Extending the Time Window for Endovascular and Pharmacological Reperfusion
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SI: CHALLENGES AND CONTROVERSIES IN TRANSLATIONAL STROKE RESEARCH
Extending the Time Window for Endovascular and Pharmacological Reperfusion Nils Henninger 1,2 & Marc Fisher 3,4
Received: 20 November 2015 / Revised: 13 December 2015 / Accepted: 14 December 2015 # Springer Science+Business Media New York 2016
Abstract Pharmacological and device-induced reperfusion therapies have demonstrated increasingly positive outcomes regarding both reperfusion efficacy and 90-day functional outcomes after acute ischemic stroke. However, presently, only a minority of patients are eligible for these treatments. Less than 10 % of all ischemic stroke patients receive intravenous thrombolysis in most centers and it has been projected that only approximately 7–15 % of ischemic stroke patients are eligible for acute endovascular intervention. Making these effective therapies safely available to a much larger number of patients is critical for expanding the benefits of acute ischemic stroke treatment. In this article, we summarize the key results from the clinical trials, challenges, and exciting novel opportunities to increase patient eligibility for these therapies as well as for better outcomes for stroke patients. Keywords Animal modeling . Endovascular . Ischemic stroke . Imaging . Neuroprotection . Recanalization . Reperfusion injury . Thrombolysis . Tissue-type plasminogen activator . Time window
* Marc Fisher [email protected]
1
Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA
2
Department of Psychiatry, University of Massachusetts Medical School, Worcester, MA, USA
3
Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
4
Division of Stroke and Cerebrovascular Diseases, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, Boston, MA 02215, USA
Overcoming the Challenges of Translating Preclinical Drug Development to the Clinical Setting The cellular consequences of reduced or absent blood flow to the brain are manifold and referred to as the ischemic cascade [1]. Therapies directed at impeding components of the ischemic cascade in an attempt to prevent ischemic tissue from progressing to irreversible infarction form the basis of the neuroprotective strategy of acute ischemic stroke treatment. A large number of approaches to acute ischemic neuroprotection were shown to be beneficial in animal stroke models, performed primarily in rodents [2]. Many purported neuroprotective drugs were then studied in clinical trials, but unfortunately none of the neuroprotective drugs were found to be effective in phase III trials in which they were compared to placebo [3]. Many reasons were identified for the failure of translation of monotherapy neuroprotection from successful animal models in clinical trials [4]. Fault can be found in how the preclinical modeling was conducted as well as how the clinical assessment programs were performed (Table 1). The failures of translation led to
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