Effect of Endothelin-Receptor Antagonists on Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage Remains Unclear

Abstract

Effect of Endothelin-Receptor Antagonists on Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage Remains UnclearTo the Editor:With great interest I have read the recent meta-analysis on the effect of endothelin-receptor antagonists (ETRAs) in patients with aneurysmal subarachnoid hemorrhage. 1 Because endothelin might have an important function in the pathogenesis of radiographic vasospasm, ETRAs are presently under intensive investigation in this group of patients. Recently, the results of a large double-blind, placebo-controlled Phase II study (Clazosentan to Overcome Neurological Ischemia and Infarction Occurring After Subarachnoid Hemorrhage [CONSCIOUS-1]) investigating the effect of the ETRA clazosentan in patients with aneurysmal subarachnoid hemorrhage for the first time revealed a 65% relative risk reduction (95% CI, 47% to 78%) of angiographically demonstrated vasospasm in the group of patients treated with the highest dose of clazosentan (15 mg/h). 2 This finding was impressive, because no other drug ever before was found to have such a spectacular effect on angiographic vasospasm. Therefore, it was even more surprising that no effect on the clinically more important predefined combined morbidity and mortality end point was observed. These recent findings more convincingly than ever suggest that no causal relation exists between angiographic vasospasm and clinical symptoms of delayed cerebral ischemia (DCI).Drs Kramer and Fletcher presented a meta-analysis on the effect of ETRAs in patients with aneurysmal subarachnoid hemorrhage. 1 Three studies were included, enrolling 867 patients. It was concluded that ETRAs reduce radiographic vasospasm and DCI, but that there is currently no evidence that these drugs improve outcomes. The observation that ETRAs decrease the incidence of DCI was new, because none of the included individual studies showed a statistically significant effect on DCI. However, in my opinion, this conclusion might not be justified. In the largest study, the CONSCIOUS-1 study, DCI was documented as "clinical vasospasm" and defined as "locally defined vasospasm on DSA or transcranial Doppler associated with neurological worsening lasting for at least 2 hours." In other words, patients were only documented to have this end point in the presence of vasospasm. Patients who were treated with clazosentan had a lower incidence of angiographic vasospasm and, as a result of the definition of "clinical vasospasm," also had a lower incidence of that end point. Because it is well-known that patients with aneurysmal subarachnoid hemorrhage can also have symptoms of DCI in the absence of angiographic vasospasm, it could well be that in the group of patients treated with clazosentan, many patients had neurological worsening in the absence of vasospasm. I understand that Drs Kramer and Fletcher had no other data available for their meta-analysis than presented in the original study; however, their conclusion that ETRAs decrease the incidence of DCI might not be justified for the reason de...

The importance of early brain injury after subarachnoid hemorrhage

“…These agents successfully reduced the incidence and intensity of vasospasm but had little effect on DINDs and on the long-term outcome (Kramer and Fletcher, 2009; Macdonald et al , 2011; Macdonald et al , 2008; Nogueira et al , 2007; Shaw et al , 2000; Vajkoczy et al , 2005; Vergouwen, 2009). …”

“…Agents such as Nimodipine (a calcium channel blocker) which reduce the incidence and severity of delayed ischemic injury and improve neurological outcome in aSAH patients do not relief angiographic vasospasm (Biondi et al , 2004; Deshaies et al , 2009; Petruk et al , 1988; Philippon et al , 1986; Pickard et al , 1989). In contrast, agents such as Clazosentan, an ET-1A antagonist, which reduce the incidence of vasospasm do not improve neurological outcomes (Kramer and Fletcher, 2009; Macdonald et al , 2011; Macdonald et al , 2008; Nogueira et al , 2007; Shaw et al , 2000; Vajkoczy et al , 2005; Vergouwen, 2009). This failure in part may involve deleterious side effects associated with most drugs (pulmonary complications for Clazosentan) that counterbalance their therapeutic benefits (Macdonald et al , 2011) or aggressive use of rescue therapy that may dilute the overall results (Macdonald et al , 2011).…”

Early Brain Injury, an Evolving Frontier in Subarachnoid Hemorrhage Research

“…Numerous interventions are currently being investigated for CVS treatment [61]. Several promising pharmacological treatments, previously demonstrated in pre-clinical animal experiments, have translated to human randomized and blinded clinical trials such as: calcium channel antagonists (nimodipine and nicardipine) [48, 79, 87, 88], endothelin antagonists [73, 119, 121], erythropoietin [107], fasudil [102], magnesium sulfate [126], statins [23, 117], tirilazad [47, 56], and tissue plasminogen activator (tPA) [36]. However, most of them failed in clinical trials for prevention and treatment of CVS [85], except fasudil which is used clinically in Japan and China [69].…”

Electroacupuncture Improves Cerebral Vasospasm and Functional Outcome of Patients With Aneurysmal Subarachnoid Hemorrhage

“…Consequently, various methods are used to prevent cerebral vasospasm on the basis of its pathogenesis, such as the endothelin antagonist clazosentan, the cholesterol-lowering agent simvastatin, and the vasodilator magnesium sulfate, calcium channel blocker nicardipine ( van Gijn and Rinkel, 2001 ; Wilson et al, 2005 ; van Gijn et al, 2007 ). However, some researchers find that the prevention of cerebral vasospasm does not improve the outcomes of aSAH patients ( Macdonald et al, 2008 ; Vergouwen, 2009 ; Macdonald et al, 2011 ).…”