Although aneurysmal subarachnoid hemorrhage (SAH) accounts for only 3% to 5% of strokes, its profound consequences and unique window of intervention justify its classification as a separate entity. Early aneurysm occlusion, expert endovascular neurosurgery and microsurgery, the use of oral nimodipine, and neurointensive care are now the standards of care.1-3 Nevertheless, aneurysmal SAH is still associated with mortality at 1 month for half of all patients, and the other half are left with disability.
After the acute bleed, many patients with SAH show deterioration as a consequence of secondary ischemic processes affecting the cerebral circulation.4 The clinical consequences manifest as delayed ischemic deficits (DIDs) and usually develop after a lag of several days. Hence, there is a potential to intervene before clinical deterioration. The diffuse nature of SAH resulting from red cell breakdown products has widespread effects on the large vessels of the circle of Willis and smaller vessels within the subpial space.5 The processes are complex and combine to impair cerebral blood flow (CBF) to many areas of the brain. Because low CBF correlates with adverse clinical outcomes after SAH, candidate neuroprotective agents may be targeted according to CBF-enhancing characteristics that offset low-flow states and the related metabolic consequences. Given the diffuse nature of the pathological process, local vascular therapies (such as angioplasty) have been disappointing.6-8 A more global approach would be more appropriate. As a reflection of the complex array of pathological processes underlying DIDs, a preferred strategy would be to target a multitude of potentially important mechanisms with a drug that has the potential for multiple efficacious actions.
Statins inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase and block the formation of mevalonate, an important precursor for both cholesterol and nonsterol products.9,10 This mechanism may account for some of the known neuroprotective properties of statins by improving endothelial vasomotor function, increasing endothelial cell fibrinolytic activities, reducing thrombogenic potential, blocking platelet activation, and suppressing cytokine responses during cerebral ischaemia.9,11 Statins also improve CBF by recoupling dysfunctional endothelial nitric oxide synthase, the properties of which are particularly relevant to SAH in light of low CBF and impaired autoregulation.12-14
Experimental evidence indicates the benefit of simvastatin in the treatment of SAH.15-17 Simvastatin is also potent in reducing low-density lipoprotein with a proven safety profile. Three randomized, placebo-controlled pilot trials have supported the use of statins (2 trials with 80 mg simvastatin and 1 trial with 40 mg pravastatin) for the treatment of aneurysmal SAH.18-21 A systemic review has suggested that simvastatin may also reduce delayed cerebral ischemia after aneurysmal SAH,22 and another meta-analysis has recommended the routine use of statins in the care of patients with aneurysmal SAH.23 Finally, there is an ongoing multicenter, placebo-controlled phase III trial assessing the clinical benefits of treatment with 40 mg simvastatin daily (Simvastatin in Aneurysmal Subarachnoid Haemorrhage; http://www.stashtrial.com/home.html).
However, no clinical data are available to compare the efficacy of different dose regimens (specifically, whether a high-dose regimen is more effective than a normal-dose regimen) or conduct related cost-effectiveness analyses, even though the biochemical actions and related neuroprotective mechanisms are thought to be dose related. This gap in our knowledge of how to use statins and to interpret trial results is very important and motivated the investigators to conduct this study.
STUDY GOAL AND OBJECTIVE
The objective of the study is to determine whether a high dose of simvastatin for aneurysmal SAH is superior to a normal dose in terms of clinical outcomes and cost-effectiveness. We hypothesized that 80 mg simvastatin daily (high dose) over 3 weeks initiated within 96 hours of the ictus will reduce the incidence of DIDs after SAH compared with 40 mg simvastatin daily (normal dose), leading to improvements in clinical outcomes and thus cost-effectiveness.
The study design is a multicenter, randomized, controlled, double-blind (participants and outcome assessors) clinical trial.
Patients 18 to 70 years of age for whom the admitting neurosurgeon has a high index of suspicion of a spontaneous aneurysmal SAH with convincing computed tomography (CT) scan findings are included. Any clinical grade, provided that there was a reasonable prospect of survival, is included. For inclusion, the delay from the time of the presenting ictus until randomization and the initiation of trial medication cannot exceed 96 hours.
Unsalvageable patients, that is, those with fixed and dilated pupils after resuscitation or a devastating scan that preluded definitive therapy, are excluded. Those with a history of previous statin therapy or a current course of warfarin-type drugs also are excluded, as are pregnant women. Patients with known renal or hepatic impairment, those with a suspected or known additional disease process that threatens life expectancy (eg, malignancy), patients with a known or strong suspicion of drug abuse or alcoholism or the likelihood of being amendable to either at the 3-month follow up, and those currently taking of amiodarone, verapamil, or potent CYP3A4 inhibitors are also excluded.
