Medical Device Daily Contributing Writer

KISSIMMEE, Florida – An anniversary, especially a 10-year one, would typically be a cause for a festive celebration. However, at this year's 31st annual International Stroke Conference, sponsored by the American Stroke Association (ASA; Dallas) and held here at the end of last week, the 10th anniversary of the FDA's 1996 approval of Genentech's (South San Francisco, California) clot-busting drug tissue plasminogen activator (tPA) was noted in muted style.

The more than 3,000 professional attendees here heard an old refrain at this annual gathering for the past several years, that is, that relatively few acute ischemic stroke (AIS) victims are benefiting from this drug and that new approaches and therapies are needed to better manage the nation's 700,000 annual strokes.

On its approval in 1996, tPA was widely hailed as a major breakthrough in the fight against AIS, which accounts for about 85% of all strokes. However, tPA is hampered by two key drawbacks. First, it must be administered within three hours of stroke symptom onset in order to achieve its maximum therapeutic effect. Second, there is a 6% to 7% risk of intracerebral hemorrhage (ICH), which can on occasion be fatal.

Despite tPA's prowess, the aggressive educational efforts by the ASA and other potent health advocacy groups and the tremendous push to improve the triage of AIS patients once they have reached out for help, the number of patients receiving this thrombolytic drug is generally believed to be under 5% of the potential eligible AIS population.

This depressing data has been a catalyst for healthcare providers to work diligently to improve the entire stroke therapy delivery system. Several sessions at this year's ASA meeting were specifically devoted to this topic.

In addition, the medical industry continues to persistently and intensely search for new technologies and approaches that can widen tPA's tight three-hour window of opportunity. The market opportunity, with about 600,000 ischemic strokes annually in the U.S. alone, is simply too enormous to ignore.

A Friday afternoon symposium on “Endovascular Treatment of Ischemic Stroke“ delved into the latest clinical trials both current and upcoming, that could bolster the success of tPA and make it more widely available to AIS victims.

Thomas Tomsick, MD, director of neuroradiology and interventional neuroradiology at the University of Cincinnati and a widely quoted stroke specialist, reported on the results of the Interventional Management of Stroke Trial II (IMS II), for which he is the principal investigator. This study was supported in part by the National Institute of Neurological Disorders and Stroke (NINDS; Bethesda, Maryland).

The protocol differed from a standard tPA protocol, which is to solely administer tPA intravenously. In this trial, which enrolled 73 patients between December 2003 and April 2005, the investigators used a low IV dose followed by an intra-arterial (IA) catheter-based strategy aimed at lysing the clot.

The study only enrolled patients who had had a severe ischemic stroke. They were initially treated within three hours of stroke onset with low dose tPA for 30 minutes and then immediately underwent angiography to assess their status.

If no additional clots were detected, therapy at that point was concluded. However, for patients who still had clots, they were treated intra-arterially with a specialized catheter developed by Ekos (Bothell, Washington), which delivered additional tPA directly to the clot site (Medical Device Daily, Feb. 17, 2006). The Ekos catheter also delivered low-energy ultrasound directly to the clot.

The IMS II study was similar to the IMS I, a trial which essentially followed the same protocol, except that the intra-arterial treatment was delivered by a standard IA micro-catheter.

Broderick reported that the results of the trial were quite positive. Patients were 65% more likely to attain functional independence at three months compared with patients who received tPA in the original tPA stroke trial. In addition, partial or complete recanalization occurred in 69% of IMS II patients, compared to 55% in IMS I.

He said that “IV thrombolysis remain the foundation of stroke therapy, but in a significant number of patients, we don't have an open artery with IV therapy alone. This approach gives us a second chance.“

At an ASA-sponsored press conference, Gregory del Zoppo, MD, associate professor in the division of experimental hemostasis and thrombosis at Scripps Research Institute (La Jolla, California) and a renowned researcher in the field of thrombolysis, speculated that a possible reason for the improved results with IMS-II is that targeted ultrasound seems to act as a “tenderizer“ for clots, making it easier for lytic agents to dissolve them.

Similarly, positive results with the use of ultrasound to better dissolve tPA were reported at last year's ASA meeting. The main conclusion last year was that “sono-thrombolysis“ may become an important new technology in the fight against acute ischemic stroke.

The encouraging results of IMS II has provided the impetus for the NINDS to proceed with the IMS-III trial, which will compare standard IV tPA administration with the use of the combined IV and intra-arterial strategy. The principal investigator for this trial will be Joseph Broderick, MD, director of the Greater Cincinnati Northern Kentucky Stroke Team (Cincinnati), who described the complex trial design to a keenly interested audience.

