IST-3: Thrombolysis Benefits Even Oldest Stroke Patients

Daniel M. Keller, PhD

June 01, 2012

June 1, 2012 (Lisbon, Portugal) — In the largest trial of a thrombolytic drug to date, for patients with acute ischemic stroke who received recombinant tissue plasminogen activator (tPA) up to 6 hours after a stroke, researchers conclude that treated patients benefited in terms of being alive and capable of independent living at 6 months compared with a control group, regardless of age.

Peter Sandercock, DM, professor of medical neurology and honorary consultant neurologist in the Centre for Clinical Brain Sciences at the University of Edinburgh in Edinburgh, United Kingdom, reported the results of the third International Stroke Trial (IST-3) showing that mortality was higher in the first week for the patients receiving tPA but was no different from controls at 6 months.

Results on the primary endpoint, the proportion of patients alive and independent as defined by an Oxford Handicap Scale (OHS) score of 0 to at 6 months, were not significantly different between the groups. However, results of a prespecified ordinal or "shift" analysis showed a significant shift toward better scores among treated patients.

The IST-3 results were published in The Lancet to coincide with their presentation here at the XXI European Stroke Conference (ESC).

In a second paper published in The Lancet at the same time, Joanna Wardlaw, MD, also from the University of Edinburgh and Western General Hospital, and colleagues reported an updated meta-analysis incorporating the new IST-3 results into an ongoing synthesis of all stroke trials using tPA.

The researchers conclude that the data, now from 12 trials enrolling 7012 patients, show that for every 1000 patients allocated to tPA up to 6 hours after a stroke, 42 additional patients are alive and independent, and 55 were alive with a favorable outcome at the end of follow-up.

The benefit was seen despite an increase in the number of early symptomatic intracranial hemorrhage (ICH), the authors note. The early hazard was offset by a reduction in later deaths, such that by the end of follow-up, no effect on all-cause mortality was seen, and the number of patients who were dependent was reduced.

Six-Month Results Balance Early ICH Risk

Between 2000 and 2011, the open-label IST-3 randomly assigned 3035 patients 18 years of age or older at 156 hospitals in 12 countries to receive, within 6 hours of symptom onset, 0.9 mg/kg intravenous tPA (n = 1515) as a 10% bolus, with the rest given over 1 hour, or to control treatment (n = 1520). The maximum tPA dose was 90 mg.

Up to now, thrombolysis with tPA has been indicated for patients younger than age 80 years and within 4.5 hours of the onset of a stroke, among other exclusions.

Dr. Sandercock noted that patients enrolled in the trial were ones for whom the benefits of tPA were "promising but unproven." Not enrolled were those who had clear indications for receiving the drug. Patients with contraindications were also excluded from the trial. The treatment and control groups were well balanced for all key factors.

In the entire study population, just over half (53%) were older than 80 years, and three quarters were treated after 3 hours.

The primary outcome was the proportion of patients alive and independent, as defined by an Oxford Handicap Scale (OHS) score of 0 to 2 at 6 months. The OHS is a modification of the Rankin Scale.

Treatment with tPA came with an increase in early risk. Seven percent of the patients in the tPA group experienced a fatal or nonfatal symptomatic ICH in the first 7 days after stroke, compared with 1% in the control group (adjusted odds ratio [OR], 6.94; 95% confidence interval [CI], 4.07 - 11.8; P < .001).

Similarly, 11% of patients in the tPA group died in the first 7 days vs 7% in the control group (adjusted OR, 1.60; 95% CI, 1.22 - 2.08; P = .001).

"However, between 7 days' and 6 months' follow-up, we observed an extremely interesting reduction in mortality, that is, 300 patients died amongst those allocated to control and 244 amongst those allocated to tPA, a significant 4% reduction," Dr. Sandercock reported.

"So that by 6 months — and I hasten to add we had complete mortality follow-up for 99.2% of all patients randomized — there were 407 deaths amongst those allocated to control vs 408 allocated to tPA," he noted. "So we can reassure people that treating this group of patients outside the license was not associated with an increase in mortality at final follow-up," Dr. Sandercock concluded. At 6 months, 27% of patients in both groups had died.

