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(Stroke. 2005;36:2024.)
© 2005 American Heart Association, Inc.

Research Reports

Simvastatin Reduces Vasospasm After Aneurysmal Subarachnoid Hemorrhage

Results of a Pilot Randomized Clinical Trial

John R. Lynch, MD; Haichen Wang, MD; Matthew J. McGirt, MD; James Floyd, BS; Allan H. Friedman, MD; Alexander L. Coon, MD; Robert Blessing, CRNP; Michael J. Alexander, MD; Carmelo Graffagnino, MD; David S. Warner, MD Daniel T. Laskowitz, MD, MHS

From the Departments of Medicine (Neurology) (J.R.L., H.W., R.B., C.G., D.T.L.), Surgery (Neurosurgery) (A.H.F., M.J.A., D.S.W., D.T.L.), and Anesthesiology (D.S.W., D.T.L.), Duke University Medical Center, Durham, NC; Department of Neurosurgery (H.W., M.J.M., A.L.C.), The Johns Hopkins Hospital, Baltimore, MD; Duke University School of Medicine (J.F.), Durham, NC; and Multidisciplinary Neuroprotection Laboratory (J.R.L., D.S.W., D.T.L.), Durham, NC.

Correspondence to John R. Lynch MD, Box 2900, Duke University Medical Center, Durham, NC 27710. E-mail lynch004{at}mc.duke.edu

	Abstract

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Background and Purpose— Cerebral vasospasm remains a major source of morbidity after aneurysmal subarachnoid hemorrhage (SAH). We demonstrate that simvastatin reduces serum markers of brain injury and attenuates vasospasm after SAH.

Methods— Patients with angiographically documented aneurysmal SAH were randomized within 48 hours of symptom onset to receive either simvastatin (80 mg daily; n=19) or placebo (n=20) for 14 days. Plasma alanine aminotransferase, aspartate aminotransferase, and creatine phosphokinase were recorded weekly to evaluate laboratory evidence of hepatitis or myositis. Serum markers of brain injury were recorded daily. The primary end point of vasospasm was defined as clinical impression (delayed ischemic deficit not associated with rebleed, infection, or hydrocephalus) in the presence of 1 confirmatory radiographic test (angiography or transcranial Doppler demonstrating mean V_MCA >160 m/sec).

Results— There were no significant differences in laboratory-defined transaminitis or myositis between groups. No patients developed clinical symptoms of myopathy or hepatitis. Plasma von Willebrand factor and S100ß were decreased 3 to 10 days after SAH (P<0.05) in patients receiving simvastatin versus placebo. Highest mean middle cerebral artery transcranial Doppler velocities were significantly lower in the simvastatin-treated group (103±41 versus 149±47; P<0.01). In addition, vasospasm was significantly reduced (P<0.05) in the simvastatin-treated group (5 of 19) compared with those who received placebo (12 of 20).

Conclusion— The use of simvastatin as prophylaxis against delayed cerebral ischemia after aneurysmal SAH is a safe and well-tolerated intervention. Its use attenuates serum markers associated with brain injury and decreases the incidence of radiographic vasospasm and delayed ischemic deficit.

Key Words: HMG-CoA reductase inhibitors • inflammation • subarachnoid hemorrhage • vasospasm, intracranial

	Introduction

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Vasospasm remains a major cause of morbidity and mortality after aneurysmal subarachnoid hemorrhage (SAH). Although treatment with nimodipine confers a modest benefit in patient outcomes after SAH, there are no definitive medical treatments for cerebral vasospasm. Studies have detected alterations in the profiles of inflammatory cytokines, markers of central nervous system and vascular injury in the setting of SAH and vasospasm. For example, plasma levels of von Willebrand factor (vWF), a marker of endothelial injury, and protein S100ß, a marker of astrocyte activation, have been correlated with prognosis and occurrence of vasospasm after SAH. Independent of their cholesterol-lowering effect, statins have multiple biological properties, including downregulating inflammation and upregulating endothelial NO synthase.^1,2

In the present study, we hypothesized that early treatment with simvastatin after aneurysmal SAH is safe, will decrease vasospasm, and will reduce biochemical surrogates of endothelial injury and inflammation.

