Abstract
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.
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References
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;333:1581–7.
• Hacke W, Kaste M, Bluhmki E, Brozman M, Davalos A, Guidetti D, for the ECASS Investigators, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008;359:1317–29. ECASS III established clinical efficacy of IV tpa up to 4.5 hours in selected patients.
Furlan AJ, Higashida R, Wechsler L, Gent M, Rowley H, Kase C, et al. Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. JAMA. 1999;282:2003–11.
•• The IST-3 Collaborative Group. The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 hours of acute ischemic stroke (the third international stroke trial IST-3): a randomized controlled trial. Lancet. 2012. doi:101016/S0140-6736(12)60768-5. Published online, Largest randomized trial of IV tpa. No benefit of IV tpa at 6 hours from stroke onset based on primary endpoint.
•• IMS3 A Descriptive Study of Interventional Management of Stroke III Trial Investigator recruitment enhancement strategies. Stroke. 2012;43:A3192. Compares standard IV tpas < 3 hours to IV tpa plus IA intervention using 5 different IA techniques. Recently halted due to futility.
O’Collins VE, Macleod MR, Donnan GA, Horky LL, van der Worp BH, Howells DW. 1026 experimental treatments in acute stroke. Ann Neurol. 2006;59:467.
The GUSTO Investigators. An international randomized trial comparing 4 thrombolytic strategies for acute myocardial infarction. N Engl J Med. 1993;329:673–82.
Muir KW. Heterogeneity of stroke pathophysiology and neuroprotective clinical trial design. Stroke. 2002;33:1545–50.
Furlan AJ, Acute Stroke Trials. Strengthening the underpowered. Stroke. 2002;33:1450–1.
• Fisher M. New approaches to neuroprotective drug development. Stroke. 2011;42 Suppl 1:S24–7. Problems in neuroprotectant trial design with potential solutions.
• Donnan GA. A new road map for neuroprotection. Stroke. 2008;39:242–8. Problems in neuroprotectant trial design with potential solutions.
Furlan AJ, Fisher M. Devices, drugs, and the Food and Drug Administration: increasing implications for ischemic stroke. Stroke. 2005;36:398–9.
• Furlan AJ. Ethics and feasibility of placebo-controlled interventional acute stroke trials. Stroke. 2009:e533–4. Highlights ethical and feasibility issues complicating the design and completion of stroke IA reperfusion trials.
• Donnan GA, Davis SM. The ethics of thrombolytic trials beyond 3 (or 4.5) hours. Randomized controlled trials are required to change clinical practice. Stroke. 2009;40:1545. Justification for further stroke IA reperfusion trials.
Stroke Therapy Academic Industry Roundtable (Fisher M, Chair). Recommendations for standards regarding preclinical neuroprotective and restorative drug development. Stroke. 1999;30:2752–8.
Stroke Therapy Academic Industry Roundtable (Fisher M, Chair). Recommendations for clinical trial evaluation of acute stroke therapies. Stroke. 2001;32:1598–606.
Fisher M. Recommendations for advancing development of acute stroke therapies. for the Stroke Therapy Academic Industry Roundtable. Stroke. 2003;34:1539–46.
Fisher M. Enhancing the development and approval of acute stroke therapies: Stroke Therapy Academic Industry Roundtable. Stroke. 2005;36:1808–13.
Fisher M, Hanley DF, Howard G, Jauch EC, Warach S. Recommendations from STAIR V meeting on acute stroke trials, technology, and outcomes. Stroke. 2007;38:245–8.
Saver JL, Albers GW, Dunn B, Johnston KC, Fisher M. Stroke Therapy Academic Industry Roundtable (STAIR) recommendations for extended window acute stroke therapy trials. Stroke. 2009;40:2594–600.
Albers GW, Goldstein LB, Hess DC, Wechsler LR, Furie KL, Gorelick PB, et al. Stroke Therapy Academic Industry Roundtable (STAIR) recommendations for maximizing the use of intravenous thrombolytics and expanding treatment options with intra-arterial, and neuroprotective therapies. Stroke. 2011;42:2645–50.
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Furlan, A.J. Challenges in Acute Ischemic Stroke Clinical Trials. Curr Cardiol Rep 14, 761–766 (2012). https://doi.org/10.1007/s11886-012-0311-9
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DOI: https://doi.org/10.1007/s11886-012-0311-9