LARRY HAIMOVITCH
CDU Contributing Writer
and HOLLAND JOHNSON
CDU Associate

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 in February, 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 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 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 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 top 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. The Ekos catheter also delivered low-energy ultrasound directly to the clot.

The Micro-Infusion Catheter MicroLysus infusion system was used in 41% of the patients in the 73-patient trial to deliver the thrombolytic drugs directly to the clot. The device is unique because it incorporates ultrasound technology into the tip of a microcatheter to accelerate the dissolving of the blood clot.

The trial, which was co-sponsored by Ekos, investigated patients between the ages of 18 and 80 at 13 centers who presented with severe ischemic stroke. Each patient was given lower-than-standard doses of tPA during a 30-minute period within three hours of the onset of stroke

Subjects were then immediately taken for an angiography where a microcatheter was placed into a groin artery and threaded to the site of the blocked artery in their brain. Twenty-one participants without a visible and treatable clot received no additional therapy. The remainder of participants (52) who had visible, treatable clots was treated with up to 22 milligrams of additional tPA delivered through the catheter directly to the blockage.

Whenever possible, patients were also given a low-energy ultrasound treatment at the site of the clot. The ultrasound, which attempted to break up the clot, was administered using the Ekos infusion system. In 18 participants, where the Ekos MicroLysus catheter could not access the clot, a standard catheter was used to deliver tPA to the clot site. Partial or complete reopening of the blocked brain artery occurred in 69 % of the 34 patients receiving the ultrasound treatment. This was an improvement when compared with the IMS-I study, in which 55% of patients involved achieved partial or complete reopening of the blocked artery. The IMS-I study used only a microcatheter to deliver tPA directly to the location of the stroke-causing clot and not the Ekos device.

“After adjustment for differences in baseline stroke severity, age and time-to-treatment, the likelihood of IMS-II subjects attaining functional independence at three months was 65% relatively greater compared to IV-only tPA-treated subjects in IMS-I,” said researcher Joseph Broderick, MD, director of the Greater Cincinnati Northern Kentucky Stroke Team (Cincinnati).

Ekos Chairman and CEO Peter Rule said that, while this is the second NIH-funded study combining IV/IA therapy for the treatment of ischemic stroke, it is the first one his company has participated in, and he said he believes the use of the Ekos system has contributed to the improvement in outcomes between IMS I and IMS II, and has laid the groundwork for a Phase III study.

He told Cardiovascular Device Update that while the results of the first IMS study were positive, the data “wasn’t as good as [the NIH] wanted.”

Instead of going straight into a Phase III randomized trial, Ekos suggested that Broderick and Tomsick – who were the principal investigators of IMS-I – do a second study using the company’s ultrasound system to see if it worked better than a “plain vanilla” catheter for the delivery of tPA to the brain. In the IMS I trial, the intra-arterial treatment was delivered by a standard IA micro-catheter.

Broderick 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 well-known 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 Broderick, 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.

Rule said he expects the IMS III trial will begin this month, but he doesn’t think it will need to enroll the full 900 patients because, based on the data that he has seen thus far for the IMS I and IMS II trial, the trial probably will be stopped early.

The IA therapy will include a choice of catheter or devices (a mechanical clot retriever retriever, Ekos catheter, standard micro-catheter) and IA t-PA 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 cork-screw-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 US.

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 magnetic resonance imaging (MRI), predicts patients most likely to respond to mechanical embol-ectomy. These patients would potentially have im-proved 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 hiurs, 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.

Test from diaDexus predicts stroke

diaDexus (South San Francisco, California) said data presented at the International Stroke Conference showed that a novel biomarker is predictive for recurrent stroke in a multi-ethnic population that included both men and women.

Dr. Mitchell Elkind and colleagues at Columbia University (New York) followed a cohort of patients from the Northern Manhattan Study (NOMAS) for an average of four years to identify the utility of novel, but easy to apply, biomarkers for patients who have already experienced an ischemic stroke. In that period, 80 recurrent strokes were recorded.

