Journal of the Neurological Sciences 340 (2014) 243–244
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Letter to the Editor Cilostazol reduces morbidity but not mortality secondary to cerebral vasospasm following aneurysmal subarachnoid hemorrhage Keywords: Cerebral vasospasm Cilostazol Intracranial aneurysm Stroke Subarachnoid hemorrhage
I have read, with great interest, a recently published article in the Journal of the Neurological Sciences by Niu et al. titled ‘Effect of cilostazol in patients with aneurysmal subarachnoid hemorrhage: A systematic review and meta-analysis’ [1]. In this meta-analysis, the authors analyze the outcomes for 340 patients from four studies (two randomized and two quasi-randomized controlled trials) which evaluated the effect of cilostazol, a phosphodiesterase inhibitor 3 (PDE3) inhibitor, on cerebral vasospasm (CV) and overall outcomes following aneurysmal subarachnoid hemorrhage (aSAH). The total numbers of patients in the cilostazol and control cohorts were 154 and 186, respectively. Of note, the vast majority of patients were treated with surgical clipping (97% of each cohort). Statistical analysis determined that treatment of aSAH patients with cilostazol significantly decreased the rate of symptomatic CV (p b 0.001), severe CV (p = 0.007), CV-related cerebral infarcts (p = 0.001), and poor outcome, defined as modified Rankin Scale score of at least 3 at follow-up (p = 0.011). The mortality rate was similar between the two cohorts (p = 0.552). Based on this meta-analysis, cilostazol appears to reduce CV-related morbidity following aSAH without affecting mortality. The aims of the following discussion are to describe the potential molecular mechanisms of cilostazol and to suggest future studies which may further evaluate its efficacy for aSAH patients. Cilostazol exerts antiplatelet effects by increasing the availability of cyclic adenosine monophosphate (cAMP) via its inhibition of PDE3 which degrades cAMP [2]. The elevated levels of cAMP result in increased activity of protein kinase A (PKA) which mediates the downstream effects of cilostazol. Cilostazol may therefore improve neurological outcomes by reducing the degree of microvascular thrombosis which occurs after aneurysm rupture [3]. In addition to its anticoagulant properties, cilostazol may prevent aSAH-induced vasoconstriction and inflammation. Hashiomoto et al. demonstrated that increased nitric oxide (NO) production by cilostazol treatment of cultured human vascular endothelial cells was mediated by PKA-dependent activation of endothelial NO synthase (eNOS) [4]. The elevated NO production, via eNOS upregulation, results in vasodilation by increasing the activity of guanylyl cyclase. Additionally, Kawanabe et al. showed that cilostazol exerts dual-antagonizing mechanisms on endothelin (ET) by inhibiting ET-induced calcium influx from the extracellular space [5]. Specifically, cilostazol may abrogate ET's potent vasoconstrictive effects and prevent
http://dx.doi.org/10.1016/j.jns.2014.03.017 0022-510X/© 2014 Elsevier B.V. All rights reserved.
ET-induced smooth muscle cell (SMC) proliferation. The link between the anti-inflammatory properties of cilostazol and CV is not well studied, but it may act by altering SMC phenotypic modulation [6]. And while SMC phenotypic modulation has been suggested to be an important component of cerebral aneurysm pathogenesis, its role in CV pathophysiology is poorly defined [7]. Endovascular coiling has been shown to be associated with lower rates of CV compared to clipping [8]. Coiling has also been demonstrated to provide superior outcomes to clipping for the treatment of ruptured aneurysms [9–12]. In a modern prospective trial, cilostazol will need to be assessed in patients undergoing coil embolization of ruptured aneurysms which only comprised 3% of the current study. Given the antiplatelet effects of cilostazol, the risk of hemorrhagic complications associated with post-aSAH intracranial procedures, such as external ventricular drains and ventriculoperitoneal shunts, remains unknown. Furthermore, in the current era of endovascular therapy, where stent-assisted coil embolization and flow-diverting stents are being utilized in the setting of aSAH with increasing frequency, the combined