CD&D Contributing Editor

SAN DIEGO — With the beginning of baseball spring training a few weeks ago, we are reminded that it is a new year, full of hopes and dreams that this will be the year when our favorite team becomes a winner.

Similarly, each year at about the same time as spring training begins, the annual International Stroke Conference, sponsored by the American Heart Association (AHA; Dallas) takes place, amid hopes that perhaps a much-needed "magic bullet" for stroke therapy will be unveiled.

However, stroke is an extraordinarily complex and heterogeneous disease and it is inconceivable that one approach could singlehandedly provide a solution. Nevertheless, several positive signs of progress were seen here at this year's meeting, although the stroke community remains frustrated that the pace is not quicker.

Acute ischemic stroke (AIS), which accounts for about 85% of the roughly 750,000 strokes that occur annually in the U.S., is severely hampered by a treatment "window of opportunity" that is frustratingly narrow.

The only FDA-approved AIS drug, tissue-plasminogen activator (tPA), which is marketed by Genentech (South San Francisco, California), triggers an enzyme cascade that will dissolve cerebral blood clots. but the drug must be administered within three hours of a stroke. It also increases intracerebral hemorrhage risks, which has had an impact on its usage.

tPA was approved well over a decade ago and the fact that it is still the only FDA-approved agent for AIS is not due to a lack of effort or commitment on the part of the pharmaceutical industry. It is estimated that there have been more than 60 failed drug trials in the past decade.

As in past years, the dominant topic at the stroke conference was the safety and efficacy of tPA beyond its three-hour window. Peter Sandercock, MD, of the University of Edinburgh's (Edinburgh, Scotland) Western General Hospital, presented data from an analysis of 600,000 stroke patients in the U.S., showing that only 2% of these patients received tPA within the three-hour time window, while 30% received the drug within six hours.

In his study, 60% of the patients were seen at a specialized stroke unit, and he found that advanced patient age was the primary limiting factor for tPA use.

Jeffrey Saver, MD, director of the University of California Los Angeles Stroke Center, discussed the concept of the "golden hour" (that is, patients arriving at the hospital within one hour from the onset of their stroke) and found that those patients were twice as likely to receive tPA as those arriving later. Other studies found that tPA usage could be optimized by establishing hotlines between rural hospitals and stroke centers, and by starting tPA prior to transfer to the stroke center.

CT scanner use raises patient population

An interesting strategy to buoy tPA's use was discussed at the 2008 annual meeting of the Radiological Society of North America (Oak Brook, Illinois).

A study conducted at the North Shore Medical Center (Salem, Massachusetts) found that the availability of a portable eight-slice computed tomography (CT) scanner in the hospital's emergency room reduced the time between the order and exam from 34 minutes to 15 minutes, a reduction of 54%. This resulting in an approximately doubling in the number of patients who were eligible for tPA.

More importantly, the researchers estimated that if this approach was used nationally, the number of stroke patients that could be treated with the thrombolytic therapy within the three-hour window would increase by a startling 86%.

The study employed a head-and-neck CT scanner called the CereTom, which is sold by NeuroLogica (Danvers, Massachusetts) for about $300,000.

Werner Hacke, MD, chairman of the department of neurology at the Heidelberg University Hospital (Heidelberg, Germany), presented a summary of the European Cooperative Acute Stroke Study (ECASS 3), in which patients were treated with tPA between three and 4.5 hours after stroke.

The ECASS 3 findings, which were published in a landmark article in the Sept. 25, 2008, issue of the New England Journal of Medicine, showed that tPA administered between three and 4.5 hours after the onset of symptoms provided significantly improved clinical outcomes in patients with acute ischemic stroke.

Based upon the results of ECASS 3, in mid-January the European Stroke Organization (ESC; Heidelberg, Germany) amended its guidelines for thrombolytic use in acute ischemic stroke. The ESC recommended that tPA could be given up to within 4.5 hours after stroke onset, even though the drug's European label still includes a three-hour limit. According to Hacke, the distributor of tPA in Europe, Boehringer Ingelheim (Ingelheim, Germany), already has initiated a process to get the drug's label updated to reflect the recommendations of the ESC.

Hacke noted that in the U.S. there has been more concern about extending the time window because of the failure of other trials. ECASS 1 and ECASS 2 both missed their primary endpoints, and the Alteplase ThromboLysis for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS) study was halted early due to a lack of efficacy and a significant increase in intracerebral hemorrhage.

However, Hacke argued that ECASS 1 and ECASS 2 "showed the same signal" as ECASS 3, and that ATLANTIS was "at least neutral" rather than negative when analyzed to consider labeling differences in Europe vs. the U.S.

