No benefit of endovascular therapy added to TPA for stroke

Functional outcomes in patients treated with intravenous tissue plasminogen activator with or without endovascular therapy after a moderate to severe acute ischemic stroke were not significantly different, and safety outcomes were similar, in a study that was stopped early because of these results.

In the IMS (Interventional Management of Stroke) III study, 40.8% of patients randomized to receive endovascular therapy plus intravenous TPA met the primary endpoint, a measure of functional independence – a modified Rankin score of 2 or less at 90 days – compared with 38.7% among those who had intravenous TPA alone, a difference that was not statistically significant, reported Dr. Joseph Broderick of the University of Cincinnati Neuroscience Institute, and the other IMS III investigators.

Mortality and other safety outcomes were also not significantly different between the two groups of patients in the study, which was stopped early because of futility after 656 of the planned 900 patients had been randomized. The study is being published online on Feb. 7 to coincide with the presentation of the results at the International Stroke Conference (N. Engl. J. Med. 2013 [doi:10.1056/NEJMoa1214300]).

Referring to the lack of randomized clinical trial data, the authors pointed out that it is uncertain whether endovascular therapy (which includes endovascular pharmacologic thrombolysis and, more recently, the use of stent retrievers) alone or combined with intravenous TPA is a more effective treatment of acute stroke than intravenous TPA alone, "the only proven reperfusion therapy for acute ischemic stroke."

In the study, conducted at 58 centers in the United States, Canada, Australia, and Europe, 434 patients were randomized to endovascular therapy plus intravenous TPA and 222 were randomized to standard treatment with intravenous TPA alone (started within 3 hours of stroke onset). The median age of those enrolled was 68-69 years (range, 23-89 years), a little over half were men, about 14% were black or Hispanic, and the median the National Institute of Health Stroke Scale (NIHSS) score was 16-17 (8-19 is a moderately severe stroke and 20 or greater is a severe stroke At the beginning of the study, only one thrombectomy device had been cleared by the Food and Drug Administration and, as the trial continued, other devices were used as they became cleared for use in the different countries.

In addition to the main finding, there were no differences in the primary outcome among those patients with an NIHSS score of 20 or more, and those with a score of 19 or lower, said the authors, who had hypothesized that endovascular therapy would have greater efficacy in patients with more-severe strokes since they "have the highest likelihood of occlusion in a major intracranial artery and the greatest volume of ischemic brain at risk."

They had also hypothesized that receiving endovascular therapy earlier would be associated with a greater benefit, but this was also not a significant factor in outcomes.

Mortality at 90 days was 19.1% in the endovascular therapy group and 21.6% in the intravenous TPA–alone group. Within 30 hours of TPA initiation, 6.2% of those on endovascular therapy and 5.9% of those on TPA alone had a symptomatic intracerebral hemorrhage. The differences in mortality at 7 days and in parenchymal hematoma rates were also not significantly different between the two groups. The rate of asymptomatic intracerebral hemorrhage, however, was significantly higher in the endovascular group.

Outcomes consistently trended better with combined therapy in patients with strokes involving larger artery occlusions and those with the shortest times from stroke onset to initiation of treatment, although because of small patient numbers the differences didn’t achieve statistical significance. These will be the subgroups that ought to be the focus of future clinical trials, Dr. Broderick said in a press briefing at the conference.

The underlying rationale for combined therapy is that intravenous TPA can quickly be started in the emergency department while the endovascular device therapy team is assembling, often at another hospital, which entails time-consuming patient transfer.

Intravenous TPA is the only proven therapy for acute ischemic stroke, but endovascular therapy is more effective at achieving recanalization. The study results bore this out: for example, the rate of partial or complete recanalization at 24 hours for an occlusion in the internal carotid artery was 81% with combined therapy compared to 35% with intravenous TPA alone. Yet this higher recanalization rate bore no clinical benefit, possibly because recanalization occurred too late, after ischemia had turned into infarction, Dr. Broderick explained.

