Advances in Emerging Therapies 2006

The past year has seen further advancement toward the goal of effective and multifaceted stroke treatment. Encouraging evidence has emerged to support mechanical intervention for large artery occlusion, late and imagingdirected thrombolytic therapy, neuroprotectant strategies and decompressive surgery for large middle cerebral artery (MCA) stroke. We have seen important advances with regard to secondary preventative strategies. The attraction of catheter-based reperfusion techniques is obvious. They may afford use of lower systemic doses of thrombolytic agents, while mechanical clot disruption and retrieval could obviate the need for drugs. This would not only be a particular advantage in those with elevated hemorrhage risk but may also improve the poor reperfusion rates after proximal carotid, basilar or M1 MCA occlusion. Although the MERCI trial1 suggested benefit some 2 years ago, this position has been supported by a recent small series of 12 patients with basilar artery occlusion2 of whom half underwent successful mechanical recanalization. Time to reperfusion was shorter in these patients and they were spared the risks of thrombolytic therapy. Preliminary data also suggest that catheter-based interventions can be applied more distally than hitherto considered possible, perhaps offering direct treatment for intracranial stenosis with reduced rates of stroke or vascular death compared with historical controls.3 Although these techniques are hugely promising and may represent a real alternative for those with major stroke who are unsuitable for recombinant tissue plasminogen activator (rt-PA), we must recognize that conclusive randomized controlled evidence is lacking and benefit is unproven. Furthermore, such techniques will only aid those fortunate enough to be treated in a major center. While we consider these complex, costly and less readily available treatments, we should note that 2006 provided further evidence that intravenous thrombolytic therapy is safe but underused4 and that it remains a valuable treatment for life-threatening conditions such as basilar artery occlusion.5 Trials such as ECASS III and the International Stroke Trial-3 are still testing whether the time window for thrombolytic therapy can be safely prolonged to 4.5 or perhaps 6 hours. Preliminary evidence suggests that use of magnetic resonance perfusion/diffusion scanning will allow us to stretch the window at least this far. MRI is the more widely studied modality but CT perfusion–imaging also identifies ischemic penumbra.6 Recently published nonrandomized data7 showed that favorable outcomes were more common after MRI guided rt-PA within 6 hours than in historical trial controls given rt-PA treatment or placebo after standard CT imaging. Reassuringly, the intracerebral hemorrhage rate was comparable to that after placebo. The Desmoteplase study program suggests that this newer fibrin-specific thrombolytic may be effective up to 9 hours after ictus in patients with MRI perfusion/diffusion mismatch. The DIAS (Desmoteplase in Acute Ischemic Stroke) trial reported nearly 2 years ago,8 but the DEDAS (Dose Escalation of Desmoteplase for Acute Ischemic Stroke) trial9 and a combined analysis of the two10 now appear to corroborate the initial findings: reperfusion rates and clinical outcomes were improved in such patients if treated with 90 to 125 g/kg of desmoteplase. A further phase IIb study (DIAS II) seeks to replicate these results while allowing a choice of MRI or CT perfusion as entry criterion. By selecting those patients most likely to benefit from thrombolytic therapy, the investigators hope that the risk benefit ratio can be further refined, while also maximizing its use. However, we must remain cautious: the data supporting CT perfusion and MRI-guided rt-PA do not yet derive from randomized controlled trials, and the desmoteplase data are based on a tiny patient cohort. We are well aware of the limitations of small trials; even relatively large and rigorously controlled trials can give misleading results. Reperfusion strategies have been the cornerstone of acute stroke treatment since introduction over a decade ago. Throughout this period a number of promising neuroprotectant drugs have been tried, tested and failed. The year 2006 appeared different; evidence emerged that NXY-059, a novel free radical trapping agent, may reduce poststroke disability and the rate of hemorrhagic transformation after rt-PA.11 In line with expectations for this approach, the benefits seen were modest but by no means economically, clinically or statistically insignificant especially in light of potentially wide applicability. A lively debate ensued. A particular focus of attention was the novel analysis method used, which was geared to measure improvement in disability across the entire range of modified Rankin scores. It seems remarkable that such methods that increase rigor and trial power are still criticized in favor of less sensitive dichotomized approaches designed instead for treatments that could threaten to increase