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Is IV TPA Needed with Mechanical Thrombectomy for Stroke?

Fitzgerald, Susan

doi: 10.1097/01.NT.0000513247.60799.24
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ARTICLE IN BRIEF

Findings from a new analysis of pooled data from two large studies suggest that IV thrombolysis may not be needed before mechanical thrombectomy for acute stroke. Some stroke neurologists don't agree with the finding.

An analysis of pooled data from two key trials of mechanical thrombectomy (MT) for stroke suggests that the routine practice of administering intravenous tissue plasminogen activator (IV tPA) along with the stent retriever procedure may be unnecessary.

Researchers reporting on the analysis in the January 9 online edition of JAMA Neurology said that for patients experiencing acute ischemic stroke (AIS) caused by large vessel occlusion, “IVT before MT does not appear to provide a clinical advantage.” They said that a randomized clinical trial is needed to compare IVT plus MT versus MT alone.

The issue is far from settled, however, as several stroke neurologists who were not involved with the study questioned the conclusions and how they might be interpreted. They also raised concerns about certain aspects of the study design and assumptions made by the investigators.

In an interview with Neurology Today, the study's lead investigator, Vitor Pereira, MD, associate professor of radiology and surgery at the University of Toronto, said that as stroke care continues to evolve it is important for researchers to re-examine assumptions. He said that mechanical thrombectomy using a stent retriever, in combination with IV tPA, has been shown in multiple studies to be superior to IV tPA alone, and that it was logical to ask to whether there was added value in the combination treatment.

“Is it still worth it to give tPA at centers that can offer mechanical thrombectomy in an efficient and fast way? What are the benefits?” Dr. Pereira asked. “To our surprise we didn't find a benefit.”

Dr. Pereira and his study coauthors noted that five trials published in 2015 reported that MT with a stent retriever in combination with IVT was superior to IVT alone for stroke caused by a large vessel occlusion in the anterior circulation. [The five trials were selected by members of the Neurology Today editorial advisory board as among the most important advances of 2015; see http://bit.ly/NT-BestAdvances2015.]

Those studies weren't designed, however, to answer the question of whether administering IVT enhanced the success of MT or perhaps had a negative influence on outcome by increasing the likelihood of hemorrhagic complications and causing fragmentation of the thrombus, they wrote.

Dr. Pereira said that “the next step is to perform a proper randomized controlled trial where IV tPA is the central question.” Researchers at the University of Toronto and the University of Bern in Switzerland are planning to soon launch such a trial, assigning a total of 530 patients to either IV tPA plus MT or MT alone, he said.

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STUDY DESIGN

To shed some light on the question, Dr. Pereira and his colleagues conducted a post-hoc analysis of data from two of the studies, SWIFT and STAR. Because not everyone in the MT arm of those studies received IV thrombolysis (IVT) for a number of reasons, the researchers were able to set up the analysis to tease out the IVT effect.

The analysis included a total of 292 patients from the SWIFT AND STAR trials, including 80 patients who received IVT and MT and 131 who had MT alone.

The analysis found that 90 days afterward, there was no statistically significant difference between the two groups when it came to functional independence: 57.7 percent of the group that received combination therapy had a 0-2 score on the Extended Disability Status Scale (EDSS) compared to 47.7 percent of the MT group. Mortality at 90 days was also similar (8.1 percent versus 12.2 percent).

Surprisingly, the analysis found less intracranial hemorrhaging in the group that received the combination therapy than in the MT alone group.

The study authors said “the finding that intravenous thrombolysis was associated with a lower risk of intracranial hemorrhage, a somewhat counterintuitive observation, should especially be interpreted with caution, given the low number of patients with a symptomatic intracranial hemorrhage in either group.”

The researchers acknowledged that their analysis had several limitations, including the fact that the patients in the original studies designed to evaluate MT were not randomly assigned to get IVT or not. The patients who had MT alone tended to have medical contraindications to IVT, which could have affected their outcomes. Another confounding factor was that not all patients who received IVT were given the same dose. The researchers also said it was possible that the sample size for the analysis was not large enough to detect differences in outcomes between IVT and MT versus MT alone.

Dr. Pereira, an interventional neuroradiologist who performs MT, said that time – getting therapy started as quickly as possible – will remain the bedrock of stroke care. “We don't have to have one single rule for everybody,” he said.

Not all stroke patients live close to a hospital that offers MT or are taken to a stroke center first and for them getting tPA started right away is important, Dr. Pereira said. But in cases where patients with acute ischemic stroke are brought to a hospital that does have MT, “why should we insist also on tPA?” Dr. Pereira asked. He said it's possible that critical time could be lost in the two-step approach, though the analysis did not find that.

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EXPERTS COMMENT

James C. Grotta, MD, FAAN, director of stroke research at Memorial Hermann-Texas Medical Center, who was not involved with the study, said that to interpret the findings as meaning that tPA should be omitted is “a dangerous and ill-found conclusion.”

He noted that the analysis had many limitations. In particular, he cited the fact it pooled data from two studies that were “not designed with the intent to be able to reach a conclusion that tPA should be omitted.”

Dr. Grotta, who started a “stroke ambulance” program in Houston that is capable of starting tPA en route to the hospital, said he worried that the new analysis could be misinterpreted, and said it could play into fears that some clinicians have about tPA.

“We know that we have a powerful treatment with thrombectomy,” Dr. Grotta said, “but that doesn't mean tPA should be abandoned just because there are clinicians who are still, after all these years, afraid of the drug.”

He agreed that a well-designed randomized, controlled trial could help answer questions that the report raised. He noted, for instance, that while the analysis did not find a statistically significant difference between IVT and MT and MT alone, “there were actually strong signals that patients treated with tPA did better (about 10 percent absolute difference) than those receiving thrombectomy alone, but the study (of pooled data) did not have the statistical power to confirm that difference.”

Mark Alberts, MD, chief of the department of neurology at Hartford Hospital in Connecticut, said the new analysis of IVT and MT versus only MT is “hypothesis-generating, but I don't think it is earth shattering or should change the care paradigm.”

He agreed that the hypothesis needs to be tested in a randomized, controlled trial, and even then there are many practical issues that need to be considered when organizing stroke protocols at the EMS level as well as at the hospital level.

“Many more people live in close range of a hospital that can administer intravenous alteplase than live close to a hospital that can perform mechanical thrombectomy,” Dr. Alberts said. In addition, “some patients get better with IV alteplase alone,” so going directly into the endovascular suite for a stent retriever procedure may not be necessary, he said. Also, not all patients with ischemic stroke are candidates for MT.

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“I wouldn't want people walking away from reading this study thinking that IV alteplase is not a beneficial treatment,” Dr. Alberts said.

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EXPERTS: IS IV THROMBOLYSIS NEEDED BEFORE MECHANICAL THROMBECTOMY?

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LINK UP FOR MORE INFORMATION:

•. Coutinho JM, Liebeskind DS, Slater LA, et al Combined intravenous thrombolysis and thrombectomy vs thrombectomy alone for acute ischemic stroke: A pooled analysis of the SWIFT and STAR Studies http://jamanetwork.com/journals/jamaneurology/article-abstract/2596239. JAMA Neurol 2017; Epub 2017 Jan 9.
    •. Atwal GS, Siddiqui AH. Mechanical thrombectomy for acute ischemic stroke: Are we done http://jamanetwork.com/journals/jamaneurology/article-abstract/2596239. JAMA Neurol 2017; Epub 2017 Jan 9.
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