"ISM III is going to be disappointing for a lot of people who are proponents of endovascular therapy. However, there is a light at the end of the tunnel in that there are these subgroups who may benefit," Dr. Brian Silver, who was not involved in the trial, said in an interview.

"The most critical feature is to treat the patients as soon as possible when they arrive in the emergency department, perhaps within 90 minutes. I think that’s the best chance for recovery. We are nowhere near what’s being done in cardiology, where there are door-to-balloon times of an hour. We need to do that in stroke. Since we’re dealing with an organ that’s more sensitive than the heart to ischemia, we probably need to be even faster than what’s being done in cardiology. There is definitely room for improvement in our systems, perhaps by having the endovascular team stay in the hospital. Expense will be the limitation," according to Dr. Silver, director of the stroke center at Brown University, Providence, R.I.

ISM III investigator and interventional neuroradiologist Dr. Thomas A. Tomsick said in an interview that the study results won’t change his own clinical practice.

"ISM III is by no means the final word on combined therapy. In Cincinnati tomorrow, if a patient with a large NIH Stroke Severity score shows up and we’re treating him with IV TPA at 2 hours from stroke onset, we’re not going to do a CT angiogram to evaluate that patient. He’s going to the cath lab for angiography to see if there’s a clot suitable for endovascular therapy," said Dr. Tomsick, professor of radiology at the University of Cincinnati.

Five different endovascular device therapies were utilized in IMS III. As new devices reached clinical practice, their use was allowed by investigators in order to keep the randomized trial clinically relevant. But recruitment for the study was slow because so many clinicians were already convinced by anecdotal experience that combined therapy is better. So the endovascular therapies used most frequently in IMS III aren’t the ones widely used in clinical practice today. Major new randomized trials are now getting underway comparing combined therapy using state-of-the-art, more effective stent clot retriever devices to intravenous TPA alone, he added.

In the New England Journal of Medicine report, the authors noted that "the use of randomization in ongoing and future stroke trials, rather than the treatment of eligible patients with endovascular therapy outside any trial, and minimization of the time to treatment will be essential for assessing the potential benefit of endovascular therapy for acute ischemic stroke."

No matter how future trials of combined therapy turn out, endovascular therapy is not going away, Dr. Broderick observed.

"It’s a very good tool. The reason why is there are patients who can’t get TPA. For example, roughly 5% of patients who undergo coronary artery bypass surgery have a stroke. If you have somebody with a big stroke 2 days after having their chest cracked, you can’t use TPA. In that case, those endovascular devices are the way we can get up in there and get rid of the clot," he explained.

In an editorial accompanying the report in the New England Journal of Medicine (doi:10.1056/NEJMe1215730), Dr. Marc I. Chimowitz declared that the clinical implication of IMS III is that endovascular therapy remains unproven and IV-tPA should continue to be the first-line treatment for patients with acute ischemic stroke within 4.5 hours after stroke onset.

While new clinical trials featuring more effective IV clot busters, such as tenecteplase, and next-generation endovascular devices are urgently needed in an effort to improve stroke outcomes, patient recruitment is likely to continue to be a challenge in the current environment. This could be overcome if Medicare were to place a moratorium on reimbursement for endovascular therapy of acute ischemic stroke except as part of a randomized trial, according to Dr. Chimowitz, professor of neurology at the Medical University of South Carolina, Charleston.

The study was supported with grants from NIH and the National Institute of Neurological Disorders and Stroke; and by Genentech (which supplied the TPA); and EKOS, Concentric Medical, and Cordis Neurovascular (which supplied catheters); and Actilyse (alteplase) manufacturer Boehringer Ingelheim (which, along with Genentech and EKOS, provided support for investigator meetings). Dr. Broderick disclosed consulting fees from PhotoThera. Of the 28 other authors, disclosures for 14 were listed and included having received consulting fees, grant support, and/or lecture fees from a variety of device and pharmaceutical companies that include Genentech. Dr. Chimowitz, Dr. Silver, and Dr. Tomsick reported having no financial conflicts.

* This story was updated February 8, 2013.

