CDU Contributing Writer

NEW ORLEANS, Louisiana – The 25th International Stroke Conference, sponsored by the American Heart Association (AHA; Dallas, Texas) and held here earlier this year, followed closely on the heels of important new information on the incidence of stroke in America. For the past several years, the annual number of strokes in the U.S. was generally accepted to be in the range of 500,000 per year, with nearly 160,000 Americans succumbing to death from stroke. Last year, the AHA, which is the most widely-recognized source of stroke data, significantly boosted its estimates of stroke to 600,000 per year.

A further increase in the incidence of stroke was presented in an article in the December 1999 issue of Stroke: Journal of the American Heart Association, which concluded that the number of new and recurrent strokes is actually closer to 750,000 per year. Researchers, who were led by the lead author, G. Rhys Williams, MS, director of the Department of Health Outcomes Management and Research of Knoll Pharmaceutical (Mount Olive, New Jersey), a division of Knoll AG (Ludwigshafen, Germany), used a larger data base than previous stroke studies which have focused on smaller patient registries, hence the larger and hopefully more accurate estimate.

Whatever the precise number of strokes, which often are described as a "brain attack," it continues to be a major scourge. Stroke is the third-leading cause of death in the United States (trailing only heart disease and cancer), is the leading cause of serious disability, accounting for more than 50% of all patients hospitalized for acute neurological disease, and results in an estimated $40 billion in annual direct and indirect costs. Given that the U.S. population is aging and that stroke increases dramatically with age (for people over 55, the incidence of stroke more than doubles in each successive decade), it is clear that stroke's incidence will surge in the future. Last year, the University of Iowa College of Medicine (Iowa City, Iowa) projected that the number of annual strokes by the year 2050 would exceed one million.

Two themes, which have been significant focal points of the past few International Stroke Conferences, were prominent at this year's gathering.

The first recurrent issue is the need for prompt treatment of acute ischemic stroke within the "therapeutic window of opportunity." Ischemic stroke, often referred to as vaso-occlusive stroke, accounts for 80% to 85% of the total strokes, while hemorrhagic stroke accounts for the balance. Clinical trials have unequivocally established that Genentech's (South San Francisco, California) FDA-approved, clot-dissolving, intravenously-delivered recombinant thrombolytic agent, t-PA, provides significant patient benefits if administered within three hours after the onset of acute ischemic stroke symptoms. The most important finding from these clinical trials is that t-PA treated patients were at least 30% more likely than the placebo group to have minimal or no disability at three months.

Further support for the benefits of thrombolytic therapy was disclosed in an article in the June 10, 1999, issue of The New England Journal of Medicine.

The article provided an analysis of the follow-up data from the landmark National Institute of Neurological Disorders and Stroke (NINDS; Bethesda, Maryland) Recombinant Tissue Plasminogen Activator Stroke Study. A review of the one-year data of this trial, which was the pivotal study that fostered the FDA's approval for t-PA in June 1996, revealed that not only do t-PA administered patients benefit in the short run (i.e., three months) but that there is also a sustained (one year) benefit as well. Thus, if patients can receive t-PA in a timely manner, they can enjoy both short-term and enduring benefits.

The urgency to deliver timely therapy to acute ischemic stroke victims has been emphasized by the Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS) study. The results of this trial, which were reported in the December 1, 1999, issue of the Journal of the American Medical Association (JAMA), showed that acute ischemic stroke patients treated between three and five hours after symptom onset gained no significant benefit. The ATLANTIS results are supported by ECASS-II (European Co-Operative Acute Stroke Study--Part 2), which found that the use of t-PA up to six hours after stroke onset produced mediocre results compared to the three-hour window. Therefore, administration of the drug is not warranted after the three-hour time window, which is the current FDA-approved protocol.

Two articles in the March 1, 2000, issue of JAMA provided an interesting view of the challenge in using t-PA for acute stroke in the community setting. In a study of 29 Cleveland, Ohio-area hospitals, researchers found that nearly 16% of t-PA patients had a symptomatic cerebral hemorrhage (a common side complication from t-PA) and an in-hospital mortality rate three times the rate for patients who did not receive the drug. On the other hand, a second contrasting study derived from 57 medical centers from throughout the U.S. that were well-trained and experienced in acute stroke thrombolysis showed the rate of cerebral bleeding to be about 3%, along with a far lower death rate. The upshot of these two studies is that t-PA therapy can be risky and therefore should only be delivered in the hospital, where the staff is well-versed in its risks and benefits. Interestingly, the disparate results of these two stroke care centers conflicts with the presentation at the conference of the findings of a group from Park Nicollet HealthSystem (Minneapolis, Minnesota). This group demonstrated, in a paper titled "Should Use of t-PA for Ischemic Stroke Be Restricted to Specialized Stroke Centers?," that there were no measurable differences in the outcome for stroke patients treated at academic and non-academic hospitals.

