The study, being published online today (Thursday, Feb. 7), by the New England Journal of Medicine, was authored by Joseph Broderick, MD, Albert Barnes Voorheis Chair of Neurology and Rehabilitation Medicine at UC and research director of the UC Neuroscience Institute, one of four institutes affiliated with the UC College of Medicine and UC Health. Results were also being presented today at the American Heart Association/American Stroke Association’s International Stroke Conference 2013 in Honolulu.
“Our study highlights that improved reopening of arteries and delivery of blood flow to the brain was not a guarantee of improved clinical efficacy,” Broderick says. “It means we still have to answer the question of who benefits most from the new technology going inside the artery, because it takes a lot of time and effort and is more expensive.”
Patients studied for this research were part of the Interventional Management of Stroke III (IMS III) trial, begun in 2006 and funded by the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health (NIH). With 656 adult stroke patients at 58 centers in the United States, Canada, Australia and Europe, it was the largest trial to date of an endovascular intervention for acute ischemic stroke (treatment delivered within the brain artery at the site of the clot), NINDS officials said. (Ischemic strokes occur as a result of an obstruction to the blood flow, typically a clot.)
UC was the clinical coordinating center for the trial, with Broderick as principal investigator and Thomas Tomsick, MD, professor of radiology and director of neuroradiology at UC, as principal neuro-interventionalist. Tomsick was also scheduled to participate in a symposium on IMS III later today.
The Medical University of South Carolina was the statistics and data coordinating center.
In May 2012, NINDS announced that it was stopping the trial because an interim analysis indicated that the combination approach was highly unlikely to demonstrate the desired minimum 10 percent benefit even if the study completed the projected full enrollment of 900 patients.
Trial participants were randomized to receive either the standard Food and Drug Administration (FDA)-approved IV treatment of tissue plasminogen activator (tPA) alone or a combination approach that provided both standard IV tPA and an endovascular therapy using either tPA delivered into the artery directly at the site of the clot or an FDA-approved device to remove the blood clot in the brain.
Based on earlier studies, researchers anticipated that adding an endovascular approach to standard IV tPA would reduce stroke-related disability by providing a means to eliminate very large clots that would otherwise persist despite IV tPA. Such approaches include administering tPA directly into the clot via a catheter, directly aspirating the clot or retrieving it via coiled wires or a stent system.
By the time the study was stopped, however, 90-day outcomes showed that patients in the IV tPA alone group were just as likely as those in the combination therapy group (39 percent vs. 41 percent) to be functionally independent, according a standardized measurement tool. The subgroup of subjects with the most severe strokes had a trend toward better outcomes with endovascular treatment, but this difference was not statistically significant, researchers said.
The stroke-related disability outcomes were similar between the two treatment groups despite an estimated 40 percent greater likelihood of clearing blockages and re-establishing blood flow with the intra-arterial method compared to IV tPA alone.
“There is some signal that suggests that if we could deliver the endovascular therapy more quickly it would make a difference, and that patients with larger strokes would benefit more,” Broderick says, “but we would need a larger trial to demonstrate that.”
Cutting the time to endovascular therapy poses significant challenges given the logistics of assembling the endovascular team, setting up the treatment room and getting the catheter from the groin to the blocked brain artery, which in itself can take 30 to 45 minutes, Broderick notes. In addition, most patients do not have immediate access to level of comprehensive stroke care services required to perform intra-arterial procedures. Instead, they are often treated with IV tPA at a local hospital then transferred to another hospital, all of which delays the time to the delivery of endovascular therapy.
“We put a lot of effort into decreasing the time to start tPA, but we haven’t done the same thing with endovascular therapy,” says Broderick. “That’s something we need to study.”
One limitation of the trial is that, at the time the trial was halted, only a handful of patients had been treated with the latest generation of stents designed to remove clots. Tomsick notes that the clot-removal devices with the highest rate of adverse outcomes in the trial are currently much less commonly used and have given way to newer devices that have been shown to be more effective. Further study will be needed with those devices, he said.
Although the lack of benefit from a direct clot treatment approach is disappointing, IMS III sheds light on research gaps that need to be addressed in ongoing and future trials of these devices before evidence-based recommendations that guide the use of intra-arterial devices can be made, says Scott Janis, PhD, program director, NINDS.
“These devices still may play a critical role in improving outcomes among people with really serious strokes involving clots that cannot be cleared or are cleared very slowly by standard IV tPA. More studies are needed to identify the circumstances in which endovascular therapy will make a difference in patient outcomes,” he said.
Media Contact: Keith Herrell, 513-558-4559