Trends in Acute Ischemic Stroke Trials Through the 20th Century

Abstract

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.

Estudo comparativo entre a relação do hemisfério acometido no acidente vascular encefálico e a evolução funcional em indivíduos destros

“…As expected, all assessed variables demonstrated improvements from the fi rst to the third month after the CVA. Th is observed functional recovery was related to the reversal of edema and biochemical alterations in the interstitial area of the injury 34 , as well as to the neural reorganization resulting from the demands of daily life and rehabilitation training 1,3,9,24,33 .…”

Tocotrienol Vitamin E Protects against Preclinical Canine Ischemic Stroke by Inducing Arteriogenesis

“…Emblematic of the high morbidity and mortality associated with stroke are the failures of potential stroke therapeutics, which showed benefit in small animal rodent stroke models but failed to translate into clinical success (Kidwell et al, 2001). As a result, rodent stroke models have been criticized for the anatomical disparity between small and large mammalian brains, large variability in infarct volumes, and inaccurate methods of inducing and confirming arterial occlusion (Gerriets et al, 2004).…”

“…Indeed, we have demonstrated that orally supplemented aTCT protects against stroke-induced lesion in the brain of spontaneously hypertensive rats (Khanna et al, 2005b). As small animal studies are recognized to be of limited reliability to predict success for stroke therapeutics in clinical trials (Kidwell et al, 2001), we developed a minimally invasive preclinical canine model (Rink et al, 2008) to test the efficacy of a tocotrienolenriched (TE) supplement in a randomized, blind, placebo (PBO)-controlled setting. Angiography, enabled in our large animal setting, helped elucidate that prophylactic TE supplementation improves collateral blood flow to the stroke-affected territory during stroke.…”

Merci Retriever

“…If there is one trait my generation of stroke researchers has acquired, it is a sense of humility. 9 Over the course of my career, I n a decade after approval of IV rt-PA for acute stroke, treatment leads to good outcomes in less than half of patients, and hemorrhage rates have not been reduced. Recanalization improves outcome 1 but is often delayed and incomplete.…”