Correspondence
3
4
Bergman P, Adori C, Vas S, et al. Narcolepsy patients have antibodies that stain distinct cell populations in rat brain and influence sleep patterns. Proc Natl Acad Sci USA 2014; 111: E3735–44. Katzav A, Arango MT, Kivity S, et al. Passive transfer of narcolepsy: anti-TRIB2 autoantibody positive patient IgG causes hypothalamic orexin neuron loss and sleep attacks in mice. J Autoimmun 2013; 45: 24–30.
Simvastatin in subarachnoid haemorrhage: beyond the short-term We are grateful to the STASH trial1 investigators for their efforts to advance the use of simvastatin in subarachnoid haemorrhage from bench to bedside. The results of the STASH trial do not support the use of 40 mg simvastatin daily to decrease delayed cerebral infarction and to improve long-term clinical outcome. The investigators, therefore, concluded that patients with subarachnoid haemorrhage should not be treated routinely with simvastatin. Unfortunately, the STASH trial and a similar study by Wong and colleagues2 underway to evaluate a dose of simvastatin higher than that used in STASH were not designed to evaluate neurocognitive outcomes. Cognitive dysfunction, such as memory deficits and executive dysfunction, is increasingly recognised as an important, and perhaps even the most prevalent, long-term complication of subarachnoid haemorrhage.3,4 We are also concerned that the length of the treatment period—up to 3 weeks—was not sufficient to investigate potential benefits of simvastatin on outcomes after subarachnoid haemorrhage. The pathophysiology of subarachnoid haemorrhage is poorly understood, as is our understanding of the duration of action of underlying mechanisms. Ischaemic stroke (eg, delayed cerebral infarction after subarachnoid haemorrhage) results in microglial activation that might persist for several
months, potentially increasing brain injury;5 and endothelial injury can be observed throughout the arterial tree for months after subarachnoid haemorrhage.6 In our opinion, it would be reasonable to continue treatment with simvastatin until the damaged thrombogenic and dysfunctional cerebrovascular endothelium has recovered fully and the neuroinflammatory responses have subsided. In fact, experimental studies that replicate cognitive decline in subarachnoid haemorrhage show that the beneficial effects of simvastatin on regional cerebral blood flow, motor function, cognitive function, and neuroprotection are forfeited when simvastatin is stopped after 2 weeks of treatment. A sustained improvement in cognitive function and neuronal survival was shown only when simvastatin administration was extended for the duration of the study7 (6 weeks). Although the STASH trial investigators report that simvastatin at a dose of 40 mg for up to 3 weeks did not prevent delayed cerebral infarction, it is unclear whether longer use could improve long-term outcomes. Statins are well tolerated with long-term use. Perhaps it is time to depart from the 2–3 week cerebral vasospasm treatment paradigm, and extend the treatment period in clinical trials of interventions for subarachnoid haemorrhage. Otherwise, we risk false negatives and might prematurely discard potentially useful treatments. We declare no competing interests.
*Frederick Lombard, Gavin W Britz, David S Warner [email protected] Duke University, NC 27705, USA 1
2
www.thelancet.com/neurology Vol 13 November 2014
Kirkpatrick PJ, MSc CLT, Turner CL, Hutchinson PJ, Murray GD, STASH Collaborators FTS. Simvastatin in aneurysmal subarachnoid haemorrhage (STASH): a multicentre randomised phase 3 trial. Lancet Neurol 2014; 13: 666–75. Wong GKC, Liang M, Tan H, et al. High-dose simvastatin for aneurysmal subarachnoid hemorrhage: a multicenter, randomized, controlled, double-blind clinical trial protocol. Neurosurgery 2013; 72: 840–44.
3
4
5 6
7
Anderson SW, Todd MM, Hindman BJ, et al. Effects of intraoperative hypothermia on neuropsychological outcomes after intracranial aneurysm surgery. Ann Neurol 2006; 60: 518–27. Al-Khindi T, Macdonald RL, Schweizer TA. Cognitive and functional outcome after aneurysmal subarachnoid hemorrhage. Stroke 2010; 41: e519–36. Thiel A, Heiss WD. Imaging of microglia activation in stroke. Stroke 2011; 42: 507–12. Hughes JT, Schianchi PM. Cerebral artery spasm. A histological study at necropsy of the blood vessels in cases of subarachnoid hemorrhage. J Neurosurg 1978; 48: 515–25. Takata K, Lombard FW, Sheng H, Laskowitz D, Borel CO, Warner DS. A rat model of cerebral vasospasm resulting in chronic motor and neurocognitive deficits following experimental SAH. J Neurosurg Anesthesiol 2006; 18: 295–301.
