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0.42-0.72, P < 0.0001). [28] observational study noted more favorable outcomes in a
3-month period in which the patients were givenstatins for
Although there have been concerned of statins increasing 3 months prior to the stroke statin group. Pretreatment
[8]
[34]
the risk of ICH, recent evidence suggest that the statins with statin was associated with decreased in-hospital
did not increase the risk of ICH. The Stroke Prevention mortality and reduced stroke severity. The largest
[44]
[43]
by Aggressive Reduction of Cholesterol Levels (SPARCL) observational study evaluated 12,689 cases with acute
study found increased risk of subsequent ICH (unadjusted ischemic stroke and found that statin use before and
hazard ratio 1.68, 95% CI 1.09-2.59) among subjects with during hospitalization was strongly associated with
prior stroke randomized to high-dose atorvastatin. improved survival (hazard ratio 0.59, 95% CI 0.53-0.65,
[34]
Mild antithrombotic properties and lipid lowering effect P < 0.001). [45]
of statins might be explained mechanism of association
between statins and risk of ICH. However, recent The question of in-hospital cessation of statin therapy
meta-analysis have been reported that low cholesterol is an important as stroke patients may be dysphagic
concentrations with intensive statin therapy did not and NPO after admission. This important question
correlated with risk for ICH. [36] A recent large systematic was addressed in the same large observational
review and meta-analysis of 23 randomized trials that cohort of 12,689 cases and statin discontinuation
provided a cumulative total of 526,518 patients years of in the acute phase of stroke, even for a brief period,
follow-up with median 3.9 years found no evidence that was associated with a substantially greater risk of
statins were associated with developing ICH (risk ratio 1.10, death (hazard ratio 2.5, 95% CI 2.1-2.9; P < 0.001). [45]
95% CI 0.86-4.14). A second meta-analysis using 12 cohort A small single-center randomized blinded study of
[35]
studies that provide a total of 219,458 patient-years of follow-up statin withdrawal vs. continuation confirmed the
or 6 case-control studies also did not show any risk of ICH with need to continue treatment in this population. The
statin (each risk ratio 0.94, 95% CI 0.81-1.10 and risk ratio 0.60, acute statin withdrawal was associated with increase
95% CI 0.41-0.88). in early neurologic deterioration (OR 8.67, 3.05-24.63)
and death/dependency (OR 4.66, 1.46-14.91). [46]
ACUTE CEREBRAL INFARCTION
There is currently not enough evidence to confirm
There are numerous published work that demonstrates the the beneficial effect of statin treatment in acute phase
beneficial effects of statins in animal models of ischemic of ischemic stroke. A recent pilot clinical trial called
stroke. These experimental models have evaluated “MISTICS” randomized 60 patients within 3 to 12 h after
effects of statin treatment prior to and after initiation acute ischemic stroke to simvastatin or placebo for 90 days.
of cerebral infarction. Statins have been shown to This study showed that simvastatin therapy improved
[37]
improve endothelial function and increase cerebral functional outcome (46.4% vs. 17.9%, P = 0.02).
[49]
perfusion in the ischemic penumbra by improving no However, there were safety concerns as statin therapy
production immediately after treatment initiation. [38,39] was associated with increased incidence of infection (OR
The anti-oxidative and anti-inflammatory properties of 2.4, 95% CI 1.06-5.4) and a trend toincrease mortality
statins can affect secondary brain injury in the setting (25.0% vs. 10.7%, P = 0.16). Other randomized trials of
of ischemia. [40,41] A meta-analysis of 1,882 animals in 41 statin therapy in acute stroke were limited by insufficient
studies with ischemic occlusive stroke models showed recruitment and insufficient data for analysis. [47,48,50]
that use of statin reduced infarction volume by 25%
(95% CI 21-30%, P < 0.001) and improved neurologic One potential strategy for translating the efficacy of
[37]
outcome by 20.36% (95% CI 14-26%, P < 0.001). statins in preclinical models may be to use very high
Furthermore pretreatment with statin (median 14 doses or intravenous routes for statin initiation. The
days, range 5-14) was more effective than initiation neuroprotection with Statin Therapy for Acute Recovery
after ischemia (median 4 h, range 1-12) in infarct size Trial [51] of 33 patients with acute ischemic stroke < 24 h
reduction (33.57%, 95% CI 28.47-38.53% vs. 16.02%, of onset wastesting a short-term high-dose lovastatin at 1,
2
95% CI 11.63-20.42%; χ = 408, P < 0.001) and improve 3, 6, 8, and 10 mg/kg per day for 3 days. Patients were
neurologic outcome (26.52%, 95% CI 15.05-37.99% vs. followed for 30 days andclinical and laboratory outcome
14.37%, 95% CI 7.26-21.48%; χ = 17, P < 0.001). measured in this Phase IB trial and the maximum
2
tolerated dose was estimated to be 8 mg/kg per day.
Most studies have shown that the use of statins at the
time of ischemic stroke may confer a beneficial effect Despite the lack of evidence for treating acute stroke
[Tables 4-6]. A population-based prospective study of with statin, there is no doubt that in-hospital initiation
953 patients did not demonstrate early improvement should occur when statin therapy is indicated. The
in functional outcome after a first ischemic stroke SPARCL study clearly defined the role of statins in
[42]
event (OR 0.76, 95% CI 0.53-1.09, P = 0.134). A small secondary stroke prevention, yet did not address the best

Neuroimmunol Neuroinflammation | Volume 3 | June 20, 2016 137