Skip to main content

Advertisement

SpringerLink
Log in

Comparison of efficacy between clazosentan and fasudil hydrochloride-based management of vasospasm after subarachnoid hemorrhage focusing on older and WFNS grade V patients: a single-center experience in Japan

  • Research
  • Published:
Neurosurgical Review Aims and scope Submit manuscript

Abstract

Subarachnoid hemorrhage often leads to poor outcomes owing to vasospasm, even after successful aneurysm treatment. Clazosentan, an endothelin receptor inhibitor, has been proven to be an effective treatment for vasospasms in a Japanese randomized controlled trial. However, its efficacy in older patients (≥ 75 years old) and those with World Federation of Neurosurgical Societies (WFNS) grade V has not been demonstrated. We retrospectively evaluated the efficacy of clazosentan in older patients and those with WFNS grade V, using real-world data. Patients with subarachnoid hemorrhage treated before and after the introduction of clazosentan were retrospectively evaluated. The patients were categorized into two groups (clazosentan era versus pre-clazosentan era), in which vasospasm management and outcomes were compared. Vasospasms were managed with fasudil hydrochloride-based (pre-clazosentan era) or clazosentan-based treatment (clazosentan era). Seventy-eight patients were included in this study: the clazosentan era (n = 32) and pre-clazosentan era (n = 46). Overall, clazosentan significantly reduced clinical vasospasms (clazosentan era: 31.3% versus pre-clazosentan era: 60.9%, p = 0.01), delayed cerebral ischemia (DCI) (9.4% versus 39.1%, p = 0.004), and vasospasm-related morbidity and mortality (M/M) (3.1% versus 19.6%, p = 0.03). In subgroup analysis of older patients or those with WFNS grade V, no significant difference was observed in clinical outcomes, although both DCI and vasospasm-related M/M were lower in the clazosentan era. Clazosentan was more effective than fasudil-based management in preventing DCI and reducing vasospasm-related M/M. Clazosentan could be used safely in older patients and those with WFNS grade V, although clinical outcomes in these patients were comparable to those of conventional treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Data availability

No datasets were generated or analysed during the current study.

References

  1. Akamatsu Y, Chida K, Miyoshi K, Kojima D, Nomura J-I, Setta K, Chiba T, Koji T, Fujiwara S, Kashimura H, Kubo Y, Ogasawara K (2023) Fluid balance management with loop diuretics in patients with aneurysmal subarachnoid hemorrhage treated with clazosentan: a case series. Brain Hemorrhages. https://doi.org/10.1016/j.hest.2023.10.003

    Article  Google Scholar 

  2. Barker FG 2nd, Ogilvy CS (1996) Efficacy of prophylactic nimodipine for delayed ischemic deficit after subarachnoid hemorrhage: a metaanalysis. J Neurosurg 84:405–414. https://doi.org/10.3171/jns.1996.84.3.0405

  3. Bauer AM, Rasmussen PA (2014) Treatment of intracranial vasospasm following subarachnoid hemorrhage. Front Neurol 5:72. https://doi.org/10.3389/fneur.2014.00072

    Article  PubMed  PubMed Central  Google Scholar 

  4. Chiang VL, Claus EB, Awad IA (2000) Toward more rational prediction of outcome in patients with high-grade subarachnoid hemorrhage. Neurosurgery 46:28–35 discussion 35 – 26

    Article  CAS  PubMed  Google Scholar 

  5. Davenport AP, Hyndman KA, Dhaun N, Southan C, Kohan DE, Pollock JS, Pollock DM, Webb DJ, Maguire JJ (2016) Endothelin Pharmacol Rev 68:357–418. https://doi.org/10.1124/pr.115.011833

    Article  PubMed  Google Scholar 

  6. Endo H, Hagihara Y, Kimura N, Takizawa K, Niizuma K, Togo O, Tominaga T (2022) Effects of clazosentan on cerebral vasospasm-related morbidity and all-cause mortality after aneurysmal subarachnoid hemorrhage: two randomized phase 3 trials in Japanese patients. J Neurosurg 137:1707–1717. https://doi.org/10.3171/2022.2.Jns212914

