Table 3.

Evidence review of drugs used in aneurysmal subarachnoid haemorrhage

Drug	Direct drug action	Possible mechanisms of action	Status	Guidelines [8–10]
Nimodipine [82]	L-type calcium channel antagonist	• Reduction of angiographic vasospasm • Increase in fibrinolytic activity • Neuroprotection • Inhibition of cortical spreading ischaemia	Meta-analysis of clinical trials found that oral nimodipine reduced the risk of DCI and poor outcome.	Class I, level A Nimodipine should be administered enterally (60 mg every 4 hours) to prevent DCI. The only drug approved for SAH in the USA and Europe.
Clazosentan [168]	Endothelin A receptor antagonist	Reduction of angiographic vasospasm	• Four randomised clinical trials and a meta-analysis • Clazosentan reduced angiographic vasospasm without a significant effect on outcome. • Hypotension and pulmonary complications associated with the drug use could have counteracted the beneficial effects of the drug.	Not addressed However, after the publication of the CONSCIOUS trials and following meta-analysis, clazosentan infusion will not be recommended for patients with SAH, as a Class I, level A.
Fasudil [172]	Rho-kinase inhibitor	Reduces smooth muscle contraction and inhibits TNF-induced IL-6 release from C6 glioma cells	• Eight randomised clinical trials • Treatment significantly reduced the incidence of angiographic vasospasm and cerebral infarction and improved the odds ratio for good recovery compared with placebo or nimodipine and other drugs.	Not addressed The drug is approved for use in patients in Japan and China but not in Europe or USA.
Statins [92–94]	Inhibit HMG-CoA reductase	• Preserve endothelial function • Anti-inflammatory effects • Antioxidant • Antithrombotic actions • Vascular protection • Neuroprotective and neurorestorative action	• Seven randomised clinical trials of statins in patients with SAH. • An additional study showing no benefit of higher dose of simvastatin (80 mg versus 40 mg) • One systematic review not including the STASH trial found no effect of statin treatment on poor outcome.	Guidelines published before the STASH trial [92]. The recommendations will probably remain the same to administer statins only if the patient was already receiving them at time of SAH, as a Class I, level A.
Magnesium [90]	Antagonism of calcium channels on vascular smooth muscle	• Vasodilation • Increased endothelial cell prostacyclin • Endothelial protection • Protect the blood–brain barrier • Reduce cerebral oedema • Anticonvulsant (N-methyl-d-aspartate receptor antagonism)	• Seven randomised clinical trials • Meta-analysis reported no effect of magnesium on poor outcome	Class I, level A Magnesium is not recommended for prevention of DCI.
Dantrolene [173]	Inhibits ryanodine receptors	Reduces intracellular calcium release in smooth muscle and may be neuroprotective	• One small dose-escalation study • Dantrolene in a dose of 2.5 mg/kg, administered over the course of 60 minutes, was associated with reduced cerebral blood-flow velocities measured by transcranial Doppler.	Not addressed Remains experimental
Intrathecal thrombolytics (i.e., urokinase and recombinant tissue plasminogen activator) [174]	Fibrinolytic agents	The rapid clearance of subarachnoid clot could reduce angiographic vasospasm and complications, such as cortical spreading ischaemia and microthrombosis.	• Five RCTs and a meta-analysis • Thrombolysis was associated with significant reductions in angiographic vasospasm, delayed neurological deficits, hydrocephalus, and poor outcome.	Not addressed Further trials are needed. Standardisation of techniques and evaluation in a larger study are required.
Antiplatelet drugs [175] • Acetylsalicylic acid • OKY-046 (Cataclot) - selective thromboxane synthetase inhibitor • Dipyridamole • Ticlopidine	Inhibition of platelet aggregation	Inhibition of platelet aggregation	• Seven randomised clinical trials and a meta-analysis found trends toward reduction in poor outcome but also toward increased intracranial haemorrhage. • Only ticlopidine was associated with statistically significant fewer occurrences of a poor outcome (only one small RCT)	Not addressed Further trials are needed. According to the meta-analysis results, treatment with antiplatelet agents to prevent DCI or poor outcome cannot be recommended.
Albumin [176]	Multiple	Neuroprotective	• One open-label dose-escalation trial • Trend toward improved outcome with 1.25 g/kg per day	Not addressed Remains experimental
Erythropoietin [177, 178]	Multiple	• Prevent loss of autoregulation • Reduce angiographic vasospasm • Inhibits apoptosis and stimulates neurogenesis and angiogenesis	• Two RCTs • One negative study and one showing that patients who received erythropoietin had fewer cerebral infarcts, shorter duration of autoregulatory dysfunction, and better clinical outcome.	Not addressed Remains experimental
Cilostazol [179]	Inhibits phosphodiesterase 3	• Antithrombotic • Vasodilatory • Anti-smooth muscle proliferation • Inotropic and chronotropic effects	• One small (109 patients) randomised, single-blind study • Cilostazol significantly reduced angiographic vasospasm, DCI, and cerebral infarction but had no effect on outcome.	Not addressed Remains experimental

CONSCIOUS Clazosentan to Overcome Neurological Ischaemia and Infarction Occurring After Subarachnoid Haemorrhage, DCI delayed cerebral ischaemia, IL-6 interleukin-6, RCT randomised controlled trial, SAH subarachnoid haemorrhage, STASH simvastatin in aneurysmal subarachnoid haemorrhage, TNF tumour necrosis factor