Meeting News CoveragePerspective

Age, stroke severity not factors in effectiveness of tPA

SAN DIEGO — Treatment of stroke with tissue plasminogen activator within 4.5 hours of stroke onset reduces disability regardless of age or stroke severity, researchers reported at the International Stroke Conference.

Tissue plasminogen activator (tPA) is the only FDA-approved treatment for acute ischemic stroke; however, there is still debate regarding the appropriate time window and its use in older patients or those with a minor or severe stroke, Jonathan Emberson, PhD, from the University of Oxford, said at a press conference.

Emberson and colleagues performed a meta-analysis of nine trials (n=6,756) that compared recombinant tPA with placebo or open control therapy.

tPA effective up to 4.5 hours

Patients who received tPA within 3 hours of stroke onset had a higher rate of modified Rankin score of 0 or 1 compared with controls (33% vs. 23%; OR=1.75; 95% CI, 1.35-2.27). The difference remained in patients who received tPA between 3 hours and 4.5 hours of stroke onset (35% vs. 30%; OR=1.26; 95% CI, 1.05-1.51), but not for those who received tPA more than 4.5 hours after onset (tPA group, 33%; control group, 31%; OR=1.15; 95% CI, 0.95-1.4).

Emberson said the benefits of treatment were similar regardless of age or stroke severity. “Importantly, there was clear evidence of benefit in patients older than 80 years,” he said.

The treatment groups did not differ in rates of 90-day mortality (tPA group, 17.9%; control group, 16.5%; HR=1.11; 95% CI, 0.99-1.25) despite an early spike in intracranial hemorrhages, which were often fatal, in the tPA group. The RR for fatal intracranial hemorrhages within 7 days for the tPA group was 7.14 (95% CI, 3.98-12.8), Emberson said.

Because of that, the tPA group had a higher rate of mortality between 1 and 7 days compared with the control group (RR=1.39, 95% CI, 1.16-1.67), but not between 8 and 30 days (RR=0.97; 95% CI, 0.79-1.2) or between 31 and 90 days (RR=0.92; 95% CI, 0.74-1.15), he said.

“While tPA increases the early risk of death from intracranial hemorrhage, it has no significant effect on other causes of early death,” Emberson said at the press conference. “Among those treated earlier, there is a suggestion that this early hazard is followed by later mortality benefits.”

No reason for age restrictions

These findings could prompt changes to regulations and guidelines for use of tPA, said study co-author Kennedy R. Lees, MD, FRCP, from the University of Glasgow, Scotland.

“In the United States, the licensing position has not yet been extended to 4.5 hours, and we wonder whether that might be altered,” Lees said. “The guidelines in the United States say it’s entirely reasonable to treat out to 4.5 hours if you’re under [age] 80, but not over 80. It seems to me to be entirely reasonable that now everybody who is eligible for thrombolysis should be treated out to 4.5 hours as early as possible within that time and regardless of age. There’s no reason for an ageist policy. There’s no reason for difference in treatment if you happen to be over 80.” – by Erik Swain

For more information:

Emberson J. Plenary Session I: Abstract LB2. Presented at: International Stroke Conference 2014; Feb. 12-14, 2014; San Diego.

Disclosure: Emberson reports no relevant financial disclosures. Lees reports financial ties with Boehringer Ingelheim, Grifols and Lundbeck.

SAN DIEGO — Treatment of stroke with tissue plasminogen activator within 4.5 hours of stroke onset reduces disability regardless of age or stroke severity, researchers reported at the International Stroke Conference.

Tissue plasminogen activator (tPA) is the only FDA-approved treatment for acute ischemic stroke; however, there is still debate regarding the appropriate time window and its use in older patients or those with a minor or severe stroke, Jonathan Emberson, PhD, from the University of Oxford, said at a press conference.

Emberson and colleagues performed a meta-analysis of nine trials (n=6,756) that compared recombinant tPA with placebo or open control therapy.

tPA effective up to 4.5 hours

Patients who received tPA within 3 hours of stroke onset had a higher rate of modified Rankin score of 0 or 1 compared with controls (33% vs. 23%; OR=1.75; 95% CI, 1.35-2.27). The difference remained in patients who received tPA between 3 hours and 4.5 hours of stroke onset (35% vs. 30%; OR=1.26; 95% CI, 1.05-1.51), but not for those who received tPA more than 4.5 hours after onset (tPA group, 33%; control group, 31%; OR=1.15; 95% CI, 0.95-1.4).

Emberson said the benefits of treatment were similar regardless of age or stroke severity. “Importantly, there was clear evidence of benefit in patients older than 80 years,” he said.