[email protected]

[email protected]

Functional outcomes in patients treated with intravenous tissue plasminogen activator with or without endovascular therapy after a moderate to severe acute ischemic stroke were not significantly different, and safety outcomes were similar, in a study that was stopped early because of these results.

In the IMS (Interventional Management of Stroke) III study, 40.8% of patients randomized to receive endovascular therapy plus intravenous TPA met the primary endpoint, a measure of functional independence – a modified Rankin score of 2 or less at 90 days – compared with 38.7% among those who had intravenous TPA alone, a difference that was not statistically significant, reported Dr. Joseph Broderick of the University of Cincinnati Neuroscience Institute, and the other IMS III investigators.

Mortality and other safety outcomes were also not significantly different between the two groups of patients in the study, which was stopped early because of futility after 656 of the planned 900 patients had been randomized. The study is being published online on Feb. 7 to coincide with the presentation of the results at the International Stroke Conference (N. Engl. J. Med. 2013 [doi:10.1056/NEJMoa1214300]).

Referring to the lack of randomized clinical trial data, the authors pointed out that it is uncertain whether endovascular therapy (which includes endovascular pharmacologic thrombolysis and, more recently, the use of stent retrievers) alone or combined with intravenous TPA is a more effective treatment of acute stroke than intravenous TPA alone, "the only proven reperfusion therapy for acute ischemic stroke."

In the study, conducted at 58 centers in the United States, Canada, Australia, and Europe, 434 patients were randomized to endovascular therapy plus intravenous TPA and 222 were randomized to standard treatment with intravenous TPA alone (started within 3 hours of stroke onset). The median age of those enrolled was 68-69 years (range, 23-89 years), a little over half were men, about 14% were black or Hispanic, and the median the National Institute of Health Stroke Scale (NIHSS) score was 16-17 (8-19 is a moderately severe stroke and 20 or greater is a severe stroke At the beginning of the study, only one thrombectomy device had been cleared by the Food and Drug Administration and, as the trial continued, other devices were used as they became cleared for use in the different countries.

In addition to the main finding, there were no differences in the primary outcome among those patients with an NIHSS score of 20 or more, and those with a score of 19 or lower, said the authors, who had hypothesized that endovascular therapy would have greater efficacy in patients with more-severe strokes since they "have the highest likelihood of occlusion in a major intracranial artery and the greatest volume of ischemic brain at risk."

They had also hypothesized that receiving endovascular therapy earlier would be associated with a greater benefit, but this was also not a significant factor in outcomes.

Mortality at 90 days was 19.1% in the endovascular therapy group and 21.6% in the intravenous TPA–alone group. Within 30 hours of TPA initiation, 6.2% of those on endovascular therapy and 5.9% of those on TPA alone had a symptomatic intracerebral hemorrhage. The differences in mortality at 7 days and in parenchymal hematoma rates were also not significantly different between the two groups. The rate of asymptomatic intracerebral hemorrhage, however, was significantly higher in the endovascular group.

Outcomes consistently trended better with combined therapy in patients with strokes involving larger artery occlusions and those with the shortest times from stroke onset to initiation of treatment, although because of small patient numbers the differences didn’t achieve statistical significance. These will be the subgroups that ought to be the focus of future clinical trials, Dr. Broderick said in a press briefing at the conference.

The underlying rationale for combined therapy is that intravenous TPA can quickly be started in the emergency department while the endovascular device therapy team is assembling, often at another hospital, which entails time-consuming patient transfer.

Intravenous TPA is the only proven therapy for acute ischemic stroke, but endovascular therapy is more effective at achieving recanalization. The study results bore this out: for example, the rate of partial or complete recanalization at 24 hours for an occlusion in the internal carotid artery was 81% with combined therapy compared to 35% with intravenous TPA alone. Yet this higher recanalization rate bore no clinical benefit, possibly because recanalization occurred too late, after ischemia had turned into infarction, Dr. Broderick explained.