effect of cilostazol with dual antiplatelet therapy (most commonly aspirin and clopidogrel) on post-aSAH hemorrhagic and thromboembolic complications will need to be further explored. A recent meta-analysis by Huang et al. suggested a statistically significant benefit from treatment of aSAH patients with the calcium channel blocker, nicardipine [13]. Therefore, a prospective trial comparing cilostazol to nicardipine for the treatment of aSAHinduced CV may be a valuable and informative study. While the rates of symptomatic cerebral vasospasm (CV) and poor clinical outcomes were significantly lower in the cilostazol cohort compared to the control cohorts, the mortality rates of the two cohorts were similar. As was observed in previous larger trials, such as CONSCIOUS 2 and 3 (phase III clinical trials which evaluated the effect of clazosentan, an ET-1 receptor antagonist, on post-aSAH CV after surgical clipping and endovascular coiling, respectively), there appears to be a dissociation between the short-term radiographic and clinical outcomes and the long-term functional outcomes of patients treated with anti-CV agents [14,15]. The reasons underlying this dissociation remain incompletely understood, but emerging evidence supports causes of aSAH-induced delayed cerebral ischemic (DCI) unrelated to CV [16]. Impaired autoregulation and global neuronal apoptosis are potentially significant causes of CV-independent DCI [17]. Until the pathophysiology of vasospasm is further elucidated, it will be difficult to develop targeted therapies for this disease process. It is likely that, in addition to preventing or attenuating vasospasm, novel therapies will need to afford neuroprotection or abrogate dysregulation of cerebral hemodynamics in order to effectively prevent aSAH-induced DCI [18]. Additionally, studies with longer follow-up durations and more detailed functional measurements will be necessary to determine the effect of cilostazol on neurocognitive outcomes following aSAH [19].
Conflict of interest None
244
Letter to the Editor
References [1] Niu PP, Yang G, Xing YQ, Guo ZN, Yang Y. Effect of cilostazol in patients with aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis. J Neurol Sci 2014;336(1–2):146–51. [2] Rao AK, Vaidyula VR, Bagga S, Jalagadugula G, Gaughan J, Wilhite DB, et al. Effect of antiplatelet agents clopidogrel, aspirin, and cilostazol on circulating tissue factor procoagulant activity in patients with peripheral arterial disease. Thromb Haemost 2006;96(6):738–43. [3] Stein SC, Browne KD, Chen XH, Smith DH, Graham DI. Thromboembolism and delayed cerebral ischemia after subarachnoid hemorrhage: an autopsy study. Neurosurgery 2006;59(4):781–7 [discussion 787–8]. [4] Hashimoto A, Miyakoda G, Hirose Y, Mori T. Activation of endothelial nitric oxide synthase by cilostazol via a cAMP/protein kinase A- and phosphatidylinositol 3-kinase/Akt-dependent mechanism. Atherosclerosis 2006;189(2):350–7. [5] Kawanabe Y, Takahashi M, Jin X, Abdul-Majeed S, Nauli AM, Sari Y, et al. Cilostazol prevents endothelin-induced smooth muscle constriction and proliferation. PLoS One 2012;7(9):e44476. [6] Shimamura N, Ohkuma H. Phenotypic transformation of smooth muscle in vasospasm after aneurysmal subarachnoid hemorrhage. Transl Stroke Res 2013 (Electronic publication ahead of print 2013 Nov 20). [7] Starke RM, Chalouhi N, Ding D, Raper DM, McKisic MS, Owens GK, et al. Vascular smooth muscle cells in cerebral aneurysm pathogenesis. Transl Stroke Res 2013 (Electronic publication ahead of print 2013 Oct 10). [8] Gross BA, Rosalind Lai PM, Frerichs KU, Du R. Treatment modality and vasospasm after aneurysmal subarachnoid hemorrhage. World Neurosurg 2013 (Electronic publication ahead of print 2013 Aug 14). [9] Molyneux A, Kerr R, Stratton I, Sandercock P, Clarke M, Shrimpton J, et al. International subarachnoid aneurysm trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised trial. Lancet 2002;360(9342):1267–74. [10] McDougall CG, Spetzler RF, Zabramski JM, Partovi S, Hills NK, Nakaji P, et al. The barrow ruptured aneurysm trial. J Neurosurg 2012;116(1):135–44. [11] Spetzler RF, McDougall CG, Albuquerque FC, Zabramski JM, Hills NK, Partovi S, et al. The barrow ruptured aneurysm trial: 3-year results. J Neurosurg 2013;119(1):146–57.
