Statins are postulated as candidate drugs for the treatment of acute stroke. The aim of this study was to critically appraise the evidence for the efficacy of statins administered after the onset of experimental focal cerebral ischemia.
Methods
We undertook a systematic review and meta-analysis of animal studies reporting the efficacy of any statin administered following middle cerebral artery occlusion. The primary outcome measure was infarct volume. Assessment of study quality and range of evidence were undertaken, and prespecified sub-group analyses were performed.
Results
Eighteen published studies describing outcome in 472 animals were identified. Statins reduced infarct volume by 11·2% (95% confidence interval 8·1% to 14·3%, P < 0·001) and improved the neurological severity score by 0·7 points (95% confidence interval 0·4 to 1·1, P < 0·0001). Efficacy was evident up to three-hours post-middle cerebral artery occlusion. Median study quality score was 7 of 13 (interquartile range, 4 to 11). No studies tested efficacy in aged, female, or hypertensive animals; or in species other than rodents.
Conclusions
These findings suggest that statins administered after middle cerebral artery occlusion have modest efficacy. Effects of potential sources of bias are considered likely to reduce the estimated effect from this review.
O'CollinsV, MacleodM, DonnanG, HorkyL, Van der WorpB, HowellsD. 1026 experimental treatments in acute stroke. Ann Neurol2006; 59:467–77.
2.
SenaE, Van der WorpH, HowellsD, MacleodM. How can we improve the pre-clinical development of drugs for stroke?Trends Neurosci2007; 30:433–9.
3.
DurukanA, TatlisumakT. Acute ischemic stroke: overview of major experimental rodent models, pathophysiology, and therapy of focal cerebral ischemia. Pharmacol Biochem Behav2007; 87:179–97.
4.
Recommendations for standards regarding preclinical neuroprotective and restorative drug development.Stroke1999; 30:2752–8.
5.
BanwellV, SenaE, MacleodM. Systematic review and stratified meta-analysis of the efficacy of interleukin-1 receptor antagonist in animal models of stroke. J Stroke Cerebrovasc Dis2009; 18:269–76.
6.
SandercockP, RobertsI. Systematic reviews of animal experiments. Lancet2002; 360:586.
7.
SenaE, WhebleP, SandercockP, MacleodM. Systematic review and meta-analysis of the efficacy of tirilazad in experimental stroke. Stroke2007; 38:388–94.
8.
EndresM, LaufsU, HuangZ,Stroke protection by 3-hydroxy-3-methylglutaryl (HMG-CoA) reductase inhibitors mediated by endothelial nitric oxide synthase. Proc Natl Acad Sci U S A1998; 95:8880–5.
9.
BalduiniW, MazzoniE, CarloniS,Prophylactic but not delayed administration of simvastatin protects against long-lasting cognitive and morphological consequences of neonatal hypoxic-ischemic brain injury, reduces interleukin-1beta and tumor necrosis factor-alpha mRNA induction, and does not affect endothelial nitric oxide synthase expression. Stroke2003; 34:2007–12.
10.
SironiL, CiminoM, GuerriniU,Treatment with statins after induction of focal ischemia in rats reduces the extent of brain damage. Arterioscler Thromb Vasc Biol2003; 23:322–7.
11.
Van der MostP, DolgaA, NijholtI, LuitenP, EiselU. Statins: mechanisms of neuroprotection. Prog Neurobiol2009; 88:64–75.
12.
FisherM, FeuersteinG, HowellsD,Update of the stroke therapy academic industry roundtable preclinical recommendations. Stroke2009; 40:2244–50.
13.
MacleodM, O'CollinsT, HowellsD, DonnanG. Pooling of animal experimental data reveals influence of study design and publication bias. Stroke2004; 35:1203–8.
14.
GerrietsT, StolzE, WalbererM,Noninvasive quantification of brain edema and the space-occupying effect in rat stroke models using magnetic resonance imaging. Stroke2004; 35:566–71.
15.
EggerM, Davey SmithG, SchneiderM, MinderC. Bias in meta-analysis detected by a simple, graphical test. BMJ1997; 315:629–34.
16.
SterneJ, EggerM. Funnel plots for detecting bias in meta-analysis: guidelines on choice of axis. J Clin Epidemiol2001; 54:1046–55.
17.
BergerC, XiaF, MaurerMH, SchwabS. Neuroprotection by pravastatin in acute ischemic stroke in rats. Brain Res Rev2008; 58: 48–56.
18.
ChenJ, ZacharekA, LlA,Vascular endothelial growth factor mediates atorvastatin-induced mammalian achaete-scute homologue-1 gene expression and neuronal differentiation after stroke in retired breeder rats. Neuroscience2006; 141:737–44.
19.
ChenJ, ZhangC, JiangH,Atorvastatin induction of VEGF and BDNF promotes brain plasticity after stroke in mice. J Cereb Blood Flow Metab2005; 25:281–90.
20.
ChenJ, ZhangZG, LiY,Statins induce angiogenesis, neurogenesis, and synaptogenesis after stroke. Ann Neurol2003; 53:743–51.
