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Clazosentan for Improvement of Time to Peak Perfusion in Patients with Angiographically Confirmed Severe Vasospasm

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Abstract

Background

Clazosentan, an endothelin-1 receptor antagonist, has been shown to prevent the development of large vessel angiographic vasospasm after aneurysmal subarachnoid hemorrhage. We hypothesized that clazosentan can improve cerebral perfusion for territories affected by angiographically confirmed vasospasm.

Methods

The REVERSE study (REversal of Vasospasm with clazosEntan post-aneuRysmal Subarachnoid hEmorrhage) was a prospective multicenter open-label pilot study of adult patients with aneurysmal subarachnoid hemorrhage who received intravenous clazosentan after developing moderate to severe angiographic vasospasm. Using the radiographic data from the REVERSE study and additional retrospective radiographic data from our tertiary medical center, we compared the impact of intravenous clazosentan with intraarterial vasodilator therapy (medical standard of care) on vasospasm reversal using time to peak perfusion (TTPP; the time interval between the peak opacification of contrast dye in the main artery supplying an anatomically defined territory and the parenchymal phase when the dye is diffusely present in the brain parenchyma).

Results

Both intravenous clazosentan (n = 7 vessels) and intraarterial vasodilator therapy (n = 11 vessels) resulted in a statistically significant improvement in TTPP at 24 h post intervention, when compared with the TTPP just prior to intervention for territories with angiographically confirmed severe vasospasm in the proximal arteries at baseline (linear mixed-effect model, p = 0.02). The clazosentan and intraarterial vasodilator therapy groups exhibited no statistically significant interaction term [time x treatment group (medical standard of care vs. clazosentan)] in our model (p = 0.71), suggesting similar temporal course of two therapies.

Conclusions

In our small pilot study, intravenous clazosentan administered for at least 24 h had an effect comparable with that of intraarterial vasodilator therapy in reversing angiographically confirmed severe vasospasm. Our results may indicate that clazosentan, in an appropriately selected patient cohort, could offer a noninvasive approach for alleviating vasospasm.

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References

  1. Chow M, Dumont AS, Kassell NF, et al. Endothelin receptor antagonists and cerebral vasospasm: an update. Neurosurgery. 2002;51(6):1333–42.

    Article  Google Scholar 

  2. MacDonald RL, Kassell NF, Mayer S, et al. Clazosentan to overcome neurological ischemia and infarction occurring after subarachnoid hemorrhage (CONSCIOUS-1): randomized, double-blind, placebo-controlled phase 2 dose-finding trial. Stroke. 2008;39(11):3015–21.

    Article  CAS  Google Scholar 

  3. Vajkoczy P, Meyer B, Weidauer S, et al. 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. 2005;103(1):9–17.

    Article  CAS  Google Scholar 

  4. Higashida RT, Bruder N, Gupta R, et al. Reversal of vasospasm with clazosentan after aneurysmal subarachnoid hemorrhage: a pilot study. World Neurosurg. 2019;128:e639–48.

    Article  Google Scholar 

  5. Donaldson C, O’Neill AH, Slater L-A, Chong W, Lai LT, Chandra RV. Feasibility of real-time angiographic perfusion imaging in the treatment of cerebral vasospasm. Interv Neurol. 2017;6(3–4):163–9.

    Article  Google Scholar 

  6. R Core Team, R Foundation for Statistical Computing. R: A Language and Environment for Statistical Computing. 2019. http://www.r-project.org/.

  7. Satterthwaite FE. An approximate distribution of estimates of variance components. Biometrics Bull. 1946;2(6):110.

    Article  CAS  Google Scholar 

  8. Besheli LD, Tan CO, Bell DL, Hirsch JA, Gupta R. Temporal evolution of vasospasm and clinical outcome after intra-arterial vasodilator therapy in patients with aneurysmal subarachnoid hemorrhage. PLoS ONE. 2017;12(3):1–12.