Sandercock recommended that physicians "set aside" ATLANTIS because it is a "tiny trial and tiny trials tend to produce very unstable results." He maintained that administration of tPA within six hours "may have quite a useful effect, although we're not quite there yet as far as statistical significance."

Another major tPA study is the Third International Stroke Trial (IST3), which is currently under way and has already enrolled about 1,500 patients. IST3 ultimately will enroll 3,100 patients and will evaluate tPA treatment within six hours of stroke onset. It is the largest tPA trial ever conducted and should put the controversy to rest, although data are not expected until 2012.

Another area of focus at the conference was strategies to combine tPA with other drugs that might improve its safety or efficacy. Researchers established several years ago that both tPA and the stroke itself activate harmful matrix metalloproteinases (MMPs), and that co-administration of an MMP inhibitor might mitigate that effect.

Yet here too, Eng Lo, PhD of the Harvard Medical School and Massachusetts General Hospital (both Boston) demonstrated that timing is key. While early administration of an MMP inhibitor can decrease the infarct size in animal models of stroke, administration days later can make the infarct worse, since the drug will interfere with the brain's attempts to heal itself, he said.

NEST-2 results stir interest

There was plenty of interest at this meeting on device-based solutions to treat AIS. Because of its previously demonstrated success in treating stroke patients far beyond the current short time window, the results of the NeuroThera Effectiveness and Safety Trial-2 (NEST-2) were eagerly anticipated by the stroke community.

Justin Zivin, MD, professor of neurosciences at the University of California San Diego and the principal investigator for the NEST-2 study presented the results, which also were published in the February edition of Stroke: Journal of the American Heart Association in an article titled "Effectiveness and Safety of a Transcranial Laser Therapy for Acute Ischemic Stroke."

The article, authored by Zivin and the other NEST-2 investigators, referred to an "urgent unmet need" for stroke therapies that could be administered for an extended period after stroke onset and noted that despite the availability of tPA and newer mechanical thrombectomy catheters that can capture cerebral clots, "fewer than 4% of patients receive any therapy ..."

The developer of the technology, privately-owned, venture capital-backed PhotoThera (Carlsbad, California), had released very promising data from its 120-patient international feasibility trial at this same conference in 2007. Very importantly and impressively, it provided initial evidence of excellent efficacy in a patient population with a mean time to treatment of over 16 hours, with a few patients being treated successfully as far out as 24 hours.

NEST-2 enrolled 660 patients at 53 sites in four countries between January 2007 and April 2008 in a randomized, double-blind, sham-controlled trial. The primary endpoint was a favorable 90-day score of 0-2 using the modified Rankin Scale (mRS). The mRS is a widely used and well-accepted scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke.

Patients were eligible for inclusion in the study if they were between 40 and 90 years of age, had moderate to severe strokes and had not received tPA. Initiation of treatment had to occur within 24 hours after stroke onset.

NEST-2 did not meet its primary endpoint, with a favorable outcome in about 36% of treated patients compared to 31% of patients in the sham group. The mean time to treatment was more than 14 hours. Mortality rates and serious adverse events did not differ between groups, which provided evidence that the procedure is safe. This safety profile had been clearly demonstrated in the earlier, smaller trial.

A post-hoc sub-group analysis of 434 patients who suffered moderate to moderately severe strokes did reveal a favorable outcome in about 52% of patients in the treated group compared to 42% of patients in the sham group. This 10% treatment effect differential was statistically significant and lends credence that it has the potential for significant success in select patient groups.

The procedure, sometimes referred to as transcranial laser therapy (TLT), features the non-invasive delivery of 808 nanometers of near-infrared (NIR) laser energy into the brain. The device consists of a mobile cart, a fiber optic cable and a handpiece that a clinician uses to direct the laser energy to 20 pre-determined treatment sites on the scalp. It delivers the laser energy at a controlled power density, in combination with a thermal management system to prevent heat buildup on the patient's head. Each site is treated for about two minutes, with the total procedure lasting about an hour.

The precise mechanism of action of TLT is not fully understood. Possibly the most plausible theory is that cytochrome c oxidase, a photoreceptor in the mitochondria, absorbs the NIR laser energy and drives adenosine triphosphate formation. The effects of the therapy may include improved energy metabolism, the prevention of apoptosis (cell death) and the enhancement of neuro-recovery mechanisms.

In the Stroke article, the authors speculated that near-infrared laser energy may have an anti-apoptotic effect and also that "it is possible that TLT acts in a neuroprotective fashion." Neuroprotection has been one of the Holy Grails in the ischemic stroke field for many years. It has been estimated that nearly 100 neuroprotective compounds have been tried in humans and all have failed to provide meaningful benefit.

