(Stroke. 2001;32:1349.)
© 2001 American Heart Association, Inc.
Original Contributions |
Trends in Acute Ischemic Stroke Trials Through the 20th Century
From the University of California at Los Angeles (UCLA) Stroke Center (C.S.K., S.S., J.L.S.), Department of Neurology (C.S.K., S.S., J.L.S.), and Department of Emergency Medicine (S.S.), UCLA Medical Center; and Comprehensive Stroke Center and Department of Neurology, University of Pennsylvania, Philadelphia (D.S.L.).
Correspondence to Chelsea S. Kidwell, MD, Department of Neurology, 710 Westwood Plaza, UCLA Medical Center, Los Angeles, CA 90095. E-mail ckidwell{at}ucla.edu
Background and Purpose—The advent of controlled clinical trials revolutionized clinical medicine over the course of the 20th century. The objective of this study was to quantitatively characterize developments in clinical trial methodology over time in the field of acute ischemic stroke.
Methods—All controlled trials targeting acute ischemic stroke with a final report in English were identified through MEDLINE and international trial registries. Data regarding trial design, implementation, and results were extracted. A formal 100-point scale was used to rate trial quality.
Results—A total of 178 controlled acute stroke trials were identified, encompassing 73 949 patients. Eighty-eight trials involved neuroprotective agents, 59 rheological/antithrombotic agents, 26 agents with both neuroprotective and rheological/antithrombotic effects, and 5 a nonpharmacological intervention. Only 3 trials met conventional criteria for a positive outcome. Between the 1950s and 1990s, the number of trials per decade increased from 3 to 99, and mean trial sample size increased from 38 (median, 26) to 661 (median, 113). During 1980–1999, median time window allowed for enrollment decreased per half decade from 48 to 12 hours. Reported pharmaceutical sponsorship increased substantially over time, from 38% before 1970 to 68% in the 1990s. Trial quality improved substantially from a median score of 12 in the 1950s to 72 in the 1990s.
Conclusions—Accelerating trends in acute stroke controlled trials include growth in number, sample size, and quality, and reduction in entry time window. These changes reflect an increased understanding of the pathophysiology of acute stroke, the imperative for treatment initiation within a critical time window, and more sophisticated trial design.
Key Words: cerebral ischemia • clinical trials • stroke, acute • stroke, ischemic • stroke management
This article has been cited by other articles:
 |
|
 |
|
  H. Karatas, Y. Aktas, Y. Gursoy-Ozdemir, E. Bodur, M. Yemisci, S. Caban, A. Vural, O. Pinarbasli, Y. Capan, E. Fernandez-Megia, et al. A Nanomedicine Transports a Peptide Caspase-3 Inhibitor across the Blood-Brain Barrier and Provides Neuroprotection J. Neurosci., November 4, 2009; 29(44): 13761 - 13769. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Mandava and T. A. Kent A Method to Determine Stroke Trial Success Using Multidimensional Pooled Control Functions Stroke, May 1, 2009; 40(5): 1803 - 1810. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. S. Kidwell, K. R. Lees, K. W. Muir, C. Chen, S. M. Davis, D. A. De Silva, C. J. Weir, S. Starkman, J. R. Alger, J. L. Saver, et al. Results of the MRI Substudy of the Intravenous Magnesium Efficacy in Stroke Trial Stroke, May 1, 2009; 40(5): 1704 - 1709. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Xu, L. Ye, and Q. Ruan Environmental Enrichment Induces Synaptic Structural Modification After Transient Focal Cerebral Ischemia in Rats Experimental Biology and Medicine, March 1, 2009; 234(3): 296 - 305. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Rink, G. Christoforidis, A. Abduljalil, M. Kontzialis, V. Bergdall, S. Roy, S. Khanna, A. Slivka, M. Knopp, and C. K. Sen Minimally invasive neuroradiologic model of preclinical transient middle cerebral artery occlusion in canines PNAS, September 16, 2008; 105(37): 14100 - 14105. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. L. Saver Novel End Point Analytic Techniques and Interpreting Shifts Across the Entire Range of Outcome Scales in Acute Stroke Trials Stroke, November 1, 2007; 38(11): 3055 - 3062. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Sakellaridis and D. Panagopoulos Significance of Experimental Infarct Size as an Indicator of Therapeutic Efficacy in Humans Stroke, September 1, 2007; 38(9): e89 - e90. [Full Text] [PDF]
