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NASHVILLE, Tenn. -- Faster reperfusion, local anesthesia, and more severe stroke after thrombolysis predicted greater benefit of endovascular thrombectomy, analyses of the MR CLEAN and IMS III trials showed.

The spate of post hoc, sub-, and pooled analyses presented at the American Heart Association/American Stroke Association's International Stroke Conference here attempted to sort out best practices -- important in the wake of three additional positive thrombectomy trials seen as a mandate for the procedure.

"There always will be many analyses because we really are exploring the data and trying to gain insights from it," noted , director of the Duke Stroke Center, and national spokesperson for the AHA.

While he cautioned against relying on such exploratory analyses, the consistency of the message that time is of the essence in stroke supports a real association, he told 木瓜直播.

There had been some speculation that better outcomes would come from giving patients more time to stabilize or waiting for tissue plasminogen activator (tPA) to work before intra-arterial thrombolysis, he noted.

But the relationship looks the same as for IV tPA: "the sooner you treat, the better," Goldstein concluded.

Time Is Brain

The advantage of endovascular thrombectomy for good functional outcome dropped nearly an absolute 7% per additional hour from stroke onset to reperfusion (P=0.038 for interaction), , a PhD student at Erasmus University Medical Center Rotterdam, the Netherlands, reported.

The absolute difference versus medical treatment alone in terms of the proportion of patients with a modified Rankin score (mRS) 0-2 at 90 days was 33% in those reperfused by 2 hours but dropped to 6.5% for those reperfused after 6 hours.

"Time is an important predictor for clinical outcome and treatment effect in all ischemic diseases," Fransen noted.

That finding agreed with a subanalysis from the earlier, failed thrombectomy study IMS III, with 10% decrease in the probability of a good outcome for every 30-minute delay in breaking up the blood clot.

The advantage to mechanical clot removal for functional independence in MR CLEAN also declined with treatment delay in initiating the procedure. While not a significant effect (P=0.26 for interaction), it is biologically plausible, Fransen told attendees.

The absolute difference in functional independence rate between the intervention and medical treatment alone groups dropped from 19% at 2 hours to just 3% at 6 hours.

In the trial, the median time from stroke onset to insertion of the microcatheter in the groin was 256 minutes.

Only 11.5% got underway within 3 hours of stroke onset, while the rest were split from a 3- to 4.5-hour treatment window (45%) to a 4.5- to 6-hour window (44%), with a few falling outside the protocol for treatment within 6 hours.

Time from stroke onset to reperfusion (TICI 2b/3 classification) or end of the procedure if reperfusion never occurred was:

• Less than 3 hours for 1.5%
• 3 to 4.5 hours for 22%
• 4.5 to 6 hours for 40%
• More than 6 hours for 37%

The findings were all adjusted for age, baseline stroke severity, diabetes, prior stroke history, atrial fibrillation, and internal carotid artery terminus occlusion.

"There is no reason to withhold treatment within the 6 hour time window," but there's every reason to be as fast as possible, Fransen concluded.

Anesthesia

Without general anesthesia, mechanical clot removal added to thrombolysis more than doubled the odds of reduced disability compared with usual medical care alone for acute large vessel ischemic stroke in MR CLEAN.

It was also associated with a 2.79-fold greater odds of functional independence with the procedure than medical treatment alone, , of the Academic Medical Center in Amsterdam, and colleagues found.

By contrast, with general anesthesia, there was no advantage to the procedure for either outcome (P=0.013 for interaction).

Delayed treatment initiation was a possible factor, Berkhemer told reporters ahead of presentation at a late-breaking plenary session.

Time from arrival at the door to start of endovascular thrombectomy was 28 minutes faster without general anesthesia on average (134 versus 162 min). The procedure lasted a similar duration and took a similar amount of time to achieve revascularization.

However, overall time to reperfusion wasn't significantly different between groups and the difference in outcome by anesthesia status was in an analysis adjusted for time to reperfusion, Berkhemer noted.

"It could be the general anesthesia itself," he said, explaining that some of the agents used can lower blood pressure and perhaps thus impact brain perfusion.

The post-hoc analysis -- of 79 patients who got general anesthesia and 137 without it in MR CLEAN -- included only those with confirmed occlusion for whom treatment within 6 hours of stroke onset was possible. Although more men in the trial were in the nongeneral anesthesia group, stroke severity and age were similar between groups.

Safety of the procedure appeared similar between groups, although progressive ischemic stroke was more common with the deeper anesthesia and the analysis wasn't powered to compare differences in uncommon adverse events.

Most participating hospitals had a fixed protocol determining which type of anesthesia patients would get.

In typical U.S. practice, general anesthesia use is highly variable even among interventionalists and is biased by stroke type and condition of the patient, noted , chief of neurology at the Medical University of South Carolina in Charleston, and vice chair of the conference.

Whether the analysis could totally eliminate confounding by how sick patients were or rule out the effect of timing was debatable, he told reporters at a press conference he moderated.

Nevertheless, "the evidence, albeit modest, is only catching up with what we already know in practice, which is anecdotally we tend not to want to put people under general anesthesia," he told 木瓜直播 in an interview. "We see the outcomes ourselves. This is just going to reinforce the notion that we should try as much as possible not to put people under general anesthesia."

Severe Strokes

One of the negative thrombectomy studies from prior years -- IMS III -- suggested benefit for the subgroup with severe strokes.

To gain statistical power, , of the University of Cincinnati, Ohio, and colleagues pooled its results with those of MR CLEAN in the group with a National Institutes of Health Stroke Scale (NIHSS) score of at least 20 treated with IV tPA within 3 hours of stroke onset.

In that subgroup, endovascular thrombectomy was associated with an adjusted odds ratio of 1.81 for better mRS score at 90 days than with IV tPA alone (95% confidence interval 1.21-2.70).

The rate of functional independence marked by an mRS score of 0-2 at 90 days after severe stroke was 24.1% in the endovascular group versus 13.9% with the medical treatment alone.

The two trials determined stroke severity at different time points. Focusing in on just the 290 patients with a NIHSS score of at least 20 at 40 minutes after tPA administration, results came out similar.

The adjusted odds of a better score with the procedure than medical treatment alone was 2.07 in that group (95% CI 1.33-3.20). The proportion functionally independent at 90 days was 22.3% versus 10.5%, respectively.

The procedure thus offered a functional outcome at 90 days to about one in four compared with one in 10 on IV tPA alone, and without any increase in mortality, Broderick noted.

"Our pooled data, as well as other reported trials, call for thoughtful consideration of current triage for patients who present with severe stroke and who are candidates for endovascular therapy within a given region," he concluded.

From the American Heart Association:

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