High-Dose Simvastatin for Aneurysmal Subarachnoid Hemorrhage
Multicenter Randomized Controlled Double-Blinded Clinical Trial
Background and Purpose—Experimental evidence has indicated the benefits of simvastatin for the treatment of subarachnoid hemorrhage. Two randomized placebo-controlled pilot trials that used the highest clinically approved dose of simvastatin (80 mg daily) gave positive results despite the fact that a lower dose of simvastatin (40 mg daily) did not improve clinical outcomes. We hypothesized that a high dose of 80 mg of simvastatin daily for 3 weeks would reduce the incidence of delayed ischemic deficits after subarachnoid hemorrhage compared with a lower dose (40 mg of simvastatin daily) and lead to improved clinical outcomes.
Methods—The study design was a randomized controlled double-blinded clinical trial. Patients with aneurysmal subarachnoid hemorrhage (presenting within 96 hours of the ictus) from 6 neurosurgical centers were recruited for 3 years. The primary outcome measure was the presence of delayed ischemic deficits, and secondary outcome measures included a modified Rankin disability score at 3 months and an analysis of cost-effectiveness.
Results—No difference was observed between the groups treated with the higher dose or the lower dose of simvastatin in the incidence of delayed ischemic deficits (27% versus 24%; odds ratio, 1.2; 95% confidence interval, 0.7–2.0; P=0.586) or in the rate of favorable outcomes (modified Rankin Scale score, 0–2) at 3 months (73% versus 72%; odds ratio, 1.1; 95% confidence interval, 0.6–1.9; P=0.770).
Conclusions—High-dose simvastatin treatment should not be prescribed routinely for aneurysmal subarachnoid hemorrhage.
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.1 Early aneurysm occlusion, expert endovascular neurosurgery and microsurgery, and the use of oral nimodipine and neurointensive care are now standard treatment procedures.2,3 Nevertheless, aneurysmal SAH is still associated with mortality after 1 month for half of all patients, whereas another quarter is left with disabilities.1
After aneurysmal SAH, 18% to 56% of patients demonstrate the evidence of secondary ischemia with clinical deterioration, which is also known as delayed ischemic deficit (DID).4,5 The time lag of 3 to 10 days is unique and offers the potential to intervene before clinical deterioration. Pathologically, the basal subarachnoid distribution of deoxyhemoglobin and early hypoxic-ischemic brain injury contribute to the diffuse distribution of complex biological processes that involve endothelial cells.6,7
Statin improves endothelial vasomotor function; increases nitric oxide bioavailability; possesses antioxidant properties; counters thrombus formation; induces angiogenesis, endogenous cell proliferation, and neurogenesis; increases the synaptic protein synaptophysin; induces vascular stabilization and neuroblast migration; and suppresses cytokine responses during cerebral ischemia.7–12 Experimental evidence also indicates the benefit of simvastatin in the treatment of aneurysmal SAH.13 Three randomized placebo-controlled pilot trials have supported the use of statins (2 with 80 mg of simvastatin and 1 with 40 mg of pravastatin) for the treatment of aneurysmal SAH.14–16 In the Duke University Medical Center study, clinical vasospasm was significantly reduced from 60% to 26% by simvastatin treatment (80 mg daily).14 In the Massachusetts General Hospital study, vasospasm-related ischemic infarct was reduced from 25% to 11% by simvastatin treatment (80 mg daily).16
However, a recently published multicenter, placebo-controlled phase III trial (Simvastatin in Aneurysmal Subarachnoid Hemorrhage [STASH] trial) recruited 803 patients with aneurysmal SAH within 96 hours after ictus and randomized them into receiving 40 mg of simvastatin (n=391) or placebo (n=412) daily for 3 weeks.17 Seventy-three percent of patients were in good World Federation of Neurosurgical Societies grade on admission, and the modified Rankin Scale (mRS) at 6 months was not different between both arms (favorable [0–2] in 72% of the 40 mg of simvastatin arm and 72% in the placebo arm).
In contrast, the initial randomized placebo-controlled pilot trials used the highest clinically approved dose of simvastatin (80 mg daily), but no clinical data were available to compare the efficacy of different dose regimens (specifically, whether a high-dose regimen is more effective than a lower dose-dose regimen).
