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High-dose Simvastatin for Aneurysmal Subarachnoid Haemorrhage

2014-07-24 14:07:21 | BioPortfolio

Summary

Experimental evidences supported the benefit of Simvastatin in subarachnoid haemorrhage. Moreover, Simvastatin is a potent agent in achieving low-density lipoprotein (LDL) reduction with a proven safety profile. However, there is no clinical data to compare the efficacy of different dosage regimens (namely whether high-dose regimen is better) and related cost-effectiveness analysis, although biochemical actions and related neuroprotective mechanisms were thought to be dosage-related. This gap in knowledge is important, on how to implement the use of statin and interpret different trial results. With these in mind, the investigators designed the current study.

Hypothesis:

Daily Simvastatin 80mg (high dose) treatment given within 96 hours of the ictus over three weeks will reduce incidence and duration of delayed ischemic deficits following subarachnoid haemorrhage when compared to daily Simvastatin 40mg (normal dose) treatment, leading to improvement in clinical outcome, which translates into advantage in terms of cost-effectiveness.

Description

Although aneurysmal subarachnoid haemorrhage (SAH) accounts for only 3-5% of strokes, its profound consequences and unique window of intervention have justified it being classified as a separate entity. Early aneurysm occlusion, expert endovascular neurosurgery and microsurgery, use of oral nimodipine, neuro-intensive care, and aggressive treatment of delayed cerebral ischemia are now the standards of care [Wong GK 2008]. Despite these standards, aneurysmal subarachnoid haemorrhage is still associated with mortality at one month for half of all patients, whereas the half that survives is left with disability.

Following the acute bleed, many patients with SAH show deterioration as a consequence of secondary ischaemic processes affecting the cerebral circulation [Knuckey NW 1985]. The clinical consequences manifest as delayed ischaemic deficits (DIDs), and usually develop after a lag of several days. There is therefore a potential to intervene before clinical deterioration. The diffuse nature of SAH by means of red cell breakdown products has widespread effects on the large vessels of the circle of Willis and smaller vessels within the sub-pial space [van Gijn 2001]. Processes are complex, and combine to impair the cerebral blood flow (CBF) to widespread areas of the brain. Low CBF correlates with clinical outcome following SAH, hence candidate neuroprotective agents may be targeted according to CBF enhancing characteristics which 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 [Andaluz N 2002, Murai Y 2005, Liu JK 2004]. A more global approach is more appropriate. As a reflection of the complex array of pathological process underlying DID, a preferred strategy would be to target a multitude of potentially important mechanisms underlying DID by using a drug which has the potential for multiple efficacious actions.

Statins inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and block the formation of mevalonate, an important precursor for both cholesterol and other nonsterol products [Delanty N 1997, Goldstein JL 1990]. 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 ischemia [Goldstein JL 1990, Vaughan CJ 1993]. Statins also improve CBF by up-regulation of endothelial nitric oxide synthase (eNOS), properties which are of particular relevance to SAH in light of low CBF and impaired autoregulation.

Experimental evidences supported the benefit of Simvastatin in subarachnoid haemorrhage [McGirt MJ 2002, Chen J 2003, Sugawara T 2008]. Moreover, Simvastatin is a potent agent in achieving LDL reduction with a proven safety profile. There are randomized placebo-controlled pilot trials in the literature supporting the use of statins (two with simvastatin 80mg and one with pravastatin 40mg) in aneurysmal subarachnoid haemorrhage [Lynch JR 2005, Tseng MY 2005, Tseng MY 2007, Chou SH 2008]. The results for the phase II trial using Pravastatin 40 suggest that the clinical benefit is likely to be a consequence of LDL reduction and related anti-inflammatory and haemorheological benefits. Simvastatin 40mg is considered to be a equal if not more potent agent than Pravastatin in achieving LDL reduction. Thus, the evidence of Pravastatin 40mg daily is equivalent to Simvastatin 40mg daily. Although different animal models use different dose regimen, it is unclear how they can translate into human aneurysmal subarachnoid model, the evidences from human studies are unclear whether higher dose is better than normal dose. There is also an ongoing multi-centre placebo controlled phase III trial assessing the clinical benefit of daily simvastatin 40mg treatment [http://www.stashtrial.com/home.html].

However, there is no clinical data to compare the efficacy of different dosage regimens (namely whether high-dose regimen is better) and related cost-effectiveness analysis, although biochemical actions and related neuroprotective mechanisms were thought to be dosage-related. This gap in knowledge is important, on how to implement the use of statin and interpret different trial results. With these in mind, we design the current study.

Hypothesis:

Daily Simvastatin 80mg (high dose) treatment given within 96 hours of the ictus over three weeks will reduce incidence and duration of delayed ischemic deficits following subarachnoid haemorrhage when compared to daily Simvastatin 40mg (normal dose) treatment, leading to improvement in clinical outcome, which translates into advantage in terms of cost-effectiveness.

Study Design

Allocation: Randomized, Control: Dose Comparison, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Outcomes Assessor), Primary Purpose: Prevention

Conditions

Subarachnoid Hemorrhage

Intervention

Simvastatin

Location

The Chinese University of Hong Kong
Hong Kong
China

Status

Recruiting

Source

Chinese University of Hong Kong

Results (where available)

View Results

Links

Published on BioPortfolio: 2014-07-24T14:07:21-0400

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Bleeding into the SUBARACHNOID SPACE due to CRANIOCEREBRAL TRAUMA. Minor hemorrhages may be asymptomatic; moderate to severe hemorrhages may be associated with INTRACRANIAL HYPERTENSION and VASOSPASM, INTRACRANIAL.

A pharmaceutical preparation of ezetimibe and simvastatin that is used in the treatment of HYPERCHOLESTEROLEMIA and HYPERLIPIDEMIAS.

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Bleeding within the SKULL induced by penetrating and nonpenetrating traumatic injuries, including hemorrhages into the tissues of CEREBRUM; BRAIN STEM; and CEREBELLUM; as well as into the epidural, subdural and subarachnoid spaces of the MENINGES.

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