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New stroke guidelines support late window paradox

Elvira Manzano
21 Feb 2018

The treatment window for endovascular thrombectomy has been extended from 6 to 24 hours within the onset of a stroke in the new stroke guidelines, expanding the number of patients eligible for thrombectomy. However, experts said this does not mean time no longer matters in thrombectomy.

“The right message to put across is that time is still brain,” said Professor Bruce Ovbiagele from the Medical University of South Carolina, Charleston, South Carolina, US. “In patients with good collateral circulation and slow infarct growth, we can delay [removal of the clot] a bit, but still time does matter.”

Currently, less than 1 in 10 ischaemic stroke patients receives thrombectomy in the absence of a strong evidence to support treatment beyond 6 hours. “By quadrupling the size of the therapeutic time window, many more patients with large vessel occlusion stroke who were previously deemed untreatable have the potential to be treated,” said Dr Tudor Jovin from the University of Pittsburgh Medical Center, co-principal investigator of the DAWN* trial that served as a basis for the new guidelines, the other being the DEFUSE 3** trial.

The DAWN showed that thrombectomy was effective for up to 24 hours after a stroke to reduce disability in certain patients selected by both clinical and brain imaging criteria. [N Engl J Med 2018; 378:11-21] Similar benefits were seen in the DEFUSE 3 trial in patients presenting 6 to 16 hours after stroke onset selected by different criteria. [N Engl J Med 2018;doi:10.1056/NEJMoa1713973]

“Time alone should no longer be a disqualifier for thrombectomy but only a source of urgency,” said co-investigator Dr Raul Nogueira from the Emory University School of Medicine and the Grady Memorial Hospital both in Atlanta, Georgia, US.

The guidelines, released by the American Heart Association/American Stroke Association during the International Stroke Conference in Los Angeles, US, were a revision of the 2013 acute ischaemic stroke guidelines and published following a careful review of 400 studies. [Stroke 2018;doi:10.1161/STR.0000000000000158]

Who qualifies for alteplase?

Another key change in the guidelines was the broadening of the list of patients who qualifies for intravenous tissue plasminogen activator (tPA) alteplase – the only clot-dissolving treatment approved by the US FDA for ischaemic stroke – by reducing the number of absolute contraindications. Alteplase is recommended not only for major stroke but for minor stroke, if administered within 3 to 4.5-hour window of the stroke event, said Dr William J. Powers from the University of North Carolina at Chapel Hill in Chapel Hill, North Carolina, US, who is the chairman of the guideline writing group.

Patients with acute stroke can potentially get a tPA and then transported immediately to a hospital for thrombectomy, if still necessary. The primary goal is to achieve a door-to-needle time within 60 minutes in ≥50 percent of stroke patients treated with IV alteplase. However, it may be reasonable to aim for a 45-minute door-to-needle goal in more than half of patients administered with alteplase.

If no emergency department (ED) doctors or neurologists trained to use alteplase are on site, video conferencing with trained stroke professionals at other institutions is recommended. Administration of alteplase using the telestroke approach is just as safe and effective at reducing disability, Powers said.

Patients who cannot receive alteplase— for example, those on warfarin—may still qualify for a thrombectomy. However, Powers cautioned that thrombectomy (and administration of alteplase) are time-dependent, hence brain imaging on stroke patients should be done within 20 minutes of ED arrival to determine which patients are suited for which treatments. Patients who undergo thrombectomy should also have immediate access to comprehensive periprocedural care. Patient outcomes should be tracked at all times.

Be guided by DAWN, DEFUSE 3

The increase in the window of time to perform thrombectomy suggests that patients with uncertain or late timing of symptom onset may still benefit from prompt thrombectomy.

But which large vessel clots to remove? The new guidelines recommend that physicians use either the DAWN criteria (intracranial internal carotid artery or proximal middle cerebral artery occlusion, with mismatch between severity of clinical deficit and infarct volume) or the DEFUSE 3 criteria (proximal mid-cerebral-artery or internal-carotid-artery occlusion and a tissue region that was ischaemic but not yet infarcted) to determine which large vessel occlusions are candidates for clot removal. DEFUSE 3 used broader inclusion characteristics allowing a larger ischaemic core and less severe strokes, with about 40 percent of patients not fitting the DAWN criteria.

What about secondary stroke and DVT?

The guidelines also recommend that secondary stroke prevention by carotid revascularization for minor, nondisabling stroke be done within 2–7 days instead of waiting. 

Getting to the ED in an ambulance is better than somebody driving a stroke patient to the hospital, said Powers. Prevention of deep vein thrombosis (DVT) for immobile patients during hospital stay should focus on intermittent pneumatic compression instead of heparin. Hospitals are also encouraged to participate in a stroke data repository to promote adherence to the new guidelines, improve patient outcomes, and facilitate quality improvement.

Next frontier to explore is space

Dr Jens Fiehler from the University Medical Center of Hamburg-Eppendorf, Germany said the DAWN study was successful in shifting the limits of stroke therapy in time, “but the next frontier to be explored is space – to define the extent of tissue damage and determine if there is enough tissue left to be saved.”

Dr Urs Fischer and Dr Johannes Kaesmacher from the University Hospital and University of Bern in Switzerland agreed that mechanical thrombectomy should still be performed as quickly as possible as there is good evidence that patients treated early after symptom onset, rather than late, have better outcomes. New studies also need to assess if patients presenting with a large infarct score, a low NIHSS score, or posterior circulation strokes could benefit from mechanical thrombectomy, they said. “We need to determine the precise threshold for a more accurate and wider patient selection so more stroke patients could receive the best possible benefit.”

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Most Read Articles
15 Mar 2019
New drug applications approved by US FDA as of 01 - 15 March 2019 which includes New Molecular Entities (NMEs) and new biologics. It does not include Tentative Approvals. Supplemental approvals may have occurred since the original approval date.