Medical Device Daily Contributing Writer

SAN FRANCISCO — If Hall of Fame baseball player Yogi Berra had been an attendee at last week's 32nd annual International Stroke Conference, sponsored by the American Stroke Association (ASA; Dallas), he might have summarized its activities as being "deja vu all over again" — one of his most famous aphorisms.

Stroke specialists at this gathering over the past several years have constantly lamented the fact that a very small percentage of acute ischemic stroke (AIS) patients in the U.S. are receiving timely treatment for their stroke. And that lament continued at this year's meeting, which drew over 4,000 participants.

According to the ASA, about 85% of the 700,000 new or recurrent strokes in the U.S. each year are ischemic, meaning the product of the occlusion of a key blood vessel in the brain.

In 1996, Genentech (South San Francisco, California) gained FDA approval for its clot-dissolving drug tissue plasminogen activator (tPA). But notwithstanding a well-demonstrated record of efficacy and safety, numerous studies have shown that tPA is administered to a paltry 5% or so of all AIS victims, the apparent result of two key drawbacks in its use.

First, it must be administered within three hours of stroke symptom onset in order to achieve its maximum therapeutic benefit.

And second, there is a 6% to 7% risk of intracerebral hemorrhage, which can on occasion be fatal, causing hospital personnel to proceed very cautiously in administering the drug. Administration of a clot-busting agent undoubtedly helps patients.

A poster abstract presented here showed that about a quarter of patients given tPA intra-arterially within six hours of stroke experienced a dramatic recovery. The intra-arterial approach has not yet received FDA approval. Only the intravenous route is cleared for unrestricted marketing.
The authors described this as a "Lazarus phenomenon," named after the biblical figure who, according to the New Testament, was raised from the dead by Jesus. In this study, the Lazarus effect was defined as at least a 50% reduction in a patient's National Institutes of Health Stroke Scale (NIHSS) score 24 hours after treatment.

According to lead author Gregory Christoforidis, MD, an associate professor of radiology at Ohio State University College of Medicine (Columbus, Ohio) "the surprising thing [from the study] was that the time to treatment had such a significant impact." Other factors that were thought to be major contributors were not that significant. The depressingly low rate of tPA usage has catalyzed numerous key organizations, such as the ASA, into developing aggressive patient education efforts. The ultimate goal is to substantially boost the triage of AIS patients once they have reached out for help. And other organizations are working to improve the delivery of AIS patients to the hospital and then ensure rapid triage after they arrive.

An example of an approach to this problem was presented at a poster session showing the results of a program begun in December 2004 by the Massachusetts Department of Public Health (Boston).

The program's goal — which included a voluntary hospital Primary Stroke Services licensure program — was to increase use of tPA in eligible patients. Lee Schwamm, MD, Associate Director, Massachusetts General Hospital Acute Stroke Service (Boston) reported that the program has rapidly achieved wide adoption, and that the safe use of tPA in the state had increased about 50% over baseline among eligible patients.

A similar program, called the Florida Stroke Act, was developed by several organizations to increase tPA usage in Florida hospitals. The legislation went into effect July 1, 2005, and early results are hopeful — the percentage of patients receiving tPA increasing from 8.4% pre-legislation to 10.5% once the legislation went into effect.

This and other similar programs around the U.S. clearly are having a positive impact on the timely treatment of AIS victims. However, the fact remains that the very narrow three-hour "window of opportunity" for intravenous tPA is a huge drawback and that new approaches, both medical and interventional, must be developed.

The failure of the healthcare industry to bring new agents and devices to the market with a longer window is not due to any lack of effort. According to one speaker at a session titled "Acute Management," a total of 88 compounds have been tried — and failed — to show safety and efficacy in humans, often despite promising animal data.
"I guess that young rats are different than old patients," quipped the moderator of that session.

A good example of a big disappointment is the result from the second Stroke Acute Ischemic NXY-059 Treatment (SAINT-II) trial. NXY-058, a neuroprotective agent, was developed by AstraZeneca (London, UK). Initial animal and the smaller SAINT-I trial results were very good, and there was widespread excitement that NXY-059 would become a major force in AIS therapy. However, the larger SAINT-II trial showed that NXY-059 do not provide any meaningful benefit in humans.

Several promising drugs are now in the pipeline, as well as several initiatives by the device industry.

In that regard, very promising preliminary data was presented on a device-based approach by Bjorn Dahlof, MD, professor of medicine, G teborg University Department of Medicine (Goteborg, Sweden), who discussed the results of a feasibility trial of the NeuroThera Laser System (NTS) for the treatment of AIS within 24 hours of stroke onset.

The device, being developed by private, venture-capital-backed PhotoThera (Carlsbad, California), features the non-invasive delivery of near-infrared (NIR) energy into the brain. The NTS delivers a NIR at 808 nm wavelength at a controlled power density, in combination with a thermal management system to prevent heat buildup on the patient's head.

The system consists of a mobile cart, a fiber optic cable and a handpiece that a clinician uses to direct the energy to 20 pre-determined treatment sites on the scalp. Each site is treated for about two minutes, and the total procedure lasts approximately one hour.

Dahlof acknowledged that the mechanism of action is not fully understood. He stated that cytochrome c oxidase, a photoreceptor in mitochondria, absorbs NIR energy and drives adenosine triphosphate (ATP) formation, and he speculated that the effects of the therapy may include improved energy metabolism, the prevention of apoptosis (cell death) and the enhancement of neuro-recovery mechanisms.

Dahlof reported that treatment effect was seen across multiple effectiveness outcome measures, that a statistically significant effect was observed on the prospectively identified effectiveness measure, and that the treatment effect was maintained at three months.

He said that 59% of NTS treated patients achieved a successful outcome on the modified Rankin scale, comparing favorably to 44% success for patients receiving sham treatment.

Particularly impressive is the median time-to-treatment for the treated patients of 18 hours, with a few patients being treated as far out as 24 hours.

As previously noted, tPA's window is a mere three hours. The safety profile of NTS was solid, with patients in both arms of the trial experiencing normal post-stroke issues.

PhotoThera has just launched a larger, pivotal trial called NEST-2, which is a double blind, 1:1 randomized, multi-center trial that will enroll 660 patients at up to 50 investigational sites around the world.

Historically, acute ischemic stroke trials have been very slow to enroll, primarily due to the very tight treatment window and narrow inclusion criteria. With a much broader time window and more modest enrollment criteria, this trial could be fully enrolled by the end of 2008.
Dahlof concluded his presentation by saying that the NeuroThera System "is very promising, and we are eager to see the results of the confirmatory, pivotal trial."