CDU Contributing Editor

PHOENIX, Arizona Ischemic stroke accounts for 80% to 85% of the estimated 750,000 strokes that occur annually in the U.S. Thus, it was no surprise that at this year's International Stroke Conference, sponsored annually by the American Heart Association (Dallas, Texas) and held here in February, issues and developments related to ischemic stroke were in the limelight.

While Genentech's (South San Francisco, California) Activase thrombolytic is both highly effective and quite safe, the medical community continues to be frustrated by its very narrow therapeutic window, which requires that it be administered within three hours after ischemic stroke onset. The upshot of this limitation is that, according to Genentech officials, only about 3% of all ischemic stroke victims are treated with Activase.

In addition to heightening the public's awareness of stroke symptoms and speeding up hospital procedures, there are numerous trials underway worldwide that all seek to increase the therapeutic window using a variety of new compounds to lyse the ischemic area. One of these trials is the Abciximab in Emergent Stroke Treatment Trial (AbESTT), which uses Reopro, currently used to prevent post-angioplasty clotting and marketed by the Centocor (Malvern, Pennsylvania) division of Johnson & Johnson (New Brunswick, New Jersey). Initial results from a Phase II safety trial reported during the stroke conference indicate that ReoPro could be administered as long as six hours after stroke onset. Although these results reflect safety only, at a news conference it was indicated that a secondary analysis of the data shows promising efficacy as well. A 1,500-patient pivotal trial is expected to begin in late 2003.

Several other compounds were discussed at the stroke conference, with perhaps the most intriguing one being desmoteplase, a vampire bat saliva-derived clot buster that targets and destroys fibrin, the structural scaffold of blood clots. Researchers believe that its therapeutic window could be three times that of Activase. A safety and efficacy trial is now under way in Europe and several other countries.

In recent years, it has become increasingly recognized that as many as 25% to 30% of all ischemic strokes (or approximately 200,000 strokes annually in the U.S.) are cryptogenic i.e., no other identifiable cause of an embolic episode to the brain is apparent. This type of stroke, which is especially common in younger patients (less than 60 years old), also has been described as a "cardiac source of stroke."

Cryptogenic stroke is most typically caused by a patent foramen ovale (PFO), which is a persistent, usually flap-like opening between the atrial septum that allows embolic material to migrate into the brain, precipitating an ischemic event. A PFO commonly is treated by a lifelong regimen of anti-coagulation medication, less frequently by open surgical repair or, in recent years, an interventional procedure that deploys an umbrella-like device to occlude the opening.

Two firms focus on PFO treatment

There has been considerable interest in the latter treatment in recent years, spearheaded by NMT Medical (Boston, Massachusetts) and AGA Medical (Golden Valley, Minnesota). The former estimates that the worldwide market potential for the treatment of PFOs approximates 500,000 procedures annually. At the stroke conference, both NMT and AGA indicated that they would soon commence multi-center, prospective randomized trials comparing PFO device closure to medical management. The latter reported on its 50-patient feasibility trial, which demonstrated that PFO closure with its Amplatzer PFO Occluder was safe.

AGA Medical soon will begin its Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment (RESPECT) trial, which will enroll 440 patients at 30 centers. The goal of this trial is to determine whether percutaneous PFO closure is equivalent to best medical management such as aspirin, warfarin or anti-platelet drugs in preventing a recurrent symptomatic stroke. Patients will be treated and then followed for two years.

NMT Medical also will soon embark on its large pivotal trial, with the goal to determine whether percutaneous PFO closure is better than medical management in preventing a recurrent symptomatic stroke. Because NMT is seeking a "superior to" claim, this trial will require a much larger number of patients to achieve statistical significance.

While ischemic stroke is a dominant force in stroke today, there also is considerable interest in hemorrhagic stroke, which accounts for 15% to 20% of all strokes. According to the National Stroke Association (Englewood, Colorado), about 50% of this type of stroke is represented by intracranial aneurysm. The rupture of an intracranial aneurysm is a devastating event and is associated with very high rates of morbidity and mortality, with more than half the patients dying within one month of this event. In addition, more than one-third of those who survive have major neurological deficit.

Historically, the standard of care for this condition has been an invasive neurosurgical clipping. However, in the past decade, this approach been challenged by less invasive interventional neuroradiology (INR) embolization techniques such as coiling. The neurology community has been wrestling with a heated controversy about which approach provides the best patient care and is the most cost effective, with neurosurgeons claiming that their approach provides the most reliable and durable method, while INR physicians state that their approach is superior due to lower cost and faster patient recovery.

