Challenges in acute ischemic stroke clinical trials.

There have been only 3 positive Phase III randomized clinical trials in acute ischemic stroke, all reperfusion therapies (NINDS; PROACT II; ECASS III). The only approved acute stroke therapy is <3-hour IV tPA. Although numerous compounds have shown benefit in animal models of brain infarction, there has never been a positive Phase III randomized clinical trial of a neuroprotectant in acute ischemic stroke. There are many challenges to acute stroke clinical trials but chief among these are the very short therapeutic window ("time is brain") and the issue of stroke heterogeneity. Stroke is a syndrome and only a very small percentage of all stroke patients present to hospitals in time to consider reperfusion therapy. Many drugs have been rushed to trial prematurely based on inadequate preclinical testing. Many trials have been seriously underpowered due to overly optimistic treatment expectations and the risk of brain hemorrhage has precluded aggressive multimodal treatment strategies. Rather than simply relying on a clock, new imaging methods are being developed to identify patients with "tissue at risk" and "salvageable brain" regardless of time of stroke onset. The 7 STAIR conferences have been convened to address these and other challenges to acute ischemic stroke trial design and completion.