The results came from a study titled “Lp-PLA₂ and CRP as Predictors of Stroke Recurrence and Death: The Northern Manhattan Study.”

“These data provide us with important observations linking higher than normal levels of the enzyme Lp-PLA₂ with the risk of recurrent stroke in a multi-ethnic population. Women, Hispanics and African-Americans –groups that are frequently overlooked in major studies – were also well-represented in our study,” said Mitchell Elkind, MD, assistant professor of neurology in the division of stroke and critical care at Columbia.

“Previous studies have demonstrated that this biomarker can help determine risk for a first stroke, but this study shows that it may also predict a second stroke. Because women and minorities are at higher risk for stroke, and yet are relatively medically underserved, these findings may have special importance,” Elkind said.

The researchers assessed Lp-PLA₂ levels using the diaDexus PLAC test, which the company calls the first blood test approved by the FDA to aid in predicting ischemic stroke. The study followed 467 patients who had experienced an initial stroke: 55% were women, 53% hispanic, 27% African-American and 18% caucasian. Patients were more than 40 years old.

The study was conducted at the university’s Neurological Institute.

Data showed there was an increased risk of recurrent ischemic stroke in patients with high levels of the enzyme Lp-PLA₂. Using a Cox proportional hazards model, the study demonstrated that increased levels of Lp-PLA₂ were associated with risk for recurrent stroke after adjusting for demographics, hypertension, diabetes, hyperlipidemia, smoking, atrial fibrillation, and coronary disease.

Researchers also found that high levels of hs-CRP, a marker of general inflammation, did not predict stroke recurrence but was associated with stroke severity and predicted death.

As part of an effort to highlight the value of stroke assessment and prevention, diaDexus is offering free stroke risk screening with the PLAC test during the ASA meeting.

Another study presented at the conference indicated that the risk for stroke is greater when you are younger and newly diagnosed with diabetes. Occurrence of stroke increases among newly diagnosed adults with Type 2 diabetes and diabetic adults who are younger than age 55, according to one study looking at this population.

“One would think that the consequences of diabetes would occur over a long period, but we found that new-onset diabetics have double the rate of stroke in the first five years after diagnosis as the general population,” said Thomas Jeerakathil, MD, lead author and assistant professor of medicine and neurology at the University of Alberta (Edmonton, Alberta). “The finding suggests some of the cardiovascular effects of diabetes are already established at the time of diagnosis and aggressive prevention is justified in this patient group.”

Most studies have focused on people who have had diabetes for years, and researchers have known that diabetic patients tend to focus on blood sugar control but don’t have optimum control of blood pressure.

To examine the short-term risk for stroke in newly diagnosed diabetics, Jeerakathil and colleagues analyzed a database of people in the province of Saskatchewan. They identified 12,272 people (average age 64) who had new prescriptions for diabetes medications between 1991 and 1996, and followed them for about five years.

More than 9% were admitted to the hospital for stroke and one-fifth of that population died during those five years. Researchers compared stroke rates to a similar-aged group in the general population.

“Our findings suggest that, particularly if people have a new diagnosis of diabetes, they should have all their cardiovascular risk factors managed optimally,” Jeerakathil said. “That means strict control of blood pressure and elevated cholesterol, avoiding a sedentary lifestyle and an adequate diet high in vegetables and whole grains – things that we’ve found in other studies to lower the risk of heart disease.”

Report highlights burden of stroke

Study results presented at the International Stroke Congress highlight the increasing financial burdens of acute ischemic stroke and its impact on a variety of healthcare resources. This growing burden was demonstrated with data showing the effect of long-term disability – primarily the length and cost of hospital stays – thus emphasizing the importance of economic assessment, according to the researchers involved.

The researchers analyzed more than 350,000 Medicare health insurance claims to estimate the cost of 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 per-stay amount actually reimbursed was $6,589, a 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. Some 72% of acute stroke patients in the U.S. are Medicare beneficiaries.

A second study provided evidence of the impact of reimbursement issues on patients hospitalized with 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.