	Methods

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This study was approved by the Duke University Medical Center institutional review board. Thirty-nine patients presenting within 48 hours of aneurysmal SAH were randomized to receive 80 mg per day simvastatin (n=19) or placebo (n=20) for 14 days. All clinicians and investigators were blinded to treatment group. All patients underwent clip ligation or coiling within 48 hours of SAH. Liver transaminases and creatine phosphokinase (CPK) were recorded weekly to evaluate for early signs of hepatitis or myositis. Transaminitis was defined as alanine aminotransferase or aspartate aminotransferase >3-fold normal (>180 U/L) and myositis as CPK >1000 U/L. Given the high predictive value mean transcranial Doppler (TCD) velocities >160 cm/s for cerebral vasospasm,³ all patients underwent thrice weekly serial TCD evaluation by a blinded neurosonologist. Our primary end point of vasospasm was defined as the clinical impression of a delayed ischemic neurological deficit (unrelated to rebleed, hydrocephalus, or infection) in the presence of a confirmatory radiographic test (V_MCA >160 m/sec by TCD or angiography). Blood samples were collected daily for 14 days. Measurements of serum markers of injury were performed by Biosite Diagnostics.⁴

Statistical Analysis
Student t test was used for normally distributed data, and Wilcoxon rank-sum test for continuous and ordinal nonparametric variables. The presence of vasospasm in the 2 groups was compared with the ² statistic. Generalized estimating equations were used to evaluate the effect of statins on biomarkers. All analysis was performed using Graphpad and SAS Enterprise Guide Version 8.2.

	Results

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There were no baseline differences between groups (Table 1 ). Two patients in the treatment arm and 1 in the placebo arm were discontinued from the study for transaminase elevations in excess of 180 U/L (Table 2 ). All patients were included in the analysis on an intention-to-treat basis, and elevations of CPK and liver function test (LFTs) normalized within 24 hours.

View this table: [in this window] [in a new window]   TABLE 1. Patient Characteristics

View this table: [in this window] [in a new window]   TABLE 2. Simvastatin Decreases Vasospasm

The mean S100ß concentration was nearly 4-fold lower in simvastatin-treated versus placebo-treated patients (69 versus 218 ng/mL; P<0.01) and vWF nearly 2-fold lower (14 versus 24 ng/mL; P<0.05; Figure ). Using generalized estimating equations, concentrations of S100ß (P<0.001) and vWF (P<0.001) were significantly lower in the simvastatin group versus the control group.

View larger version (15K): [in this window] [in a new window]   A, vWF, a marker of endothelial dysfunction that predicts vasospasm, was significantly decreased with simvastatin treatment on days 1 through 14 after aneurysmal rupture (P<0.01). B, Protein S100ß, a marker of astrocyte activation and central nervous system inflammation, was also lower with simvastatin treatment (**P<0.01). Data presented as mean±SD.

The overall rate of vasospasm was 43%. Five of 19 (26%) patients receiving simvastatin developed evidence of cerebral vasospasm during the study period versus 12 of 20 placebo patients (60%; P<0.05). Maximum mean middle cerebral artery (MCA) TCD velocity (cm/s) was also significantly decreased in the simvastatin group compared with the placebo group (103±41 and 149±47, respectively; P<0.01).

	Discussion

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Our primary finding was that patients treated with simvastatin had a lower incidence (P<0.05) of clinical vasospasm (confirmed by TCD criteria or angiographically) and a significant (P<0.01) reduction in MCA velocities as a function of simvastatin treatment.