"ISM III is going to be disappointing for a lot of people who are proponents of endovascular therapy. However, there is a light at the end of the tunnel in that there are these subgroups who may benefit," Dr. Brian Silver, who was not involved in the trial, said in an interview.

"The most critical feature is to treat the patients as soon as possible when they arrive in the emergency department, perhaps within 90 minutes. I think that’s the best chance for recovery. We are nowhere near what’s being done in cardiology, where there are door-to-balloon times of an hour. We need to do that in stroke. Since we’re dealing with an organ that’s more sensitive than the heart to ischemia, we probably need to be even faster than what’s being done in cardiology. There is definitely room for improvement in our systems, perhaps by having the endovascular team stay in the hospital. Expense will be the limitation," according to Dr. Silver, director of the stroke center at Brown University, Providence, R.I.

ISM III investigator and interventional neuroradiologist Dr. Thomas A. Tomsick said in an interview that the study results won’t change his own clinical practice.

"ISM III is by no means the final word on combined therapy. In Cincinnati tomorrow, if a patient with a large NIH Stroke Severity score shows up and we’re treating him with IV TPA at 2 hours from stroke onset, we’re not going to do a CT angiogram to evaluate that patient. He’s going to the cath lab for angiography to see if there’s a clot suitable for endovascular therapy," said Dr. Tomsick, professor of radiology at the University of Cincinnati.

Five different endovascular device therapies were utilized in IMS III. As new devices reached clinical practice, their use was allowed by investigators in order to keep the randomized trial clinically relevant. But recruitment for the study was slow because so many clinicians were already convinced by anecdotal experience that combined therapy is better. So the endovascular therapies used most frequently in IMS III aren’t the ones widely used in clinical practice today. Major new randomized trials are now getting underway comparing combined therapy using state-of-the-art, more effective stent clot retriever devices to intravenous TPA alone, he added.

In the New England Journal of Medicine report, the authors noted that "the use of randomization in ongoing and future stroke trials, rather than the treatment of eligible patients with endovascular therapy outside any trial, and minimization of the time to treatment will be essential for assessing the potential benefit of endovascular therapy for acute ischemic stroke."

No matter how future trials of combined therapy turn out, endovascular therapy is not going away, Dr. Broderick observed.

"It’s a very good tool. The reason why is there are patients who can’t get TPA. For example, roughly 5% of patients who undergo coronary artery bypass surgery have a stroke. If you have somebody with a big stroke 2 days after having their chest cracked, you can’t use TPA. In that case, those endovascular devices are the way we can get up in there and get rid of the clot," he explained.

In an editorial accompanying the report in the New England Journal of Medicine (doi:10.1056/NEJMe1215730), Dr. Marc I. Chimowitz declared that the clinical implication of IMS III is that endovascular therapy remains unproven and IV-tPA should continue to be the first-line treatment for patients with acute ischemic stroke within 4.5 hours after stroke onset.

While new clinical trials featuring more effective IV clot busters, such as tenecteplase, and next-generation endovascular devices are urgently needed in an effort to improve stroke outcomes, patient recruitment is likely to continue to be a challenge in the current environment. This could be overcome if Medicare were to place a moratorium on reimbursement for endovascular therapy of acute ischemic stroke except as part of a randomized trial, according to Dr. Chimowitz, professor of neurology at the Medical University of South Carolina, Charleston.

The study was supported with grants from NIH and the National Institute of Neurological Disorders and Stroke; and by Genentech (which supplied the TPA); and EKOS, Concentric Medical, and Cordis Neurovascular (which supplied catheters); and Actilyse (alteplase) manufacturer Boehringer Ingelheim (which, along with Genentech and EKOS, provided support for investigator meetings). Dr. Broderick disclosed consulting fees from PhotoThera. Of the 28 other authors, disclosures for 14 were listed and included having received consulting fees, grant support, and/or lecture fees from a variety of device and pharmaceutical companies that include Genentech. Dr. Chimowitz, Dr. Silver, and Dr. Tomsick reported having no financial conflicts.

* This story was updated February 8, 2013.