Authors’ reply We welcome the comments by Frederick Lombard and colleagues in relation to the publication of results from the STASH trial.1 An important issue is raised of neurocognitive deficits after subarachnoid haemorrhage, which are often apparent despite a seemingly good physical outcome. The Rankin Disability Scale does not evaluate cognitive outcome but it is unusual in our experience for patients with severe cognitive impairment to fall into the category of a good outcome in terms of their mRS score. Although we did not do cognitive assessments in the STASH trial, we used the well characterised SF-36 questionnaire, which does substantially explore non-physical outcomes. Data for 656 patients did not show any significant differences in the mental, physical, or overall scores of those receiving statin therapy compared with patients receiving placebo. The details of these assessments are the subject of further post-hoc analyses to be published . Lombard and colleagues also invite commentary with respect to the duration of drug administration in trials of subarachnoid haemorrhage. Although concern exists that the processes involved in tissue damage after subarachnoid haemorrhage might be ongoing for some weeks after the ictus, most patients who 1073
Correspondence
have had a subarachnoid haemorrhage and are discharged rarely return with a worsening clinical picture. Patients with post-subarachnoid haemorrhage hydrocephalus and progressive cognitive decline in the weeks after a subarachnoid haemorrhage are rare.1 Prolonged therapy with simvastatin is, therefore, unlikely to yield a difference in outcome when compared with the
1074
results of the STASH trial, with respect to cognition or otherwise. Targeted trials might, however, formally answer this question.
1
We declare no competing interests.
2
Peter J Kirkpatrick, *Carole L Turner
Kirkpatrick PJ, Turner CL, Hutchinson PJ, Murray GD, for the STASH Collaborators. Simvastatin in aneurysmal subarachnoid haemorrhage (STASH): a multicentre randomised phase 3 trial. Lancet Neurol 2014; 13: 666–75. van Gijn J, Rinkel GJE. Subarachnoid haemorrhage: diagnosis, causes and management. Brain 2001, 124: 249–78.
[email protected] Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK (PJK, CT)
www.thelancet.com/neurology Vol 13 November 2014
3
4
Bergman P, Adori C, Vas S, et al. Narcolepsy patients have antibodies that stain distinct cell populations in rat brain and influence sleep patterns. Proc Natl Acad Sci USA 2014; 111: E3735–44. Katzav A, Arango MT, Kivity S, et al. Passive transfer of narcolepsy: anti-TRIB2 autoantibody positive patient IgG causes hypothalamic orexin neuron loss and sleep attacks in mice. J Autoimmun 2013; 45: 24–30.
Simvastatin in subarachnoid haemorrhage: beyond the short-term We are grateful to the STASH trial1 investigators for their efforts to advance the use of simvastatin in subarachnoid haemorrhage from bench to bedside. The results of the STASH trial do not support the use of 40 mg simvastatin daily to decrease delayed cerebral infarction and to improve long-term clinical outcome. The investigators, therefore, concluded that patients with subarachnoid haemorrhage should not be treated routinely with simvastatin. Unfortunately, the STASH trial and a similar study by Wong and colleagues2 underway to evaluate a dose of simvastatin higher than that used in STASH were not designed to evaluate neurocognitive outcomes. Cognitive dysfunction, such as memory deficits and executive dysfunction, is increasingly recognised as an important, and perhaps even the most prevalent, long-term complication of subarachnoid haemorrhage.3,4 We are also concerned that the length of the treatment period—up to 3 weeks—was not sufficient to investigate potential benefits of simvastatin on outcomes after subarachnoid haemorrhage. The pathophysiology of subarachnoid haemorrhage is poorly understood, as is our understanding of the duration of action of underlying mechanisms. Ischaemic stroke (eg, delayed cerebral infarction after subarachnoid haemorrhage) results in microglial activation that might persist for several
months, potentially increasing brain injury;5 and endothelial injury can be observed throughout the arterial tree for months after subarachnoid haemorrhage.6 In our opinion, it would be reasonable to continue treatment with simvastatin until the damaged thrombogenic and dysfunctional cerebrovascular endothelium has recovered fully and the neuroinflammatory responses have subsided. In fact, experimental studies that replicate cognitive decline in subarachnoid haemorrhage show that the beneficial effects of simvastatin on regional cerebral blood flow, motor function, cognitive function, and neuroprotection are forfeited when simvastatin is stopped after 2 weeks of treatment. A sustained improvement in cognitive function and neuronal survival was shown only when simvastatin administration was extended for the duration of the study7 (6 weeks). Although the STASH trial investigators report that simvastatin at a dose of 40 mg for up to 3 weeks did not prevent delayed cerebral infarction, it is unclear whether longer use could improve long-term outcomes. Statins are well tolerated with long-term use. Perhaps it is time to depart from the 2–3 week cerebral vasospasm treatment paradigm, and extend the treatment period in clinical trials of interventions for subarachnoid haemorrhage. Otherwise, we risk false negatives and might prematurely discard potentially useful treatments. We declare no competing interests.
