SAN DIEGO—Lessons learned from past mistakes are paving the way for improved design and better outcomes in recent and ongoing clinical stroke trials. According to James Grotta, MD, efforts to standardize stroke severity among participants, to ensure adequate sample size and appropriate patient selection, and to shorten the delay to treatment, combined with comprehensive drug evaluations and aggressive pharmacologic and mechanical methods, are leading to positive results. He summarized a number of recent promising findings from various stroke trials at the 130th Annual Meeting of the American Neurological Association.

Measuring outcome has long been one of the biggest challenges in conducting clinical stroke trials, and its roots can be traced back to the 1995 NINDS trial that found that IV t-PA administered within three hours of stroke symptom onset improved clinical outcome at three months. The primary outcome was the percentage of patients who had an excellent outcome, which was defined by a Modified Rankin Scale score of 0 to 1. “But what’s ignored in the primary analysis was that at the other end of the Rankin scale, there was also less death and severe disability,” said Dr. Grotta, Professor of Neurology and Director of the Stroke Program at the University of Texas Health Science Center in Houston.

Another critical issue is how to protect the small benefit that has been observed beyond three hours, and one solution may lie in the power of these trials. For example, beyond six hours, 800 to 5,000 patients in each treatment arm are needed to detect any benefit, Dr. Grotta pointed out. “Instead of putting thousands of patients in these trials, selecting patients who are likely to have a dramatic response may be the better way to go,” he said. “Right now, at least, imaging is the most commonly used method to try and help select these patients.”

The Australian Trial of t-PA is currently looking at benefits up to six hours, with all participants undergoing MRI. Desmoteplase—a plasminogen activator derived from vampire bat saliva—was shown to be safe and appeared to improve clinical outcomes in patients three to nine hours after an acute ischemic stroke in two trials that were the first stroke studies to use MRI to select patients who still had salvageable brain tissue.

“The bottom line is that we are turning our attention to not only getting our patients in urgently so we get the most effect, but can we see some benefit beyond three hours using these methods?” Dr. Grotta asked.

NEUROPROTECTION TRIALS AND TRAVAILS

Differences between strokes in animal models and humans, weak drugs, and clinical design failures have plagued neuroprotection trials. “A lot of the drugs that we tested, we know that they get into the blood, but we don’t know how well they penetrate into the target areas of the penumbra that we’re interested in,” noted Dr. Grotta. Also, most neuroprotective drugs have been effective in animal models within a maximum of two to three hours, yet the median time to treatment in most of the neuroprotective trials has been greater than five hours. “We’re not likely to see the same benefit that we see by getting an artery open by giving a neuroprotective drug, so we need to power our trials to detect smaller treatment benefits,” said Dr. Grotta. “Why put patients into trials who have such severe strokes that they are likely to die? Similarly, if patients are going to get better spontaneously, why put those patients in the trial as well?”

In the Field Administration of Stroke Therapy–Magnesium (FAST-MAG) trial, paramedics are administering t-PA to patients in the field. “I think this is where neuroprotective therapy needs to go,” said Dr. Grotta. “Why not start [these drugs] as early as we can, as soon as a stroke is suspected?”

NXY-059

NXY-059, a novel, free radical–trapping neuroprotectant that in animal models has reduced infarct size and preserved brain function in acute ischemic stroke, is being investigated in two large, phase III trials. The first one, the SAINT (Stroke-Acute Ischemic-NXY Treatment) I trial, enrolled 1,700 patients internationally and earlier this year found a statistically significant reduction in patients receiving NXY-059 versus placebo on the primary outcome of disability after an acute ischemic stroke, though no significant difference between groups was observed regarding change in neurologic impairment. The SAINT II trial is ongoing in North America, with plans to enroll 3,200 patients to try to confirm the results observed in SAINT I.

