Cytoprotection for Acute Ischemic Stroke: Critical Appraisal of Recent Clinical Trials

Several phase III clinical trials testing cytoprotective approaches have recently been completed, and many of these studies report a clinical benefit. Reviewing the outcomes of these trials in light of their specific designs reveals intriguing results. Trials designed with shorter treatment time windows (≤24 hours) and featuring high rates of recanalization therapies predominantly show neutral outcomes, that is, no therapeutic benefit. Studies using later time points (>24 hours to 14 days) and often enrolling patients in whom recanalization is not or only infrequently established show clear treatment effects. These results challenge our current understanding of cytoprotective approaches, which are believed to primarily target the penumbra as the key to therapeutic success. The reasons for this are unclear. They may include other, potentially unknown mechanisms of action that improve clinical outcome even when applied within longer time windows rather than exerting acute cytoprotection. Here, we discuss such potential mechanisms, to what extent they could explain the results of recent cytoprotection trials, and review consequences for future translational and clinical research.