Like mechanical revascularization, IV thrombolysis with a
pharmacologic agent can help preserve the functional capabilities of
patients even 4.5 to 9 hours after stroke onset -- provided they still
have salvageable brain tissue, published data from the EXTEND trial
showed.
People who presented late but with imaging results showing relatively
small infarct cores still had better odds of
good functional outcomes
after getting alteplase, as 35.4% of this group scored a 0 or a 1 on the
modified Rankin scale (mRS) at 90 days, compared with 29.5% of the
placebo arm (adjusted RR 1.44, 95% CI 1.01-2.06), reported Geoffrey
Donnan, MD, of Royal Melbourne Hospital, and colleagues in the
New England Journal of Medicine.
The
trial randomized 225 stroke patients who had arrived at the hospital
later than the first 4.5 hours after symptom onset or after waking up
with a stroke. They were imaged with CT perfusion imaging and
perfusion-diffusion MRI.
Main results from EXTEND were first presented in February at the American Heart Association's
International Stroke Conference.
Yet a secondary ordinal analysis of the distribution of mRS scores
did not show better functional improvement at 90 days with late
thrombolysis, according to the full
New England Journal paper, which also came with an accompanying editorial.
In addition, the risk of symptomatic intracerebral hemorrhage was
increased with alteplase (6.2% vs 0.9%, adjusted RR 7.22, 95% CI
0.97-53.5).
"The authors are to be commended for a groundbreaking trial. It
suggests, for the first time, that the benefit of alteplase may persist
after more than 4.5 hours of symptoms in selected patients," Pooja
Khatri, MD, MSc, of the University of Cincinnati, told
MedPage Today.
"Currently, such patients are denied a potentially life saving
therapy just because we as physicians do not know when the stroke
happened," said Bijoy Menon, MD, MSc, of the University of Calgary,
Alberta, who asserted that society would benefit if the study's results
are incorporated into practice.
In
the NEJM editorial,
Randolph Marshall, MD, of Columbia University in New York City, wrote,
"As of 2013, only 6.5% of patients hospitalized for ischemic stroke in
the United States received intravenous thrombolysis treatment. Extending
the time window for treatment could result in greater numbers of
patients eligible to receive treatment for acute stroke."
"Perhaps more importantly, stroke centers with imaging capability to
detect a mismatch between the size of the ischemic core and the penumbra
could treat patients with stroke many hours after the onset of stroke
symptoms and treat those who awaken with a stroke, without the need for
an interventionalist to be present," he continued. "Furthermore, because
the image analysis software is available commercially and is automated
for CT and MRI,
primary stroke centers could provide this service."
Notably, EXTEND was terminated before achieving the 310 planned recruits, after the
WAKE-UP trial investigators reported benefit from thrombolysis even when the time of ischemic stroke onset was unknown.
EXTEND and WAKE-UP did not have the same patient population and imaging selection, however.
"The clinical severity of stroke was milder in the WAKE-UP trial,
with a median NIHSS [NIH Stroke Scale] score of 6, and the MRI-based
selection model aimed to identify patients with stroke onset within the
standard 4.5-hour thrombolysis window," according to Donnan's group.
"Because
of the limited power of our conclusions as a result of premature
termination of the trial and the lack of a significant between-group
difference in the secondary outcome of functional improvement, further
trials of thrombolysis in this time window are required," the authors
said.
That the trial excluded patients treated with thrombectomy is another
reason why a second, confirmatory trial may be helpful, Khatri said.
She added that the perfusion imaging selection criteria of EXTEND likely
excluded
lacunar infarcts with unknown time of onset, a group shown to benefit from alteplase treatment using a different MRI-based selection criteria.
"That being said, it does push the needle towards treatment. I'd be
more likely to consider treating EXTEND-eligible patients beyond 4.5
hours based on this trial," she said.
On the other hand, Patrick Lyden, MD, of Cedars-Sinai Medical Center
in Los Angeles, said he didn't need any more data on the matter.
"[F]or me the standard approach should include advanced imaging in
all patients presenting after 4.5 hours from LKW [last well known]," he
said in an email. "This study confirms a wide appreciation that patient
selection for thrombolysis and thrombectomy
beyond the standard time windows
must be guided by imaging. Advanced imaging allows us to identify
patients who can benefit, and exclude those who cannot benefit."
Last Updated May 09, 2019
EXTEND was supported by the
Australian National Health and Medical Research Council and the
Commonwealth Scientific and Industrial Research Organization Flagship
Program.
Donnan disclosed receiving advisory board fees from
AstraZeneca Australia, Bayer, Boehringer Ingelheim, Merck, Pfizer, and
Servier.
Khatri reported receiving institutional research funding
from Genentech and being a co-Principal Investigator of the NIH
StrokeNet's National Coordinating Center.
Primary Source
New England Journal of Medicine
Secondary Source
New England Journal of Medicine
