A 63 yr old woman collapsed at home and was brought into ED with a GCS of 3/15. She was a known hypertensive and hypercholesterolaemic. CT scan revealed a Fisher grade 3 subarachnoid haemorrhage. A ruptured middle cerebral artery was secured 24 hours later. She extubated on day 3 with a GCS of 13, but dropped her GCS to 10 on day 5 and was treated for vasospasm, which included continuing the nimodipine and simvastatin from her admission.

What is the evidence for ‘statins’ for the prevention of Vasospasm in Aneurysmal Subarachnoid Haemorrhage?

Helen Vollmer

Subarachnoid haemorrhage is a common condition and accounts for 5% of all strokes. Despite improved diagnostic imaging and the ability to secure ruptured aneurysms promptly using endovascular techniques, mortality rates remain up to 45% and morbidity is significant. Following aneurysmal SAH, vasospasm is seen angiographically in 30-70% of patients. It typically starts from day 3 post-initial bleed and in half of cases it presents as the occurrence of a delayed neurological ischaemic deficit (DNID), which has a 50% risk of progressing to cerebral infarct. Vasospasm is seen radiologically as the narrowing of large capacitance arteries in the base of the brain, however a direct association between radiological vasospasm and DIND may be overly simplistic.15-20% of patients suffer a stroke or die of vasospasm despite maximal therapy(1,2).

Nimodipine administration is considered a standard of care and has class 1, grade A evidence (an absolute risk reduction of 5.1%). Several RCTs have demonstrated a reduced incidence of vasospasm-associated delayed cerebral infarction (DCI) and poor clinical outcomes (3). However this is believed to be due to neuroprotective mechanisms, possibly by blocking calcium influx at a neuronal level. It has no effects on angiographic vasospasm, probably due to its predilection for small perforating arterioles not large capacitance arteries.

HMG-CoA (3-hydroxy-3-methyl-glutaryl-coenzyme A) reductase inhibitors (“statins”) have become routine in the management of aneurysmal SAH despite them being absent from the Guidelines for the Management of Aneurysmal SAH published by the Stroke Council in 2009(1). They improve endothelial function and upregulate endothelial nitric oxide synthase. They inhibit platelet aggregation, are anti-inflammatory and decrease oxidative stress as well as inhibiting cholesterol synthesis.

There have been several randomised controlled trials of statins versus placebo to look for a reduction in vasospasm(2,3). 3 double blind RCTs in 2005 (Lynch et al, McGirt et al and Tseng et al) demonstrated a significant reduction in the incidence of vasospasm and DCI with the number needed to treat between 5 and 6.7. These were small trials, had different methods of diagnosing vasospasm and heterogeneous primary endpoints. Lynch’s study had a DIND incidence of 60% in the placebo arm which is higher than that found in the literature and only 50% of patients completed the treatment in Tang’s study. Two larger RCTs done by Chou et al and Vergouwen et al in 2008/9(4) were unable to replicate these results and both concluded no benefits from statin use in vasospasm incidence or outcome. Kern et al looked retrospectively at patients, both pre and post the introduction of a unit policy to start pravastatin in all patients admitted with aneurysmal SAH. He failed to find a statistically significant difference in rates of clinical or angiographic vasospasm between the pre- and post-statin era patients(5). There were 135 patients in this cohort study.

A meta-analysis including 4 out of the above 5 studies did not find a statistically significant reduction in vasospasm, DCI or poor outcome (6). However an early meta-analysis in 2008 of the 3 trials available at that point reached the opposite conclusion and supported the routine use of statins in patients with aneurysmal SAH(7). Both had estimates of effect which were similar in size and direction for all outcomes and the confidence intervals were similarly wide. The different conclusions are due to the interpretation. The continued widespread use of statins in SAH may be in part due to the favourable benefit-risk ratio.

Moskowitz et al retrospectively looked at the risk of vasospasm with statin use prior to subarachnoid haemorrhage. Only 8% of the 308 patients were taking a statin medication at presentation. This group was older and more likely to be hypertensive. Hunt and Hess grades and Fisher scores were similar; more of the statin group underwent endovascular coiling instead of surgical clipping. Occurrence of vasospasm was markedly different (23% in statin group v 31%) but did not achieve statistical significance. I was unable to find any further studies looking at statin use prior to SAH, but it would be interesting to see if a study with a larger statin-use group would achieve statistical significance as this might indicate the possibility of long-term statin use having a beneficial effect on vasospasm instead of statins commenced shortly after the presentation of SAH.

The SimvaSTatin in Aneurysmal Subarachnoid Hemorrhage (STASH) trial(2,10), is a multicentre placebo-controlled double blind phase 3 trial, looking at 40mg Simvastatin versus placebo given within 96 hours of SAH over 3 weeks and the incidence and duration of DCI. It is aiming to recruit over 1600 patients by late 2012, which is considerably larger than any of the above studies. It is hoped that this may provide a definitive answer to the role of statins in SAH management.

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References:

1) Bederson J, Connolly E, Batjer H et al. Guidelines for the management of aneurysmal subarachnoid haemorrhage: A statement for healthcare professionals froma a special writing group of the Stroke Council, American Heart Association. Stroke 2009; 40:994-1025
2) Lazaridis C, Naval N. Risk factors and medical management of vasospasm after sub-arachnoid haemorrhage. Neurosurgical Clinics of North America 2010; 21:353-364
3) Velat G, Kimball M, Mocco J et al. Vasospasm after aneurysmal sub-arachnoid haemorrhage: Review of randomised controlled trials and meta-analyses in the literature. World Neurosurgery 2011; 76(5):446-454
4) Kramer A, Fletcher J. Statins in the Management of Patients with Aneurysmal Subarachnoid haemorrhage: A systematic review and meta-analysis. Neurocritical Care 2010; 12(2):285-296
5) Kern M, Lam M, Knuckey N et al. Statins may not protect against vasospasm, in subarachnoid haemorrhage. Journal of Clinical Neuroscience 2009; 16:527-530
6) Vergouwen M, de Haan R, Vermeulen M et al. Effect of statin treatment on vasospasm,delayed cerebral ischaemia and functional outcome in patients with aneurysmal subarachnoid haemorrhage. Stroke 2010; 41:e47-52
7) Sandercock P. ‘Yes’ or ‘No’ to routine statins after subarachnoid haemorrhage to prevent delayed cerebral ischaemia, vasospasm and death? Stroke 2010; 41:e1-e2
8) Al-Tamimi Y, Orsi N, Quinn A et al. A review of delayed ischaemic neurologic deficit following aneurysmal subarachnoid haemorrhage: Historical overview, current treatment and pathophysiology. World neurosurgery 2010; 73(6):654-667
9) Moskowitz S, Ahrens C, Provencio J et al. Prehaemorrhage statin use and the risk of vasospasm after aneurysmal subarachnoid haemorrhage. Surgical Neurology 2009; 71:311-318
10) Kirkpatrick P (CI) http://www.stashtrial.com 2006