CDU Contributing Editor
NEW ORLEANS While a festive atmosphere was building outside as the annual Mardi Gras events began, inside the huge Ernest Morial Convention Center, the approximately 3,000 attendees at the 30th annual International Stroke Conference, held here in early February under the sponsorship of the American Stroke Association (ASA; Dallas), were hearing the same old refrain from earlier meetings. That is, stroke victims are receiving inadequate treatment and new approaches and therapies are needed to manage the nation's 750,000 annual strokes.
The FDA's approval of Genentech's (South San Francisco, California) clot-busting drug tissue plasminogen activator (tPA) in 1996 was hailed as a major breakthrough in the fight against acute ischemic stroke (AIS), which accounts for about 85% of all strokes. The landmark National Institute of Neurological Disorders and Stroke (Bethesda, Maryland) trial demonstrated that tPA fosters an impressive 30% reduction in severe disability in ischemic stroke patients.
However, tPA is hampered with two 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 occasionally be fatal.
Despite tPA's clearcut benefits, the number of patients receiving it is pitifully low, extremely frustrating to physicians that treat AIS. An article in the Oct. 26, 2004, issue of the Journal of the American Medical Association, authored by Peter Heuschmann, et al., noted that only 1.6% to 2.7% of acute ischemic stroke patients treated in community hospitals and 4.1% to 6.3% of AIS patients treated at academic hospitals or specialized stroke centers received thrombolytic therapy.
This depressing data, which is consistent with several other studies, has numerous explanations, including tPA's highly restrictive three-hour "window of opportunity," the oft-subtle symptoms of ischemic stroke (especially compared with an acute heart attack) that cause patients to delay their departure to the hospital, the limitations and lack of availability of current diagnostic technologies, inadequate physician reimbursement and the lack of a written protocol and trained staff.
Several prominent stroke specialists addressed this critical problem and potential means to attack it at an ASA-sponsored press conference titled "Watching the Clock: What's New with Time-Dependent tPA." The moderator of this meeting, Mark Alberts, MD, of Northwestern University Medical School (Chicago) set the stage by saying that "any therapy that could extend the time window would make a huge impact" on the management of acute ischemic stroke.
William Barsan, MD, chairman of the emergency department of the University of Michigan Medical Center (Ann Arbor, Michigan), reported that a survey of more than 1,000 emergency medicine physicians indicated that tPA's low usage is heavily related to the risks, perceived and real, of ICH. The survey, done in conjunction with the American College of Emergency Physicians (Irving, Texas), concluded that tPA's ICH rate needed to be reduced to 3% or about 50% below its current levels for emergency room doctors to more fully embrace it.
Responding to a question at the press conference from Cardiovascular Device Update, Barsan said he was "absolutely certain" that litigation risk was an important factor in the cautious use of tPA by emergency room personnel. "I know of several lawsuits that have been filed against physicians [relative to its use]," he said.
A second concept, presented by Marc Ribo, MD, PhD, of Hospital Vall d'Hebron (Barcelona, Spain), showed that the limited window of opportunity of tPA can be significantly and safely extended using a multi-modality MRI protocol. Specifically, using a combination of perfusion-weighted MRI, diffusion-weighted MRI and magnetic resonance angiography, Spanish physicians have shown that patients carefully assessed with this advanced diagnostic protocol could be properly identified and successfully treated despite falling well outside the approved window.
This concept is consistent with discussions at last year's stroke conference, when researchers noted that MRI could be used to identify patients outside the therapeutic time window but can still enjoy significant benefit from tPA infusion.
A third concept, presented at the ASA press conference by Carlos Molina, MD, also of Hospital Vall d'Hebron, showed that the addition of microbubbles to tPA administration and ultrasound monitoring improves the rate of ischemic clot lysis. Molina's relatively small microbubble study builds on the success of ultrasound-based trials demonstrating that galactose-based microbubbles can boost the efficacy of ultrasound. These microbubbles, which are manufactured by Schering (Berlin, Germany) and sold under the brand name Levovist, are injected intravenously. Levovist is a contrast medium which temporarily enhances ultrasound echoes.
There were three arms of this trial: one tPA with ultrasound, another tPA plus placebo monitoring and the third, tPA with ultrasound and microbubbles. Molina indicated that the latter approach provided the fastest and highest rate of complete recanalization and short-term neurological outcome. "It appears that these microbubbles explode in combination with tPA and ultrasound," he said. Although a larger trial will be required to substantiate these results, Molina said that this is a "very promising concept."
