High-Dose Simvastatin for Aneurysmal Subarachnoid Hemorrhage

Abstract

A lthough 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][8][9][10][11][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][15][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). 16Background 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 ...

High-Dose Simvastatin Is Effective in Preventing Cerebral Vasospasm after Aneurysmal Subarachnoid Hemorrhage: A Prospective Cohort Study in Korean Patients

“…The effects of statin in the prevention of cerebral vasospasm after SAH are still controversial. Some randomized trials showed a decrease in the incidence of vasospasm in the statin groups unlike in the control group, but other studies did not show a significant difference 1 6 8 11 15 16 17) . The result of a recent multicenter prospective study that compared patients treated with 40 mg of statin for 14 days with the control group showed no difference in the incidence of vasospasm and the clinical outcome 6) .…”

“…The informed consent of either the patient or his or her next of kin was obtained. Previous studies showed that the short-term use of high-dose statin did not compromise safety 7 8 17) . Thus, we treated aneurysmal SAH patients with 80 mg, 40 mg, or 20 mg simvastatin (Simvastatin®; Yuhan Corporation, Seoul, Korea) for preventing cerebral vasospasm and retrospectively reviewed prospectively collected database.…”

“…Statins are known to influence various pathogenesis involving the maintenance of endothelial integrity and inhibition of vascular smooth muscle proliferation in experimental studies 14) . However, the studies in which statin was used for prophylaxis of cerebral vasospasm after aneurysmal SAH had different results 1 6 8 11 15 16 17) . A randomized clinical trial demonstrated that 80 mg simvastatin treatment significantly reduced the development of vasospasm, but recent multicenter randomized trial to assess the effects of 80 mg simvastatin failed to demonstrate a reduction in cerebral vasospasm compared with 40 mg simvastatin 8 17) .…”

Effect of High-Dose Simvastatin on Cerebral Blood Flow and Static Autoregulation in Subarachnoid Hemorrhage

“…The primary ordinal analysis of the mRS, adjusted for age and WFNS grade on admission, showed no benefit. In another study Wong et al compared low and high dose simvastatin, 40 vs. 80 mg. [25] The groups did not differ in the incidence of delayed ischemic deficits (27% versus 24%) or in the rate of favorable outcomes (mRS score 0–2) at 3 months (73% versus 72%). Taken together these data indicate that simvastatin likely does not improve functional outcome in SAH.…”

Aneurysmal Subarachnoid Hemorrhage—Status Quo and Perspective

“…Numerous clinical trials studied novel pharmaceutical treatments (i.e., nicardipine, tirilazad, statins, clazosentan, magnesium, etc.) against DCI, but oral nimodipine remains the only drug to improve neurological outcome in SAH patients [50,19,51,20,52]. Whether the lack of efficacy of these drugs originated from small sample sizes, insensitive outcome measures, insensitive pharmacological targets, or detrimental systemic effects is uncertain [53].…”