Cardiovascular Device Update Contributing Writer

SAN FRANCISCO — The more than 4,000 attendees at the 32nd annual International Stroke Conference last month, sponsored by the American Stroke Association (ASA; Dallas) put their focus on the third deadliest and one of the most debilitating diseases in the world. While the overall therapeutic emphasis of this conference is consistently on the best pharmaceutical interventions — especially the clot-dissolving drug tissue plasminogen activator (tPA), best delivered at the earliest onset of stroke — a variety of new developments on the device side highlighted at the conference promise hopeful therapeutic possibilities.

Very promising preliminary data from a feasibility trial of the NeuroThera Laser System (NTS) was presented by Bjorn Dahlof, MD, professor of medicine at the Department of Medicine at G teborg University (G teborg, Sweden). Developed by venture-capital-backed PhotoThera (Carlsbad, California) — thus far having raised $51 million — the NTS features the non-invasive delivery of near-infrared (NIR) energy into the brain.

It consists of a console producing laser light; a hand-held (handpiece) probe that administers laser light to the patient’s head; the TheraLens, an optical lens placed in contact with the patient’s scalp; the TheraCap, a cap fitted to the patient’s shaved head to distribute the laser light evenly and guiding treatment; and protective eye wear used to shield eyes from laser light that is not visible to the human eye. A trained clinician uses the handpiece to direct the laser to 20 treatment sites on the TheraCap, two minutes to each treatment site, for a total treatment time of about one hour.

The NTS delivers 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.

Mechanism of action unclear

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

He also reported that the 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. The most impressive aspect of these results is that the median time-to-treatment for the treated patients was 18 hours, with a few patients being treated as far out as 24 hours.

Importantly, these numbers compare to the early treatment window of just three hours for delivering the “gold standard” pharmaceutical.

Additionally, the safety profile of NTS was solid, with patients in both arms of the trial experiencing only the normal post-stroke issues.

Dahlof disclosed that an article titled “Infrared Laser Therapy for Ischemic Stroke — A New Treatment Strategy: Results of the NeuroThera Effectiveness and Safety Trial-1” will appear in an upcoming issue of Stroke, published by the ASA.

PhotoThera also has just launched a larger, pivotal trial called NEST-2, which is enrolling patients in four countries — Israel, the U.S., Peru and Sweden.

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 characterizing the NeuroThera System as “very promising,” adding: “We are eager to see the results of the confirmatory, pivotal trial.”

Merci I and II

Another device approach that offers promise for ischemic stroke therapy is being marketed by the private, venture-capital-backed Concentric Medical (Mountain View, California). Its original device, called the Merci Retrieval System received FDA approval a few years ago. A second-generation device, called the Merci L5 Retrieval System, was cleared by the FDA early last month.

These two systems, cleared under the FDA’s 510(k) protocol for clot removal in ischemic stroke patients, are the only devices that have been approved for clot removal. Importantly, they offer another option for patients, especially those who have failed intravenous thrombolysis or who could not be treated within the three-hour time-limit window.

The original Merci Retriever is a “corkscrew-type” device delivered into the brain using standard catheterization techniques. Upon reaching the targeted area, the Merci Retriever helps to restore blood flow in ischemic stroke patients by engaging, capturing and removing the blood clot.

The recently approved Merci L5 incorporates a cylindrical helix with attached filaments. The filaments provide an additional mechanism for securing the clot during retrieval.

The new design was investigated as part of the Multi MERCI trial, a multi-center, prospective trial that included 164 patients treated at 15 hospitals in the U.S. and Canada.

The trial included patients with moderate to severe strokes who were ineligible for or had failed treatment with tPA. Many of these large vessel strokes have a large clot burden that may make it difficult for clot-dissolving drugs to be effective, with the result that there is a high mortality rate if left untreated. Treatment was initiated within eight hours of ischemic stroke onset.

Wade Smith, MD, the principal investigator and professor of neurology at the University of California San Francisco reported results of the Multi MERCI trial at the stroke meeting. The results were solid, with more than two-thirds of ischemic stroke patients treated having restoration of blood flow, which led to better outcomes.

Smith said that “the overall revascularization rate of 68.3% is the highest among any major acute ischemic stroke trial. These results further underscore the importance of restoring blood flow in patients suffering an ischemic stroke.”

A boost by Medicare

On Oct. 1, 2006, Medicare reimbursement for the treatment of acute ischemic stroke was altered, which resulted in many stroke-related DRGs gaining a significantly higher reimbursement level. In the past, hospitals have found that reimbursement levels for stroke-related procedures have been inadequate, with the result that many did not establish stroke programs. The new reimbursement scheme will be a boon to hospitals and to their stroke patients.

The newly enacted DRG 543 — “Craniotomy with implant of chemo agent or acute complex CNS principal diagnosis” — resulted in an average national hospital payment of about $23,000 for mechanical embolectomy procedures. The new DRG reimbursement level was a 35% increase above the prior level.

Since Concentric’s devices are currently the only mechanical devices approved by FDA for the removal of embolic material in the brain, the combination of higher reimbursement levels and solid clinical results should bode well for this company.

Déjà vu’ about tPA

Against the background of these device developments was a continuing theme at the conference, and if baseball Hall of Famer Yogi Berra had been attending, he might have used his famous aphorism — “deja vu all over again” — to describe this emphasis.

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. And that lament continued at this year’s meeting.

According to the ASA, about 80% to 85% of the 700,000 new or recurrent strokes in the U.S. each year are ischemic, meaning the result of an occlusion of a key blood vessel in the brain. The remaining 15% to 20% of strokes are termed hemorrhagic, because caused by bleeding in the brain, generally due to bursting of an aneurysm or arterio-venous malformation.