We also examined biochemical surrogates defined previously to predict vasospasm and outcome. For example, we demonstrated that markers of endothelial injury such as vWF predicts occurrence of vasospasm.² vWF is a multimeric glycoprotein involved in platelet–endothelial interactions under conditions of high shear stress.⁵ In the present study, treatment with simvastatin was associated with plasma concentrations of vWF on average nearly 30% lower when compared with controls. Plasma and serum concentrations of S100ß, a marker of astrocyte activation, have also been associated with vasospasm and functional outcome in this patient population.⁶ In the current study, we found that S100ß was also significantly reduced in the simvastatin-treated group. This is consistent with the hypothesis that simvastatin exerts its therapeutic effect by endothelial-protective and anti-inflammatory properties.

Although we found that simvastatin treatment resulted in a decreased incidence of vasospasm, the question of whether this will translate into improved functional outcomes remains to be determined in a larger multicenter trial. The second limitation of this study is that the optimal dosage of simvastatin in the clinical setting has yet to be defined, and it is plausible that the short-term administration of higher doses may increase efficacy without compromising safety, although further dose escalation studies will be needed.

In conclusion, we demonstrate that simvastatin was well tolerated in this critically ill patient population. Moreover, statin therapy significantly reduced biochemical surrogates of inflammation and endothelial injury believed to play a mechanistic role in the development of vasospasm.^2,6 Treatment with simvastatin reduced vasospasm incidence and was also associated with a reduction in TCD velocities and biochemical markers associated with vasospasm risk. The results of this pilot study suggest that the administration of simvastatin is as safe and well tolerated as any other intervention routinely used in the treatment of SAH, but that CPK and LFTs should be monitored.

	Acknowledgments

 
This study was supported by NIH research grant R21NS4487-01, and an unrestricted Medical School Study grant by Merck and Co, Inc. D.T.L. serves as a consultant for Biosite, Inc which performed the plasma marker assays.

Received May 19, 2005; accepted June 14, 2005.

	References

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1. Liao JK, Laufs U. Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol. 2005; 45: 89–118.[CrossRef][Medline] [Order article via Infotrieve]

2. McGirt MJ, Lynch JR, Parra A, Sheng H, Pearlstein RD, Laskowitz DT, Pelligrino DA, Warner DS. Simvastatin increases endothelial nitric oxide synthase and ameliorates cerebral vasospasm resulting from subarachnoid hemorrhage. Stroke. 2002; 33: 2950–2956.[Abstract/Free Full Text]

3. Lysakowski C, Walder B, Costanza MC, Tramer MR. Transcranial Doppler versus angiography in patients with vasospasm due to a ruptured cerebral aneurysm: a systematic review. Stroke. 2001; 32: 2292–2298.[Abstract/Free Full Text]

4. Lynch JR, Blessing R, White WD, Grocott HP, Newman MF, Laskowitz DT. Novel diagnostic test for acute stroke. Stroke. 2004; 35: 57–63.[Abstract/Free Full Text]

5. McGirt MJ, Lynch JR, Blessing R, Warner DS, Friedman AH, Laskowitz DT. Serum von Willebrand factor, matrix metalloproteinase-9, and vascular endothelial growth factor levels predict the onset of cerebral vasospasm after aneurysmal subarachnoid hemorrhage. Neurosurgery. 2002; 51: 1128–1134.[CrossRef][Medline] [Order article via Infotrieve]

6. Wiesmann M, Missler U, Hagenstrom H, Gottmann D. S-100 protein plasma levels after aneurysmal subarachnoid hemorrhage. Acta Neurochir (Wien). 1997; 139: 1155–1160.[CrossRef][Medline] [Order article via Infotrieve]

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This Article Abstract Full Text (PDF) All Versions of this Article: 36/9/2024    most recent 01.STR.0000177879.11607.10v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lynch, J. R. Articles by Laskowitz, D. T. Search for Related Content PubMed PubMed Citation Articles by Lynch, J. R. Articles by Laskowitz, D. T. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Related Collections Cerebral Aneurysm, AVM, & Subarachnoid hemorrhage Angiography Other imaging Other Stroke Treatment - Medical Endothelium/vascular type/nitric oxide