PHOENIX—“Many advances in our understanding of the mechanisms of ischemic injury have given us a wealth of knowledge for thinking about where we go from here,” said Marc Fisher, MD. “The key question is: How do we integrate all this information that has exploded over the last decade with what we’ve learned in developing therapies that work in a more extended time window than the current three-hour window to maximize our treatment effects?”

While data from several trials suggest that the degree of therapeutic benefit is directly related to the promptness of treatment, Dr. Fisher, a Professor in the Department of Neurology at the University of Massachusetts Medical School in Worcester, noted that it is extremely difficult to provide treatment for many stroke patients within the first three hours after the onset of symptoms. He addressed the critical issue of “How do we extend the window?” in his presentation at the 28th International Stroke Conference.

“There are four main areas: We need to increase the number of patients treated very early. We need to think about extending the time window for penumbral survival. We need to use imaging technology to identify patients with existing penumbra so that we move away from rigid time-window– based treatments and towards physiologically individualized treatments. Lastly, we need to think about how we move to the combination therapy era sooner rather than later,” he said.

AN IMPETUS FOR EARLY TREATMENT

The first goal is enhancing hyperacute therapy by increasing the number of patients treated within the three-hour window, Dr. Fisher related. “We need to educate patients to recognize the signs of stroke and get to the appropriate facility as quickly as possible. We need to organize medical care delivery systems to treat these patients in the most rapid and efficient manner possible. We need to think about prehospital initiation therapy.” He postulated that in the future, safe and effective therapies might exist “that do not require imaging or precise stroke subtyping, such as perhaps magnesium or other therapies that can be given in the ambulance. At least in my opinion, these are ways that we can increase the percentage of patients treated very early within the three-hour window,” he said.

A WIDER WINDOW

Dr. Fisher next addressed extending penumbral salvage to generate a longer period of time during which to initiate other therapies. “If we can prolong the existence of the penumbra then there’s a target for which lytic therapy may actually be effective,” he explained. A wider window of penumbral salvage would also enhance the possibility of demonstrating lytic therapy to be effective four, six, or even more hours after stroke onset, he noted, adding that there are trials already that are pursuing this.

Possible approaches to freezing the penumbra include initiating hypothermia before or with lytic therapy, or using neuroprotectants of various types to stabilize or freeze the penumbra before lytic therapy is initiated, “so that the target of acute stroke therapy still persists at the time we’re giving our delayed stroke therapy,” Dr. Fisher elaborated.

PICTURING THE PENUMBRA

“Using imaging to detect the penumbra is very important because it allows us to identify patients who have extended targets of acute stroke therapy,” Dr. Fisher said. “We know from many published works that we can identify penumbra with various imaging technologies beyond three hours—and diffusion/perfusion MRI and perfusion CT appear to have the most likely promise for use in clinical trials, and more importantly, in clinical practice.” MRI technologies can be employed to enhance patient selection because they can identify or approximate penumbra, he explained. They also provide an in vivo assessment of treatment effects, allowing researchers to reproduce in humans some of the animal experiments that demonstrated neuroprotective drug efficacy.

“We think that perfusion CT is coming along as a potential tool for the identification of penumbra. As this technology becomes more validated and we understand the thresholds better and it becomes more widely available, I think that diffusion CT will also give us another important technology that we can use in our clinical drug trial paradigms to enhance patient selection and extend the therapeutic window,” he added.

COMBINATION THERAPY

Dr. Fisher presented a few ideas for combination therapy trials to maximize tissue salvage and improve outcome in stroke patients. Some concepts he proposed include neuroprotection or hypothermia followed by delayed intravenous tissue plasminogen activator (t-PA) “in patients in which we hope that these initial therapies freeze penumbra.” Another option would be two neuroprotective drugs targeted at different portions of the ischemic cascade, and a third approach would involve a monotherapy that has multiple effects on the ischemic cascade. “On some levels, that is actually potentially more attractive because you avoid some of the problems of combination therapy trials,” Dr. Fisher commented. “It’s unclear at this time whether the US Food and Drug Administration is going to actually let us do a stroke trial with two unapproved drugs.”

A fourth approach would be intravenous t-PA followed by a drug targeted at reperfusion injury, and a final possibility is endovascular clot dissolution with neuroprotection. Dr. Fisher termed this last a “potentially very interesting area” because “then we can deliver the neuroprotection drug after the clot is dissolved by endovascular therapy and use the catheter to deliver the drug right at the target tissue that we’re trying to save from parts of the ischemic cascade.”

WINDOW OF OPPORTUNITY

“Much has been learned about stroke pathophysiology and clinical trial design over the last several decades,” Dr. Fisher remarked. “We have several promising new therapies available to us at the moment and I believe we can test them rationally and efficiently. Developing acute therapies and extending the therapeutic window will be difficult, but not impossible. There’s a lot of reason to be optimistic at this point in time. I think we can really extend the window, maximize benefits, and get new therapies out there for acute stroke in the next couple years,” he concluded.

NR

—C. Justin Romano

Suggested Reading
Fisher M, Brott TG. Emerging therapies for acute ischemic stroke: new therapies on trial. Stroke. 2003;34:359-361.
Fisher M, Ratan R. New perspectives on developing acute stroke therapy. Ann Neurol. 2003;53:10-20.
Wintermark M, Bogousslavsky J. Imaging of acute ischemic brain injury: the return of computed tomography. Curr Opin Neurol. 2003;16:59-63.

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