Recanalization and reperfusion therapies of acute ischemic stroke: what have we learned, what are the major research questions, and where are we headed?

Two placebo-controlled trials have shown that early administration of intravenous recombinant tissue plasminogen activator (rt-PA) after ischemic stroke improves outcomes up to 4.5 h after symptoms onset; however, six other trials contradict these results. We also know from analysis of the pooled data that benefits from treatment decrease as time from stroke onset to start of treatment increases. In addition to time, another important factor is patient selection through multimodal imaging, combining data from artery status, and salvageable tissue measures. Nonetheless, at the present time randomized controlled trials (RCTs) cannot demonstrate any beneficial outcomes for neuroimaging mismatch selection after 4.5 h from symptoms onset. By focusing on cases of large arterial occlusion, we know that recanalization is crucial, so endovascular treatment is an approach of interest. The use of intra-arterial thrombolysis was tested in two small RCTs that demonstrated clear benefits in terms of higher recanalization and also in clinical outcomes. But a new paradigm of stroke treatment may have begun with mechanical thrombectomy. In this field, Merci devices have been overtaken by fully deployed closed-cell self-expanding stents (stent-retrievers or "stent-trievers"). However, despite the high rate of recanalization achieved with stent-retrievers compared with other recanalization treatments, the use of these devices cannot clearly demonstrate better outcomes. Thus, futile recanalization occurs when successful recanalization fails to improve functional outcome. Recently, three RCTs, namely synthesis, IMS-III, and MR-rescue, have not been demonstrated any clear benefit for endovascular treatment. Most likely, these trials were not adequately designed to prove the superiority of endovascular treatment because they did not use optimal target populations, vascular status was not evaluated in all patients, relatively high rates of patients did not have enough mismatch, time from baseline neuroimaging to recanalization were too long or the devices used are now obsolete relative to stent-retrievers. Several RCTs currently underway are trying to determine whether bridging therapy is more effective than intravenous treatment and if mechanical thrombectomy is more effective than best medical treatment in patients ineligible for intravenous thrombolysis.