In 1996, Genentech (South San Francisco, California) gained FDA approval for the clot-dissolving drug tPA. However, notwithstanding a well-demonstrated record of efficacy and safety, numerous studies have shown that tPA is administered to a relatively few patients.

Specifically, data from the Paul Coverdell National Acute Stroke Registry, funded by the Centers for Disease Control and Prevention (Atlanta) to enable state-based registries to measure, track and improve the delivery and quality of stroke care. This project was named after the late U.S. Senator Paul Coverdell of Georgia, who suffered a fatal stroke in 2000 .

Similar to many earlier studies, the Coverdell registry indicated that only between 3% and 8.5% of ischemic stroke patients received tPA.

There are a plethora of reasons for this poor performance but the main reason is that tPA must be administered within three hours of stroke symptom onset in order to achieve maximum therapeutic benefit.

And second, there is a 6% -7% risk of intracerebral hemorrhage (ICH), which can on occasion be fatal. As a result of the risk of ICH, physicians and emergency room personnel proceed very cautiously before administering the drug, because if the stroke is hemorrhagic tPA infusion could be catastrophic.

Intra-arterial approach

Administration of a clot-busting agent undoubtedly helps patients.

A poster abstract presented at the meeting showed that about one-quarter of patients given tPA intra-arterially within six hours of stroke experienced a dramatic recovery. However, the intra-arterial approach has not yet received FDA approval. Only the intravenous route is cleared for unrestricted marketing.

The authors who presented this data described the data showing recovery as a “Lazarus phenomenon,” named after the biblical figure 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 The Ohio State University College of Medicine (Columbus, Ohio): “The surprising thing was that the time to treatment had such a significant impact, whereas, other factors — such as age, gender, blood sugar and blood pressure — did not.”

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 was developed primarily because there was recognition of a significant disparity in the methods by which acute ischemic stroke patients were evaluated and the frequency with which they were receiving thrombolysis or other acute stroke interventions.

The key goal of the program — 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.

Legislated pharmaceutical delivery

A similar program, called the Florida Stroke Act (FSA), was developed by several state organizations because acute stroke care and tPA usage was so inconsistent and widely variable across the state. The legislation went into effect July 1, 2005.

After reviewing data from two key hospitals for a period before enactment of the FSA and for a period six months after the FSA’s launch, the percentage of patients receiving tPA increased from 8.4% pre-legislation to 10.5% post-legislation.

The lead author of this study, Scott Silliman, MD, associate professor of neurology at the University of Florida College of Medicine (Jacksonville), said, “these studies indicate that stroke care can be improved.”

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.

Real and continuing effort

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 vivid example of the trials and tribulations of developing an effective and safe AIS agent was seen in the Stroke Acute Ischemic NXY-059 Treatment (SAINT-II) trial. NXY-058, a neuroprotective agent, was developed by Renovis (South San Francisco) and licensed exclusively worldwide to AstraZeneca (London, UK).

Initial animal and the smaller SAINT-I trial results were very encouraging and there was widespread excitement that NXY-059 would become a major force in AIS therapy. The larger SAINT II trial, the largest AIS neuroprotective trial to date with an enrollment of nearly 3,400 patients, was conducted worldwide in about 350 centers in 30 countries

However, in late October 2006, Renovis reported that the agent did not demonstrate a statistically significant reduction on the primary endpoint of stroke-related disability in patients treated with NXY-059.

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

On the medical management side, two thrombolytic compounds — desmoteplase and ancrod— are showing strong AIS potential. Both offer the possibility for a significantly longer therapeutic window, which would be a boon in the quest to use thrombolysis in a larger proportion of acute ischemic stroke victims.

Even from vampire bats . . .

Desmoteplase, originally found in the saliva of vampire bats, acts in a similar way to tPA but works almost exclusively by targeting and destroying fibrin, the structural scaffold of blood clots. Its key advantage is that it could extend the window of opportunity to up to nine hours.

Human clinical trials have been under way for several years and the enrollment of the pivotal, prospective, randomized, double blind, placebo- controlled Desmoteplase in Acute Ischemic Stroke-2 (DIAS-2) trial was recently completed.

The analysis of the data is now underway and the final results will be presented at European Stroke Conference, to be held in Glasgow, UK, May 29-June 1.

This trial is sponsored by its developer PAION AG (Aachen, Germany) and its North American licensee Forest Laboratories (New York).

. . . and vipers

Viprinex, which is derived from the venom of the Malayan pit viper, has a two-fold mechanism of action to address three dynamics in acute ischemic stroke: anti-coagulation (preventing clots from forming), fibrinolysis (dissolving existing clots) and improved blood viscosity (thinning out the blood and improving blood flow to the brain).

Viprinex has been studied in over 2,000 patients in clinical studies in the U.S. and Europe. One Phase II and one Phase III study conducted in the U.S. have demonstrated that Viprinex preserves neurological function when used within a three-hour or six-hour treatment window, while one European Phase III study failed to demonstrate a benefit for Viprinex when used within six-hours of stroke onset.

Currently, a new dosing strategy for Viprinex is being used in two international Phase III studies, collectively known as the Ancrod Stroke Program (ASP). These two trials will assess whether a modified dosing regimen of Viprinex, administered up to six hours after onset of stroke symptoms, can minimize neurological damage and adverse effects and maximize functional outcomes in stroke patients. NTI hopes to complete enrollment in these two studies sometime in 2008.

According to Bart Demaerschalk, MD, assistant professor of neurology of the Mayo Clinic (Scottsdale, Arizona), “it appears that ancrod may be promising for the treatment of acute ischemic stroke, but we need more data, particularly from the ASP-I and ASP-II studies.”