OUTCOME MEASURES AND FOLLOW-UP
Primary Outcome Measures
Primary outcome measure include the presence of DIDs: a fall of ≥ 2 on the modified Glasgow Coma Scale, new focal neurological deficit lasting > 2 hours, new cerebral infarction, or CT perfusion evidence of cerebral ischemia unrelated to surgery/embolization, rebleed, hydrocephalus, infection, or electrolyte or metabolic disturbance.
Secondary Outcome Measures
Secondary outcome measures include modified Rankin Disability Score (favorable if 0-2) at 3 months and cost-effective analysis in terms of overall direct cost per patient and incremental cost-effectiveness ratio of the high-dose group vs normal-dose group, ie, the cost difference per patient divided by the difference in the percentage of favorable outcomes and delayed cerebral ischemia. Sensitivity analyses for the incremental cost-effectiveness ratio will be carried out using the percentages of favorable outcomes and delayed cerebral ischemia.
Ethics approval has been obtained from the respective institutional review boards. The study is adhering to the international quality standards provided in the Good Clinical Practice guidelines. After informed consent from patients or their next of kin is obtained, subjects are randomized to receive 80 mg simvastatin (2 tablets of 40 mg each) or 40 mg simvastatin (1 tablet of 40 mg and 1 placebo tablet) per day for 21 days orally or through a nasogastric tube.
Once the eligibility criteria have been fulfilled, a permuted-block randomization is carried out using a computer system with an allocation list in random order generated by a statistician not related to the project team to protect the blinding and integrity of the study. The study drug assignments are concealed in sealed envelopes. These envelopes are opened only by site study investigators not involved in the clinical management of the recruited patients. The allocation ratio is 1:1. Both the clinical team (medical and nursing) and the patients are blinded to the study drug allocation.
Assuming that the high-dose group has a 35% delayed cerebral ischemia risk with a 20% absolute reduction in delayed cerebral ischemia compared with the standard-dose group with a 55% delayed cerebral ischemia risk, a total of 212 patients will be required (80% power and 2-sided α = 0.05). However, further assuming a 10% loss to follow-up, 236 patients will need to be recruited. The study was designed with the expectation of 30 patients being recruited at each of 4 centers per year24,25; a total of 240 patients is thus expected to be recruited over a 24-month period. Because of delays in starting patient recruitment in some centers, 2 extra centers (a total of 6) were initiated for patient recruitment.
Randomized clinical trials for acute treatment of aneurysmal SAH typically require multicenter patient recruitment efforts. The adoption of modern Internet-based trial registries has allowed further “division of labor” in clinical researches. For example, in the present trial, we are comparing a high dose of simvastatin with a normal (or moderate) dose of simvastatin, and we know that another ongoing phase III multicenter trial is comparing normal dose and no simvastatin (http://www.stashtrial.com/home.html). When the results from these 2 trials are interpreted together, the research question of possible beneficial effect of high-dose simvastatin in acute aneurysmal SAH could be answered.
The trial recruitment has been slowed momentarily after the warning from the US Food and Drug Administration and the Department of Health of Hong Kong in June 2011 that the highest approved dose of simvastatin (80 mg) has been associated with an elevated risk of muscle injury or myopathy. Safety data were reviewed and submitted to the Chinese University of Hong Kong and New Territories East Cluster (CUHK-NTEC) Clinical Ethics Committee, and the decision was made to continue the study.
Patient recruitment will be completed in March 2013, and the last recruited patient will be due for final outcome assessment in June 2013. Data archiving, data analyses, and the dissemination of study results will take place in early 2014.
Drug-related morbidities, including rhabdomyolysis and hepatitis, have been rare. In the 2 reported pilot studies, only 1 patient withdrew as a result of elevated liver parenchymal enzymes, which reversed on cessation of medication. Plasma creatinine phosphokinase, alanine aminotransferase, and aspartate aminotransferase are being monitored for early signs of hepatitis or myositis every 7 days or on clinical suspicion. Administration of the study drug ceases if alanine aminotransferase/aspartate aminotransferase is more than 3 times the normal level of > 180 U/L or creatinine phosphokinase is > 1000 U/L. Cholesterol levels are also monitored weekly.
In addition to the laboratory tests mentioned above, the patients are followed up daily by the clinical team for any adverse events during initial admission and weekly for the first 3 weeks if discharged. A 3-month clinical visit is arranged for assessment of outcomes and possible adverse events. A contact number is available for the enrolled patients for queries and suspected adverse event report.
