New Study EXTENDs Time for Using tPA in Ischemic Stroke


Ed Susman

Mr. Susman is a freelance medical writer based in Florida, USA. H e travels worldwide to report from medical conferences, writing regularly for wire services, inter net websites, and medical journals such as the Journal of the National Cancer Institute and AIDS.

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HONOLULU, Hawaii – A new study suggests that the window of opportunity for using the clot-busting tissue plasminogen activator (tPA) can be extended as long as 9 hours after onset of stroke symptoms in carefully selected patients.

Current guidelines now suggest using tPA in ischemic stroke patients only to 4 ½ – 6 hours, but Henry Ma, MD, PhD, director of physician training at Monash University, Melbourne, Australia., said here that outcomes for patients who have viable brain tissue as seen through imaging studies may benefit from tPA for a longer period.

At the 2019 International Stroke Conference, sponsored by the American Stroke Association, Dr. Ma said that in the primary outcome measure, 37 percent of patients treated with tPA in the 9-hour window – including those with so-called ‘wake up’ strokes – achieved a modified Rankin score of 0-1 at 90 days compared with 29% of patients who were treated with placebo in the EXTEND trial (P=0.045).

In the secondary outcome measure of achieving a modified Rankin score of 0-2 at 90 days, the milestone was achieved by 51 percent of the patients treated with tPA compared with 43 percent of the patients on placebo therapy (P=0.022), Dr. Ma said in his late breaker oral presentation.

“EXTEND (Extending the Time for Thrombolysis in Emergency Neurological Deficits) is the first positive thrombolysis trial in an extended time window using automated penumbral imaging,” he said. “The current guideline for thrombolysis in acute ischemic stroke is less than 4.5 hours from stroke onset. But advanced imaging studies from our group and others suggest that the ischemic penumbra can exist up to 24 hours after onset and its salvage can lead to improved outcome.”

An automated algorithm uses computer assisted tomography scans to determine penumbral mismatch and to select likely candidates for tPA thrombolysis.

In the study, 113 patients received thrombolysis and 112 patients were assigned to placebo. The patients receiving tPA were older – a mean age of 74 compared to a mean age of 71.4 for placebo patients; 59 percent of placebo patients were men compared with 54 percent of the tPA patients; the median NIHSS score was about 12; 10 percent of the patients were treated in the 4.5-6 hour time frame; 25 percent were treated in the 6-9 hour time frame; 65 percent of the patients had wake up strokes.

The median time from onset of symptoms to therapy was 7.2 hours; the median time from last known well to therapy was 8.9 hours for placebo patients and 9.9 hours for tPA patients.

Death at 90 days occurred in 9.5 percent of the placebo patients and in 10 percent of the tPA patients (P=0.94). Symptomatic intracranial hemorrhage occurred in 1 percent of the placebo patients and in 6 percent of the tPA patients (P=0.071).

“There was an increase in the rate of symptomatic intracranial hemorrhage consistent with other thrombolytic trials, but this was not associated with increased mortality and did not negate the positive results of the improved rate of excellent functional outcome,” Dr. Ma said.

MISTIE misses

In another major study presented before more than 4,000 stroke specialists and allied healthcare professions, researchers suggested an aggressive but minimally invasive surgical technique might help patients with intracerebral hemorrhage.

In the Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation (MISTIE-3) trial, about 45 percent of patients who underwent the combination of surgery and catheter-based clot evacuation and about 41 percent of patients treated medically achieved a modified Rankin Scale score of 0-3 – an indication of good functioning, but that difference failed to reach statistical significance, said Daniel Hanley, MD, professor of acute neurology at Johns Hopkins University, Baltimore, Maryland.

There were 9 deaths among the 256 patients who were assigned to receive the surgical treatment compared to 15 deaths among the 250 patients treated medically (P=0.037), Dr. Hanley reported in his oral, late-breaker presentation.

Outcomes were enhanced, said co-author Issam Awad, MD, director of Neurovascular Surgery at the University of Chicago Medicine and Biological Sciences, if surgeons made a concerted effort to get more than an average amount of the clot out of the brain. He said that if 50 percent of more of the clot was removed, there was a benefit in mortality, but if more than 70 percent was removed to a point where less than 15mL of the clot remained; there was also a benefit in function.

