ARTICLE IN BRIEF
THE MR CLEAN investigators have established a registry of patients from the trial to see how they fare in the long run. They will also analyze the cost-effectiveness of the treatment.
In a landmark study, investigators reported that administering an intra-arterial intervention in addition to intravenous tissue plasminogen activator significantly improved functional outcomes in patients with ischemic stroke.
In what is being described as one of the most exciting developments in stroke treatment in 20 years, Dutch researchers reported that administering an intra-arterial intervention in addition to intravenous tissue plasminogen activator (tPA) significantly improved functional outcomes in patients with ischemic stroke.
The study, which involved 500 patients with a proximal intracranial arterial occlusion, found that 32.6 percent of patients who had their clot removed with a retrievable stent or other means achieved functional independence, compared with 19.1 percent of patients who received standard treatment with intravenous alteplase, or tPA, alone.
“Our study, MR CLEAN, is the first to show that intra-arterial treatment of ischemic stroke really works. It leads to recovery and less [disability],” said Diederik Dippel, MD, PhD, one of the study's principal investigators.
“With standard treatment, less than one out of five patients recovers without handicap. But with this new treatment, it could be one out of three,” Dr. Dippel, a professor of neurology at Erasmus MC University Medical Center in Rotterdam, told Neurology Today in an email.
STUDY METHODOLOGY
The MR CLEAN study enrolled stroke patients at 16 medical centers in the Netherlands. A total of 233 patients were assigned to intra-arterial treatment and 267 to usual care alone. The patients had an occlusion of the distal intracranial carotid artery, middle cerebral artery, or anterior cerebral artery as seen by computed tomographic angiography, magnetic resonance angiography, or digital-subtraction angiography. They had a score of 2 or higher on the National Institutes of Health Stroke Scale, which ranges from 0-42, with higher scores indicating more severe neurologic deficits. The patients ranged in age from 23 to 96.
EXPERTS say that improvements in stent retriever technology likely led to better success in removing clots safely.
Nearly all of the patients in the intra-arterial treatment group received tPA before the intervention, which involved mechanical methods such as aspiration, wire disruption, or, most often, the use of a retrievable stent to capture the clot and pull it out through a catheter, as well as localized delivery of a thrombolytic agent.
The primary outcome was the score on the modified Rankin scale at 90 days. This seven-point scale ranges from 0 (no symptoms) to 6 (death); a score of 2 or less indicates functional independence.
“We found that intra-arterial treatment in patients with acute ischemic stroke caused by a proximal intracranial occlusion of the anterior circulation was effective and safe when administered within 6 hours after stroke onset,” the researchers concluded. Even patients in their 80s did well with the therapy.
An editorial accompanying the study noted that “most other prespecified clinical endpoints and the rate of recanalization favored transvascular treatment,” although that rate — about 75 percent — “was a little lower than expected.”
“There were no significant differences in mortality or the occurrence of symptomatic intracranial hemorrhage,” wrote Werner Hacke, MD, PhD, professor and chair of neurology at the University of Heidelberg in Germany.
Dr. Werner said that while the MR CLEAN study is “the first step in the right direction,” clinicians should exercise caution in interpreting the findings until the results of several similar trials are reported later in 2015.
EXPERTS COMMENT
Researchers not involved with the study were enthusiastic about the findings, noting that there has not been a significant development in stroke treatment since the approval of tPA in 1996.
“This is a major landmark study,” said Lee Schwamm, MD, a professor of neurology at Harvard Medical School and executive vice chairman of neurology at Massachusetts General Hospital. “The study leadership should be commended for a fantastic study. It was rigorously done, it was done quickly, and it was done in a uniform manner using all the best technology.”
The study's positive findings differed from three previous studies of intra-arterial treatment that resulted in negative or somewhat ambiguous findings, another stroke expert noted.
“I think there were some important differences” from past studies, said James Grotta, MD, FAAN, director of stroke research and clinical innovation at Memorial Hermann Hospital in Houston and a member of the Neurology Today editorial advisory board.
The latest study involved patients “with very severe stroke” confirmed by imaging who had not responded to tPA alone, he noted. Also, stent retriever technology has improved since the older studies were done, likely leading to better success in removing clots safely.
DR. DIEDERIK DIPPEL: “Our study, MR CLEAN, is the first to show that intra-arterial treatment of ischemic stroke really works. It leads to recovery and less [disability].”
“They were able to get the artery open in patients with [very severe] strokes,” said Dr. Grotta, who is also director of the Houston Mobile Stroke Unit Consortium.
Joseph Broderick, MD, a professor of neurology and director of the University of Cincinnati Neuroscience Institute — who also headed one of the previous studies of intra-arterial stroke treatment, IMS III, which found no benefit from mechanical intervention — said it was “a big deal” that this latest study found that “we can do better for this subgroup of patients who have bigger strokes with large artery occlusions and, at least in this study, failed to respond to tPA.” He added that it was impressive that the Dutch researchers were able to administer tPA to patients in under 90 minutes.
The results of three similar trials will likely be reported at the International Stroke Conference in Nashville in February. Dr. Broderick said that these additional studies should help determine how well endovascular therapy works in different circumstances and patient populations.
“There is going to be a whole lot more data that we can use to determine who is best suited for the therapy and what is the chronologic and physiologic time window,” he said.
The study from the Netherlands was noteworthy because the Dutch government made a decision to only reimburse for clot-busting devices when they were used in the context of a clinical trial, Dr. Broderick noted. Trials in the US have had trouble enrolling patients because doctors can be paid for the procedure outside of a trial.
Dr. Schwamm said the study results also speak to the need for a systematic approach to stroke care that focuses on both speed and expertise. “This study has important implications because it means we really need to develop a system that can deliver IV tPA to everyone as rapidly as possible, and then go to this rescue therapy [intra-arterial intervention] as needed.”
He said that while the encouraging results could lead to a rush among medical centers to add stent retrievers and similar clot-removal devices to their repertoires, the technology is probably best suited for high-volume centers that specialize in stroke treatment.
Dr. Dippel said his research team has established a registry of patients from the MR CLEAN trial to see how they fare in the long run. The team will also analyze the cost-effectiveness of the treatment.
“There are many new research questions ahead of us,” he said. “Will immediate percutaneous treatment be more efficacious than secondary intervention? What co-medication should we use during the treatment and immediately after? We are preparing new trials to tackle these issues.”
EXPERTS: ON INTRA-ARTERIAL TREATMENT FOR STROKE
DR. LEE SCHWAMM: “This is a major landmark study. The study leadership should be commended for a fantastic study. It was rigorously done, it was done quickly, and it was done in a uniform manner using all the best technology.”
DR. JAMES GROTTA noted that the MR CLEAN study involved patients “with very severe stroke” confirmed by imaging who had not responded to tPA alone. He added that stent retriever technology has improved since the older studies were done, likely leading to better success in removing clots safely.
DR. JOSEPH BRODERICK said it was “a big deal” that this latest study found that “we can do better for this subgroup of patients who have bigger strokes with large artery occlusions and, at least in this study, failed to respond to tPA.” He added that it was impressive that the Dutch researchers were able to administer tPA to patients in under 90 minutes.