The objective of this study was to determine whether a high dose of simvastatin for the treatment of aneurysmal SAH is superior to a lower dose in terms of clinical outcomes and cost-effectiveness. We hypothesized that 80 mg of simvastatin (high dose) daily for 3 weeks initiated within 96 hours of the ictus would reduce the incidence of DID after SAH compared with a normal dose of 40 mg of simvastatin daily and lead to improvements in clinical outcomes and thus cost-effectiveness.
This study was an investigator-initiated, multicenter, randomized controlled trial with blinded outcome assessment, conducted at 6 sites in Hong Kong and in Guangxi and Xichuan, China, between September 2010 and September 2013. The study protocol was published, and it received ethics committee approval from all of the participating centers.18 All participants or their legally acceptable representatives provided written informed consent. The study adhered to the international quality standards provided in good clinical practice guidelines.
Patients who were diagnosed with aneurysmal SAH were randomly assigned to receive either 80 mg (high dose) or 40 mg (lower dose) of simvastatin daily for 3 weeks. The inclusion criteria were as follows: age, 18 to 70 years; radiological diagnosis of SAH; an intracranial aneurysm that was considered to be the cause of the SAH; ability to be randomized within 96 hours after the onset of SAH; and nonchildbearing potential (ie, physiologically incapable of becoming pregnant, including any woman who was postmenopausal) or childbearing potential but with a negative urine pregnancy test immediately before randomization. The exclusion criteria were as follows: probably unsalvageable patients on admission; pre-existing major hepatic, renal, neurological (other than unruptured intracranial aneurysms), pulmonary, or cardiac disease; statin therapy at the time of ictus; current course of warfarin-type drugs or of amiodarone, verapamil, or potent cytochrome P4503A4 inhibitors; suspected or known additional disease process that threatens life expectancy (eg, malignancy); unlikely to return for the 3-month follow-up assessment; known or strong suspicion of drug abuse or alcoholism; and participation in another clinical trial.
Standard of Care
In the 6 participating centers, ruptured aneurysms would usually be treated within 24 hours after admission. Nimodipine would routinely be started on admission and continued for 21 days. When clinical vasospasm developed, hypertensive treatment with an elevated mean arterial blood pressure of ≥20 mm Hg would be started. Computed tomographic perfusion may be performed in one of the participating centers for research purpose. Cerebral digital subtraction angiography was not usually performed, and no balloon angioplasty was done within the trial cohort.
A permuted-block randomization was performed using a computer system with an allocation list in random order generated by a statistician not associated with the project team to protect the blinding and integrity of the study. The study drug assignments were kept in sealed envelopes that were opened by site study investigators who were not involved in the clinical management of recruited patients. Both the assessors and the patients were blinded to the study drug allocation. Participants were randomized to receive 2 identical tablets of study drugs (80 mg or 40 mg of simvastatin) per day for 21 days orally or through a nasogastric tube. Plasma creatinine phosphokinase, alanine aminotransferase (ALT), and aspartate aminotransferase were monitored for early signs of hepatitis or myositis every 7 days or on clinical suspicion. Administration of the study drug was stopped if ALT/aspartate aminotransferase was greater than the normal level of >180 U/L or if plasma creatinine phosphokinase was >1000 U/L. Rhabdomyolysis (a subset of myopathy) was defined as plasma creatinine phosphokinase >6000 U/L plus the evidence of end-organ damage (ie, doubling of plasma creatinine).19
Patient demographics, medical history, and relevant investigation results were collected. The severity of the SAH was scored clinically using the World Federation of Neurosurgical Societies grading scale and radiologically using the Fisher scale. At 3 months after randomization, patients were interviewed with a Chinese version of mRS questionnaire by a nurse or clinician with no knowledge of the treatment allocation. The presence of DIDs was defined as (1) clinical vasospasm as manifested by a fall of ≥2 points on the modified Glasgow Coma Scale or a new focal neurological deficit when compared with the best neurological status after admission, which lasts >2 hours, or (2) delayed cerebral infarction, unrelated to surgery/intervention, rebleed, hydrocephalus, infection, electrolyte, or metabolic disturbance. Rebleed (as confirmed by computed tomography of the brain), hydrocephalus, delayed cerebral infarction (as confirmed by interval computed tomography of the brain), post-treatment (coiling or clipping) complications, adverse events, and overall mortality during treatment and follow-up were also documented. Suspected simvastatin-related serious adverse events (fatal, life threatening, requiring or prolonging hospitalization, or others) were reported to and assessed by the Data Monitoring and Safety Committee. Delayed cerebral infarction was assessed by a site investigator and in consultation with a radiologist if necessary.
