Marc Fisher , MD , and

Only months from now, another decade will dawn on stroke research with a dearth of therapeutic innovations developed to reverse the devastating effects of acute ischemic stroke. Despite generations of academic research investigators and associated industry collaborations, our clinical trials have marked each decade by successive eras of failed treatments with only a few exceptions. The recent publication of results from the Desmoteplase In Acute ischemic Stroke (DIAS)-2 trial provides important lessons that may hold the clues to reversing stroke in the 2010s.1 DIAS-2 was undoubtedly a landmark study, incorporating sophisticated trial design with the latest innovations in CT and MRI techniques to confirm benefit of a novel fibrinolytic agent to treat acute ischemic stroke up to 9 hours after symptom onset. The potential for another stroke therapy in clinical practice was replaced by collective introspection on the determinants of yet another negative trial after earlier positive results.2 Once again, an article starts by underscoring the limited treatment options for stroke, details the saga of an elaborate yet negative clinical trial, and ends by noting that the “criteria to optimize the selection and treatment outcomes” remain elusive. The perpetual motion of academia echoes the familiar chorus that further studies are indicated, but perhaps this philosophical juncture provides an opportunity to heed important lessons learned. An endless list of reasons can be cited for failure, like in the litany of articles on neuroprotective trials or the thoughtful considerations of Stroke Therapy Academic Industry Roundtable (STAIR),3,4 yet most are difficult to prove or easily remedy without a comprehensive overhaul. Overall, DIAS-2 teaches us that the traditional approaches to stroke therapy may require revision of our currently engrained textbook approach to key variables such as time, imaging of the penumbra, ischemic pathophysiology, predictors of outcome, and the paradigm of randomized, controlled trials to prove efficacy of a single intervention. Tweaking such aspects may translate into therapeutic breakthroughs and allow us to reflect on a very different decade of stroke research by 2020. Time was a key focus of DIAS-2, using an extended window from 3 to 9 hours after symptom onset to test a novel fibrinolytic drug for late reperfusion. Like in the recent success of European Cooperative Acute Stroke Study (ECASS) III with thrombolysis up to 4.5 hours after onset,5 offering treatment beyond the strict and perhaps arbitrary time limit of 3 hours has been a critical goal. “Time is brain” may be a useful slogan to accelerate triage of acute stroke, but such dogma defies the vascular pathophysiology of cerebral blood flow. Faster treatment always seems better, yet hemodynamics and the time course of collateral perfusion and subsequent failure vary substantially across individuals.6,7 Time from symptom onset is not synonymous with stroke onset, because it only reflects when collaterals become insufficient to sustain normal neurological function. The time course of collateral failure and clinical deterioration vary and are influenced by numerous factors such as lesion location. In fact, patient presentation to the emergency room may be driven by such features because many are often dissuaded from seeking medical attention due to fluctuation or mild symptoms. Starting the clock in such cases remains a challenge. Reperfusion of mismatch at later time points, like in DIAS-2, may also not translate into substantial clinical improvement because these “survivors” may have tolerated prolonged hypoperfusion with only modest impairment. Interestingly, the DIAS-2 investigators found no difference in response rates based on time, an emerging pattern evidenced with other stroke interventions despite several prior studies to the contrary, raising questions about the accuracy of defining time windows without imaging. Imaging may reveal why time is important, disclosing facets that relate to vascular changes such as no reflow and endothelial ischemia aside from evolving ischemic injury in tissue. DIAS-2 highlighted multimodal CT and MRI, including parenchymal images with both angiography and perfusion measures. These techniques have rapidly gained traction in routine clinical practice, yet equating mismatch with penumbra may be especially misleading if CT and MRI approaches