Effects of a hydroxyl radical scavenger on delayed ischemic neurological deficits following aneurysmal subarachnoid hemorrhage: results of a multicenter, placebo-controlled double-blind trial

Abstract

A water-soluble, novel synthetic compound, AVS ((+/-)-N, N'-propylenedinicotinamide; nicaraven) has no demonstrable vasoactive properties but scavenges hydroxyl radicals in aqueous environmental conditions at neutral pH. Based on the results of preceding experimental and clinical studies showing marked ameliorative effects of AVS on cerebral vasospasm and ischemic brain damage, a multicenter, placebo-controlled double-blind clinical trial was undertaken to verify its beneficial effects on delayed ischemic neurological deficits (DINDs) due to vasospasm and on the overall outcome of patients with subarachnoid hemorrhage (SAH). A total of 162 patients with SAH who had Glasgow Coma Scale scores between 7 and 15 on admission were enrolled in the trial. Drug administration (4 g AVS or 4 g glucose as placebo; infused intravenously for 6-8 hours once a day) was begun within 5 days post-SAH and continued for 10 to 14 days. Intent-to-treat analysis of these patients revealed that the overall incidence of DINDs, which was defined as an exacerbation of impaired consciousness and/or focal neurological deficits, was significantly reduced, by 34.5% (placebo 54.2%, AVS 35.5%; p < 0.05, Mann-Whitney U-test). The Glasgow Outcome Scale (GOS) score at 1 month was significantly improved by AVS (p < 0.05, U-test). At 3 months, the difference in the GOS scores between the groups became marginal on U-tests (p < 0.10), but the percentage of good outcome tended to increase, with a relative increase of 20.3% (AVS 76.3%, placebo 63.4%; p < 0.10, chi-square test), and the cumulative incidence of death was significantly reduced (p < 0.05, log-rank test). No significant adverse reaction attributable to treatment was observed. the usefulness of AVS in therapy for SAH is strongly indicated by the fact that the agent significantly ameliorated DINDs, leading to a marked improvement in the GOS scores at 1 month, as well as a reduction in the cumulative incidence of death by 3 months.

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).…”

“…Heterogeneity between the trials was significant in the cerebral infarction analysis (I 2 = 45% and P = 0.04), but not in the poor outcome analysis (I 2 = 0% and P = 0.62). In the sensitivity analysis that only included studies with an outcome assessment 3 months after SAH, 16 studies were included with 7,530 patients (Macdonald et al, 2008;Asano et al, 1996;Haley et al, 1993Haley et al, , 1997Kassell et al, 1996;Ohman and Heiskanen, 1988;Petruk et al, 1988;Pickard et al, 1989;Saito et al, 1998;Shaw et al, 2000;Siironen et al, 2003;Suzuki et al, 1989;van den Bergh et al, 2005van den Bergh et al, , 2006. The pooled RR for cerebral infarction was 0.87 (95% CI: 0.78 to 0.98) and for poor outcome 0.93 (95% CI: 0.86 to 1.00) (figures not shown).…”