A total of 900 moderate-to-severe acute ischemic stroke patients will be enrolled, and they will be randomized to combined IV/IA approach or to standard IV t-PA in a 2:1 ratio. The primary endpoint will be to evaluate the patient's neurological function at three months.

The IA therapy will include a choice of catheter or devices (a mechanical clot retriever retriever, Ekos catheter, standard micro-catheter) and IA tPA depending upon lesion, experience and training of investigator, and specified use of devices.

The mechanical device, which was FDA-approved in August 2004 for the treatment of ischemic stroke, is a catheter that contains a corkscrew-like wire that snares clots and then plucks them from the artery. The device, which is made by privately owned, venture capital-backed Concentric Medical (Mountain View, California), is called the Mechanical Embolus Removal in Cerebral Ischemia Retriever (Merci).

Broderick said that IMS III addresses a question that already has been answered in cardiology, i.e., how does an interventional approach (angioplasty) compare to standard IV dose of a thrombolytic agent? “It's time for us to answer this question for ischemic stroke in a randomized trial,“ he said.

Another promising approach to AIS was shared by Chelsea Kidwell, MD, an associate professor in the department of neurology at Georgetown University (Washington) and medical director at the Washington Hospital Center stroke center. She reported on the MR and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE) trial, a multi-center phase II trial that intends to enroll 120 patients with large vessel anterior circulation occlusions at 20 stroke centers in the U.S.

This trial follows on the heels of promising retrospective pilot data on 23 patients, which demonstrated a pre-treatment penumbral MRI pattern in 54% of the patients and a 70% partial or complete recanalization.

The primary hypothesis of MR RESCUE is that the presence of substantial penumbral tissue, as measured by MRI, predicts patients most likely to respond to mechanical embolectomy. These patients would potentially have improved functional outcome compared to a randomized control. Patients will be randomized to embolectomy, using the Merci catheter, plus standard IV thrombolysis vs. IV thrombolysis.

It is noteworthy that the protocol allows patients to be treated up to eight hours after symptom onset, once again demonstrating the huge appetite in the stroke community to increase the window of opportunity. Indeed, the time to treatment in the first 15 patients entered into this pivotal phase was nearly six hours, a remarkable difference from the three hours that tPA can be administered.

While the Merci Retriever's FDA approval is for removing clots from cerebral arteries in patients experiencing ischemic stroke, it has not yet been demonstrated that it is effective in improving outcomes. Although some in the stroke community believe that a randomized trial is not appropriate, Kidwell closed her talk by saying that “a trial must be done to scientifically advance the field.“

The fourth speaker in this symposium was Wade Smith, MD, director of the neurovascular service at the University of California, San Francisco. He discussed the ongoing, international, multi-center single-arm trial Multi-MERCI trial. Key details of this study are that it also uses up to an eight hour window, allowing for IV tPA pre-treatment. Endpoints include the success of recanalization and various safety parameters.

Favorable results of Concentric's earlier trial, dubbed MERCI, was reported in the July 2005 issue of Stroke. Smith was the author, and his conclusion, based on a 46% recanalization rate on intention to treat, was that “this device can restore vascular patency . . . and provides an alternative intervention for patients who are otherwise ineligible for thrombolytics.“

It is interesting to note that more than 1,800 patients were screened for this trial and only about 8% were actually enrolled in the study. Smith did not specifically comment on that statistic, but it is a common problem in AIS therapeutic trials that patient enrollment is a vexing issue.

Also at ASA, study results highlighted the increasing financial burden caused by the outcomes of acute ischemic stroke and its impact on a variety of healthcare resources.

The data show the effect of long-term disability caused by stroke on healthcare resources and emphasize the importance of wide economic assessment in evaluating the benefit of new stroke treatments.

One of the studies presented examined the impact of the length and cost of hospital stays on the ability of hospitals to treat ischemic patients. U.S. researchers analyzed more than 350,000 Medicare health insurance claims to estimate the current cost of providing standard inpatient stroke care, based on a mean hospital stay of 5.7 days. The study found that while the mean cost per stay for a stroke patient was $9,433, the average amount actually reimbursed per stay came to $6,589, representing an average shortfall to the hospital of $2,845 per patient stay.

To provide standard stroke care on a break-even basis, the average hospital stay would need to be reduced to just 3.5 days.

A second study provided further evidence of the impact of reimbursement issues on patients hospitalized with ischemic or hemorrhagic stroke, revealing that various financial incentives over the past decade have led to a decrease in the initial intensity of care for patients with stroke.

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