TY - JOUR
T1 - Reversal of Vasospasm with Clazosentan After Aneurysmal Subarachnoid Hemorrhage
T2 - A Pilot Study
AU - Higashida, Randall T.
AU - Bruder, Nicolas
AU - Gupta, R.
AU - Guzman, Raphael
AU - Hmissi, A.
AU - Marr, Angelina
AU - Mayer, Stephan A.
AU - Roux, Sébastien
AU - Weidauer, Stefan
AU - Aldrich, E. François
N1 - Publisher Copyright:
© 2019 Elsevier Inc.
PY - 2019/8
Y1 - 2019/8
N2 - Background: Clazosentan, an endothelin-1 receptor antagonist, has been shown to prevent the development of large vessel angiographic vasospasm after aneurysmal subarachnoid hemorrhage (aSAH). It has been hypothesized that clazosentan can also reverse established angiographic vasospasm. Methods: The REVERSE (resynchronization reverses remodeling in systolic left ventricular dysfunction) study was a prospective, multicenter, open-label, 2-stage pilot study of adult patients with aSAH who had received intravenous clazosentan (15 mg/hour) after developing moderate-to-severe angiographic vasospasm. The primary efficacy endpoint was the reversal of global cerebral vasospasm in large cerebral artery segments 3 hours after clazosentan initiation. The secondary endpoints included large artery vasospasm reversal at 24 hours and the maximum change in the angiographic cerebral circulation time. The change in vasospasm severity in the proximal and distal segments was investigated in an exploratory analysis. Results: The primary efficacy endpoint was met in 3 of 11 evaluable patients (27.3%; 95% confidence interval, 6.0–61.0). However, recruitment was stopped after stage 1 in accordance with the predefined interim analysis criteria. In the exploratory analysis, 50.0% and 77.8% of the patients showed a significant reversal of vasospasm or improvement to the admission state in ≥2 distal segments at 3 and 24 hours and 28.6% and 77.8% in ≥2 proximal segments, respectively. Conclusions: Although the main analysis showed a reversal of large vessel vasospasm 3 hours after clazosentan initiation in a few patients, the exploratory analysis indicated a clear pharmacodynamic dilating effect on vasospastic cerebral vessels at 24 hours in most patients, in particular, in the distal arterial beds. This observation supported the inclusion of patients with established vasospasm in the ongoing REACT (prevention and treatment of vasospasm with clazosentan) trial.
AB - Background: Clazosentan, an endothelin-1 receptor antagonist, has been shown to prevent the development of large vessel angiographic vasospasm after aneurysmal subarachnoid hemorrhage (aSAH). It has been hypothesized that clazosentan can also reverse established angiographic vasospasm. Methods: The REVERSE (resynchronization reverses remodeling in systolic left ventricular dysfunction) study was a prospective, multicenter, open-label, 2-stage pilot study of adult patients with aSAH who had received intravenous clazosentan (15 mg/hour) after developing moderate-to-severe angiographic vasospasm. The primary efficacy endpoint was the reversal of global cerebral vasospasm in large cerebral artery segments 3 hours after clazosentan initiation. The secondary endpoints included large artery vasospasm reversal at 24 hours and the maximum change in the angiographic cerebral circulation time. The change in vasospasm severity in the proximal and distal segments was investigated in an exploratory analysis. Results: The primary efficacy endpoint was met in 3 of 11 evaluable patients (27.3%; 95% confidence interval, 6.0–61.0). However, recruitment was stopped after stage 1 in accordance with the predefined interim analysis criteria. In the exploratory analysis, 50.0% and 77.8% of the patients showed a significant reversal of vasospasm or improvement to the admission state in ≥2 distal segments at 3 and 24 hours and 28.6% and 77.8% in ≥2 proximal segments, respectively. Conclusions: Although the main analysis showed a reversal of large vessel vasospasm 3 hours after clazosentan initiation in a few patients, the exploratory analysis indicated a clear pharmacodynamic dilating effect on vasospastic cerebral vessels at 24 hours in most patients, in particular, in the distal arterial beds. This observation supported the inclusion of patients with established vasospasm in the ongoing REACT (prevention and treatment of vasospasm with clazosentan) trial.
KW - Aneurysm
KW - Cerebral vasospasm
KW - Endothelin-1 receptor antagonist
KW - Subarachnoid hemorrhage
UR - http://www.scopus.com/inward/record.url?scp=85066112298&partnerID=8YFLogxK
U2 - 10.1016/j.wneu.2019.04.222
DO - 10.1016/j.wneu.2019.04.222
M3 - Article
C2 - 31054336
AN - SCOPUS:85066112298
SN - 1878-8750
VL - 128
SP - e639-e648
JO - World Neurosurgery
JF - World Neurosurgery
ER -