Reassuring Results for tPA on Long-term Mortality in Stroke

May 18, 2016

BARCELONA — Long-term results from the IST-3 trial of tissue plasminogen activator (tPA, alteplase) in acute stroke have shown a trend toward a reduced mortality rate in patients who received the thrombolytic.

Presenting the data at the European Stroke Organisation Conference (ESOC) 2016, Eivind Berge, MD, Oslo University Hospital, Norway, reported that despite an early hazard with tPA, there was a nonsignificant 3.6% absolute improvement in survival at 3 years, and among patients alive at 7 days, there was a significant 22% relative improvement in survival at 3 years in the group given tPA.

"Alteplase does not worsen long-term survival as feared by some. And if a patient survives to 7 days, there is a significant benefit of alteplase on long-term mortality," he concluded.

Session chair, Stephen Davis, MD, Royal Melbourne Hospital, Australia, noted that many other interventions in medicine have a short-term hazard but a long-term benefit, but "we have a hard time convincing some of our colleagues — particularly ER [emergency room] physicians — of the benefits of giving tPA."

Professor Berge agreed, saying: "Yes, there is an early hazard of giving tPA — that cannot be overlooked — but our data show that during the long term there are real benefits."

He added: "We have known about the benefits on functional outcomes for some time but now we can also show a benefit on long-term survival. We hope and believe these data will make it easier for clinicians to discuss the early hazard and long-term benefits of alteplase."

Outside experts appeared pleased with these latest results from IST-3.

"These data are very reassuring," Ralph Sacco, MD, University of Miami, Florida, told Medscape Medical News. "They show that once a patient gets past the acute phase, the long-term outcome and mortality is favorable."

Heinrich Mattle, MD, University of Bern, Switzerland, said, "The data show that for every 1000 patients treated with alteplase, there will be 36 fewer deaths by 3 years — an excellent result."

In his presentation, Professor Berge explained that observational studies suggest that better functional outcomes in stroke patients is translated into improved survival. But while alteplase has shown better functional outcomes at 6 months, it has not been shown to improve survival at 6 months. "We wanted to ask the question of whether survival is improved with longer-term follow up."

To do this, Professor Berge and colleagues analyzed long-term data from the IST-3 trial. In this trial, 3035 acute stroke patients within 6 hours of symptom onset were randomly assigned to alteplase (0.9 mg/kg) or standard care.

The main results, first reported in 2012, showed a nonsignificant improvement in the primary endpoint — good functional outcome (Oxford Handicap Scale [OHS] score, 0 - 2) at 6 months (odds ratio, 1.13) but a shift analysis showed a significant improvement in OHS score, with an odds ratio of 1.27.

To look at longer-term follow-up on mortality, the IST-3 investigators focused on patients recruited into the trial in the United Kingdom, Sweden, and Norway, where data from national death registries are available. They tracked mortality data on 1946 patients (two thirds of those enrolled in the trial) up to 3 years.

Results showed a 3.6% absolute reduction in mortality in the alteplase group. This was nonsignificant, with 95% confidence intervals ranging from a 0.8% increase in mortality to an 8.1% reduction in mortality.

Noting that alteplase is known to have an early hazard, Professor Berge reported an increased risk for death in the first 7 days, but this was offset by the long-term reduction in mortality.

In an analysis of patients who were alive at 7 days, there was a significant reduction in mortality by 3 years in the alteplase group (hazard ratio, 0.78; 95% confidence interval, 0.68 - 0.90).

No difference was seen in subgroups defined by age or stroke severity or time to treatment, and no healthy survivor effect was seen in terms of these characteristics at 7 days, Professor Berge said.

He commented: "Yes, there is an early hazard, but from 6 months onwards there is a clear separation of the survival curves in favor of alteplase."

He noted that the risk for early hazard — ICH and death — in the first few days after alteplase is increased in certain subgroups, such as the elderly and those with very severe strokes, "but we should still give alteplase to these patients as they benefit just as much as other patients in the long term."

He added, however, that maybe after the ENCHANTED data, also presented at the ESOC 2106, these patients could be considered for a lower dose of alteplase.

Co-investigator William Whiteley, MD, University of Edinburgh, United Kingdom, said, "As a clinician I can reassure acute ischemic stroke patients that thrombolysis does not worsen long-term survival, despite the risk of intracerebral bleeding."

He added: "As researchers, we found that using electronic health records for long-term follow up was cheap, simple, and informative. We encourage trialists to incorporate consent for follow-up into national electronic health records in all their studies."

European Stroke Organisation Conference (ESOC) 2016. Presented May 10, 2016.

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