One caveat with the SAINT I trial was that all participants were older than 18. “So we still don’t know at the end of this trial whether we have a treatment that will work in children,” said Dr. Grotta. “We are focusing on at least moderately severe strokes by requiring limb weakness and an NIH Stroke Scale score of at least 6. Most importantly, t-PA is permitted. A lot of neuroprotection trials for some reason excluded t-PA patients, who may actually be the best ones to qualify…. The time window was probably the area of biggest debate. In animal models, the drug was effective out to four to five hours. There were trends at six hours, but it was not effective at six hours.”

The demographics of SAINT I were typical of stroke patients, and the average time of treatment was three hours, 45 minutes, noted Dr. Grotta. “[Regarding] the average NIH Stroke Scale score, these were moderately severe strokes, very similar to those in patients put in thrombolytic trials,” he said. “Importantly, even though the study was carried out for the most part in Europe, almost 30% of patients got t-PA, even in Great Britain, where t-PA use has only relatively recently been endorsed.” There was no difference between patients receiving NXY-059 and those receiving placebo with respect to the number of adverse or serious adverse events.

“The conclusion from this trial [is that] there seems to be a signal there that this is the first positive, properly powered phase III trial of a neuroprotective drug,” said Dr. Grotta. “But I think we obviously have to wait and see what the results are of the parallel study that’s now ongoing.”

ALTERNATIVE APPROACHES TO STROKE TREATMENT

Other recent examples of successful approaches to stroke treatment include an endovascular embolectomy device—the Merci Retriever—which significantly restored vascular patency during an acute ischemic stroke within eight hours of symptom onset, thus providing an alternative for patients who are ineligible for thrombolytics. In addition, another study showed that continuous transcranial Doppler ultrasonography augmented t-PA–induced arterial recanalization, with a nonsignificant trend toward increasing the rate of recovery after stroke. Middle cerebral artery occlusion has been combined with various techniques, including hypothermia, which led to a reduction in infarct volume. Also, a combination of ethanol and caffeine (caffeinol) has been shown to reduce infarct volume by about half.

“When you couple these therapies together, that’s when you start getting really robust effect,” Dr. Grotta commented. “If it’s confirmed, we’re still only going to see a modest clinical effect when we target elegantly single pathways in the brain. But we have to be a little dirtier than that if we want to make a robust effect with neuroprotective strategies. I think we have to look at combination therapy. We’re actually doing a small trial where just like with our rats we’re giving the equivalent of two [cups of coffee] and one margarita and also cooling them a little bit. We appropriately call this the Cocktail Trial. Patients get t-PA, and we’re trying to see reasonably and safely whether we can give this combination of caffeine/ethanol and hypothermia. So far, we’ve done this in 37 patients, with caffeinol extremely well tolerated. I’m not sure that we quite have the cooling system down, but I’m not giving up yet. I think it’s going to be a question of how we can get studies like this funded.”

NR

—Colby Stong

Suggested Reading
Alexandrov AV, Molina CA, Grotta JC, et al. Ultrasound-enhanced systemic thrombolysis for acute ischemic stroke. N Engl J Med. 2004;351:2170-2178.
Aronowski J, Strong R, Shirzadi A, Grotta JC. Ethanol plus caffeine (caffeinol) for treatment of ischemic stroke: preclinical experience. Stroke. 2003;34:1246-1251.
Hacke W, Albers G, Al-Rawi Y, et al. The Desmoteplase in Acute Ischemic Stroke Trial (DIAS): a phase II MRI-based 9-hour window acute stroke thrombolysis trial with intravenous desmoteplase. Stroke. 2005;36:66-73.
Lees KR, Barer D, Ford GA, et al. Tolerability of NXY-059 at higher target concentrations in patients with acute stroke. Stroke. 2003;34:482-487.
Saver JL, Kidwell C, Eckstein M, et al. Prehospital neuroprotective therapy for acute stroke: results of the Field Administration of Stroke Therapy-Magnesium (FAST-MAG) pilot trial. Stroke. 2004;35:e106-e108.
Smith WS, Sung G, Starkman S, et al. Safety and efficacy of mechanical embolectomy in acute ischemic stroke: results of the MERCI trial. Stroke. 2005:36:1432-1438.

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