In an effort to develop high-quality evidence comparing surgical and endovascular treatment of ruptured brain aneurysms, the International Subarachnoid Aneurysm Trial (ISAT) was initiated in 1994. ISAT's goal was to compare endovascular coiling to neurosurgical clipping, with the primary objective of determining whether endovascular coiling reduces the number of patients with poor outcomes compared to neurosurgical clipping.

This large study, which enrolled more than 2,100 patients at 43 neurosurgical centers in Europe, North America and Australia, represented the first randomized prospective clinical trial in this arena. It was terminated before enrollment was completed in May of last year because the difference in outcomes between the two procedures was so great that it was no longer deemed ethical to continue randomizing patients to neurosurgical clipping.

ISAT's principal investigator, Andrew Molyneux, MD, a consultant neuroradiologist with the department of neuroradiology at the Radcliffe Infirmary (Oxford, UK), reviewed ISAT's results and enumerated the several benefits of the endovascular technique. Most notably, there was a 23% reduction in the risk of death or significant disability at one year for patients treated endovascularly compared to those treated neurosurgically.

In an interview with Cardiovascular Device Update, Molyneux noted that the release of ISAT's results, which were reported in detail in the Oct. 26, 2002, issue of The Lancet, has had a "dramatic impact" on the treatment of intracranial aneurysms in centers in the UK that participated in ISAT. In these centers, he estimated that 80% to 90% of the aneurysm patients are being treated interventionally, compared to only 50% prior to the release of the ISAT data less than one year ago.

In the U.S., about only 15% to 20% of aneurysms are currently being treated interventionally, as neurosurgeons control the patient and make the clinical decisions in most centers. Whereas European neurosurgeons apparently have readily accepted the ISAT results, there appears to be considerable resistance in the U.S. As a result, there has been only a modest uptick in the market share of interventional procedures.

One notable exception to the limited penetration of neuro-interventional aneurysm treatment has occurred at the Methodist Stroke Center (Houston, Texas). Speaking at the stroke conference, neuro-interventionalist Michel Mawad, MD, said that more than 80% of the 1,105 aneurysms treated at his center in the past decade were sealed with embolic coils. Mawad told CDU that the key factor in the very high endovascular market share was a "cordial, cooperative working arrangement with the neurosurgeons at the center," with optimum patient care being the most important determinant of treatment modality.

Taking a decidedly different stance in a talk delivered at the meeting was Robert Harbaugh, MD, a neurosurgeon from Dartmouth Hitchcock Medical Center (Lebanon, New Hampshire), who said that the data from ISAT and other studies is not conclusive enough and that "we need a North American study to resolve these questions."

Based on the results of the ISAT trial, most neuro-interventionalists such as Mawad would likely disagree.

Stroke remains a frustrating disease

Several important themes emerged from this year's conference. Despite considerable progress, stroke remains a devastating, costly and frustrating disease for physicians, patients and public health officials. The trials and tribulations of stroke were discussed by Joseph Broderick, MD, chairman of the department of neurology at the University of Cincinnati (Cincinnati, Ohio), who received the William M. Feinberg Award for excellence in clinical stroke this year.

In a provocative talk, "Stroke Therapy in the Year 2025: Burdens, Breakthroughs and Barriers to Progress," Broderick noted that despite improvements in anti-hypertensive and lipid-reducing agents, stroke rates have continued an inexorable rise, reaching about 750,000 this year in the U.S. He estimated that by 2020, about 1 million Americans would suffer a stroke annually and that a recent study in Ohio showed that key stroke risk factors such as smoking, obesity, high blood pressure and cholesterol levels all have increased in the past decade. In addition, the aging of the U.S. population is an important contributor, as stroke rates rise substantially with age.

Referring to the failure of primary stroke preventive measures such as improved diet, exercise and elimination of smoking to be adopted widely, he quoted the onetime comic character Pogo: "We have met the enemy and he is us."

Broderick lamented that in spite of the availability of the excellent clot lysing agent tPA for treating acute ischemic stroke, fewer than 10% of potential ischemic stroke patients currently receive tPA therapy. He noted that the same problems that existed a decade ago a tremendous lack of public awareness of stroke symptoms and a very short three-hour "therapeutic window" continue to plague stroke treatment.

In order to improve stroke survival and mitigate disastrous post-stroke disability, he said, "we need better education, bigger studies to find more efficacious drugs with a longer therapeutic window, a more efficiently organized system for the delivery of stroke therapy and better mechanical devices for clot removal." Broderick added that he hoped future acute stroke therapy "will look like acute myocardial infarction" in terms of its efficacy and efficiency in emergent care delivery.