We hypothesized that compared with 40 mg of simvastatin (lower dose) daily, 80 mg of simvastatin (high dose) daily for 3 weeks initiated within 96 hours of the ictus would reduce the incidence of DIDs after SAH and lead to improvements in clinical outcomes and thus cost-effectiveness. The primary outcome was DID, as defined above. Secondary outcome measures were mRS at 3 months (favorable if 0–2), clinical vasospasm, delayed cerebral infarction, and an analysis of cost-effectiveness (and sensitivity analyses) in terms of the overall direct cost per patient and incremental cost-effectiveness ratio of the high-dose group versus the normal-dose group, ie, the cost difference per patient divided by the difference in the percentage of (1) favorable outcomes and (2) delayed cerebral ischemia (DID, clinical vasospasm, and delayed cerebral infarction).
Data management and statistical analyses were performed by the research team of the Division of Neurosurgery, Prince of Wales Hospital, the Chinese University of Hong Kong, Hong Kong. For sample size estimation, we assumed that the high-dose group had a 35% risk of delayed cerebral ischemia with a 20% absolute reduction in delayed cerebral ischemia compared with the lower-dose group and that 212 patients would be required (80% power and 2-sided α=0.05).18 Further assuming a 10% loss to follow-up, ≥236 patients were planned to be recruited.20,21 Because of delays in starting patient recruitment in some centers, 2 extra centers (a total of 6) were initiated for patient recruitment. When a 3-month mRS outcome could not be obtained because of withdrawal or loss to follow-up, the last available outcome was planned to be used in its place (last observation carried forward method). In practice, last observation carried forward was not necessary in the current study. Data were collected on handwritten forms and archived in a password-protected electronic database.
We performed an intention-to-treat analysis using 2-sided probability, with P<0.05 considered to be statistically significant. Proportions with (1) DID and (2) favorable outcomes were compared using χ2 statistics. A sensitivity analysis for the incremental cost-effectiveness ratio was planned to find the limits of proportions of groups with (1) DID and (2) favorable outcomes that showed threshold values. The odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. For mRS, OR values >1.0 or a positive value of mean differences indicated an advantage of high-dose simvastatin treatment compared with lower-dose simvastatin treatment. For DID, clinical vasospasm, and delayed cerebral infarction, OR values <1.0 indicated an advantage of high-dose simvastatin treatment compared with lower-dose simvastatin treatment.
Planned exploratory analyses of DID and favorable outcomes also included multivariable logistic regression using the grade of SAH at presentation, age, and the presence or absence of immediate postprocedural neurological deficits as the key covariates.
Role of the Funding Sources
The funding sources had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all of the data in the study and had the final responsibility for the decision to submit for publication.
The initially targeted 24-month patient recruitment period had to be extended to 30 months, with an additional 6 months required to complete the patient follow-up. Thus, the total study period was 36 months. A flow diagram per Consolidated Standards of Reporting Trials guideline is shown in the Figure. Barriers to recruitment included late presentation, refusal, or next of kin or investigator unavailable for consent. Of the 549 patients with SAH assessed, 428 were eligible. Of the 428 eligible patients, 255 patients or their next of kin consented to participate and were randomized to receive either the high-dose or normal-dose simvastatin treatment (131 normal-dose simvastatin treatment and 124 high-dose simvastatin treatment). Profiles of recruited and nonrecruited eligible patients are shown in Table 1. Recruited patients were more likely to be smokers and less likely to have acute hydrocephalus requiring external ventricular drain.
The patient profiles and outcomes of lower-dose (40 mg) and high-dose (80 mg) simvastatin treatments are shown in Table 2. There was no difference in the patient profiles between the 2 treatment arms. Five (2.0%) patients (3 normal-dose simvastatin treatment and 2 lower-dose simvastatin treatment) had adverse events, requiring earlier cessation of treatment. Otherwise, patients reported completion of the 21-day course of simvastatin treatment. Of the 3 patients on the normal-dose simvastatin treatment, 1 had plasma creatinine phosphokinase 3437 U/L at day 3 with confirmed acute coronary syndrome and no clinical myopathy, 1 had ALT 229 U/L at day 11, and 1 had ALT 269 U/L at day 10. Of the 2 patients on the high-dose simvastatin treatment, 1 had ALT 194 U/L at day 9 and 1 had ALT 331 U/L. All of these changes were reversible on cessation of simvastatin treatment.
