Thrombolysis Benefits WAKE-UP Strokes

May 17, 2018

GOTHENBURG, Sweden — Certain patients who experience ischemic stroke while asleep, so that the time of onset is unknown, now have the chance to benefit from thrombolysis treatment after the results of the WAKE-UP trial.

The trial used new MRI technology to identify patients who had less brain tissue damage, suggesting the stroke had occurred more recently (approximately within the 4.5-hour  cutoff used for thrombolysis treatment). In these patients, researchers found that thrombolysis with tissue plasminogen activator (tPA, alteplase) led to an increased chance of a favorable outcome, defined as a score of 0 or 1 on the modified Rankin scale (mRS) of neurologic disability at 90 days.

Dr Götz Thomalla

The WAKE-UP trial was presented here at the 4th European Stroke Organisation Conference (ESOC), where lead investigator, Götz Thomalla, MD, University Medical Center, Hamburg, Germany, was greeted with applause from the audience on reporting the primary outcome.

The European Union–funded study was also published online simultaneously in the New England Journal of Medicine.

"This is the first positive trial of IV thrombolysis in stroke with unknown time of onset and will lead to a paradigm change," Thomalla said. "It will make a big impact on clinical practice as about 25% of stroke patients have undetermined time of onset, and approximately one third to one half of these will now qualify for the treatment based on these imaging criteria."

Commenting on the trial for Medscape Medical News, former ESOC president, Kennedy Lees, MD, University of Glasgow, United Kingdom, said, "This was a superbly organized academic-led trial. This was difficult to do technically because of the need for MRI scans, and many of us thought they might struggle to complete it, but not only have they completed it they have brought it through to the kind of conclusion we were hoping for:  a clear-cut result."

"We now know that it's not just about selecting patients for thrombolysis by time," Lees added. "If you don't know the time, you can select them instead according to tissue appearance on an MRI scan. That is great because patients are not convenient people. They don't always have their strokes in front of family members. They are often found after having a stroke in their sleep."

For the study, researchers screened 1362 patients presenting with an ischemic stroke of unknown time of onset to identify those with an ischemic lesion visible on diffusion-weighted MRI  but no parenchymal hyperintensity on fluid-attenuated inversion recovery (FLAIR). This finding indicated that the stroke had occurred approximately within the previous 4.5 hours. Patients for whom thrombectomy was planned were excluded.

Of these patients, 503 had suitable imaging results and were randomly assigned to alteplase or placebo. Most patients had mild to moderate strokes.

The primary endpoint was favorable outcome, as defined by a score of 0 or 1 on the mRS, at 90 days. This occurred in 53.3% of the alteplase group and 41.8% of the placebo group (adjusted odds ratio, 1.61; 95% confidence interval [CI], 1.09 - 2.36; P = .02).

The shift analysis also showed benefit with alteplase: The median mRS score at 90 days was 1 in the alteplase group and 2 in the placebo group (adjusted common odds ratio, 1.62; 95% CI, 1.17 - 2.23; P = .003).

Trend to Increased Mortality

There was a trend toward increased mortality in the alteplase group, with 10 deaths (4.1%) in patients receiving the thrombolytic vs 3 (1.2%) in the placebo group (odds ratio, 3.38; 95% CI, 0.92 - 12.52; P = .07).  

In the alteplase group, 4 deaths were attributed to symptomatic intracranial hemorrhage and 1 to recurrent ischemic stroke. The other 5 deaths were attributed to noncerebral causes unrelated to the initial stroke or treatment.  

The rate of symptomatic intracranial hemorrhage was 2.0% in the alteplase group and 0.4% in the placebo group (odds ratio, 4.95; 95% CI, 0.57 - 42.87; P = .15).

Dr Christian Gerloff

Addressing the risk-benefit ratio, senior author, Christian Gerloff, MD, University Medical Center, Hamburg, pointed out that results from the shift analysis suggested that the benefits of treatment outweighed the harms.