    Article  CAS  PubMed  Google Scholar 

  7. Etminan N, Vergouwen MD, Ilodigwe D, Macdonald RL (2011) Effect of pharmaceutical treatment on vasospasm, delayed cerebral ischemia, and clinical outcome in patients with aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis. J Cereb Blood Flow Metab 31:1443–1451. https://doi.org/10.1038/jcbfm.2011.7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Francoeur CL, Mayer SA (2016) Management of delayed cerebral ischemia after subarachnoid hemorrhage. Crit Care 20:277. https://doi.org/10.1186/s13054-016-1447-6

    Article  PubMed  PubMed Central  Google Scholar 

  9. Fujimura M, Joo JY, Kim JS, Hatta M, Yokoyama Y, Tominaga T (2017) Preventive effect of Clazosentan against Cerebral Vasospasm after clipping surgery for Aneurysmal Subarachnoid hemorrhage in Japanese and Korean patients. Cerebrovasc Dis 44:59–67. https://doi.org/10.1159/000475824

    Article  CAS  PubMed  Google Scholar 

  10. Ibrahim GM, Macdonald RL (2013) The effects of fluid balance and colloid administration on outcomes in patients with aneurysmal subarachnoid hemorrhage: a propensity score-matched analysis. Neurocrit Care 19:140–149. https://doi.org/10.1007/s12028-013-9860-z

    Article  CAS  PubMed  Google Scholar 

  11. Ido K, Kurogi R, Kurogi A, Nishimura K, Arimura K, Nishimura A, Ren N, Kada A, Matsuo R, Onozuka D, Hagihara A, Takagishi S, Yamagami K, Takegami M, Nohara Y, Nakashima N, Kamouchi M, Date I, Kitazono T, Iihara K (2020) Effect of treatment modality and cerebral vasospasm agent on patient outcomes after aneurysmal subarachnoid hemorrhage in the elderly aged 75 years and older. PLoS ONE 15:e0230953. https://doi.org/10.1371/journal.pone.0230953

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Japan Stroke Society (2023) Guideline 2021 for the treatment of stroke [Revised version 2023]. In. KYOWA KIKAKU, Tokyo, p 171

    Google Scholar 

  13. Kusaka G, Ishikawa M, Nanda A, Granger DN, Zhang JH (2004) Signaling pathways for early brain injury after subarachnoid hemorrhage. J Cereb Blood Flow Metab 24:916–925. https://doi.org/10.1097/01.Wcb.0000125886.48838.7e

    Article  CAS  PubMed  Google Scholar 

  14. Lennihan L, Mayer SA, Fink ME, Beckford A, Paik MC, Zhang H, Wu YC, Klebanoff LM, Raps EC, Solomon RA (2000) Effect of hypervolemic therapy on cerebral blood flow after subarachnoid hemorrhage: a randomized controlled trial. Stroke 31:383–391. https://doi.org/10.1161/01.str.31.2.383

    Article  CAS  PubMed  Google Scholar 

  15. Macdonald RL, Kassell NF, Mayer S, Ruefenacht D, Schmiedek P, Weidauer S, Frey A, Roux S, Pasqualin A (2008) Clazosentan to overcome neurological ischemia and infarction occurring after subarachnoid hemorrhage (CONSCIOUS-1): randomized, double-blind, placebo-controlled phase 2 dose-finding trial. Stroke 39:3015–3021. https://doi.org/10.1161/strokeaha.108.519942

    Article  CAS  PubMed  Google Scholar 

  16. Macdonald RL, Higashida RT, Keller E, Mayer SA, Molyneux A, Raabe A, Vajkoczy P, Wanke I, Bach D, Frey A, Nowbakht P, Roux S, Kassell N (2012) Randomized trial of clazosentan in patients with aneurysmal subarachnoid hemorrhage undergoing endovascular coiling. Stroke 43:1463–1469. https://doi.org/10.1161/strokeaha.111.648980

