01.STR.0000165920.67784.58
1 by on November 5, 2009 stroke.ahajournals.org Downloaded from
were independently associated with better outcome
(
2
11.91; P0.008). Patients on citicoline (P0.046) were
more likely to have a positive outcome. Hypertension
(P0.009), diabetes (P0.001), cardiac disease (P0.001),
previous stroke or transient ischemic attack (P0.007), or
early antihypertensive medication use (P0.001) were asso-
ciated with poor outcome.
In the multivariate analysis, only statin use after stroke
(P0.033; OR, 1.57; CI, 1.04 to 2.38), treatment with
citicoline (P0.028; OR, 1.39; CI, 1.04 to 1.85), and small-
vessel stroke (P0.008; OR, 2.05; CI, 1.21 to 3.48) were
positive and independent predictors of mRS 2. Predictors of
poor outcome were similar to those on the NIHSS on the mRS
2 analysis (Table 3).
Discussion
Our data suggests that treatment within 4 weeks after acute
ischemic stroke with statins was associated with improved
TABLE 1. Univariate Inclusions
Variable Statins Before Stroke Statins After Stroke Never Used Statins
2
P
No. 129 123 600
Gender
Male 63 79 305 8.15 0.017
Female 66 44 295 8.15 0.017
Hypertension 114 85 407 22.11 0.001
Diabetes 49 38 138 13.75 0.001
Cardiac disease 94 45 321 33.57 0.001
Hypercholesterolemia 120 61 104 290.07 0.001
Peripheral vascular disease 21 12 54 6.17 0.046
Previous stroke or TIA 55 50 176 12.33 0.002
Antihypertensive medications
before or after stroke
111 90 444 8.88 0.012
Stroke type
Undetermined 11 22 97 21.16 0.002
Small-vessel 15 15 54 21.16 0.002
Atherothrombotic 63 69 261 21.16 0.002
Cardioembolic 40 17 188 21.16 0.002
Smoking 63 70 275 5.08 0.079
Obesity 31 35 124 3.84 0.147
Alcohol 10 17 73 2.60 0.273
Citicoline 63 67 299 1.02 0.601
Baseline NIHSS 13.13.8 12.94.1 13.13.7 1.33 0.672
Continues variable Using statins
before stroke
Started statins
after stroke
Never used
statins
F P
Age 70.08 64.11 67.69 7.58 0.001
NIHSS indicates National Institutes of Health Stroke Scale score; TIA, transient ischemic attack.
TABLE 2. Multivariate Analysis: Predictors of NIHSS <2
Factor P OR 95% CI
Diabetes 0.007 0.61 0.420.87
Antihypertensives 0.001 0.51 0.360.72
Statin group 0.008 1.07 0.691.66
Before stroke 0.07 1.92 1.272.91
After stroke 0.002 1.00

Never used statins

Previous stroke or TIA 0.013 0.66 0.480.92
Stroke type 0.042 1.57
Undetermined 0.058 1.77 0.992.50
Small-vessel 0.039 1.02 1.033.05
Atherothrombotic 0.915 1.00 0.711.48
Cardioembolic

OR indicates odds ratio.
TABLE 3. Multivariate Analysis: Predictors of MRS <2
Factor P OR 95% CI
Diabetes 0.001 0.57 0.400.81
Antihypertensives 0.001 0.52 0.370.73
Age 0.001 0.97 0.960.98
Statin group 0.045 1.03 0.541.27
Before stroke 0.08 1.57 1.042.38
After stroke 0.033 1.00

Never used

Citicoline 0.028 1.385 1.0351.853
Stroke Type 0.015 1.45
Undetermined 0.115 2.05 0.912.30
Small-vessel 0.008 1.00 1.213.50
Atherothrombotic 0.984 1.00 0.701.44
Cardioembolic

2 Stroke June 2005
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stroke outcome at 90 days. There were insufficient numbers
in each statin type to reliably analyze if one type of statin was
better than others.
Acute lipid-lowering improves outcome from coronary
attacks and reduces stroke risk and other properties of statins
(improving endothelial function by enhancing endothelial
nitric oxide production and antioxidant and anticoagulant
effect) may be possible mechanisms of delayed improved
outcome,
46
the more likely explanation for poststroke statin
use lies in their capability to induce angiogenesis, neurogen-
esis, and synaptogenesis, factors that may be important in
enhancing neuronal recovery and hence stroke outcome.
7,8
Improved functional outcome at day 14 was demonstrated in
Wistar rats treated with atorvastatin beginning 1 day after
stroke onset by inducing angiogenesis, neurogenesis, and
synaptogenesis by induction of vascular endothelial growth
factor, which promotes angiogenesis and brain cGMP, which
promotes neurogenesis.
7
These results suggest a potential
explanation for the outcome in the group that started statins
after stroke onset.
One prestroke statin treatment study demonstrated im-
proved stroke outcome.
9
In our study, prestroke statin use
demonstrated a trend toward significance (NIHSS 2;
P0.07; OR, 1.07; CI, 0.69 to 1.66). Possible explanations
include the short duration of treatment with statins before
stroke onset, exclusion of subcortical stroke in the citicoline
trial (more likely to have been on statins), and a possible
saturation effect on potential enhancers of poststroke recov-
ery in patients that had been on statins before stroke onset.
7
Although previous studies
7,9
and our t test results are
suggestive of the usefulness of statins in improving ischemic
stroke outcome, larger prospective trials are needed to con-
firm these observations.
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