Advances in emerging therapies 2007.

Cynics may consider that review of emergent stroke therapies in 2007 is likely to make for quick reading—it is certainly true that many high profile trials reported unexpected neutral outcomes. However, although these disappointments made for headline medical news, there were still a number of encouraging results of novel acute therapies. The first “casualty” of the year was neuroprotection. The free radical trapping agent NXY-059 had been consistently shown to reduce infarct size and improve functional outcomes in published reports of animal models. The first phase III study in humans (SAINT) was positive, reporting a statistically significant improvement in global disability (Figure).1 Unfortunately, the follow up SAINT II trial did not confirm this result (Figure).2 This randomized placebocontrolled study of 3306 ischemic stroke patients up to 6 hours from ictus demonstrated no significant improvement in the primary end point of day 90 modified Rankin score (mRS). Subgroup analyses also failed to replicate the previous finding of reduced hemorrhagic transformation rate in patients treated with thrombolytic. Although the result was disappointing, the trial itself was rigorous and it optimized statistical analyses to describe functional outcomes across the treatment groups. A clear message from the SAINT trials is that even large-scale meticulously planned trials are subject to the play of chance, and that initial positive results require verification with a second adequately powered study. These themes have been echoed in other acute stroke trials throughout the year. As the European Safe Implementation of Thrombolysis in Stroke Monitoring Study (SITS-MOST) confirmed safety and efficacy of intravenous thrombolysis in routine practice, the stroke community were already advancing knowledge on novel approaches to reperfusion. The second Desmoteplase in Ischemic Acute Stroke (DIAS II) study sought to build on the success of previous studies using the fibrin specific plasminogen activator desmoteplase.3 The aim was to target therapy to those most likely to benefit by including only patients with perfusion-diffusion mismatch of at least 20% total infarct volume or equivalent CT-perfusion findings. In a cohort of patients 3 to 9 hours after event, placebo was tested against intravenous boluses of 90 g/kg and 125 g/kg desmoteplase. In contrast to previous results, no benefit was found from desmoteplase; in fact patients treated at highest dose showed a trend toward excess mortality. The reasons for this neutral result remain unclear and may relate to the active agent, to the imaging based protocol, or to statistical underpowering—at 186 patients this was still a small trial. It seems unlikely that patients selected for persistence of penumbra 3 to 9 hours after stroke will show a greater response to thrombolysis than we achieve with rapid alteplase use. Groups of 60 patients are too small to confirm treatment effects comparable to those of alteplase when used under optimal conditions. The excess mortality in the higher desmoteplase dosage group seems unlikely to relate directly to desmoteplase as, of the 14 deaths, 9 were considered nonneurological and 9 occurred 1 week or later after treatment. Were the DIAS trialists simply victims of “significant” bad luck? At present the future of desmoteplase is unclear. However, the evidence base for using penumbral imaging to target acute therapies continues to grow. The DEFUSE study successfully used MRI imaging to predict patients likely to benefit from tPA in the 3to 6-hour time period,4 a result confirmed in a recent analysis of pooled data from 5 European centers.5 Intraarterial delivery of thrombolytic has theoretical advantages over intravenous administration, including local delivery of agent and reduced systemic effects. It is almost a decade since the PROACT-II study first suggested efficacy of intraarterial thrombolysis.6 A confirmatory trial was never completed, although many centers continued to use intraarterial lytics for patients ineligible for standard intravenous therapy. The MELT study (MCA Embolism Local fibrinolytic intervention Trial) helps reassure us that the intraarterial approach represents a viable treatment option.7 This prospective trial randomized 114 patients, with confirmed occlusion of the M1 or M2 MCA segment and within 6 hours of event, to intraarterial urokinase or medical therapy. The trial was terminated early when intravenous tPA was licensed for clinical use in Japan. Although no difference was seen on primary end point (mRS 0 to 2; P 0.345; Figure), on prespecified secondary end point analysis an increase in patients showing excellent recovery was demonstrated (mRS 0 to 1; P 0.045; Figure) with no significant difference in mortality or hemorrhage. Primary intracerebral hemorrhage (ICH) is a frustrating entity, with higher levels of mortality and disability than ischemic stroke and few proven therapies. Pilot results using the hemostatic agent recombinant factor VII (rFVII) had