    Article  CAS  PubMed  Google Scholar 

  17. Maeda T, Okawara M, Osakabe M, Yamaguchi H, Maeda T, Kurita H (2024) Initial real-world experience of clazosentan for subarachnoid hemorrhage in Japan. World Neurosurg X 21:100253. https://doi.org/10.1016/j.wnsx.2023.100253

    Article  PubMed  Google Scholar 

  18. Maruhashi T, Higashi Y (2021) An overview of pharmacotherapy for cerebral vasospasm and delayed cerebral ischemia after subarachnoid hemorrhage. Expert Opin Pharmacother 22:1601–1614. https://doi.org/10.1080/14656566.2021.1912013

    Article  CAS  PubMed  Google Scholar 

  19. Miyamoto S, Ogasawara K, Kuroda S, Itabashi R, Toyoda K, Itoh Y, Iguchi Y, Shiokawa Y, Takagi Y, Ohtsuki T, Kinouchi H, Okada Y, Takahashi JC, Nakase H, Kakuda W (2022) Japan Stroke Society Guideline 2021 for the treatment of stroke. Int J Stroke 17:1039–1049. https://doi.org/10.1177/17474930221090347

    Article  PubMed  PubMed Central  Google Scholar 

  20. Molyneux A, Kerr R, Stratton I, Sandercock P, Clarke M, Shrimpton J, Holman R (2002) International Subarachnoid Aneurysm Trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomized trial. J Stroke Cerebrovasc Dis 11:304–314. https://doi.org/10.1053/jscd.2002.130390

    Article  PubMed  Google Scholar 

  21. Muraoka S, Asai T, Fukui T, Ota S, Shimato S, Koketsu N, Nishizawa T, Araki Y, Saito R (2023) Real-world data of clazosentan in combination therapy for aneurysmal subarachnoid hemorrhage: a multicenter retrospective cohort study. Neurosurg Rev 46:195. https://doi.org/10.1007/s10143-023-02104-2

    Article  PubMed  Google Scholar 

  22. Nieuwkamp DJ, Setz LE, Algra A, Linn FH, de Rooij NK, Rinkel GJ (2009) Changes in case fatality of aneurysmal subarachnoid haemorrhage over time, according to age, sex, and region: a meta-analysis. Lancet Neurol 8:635–642. https://doi.org/10.1016/s1474-4422(09)70126-7

    Article  PubMed  Google Scholar 

  23. Nishii R, Ohta T, Fukui N, Koyanagi M, Goto M, Takeda J, Fukumitsu R, Sunohara T, Takano Y, Teranishi K, Nakajima K, Naramoto Y, Yamamoto Y, Kawade S, Sakisuka R, Takamatsu T, Tokuda M, Tomita H, Yoshimoto M, Sakai N (2023) A high cardiothoracic ratio increases the risk of severe pulmonary complications after early initiation of clazosentan in patients with aneurysmal subarachnoid hemorrhage. Brain Hemorrhages. https://doi.org/10.1016/j.hest.2023.11.007

    Article  Google Scholar 

  24. Peeyush Kumar T, McBride DW, Dash PK, Matsumura K, Rubi A, Blackburn SL (2019) Endothelial cell dysfunction and Injury in Subarachnoid Hemorrhage. Mol Neurobiol 56:1992–2006. https://doi.org/10.1007/s12035-018-1213-7

    Article  CAS  PubMed  Google Scholar 

  25. Report of World Federation of Neurological Surgeons Committee on a Universal Subarachnoid Hemorrhage Grading Scale (1988) J Neurosurg 68:985–986. https://doi.org/10.3171/jns.1988.68.6.0985

