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Three Part Question

In [a patient with a subarachnoid haemorrhage caused by a cerebral aneurysm confirmed by angiographic imaging] are [statins and conventional therapy better than just conventional therapy] in [preventing cerebral vasospasm and delayed ischaemic deficits]?

Clinical Scenario

A 54-year-old male presents to the emergency department with a sudden onset occipital headache, vomiting, photophobia and confusion. A diagnosis of subarachnoid haemorrhage is confirmed by computer tomography. The neurosugical registrar on-call advises you to start nimodipine and a statin to reduce the risk of the patient developing ischaemic deficits secondary to vasospasm. Is there any evidence to support the use of statins in this situation?

Search Strategy

Search conducted September 2008 of Medline, EMBASE, Cochrane Database of Systematic Reviews & CINAHL.
[SAH.mp OR [subarachnoid.mp AND [hemorrhage.mp OR bleed.mp OR bled.mp OR haemorrhage.mp]]] AND [statin$.mp OR atorvastatin.mp OR cerivastatin.mp OR fluvastatin.mp OR pravastatin.mp OR simvastatin.mp] LIMIT to human and English language.

Search Outcome

109 studies were found, of which 3 were considered relevant.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Tseng et al 2005 UK	80 patients with acute aneurysmal subarachnoid haemorrhage confirmed by angiography in a tertiary centre were recruited out of 86 potential patients. Vasospasm was defined by daily Trans-Cranial Doppler (TCD) scans that measured the mean flow velocities in the middle cerebral arteries.	Patients were randomised in a double-blind fashion to receive either 40mg pravastatin or placebo within 72h of the ictus and to continue treatment for 14 days or up until discharge.	Incidence of vasospasm measured with TCD	17/40 of patients receiving statin vs. 25/40 patients receiving placebo (P calculated by log-rank test =0.006, by Fisher's exact test =0.1165)	Study carried with patients accepted by a neurosurgical unit so does not represent the spectrum of patients with SAH presenting to an emergency department. Surrogate mechanism for measuring vasospasm and only measured once a day. Patients with 'symptomatic vasospasm' were treated with Hypertensive Hypervolaemic Hemodilution which has been shown to reverse vasospasm, not clear how many patients had this treatment and if it was only started after vasospasm had been confirmed by TCD. Small study, not powered to show improvement in clinical outcome. Short time period for study. In the patients receiving statins who had vasospasm the time of onset appeared to be delayed and states in text that these patients had delayed ischaemic deficits following the trial, not clear if patients had stopped taking statins at that point.
			Mortality	2/40 patients receiving statin, 12/40 patients receiving placebo. (P calculated by log-rank test <0.001, by Fisher's exact test = 0.0064)
Lynch et al 2005 USA	39 patients with acute aneurysmal subarachnoid haemorrhage presenting to one hospital with 48h of onset of symptoms. Not clear if patients were referred to this unit from other centres.	Patients were randomised to receive 80mg simvastatin (19) or placebo (20) in double-blinded fashion, for 14 days. Assessed for vasospasm by TCD 3 times per week. Primary end-point of vasospasm defined as the clinical impression of a delayed ischaemic deficit in the presence of a confirmatory radiological test (TCD or angiogram).	Presence of vasospasm	5/19 patients receiving simvastatin vs. 12/20 patients receiving placebo (P=0.03 given in paper by Chi square test, p=0.11 when I attempted calculation. )	The definition of vasospasm was not clearly defined relying on a 'clinical impression of a delayed ischaemic neurological deficit'. A small study not powered to detect a signicant clinical difference with no long-term follow-up.
Kramer AH. Gurka MJ. Nathan B. Dumont AS. Kassell NF. Bleck TP. 2008 Canada	A total of 150 patients admitted to one neurosurgical intensive care unit with a subarachnoid haemorrhage due to a ruptured cerebral aneurysm. This was a retrospective study examining outcomes before and after the management of these patients was changed to include the administration of 80mg of simvastatin daily in addition to the standard treatment. Exclusion criteria included patients who were admitted 72h or more following the ictus and patients who deteriorated within 5 days to the point that therapy was withdrawn.	Compared clinical and radiographic episodes of vasospasm in these patients and looked at adverse outcomes including death using the Glasgow Outcome Scale. 71 patients received treatment with a statin and 79 patients received standard treatment.	Clinical vasospasm	20 (no statin) vs. 23 (statin group), p=0.34	Retrospective study. Not directly applicable to the emergency department as a selected group of patients who had been admitted to a neurosurgical unit.
			Delayed infarct	22 (no statin group) vs. 16 (statin group), p=0.46
			Poor outcome (GOS 1-3)	28 (no statin group) vs. 28 (statin group), p=0.61

Comment(s)

There is some evidence to suggest that statins have a tendency to protect against delayed ischaemic deficits associated with vasospasm following subarachnoid haemorrhage. Both randomised controlled trials had small numbers involved meaning that they weren't powered to look at clinical outcome and the follow up the patients was for a relatively short period of time so it is not clear if the beneficial effects would continue. The larger study was carried out in a neurosurgical centre and so concerned a selected population of the patients who present to the Emergency Department with SAH. Statins are only available in oral form so would not be of benefit to the patient with impaired swallowing. Kramer et al reported a disappointing lack of benefit in the patients treated with a statin at one neurosurgical unit following a change in the departmental treatment protocol in a retrospective cohort study. Larger randomised clinical trails are clearly warranted but will require a multi-centre study in view of the small numbers of patients admitted to each unit. Given the benefits shown by starting statins early following acute myocardial infarction it may be wise to commence the study while the patients are in the Emergency Department rather than waiting until the patient is received onto the neurosurgical unit. None of the patients in these studies had any adverse effects reported which could be attributed to this class of drubs but there are recognised side effects including myositis and altered liver function.

Clinical Bottom Line

2 small studies have shown that commencing statins causes a reduction in vasospasm, as measured by TCD, over a 14 day period and a tendency to improve clinical outcome. One retrospective cohort study failed to show any benefit in patients who received a statin in addition to standard treatment. Local advice following discussion with the neurosurgical team should be followed.

Level of Evidence

Level 3 - Small numbers of small studies or great heterogeneity or very different population.

References

1. M Tseng, M Czosnyka, H Richards, J Pickard, P Kirkpatrick Effects of acute treatment with pravastatin on cerebral vasospasm, autoregulation, and delayed ischaemic deficits after aneurysmal subarachnoid haemorrhage. Stroke 2005;36:1627-1632
2. J Lynch, H Wang, M McGirt, J Floyd, A Friedman, A Coon, R Blessing, M Alexander, C Graffagnino, D Warner, D Laskowitz Simvastatin reduces vasospasm after aneurysmal subarachnoid hemorrhage. Results of a pilot randomized clinical trial Stroke 2005;36:2024-2026
3. Kramer AH. Gurka MJ. Nathan B. Dumont AS. Kassell NF. Bleck TP. Statin use was not associated with less vasospasm or improved outcome after subarachnoid hemorrhage Neurosurgery Feb 2008; 62(2): 422-7