In Anticipation of International Stroke Trial-3 (IST-3)

Few medical advances have polarized physicians so powerfully as thrombolytic therapy for stroke.1 After years of delays, this highly efficacious treatment fully entered mainstream clinical use with the publication of the European Cooperative Acute Stroke Study (ECASS)-3 study; annually we see increasing rates of use globally.2 Along the way, many self-appointed “expert critiques” challenged the original trials and sought to insinuate that the therapy was less effective than primary data indicated. Seeking to use data and science to quell some of the hostility toward recombinant tissue-type plasminogen activator (rtPA), a highly dedicated and rigorous group of investigators at Edinburgh organized a trial in the late 1990s named the International Stroke Trial (IST).3 Because 2 previous trials shared the name IST—1 of aspirin for stroke and the other for a neuroprotectant—the trial became known as the IST-3. Originally planned for a sample size of 6000 patients, IST-3 sought to become the largest acute stroke trial ever done.4 After a decade and a half, the IST-3 study group has thrown in the towel approximately halfway short of their finish line, and will soon publish the results of their truncated trial. The investigators have been refreshingly transparent throughout and have posted on their web site their statistical analysis plan, their protocol, and the baseline characteristics of their study sample (www.dcn.ed.ac.uk/ist3/). These documents lead to a number of questions about IST-3 and how—no matter what the results—thoughtful clinicians might anticipate using the IST-3 data in clinical decision-making. Design IssuesA number of design issues in IST-3 deserve thoughtful review before seeing the results. The study leadership invoke a concept known as “large simple” trials, meaning trials that seek power by simplifying protocols and reducing data collection to a bare minimum in hopes of enhanced recruitment. Large simple trials may be an answer …