Cardiovascular Devices & Drugs Contributing Editor

NEW ORLEANS – As balmy spring days bathed "The Big Easy" last month during the 33rd annual International Stroke Conference, sponsored by the American Stroke Association (ASA; Dallas), one could not help but think of the saying "hope springs eternal" – even concerning one of the most troubling of all healthcare issues.

Stroke, typically either excessive bleeding or inadequate blood flow in the brain, has proven to be one of the most, if not the most frustrating diseases for the healthcare community to treat successfully. It is especially frustrating because stroke is such a huge medical problem, with roughly 700,000 events per year in the U.S., causing an estimated 150,000 deaths. After heart attack and cancer, it is the third most deadly disease and accounts for about one out of every 16 deaths in the U.S.

The cost burden to the U.S. from stroke is enormous, especially since it does not always kill, thus the ongoing treatment, maintenance and attempted rehabilition of those who survive presents a huge burden to the healthcare system. According to ASA, more than $62 billion was spent on stroke in 2007 in the U.S., about 32% for nursing home care, drugs, other medications and home healthcare. Additionally, stroke is a condition that has ongoing impact, far behind the health status of the individual victims/survivors, but also on all those around them.

Hope — coming in glimmers

Against this bleak backdrop, researchers, physicians and industry met here at the Ernest N. Morial Convention Center, seeking to learn about any encouraging developments made over the past year. While there were no blockbuster developments, glimmers of hope for better treatment modalities did appear.

Perhaps the most encouraging news came from privately-owned Penumbra (San Leandro, California), which reported its results at a late-breaking clinical trial session from its recently completed acute ischemic stroke (AIS) trial. As previously reported, the company had received FDA 510(k) clearance at the beginning of the year.

The Penumbra system uses a microcatheter-based thrombus aspiration and debulking/removal device that offers a multi-modality approach to the revascularization of occlusions occurring in the intracranial circulation. There are three key advantages of its system: it works in the proximal position, meaning it does not have to be navigated through or beyond the occlusion; second, it provides continuous aspiration to remove clot debris and third, it has three different sized catheters, which serve different vessel sizes.

The company believes that not all clots are alike and that a single catheter will not always work. Its device not only can remove both soft thrombi and harder plaque with its continuous aspiration and built-in clot capture feature but it can remove blockages in smaller intracranial vessels.

Cameron McDougall, MD, chief of endovascular neurosurgery at the Barrow Neurological Institute (Phoenix) and a study participant, presented the trial detail (summarized in Table 1). McDougall noted that 42% of the patients treated experienced an improvement in their neurological status, as measured by the National Institutes of Health Stroke Scale (NIHSS).

McDougall concluded his presentation by saying that "these results suggest that the Penumbra System may allow safe and effective revascularization in patients experiencing is-chemic stroke secondary to large vessel occlusion."

Penumbra has recently hired several sales reps and has launched the product into the domestic market.

AIS competitors

The company faces two key competitors in the AIS market – Concentric Medical (Mountain View, California), with its Mechanical Embolus Removal in Cerebral Ischemia Retriever (MERCI) device, and Genentech's (South San Francisco, California) drug compound tissue plasminogen activator (tPA).

The MERCI, initially FDA-approved in August 2004 for the treatment of acute ischemic stroke, is a catheter that contains a corkscrew-like wire that is used to snare clots and then plucks them from the artery.

Whereas the Penumbra can treat smaller intracranial vessels, the MERCI is designed to restore blood flow only in large vessels. In the company's S-1 filing with the SEC in August 2007, which was prepared in anticipation of an initial public offering in late 2007 or early 2008, it was noted that between 30% and 50% of all ischemic strokes in the U.S. emanate in large vessels.

The results of Concentric's first trial, dubbed MERCI, reported in the July 2005 issue of Stroke, revealed a relatively modest 46% recanalization rate, based on intention to treat. Concentric's second trial, called Multi MERCI, was somewhat more effective, restoring blood flow in 55% of AIS patients,

According to its S-1 filing, Concentric has "no plans to conduct any additional clinical trials that may be essential for the medical community to endorse the adoption of our system." With the recent very difficult stock market conditions, Concentric has abandoned its IPO aspirations and in-stead has raised money from private sources.