The hopes for extending the therapeutic window of opportunity have been buoyed in recent times by the favorable results of using Prolyse (recombinant pro-urokinase or r- pro-UK) delivered with a catheter intra-arterially by an interventionalists in the cath lab for up to six hours after ischemic stroke onset. The December 1, 1999, issue of JAMA reported on the Phase III (pivotal trial) results of Prolyse in Acute Cerebral Thrombosis-II (PROACT-II), which echoed the positive results of the PROACT-I trial. The first PROACT study randomized patients to either Prolyse or saline, while in PROACT-II patients were randomized to either Prolyse plus intravenous heparin or IV heparin alone. The authors of the JAMA article conclude that r-pro-UK treatment administered within six hours of acute ischemic stroke onset significantly improved clinical outcome at 90 days.

Unfortunately, despite these favorable results, it appears that Prolyse's debut on the U.S. market will be significantly delayed. Industry sources are indicating that the FDA is insisting upon another randomized, blinded, multicenter trial to substantiate the results of the earlier PROACT trials. The developer of Prolyse, Abbott Laboratories (Abbott Park, Illinois), reportedly is attempting to negotiate this matter with the FDA but has so far been stymied.

The potential delay in the approval of Prolyse for acute ischemic stroke is a huge setback for patients and the health care system and a major frustration for physicians who believe its availability would offer an important therapy for ischemic stroke victims.

Another compound, Viprinex (ancrod) has demonstrated promise as a new pharmacological agent for ischemic stroke therapy. albeit with a three-hour time window. Derived from a pit viper snake's venom, Viprinex has completed a successful five-year, 500-patient Phase III trial called the Stroke Therapy with Ancrod Trial (STAT), and a year ago appeared headed toward an FDA approval sometime in 2000. Unfortunately, this agent, which is intravenously administered over a three-to-five-day span in the hospital, also appears to have fallen into a regulatory morass with the FDA in its attempt to parlay the excellent results from its six-hour post-stroke results from Europe to the U.S. Thus, the timing of its market entry in the U.S. is murky. Ancrod was developed by Knoll AG and would be marketed in the domestic market through its Knoll Pharmaceutical subsidiary.

The search for new thrombolytic agents, notably those that can expand the therapeutic window of opportunity, remains active. One promising agent is abciximab, a well-known platelet glycoprotein IIb/IIIa inhibitor drug that is sold worldwide (except in Japan) by Eli Lilly & Co. (Indianapolis, Indiana) under the brand name Reopro and widely used in combination with aspirin and heparin to prevent ischemic complication following percutaneous coronary interventional procedures and in those with unstable angina not responding to conventional medical therapy when a percutaneous coronary interventional procedure is planned within 24 hours.

Results from a Phase II clinical study of patients with acute ischemic stroke, presented in the March 2000 issue of Stroke, showed that abciximab improved patients' clinical function even when administered for up to 24 hours after first symptoms, with no increased risk of major intracranial bleeding. This international, multicenter Phase II trial involved 74 patients with acute ischemic stroke, who were followed for three months. Approximately 35% of patients treated with any dose of abciximab had minimal or no residual disability, compared with 20% who received placebo. In addition, 50% of patients treated with abciximab showed improved function in carrying out daily activities, compared with 40% given placebo.

Most impressively, this degree of improvement was seen despite the fact that half of the patients were treated more than 12 hours after stroke onset; nearly all were treated more than three hours after onset. In addition, although abciximab is a potent antiplatelet drug and therefore can increase the risk of bleeding, none of the patients in the stroke trial suffered from major (symptomatic) intracerebral hemorrhage, a potentially fatal side effect of current therapy.

Eli Lilly is launching a larger, 400-patient, 40-site Phase IIb safety and efficacy trial in the U.S., with international trials in this study slated to begin shortly. The trial is expected to take two years to complete. The principal investigator of the study is Harold Adams, MD, a neurologist at the University of Iowa Hospitals and Clinics (Iowa City, Iowa).

The battle to reduce vaso-occlusive stroke morbidity and mortality is not restricted to the timely thrombolysis of the obstructive clot, but has also been directed toward protecting cells downstream from the site of an ischemic blockage. In areas where the blood flow is blocked, brain cells can only survive for a few minutes before a cascade of biochemical reactions causes brain cell death; thus, so-called neuroprotective drugs have been developed to interfere with this cascade, in a bid to reduce the damage from inadequate blood flow.

Unfortunately, the news at this year's conference on neuroprotective drugs was negative, with heretofore promising agents showing disappointing results.