|
|
|
|
|
|
D. C. Hess NXY-059: A Hopeful Sign in the Treatment of Stroke Stroke, October 1, 2006; 37(10): 2649 - 2650. [Full Text] [PDF]
|
|
|
|
 |
|
 D. S. Liebeskind, C. S. Kidwell, J. W. Sayre, and J. L. Saver Evidence of publication bias in reporting acute stroke clinical trials. Neurology, September 26, 2006; 67(6): 973 - 979. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. L. Saver Does the Merci Retriever Work?: For Stroke, May 1, 2006; 37(5): 1340 - 1341. [Full Text] [PDF]
|
|
|
|
|
|
J. S. Elkins, T. Khatabi, L. Fung, J. Rootenberg, and S. C. Johnston Recruiting Subjects for Acute Stroke Trials: A Meta-Analysis Stroke, January 1, 2006; 37(1): 123 - 128. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Y. Palesch, B. C. Tilley, D. L. Sackett, K. C. Johnston, and R. Woolson Applying a Phase II Futility Study Design to Therapeutic Stroke Trials Stroke, November 1, 2005; 36(11): 2410 - 2414. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Fisher and T. Tatlisumak Use of Animal Models Has Not Contributed to Development of Acute Stroke Therapies: Con Stroke, October 1, 2005; 36(10): 2324 - 2325. [Full Text] [PDF]
|
|
|
|
|
|
M. Fisher and for the Stroke Therapy Academic Industry Roundtabl Enhancing the Development and Approval of Acute Stroke Therapies: Stroke Therapy Academic Industry Roundtable Stroke, August 1, 2005; 36(8): 1808 - 1813. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Krams, K. R. Lees, and D. A. Berry The Past Is the Future: Innovative Designs in Acute Stroke Therapy Trials Stroke, June 1, 2005; 36(6): 1341 - 1347. [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Murakami, H. Takamatsu, A. Noda, K. Osoda, R. Ichise, M. Tatsumi, K. Tabata, T. Sawamoto, and S. Nishimura Pharmacokinetic Animal PET Study of FK506 as a Potent Neuroprotective Agent J. Nucl. Med., November 1, 2004; 45(11): 1946 - 1949. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. J. Weir, M. Kaste, K. R. Lees, and for the Glycine Antagonist in Neuroprotection Int Targeting Neuroprotection Clinical Trials to Ischemic Stroke Patients With Potential to Benefit From Therapy Stroke, September 1, 2004; 35(9): 2111 - 2116. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. C. Fagan, D. C. Hess, E. J. Hohnadel, D. M. Pollock, and A. Ergul Targets for Vascular Protection After Acute Ischemic Stroke Stroke, September 1, 2004; 35(9): 2220 - 2225. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. L. Saver, C. Kidwell, M. Eckstein, S. Starkman, and for the FAST-MAG Pilot Trial Investigators Prehospital Neuroprotective Therapy for Acute Stroke: Results of the Field Administration of Stroke Therapy-Magnesium (FAST-MAG) Pilot Trial Stroke, May 1, 2004; 35(5): e106 - e108. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. H. Danton and W. D. Dietrich The Search for Neuroprotective Strategies in Stroke AJNR Am. J. Neuroradiol., February 1, 2004; 25(2): 181 - 194. [Full Text] [PDF]
|
|
|
|
 |
|
 S C Lewis and C P Warlow How to spot bias and other potential problems in randomised controlled trials J. Neurol. Neurosurg. Psychiatry, February 1, 2004; 75(2): 181 - 187. [Full Text] [PDF]
|
|
|
|
|
|
T. Crocco, T. Gullett, S. M. Davis, N. Flores, L. Sauerbeck, E. Jauch, B. Threlkeld, B. Pio, M. Ottaway, A. Pancioli, et al. Feasibility of Neuroprotective Agent Administration by Prehospital Personnel in an Urban Setting Stroke, August 1, 2003; 34(8): 1918 - 1922. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Fisher Recommendations for Advancing Development of Acute Stroke Therapies: Stroke Therapy Academic Industry Roundtable 3 Stroke, June 1, 2003; 34(6): 1539 - 1546. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Gladstone, S. E. Black, and A. M. Hakim Toward Wisdom From Failure: Lessons From Neuroprotective Stroke Trials and New Therapeutic Directions Stroke, August 1, 2002; 33(8): 2123 - 2136. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. G. Sorensen Apparently, Diffusion Coefficient Value and Stroke Treatment Remains Mysterious AJNR Am. J. Neuroradiol., February 1, 2002; 23(2): 177 - 178. [Full Text] [PDF]
|
|
|
|
|
|
J. Fang, M. H. Alderman, and J. V. Tu Trend of Stroke Hospitalization, United States, 1988-1997 Editorial Comment Stroke, October 1, 2001; 32(10): 2221 - 2226. [Abstract] [Full Text] [PDF]
|
|