Outcome data are shown in Table 3. From the intention-to-treat analyses, no difference was observed between the high-dose and lower-dose simvastatin groups in DID (27% versus 24%; OR, 1.2; 95% CI, 0.7–2.0; P=0.586), in clinical vasospasm (15% versus 12%; OR, 1.2; 95% CI, 0.6–2.5; P=0.589), or in delayed cerebral infarction (16% versus 17%; OR, 1.0; 95% CI, 0.5–1.8; P=0.886); also no difference in favorable outcome (mRS, 0–2) at 3 months was observed between the high-dose and normal-dose simvastatin groups (73% versus 72%; OR, 1.1; 95% CI, 0.6–1.9; P=0.770). Thus, no cost-effectiveness analysis was performed.
Similarly, in the 250 patients who completed the full allocated course of simvastatin treatment, no difference was observed between the high-dose and lower-dose treatment groups in DID, clinical vasospasm, delayed cerebral infarction, and favorable outcome.
Exploratory analyses with multivariable logistic regression using the covariates of grade of SAH at presentation, age, and the presence or absence of immediate postprocedural neurological deficits showed no significant difference in DID (OR, 1.2; 95% CI, 0.7–2.0; P=0.603) or favorable outcome (mRS, 0–2) at 3 months (OR, 1.0; 95% CI, 0.5–1.8; P=0.943).
Randomized clinical trials for the acute treatment of aneurysmal SAH typically require a multicenter patient recruitment effort. The adoption of modern trial registries allows for further division of labor in design and implementation of clinical studies. For example, in the current trial, we compared a high dose with a lower (or moderate) dose of simvastatin, whereas the STASH trial compared a lower dose with no simvastatin.17 The STASH trial to assess the effects of 40 mg of simvastatin daily did not show a reduction in DID or improvements in clinical outcomes.17 Our High-Dose Simvastatin for Aneurysmal SAH (HDS-SAH) trial, on the other hand, did not support the superiority of high-dose compared with lower-dose simvastatin treatment for patients with aneurysmal SAH. STASH,17 our local Cognitive Dysfunction After Aneurysmal SAH,22 and HDS-SAH trials had similar rates of clinical vasospasm (16% versus 15% versus 13%) and delayed cerebral infarction (16% versus 15% versus 16%). Nearly half of our patient cohort had poor World Federation of Neurosurgical Societies grade on admission, and thus, the negative results could not be explained by the recruitment of a low-risk patient cohort. Taken together, these trials did not support the benefit of high-dose simvastatin treatment in patients with aneurysmal SAH.
The trial recruitment was decelerated after warnings 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, ie, 80 mg, was associated with an elevated risk of muscle injury or myopathy. Safety data were reviewed, and it was decided that the study should continue. The above-mentioned problem partially accounted for the need to extend the study to a 3-year period. In our HDS-SAH trial, 1 unique design was the adoption of different dose comparisons without a placebo group. We did so because we knew that the STASH trial would compare simvastatin (40 mg) treatment and placebo. Secondarily, the study design allowed us to finish the HDS-SAH trial at around the same time as the STASH trial.
In our study, simvastatin treatment was well tolerated, and only 5 (2%) patients developed reversible side effects that required earlier cessation of simvastatin treatment. Typically, these study patients had the full course of simvastatin treatment completed and monitored in hospitals. Our study weakness was that no pill counts were done to confirm compliance and as a quality assurance that the trial medications were taken in full. Nevertheless, the low overall withdrawal and compliance rate (8%) of the STASH trial supported that simvastatin treatment was a well-tolerated treatment.17 The intention-to-treat (effectiveness) data should be the key to interpret clinical effects.
