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Neurology Today:
doi: 10.1097/01.NT.0000419196.40985.f8
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New Data Support Expanded Use Of tPA for Stroke

Fitzgerald, Susan

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ARTICLE IN BRIEF

Two papers — one, reporting on an international randomized, open-treatment study and the other, a meta-analysis — stress that early administration of tPA, ideally under three hours, offers the best chance for stroke patients to survive with good function, but also suggest that there could be benefits in using more latitude in deciding when and whom to treat with the clot-busting drug.

Far more patients with acute ischemic stroke could benefit from tissue plasminogen activator (tPA), including those over the age of 80, people with severe symptoms, and possibly even some who get care up to six hours after the onset of symptoms, according to two new studies reported in the June 23 Lancet.

Both studies — the International Stroke Trial (IST-3), a randomized, open-treatment study involving 3,035 patients in 12 countries, and the other, a meta-analysis of a dozen randomized, controlled studies, including the IST-3 — stress that early administration of tPA, ideally under three hours, offers the best chance for stroke patients to survive with good function, but the new findings also suggest that there could be benefits in using more latitude in deciding when and whom to treat with the clot-busting drug.

The IST-3 trial sought to enroll patients outside the typical treatment profile: Three-quarters of the study participants received treatment more than three hours after onset of stroke; more than half of the participants were older than 80; and about one-third of the patients were treated between 4.5 to 6 hours after symptom onset.

“The key finding from both our trial and the meta-analysis is that it is imperative to treat patients early,” Peter Sandercock, DM, professor of medical neurology at the University of Edinburgh and a co-chief investigator for the IST-3 trial, told Neurology Today in an interview.

He added that the new findings also demonstrate that doctors need to think more broadly about which patients could benefit from t-PA. “There is a tendency to be less aggressive in older people, but the findings provide clear evidence that people over 80 do benefit,” he said.

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STUDY DATA

The IST-3 trial, which involved 1,515 patients given t-PA and 1,520 controls, was designed to test the hypothesis that 0.9 mg/kg rt-PTA (maximum 90 mg) given to adult patients of all ages with acute ischemic stroke, within six hours of symptom onset, increased the proportion of people who were alive and independent at six months.

The primary endpoint — that patients were alive and independent at six months — was measured using the Oxford Handicap Score (OHS), a 0–5 scale that is a commonly used variation of the modified Rankin score (mRS). (0 means the patient has no handicap after stroke; 5 means total dependency.) Patients with an OHS score of 0, 1 or 2 were classified as independent in the IST-3 study.

At six months, 554 (37 percent) patients in the rt-PA group versus 534 (35 percent) in the control group were alive and independent, the researchers reported. While more patients who received the drug died in the first seven days, usually from intracranial bleeding, between seven days and six months fewer patients in the treated group died and by six months the two groups had similar death rates.

The meta-analysis, which was based on pooled data on 7,012 patients, likewise concluded that more stroke patents could benefit from tPA. The meta--analysis concluded that “for every 1,000 patients allocated rt-PA up to 6 hours after stroke, 42 more patients were alive and independent (mRS 0–2); 55 more were alive with a favorable outcome (mRS 0–1) at the end of follow-up.”

Joanna M. Wardlaw, MD, professor of applied neuroimaging at the University of Edinburgh, who headed up the meta-analysis, told Neurology Today in an e-mail that her team's analysis of the pooled data found that “fast treatment works better but some patients may still benefit out to six hours.”

She said the IST-3 study was especially important because it “squashes some myths, for example, that patients with early infarct signs or severe stroke should be excluded. No other trials included patients aged over 80 as it was assumed that rt-PA would be too risky or ineffective — completely wrong.”

“Patients aged over 80 benefit as much if not more than those under 80, especially if treated within three hours,” Dr. Wardlaw said.

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QUESTIONING THE TREATMENT WINDOW

An accompanying editorial in the same issue noted that the license for the use of tPA in the European Union was recently expanded to include a treatment window of 4.5 hours, rather than the original three hours, but the drug is not approved for use in patients over 80.

In the US, tPA was approved based on a three-hour treatment window, though a science advisory issued by the American Heart Association and American Stroke Association in 2009 said the drug could be given up to 4.5 hours after the start of stroke symptoms.

The FDA recently considered whether the label for tPA in this country should be expanded to include treatment up to 4.5 hours, based on data that emerged from the European Cooperative Acute Stroke Study (ECASS) and other trials, a spokesman for Genentech, the company that manufactures alteplase, told Neurology Today in an e-mail.

Genentech had filed an application with the FDA to extend the treatment window for tPA last August, but on May 7, the FDA rejected the application, claiming the ECASS data were not “sufficiently compelling to warrant a label extension.”

Mark J. Alberts, MD, professor of neurology at Northwestern University, who was not involved with the Lancet studies discussed here, said:“The bottom line is that in the US, at institutions such as ours, we're not expanding to use IV t-PA in a six-hour treatment window,” Dr. Alberts said. He noted that the results from the IST-3 study were difficult to compare to previous tPA studies because of differences in inclusion criteria, pre-treatment screening and the end points selected as outcome measures.

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WHERE RESEARCH IS NEEDED

Dr. Wardlaw said more research was needed to identify how best to select patients who might benefit because of an extended treatment window. “If small gains in functional ability by 3–6 months translate into greater long-term survival free of disability, this is likely to reduce health-care costs and increase quality of life and cost-effectiveness,” her team wrote.

Patrick Lyden, MD, chair of the department of neurology and director of the Stroke Center at Cedars-Sinai Medical Center, said stroke experts in this country are already, depending on the circumstances of the case, treating patients over age 80 and beyond the three-hour window. He said the findings from the IST-3 study are “reassuring. We know we're doing the right thing and IST-3 should stimulate us to bring the therapy to less experienced centers.”

Dr. Lyden said there is already a plethora of evidence on the effectiveness of tPA for stroke. “Where we need to focus more research is in finding a better way to select patients using imaging. We live and die by the clock, but that's not the end-all and be-all. There needs to be a better way.”

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REFERENCES:

• The IST-3 collaborative group. The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): A randomised controlled trial. Lancet 2012; 379: 2352–2363.
• Wardlaw JM, Murray V, Cohen G, et al. Recombinant tissue plasminogen activator for acute ischaemic stroke: An updated systematic review and meta-analysis. Lancet 2012; 379: 2364–2372.

• Leys D, Cordonnier C. Commentary: rt-PA for ischaemic stroke: What will the next question be? Lancet 2012;379(9834):2320–2321.

©2012 American Academy of Neurology

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