"The shift analysis was even more significant than the primary endpoint. This includes all categories, including death — so the mortality data do not weaken the overall benefit," he commented.

Further results showed that death or an inability to live independently (mRS score of 4 to 6) occurred in 13.5% of the alteplase group and 18.3% of the placebo group (adjusted odds ratio, 0.68; 95% CI, 0.39 - 1.18; P = .17).     

Commenting for Medscape Medical News, Alistair Webb, MD, University of Oxford, United Kingdom, said the suggestion of an early increase in mortality was not surprising. "This has been seen in other thrombolytic trials in stroke, and the death rate usually evens up over the longer term."

"This is clearly a very important study that answers a question that has been debated for a long time," he added. "This trial shows a clear-cut benefit for these patients of unknown time of stroke onset selected by imaging." 

Other experts in the field were also impressed with the results.

Jeffrey Saver, MD, University of California, Los Angeles, noted: "WAKE-UP shows we can use imaging to select patients for thrombolysis up to 9 hours after 'last known well.' This will have an immediate impact on care."

Using tissue as well as time to select patients for treatment has already been shown as an effective strategy in the thrombectomy trials, Saver said. "Now it also applies to intravenous reperfusion therapy as well. It is tissue that matters and reperfusing that tissue."

"This is great news as it gives us a therapy for later patients who are not candidates anatomically for mechanical reperfusion with thrombectomy — they can now get chemical reperfusion with lytics," Saver added.  

But the study does present some logistic issues because in clinical practice the use of MRI scans will be necessary. President-elect of ESOC, Bart Van de Worp, MD, University Medical Center in Utrecht, the Netherlands, explained.

"MRI is not used routinely in most centers in acute stroke care," he said. "Certainly in the Netherlands we don't do that at present. But we can implement it. The technology is readily available, but it is a bit more difficult than CT from a logistical point of view so we will probably now change our logistics. There will now be a push to do more MRI, especially in wake-up strokes. This may be more difficult for smaller hospitals, but I expect the larger centers will all start doing this now."

Lees agreed. "It may be difficult to implement this at first as although MRI scanners are available in most centers, it takes time to screen patients as maybe 10% are excluded because of contraindications.

"But the WAKE-UP trial shows it is the right thing to do it," he said. "The good thing is we can still use CT for the majority of patients and to screen for thrombectomy candidates but if we don't know time of onset we should go straight to MRI. It will change logistics — it just gives us the justification for having acute MRI available."

Clinical Equipoise

In an editorial accompanying the New England Journal of Medicine publication, Tudor G. Jovin, MD, University of Pittsburgh Medical Center, Pennsylvania, who was lead investigator of the DAWN late thrombectomy trial, says that the WAKE-UP trial raises several questions.

These include which form of imaging to use as first choice (most endovascular centers use CT perfusion rather than MRI for first-line imaging) and whether stroke patients with an unknown time of symptom onset and occlusion of large cerebral arteries who are candidates for thrombectomy should receive thrombolysis first.

He notes that subgroup analysis of WAKE-UP showed no evidence of benefit with alteplase in patients with larger strokes, who make up the majority of participants in the thrombectomy trials. He says there were also "tentative safety concerns" in the thrombolysis group. 

"The potential benefit of intravenous thrombolysis…before thrombectomy in patients with an unknown time of symptom onset requires testing in randomized trials. Nevertheless, the MRI signature as applied in the WAKE-UP trial may be a useful selection method for systemic thrombolysis in patients who cannot undergo thrombectomy," he writes.

"Although the findings of the WAKE-UP trial provide reason for optimism, many questions remain. It is important that clinical equipoise be maintained so that confirmatory trials can be performed," he concludes. "If the results of such trials are positive, they would expand the population of patients with acute stroke who are eligible for intravenous thrombolysis."

The WAKE-UP trial was funded by the European Union Seventh Framework Program. There was no industry funding in any aspect of the trial. 

4th European Stroke Organisation Conference (ESOC) 2018. Presented May 16, 2018.

N Engl J Med. Published online May 16. Abstract, Editorial 

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