There was a nonsignificant difference in the number of patients alive and independent in the 2 groups: 37% in the tPA group and 35% in the control group (OHS score, 0 to 2; adjusted OR, 1.13; 95% CI, 0.95 - 1.35, P = .181), the primary endpoint of the trial.

However, when the researchers performed an ordinal ("shift") analysis of the shift in OHS scores among all the OHS groups (0 to 6), a prespecified analysis, they found a significant shift toward lower (better) scores in treated vs untreated patients (adjusted common OR, 1.27; 95% CI, 1.10 - 1.47; P = .001).

"Put in more simple language, the odds of surviving with less disability were 27% greater for patients treated with tPA," Dr. Sandercock said.

Contrary to the researchers' expectations, patients older than 80 years appeared to benefit more from tPA treatment than did their younger counterparts (P = .027). Dr. Sandercock was conservative in his assessment of this finding, though, saying that one should just conclude that older patients do not benefit less than younger ones.

There was also a trend toward greater benefit of tPA with more severe strokes, as assessed by the National Institutes of Health (NIH) Stroke Scale and by predicted probability of a poor outcome. It also appeared that treatment within 3 hours was most beneficial, but treatment up to 6 hours was effective.

The study did not have sufficient power to determine a decay of benefit over time. For patients treated with tPA within 3 hours, 30.6% were alive and independent at 6 months vs 22.7% of controls, a 7.9–percentage point absolute benefit in favor of tPA.

In summary, Dr. Sandercock said, "For the types of patients included in the study...despite the early hazards, thrombolysis within 6 hours improved functional outcome. Benefit did not appear to be diminished among elderly patients over 80, and benefit was greatest amongst those randomized within 3 hours."

Large Population Over 80 Now Eligible

At a news conference here, coauthor Richard Lindley, MBChB, MD, professor of medicine at the University of Sydney, Australia, was asked if it was legitimate to call a secondary endpoint of the shift analysis significant if the primary endpoint of an OHS score of 0 to 2 was not reached. He responded that the shift analysis was a prespecified endpoint and could be relied upon. He pointed out that a third of people having a stroke in western countries are older than age 80, and before IST-3 there was no evidence of the efficacy of tPA for them. "So it's the huge group of people that we have to look after.... And what's really amazing in the data is that the benefit for the over-80s was just as good as the under-80s."

Dr. Lindley noted that if left untreated in the acute phase, moderately severe or severe stroke in patients older than age 80 years results in death or dependency in nearly everyone. "We now have got information that the treatment is appropriate for people who previously would have not been considered for treatment."

There are precious few treatments in medicine that have such a powerful effect, which is why it's worth all the extra expense to get people into hospitals and treated so quickly.

He said the investigators did not expect this result "for all sorts of medical reasons — cerebral amyloid, atrophy, previous stroke burden, white matter lesions." But "if you can treat people within 3 hours...we're talking about 90 extra independent survivors per 1000 treated. There are precious few treatments in medicine that have such a powerful effect, which is why it's worth all the extra expense to get people into hospitals and treated so quickly," he emphasized.

Didier Leys, MD, PhD, professor and head of Neurology at Lille University Hospital in France, and past-president of the European Stroke Organization, who did not participate in IST-3, told Medscape Medical News that he considers the trial very important "because in IST-3 you have more patients than in all previous trials."

A second important strength of the study, he said, was that it included patients who did not fulfill the licensed criteria: older patients and patients with more severe strokes. "In most trials we could not include very severe strokes, and here there was no limitation and [no] limitation in the effects because they showed that the effect was still present in very severe patients. The main strength of IST-3 is to have included patients who are not typically [included] in terms of the license."

Although the drug has not been licensed for use in patients older than 80 years, physicians in larger stroke centers in Europe have been treating them with tPA for the past few years on the basis of expert opinion, which is level 4 evidence. "Now it will be level 1, a high level of evidence" based on results of a large randomized clinical trial, Dr. Leys said. He thinks practice in many specialized stroke centers will not change but predicts that "in smaller centers where physicians are more reluctant to give tPA, I think this may change."