Hypothermia grows as promising therapy

One of the most promising areas for such therapy, though it was not specifically part of Broderick's discussion, is temperature management. Over the past several years, researchers have shown that lowering the body temperature decreases the final infarct volume and, very significantly, extends the duration or therapeutic window that the brain can tolerate ischemia before permanent damage occurs. Several studies are under way worldwide to test the hypothesis that inducing hypothermia can minimize the damage from stroke. However, it appears that hypothermic therapy may first find its commercial role for post-acute myocardial infarction (MI) patients, with several pivotal trials under way. The Feb. 21, 2002, issue of The New England Journal of Medicine featured two articles and an accompanying editorial supported the use of mild hypothermia as a means to improve outcomes from post-MI survivors.

One of the NEJM articles discussed the Hypothermia After Cardiac Arrest (HACA) trial, which was a four-year randomized trial investigating to see whether mild hypothermia (target temperature 34^o to 36^o C) would improve neurologic outcome after resuscitated cardiac arrest. The study's principal investigator, Fritz Sterz, MD, of the University Clinic of Emergency Medicine (Vienna, Austria), reported to a large audience during the stroke conference that the most recent HACA results show that patients randomized to mild hypothermia experience a "favorable neurologic outcome and reduced mortality."

It is interesting to note that the HACA trial used a fairly crude non-invasive device, a mattress with a cover that delivers cold air over the entire body, to achieve a hypothermic effect. Other companies are using more invasive, sophisticated approaches to this end. For example, privately held, venture capital-backed Radiant Medical (Redwood City, California) has developed a catheter-based approach which involves placing its device in the inferior vena cava via the femoral vein. Cool saline is circulated over the catheter, thereby cooling the blood. A microprocessor-controlled redundant safety system allows for precise achievement of the target temperature.

Radiant CEO Ken Hayes told CDU during the conference that enrollment for the company's COOL-MI pivotal trial was close to reaching its target of 400 patients. The trial, which is being conducted at 24 centers in the U.S., is randomizing acute MI patients to one of two modalities either percutaneous (angioplasty/stenting) intervention alone or percutaneous intervention along with mild hypothermia of 33^o C induced by the company's Reprieve endovascular temperature therapy system. Based on the enrollment thus far, Radiant likely will apply to the FDA for premarket approval in mid-year.

Other private and VC-backed companies pursuing this same market opportunity include Innercool Therapies (San Diego, California) and Alsius (Irvine, California). They also use a control console and a catheter to lower body temperature. The former is in the midst of its 400-patient, 18-center pivotal clinical trial, while the latter is halfway through its feasibility trial. Alsius already is aggressively addressing the European market, having signed up ev3 (Plymouth, Minneapolis) as its exclusive distributor for that market.

Another important study on the benefits of hypothermia is the Cooling for Acute Ischemic Brain Damage Phase II (COOL AID-II) trial, which is being sponsored by Radiant Medical. This study is being conducted at five centers, under the auspices of Derk Krieger, MD of the Cerebrovascular Center of the Cleveland Clinic Foundation (Cleveland, Ohio). He reported at the conference that this randomized, multi-center feasibility trial has enrolled 40 patients, with 18 patients receiving the hypothermic regimen. According to Krieger, Radiant's device is performing admirably, with very rapid and predictable cooling and re-warming of the patients. This study was designed to show that moderate hypothermia (33^o C) is feasible and safe for patients with severe acute ischemic stroke. The next phase of this study will be a larger efficacy trial.

Medivance (Louisville, Colorado) has launched the Arctic Sun Temperature Management System, which is initially targeted toward maintaining normothermia in the surgical setting. In addition, the company is actively involved in the Nordic Cooling Stroke Study study, which has enrolled 30 patients to date. The goal of this trial is to enroll 1,000 patients, half randomized to the control arm and half to the treatment arm. The latter group will be awake, moderate stroke patients who will be treated with mild hypothermia.

In an earlier stage of development is Seacoast Technologies (Portsmouth, New Hampshire), which is developing products that induce profound hypothermia in brain tissue locally, either intraoperatively or through a neurosurgical burr hole in the skull. Its novel approach involves neurosurgical placement of the device, allowing for rapid, profound and reliable cooling. It hopes to begin its human trials for neurosurgical applications about mid-year and follow that product with a stroke application project shortly thereafter.