Although we labeled the groups as high dose and lower dose in accordance with the clinical dose range, these doses of simvastatin therapy are in keeping with the effective concentrations that enhance endothelial cell proliferation, migration, and differentiation at low doses in the biphasic effects of experimental studies.23,24 These activities were modulated via effects on geranylated proteins.23 Our results related to simvastatin doses and hence to serum simvastatin concentrations that corresponded to the low proangiogenic doses in experimental studies. One shortcoming was that we did not measure serum simvastatin concentrations to compare outcomes with the concentrations achieved.25
The focus of the current study was whether an increase in the dose of simvastatin therapy supported the hypothesis of its neuroprotective action against delayed cerebral ischemia between day 3 and day 10, and it could not rule out whether simvastatin could have a neuroprotective effect against the pathophysiological process of early brain injury that occurs within the first 24 to 48 hours. We had not specifically collected the time of first dose of study treatment, and thus, analysis of efficacy with respect to study drug initiation time could not be done. In fact, a recent experimental study supported that rosuvastatin ameliorates early brain injury after SAH via the suppression of superoxide formation and nuclear factor-κ B activation in rats.26
Cognitive function is another important outcome after SAH.22,27 Abnormalities in cognitive function are common after surgery/intervention for aneurysmal SAH, even among patients with a good functional outcome, and can occur in ≤44% of survivors.28,29 Cognitive assessments would be of interest to investigate in future neuroprotective clinical trials for aneurysmal SAH.
Other limitations of the study included the following. We did not include generic or disease-specific quality of life assessments. No central adjudication of radiological data was done because of funding restraints. The event rate of DID was lower than expected, but no trend of difference between the 2 treatment arms was noted to suggest that increasing the patient number might show a significant difference in outcomes. All patients were Chinese, but there was no data to suggest that ethnicity played a role in simvastatin treatment response. Whether a newer and more potent statin could be effective was uncertain. A remote randomization system by phone or internet could provide better theoretical allocation concealment than sealed envelopes. Compliance could only be inferred from patients’ report during follow-up, and missed doses could otherwise be undetected. Finally, angiographic studies were not mandated for patients with DIDs or delayed cerebral infarction, and thus, angiographic outcomes could not be assessed.
Randomized controlled trials in surgical patients with hemorrhagic stroke, especially when a disturbance of consciousness is involved, are difficult to undertake.30 This academically funded study was carried out with no industry support, using generic medications. Nevertheless, the population recruited was representative of patients with acute aneurysmal SAH managed in daily practice. We performed a systemic search of PubMed on April 7, 2014, for additional SAH trials comparing different doses of statin treatment. Search terms included SAH and statin. Of the 97 articles found, 11 compared statin treatment with no statin treatment, but none compared different doses of statin treatment in patients with SAH. Our results represented the only available data in the literature and did not support a significant clinical benefit of high-dose simvastatin treatment in patients with acute aneurysmal SAH.
No evidence was found that high-dose simvastatin treatment is superior to normal-dose simvastatin treatment in SAH. Simvastatin treatment should not be prescribed routinely after SAH.
Appendix HDS-SAH Investigators
Steering Committee: G.K. Wong, M.T. Chan, T. Gin, D.Y. Siu, M.C. Leung. Safety and data monitoring committee: W.S. Poon, B. Zee. Biostatistics: B. Zee.
Department of Surgery, Prince of Wales Hospital, Hong Kong, China (79 patients): X.L. Zhu, G.K. Wong;
Department of Neurosurgery, the 8th Affiliated Hospital of Guangxi Medical University, Guangxi, China (100 patients): M. Liang;
Department of Neurosurgery, Sichuan Province People’s Hospital, Sichuan, China (41 patients): H.B. Tan;
Department of Neurosurgery, Pamela Youde Nethersole Eastern Hospital, Hong Kong, China (5 patients): M.W. Lee, C.K. Wong;
Department of Neurosurgery, Princess Margaret Hospital, Hong Kong China (15 patients): T.K. Chan, Y.C. Po;
Department of Neurosurgery, Kwong Wah Hospital, Hong Kong China (15 patients): P.Y. Woo, K.Y. Chan.
Dr Wong conceived the study, contributed to grant writing, study planning, data analysis and data interpretation, and drafted and revised the article. The steering committee and safety and data monitoring committee members contributed to the trial design, trial supervision, and interpretation of the data. Site investigators contributed to patient recruitment and study drug administration. All listed collaborators approved the statistical section of the article and edited, revised, and approved the final version of the article.
Sources of Funding
This study was supported by Health and Health Service Research Fund Project Number 07080401 of the Food and Health Bureau of Hong Kong. The funding source was not involved in the study design, in the collection, analysis, and interpretation of data, and in writing the report or in the decision to submit the article for publication.
- Received August 7, 2014.
- Revision received October 15, 2014.
- Accepted November 13, 2014.
- © 2014 American Heart Association, Inc.
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