In an interview with Cardiovascular Devices & Drugs, Zivin said that despite the failure of NEST-2 in meeting its primary endpoint, TLT is "as promising a device technology as I have ever seen for treating acute ischemic stroke."

Hacke, who participated in NEST-2 and will be more involved in the future, was equally enthused. "TLT is one of the most promising new therapies that we've seen in a long time," he said, "especially as it may expand the treatment window for acute ischemic stroke to 24 hours."

PhotoThera is planning to initiate another TLT trial, called NEST-3 later this year. It is expected to enroll about 1,000 patients with some revisions in the entry criteria vs. NEST-2.

There were numerous other devices that showed potential to help manage AIS better. Results from a Phase I/II trial, combining tPA with transcranial Doppler (TCD) ultrasound and a specific microsphere revealed that it was twice as likely to cause a complete recanalization of the blocked and ischemic vessel than tPA alone. The manufacturer of the microspheres is ImaRx Therapeutics (Redmond, Washington), a small, publicly-traded company.

The procedure, which is called SonoLysis therapy, leverages the energy from ultrasound waves to cavitate tiny gas-filled lipid microspheres tradenamed MRX-801 within stroke-causing blockages to reopen arteries and restore blood flow.

The trial randomized 35 patients to receive tPA alone or in combination with ultrasound and either a high or low dose of MRX-801. Sustained complete recanalization after 36 hours was achieved in 67% of the low-dose patients, 46% of the high-dose patients, and 33% of the tPA patients.

Three months following treatment, improvement in clinical outcomes measured by the modified Rankin score was reported in 75% of the low-dose patients, 50% of the high-dose patients, and 36% of the tPA patients.

Commenting on these results at a press conference, Andrei Alexandrov, MD, director of the University of Alabama Comprehensive Stroke Center (Birmingham), said that "these findings demonstrate that ultrasound combined with microspheres and tPA can be tested further in a pivotal clinical trial with the goal to provide a more effective treatment option for stroke patients by promoting faster clearing of blocked blood vessels as well as improved patient outcomes."

He further commented that "It is very promising to see such results, which support the potential of this therapy as a more effective and expansive therapy for stroke patients."

NeuroFlo augments blood flow

Another interesting approach and a potential means to substantially extend the time window to treat AIS was presented at a poster session. The sponsor is privately-owned, venture capital-backed CoAxia (Maple Grove, Minnesota).

It has developed a unique, dual-balloon endovascular device, trade-named the NeuroFlo catheter, which augments the blood flow to the brain, and in particular increases blood flow in the collateral blood vessels. This increases perfusion in the ischemic regions of the brain.

The device is inserted through the femoral artery into the descending aorta and has independently inflatable balloons located immediately above and below the renal arteries. The balloons, which are sequentially inflated to produce occlusions of about 70%, are left inflated for 45 minutes then removed. This procedure partially restricts blood flow in the descending aorta, diverting blood flow from the lower extremities to the cerebral collaterals.

The extensive interconnected collateral vascular network in the brain, which are ready somewhat active following an ischemic stroke, are capable of further increasing the delivery of oxygenated blood to the stroke's ischemic penumbra.

The essential premise of this approach is that the ability to salvage the penumbra and minimize the eventual size of the infarct may lead to improved neurological recovery.

An article in the November 2008 issue of Current Cardiology Reports titled "Aortic Occlusion for Cerebral Ischemia: From Theory to Practice," carefully considered the theoretical basis for aortic occlusion as a therapeutic strategy. The author, David Liebeskind, MD, a neurologist from the University of California Los Angeles Stroke Center, noted that "targeting ischemia rather than clot disruption or consideration of venous hemodynamics and flow redistribution may initiate a radical transformation in stroke care." Liebeskind did caution, however, that "ultimately, demonstration of a rational mechanism that averts ischemia will be essential."

CoAxia initiated its human studies in 2002 to demonstrate the safety of the procedure, which was successfully completed. In 2005, the company began its pivotal trial, which is called Safety and Efficay of NeuroFlo for Treatment of Ischemic Stroke (SENTIS). A key aspect of this trial is that patients can be enrolled up to 14 hours after the onset of their stroke, a huge increase over the time window afforded by thrombolysis.

SENTIS is a prospective, randomized, multi-center, 440-patient trial designed to demonstrate the safety and efficacy of this approach compared to medical management. As in common with other trials, the primary endpoint is neurological outcome at 90 days. To date, 308 patients have been enrolled and the company believes that the trial could be completed in about one year.