Advantages over tPA

A critical advantage of these two device-based approaches to AIS over tPA – which still remains the therapeutic gold standard of stroke treatment – is that they are approved to treat patients for up to eight hours after an AIS. Conversely, intravenous (IV) tPA is currently only FDA-approved for use up to three hours. This narrow "therapeutic window" in part explains why a paltry 3% of AIS victims are receiving IV tPA therapy. Intra-arterial tPA, delivered via a catheter threaded from the femoral artery into the brain, is often used up to six hours after the three hour tPA IV window has expired but this approach is not expressly approved by the FDA.

tPA can be delivered intravenously at virtually all hospital emergency room, whereas these two clot removal devices will require the considerable skills of an interventional neuroradiologist. CD&D estimates that there are approximately 300 hospitals in the USA with active neuro-interventional programs.

The Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET) Australian study, reported at a late breaking clinical trial session, tested the hypothesis in a randomized, double-blind, placebo-controlled trial that IV tPA could be used successfully up to six hours after an AIS event. Although the study was fairly small and missed its primary endpoint of showing that tPA could significantly reduce infarct size, as measured by MRI, it demonstrated some meaningful benefits.

According to the lead author, Stephen Davis, MD, professor of neurology at the University of Melbourne (Melbourne, Australia), "tPA was associated with a significant restoration in blood flow and improved functional outcomes." He said these results were encouraging enough to warrant a larger pivotal trial.

Other device-based approaches

Device-based approaches for treating an AIS continue to receive a lot of attention from industry and academia. For example, ev3 (Plymouth, Minnesota), which is a major neurovascular player with its MicroTherapeutics division, has been actively evaluating several technologies.

ev3 is a minority shareholder in phenox GmbH, (Bochum, Germany), whose CE mark-approved phenox Clot Retrieval (PCR) device was presented at this meeting in a poster titled "Early Clinical Experiences with a New Thrombectomy Device for the Treatment of Ischemic Stroke."

This device consists of an array of radially circumferential oriented polyamid microfilaments on a highly flexible nitinol platinum-alloy compound core wire. It can be deployed through a standard microcatheter and is capable of recanalizing tiny vessel diameters to as low as well below 2 mm.

The poster reported on 45 European patients and showed that recanalization was achieved in 69% of the treated vessels with no device related morbidity and mortality recorded during these 48 treatments. This excellent safety profile is most likely attributable to its highly flexible and atraumatic design.

The authors concluded that that this device "is a potentially useful supplement to the repertoire of currently available devices for endovascular intracranial thrombectomy."

According to ev3's CEO Jim Corbett, while this device achieved reasonable good success, it did not demonstrate a high enough level of restored blood flow and thus ev3 did not elect to exercise its option to acquire the product.

In a recent interview with, CD&D, Corbett stated that ev3 is eager to find or develop better "flow restoration" devices to attack AIS. He said that "we believe that better intracranial blood flow should lead to a better neurological outcome."

In this light, he spoke enthusiastically about its Solitaire retrievable neuro-stent and its neuro-angioplasty balloon, both of which have significant potential to reach both the European and domestic markets in the next year or two.

Corbett's comments raise a very significant point about all the single arm, non-randomized AIS clot-removal trials, that is although it would seem intuitive that an open vessel is better than a closed one, to date none of the approved or investigational devices have been shown to actually improve neurological outcomes in a randomized trial.

In a recent interview at this meeting Larry Goldstein, MD, and a neurologist from Duke University Medical Center (Durham, North Carolina) said that "this is a prospective, Phase II single-arm trial, so that's the beginning and end of the story. He further noted that "the device can apparently remove clots. Whether that leads to better patient outcomes is not proven by this study."

