Effect of AT877 on cerebral vasospasm after aneurysmal subarachnoid hemorrhage

Abstract

With the cooperation of 60 neurosurgical centers in Japan, a prospective randomized placebo-controlled double-blind trial of a new calcium antagonist AT877 (hexahydro-1-(5-isoquinolinesulfonyl)-1H-1,4-diazepine hydrochloride, or fasudil hydrochloride) was undertaken to determine the drug's effect on delayed cerebral vasospasm in patients with a ruptured cerebral aneurysm. A total of 276 patients, who underwent surgery within 3 days after subarachnoid hemorrhage (SAH) of Hunt and Hess Grades I to IV, were entered into the study. Nine patients were excluded because of protocol violation. The remaining 267 patients received either 30 mg AT877 or a placebo (saline) by intravenous injection over 30 minutes, three times a day for 14 days following surgery. Demographic and clinical data were well matched between the two groups. It was found that AT877 reduced angiographically demonstrable vasospasm by 38% (from 61% in the placebo group to 38% in the AT877 group, p = 0.0023), low-density regions on computerized tomography associated with vasospasm by 58% (from 38% to 16%, p = 0.0013), and symptomatic vasospasm by 30% (from 50% to 35%, p = 0.0247). Furthermore, AT877 reduced the number of patients with a poor clinical outcome associated with vasospasm (moderate disability or worse on the Glasgow Outcome Scale at 1 month after SAH) by 54% (from 26% to 12%, p = 0.0152). There were no serious adverse events reported in the AT877 group. This is the first report of a placebo-controlled double-blind trial that has demonstrated a significant reduction in angiographically revealed vasospasm by intravenous drug therapy.

The Rho Kinase Pathway Regulates Mouse Adult Neural Precursor Cell Migration

“…ROCK inhibitors are currently in use or in human trials for a variety of CNS and non-CNS conditions [37,[79][80][81][82][83][84][85][86][87][88]. Application of ROCK inhibitors in vivo may affect NPC cell-cell association and promote aberrant NPC migration, leading to altered NPC signal transduction.…”

Lower incidence of cerebral infarction correlates with improved functional outcome after aneurysmal subarachnoid hemorrhage

“…The remaining 24 trials were included in the analysis, including 8,552 patients (Macdonald et al, 2008;Asano et al, 1996;Chou et al, 2008;Gomis et al, 2010;Haley et al, 1993Haley et al, , 1997Hop et al, 2000;Kassell et al, 1996;Ohman and Heiskanen, 1988;Petruk et al, 1988;Pickard et al, 1989;Saito et al, 1998;Shaw et al, 2000;Shibuya et al, 1992;Siironen et al, 2003;Juvela et al, 2005;Springborg et al, 2007;Suzuki et al, 1989;Tseng et al, 2009;van den Bergh et al, 2005van den Bergh et al, , 2006Westermaier et al, 2010;Wong et al, 2010Wong et al, , 2011. A total of 4,818 patients were randomized to pharmaceutical treatment, and 3,734 patients to placebo.…”

“…For blinding, risk of bias was low in 20 studies (Macdonald et al, 2008;Asano et al, 1996;Gomis et al, 2010;Haley et al, 1993Haley et al, , 1997Hop et al, 2000;Kassell et al, 1996;Petruk et al, 1988;Pickard et al, 1989;Shaw et al, 2000;Shibuya et al, 1992;Siironen et al, 2003;Springborg et al, 2007;Tseng et al, 2009;van den Bergh et al, 2005van den Bergh et al, , 2006Westermaier et al, 2010;Wong et al, 2010), and unclear in four studies (Chou et al, 2008;Ohman and Heiskanen, 1988;Saito et al, 1998;Suzuki et al, 1989). High risk of bias was not observed in any of the studies.…”

“…For allocation concealment, risk of bias was low in 13 (Macdonald et al, 2008;Asano et al, 1996;Haley et al, 1993;Hop et al, 2000;Petruk et al, 1988;Pickard et al, 1989;Shaw et al, 2000;Shibuya et al, 1992;Springborg et al, 2007;Tseng et al, 2009;van den Bergh et al, 2005van den Bergh et al, , 2006Wong et al, 2010) and unclear in 11 studies (Chou et al, 2008;Gomis et al, 2010;Haley et al, 1997;Kassell et al, 1996;Ohman and Heiskanen, 1988;Saito et al, 1998;Siironen et al, 2003;Suzuki et al, 1989;Westermaier et al, 2010) ( Table 1). For blinding, risk of bias was low in 20 studies (Macdonald et al, 2008;Asano et al, 1996;Gomis et al, 2010;Haley et al, 1993Haley et al, , 1997Hop et al, 2000;Kassell et al, 1996;Petruk et al, 1988;Pickard et al, 1989;Shaw et al, 2000;Shibuya et al, 1992;Siironen et al, 2003;Springborg et al, 2007;Tseng et al, 2009;van den Bergh et al, 2005van den Bergh et al, , 2006Westermaier et al, 2010;…”

“…In the sensitivity analysis that only included studies with a low risk of bias, as assessed on the items 'allocation concealment' and 'blinding,' 13 studies were included with 3,831 patients (Macdonald et al, 2008;Asano et al, 1996;Haley et al, 1993;Hop et al, 2000;Petruk et al, 1988;Pickard et al, 1989;Shaw et al, 2000;Shibuya et al, 1992;Springborg et al, 2007;Tseng et al, 2009;van den Bergh et al, 2005van den Bergh et al, , 2006Wong et al, 2010). The pooled RR for cerebral infarction was 0.70 (95% CI: 0.56 to 0.88) and for poor outcome 0.78 (95% CI: 0.67 to 0.90) (figures not shown).…”