Long-acting statin for aneurysmal subarachnoid hemorrhage: A randomized, double-blind, placebo-controlled trial

Abstract

Statins have pleiotropic effects that are considered beneficial in preventing cerebral vasospasm and delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage (aSAH). Many studies using statins have been performed but failed to show remarkable effects. We hypothesized that a long-acting statin would be more effective, due to a longer half-life and stronger pleiotropic effects. Patients with aSAH were randomly assigned to a pitavastatin group (4 mg daily; n = 54) and a placebo group ( n = 54) after repair of a ruptured aneurysm. The primary efficacy end point was vasospasm-related delayed ischemic neurological deficits (DIND), and the secondary end points were cerebral vasospasm evaluated by digital subtraction angiography (DSA), vasospasm-related new cerebral infarctions, and outcome at three months. Severe cerebral vasospasms on DSA were statistically fewer in the pitavastatin group than in the placebo group (14.8% vs. 33.3%; odds ratio, 0.32; 95% confidence interval, 0.11-0.87, p = 0.042); however, the occurrence of DIND and new infarctions and outcome showed no statistically significant differences between the groups. The present study is the first to prove the definite, statin-induced amelioration of cerebral vasospasm on DSA. However, administration of any type of statin at the acute phase of aSAH is not recommended.

Dose-Dependent Effects of Statins for Patients with Aneurysmal Subarachnoid Hemorrhage: Meta-Regression Analysis

“…The literature search strategy yielded a total of 18 studies for analysis, which comprised of randomized controlled trials (RCTs) [16,17,19,20,[36][37][38][39][40][41][42][43], prospective observational cohort studies [15,44] and retrospective observational studies [18,[45][46][47]. This represented 2594 patients.…”

“…If bias was not addressed in the trials, we assumed an unclear risk. Nine studies (50.0%) were randomized control trials, with blinding of participants and personnel [16,17,19,20,36,38,40,41,43]. Risk of overall bias was considered high in 7 studies (39.0%) [15,37,39,42,[44][45][46], whereas the risk was minimal in 8 studies (44.4%) [16,17,19,20,36,38,40,41].…”

“…Definitions of study outcomes (vasospasm, DIND, mortality) are shown in Table 3 and characteristics of study interventions are shown in Table 4. Of the 18 studies, twelve investigated simvastatin [15-17, 20, 36, 38-41, 44, 46, 47], three investigated pravastatin [19,37,45] two investigated atorvastatin [18,42] while a single study investigated pitavastatin [43]. Simvastatin dose ranged from 20 mg to 80 mg daily and atorvastatin ranged from 20 mg to 40 mg daily.…”

The role and therapeutic potential of heat shock proteins in haemorrhagic stroke

“…Moreover, randomized controlled phase II studies have demonstrated that acute administration of statin directly after SAH decreased the incidence of radiological vasospasm, and reduced the clinical signs of delayed ischaemic neurological deficits and mortality . However, some experimental and clinical studies demonstrated the different or even contradictory results . Thus, further well‐designed multicentre randomized controlled trials are required.…”

Efficacy of fasudil for the treatment of aneurysmal subarachnoid hemorrhage

“…A variety of managements can help patients with ASH, including statin, clazosentan, cilostazol, simvastatin, diltiazem, simvastatin, methylprednisolone, rehabilitation, and fasudil, [11–23] especially for fasudil. Although several studies have reported that fasudil can be utilized for ASH treatment effectively, [20–23] its conclusion is still unconfirmed.…”