DATA MANAGEMENT AND STATISTICAL ANALYSIS
Data are being collected on handwritten forms and archived in a password-protected electronic database.
We aim to perform an intention-to-treat analysis using 2-sided probability, with values of P < .05 considered statistically significant. Proportions with delayed cerebral ischemia and favorable outcomes will be compared by use of χ2 statistics. A sensitivity analysis for incremental cost-effectiveness ratio will be carried out to find the limits of proportions of groups with delayed cerebral ischemia and favorable outcomes that show threshold values.
Planned exploratory analyses of delayed cerebral ischemia and favorable outcomes will include multivariate logistic regression using presentation SAH grade, age, and the presence or absence of immediate postprocedural neurological deficits as the key covariates. Additional exploratory analyses with similar multivariate logistic regressions are planned with the extra postrandomization variables of the development of hydrocephalus, timing of hydrocephalus treatment, and timing of aneurysm treatment.
The study conforms to the guidelines of Good Clinical Practice. Data are managed in a secured computer system by a dedicated research assistant supervised by the principal investigator. The site investigators are contacted in case of doubt or uncertainty about data forms. The Safety and Data Monitoring Committee is being led by Wai Sang Poon, professor of surgery at the Chinese University of Hong Kong. The committee is responsible for handling issues arising from the drugs used in the study, for interpreting unexpected major adverse events, for reviewing the study progress, and for submitting related recommendations to the study Steering Committee.
EXPECTED STUDY OUTCOME
This will be the first study to clarify whether high-dose simvastatin is more effective than normal-dose simvastatin for patients with acute aneurysmal SAH in terms of neurological outcomes and cost-effectiveness. This gap in our knowledge of how to use statins and interpret trial results is very important.
The initially targeted 24-month patient recruitment period has been extended to 30 months, with an additional 6 months required to complete the patient follow-up and data archive. The total study period will thus be 36 months.
The study Steering Committee is being led by the principal investigators. The committee is responsible for the study design, study implementation, ethics and health authority applications, protocol amendments, eventual data interpretation, and dissemination of results.
Statistical design and randomization are being supervised by Benny Zee, Division of Biostatistics, Jockey Club School of Public Health and Primary Care, Chinese University of Hong Kong.
The site study investigators are responsible for recruiting patients, reporting adverse events, and completing the data collection.
The study protocol was approved by the Joint CUHK-NTEC Clinical Research Ethics Committee, Hong Kong SAR, China. Ethical approval was obtained from the institutional review boards of the 6 neurosurgical centers. Written informed consent was obtained from eligible patients or next of kin for recruitment into the study.
Financial support was provided by the Health and Health Service Research Fund (reference 07080401), Food and Health Bureau, Hong Kong government, HKSAR, China. The authors have no personal financial or institutional interest in any of the drugs, materials, or devices described in this article.
We acknowledge all the participating centers listed in the affiliations. Protocol title: High-Dose Simvastatin for Aneurysmal Subarachnoid Haemorrhage (HDS-SAH). URL: www.ClinicalTrials.gov. Identifier: NCT01077206 (full protocol available online). Other study identification number: GW005. Name and address of the funding agency: Health and Health Service Research Fund (reference 07080401), Food and Health Bureau, Hong Kong Government, HKSAR, China. Study protocol confirmed with grant funding body: September 15, 2009. Ethics approval of the study protocol: Joint CUHK-NTEC Clinical Research Ethics Committee, Hong Kong SAR, China. Study investigators: Steering Committee: G.K. Wong, M.T. Chan, T. Gin, D.Y. Siu, and M.C. Leung; Safety and Data Monitoring Committee: W.S Poon and B. Zee; and Biostatistics: B. Zee. Site investigators: Department of Surgery, Prince of Wales Hospital, Hong Kong, China: X.L. Zhu and G.K. Wong; Department of Neurosurgery, Eighth Affiliated Hospital of Guangxi Medical University, Guangxi, China: M Liang; Department of Neurosurgery, Sichuan Province People’s Hospital, Sichuan, China: H.B. Tan; Department of Neurosurgery, Pamela Youde Nethersole Eastern Hospital, Hong Kong, China: M.W. Lee and C.K. Wong; Department of Neurosurgery, Princess Margaret Hospital, Hong Kong, China: T.K. Chan and Y.C. Po; and Department of Neurosurgery, Kwong Wah Hospital, Hong Kong, China: P.Y. Woo and K.Y. Chan.
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