The use of ultrasound to buoy tPA's effect has become an exciting emerging concept in AIS therapy. At a session on "Use of Ultrasound as Therapy for Acute Stroke," several speakers extolled the benefit of ultrasound. George Shaw, MD, PhD, of the University of Cincinnati, said that his models show that ultrasound improves thrombolysis seven-fold. He concluded his talk with the comment that "ultrasound dramatically improves the lysis of clots."
Another speaker, Andrei Alexandrov, MD, of the University of Texas-Houston Medical School, discussed the results of the Combined Lysis of Thrombus in Brain Ischemia Using Transcranial Ultrasound and Systemic tPA (CLOTBUST) trial, which appeared in the Nov. 18, 2004, issue of The New England Journal of Medicine. The article, titled "Ultrasound-Enhanced Systemic Thrombolysis for Acute Stroke," authored by Alexandrov et al., discussed the use of continuous 2 MHz, single-element pulsed-wave transcranial Doppler (TCD) ultrasound monitoring of intracranial occlusion in combination with tPA administration.
This technique achieved a higher rate of complete recanalization and early or dramatic clinical recovery from stroke. The authors noted that a biologic effect of diagnostic ultrasound appears to aid systemic thrombolytic therapy and concluded that there is "potential of diagnostic ultrasonography to improve the efficacy of systemic therapy with tPA in cases of acute ischemic stroke."
Speaking to a packed room, Alexandrov noted that a larger study, now under way, will be needed to provide further evidence of safety and efficacy. Further, he noted that many centers either do not have TCD available or enough trained operators to provide round-the-clock TCD and tPA therapy.
Another interesting trial, which is supported by the French Ministry of Health, is Microbubbles and Ultrasound in Stroke (MUST). This multi-center, randomized trial, which began enrolling in mid-2004, will evaluate whether the addition of TCD and intravenous microbubbles to tPA is superior to tPA alone in treating AIS. The study investigators are led by Vincent Larrue, MD and colleagues at the University of Toulouse Hopital Rangueil (Toulouse, France), who hope to complete enrollment by the end of this year.
Other speakers presented different ultrasound approaches to enhanced thrombolysis, and while the best ultrasound and microbubble technology is yet undetermined, there is hope that "sono-thrombolysis" may become an important new technology in the fight against acute ischemic stroke.
The quest to improve the treatment of AIS through extending the therapeutic window continues unabated and some progress was reported here. The most promising compound is desmoteplase, which has been in human clinical trials for more than three years. This substance, a genetically engineered thrombolytic enzyme, was originally found in the saliva of vampire bats, where its role is to support the feeding activity of the bat. It acts in a similar way to tPA but works almost exclusively by targeting and destroying fibrin, the structural scaffold of blood clots. It is able to dissolve the blood clot with less risk of ICH than tPA and is even thought to have neuroprotective properties.
Demoteplase, selected as one of the American Heart Association's (Dallas) "Top 10 advances for 2003,"continues to show solid clinical progress. At this year's meeting, the developer, PAION (Aachen, Germany), released the results of the multi-center, placebo-controlled, randomized, dose-finding Dose Escalation Study of Desmoteplase in Acute Ischemic Stroke (DEDAS) trial, which mimicked the same study design as the previous trial, Desmoteplase in Acute Ischemic Stroke (DIAS).
Anthony Furlan, MD, the principal investigator of DEDAS and medical director of the Cerebrovascular Center at the Cleveland Clinic (Cleveland), reported that despite a relatively small number of enrollees, DEDAS essentially confirmed the DIAS results, with the higher dosage of 125 mk/kg showing roughly the same results as the lower dose. The drug improved reperfusion and resulted in a much better clinical outcome as measured by several widely accepted neurological measures. Furlan said that he was very encouraged by the "impressively low rate of ICH" and the fact that safety and efficacy were similar whether patients were treated in three to six hours or six to nine hours from stroke onset.
The larger multi-country DIAS-II trial will soon begin enrolling patients at 75 to 100 sites worldwide and if these results corroborate the DIAS and DEDAS finding, the Phase III pivotal trial could begin soon afterwards. Furlan said that desmoteplase could have an "enormous impact" on the treatment of AIS if its safety and efficacy is borne out in the pivotal trial.
The desmoteplase trials all are using MRI as a key inclusion criteria to identify patients who will benefit the most from this regimen. This represents an important departure from earlier clinical trials, which strictly limited thrombolytic therapy based on a rigid time window. MRI can identify and quantify the amount of tissue that is still alive due to collateral or adjacent blood flow. Patients with this penumbra, or an area of brain that can be salvaged by restored blood flow, will likely benefit from the MR imaging approach.
Going forward, it is likely that acute ischemic stroke patients not only will be evaluated for the time window but their physiological parameters also will be an important determinant in whether they qualify for thrombolysis.