Addressing the results specifically, he noted that mortality with tPA increased over controls in the first 7 days but was then lower out to 6 months. "That means it anticipated probably the death of patients who would have died a few days later," he speculated. "I was a little bit surprised [by] the results with the NIH [Stroke Scale] to see that severe patients benefit more."

But he cautioned that the sample size is small for the most severe strokes, and the results are not statistically significant. One explanation may be that delay is the most important factor in treatment failure, and patients with the most severe strokes usually present to the hospital more quickly.

Dr. Leys was less surprised that older people receiving tPA did as well as or better than controls. Because older people usually die within 3 months if not treated, he thinks treatment could actually benefit them more. Again, though, he cautioned that the study was not powered to answer that question.

"I think that the message should be that thrombolysis is effective, and it's probably not less effective in old people, and it's probably not less effective in severe patients, and these patients should be treated," he concluded.

He noted that a limitation of the study is that it was conceived 15-20 years ago, with the first patients randomized in 2000. "A lot has changed in our practice during this time," Dr. Leys noted, especially an extension in Europe of the approved allowable time of administration of tPA from 3 to 4.5 hours after symptom onset. "But this is also a strength of the study because we have an over-representation of all those patients who did not really meet the criteria for the license — old people, severe people — after 4.5 hours, and so on," Dr. Leys said.

In the past year, investigators in Europe and the United States have agreed to use a shift analysis on the modified Rankin scale and not a dichotomized analysis. So a limitation in IST-3 was that the primary endpoint was a dichotomized analysis (the proportion of patients alive and independent), giving a neutral result overall. "Otherwise it would have been clearly positive [for] the primary endpoint," Dr. Leys said.

A dichotomized analysis evaluates only patients crossing the border between OHS score 2 and 3, that is, the number of patients with scores of 0 to 2 or greater than 2, so the number of patients, for example, crossing from 4 to 3 or 2 to 1 aren't broken out. Shift analysis is more sensitive.

"You need less patients, and it's more realistic also as an endpoint," Dr. Leys explained. Shift analysis was a prespecified secondary endpoint in IST-3.

"Default Situation"

Dr. Leys also co-authored a commentary on both Lancet publications with colleague Charlotte Cordonnier, MD, PhD, from the Department of Neurology, Stroke Unit at Roger Salengro Hospital, Lille, France.

"The key message of IST-3 and the updated meta-analysis is that many eligible patients from subgroups excluded by the European licence should now be given rt-PA," they write. "Every stroke patient should therefore be classed as a candidate for thrombolysis and managed as a medical emergency irrespective of age, severity, and clinical presentation."

Ongoing trials with lower doses of tPA that use advance imaging to select patients beyond the 4.5-hour window, or with new thrombolytic agents, "are awaited," they conclude.

"In the meantime, the default situation for the first health-care professional who identifies the stroke patient should be to treat, and the role of stroke and emergency physicians is now not to identify patients who will be given rt-PA, but to identify the few who will not."

Boehringer Ingelheim donated tPA and placebo for the first 300 patients but had no further involvement in the study. Dr. Sandercock has received lecture fees (paid to his university) and travel expenses from Boehringer Ingelheim for occasional lectures given at international conferences. He was a member of the Independent Data and Safety Monitoring Board (DSMB) of the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial was funded by Boehringer Ingelheim and received fees and travel expenses for attending DSMB meetings (paid to the university). Dr. Lindley received payment in his role as conference scientific committee member and for occasional lectures for Boehringer Ingelheim and has attended national stroke meetings organized and funded by Boehringer Ingelheim. Dr. Leys was on the steering committee of the ECASS 3 trial and will be on the steering committee of ECASS 4. Both studies involve tPA. He has participated in a symposium organized by Boehringer Ingelheim. Dr. Cordonnier was an investigator on the ECASS 3 trial.

Lancet. Published online May 23, 2012. Abstract Abstract Editorial.

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