Endovascular Stroke Therapy Beneficial Up to 7.3 Hours

September 29, 2016

A new analysis of the five published trials of endovascular thrombectomy for stroke has suggested that the procedure is beneficial up to 7.3 hours after symptom onset.

The results also emphasize the importance of early treatment, showing better functional outcomes the sooner after symptom onset that endovascular reperfusion was achieved.

These findings, published in JAMA on September 27, come from an individual patient data meta-analysis made possible by the investigators of the five key trials, who agreed to pool their data in an initiative known as the HERMES (Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke Trials) Collaboration. Other findings from the meta-analysis have been reported previously, but the current paper focuses purely on the issue of time.

The authors, led by Jeffrey L. Saver, MD, University of California Los Angeles, say their result "emphasizes the importance of programs to enhance patient awareness, out-of-hospital care, and in-hospital management to shorten symptom onset–to-treatment times."

Coauthor Michael D. Hill, MD, University of Calgary, Alberta, Canada, commented to Medscape Medical News: "The 7.3 hours is a modeled number — an average estimate. Of course this isn't set in stone for individual patients. There will be some patients who still benefit at 10 hours and others who won't benefit at all at 7 hours. But when we are setting up our paramedic services, we need a guide to effect policy, and this 7.3 hours is a good starting point."

It was already clear that earlier treatment produced better outcomes, Dr Hill said, "but these latest data help us understand the magnitude of this effect. At 2 hours there is a massive benefit — at 7 hours the effect is much more muted. The mantra has to be 'faster is better' — it's all about speed."

Reducing Door-to-Reperfusion Times

They point out that speeding up in-hospital processes will have a major effect on patient outcome.

"Assuming the findings are generalizable to the population of patients with acute ischemic stroke due to large-vessel occlusion, among every 1000 patients achieving substantial endovascular reperfusion, for every 15-minute faster emergency department door-to-reperfusion time, an estimated 39 patients would have a less-disabled outcome at 3 months, including 25 more who would achieve functional independence (mRS [modified Rankin Scale] 0-2)," they write.

As background, the authors note that five randomized trials have demonstrated the benefit of second-generation endovascular recanalization therapies (primarily stent retrievers) over medical therapy alone among patients with acute ischemic stroke due to large-vessel occlusions. However, uncertainties remain about the benefit and risk of endovascular intervention undertaken more than 6 hours after symptom onset, as well as the degree to which benefit varies with time within the first 6 hours after symptom onset.

In addition, they point out that evaluation of the workflow speeds achieved in the trials could guide time targets for quality improvement in clinical practice, current recommendations for which are inconsistent.

National guidelines and consensus statements in the United States, Europe, and Canada recommend endovascular recanalization up until 6 hours after symptom onset, but thrombectomy devices are cleared by the US Food and Drug Administration for use up to 8 hours after symptom onset, and the Canadian guidelines additionally recommend thrombectomy for selected patients up to 12 hours after symptom onset.

To address these uncertainties, the current analysis aimed to establish the period in which endovascular thrombectomy is associated with benefit and the extent to which treatment delay affects this.

The meta-analysis includes data from the five randomized trials reported in 2015 — MR CLEAN, ESCAPE, REVASCAT, SWIFT PRIME, and EXTEND IA — all of which showed benefits of endovascular thrombectomy in patients with acute ischemic stroke caused by a large anterior occlusion.

The current analysis included data from 1287 patients: 634 who received endovascular thrombectomy plus thrombolysis and 653 who received thrombolysis alone. In the endovascular group, the mean time from symptom onset to arterial puncture was 238 minutes and mean time from symptom onset to reperfusion was 286 minutes.

At 90 days, the mean mRS score was 2.9 in the endovascular group and 3.6 in the thrombolysis-alone group.

The results of this analysis show that the odds of better disability outcomes at 90 days (mRS distribution) with the endovascular group declined with longer time from symptom onset to arterial puncture: odds ratio (OR) at 3 hours, 2.79, vs 1.98 at 6 hours and 1.57 at 8 hours. Statistical significance was retained through 7 hours and 18 minutes.