Dr. Hanley said that there was a 10.5 difference in achieving a modified Rankin score of 0-3 in favor of the surgery technique if the clot volume was below 15 mL when compared with the medicallytreated controls (P=0.03).

The researchers noted that the minimally invasive treatment can be taught to those who have not attempted the procedure before the trial. In MISTIE III, 88 percent of the doctors were performing their first procedure. There is currently no effective surgical treatment for intracerebral hemorrhage, which is the most common type of lethal brain bleed. The MISTIE procedure avoids the damage of traditional craniotomy by using imaging to guide placement of a soft tube into the blood clot through a small hole in the skull to remove large amounts of blood and toxic blood components, Dr. Awad said. Through a low mechanical impact procedure with suction and up to three days of gentle irrigation with the clot-busting drug alteplase.

Alteplase was delivered every 8 hours and up to 9 doses were permitted, but the average number of doses was 3, Dr. Awad said. He suggested that many of the doctors, after removing a substantial amount of clot, decided to stop before reaching the 15 mL threshold.

“The more clot removed, the better the patient’s outcome was,” Dr. Awad said. “For every 1 mL removed beyond 15 mL, there was a subsequent 10% chance of further improvement in functional outcomes.”

“The trial confirmed that removal of the blood clot using the MISTIE procedure can be done safely as compared to supportive therapy. But there was no difference in functional recovery between those in the surgery group and the medical group,” said Dr. Hanley. “The trial results do suggest that patients have improved functional recovery when the blood clot size is reduced to about 3 tablespoonsful or less of blood. This will require further study, but, at a minimum, the trial data provide a sound basis to avoid limiting care in patients with large brain blood clots.”

Patch fails

Another study sought to determine if using glyceryl trinitrate patches in the ambulance by paramedic could improve outcomes in patients suspected of having an ischemic stroke – but the study proved futile.

The risk of having a poor outcome as assessed by the modified Rankin Score at discharge was an odds ratio of 1.25 [95 percent CI 0.97-1.60], (P=0.083) – or almost a negative result, said Philip Bath, MBBS, DSc, the Stroke Association Professor of Stroke Medicine at the University of Nottingham, United Kingdom.

In the intention-to-treat population, which included patients with stroke mimics, the risk of a poor outcome was OR 1.04 (95 percent CI 0.84-1.29), P=0.69, he reported in his oral late breaker presentation.

“What we learned from this trial is that glyceryl trinitrate should not be applied to patients with suspected stroke as they are being transported to the hospital by paramedics except in the setting of a clinical trial,” Bath said.

He said that it appears that the treating with the nitroglycerin patches had no effect on treating patients with ischemic strokes – but appeared to have a worsening effect on people who were having a hemorrhagic stroke. It was the poorer outcomes seen with hemorrhagic stroke that drove the overall results toward a borderline negative trial, he said.

Patients who were observed with a suspected stroke – adults, with a Face/Arm/Speech Time (FAST) score of 2 or more who were seen within 4 hours of symptom onset and a systolic blood pressure of 120 mmHG or greater were treated with a 5mg nitroglycerin patch or a sham patch by the paramedics, and were given the same patch 3 more times at the hospital. The paramedics had been trained in the procedures developed for the Rapid Intervention with Glyceryl trinitrate in Hypertension stroke Trial-2 (RIGHT-2).

The patients had to have at least 2 abnormalities suggestive of stroke and be conscious to enter the trial. More than 50 percent of the patients consented be included in the study themselves; the others were consented by family members, or proxy consent by the paramedic, one of several novel parts of the study, Dr. Bath said.

The researchers planned to enroll 850 patients in the trial, expecting that 12 percent would have so-called stroke mimics – seizures, migraines or ‘hysterical’ strokes, he said. But the trial actually enrolled 26 percent of the patients with these mimic events which required enrolling a total of 1149 individuals. Of the 419 patients with investigator confirmed stroke or transient ischemic attack (TIA) and who were give the active patch, 71 experienced an intracerebral hemorrhage; 292 were diagnosed with an ischemic stroke and 56 were diagnosed with a TIA.

The excess numbers of mimic strokes and TIAs might have skewed the results of the trial, Dr. Bath said.

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