    Article  Google Scholar 

  26. Sakr Y, Dünisch P, Santos C, Matthes L, Zeidan M, Reinhart K, Kalff R, Ewald C (2016) Poor outcome is associated with less negative fluid balance in patients with aneurysmal subarachnoid hemorrhage treated with prophylactic vasopressor-induced hypertension. Ann Intensive Care 6:25. https://doi.org/10.1186/s13613-016-0128-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Shirao S, Yoneda H, Ishihara H, Kajiwara K, Suzuki M (2011) A proposed definition of symptomatic vasospasm based on treatment of cerebral vasospasm after subarachnoid hemorrhage in Japan: Consensus 2009, a project of the 25 Spasm Symposium. Surg Neurol Int 2:74. https://doi.org/10.4103/2152-7806.81968

  28. Solomon RA, Fink ME, Lennihan L (1988) Early aneurysm surgery and prophylactic hypervolemic hypertensive therapy for the treatment of aneurysmal subarachnoid hemorrhage. Neurosurgery 23:699–704. https://doi.org/10.1227/00006123-198812000-00002

    Article  CAS  PubMed  Google Scholar 

  29. Stauffer BL, Westby CM, DeSouza CA (2008) Endothelin-1, aging and hypertension. Curr Opin Cardiol 23:350–355. https://doi.org/10.1097/HCO.0b013e328302f3c6

    Article  PubMed  PubMed Central  Google Scholar 

  30. Suwatcharangkoon S, Meyers E, Falo C, Schmidt JM, Agarwal S, Claassen J, Mayer SA (2016) Loss of consciousness at Onset of Subarachnoid Hemorrhage as an important marker of Early Brain Injury. JAMA Neurol 73:28–35. https://doi.org/10.1001/jamaneurol.2015.3188

    Article  PubMed  Google Scholar 

  31. Suzuki Y, Shibuya M, Satoh S, Sugimoto Y, Takakura K (2007) A postmarketing surveillance study of fasudil treatment after aneurysmal subarachnoid hemorrhage. Surg Neurol 68:126–131 discussion 131 – 122. https://doi.org/10.1016/j.surneu.2006.10.037

    Article  PubMed  Google Scholar 

  32. Suzuki H, Kanamaru H, Kawakita F, Asada R, Fujimoto M, Shiba M (2021) Cerebrovascular pathophysiology of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage. Histol Histopathol 36:143–158. https://doi.org/10.14670/hh-18-253

    Article  CAS  PubMed  Google Scholar 

  33. Suzuki H, Nakajima H, Ichikawa T, Yasuda R, Okada T, Goto F, Ito S, Horiuchi Y, Kitano Y, Nishikawa H, Fujimoto M, Toma N (2023) Beneficial effects of clazosentan add-on treatment on delayed cerebral microcirculatory disturbances after aneurysmal subarachnoid hemorrhage. Brain Hemorrhages. https://doi.org/10.1016/j.hest.2023.10.006

    Article  Google Scholar 

  34. Takahashi S, Akiyama T, Horiguchi T, Miwa T, Takemura R, Yoshida K (2020) Loss of consciousness at ictus and/or poor World Federation of Neurosurgical Societies grade on admission reflects the impact of EBI and predicts poor outcome in patients with SAH. Surg Neurol Int 11:40. https://doi.org/10.25259/sni_551_2019

    Article  PubMed  PubMed Central  Google Scholar 

  35. Tokiyoshi K, Ohnishi T, Nii Y (1991) Efficacy and toxicity of thromboxane synthetase inhibitor for cerebral vasospasm after subarachnoid hemorrhage. Surg Neurol 36:112–118. https://doi.org/10.1016/0090-3019(91)90228-2

    Article  CAS  PubMed  Google Scholar 

  36. Tsolaki V, Aravantinou-Fatorou A, Georgakopoulou VE, Spandidos DA, Papalexis P, Mathioudakis N, Tarantinos K, Trakas N, Sklapani P, Fotakopoulos G (2022) Early diagnosis of cerebral vasospasm associated with cerebral ischemia following subarachnoid hemorrhage: evaluation of computed tomography perfusion and transcranial doppler as accurate methods. Med Int (Lond) 2:34. https://doi.org/10.3892/mi.2022.59