Rates of functional independence after thrombectomy were 64% with reperfusion at 3 hours vs 46% with reperfusion at 8 hours.

Among 390 patients who achieved substantial reperfusion with endovascular thrombectomy, each 1-hour delay to reperfusion was associated with a less favorable degree of disability (OR, 0.84) and less functional independence (OR, 0.81) but no significant change in mortality.

"The results of this study reinforce guideline recommendations to pursue endovascular treatment when arterial puncture can be initiated within 6 hours of symptom onset, and provide evidence that potentially supports strengthening of recommendations for treatment from 6 through 7.3 hours after symptom onset," the authors conclude.

"Although point estimates suggested that benefit may continue to accrue up to and beyond 8 hours, there were insufficient numbers of patients in the extended time window to provide firm insights," they add. "These observations underline the importance of enrollment of brain imaging-selected patients in ongoing randomized trials evaluating endovascular reperfusion patients in longer time windows."

New Triage Protocols Needed

In an accompanying editorial, Steven Warach, MD, and S. Claiborne Johnston, MD, Dell Medical School, University of Texas at Austin, say these new data have important implications for how stroke services should be organized.

They stress that transfers from local hospitals to endovascular-capable stroke centers must increase and must be accomplished with the utmost speed. And they suggest that if the referring facilities and receiving facilities could share information and vascular imaging by video links, then the patients could be transported directly to the angiography suite, potentially saving an estimated 30 to 45 minutes.

The editorialists point out that in this latest analysis, patients transferred between facilities had a delay of 2 hours compared with those taken straight to an endovascular center, but as less than 5% of all stroke patients may be candidates for endovascular thrombectomy therapy, finding the right protocols to triage patients to the right place is key.

They note that questions to be asked include the following:

  • Which out-of-hospital stroke scale to use for identifying large artery occlusions?

  • Would telemedicine directed by a remote stroke physician be a better triage technique?

  • Should primary stroke centers be bypassed to transport patients to comprehensive centers, even if it means delaying the start of intravenous tissue plasminogen activator (tPA)?

  • How much delay in bypass is acceptable?

  • Would a mobile stroke unit with computed tomographic

They add that so far there is no consensus on these issues, but new triage approaches for stroke need to be evaluated, as has previously occurred in the successful evolution of care for trauma and acute coronary syndrome.

The HERMES pooled analysis project is supported by a grant from Medtronic to the University of Calgary. Dr Saver reports being an employee of the University of California; serving as an unpaid site investigator in multicenter trials run by Medtronic and Stryker, for which the University of California Regents received payments on the basis of clinical trial contracts for many patients enrolled; receiving stock options for services as a scientific consultant regarding trial design and conduct to Cognition Medical; receiving funding for services as a scientific consultant regarding trial design and conduct to Covidien/Medtronic, Stryker, Neuravi, BrainsGate, Pfizer, BristolMyers-Squibb, Boehringer Ingelheim (prevention only), ZZ Biotech, and St Jude Medical; and serving as an unpaid consultant to Genentech advising on the design and conduct of the PRISMS trial (neither the University of California nor Dr Saver received any payments for this voluntary service). The University of California has patent rights in retrieval devices for stroke. As an associate editor of JAMA, Dr Saver was not involved in editorial review of this paper. Dr Hill reports unrestricted grant funding for the ESCAPE trial to the University of Calgary from Covidien/Medtronic and active/in-kind support consortium of public/charitable sources (Heart and Stroke Foundation, Alberta Innovates Health Solutions, Alberta Health Services) and the University of Calgary (Hotchkiss Brain Institute, Departments of Clinical Neurosciences and Radiology, and Calgary Stroke Program); personal fees from Merck; and nonfinancial support from Hoffmann-La Roche Canada. In addition, Dr Hill has a submitted patent for triaging systems in ischemic stroke and owns stock in Calgary Scientific, a company that focuses on medical imaging software.

JAMA. Published September 27, 2016. Full text, Editorial

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