Preliminary analysis of the data from the Effects of Citicoline on Clinical Outcome-2000 mg (ECCO-2000) Phase III trial of citicoline showed that it did not achieve its primary endpoint, i.e., a significant improvement in neurological outcome for patients who have suffered a moderate to severe stroke. The trial, sponsored by Interneuron Pharmaceuticals (Lexington, Massachusetts), did not achieve the required seven-point improvement in the National Institutes of Health (Bethesda, Maryland) Stroke Scale through the 12-week treatment. Interestingly, the drug demonstrated excellent safety and generated good results for several secondary endpoints, but any trial that does not attain its primary endpoint is doomed for rejection by the FDA.

The second reported setback was the news that a combination of a t-PA with the neuroprotective agent lubeluzole did not provide significant improvement over t-PA in acute ischemic stroke patients and the trial was stopped by its sponsor, Janssen Pharmaceutica (Titusville, New Jersey), a division of Johnson & Johnson (New Brunswick, New Jersey), after less than half of the target number of patients were enrolled. In delivering these results, James Grotta, MD, of the University of Texas Medical School (Houston, Texas), noted that "... effective neuroprotection and the means to achieve it remain an elusive goal."

Finally, very disappointing results were reported in the Glyycine Antagonist in Neuroprotection (GAIN) international trial of more than 1,400 patients. Using glycine, a specific antagonist of the glycine site of the NMDA receptor, within six hours after stroke onset, clinical outcomes were nearly identical between the placebo group and the glycine cohort. Kennedy Lees, MD, of the University of Glasgow (Glasgow, Scotland), noted that while these results clearly were disappointing, another study from the U.S., currently under way, may show more encouraging results. Commenting on the dismal results of neuroprotective compounds at a press conference, Marc Mayberg, MD, of the Cleveland Clinic (Cleveland, Ohio) said that clinicians may need to consider a new neuroprotective drug strategies, perhaps using multiple agents (cocktails) or employing other modalities, such as hypothermia, to mitigate the damage from the biochemical cascade. Several early-stage medical device companies are now actively developing hypothermic devices toward this end.

The disappointing results of the neuroprotective trials and the inability to broaden the therapeutic window of opportunity strongly point to the continued need on the part of stroke victims and the health care system to either reduce the incidence or prevent stroke (through dietary and lifestyle measures). Acute ischemic stroke victims or their families must rapidly acknowledge their situation and receive immediate medical care, and hospitals must be properly equipped with trained personnel and imaging modalities to confidently diagnose and expeditiously treat acute ischemic stroke.

Numerous educational and other programs must be initiated to mitigate the devastating impact of stroke. However, the public continues to exhibit an appalling lack of understanding of the telltale signs of acute stroke and must be better educated. Physicians and patients must become more savvy about preventive measures, both with lifestyle changes and pharmacological agents. In this regard, a paper presented at this conference discussing results from the University Health System Consortium Ischemic Stroke Benchmarking Project, revealed that 40% of patients who had a prior stroke and were admitted to the hospital with another stroke were not receiving well-established medical therapies (aspirin, warfarin, or other drugs such as platelet aggregation inhibitors) to protect from another stroke episode.

Additionally, another group of high-risk patients (prior heart attack, significantly stenosed carotid arteries, atrial fibrillation) were not receiving appropriate medication. At a press conference, Judith Lichtman, PhD, of the Center for Outcomes Research and Evaluation at Yale University (New Haven, Connecticut), expressed deep concern and dismay about this situation.

Tremendous progress has been made in the past several years in the diagnostic imaging equipment that is used to determine if an acute stroke has occurred and how it can best be treated. Several variations of magnetic resonance imaging (MRI), including diffusion-weighted imaging (DWI), continuous arterial spin labeled perfusion MRI, perfusion imaging, and magnetic resonance angiography were discussed at the conference, with all favorably adding to the diagnostic prowess of the neurology and radiology communities. DWI, in particular is demonstrating far higher accuracy than conventional computed tomography and MRI in detecting acute stroke and assessing the amount of salvageable brain tissue. In a study presented at the AHA stroke conference by David Tong, MD, of the Stanford Stroke Center (Palo Alto, California), DWI provided such improved diagnostic information that a major change in therapy was prescribed in one-third of the cases. However, the cost of these devices, well in excess of $1 million each, remains a major hurdle for market acceptance.

Finally, as discussed earlier, thrombolytic agents that can extend the therapeutic window are desperately needed. Fewer than 2% of acute stroke patients arrive in time to receive thrombolysis, with a paltry 1% from rural areas arriving within three hours. A thrombolytic agent that could widen that window, with the appropriate safety and efficacy, would be eagerly embraced by the physician community.

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