[email protected]

[email protected]

Functional outcomes in patients treated with intravenous tissue plasminogen activator with or without endovascular therapy after a moderate to severe acute ischemic stroke were not significantly different, and safety outcomes were similar, in a study that was stopped early because of these results.

In the IMS (Interventional Management of Stroke) III study, 40.8% of patients randomized to receive endovascular therapy plus intravenous TPA met the primary endpoint, a measure of functional independence – a modified Rankin score of 2 or less at 90 days – compared with 38.7% among those who had intravenous TPA alone, a difference that was not statistically significant, reported Dr. Joseph Broderick of the University of Cincinnati Neuroscience Institute, and the other IMS III investigators.

Mortality and other safety outcomes were also not significantly different between the two groups of patients in the study, which was stopped early because of futility after 656 of the planned 900 patients had been randomized. The study is being published online on Feb. 7 to coincide with the presentation of the results at the International Stroke Conference (N. Engl. J. Med. 2013 [doi:10.1056/NEJMoa1214300]).

Referring to the lack of randomized clinical trial data, the authors pointed out that it is uncertain whether endovascular therapy (which includes endovascular pharmacologic thrombolysis and, more recently, the use of stent retrievers) alone or combined with intravenous TPA is a more effective treatment of acute stroke than intravenous TPA alone, "the only proven reperfusion therapy for acute ischemic stroke."

In the study, conducted at 58 centers in the United States, Canada, Australia, and Europe, 434 patients were randomized to endovascular therapy plus intravenous TPA and 222 were randomized to standard treatment with intravenous TPA alone (started within 3 hours of stroke onset). The median age of those enrolled was 68-69 years (range, 23-89 years), a little over half were men, about 14% were black or Hispanic, and the median the National Institute of Health Stroke Scale (NIHSS) score was 16-17 (8-19 is a moderately severe stroke and 20 or greater is a severe stroke At the beginning of the study, only one thrombectomy device had been cleared by the Food and Drug Administration and, as the trial continued, other devices were used as they became cleared for use in the different countries.

In addition to the main finding, there were no differences in the primary outcome among those patients with an NIHSS score of 20 or more, and those with a score of 19 or lower, said the authors, who had hypothesized that endovascular therapy would have greater efficacy in patients with more-severe strokes since they "have the highest likelihood of occlusion in a major intracranial artery and the greatest volume of ischemic brain at risk."

They had also hypothesized that receiving endovascular therapy earlier would be associated with a greater benefit, but this was also not a significant factor in outcomes.

Mortality at 90 days was 19.1% in the endovascular therapy group and 21.6% in the intravenous TPA–alone group. Within 30 hours of TPA initiation, 6.2% of those on endovascular therapy and 5.9% of those on TPA alone had a symptomatic intracerebral hemorrhage. The differences in mortality at 7 days and in parenchymal hematoma rates were also not significantly different between the two groups. The rate of asymptomatic intracerebral hemorrhage, however, was significantly higher in the endovascular group.

Outcomes consistently trended better with combined therapy in patients with strokes involving larger artery occlusions and those with the shortest times from stroke onset to initiation of treatment, although because of small patient numbers the differences didn’t achieve statistical significance. These will be the subgroups that ought to be the focus of future clinical trials, Dr. Broderick said in a press briefing at the conference.

The underlying rationale for combined therapy is that intravenous TPA can quickly be started in the emergency department while the endovascular device therapy team is assembling, often at another hospital, which entails time-consuming patient transfer.

Intravenous TPA is the only proven therapy for acute ischemic stroke, but endovascular therapy is more effective at achieving recanalization. The study results bore this out: for example, the rate of partial or complete recanalization at 24 hours for an occlusion in the internal carotid artery was 81% with combined therapy compared to 35% with intravenous TPA alone. Yet this higher recanalization rate bore no clinical benefit, possibly because recanalization occurred too late, after ischemia had turned into infarction, Dr. Broderick explained.