CoAxia also is involved in other trials as well. In conjunction with several leading stroke centers, it has co-authored an additional protocol to test the feasibility of treating patients with the NeuroFlo catheter for 10 to 24 hours after the onset of a stroke, potentially making this an option for victims who suffer their stroke while sleeping or otherwise do not seek treatment for many hours.

This study, called Flo24, was designed to be a safety and feasibility study to assess the safety of treating late presenting stroke patients who demonstrate an ischemic penumbra in an MRI perfusion scan. This study, which enrolled 26 patients at seven sites, has concluded and the results are being prepared for publication.

CoAxia also has completed a small feasibility trial called FASTFlo with 22 patients, which employed the NeuroFlo catheter in patients who initially were treated with tPA but showed no neurological improvement after receiving tPA.

Brainsgate eyes SPG stimulation

Another approach to AIS treatment, developed by privately-owned, venture capital-backed Brainsgate Ltd. (Caesarea, Israel), was presented at a poster session. Key investors in this company include Boston Scientific (Natick, Massachusetts) and the venture capital arm of Johnson & Johnson (New Brunswick, New Jersey).

The company's novel technology is based on emerging scientific evidence that electrical stimulation of the Spheno-Palatine Ganglion (SPG) increase blood flow to the brain. The SPG is a parasympathetic nerve center located near the sinus cavities behind the nasal cavity. In the 1990s, it was discovered that the SPG also innervates the anterior cerebral circulation, which formed the basis for BrainsGate approach.

Electrical stimulation of the SPG increases the diameter of blood vessels supplying the brain and moderately dilating these blood vessels has been shown to increase blood flow to the brain, and release various neurotransmitters In the case of an AIS, where blood circulation has been compromised, SPG stimulation can increase perfusion to the areas suffering from reduced blood supply and help salvage brain tissue.

The easy-to-use device includes a one-inch long sewing needle thin implantable electrode which is inserted through the greater palatine canal in a 10-minute, minimally invasive, oral procedure performed under local anesthesia.

Treatment is provided by a driver worn by the patient on an armband and a transmitter placed on the patient's cheek, held by a headset to transmit electrical energy from the driver to the implant. The treatment sessions are generally for four hours daily for five consecutive days, after which the implant is removed.

The first trial, which was initiated in mid-2006, was a prospective, multinational, open label, pilot clinical trial called Implant for Augmentation of CBF Trial (ImpACT-1), which aimed to assess the safety and effectiveness of SPG stimulation in acute ischemic stroke patients within 24 hours of stroke onset.

This pilot trial was successfully completed in mid-2008 with promising data, which fostered the initiation of Implant for Augmentation of CBF Trial for 24 hours (ImpACT-24) in late 2008.

The latter is a multinational, sham-controlled, randomized, parallel arm pivotal trial. The study will include 480 patients at 60 centers worldwide, randomized in a 2:1 ratio to either SPG stimulation or sham stimulation. After 90 days, the patients will be assessed for their modified Rankin Scale scores.

One of the most promising device technologies for treating an AIS is a microcatheter system marketed by privately-owned Penumbra (San Leandro, California). It debuted at last year's meeting.

The Penumbra system offers a multi-modality approach to the revascularization of occlusions occurring in the intracranial circulation. It uses a microcatheter-based thrombus aspiration and debulking/removal approach, which has three key advantages:

1) It works in the proximal position, meaning it does not have to be navigated through or beyond the occlusion.

2) It provides continuous aspiration to remove clot debris.

3) It has three different sized catheters, which serve different vessel sizes.

At last year's stroke conference, solid clinical results were reported, with 82% of the 125 treated vessels achieving either near normal (TIMI score II) or normal blood flow (TIMI III). At a "Best Science of the ISC" session here this year, new data demonstrated that the primary and secondary endpoints of "real-world" experience with the device closely matched the results of the pivotal trial.

Robert Tarr, MD, chief of neuroradiology at University Hospitals Case Medical Center (Cleveland), reported on a retrospective multi-center trial that enrolled 139 patients at seven sites in the U.S. and Europe. Similar to the pivotal trial, the data was strong, with an 84% revascularization rate (TIMI score II or III) and an acceptable level of adverse events. The median time from symptom stroke onset to the start of the procedure was 4.5 hours.

Tarr said that "it is encouraging to see the primary outcomes of revascularization and safety in this real-world clinical experience mirror the results of the pivotal trial."

The Penumbra System was launched in Europe in June 2007 and in the U.S. in January 2008. It is now commercially available worldwide, including Asia and South America.

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