    Article  PubMed  Google Scholar 

  37. Vajkoczy P, Meyer B, Weidauer S, Raabe A, Thome C, Ringel F, Breu V, Schmiedek P (2005) Clazosentan (AXV-034343), a selective endothelin A receptor antagonist, in the prevention of cerebral vasospasm following severe aneurysmal subarachnoid hemorrhage: results of a randomized, double-blind, placebo-controlled, multicenter phase IIa study. J Neurosurg 103:9–17. https://doi.org/10.3171/jns.2005.103.1.0009

    Article  CAS  PubMed  Google Scholar 

  38. Vercauteren M, Trensz F, Pasquali A, Cattaneo C, Strasser DS, Hess P, Iglarz M, Clozel M (2017) Endothelin ET(A) receptor blockade, by activating ET(B) receptors, increases vascular permeability and induces Exaggerated Fluid Retention. J Pharmacol Exp Ther 361:322–333. https://doi.org/10.1124/jpet.116.234930

    Article  CAS  PubMed  Google Scholar 

  39. Young AP, Zhu J, Bagher AM, Denovan-Wright EM, Howlett SE, Kelly MEM (2021) Endothelin B receptor dysfunction mediates elevated myogenic tone in cerebral arteries from aged male Fischer 344 rats. GeroScience 43:1447–1463. https://doi.org/10.1007/s11357-020-00309-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We would like to thank Editage (www.editage.com) for English language editing.

Funding

This research received no specific grants from any funding agency in the public, commercial, or not-for-profit sectors.

Author information

Authors and Affiliations

  1. Department of Neurosurgery, St. Luke’s International Hospital, 9-1 Akashi-cho, Chuo-ku, Tokyo, 104- 8560, Japan

    Tatsuki Mochizuki, Bikei Ryu, Shogo Shima, Eriko Kamijyo, Koki Ito, Tamon Ando, Kazuki Kushi, Shinsuke Sato, Tatsuya Inoue, Akitsugu Kawashima & Yoshikazu Okada

  2. Department of Neuroendovascular Therapy, St. Luke’s International Hospital, 9-1 Akashi-cho, Chuo-ku, Tokyo, 104-8560, Japan

    Bikei Ryu, Shinsuke Sato & Yasunari Niimi

  3. Department of Neurosurgery, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan

    Bikei Ryu, Tamon Ando & Takakazu Kawamata

Authors
  1. Tatsuki Mochizuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bikei Ryu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shogo Shima
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Eriko Kamijyo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Koki Ito
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tamon Ando
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kazuki Kushi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shinsuke Sato
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Tatsuya Inoue
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Akitsugu Kawashima
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Takakazu Kawamata
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Yoshikazu Okada
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Yasunari Niimi
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by T.M. and B.R. The first draft of the manuscript was written by T.M. and B.R. and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Bikei Ryu.

Ethics declarations

Competing interests

Dr. Ryu, Dr. Mochizuki, and Dr. Sato report lecture fees from Idorsia outside the scope of the submitted work. The other authors declare no financial interest.

Ethics approval and consent to participate

All procedures involving human participants conducted in this study were according to the ethical standards of the Institutional and National Research Committee (Saint Luke’s International Hospital, No.23-R031) and the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Consent to participate

The participants consented to the submission of the article to the journal.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mochizuki, T., Ryu, B., Shima, S. et al. Comparison of efficacy between clazosentan and fasudil hydrochloride-based management of vasospasm after subarachnoid hemorrhage focusing on older and WFNS grade V patients: a single-center experience in Japan. Neurosurg Rev 47, 113 (2024). https://doi.org/10.1007/s10143-024-02345-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s10143-024-02345-9

Keywords

Search

Navigation