[12] Li H, Pan R, Wang H, Rong X, Yin Z, Milgrom DP, et al. Clipping versus coiling for ruptured intracranial aneurysms: a systematic review and meta-analysis. Stroke 2013;44(1):29–37. [13] Huang RQ, Jiang FG, Feng ZM, Wang TY. Nicardipine in the treatment of aneurysmal subarachnoid haemorrhage: a meta-analysis of published data. Acta Neurol Belg 2013;113(1):3–6. [14] Macdonald RL, Higashida RT, Keller E, Mayer SA, Molyneux A, Raabe A, et al. Randomized trial of clazosentan in patients with aneurysmal subarachnoid hemorrhage undergoing endovascular coiling. Stroke 2012;43(6):1463–9. [15] Macdonald RL, Higashida RT, Keller E, Mayer SA, Molyneux A, Raabe A, et al. Clazosentan, an endothelin receptor antagonist, in patients with aneurysmal subarachnoid haemorrhage undergoing surgical clipping: a randomised, double-blind, placebo-controlled phase 3 trial (CONSCIOUS-2). Lancet Neurol 2011;10(7):618–25. [16] Macdonald RL, Pluta RM, Zhang JH. Cerebral vasospasm after subarachnoid hemorrhage: the emerging revolution. Nat Clin Pract Neurol 2007;3(5):256–63. [17] Budohoski KP, Czosnyka M, Kirkpatrick PJ, Smielewski P, Steiner LA, Pickard JD. Clinical relevance of cerebral autoregulation following subarachnoid haemorrhage. Nat Rev Neurol 2013;9(3):152–63. [18] Macdonald RL. Delayed neurological deterioration after subarachnoid haemorrhage. Nat Rev Neurol 2014;10(1):44–58. [19] Mayer SA, Kreiter KT, Copeland D, Bernardini GL, Bates JE, Peery S, et al. Global and domain-specific cognitive impairment and outcome after subarachnoid hemorrhage. Neurology 2002;59(11):1750–8.
Dale Ding University of Virginia, Department of Neurological Surgery, P.O. Box 800212 Charlottesville, VA 22908, United States Tel.: +1 434 924 2203; fax: +1 434 243 6726. E-mail address: [email protected]. 27 January 2014
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Letter to the Editor Cilostazol reduces morbidity but not mortality secondary to cerebral vasospasm following aneurysmal subarachnoid hemorrhage Keywords: Cerebral vasospasm Cilostazol Intracranial aneurysm Stroke Subarachnoid hemorrhage
I have read, with great interest, a recently published article in the Journal of the Neurological Sciences by Niu et al. titled ‘Effect of cilostazol in patients with aneurysmal subarachnoid hemorrhage: A systematic review and meta-analysis’ [1]. In this meta-analysis, the authors analyze the outcomes for 340 patients from four studies (two randomized and two quasi-randomized controlled trials) which evaluated the effect of cilostazol, a phosphodiesterase inhibitor 3 (PDE3) inhibitor, on cerebral vasospasm (CV) and overall outcomes following aneurysmal subarachnoid hemorrhage (aSAH). The total numbers of patients in the cilostazol and control cohorts were 154 and 186, respectively. Of note, the vast majority of patients were treated with surgical clipping (97% of each cohort). Statistical analysis determined that treatment of aSAH patients with cilostazol significantly decreased the rate of symptomatic CV (p b 0.001), severe CV (p = 0.007), CV-related cerebral infarcts (p = 0.001), and poor outcome, defined as modified Rankin Scale score of at least 3 at follow-up (p = 0.011). The mortality rate was similar between the two cohorts (p = 0.552). Based on this meta-analysis, cilostazol appears to reduce CV-related morbidity following aSAH without affecting mortality. The aims of the following discussion are to describe the potential molecular mechanisms of cilostazol and to suggest future studies which may further evaluate its efficacy for aSAH patients. Cilostazol exerts antiplatelet effects by increasing the availability of cyclic adenosine monophosphate (cAMP) via its inhibition of PDE3 which degrades cAMP [2]. The elevated levels of cAMP result in increased activity of protein kinase A (PKA) which mediates the downstream effects of cilostazol. Cilostazol may therefore improve neurological outcomes by reducing the degree of microvascular thrombosis which occurs after aneurysm rupture [3]. In addition to its anticoagulant properties, cilostazol may prevent aSAH-induced vasoconstriction and inflammation. Hashiomoto et al. demonstrated that increased nitric oxide (NO) production by cilostazol treatment of cultured human vascular endothelial cells was mediated by PKA-dependent activation of endothelial NO synthase (eNOS) [4]. The elevated NO production, via eNOS upregulation, results in vasodilation by increasing the activity of guanylyl cyclase. Additionally, Kawanabe et al. showed that cilostazol exerts dual-antagonizing mechanisms on endothelin (ET) by inhibiting ET-induced calcium influx from the extracellular space [5]. Specifically, cilostazol may abrogate ET's potent vasoconstrictive effects and prevent
http://dx.doi.org/10.1016/j.jns.2014.03.017 0022-510X/© 2014 Elsevier B.V. All rights reserved.