21.
CuiX, ChoppM, ZacharekA,Chemokine, vascular and therapeutic effects of combination simvastatin and BMSC treatment of stroke. Neurobiol Dis2009; 36:35–41.
22.
ElewaHF, KozakA, El-RemessyAB,Early atorvastatin reduces hemorrhage after acute cerebral ischemia in diabetic rats. J Pharmacol Exp Ther2009; 330:532–40.
23.
KilicU, BassettiCL, KilicE, XingH, WangZ, HermannDM. Post-ischemic delivery of the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor rosuvastatin protects against focal cerebral ischemia in mice via inhibition of extracellular-regulated kinase-1/-2. Neuroscience2005; 134:901–6.
24.
KilicE, KilicU, MatterCM, LuescherTF, BassettiCL, HermannDM. Aggravation of focal cerebral ischemia by tissue plasminogen activator is reversed by 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor but does not depend on endothelial NO synthase. Stroke2005; 36:332–6.
25.
NagarajaTN, KnightRA, CroxenRL, KondaKP, FenstermacherJD. Acute neurovascular unit protection by simvastatin in transient cerebral ischemia. Neurol Res2006; 28:826–30.
26.
PrinzV, LaufsU, GertzK,Intravenous rosuvastatin for acute stroke treatment – an animal study. Stroke2008; 39:433–8.
27.
ShimamuraM, SatoN, SataM,Delayed postischemic treatment with fluvastatin improved cognitive impairment after stroke in rats. Stroke2007; 38:3251–8.
28.
SugiuraS, YagitaY, SasakiT,Postischemic administration of HMG CoA reductase inhibitor inhibits infarct expansion after transient middle cerebral artery occlusion. Brain Res2007; 1181: 125–9.
29.
WangL, ZhangX, LiuL, YangR, CuiL, LiM. Atorvastatin protects rat brains against permanent focal ischemia and downregulates HMGB1, HMGB1 receptors (RAGE and TLR4), NF kappaB expression. Neurosci Lett2010; 471:152–6.
30.
ZhangL, ChoppM, JiaL, CuiY, LuM, ZhangZG. Atorvastatin extends the therapeutic window for tPA to 6 h after the onset of embolic stroke in rats. J Cereb Blood Flow Metab2009; 29:1816–24.
31.
ZhangL, ZhangZG, LiuXS, Hozeska-SolgotA, ChoppM. The PI3K/Akt pathway mediates the neuroprotective effect of atorvastatin in extending thrombolytic therapy after embolic stroke in the rat. Arterioscler Thromb Vasc Biol2007; 27:2470–5.
32.
ZhangL, ZhangZG, DingGL,Multitargeted effects of statin-enhanced thrombolytic therapy for stroke with recombinant human tissue-type plasminogen activator in the rat. Circulation2005; 112:3486–94.
33.
SironiL, BanfiC, BrioschiM,Activation of NF-kB and ERK 1/2 after permanent focal ischemia is abolished by simvastatin treatment. Neurobiol Dis2006; 22:445–51.
34.
DingG, JiangQ, LiL,MRI of combination treatment of embolic stroke in rat with rtPA and atorvastatin. J Neurol Sci2006; 246:139–47.
35.
MinnerupJ, HeidrichJ, RogalewskiA, SchäbitzW, WellmannJ. The efficacy of erythropoietin and its analogues in animal stroke models: a meta-analysis. Stroke2009; 40:3113–20.
36.
MacleodM, Van der WorpH, SenaE, HowellsD, DirnaglU, DonnanG. Evidence for the efficacy of NXY-059 in experimental focal cerebral ischaemia is confounded by study quality. Stroke2008; 39: 2824–9.
37.
MinnerupJ, HeidrichJ, WellmannJ, RogalewskiA, SchneiderA, SchäbitzW. Meta-analysis of the efficacy of granulocyte-colony stimulating factor in animal models of focal cerebral ischemia. Stroke2008; 39:1855–61.
National collaborating centre for chronic conditions.Stroke: National Clinical Guideline for Diagnosis and Initial Management of Acute Stroke and Transient Ischaemic Attack (TIA). London, Royal college of physicians. National Institute for Health and Clinical Excellence, (Internet) July 2008. Available at http://www.nice.org.uk/CG068 fullguideline (accessed May 2010).
40.
MontanerJ, ChacónP, KrupinskiJ,Simvastatin in the acute phase of ischemic stroke: a safety and efficacy pilot trial. Eur J Neurol2008; 15:82–90.
41.
Clinicaltrials.Gov.A service of the U.S. National Institutes of Health: stroke treatment with acute reperfusion and simvastatin [clinicaltrials.Gov identifier: NCT01073007], (Internet) February 2010. Available at http://clinicaltrials.gov/ct2/show/NCT01073007 (accessed May 2010).
42.
ElkindM, SaccoR, MacarthurR,High-dose lovastatin for acute ischemic stroke: results of the phase I dose escalation neuroprotection with statin therapy for acute recovery trial (NeuSTART). Cerebrovasc Dis2009; 28:266–75.