In July of last year, Forest Laboratories (New York) announced that it had signed an agreement with PAION for the North American marketing and development rights to desmoteplase. Complete terms of the deal were not disclosed but Forest will pay PAION milestone payments and a royalty based on sales, in addition to an undisclosed up-front payment. Forest will be responsible for funding all continuing clinical development activities for the U.S. and Canadian markets.
Another thrombolytic agent showing potential is the platelet-blocking glycoprotein IIb/IIIa inhibitor abciximab (which is marketed under the brand name Reopro), which has been used for many years by interventional cardiologists to prevent blood clots arising from an angioplasty procedure. At last year's stroke meeting, promising results in the Phase IIb Abciximab in Emergent Stroke Treatment Trial (AbESTT) for up to six hours after symptom onset were disclosed. The trial, which enrolled a total of 474 patients, demonstrated that abciximab is safe and improves neurological function for patients treated in the three- to six-hour time window.
A 1,500-patient pivotal Phase III trial, called AbESTT-II is now under way. This multi-center, multinational, randomized, double-blind, placebo-controlled trial is planning to enroll 1,800 patients at 150 centers in 18 countries. Some 1,200 patients will be treated within five hours of stroke onset and another 600 patients will be treated within five to six hours. The trial began in December 2003 and its completion date is not known at this time.
Finally, thrombolytic "cocktails" are another promising avenue to boost the time window. A poster from Ulf Becker, MD, et al., from the University Hospital (Dresden, Germany) said that the combination of tPA and abciximab was safe and showed an impressive rate of recanalization within the three- to six-hour window.
Another facet of the ongoing campaign to better care for acute ischemic stroke patients is to upgrade the infrastructure that serves these patients. An example is the "Get with the Guidelines-Stroke (GWTG-Stroke) initiative, a voluntary, in-hospital acute stroke treatment and quality improvement program sponsored by the American Stroke Association. GWTG-Stroke, which focuses on providing an infrastructure for better care to ensure that patients are treated and discharged appropriately, uses collaborative meetings, best practice sharing and an Internet tool for data collection, reporting and decision-making.
Early returns from GWTG-Stroke are quite encouraging. For example, Lee Schwamm, MD, of Massachusetts General Hospital (Boston), reported that there was a "dramatic" 89% improvement in rates of tPA use in eligible patients who arrived within two hours of stroke symptoms. In addition, 85% of all acute stroke patients who did not receive tPA had a documented reason for ineligibility. Schwamm commented that GWTG-Stroke is "the first program that has been able to show this much improvement in stroke care."
Another important initiative has come from the Joint Commission on Accreditation of Healthcare Organizations (JCAHO; Oakbrook Terrace, Illinois), which in July 2004 established a standardized performance measure set for primary stroke centers. JCAHO said this is the first nationwide certification program to evaluate stroke care provided by hospitals using criteria developed in conjunction with the American Stroke Association.
The Joint Commission's hopes that with disease-specific care standards and the use of guidelines and performance measurements for accountability for clinical improvement, the clinical outcomes for stroke patients would improve. A panel of 16 stroke experts selected by JCAHO and ASA recommended the standardized performance measures. Certified stroke programs also will have the opportunity to voluntarily participate in a pilot study of all 10 measures. The Joint Commission will evaluate results from the year-long pilot study to determine which measures should be included in the standardized performance measure set for stroke in the future.
JCAHO launched the disease-specific care certification program for stroke in November 2003, based on the recommendations for primary stroke centers published by the Brain Attack Coalition (Bethesda, Maryland) and ASA's guidelines for stroke care.
Reviews of early-adopter hospitals that seek certification currently require submission of four clinical process or outcome measures related to stroke care. In addition to performance measurement requirements, the Primary Stroke Center Certification includes an onsite review every two years and an offsite review every other year. Reviewers will evaluate compliance with national standards and emphasize the management of stroke patients through clinical guidelines and performance measurement assessment.
A robust example of how these types of programs can work effectively was seen in a poster titled "Impact of a Dedicated Stroke Team on the Use of Thrombolysis for Patients with Acute Ischemic Stroke," presented by Pansy Harris-Lane, RN, et al., from the Zeenat Qureshi Stroke Research Center (Newark, New Jersey). Their study showed that in 2001-02, only 2% of patients in their institution received tPA for AIS. With the implementation of a dedicated stroke team, the number of AIS patients receiving tPA in 2003-04 soared seven-fold to 14%.
According to Drs. Barsan and Alberts, if all acute stroke patients arrived within the three-hour time window, about 40% of patients who could receive tPA. Thus, while the progress made at a dedicated stroke center is highly commendable, much more progress still can be made.