ET-induced smooth muscle cell (SMC) proliferation. The link between the anti-inflammatory properties of cilostazol and CV is not well studied, but it may act by altering SMC phenotypic modulation [6]. And while SMC phenotypic modulation has been suggested to be an important component of cerebral aneurysm pathogenesis, its role in CV pathophysiology is poorly defined [7]. Endovascular coiling has been shown to be associated with lower rates of CV compared to clipping [8]. Coiling has also been demonstrated to provide superior outcomes to clipping for the treatment of ruptured aneurysms [9–12]. In a modern prospective trial, cilostazol will need to be assessed in patients undergoing coil embolization of ruptured aneurysms which only comprised 3% of the current study. Given the antiplatelet effects of cilostazol, the risk of hemorrhagic complications associated with post-aSAH intracranial procedures, such as external ventricular drains and ventriculoperitoneal shunts, remains unknown. Furthermore, in the current era of endovascular therapy, where stent-assisted coil embolization and flow-diverting stents are being utilized in the setting of aSAH with increasing frequency, the combined effect of cilostazol with dual antiplatelet therapy (most commonly aspirin and clopidogrel) on post-aSAH hemorrhagic and thromboembolic complications will need to be further explored. A recent meta-analysis by Huang et al. suggested a statistically significant benefit from treatment of aSAH patients with the calcium channel blocker, nicardipine [13]. Therefore, a prospective trial comparing cilostazol to nicardipine for the treatment of aSAHinduced CV may be a valuable and informative study. While the rates of symptomatic cerebral vasospasm (CV) and poor clinical outcomes were significantly lower in the cilostazol cohort compared to the control cohorts, the mortality rates of the two cohorts were similar. As was observed in previous larger trials, such as CONSCIOUS 2 and 3 (phase III clinical trials which evaluated the effect of clazosentan, an ET-1 receptor antagonist, on post-aSAH CV after surgical clipping and endovascular coiling, respectively), there appears to be a dissociation between the short-term radiographic and clinical outcomes and the long-term functional outcomes of patients treated with anti-CV agents [14,15]. The reasons underlying this dissociation remain incompletely understood, but emerging evidence supports causes of aSAH-induced delayed cerebral ischemic (DCI) unrelated to CV [16]. Impaired autoregulation and global neuronal apoptosis are potentially significant causes of CV-independent DCI [17]. Until the pathophysiology of vasospasm is further elucidated, it will be difficult to develop targeted therapies for this disease process. It is likely that, in addition to preventing or attenuating vasospasm, novel therapies will need to afford neuroprotection or abrogate dysregulation of cerebral hemodynamics in order to effectively prevent aSAH-induced DCI [18]. Additionally, studies with longer follow-up durations and more detailed functional measurements will be necessary to determine the effect of cilostazol on neurocognitive outcomes following aSAH [19].