*Frederick Lombard, Gavin W Britz, David S Warner [email protected] Duke University, NC 27705, USA 1
2
www.thelancet.com/neurology Vol 13 November 2014
Kirkpatrick PJ, MSc CLT, Turner CL, Hutchinson PJ, Murray GD, STASH Collaborators FTS. Simvastatin in aneurysmal subarachnoid haemorrhage (STASH): a multicentre randomised phase 3 trial. Lancet Neurol 2014; 13: 666–75. Wong GKC, Liang M, Tan H, et al. High-dose simvastatin for aneurysmal subarachnoid hemorrhage: a multicenter, randomized, controlled, double-blind clinical trial protocol. Neurosurgery 2013; 72: 840–44.
3
4
5 6
7
Anderson SW, Todd MM, Hindman BJ, et al. Effects of intraoperative hypothermia on neuropsychological outcomes after intracranial aneurysm surgery. Ann Neurol 2006; 60: 518–27. Al-Khindi T, Macdonald RL, Schweizer TA. Cognitive and functional outcome after aneurysmal subarachnoid hemorrhage. Stroke 2010; 41: e519–36. Thiel A, Heiss WD. Imaging of microglia activation in stroke. Stroke 2011; 42: 507–12. Hughes JT, Schianchi PM. Cerebral artery spasm. A histological study at necropsy of the blood vessels in cases of subarachnoid hemorrhage. J Neurosurg 1978; 48: 515–25. Takata K, Lombard FW, Sheng H, Laskowitz D, Borel CO, Warner DS. A rat model of cerebral vasospasm resulting in chronic motor and neurocognitive deficits following experimental SAH. J Neurosurg Anesthesiol 2006; 18: 295–301.
Authors’ reply We welcome the comments by Frederick Lombard and colleagues in relation to the publication of results from the STASH trial.1 An important issue is raised of neurocognitive deficits after subarachnoid haemorrhage, which are often apparent despite a seemingly good physical outcome. The Rankin Disability Scale does not evaluate cognitive outcome but it is unusual in our experience for patients with severe cognitive impairment to fall into the category of a good outcome in terms of their mRS score. Although we did not do cognitive assessments in the STASH trial, we used the well characterised SF-36 questionnaire, which does substantially explore non-physical outcomes. Data for 656 patients did not show any significant differences in the mental, physical, or overall scores of those receiving statin therapy compared with patients receiving placebo. The details of these assessments are the subject of further post-hoc analyses to be published . Lombard and colleagues also invite commentary with respect to the duration of drug administration in trials of subarachnoid haemorrhage. Although concern exists that the processes involved in tissue damage after subarachnoid haemorrhage might be ongoing for some weeks after the ictus, most patients who 1073
Correspondence
have had a subarachnoid haemorrhage and are discharged rarely return with a worsening clinical picture. Patients with post-subarachnoid haemorrhage hydrocephalus and progressive cognitive decline in the weeks after a subarachnoid haemorrhage are rare.1 Prolonged therapy with simvastatin is, therefore, unlikely to yield a difference in outcome when compared with the
1074
results of the STASH trial, with respect to cognition or otherwise. Targeted trials might, however, formally answer this question.
1
We declare no competing interests.
2
Peter J Kirkpatrick, *Carole L Turner
Kirkpatrick PJ, Turner CL, Hutchinson PJ, Murray GD, for the STASH Collaborators. Simvastatin in aneurysmal subarachnoid haemorrhage (STASH): a multicentre randomised phase 3 trial. Lancet Neurol 2014; 13: 666–75. van Gijn J, Rinkel GJE. Subarachnoid haemorrhage: diagnosis, causes and management. Brain 2001, 124: 249–78.
[email protected] Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK (PJK, CT)
www.thelancet.com/neurology Vol 13 November 2014