The treatment groups did not differ in rates of 90-day mortality (tPA group, 17.9%; control group, 16.5%; HR=1.11; 95% CI, 0.99-1.25) despite an early spike in intracranial hemorrhages, which were often fatal, in the tPA group. The RR for fatal intracranial hemorrhages within 7 days for the tPA group was 7.14 (95% CI, 3.98-12.8), Emberson said.

Because of that, the tPA group had a higher rate of mortality between 1 and 7 days compared with the control group (RR=1.39, 95% CI, 1.16-1.67), but not between 8 and 30 days (RR=0.97; 95% CI, 0.79-1.2) or between 31 and 90 days (RR=0.92; 95% CI, 0.74-1.15), he said.

“While tPA increases the early risk of death from intracranial hemorrhage, it has no significant effect on other causes of early death,” Emberson said at the press conference. “Among those treated earlier, there is a suggestion that this early hazard is followed by later mortality benefits.”

No reason for age restrictions

These findings could prompt changes to regulations and guidelines for use of tPA, said study co-author Kennedy R. Lees, MD, FRCP, from the University of Glasgow, Scotland.

“In the United States, the licensing position has not yet been extended to 4.5 hours, and we wonder whether that might be altered,” Lees said. “The guidelines in the United States say it’s entirely reasonable to treat out to 4.5 hours if you’re under [age] 80, but not over 80. It seems to me to be entirely reasonable that now everybody who is eligible for thrombolysis should be treated out to 4.5 hours as early as possible within that time and regardless of age. There’s no reason for an ageist policy. There’s no reason for difference in treatment if you happen to be over 80.” – by Erik Swain

For more information:

Emberson J. Plenary Session I: Abstract LB2. Presented at: International Stroke Conference 2014; Feb. 12-14, 2014; San Diego.

Disclosure: Emberson reports no relevant financial disclosures. Lees reports financial ties with Boehringer Ingelheim, Grifols and Lundbeck.

    Perspective

    The findings confirm that tPA is highly effective when given within 3 hours of symptom onset. They also again suggest that tPA is effective to 4.5 hours after symptom onset, although the effects are not as robust as when it is given earlier. Further, the data show that age should not be a criterion by which we decide whether to give tPA — it is effective in both young and adult patients. 

    • Kyra Becker, MD, FAHA
    • Professor of Neurology University of Washington School of Medicine, Seattle

    Disclosures: Becker reports no relevant financial disclosures.

    Perspective
    Thabele M. Leslie-   Mazwi

    Thabele M. Leslie- Mazwi

    The basis of all modern acute stroke care is the recanalization hypothesis: rapid restoration of flow after abrupt intracranial vessel occlusion preserves threatened brain tissue. This makes biological sense, underscored by the brain’s almost unmatched sensitivity to ischemia. Recanalization can be achieved by intravenous or, in a small subset of stroke patients, endovascular means. Intravenous treatment is therefore the mainstay of therapy, robustly supported by data and with a track record extending back to the seminal publication that led to FDA approval of tPA in the 3-hour window more than 17 years ago. However, rates of tPA administration hover around only 5% for stroke admissions nationally in the United States. While many factors can be identified as contributors to low thrombolysis rates, time remains a major challenge. Most patients present too late, or are evaluated too slowly to qualify for intravenous treatment. 

    The research presented highlights both the benefit of intravenous tPA and the strong time dependence for its administration. The authors assess the chance of normal or near normal outcomes after IV tPA in a pooled analysis of almost 6,800 stroke patients. Under 3 hours, an OR of 1.75 was found for excellent outcome when IV tPA was compared to controls. Up to 4.5 hours, the benefit of tPA administration was maintained, with an OR of 1.25. Hemorrhage rates were higher in the tPA cohort, and occurred early after administration, but did not affect 90-day mortality.

    These findings emphasize the importance of IV tPA for the stroke population. It remains the first and most important treatment upon presentation for every single eligible stroke patient. Future developments will include FDA acceptance of IV tPA delivery in the 3-4.5 hour window in the United States (where it still represents an off-label indication, unlike in Europe). The role of other thrombolytics (desmoteplase, tenectaplase) will be evaluated and potentially challenge tPA as the preferred agent for IV stroke thrombolysis. Finally, improving time metrics will represent a major focus for stroke care, at all levels of stroke pathology. Stroke is a leading cause of adult disability in the United States. Expansion of thrombolysis rates and better patient outcomes will have a tremendous societal impact. This abstract supports the benefit and safety of such.

    • Thabele M. Leslie- Mazwi, MD
    • Director, Interventional Neurology Neuroendovascular, Neurocritical Care Massachusetts General Hospital Institute for Heart, Vascular and Stroke Care

    Disclosures: Leslie-Mazwi reports no relevant financial disclosures.

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