But with an important caveat
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.
New England Journal of Medicine
Source Reference: Ma H, et al "Thrombolysis guided by perfusion imaging up to 9 hours after onset of stroke" New Engl J Med 2019; DOI: 10.1056/NEJMoa1813046.
New England Journal of Medicine
Source Reference: Marshall RS "Image-guided intravenous alteplase for stroke -- shattering a time window" New Engl J Med 2019; DOI: 10.1056/NEJMe1904791.
Read the original article on Medpage Today: Benefits of tPA for Stroke Extend to 9 Hours Post-Onset