Biological effects of acute pravastatin treatment in patients after aneurysmal subarachnoid hemorrhage: a double-blind, placebo-controlled trial

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Object

The authors previously demonstrated that acute pravastatin therapy in patients after aneurysmal subarachnoid hemorrhage (SAH) ameliorates vasospasm-related delayed ischemic neurological deficits. The object of this study was to continue to examine potential mechanisms of these beneficial effects.

Methods

Eighty patients with aneurysmal SAH (age range 18–84 years; time to onset 1.8 ± 1.3 days) were enrolled in a double-blind study and randomized to receive 40 mg of oral pravastatin or placebo daily for as long as 14 days. Daily transcranial Doppler ultrasonography and blood tests every 3 days (including full blood cell counts, coagulation profiles, fasting glucose and lipid profiles, and serum biochemistry) were performed during the trial period.

Results

No significant differences were found in baseline laboratory data between the trial groups. Subsequent measurements during the 14-day trial showed reduced low-density lipoprotein (LDL) cholesterol levels and total/high-density lipoprotein cholesterol ratios between Days 3 and 15 (p < 0.05), and increased D-dimer levels (p < 0.05) on Day 6, in the pravastatin group. Patients who received pravastatin but developed vasospasm had significantly lower baseline LDL cholesterol levels or a less extensive reduction in LDL cholesterol levels (p < 0.05), and greater increases in plasma fibrinogen (p = 0.009) and serum C-reactive protein on Day 3 (p = 0.007), compared with those patients without vasospasm. The reduction in LDL cholesterol levels on Day 3 in the placebo group correlated with the duration of normal cerebral autoregulation on the ipsilateral side of the ruptured aneurysm (p = 0.002).

Conclusions

In addition to functioning through a cholesterol-independent pathway, cerebrovascular protection from acute statin therapy following aneurysmal SAH may also function through cholesterol-dependent mechanisms.

Abbreviations used in this paper:ALT = alanine aminotransferase; ANOVA = analysis of variance; CI = confidence interval; CPK = creatine phosphokinase; CRP = C-reactive protein; CT = computed tomography; DIND = delayed ischemic neurological deficit; eNOS = endothelial nitric oxide synthase; FEU = fibrinogen equivalent unit; HDL = high-density lipoprotein; IVH = intraventricular hemorrhage; LDL = low-density lipoprotein; mRS = modified Rankin Scale; NO = nitric oxide; OR = odds ratio; SAH = subarachnoid hemorrhage; SD = standard deviation; TCD = transcranial Doppler; WFNS = World Federation of Neurological Surgeons.

Article Information

Address correspondence to: Peter J. Kirkpatrick, F.R.C.S.(SN), Box 167, Department of Neurosurgery, Addenbrooke's Hospital, Cambridge CB2 2QQ, United Kingdom. email: pjk21@medschl.cam.ac.uk.

© AANS, except where prohibited by US copyright law.

Headings

Figures

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    Box plots comparing hematocrit levels between the two trial groups (upper) and between patients with favorable or unfavorable outcome (lower). Each whisker represents the 75th (upper hinge) and 25th (lower hinge) percentiles. Dots above and below bars represent outliers (1.5 × the interquartile range). *p < 0.05 after repeated-measures ANOVA and Dunnett correction.

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    Box plots comparing baseline (Day 0) and later measurements of neutrophils (A), lymphocytes (B), monocytes (C), and platelets (D) during the trial course. *p < 0.05.

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    Box plots comparing baseline (Day 0) and subsequent measurements in corrected serum calcium (A), CRP (B), muscle CPK (C), and ALT (D) during the trial course. *p < 0.05.

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    Box plots comparing levels of LDL cholesterol (A) and total/HDL cholesterol ratio (B) between the trial groups, and between patients with or without vasospasm (C) or severe vasospasm (D) in the pravastatin group. *p < 0.05.

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