Conflict of interest None
244
Letter to the Editor
References [1] Niu PP, Yang G, Xing YQ, Guo ZN, Yang Y. Effect of cilostazol in patients with aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis. J Neurol Sci 2014;336(1–2):146–51. [2] Rao AK, Vaidyula VR, Bagga S, Jalagadugula G, Gaughan J, Wilhite DB, et al. Effect of antiplatelet agents clopidogrel, aspirin, and cilostazol on circulating tissue factor procoagulant activity in patients with peripheral arterial disease. Thromb Haemost 2006;96(6):738–43. [3] Stein SC, Browne KD, Chen XH, Smith DH, Graham DI. Thromboembolism and delayed cerebral ischemia after subarachnoid hemorrhage: an autopsy study. Neurosurgery 2006;59(4):781–7 [discussion 787–8]. [4] Hashimoto A, Miyakoda G, Hirose Y, Mori T. Activation of endothelial nitric oxide synthase by cilostazol via a cAMP/protein kinase A- and phosphatidylinositol 3-kinase/Akt-dependent mechanism. Atherosclerosis 2006;189(2):350–7. [5] Kawanabe Y, Takahashi M, Jin X, Abdul-Majeed S, Nauli AM, Sari Y, et al. Cilostazol prevents endothelin-induced smooth muscle constriction and proliferation. PLoS One 2012;7(9):e44476. [6] Shimamura N, Ohkuma H. Phenotypic transformation of smooth muscle in vasospasm after aneurysmal subarachnoid hemorrhage. Transl Stroke Res 2013 (Electronic publication ahead of print 2013 Nov 20). [7] Starke RM, Chalouhi N, Ding D, Raper DM, McKisic MS, Owens GK, et al. Vascular smooth muscle cells in cerebral aneurysm pathogenesis. Transl Stroke Res 2013 (Electronic publication ahead of print 2013 Oct 10). [8] Gross BA, Rosalind Lai PM, Frerichs KU, Du R. Treatment modality and vasospasm after aneurysmal subarachnoid hemorrhage. World Neurosurg 2013 (Electronic publication ahead of print 2013 Aug 14). [9] Molyneux A, Kerr R, Stratton I, Sandercock P, Clarke M, Shrimpton J, et al. International subarachnoid aneurysm trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised trial. Lancet 2002;360(9342):1267–74. [10] McDougall CG, Spetzler RF, Zabramski JM, Partovi S, Hills NK, Nakaji P, et al. The barrow ruptured aneurysm trial. J Neurosurg 2012;116(1):135–44. [11] Spetzler RF, McDougall CG, Albuquerque FC, Zabramski JM, Hills NK, Partovi S, et al. The barrow ruptured aneurysm trial: 3-year results. J Neurosurg 2013;119(1):146–57.
[12] Li H, Pan R, Wang H, Rong X, Yin Z, Milgrom DP, et al. Clipping versus coiling for ruptured intracranial aneurysms: a systematic review and meta-analysis. Stroke 2013;44(1):29–37. [13] Huang RQ, Jiang FG, Feng ZM, Wang TY. Nicardipine in the treatment of aneurysmal subarachnoid haemorrhage: a meta-analysis of published data. Acta Neurol Belg 2013;113(1):3–6. [14] Macdonald RL, Higashida RT, Keller E, Mayer SA, Molyneux A, Raabe A, et al. Randomized trial of clazosentan in patients with aneurysmal subarachnoid hemorrhage undergoing endovascular coiling. Stroke 2012;43(6):1463–9. [15] Macdonald RL, Higashida RT, Keller E, Mayer SA, Molyneux A, Raabe A, et al. Clazosentan, an endothelin receptor antagonist, in patients with aneurysmal subarachnoid haemorrhage undergoing surgical clipping: a randomised, double-blind, placebo-controlled phase 3 trial (CONSCIOUS-2). Lancet Neurol 2011;10(7):618–25. [16] Macdonald RL, Pluta RM, Zhang JH. Cerebral vasospasm after subarachnoid hemorrhage: the emerging revolution. Nat Clin Pract Neurol 2007;3(5):256–63. [17] Budohoski KP, Czosnyka M, Kirkpatrick PJ, Smielewski P, Steiner LA, Pickard JD. Clinical relevance of cerebral autoregulation following subarachnoid haemorrhage. Nat Rev Neurol 2013;9(3):152–63. [18] Macdonald RL. Delayed neurological deterioration after subarachnoid haemorrhage. Nat Rev Neurol 2014;10(1):44–58. [19] Mayer SA, Kreiter KT, Copeland D, Bernardini GL, Bates JE, Peery S, et al. Global and domain-specific cognitive impairment and outcome after subarachnoid hemorrhage. Neurology 2002;59(11):1750–8.
Dale Ding University of Virginia, Department of Neurological Surgery, P.O. Box 800212 Charlottesville, VA 22908, United States Tel.: +1 434 924 2203; fax: +1 434 243 6726. E-mail address: [email protected]. 27 January 2014