Micrus active in AIS space

Another prominent neurovascular company, Micrus (San Jose, California), has also been active in the AIS device space. In December 2007, the company acquired ReVasc, a wholly-owned subsidiary of The Cleveland Clinic (Cleveland, Ohio). Following this deal, Micrus became the direct recipient of the license of this device, which Micrus described as a self-expanding, retievable stent-like structure with an embolic filter.

In January 2008, Micrus licensed the rights to the F.A.S.T. Funnel Catheter and clot-retrieval system for treating AIS from privately-owned Genesis Medical Interventional (Redwood City, California). This device is comprised of a funnel deployed at the distal end of the catheter through which a physician can deploy a proprietary clot retrieval system with an umbrella or parachute-like device. This novel design harnesses a patient's blood pressure to provide the sealing force for occlusion. Clots and other debris are removed and the device is then collapsed and removed from the patient.

Perhaps the most intriguing device-based therapy is the NeuroThera Laser System (NTS), being developed by privately-owned, venture capital-backed PhotoThera (Carlsbad, California). This device, which was presented for the first time at last year's International Stroke Conference, features the non-invasive delivery of near-infrared energy into the brain.

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 time, including all pre- and post-activities lasts approximately two to three hours.

Building on NEST-1

The most fascinating aspect of the NTS is that it may offer a dramatically longer "therapeutic window" of treatment time. Indeed, in the feasibility NeuroThera Effectiveness and Safety Trial-1 (NEST-1) that was presented at last year's meeting and reported in the June 2007 issue of Stroke, the median time-to-treatment for the treated patients was 18 hours, with a few patients being treated as far out as 24 hours.

Despite the fact that patients were treated so much longer after the onset of their ischemic stroke, 59% of the 79 NTS treated patients achieved a successful neurological outcome, compared to a 44% success for the 41 patients receiving sham treatment.

In a poster presentation, PhotoThera provided details of its NEST-2 pivotal trial called. This study is a prospective, double blind, randomized, sham controlled, parallel group, multi-center study that will enroll up to 660 subjects. Subjects will be followed for 90 days post-stroke onset. The primary endpoint is the measurement of neurological recovery, using the modified Rankin Scale.

The company is expected to complete enrollment within the next several weeks and may choose to release the results of this trial before year-end 2008 or await a formal publication and presentation, perhaps at the 2009 International Stroke Conference.

Caffeinating neuroprotection

We know that a strong cup of coffee or two will provide us with a temporary surge of energy. And, we know that a glass or two of wine or beer or a shot of spirits will provide a feeling of relaxation for a time. So, what effect would be produced by an intravenous infusion of the caffeine equivalent of four to six cups of strong coffee, combined with the ethanol equivalent of two drinks?

It is safe to say that you probably did not guess "neuroprotection." If you did, you must have attended last month's International Stroke Conference at the Ernest N. Morial Convention Center here.

In the world of stroke, the term neuroprotection, which is derived from the Greek and Latin roots that means "saving nerve cells," has been one of the Holy Grails in this field.

There has been a longstanding notion that neuroprotection, administered within hours after the onset of an acute ischemic stroke (AIS), could preserve precious brain tissue until adequate blood supply could be re-established, either through spontaneous or therapeutic recanalization or via collateral blood flow. While great in theory, the concept has failed miserably under clinical investigation.

According to an article titled "Acute Ischemic Stroke Treatment in 2007," published in the Sept. 25, 2007, issue of Circulation, "There have been published reports of more than 1,000 experimental neuroprotective treatments for acute stroke ... with more than 100 coming to clinical trials. To date, none has proved efficacious."

At this meeting, Sheryl Martin-Schild, MD, a neurovascular fellow at the University of Texas Health Science Center (Houston), presented a small human study that showed that the combination of caffeine and alcohol, called caffeinol, in intravenous combination with tPA, reduced brain damage, enhanced neurological recovery and proved to be safe to use. In this feasibility trial, only 10 patients received the combination therapy, compared to 90 patients who received just tPA.

