Article
The selective endothelin A (ETA
) receptor antagonist clazosentan not only reduces the incidence of angiographic vasospasm, but also prevents and reverses symptomatic vasospasm following severe subarachnoid hemorrhage
Der selektive Endothelin A (ETA
) Rezeptor Antagonist Clazosentan vermindert nicht nur die Inzidenz des angiographischen Vasospasmus, sondern verhindert und hebt auch den symptomatischen Vasospasmus nach schwerer Subarachnoidalblutung auf
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Published: | May 4, 2005 |
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Outline
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Objective
In a recent phase IIa multicenter trial, the effectiveness of the ETA-receptor antagonist clazosentan on prevention and reversal of angiographic vasospasm in patients with aneurysmal subarachnoid hemorrhage (SAH) following aneurysm clipping has been demonstrated. However, no information exists about the influence of the drug on cerebral perfusion and the development of symptomatic vasospasm. Therefore, we investigated in a subset of patients within this phase IIa trial whether the positive effect of clazosentan on vessel-diameter also translates into an improved cerebral perfusion.
Methods
We included 10 patients with severe SAH that were treated in the context of the multicenter phase IIa trial. In addition to the trial protocol, these patients received a thermal diffusion microprobe to continuously measure regional cerebral blood flow (TD-rCBF). The probe was implanted into the vascular territory deemed to be at highest risk for developing vasospasm. The study consisted of two parts: a double-blind, randomized part A (clazosentan 0.2 mg/kg/h versus placebo starting within 48 h post SAH up to day 14) and an open-label Part B (clazosentan 0.4 mg/kg/h for 12 h followed by 0.2 mg/kg/h up to day 14 for patients with established angiographic vasospasm). Extended neuromonitoring included continuous measurements of mean arterial blood pressure, intracranial pressure, cerebral perfusion pressure, and TD-rCBF.
Results
Clazosentan not only reduced the incidence/severity of angiographic vasospasm, but also significantly reduced the vasospasm-associated reduction of cerebral perfusion (i.e. hemodynamically relevant vasospasm; TDrCBF day 5-7: placebo (n=4) 19 ml/100g/min versus clazosentan (n=6) 27 ml/100g/min, p<0.05). Moreover, while 75% of placebo treated patients suffered TD-rCBF values below the ischemic threshold of 15 ml/100g/min only 33% did so in the clazosentan group. In part B of the study, secondary treatment with clazosentan of patients that were initially randomized into the placebo group and had developed symptomatic vasospasm (n=3) resulted in successful reversal of vasospasm-associated cerebral hypoperfusion.
Conclusions
The results of this study indicate that clazosentan not only exerts beneficial effects on the incidence of morphological, i.e. angiographic, vasospasm, but is also capable of preventing and reversing hemodnamically relevant, i.e. symptomatic, vasospasm.