"ISM III is going to be disappointing for a lot of people who are proponents of endovascular therapy. However, there is a light at the end of the tunnel in that there are these subgroups who may benefit," Dr. Brian Silver, who was not involved in the trial, said in an interview.

"The most critical feature is to treat the patients as soon as possible when they arrive in the emergency department, perhaps within 90 minutes. I think that’s the best chance for recovery. We are nowhere near what’s being done in cardiology, where there are door-to-balloon times of an hour. We need to do that in stroke. Since we’re dealing with an organ that’s more sensitive than the heart to ischemia, we probably need to be even faster than what’s being done in cardiology. There is definitely room for improvement in our systems, perhaps by having the endovascular team stay in the hospital. Expense will be the limitation," according to Dr. Silver, director of the stroke center at Brown University, Providence, R.I.

ISM III investigator and interventional neuroradiologist Dr. Thomas A. Tomsick said in an interview that the study results won’t change his own clinical practice.

"ISM III is by no means the final word on combined therapy. In Cincinnati tomorrow, if a patient with a large NIH Stroke Severity score shows up and we’re treating him with IV TPA at 2 hours from stroke onset, we’re not going to do a CT angiogram to evaluate that patient. He’s going to the cath lab for angiography to see if there’s a clot suitable for endovascular therapy," said Dr. Tomsick, professor of radiology at the University of Cincinnati.

Five different endovascular device therapies were utilized in IMS III. As new devices reached clinical practice, their use was allowed by investigators in order to keep the randomized trial clinically relevant. But recruitment for the study was slow because so many clinicians were already convinced by anecdotal experience that combined therapy is better. So the endovascular therapies used most frequently in IMS III aren’t the ones widely used in clinical practice today. Major new randomized trials are now getting underway comparing combined therapy using state-of-the-art, more effective stent clot retriever devices to intravenous TPA alone, he added.

In the New England Journal of Medicine report, the authors noted that "the use of randomization in ongoing and future stroke trials, rather than the treatment of eligible patients with endovascular therapy outside any trial, and minimization of the time to treatment will be essential for assessing the potential benefit of endovascular therapy for acute ischemic stroke."

No matter how future trials of combined therapy turn out, endovascular therapy is not going away, Dr. Broderick observed.

"It’s a very good tool. The reason why is there are patients who can’t get TPA. For example, roughly 5% of patients who undergo coronary artery bypass surgery have a stroke. If you have somebody with a big stroke 2 days after having their chest cracked, you can’t use TPA. In that case, those endovascular devices are the way we can get up in there and get rid of the clot," he explained.

In an editorial accompanying the report in the New England Journal of Medicine (doi:10.1056/NEJMe1215730), Dr. Marc I. Chimowitz declared that the clinical implication of IMS III is that endovascular therapy remains unproven and IV-tPA should continue to be the first-line treatment for patients with acute ischemic stroke within 4.5 hours after stroke onset.

While new clinical trials featuring more effective IV clot busters, such as tenecteplase, and next-generation endovascular devices are urgently needed in an effort to improve stroke outcomes, patient recruitment is likely to continue to be a challenge in the current environment. This could be overcome if Medicare were to place a moratorium on reimbursement for endovascular therapy of acute ischemic stroke except as part of a randomized trial, according to Dr. Chimowitz, professor of neurology at the Medical University of South Carolina, Charleston.

The study was supported with grants from NIH and the National Institute of Neurological Disorders and Stroke; and by Genentech (which supplied the TPA); and EKOS, Concentric Medical, and Cordis Neurovascular (which supplied catheters); and Actilyse (alteplase) manufacturer Boehringer Ingelheim (which, along with Genentech and EKOS, provided support for investigator meetings). Dr. Broderick disclosed consulting fees from PhotoThera. Of the 28 other authors, disclosures for 14 were listed and included having received consulting fees, grant support, and/or lecture fees from a variety of device and pharmaceutical companies that include Genentech. Dr. Chimowitz, Dr. Silver, and Dr. Tomsick reported having no financial conflicts.

* This story was updated February 8, 2013.

[email protected]

[email protected]