Responding to a question at a press conference, Martin-Schild admitted, "We have no idea why this regimen worked" and said that a larger, randomized controlled trial would be necessary to firmly establish safety and efficacy. She indicated that researchers at the University of California San Diego were in the midst of designing such a trial but no starting date was indicated. Patients will be randomized prospectively into two arms, tPA alone or tPA in combination with caffeinol.

Showing that caffeinol is versatile, Martin-Schild also presented data on a trial for a combination of caffeinol and mild hypothermia, which showed that there is a positive benefit of combining the two modalities.

A prospective, multi-center placebo-controlled Phase II trial had been designed to test the efficacy of caffeinol, hypothermia or both within three hours after an AIS.

Variations on tPA

Another drug trial discussed at a news conference here was Genentech's (South San Francisco, California) TNKase, generically tenecteplase. This agent is a bioengineered variant of tPA, remaining in the blood stream longer and attaching itself to fibrin, a protein that is involved in the clotting process. It was FDA-approved in June 2000 for the treatment of an acute myocardial infarction.

Researchers from Spain compared tPA to TNKase and concluded that the latter "did a faster and more complete job of re-opening blocked brain arteries and is associated with better short and long term neurological outcomes." The trial directly compared the two drugs in reopening the middle cerebral artery, one of the three key arteries that supplies blood to the brain and showed a similar safety profile as tPA.

Commenting on this trial, which enrolled 122 patients in a 2:1 ratio favoring tPA, Jeffrey Saver, MD, director of the University of California Stroke Center (Los Angeles) said that TNKase could represent "the next generation of clot-lysing drugs" but that a larger trial would be required to establish its role in treating an acute ischemic stroke.

As the developer of the first and only FDA-approved drug to treat an AIS, Genentech has both prospered from its commercial success but also been frustrated that it is being used in only about 3% of AIS patients. Numerous presentations throughout the conference thaddressed this issue.

Most important of all — faster treatment

One poster, titled "Use of Tissue Plasminogen Activator: Have we Improved," analyzed data from four hospitals in Ssoutheastern Michigan from January 1996 to January 2005 into three distinct time frames. Its discouraging conclusion was that from both the onset of an AIS to delivery to the emergency room to arrival at the hospital to actual treatment had not improved over the nine-year period studied in that geographic area.

Conversely, a more positive poster titled "The Impact of Improved Hospital Reimbursement on National Rates of tPA Use," noted that in 2006 reimbursement for tPA infusion was doubled and a new DRG code 559 was introduced. National tPA use increased 60% over a two-year period, although the rate of utilization was still a paltry 3% of potential cases.

Even more dramatic results were shown in a poster titled "Increasing Thrombolytic Treatment Rates: Results Utilizing Revised Treatment Criteria and a Multidisciplinary Stroke Education Program," with data generated by David Tong. MD and and his stroke neurology colleagues at California Pacific Medical Center (San Francisco).

The authors hypothesized that a rapid stroke triage system using revised criteria reported to permit safe thrombolysis, coupled with a comprehensive education program could substantially increase the currently "dismally low" level thrombolysis treatment rates, without the need for a formal stroke network. Indeed, this hypothesis was well-borne out, as 25% of all patients were treated after implementation of these initiatives. Note that the patients treated included both IV and intra-arterial therapy. More importantly, its patient cohort enjoyed much better neurological recovery results than any other large scale clinical trials, despite treating a significantly older patient population.

The details of their acute stroke management program, initiated in July 2006 (detailed in Table 2).

Another successful approach to increasing tPA use was presented in a poster titled "Safety and Feasibility of 'Drip & Ship' Paradigm in Patients Transferred to a Tertiary Care Center with Acute Ischemic Stroke." The drip and ship strategy essentially initiates tPA therapy during the patient's initial visit to their local hospital and continues it through to a transfer to the tertiary care center. The authors, from the University of Minnesota (Minneapolis), concluded that transport to a tertiary care center should not delay the initiation of intravenous tPA and was a safe and effective protocol.