    Google Scholar 

  9. Hattingen E, Blasel S, Dettmann E, et al. Perfusion-weighted MRI to evaluate cerebral autoregulation in aneurysmal subarachnoid haemorrhage. Neuroradiology. 2008;50(11):929–38.

    Article  Google Scholar 

  10. Weidauer S, Vatter H, Beck J, et al. Focal laminar cortical infarcts following aneurysmal subarachnoid haemorrhage. Neuroradiology. 2008;50(1):1–8.

    Article  Google Scholar 

  11. Weidauer S, Lanfermann H, Raabe A, Zanella F, Seifert V, Beck J. Impairment of cerebral perfusion and infarct patterns attributable to vasospasm after aneurysmal subarachnoid hemorrhage: a prospective MRI and DSA Study. Stroke. 2007;38(6):1831–6.

    Article  Google Scholar 

  12. Yundt KD, Grubb RL, Diringer MN, Powers WJ. Autoregulatory vasodilation of parenchymal vessels is impaired during cerebral vasospasm. J Cereb Blood Flow Metab. 1998;18(4):419–24.

    Article  CAS  Google Scholar 

  13. Ohkuma H, Manabe H, Tanaka M, Suzuki S. Impact of cerebral microcirculatory changes on cerebral blood flow during cerebral vasospasm after aneurysmal subarachnoid hemorrhage. Stroke. 2000;31:1621–7.

    Article  CAS  Google Scholar 

  14. MacDonald RL, Higashida RT, Keller E, et al. Randomized trial of clazosentan in patients with aneurysmal subarachnoid hemorrhage undergoing endovascular coiling. Stroke. 2012;43(6):1463–9.

    Article  CAS  Google Scholar 

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Acknowledgements

We would like to acknowledge Angelina Marr and Sébastien Roux of Idorsia Pharmaceuticals Ltd. for their courtesy review, advice, and input on this manuscript.

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Authors and Affiliations

  1. Massachusetts General Hospital, Boston, MA, USA

    Austin Lai, Can Ozan Tan, Justin Vranic, Thabele Leslie-Mazwi, Joshua A. Hirsch & Rajiv Gupta

  2. Spaulding Rehabilitation Hospital, Boston, MA, USA

    Can Ozan Tan

  3. Sankt Katharinen-Krankenhaus, Frankfurt, Germany

    Stefan Weidauer

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  1. Austin Lai
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  2. Can Ozan Tan
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  4. Stefan Weidauer
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  5. Thabele Leslie-Mazwi
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Contributions

RG conceived and designed the study. AL collected the data. RG monitored data collection. AL, JV, CT, RG, JH, and SW analyzed the data. CT provided the statistical analysis of the data. TLM, SW, AL, RG, and CT made contributions to interpretation of the data. AL drafted the article. All authors provided critical feedback and revisions to the article. All parties interested in data sharing may contact RG. All authors approved the final manuscript.

Corresponding author

Correspondence to Austin Lai.

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Source of Support

This research has not received any specific grant from any funding agency in the public, commercial or not-for-profit sectors.

Conflict of interest

RG and SW have been consultants and scientific advisors for Actelion Pharmaceuticals Ltd and Idorsia Pharmaceuticals Ltd and have received consulting fees. COT has been a consultant for Lokavant Inc and has received consulting fees. RG, SW, and JH served as members of the independent review committee on the REVERSE study.

Ethical Approval/Informed Consent

Ethical approval was obtained from the Partners Human Research Committee, Boston, USA. Reference number: 2014P002368.

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Lai, A., Tan, C.O., Vranic, J. et al. Clazosentan for Improvement of Time to Peak Perfusion in Patients with Angiographically Confirmed Severe Vasospasm. Neurocrit Care 36, 240–247 (2022). https://doi.org/10.1007/s12028-021-01291-4

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  • DOI: https://doi.org/10.1007/s12028-021-01291-4

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