Endovascular Therapy May Provide No Benefit When Combined With t-PA

HONOLULU—Functional and safety outcomes were not significantly different between patients with acute ischemic stroke treated with IV t-PA and those treated with IV t-PA and endovascular therapy, said investigators at the 2013 International Stroke Conference.

In the Interventional Management of Stroke (IMS) III study, 40.8% of patients randomized to receive endovascular therapy plus IV t-PA had a modified Rankin Scale (mRS) score of 2 or lower at 90 days, compared with 38.7% of patients who received IV t-PA alone, said Joseph Broderick, MD, Chair of the Department of Neurology at the University of Cincinnati and lead investigator of IMS III. The difference between the groups was not statistically significant. Mortality and other safety outcomes also were not significantly different between the two groups of patients in the study, which was halted early because of futility after 656 of the planned 900 patients had been randomized. The study was published online ahead of print on February 7 in the New England Journal of Medicine.

Comparing Two Reperfusion Therapies
Because of the lack of randomized clinical trial data, it was uncertain whether endovascular therapy, including endovascular pharmacologic thrombolysis and stent retrievers, alone or combined with IV t-PA is a more effective treatment for acute stroke than IV t-PA alone, “the only proven reperfusion therapy for acute ischemic stroke,” said Dr. Broderick.

In the IMS III study, which was conducted at 58 centers in the United States, Canada, Australia, and Europe, 434 patients were randomized to endovascular therapy plus IV t-PA, and 222 were randomized to standard treatment with IV t-PA alone. Treatment began within three hours of stroke onset. Patients’ median age was approximately 68 (range, 23 to 89). More than half of patients were men, approximately 14% were black or Hispanic, and the median NIH Stroke Scale (NIHSS) score was 17. At the beginning of the study, only one thrombectomy device had been approved by the FDA. As the trial continued, the researchers used other devices as they were approved.

Time to Endovascular Therapy Did Not Affect Outcomes
The investigators observed no differences in the primary outcome (ie, mRS of 2 or less at 90 days) between patients with an NIHSS score of 20 or greater and patients with an NIHSS score of 19 or less. The neurologists had hypothesized that endovascular therapy would have greater efficacy in patients with severe strokes, because these patients “have the highest likelihood of occlusion in a major intracranial artery and the greatest volume of ischemic brain at risk.”

The researchers also had hypothesized that receiving endovascular therapy earlier rather than later would be associated with a greater benefit. Time of endovascular therapy was not a significant factor in outcomes, however.

Mortality at 90 days was 19.1% in the endovascular therapy group and 21.6% in the IV t-PA–alone group. Within 30 hours of t-PA initiation, 6.2% of subjects who received endovascular therapy and 5.9% of subjects who received t-PA alone had a symptomatic intracerebral hemorrhage. The differences in mortality at seven days and in the parenchymal hematoma rate also were not significantly different between the two groups. The rate of asymptomatic intracerebral hemorrhage, however, was significantly higher in the endovascular group.

Outcomes of combined therapy tended to be better in patients with strokes that involved larger artery occlusions and in patients with the shortest times from stroke onset to initiation of treatment. Because of the small patient population, however, the differences did not achieve statistical significance. These subgroups should be the focus of future clinical trials, said Dr. Broderick.

Endovascular Therapy Provided More Effective Recanalization Than t-PA
The predicted advantage of combined therapy was that IV t-PA could be started quickly in the emergency department, while endovascular therapy, which requires time to mobilize the interventional team, would increase the likelihood of early recanalization.

The study results provided further evidence that endovascular therapy is more effective than IV t-PA at achieving recanalization. The rate of partial or complete recanalization at 24 hours for an occlusion in the internal carotid artery was 81% in patients who received combined therapy, compared with 35% in patients who received IV t-PA alone. The higher recanalization rate among patients who received endovascular therapy did not entail a clinical benefit, however. This result may have occurred because recanalization occurred too late—after ischemia had turned into infarction, explained Dr. Broderick.

“IMS 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,” said Brian Silver, MD, Director of the Stroke Center at Brown University in Providence, Rhode Island, who was not involved in the trial.

“The most critical feature is to treat the patients as soon as possible when they arrive in the emergency department, perhaps within 90 minutes. That’s the best chance for recovery,” said Dr. Silver in an interview. “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,” he added.

The results of IMS III may not change neurologists’ clinical practice. “IMS III is by no means the final word on combined therapy,” said Thomas A. Tomsick, MD, in an interview. “In Cincinnati tomorrow, if a patient with a large NIHSS score shows up, and we’re treating him with IV t-PA at two 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,” he added. Dr. Tomsick is a Professor of Radiology at the University of Cincinnati.

Five endovascular devices were used in IMS III. As new devices were adopted in clinical practice, investigators allowed them to be used in the trial to keep it clinically relevant. But recruitment for the study was slow, because experience already had convinced many clinicians that combined therapy is better than t-PA alone. As a result, the endovascular therapies used most frequently in IMS III were not the devices most widely used in clinical practice today. Major new randomized trials that compare combined therapy using state-of-the-art, more effective stent clot retriever devices to IV t-PA alone are now under way, added Dr. Tomsick.

The Future of Endovascular Therapy
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,” noted Dr. Broderick in the New England Journal of Medicine.

No matter how future trials of combined therapy turn out, endovascular therapy is not going away because some patients are not eligible to receive t-PA, Dr. Broderick observed. “Roughly 5% of patients who undergo coronary artery bypass surgery have a stroke. If you have somebody with a big stroke two days after having his or her chest cracked, you can’t use t-PA. In that case, those endovascular devices are the way we can get up in there and get rid of the clot,” he explained.

The clinical implications of IMS III are that endovascular therapy remains unproven and IV t-PA should remain the first-line treatment for patients with acute ischemic stroke within 4.5 hours after stroke onset, said Marc I. Chimowitz, MD, in an editorial published online in the February 8

Although new clinical trials of more effective IV clot busters, such as tenecteplase, and next-generation endovascular devices are urgently needed to improve stroke outcomes, patient recruitment is likely to remain a challenge. This obstacle could be overcome if Medicare placed a moratorium on reimbursement for endovascular therapy of acute ischemic stroke, except as part of a randomized trial, according to Dr. Chimowitz, who is a Professor of Neurology at the Medical University of South Carolina in Charleston.

HONOLULU—Functional and safety outcomes were not significantly different between patients with acute ischemic stroke treated with IV t-PA and those treated with IV t-PA and endovascular therapy, said investigators at the 2013 International Stroke Conference.

In the Interventional Management of Stroke (IMS) III study, 40.8% of patients randomized to receive endovascular therapy plus IV t-PA had a modified Rankin Scale (mRS) score of 2 or lower at 90 days, compared with 38.7% of patients who received IV t-PA alone, said Joseph Broderick, MD, Chair of the Department of Neurology at the University of Cincinnati and lead investigator of IMS III. The difference between the groups was not statistically significant. Mortality and other safety outcomes also were not significantly different between the two groups of patients in the study, which was halted early because of futility after 656 of the planned 900 patients had been randomized. The study was published online ahead of print on February 7 in the New England Journal of Medicine.

Comparing Two Reperfusion Therapies
Because of the lack of randomized clinical trial data, it was uncertain whether endovascular therapy, including endovascular pharmacologic thrombolysis and stent retrievers, alone or combined with IV t-PA is a more effective treatment for acute stroke than IV t-PA alone, “the only proven reperfusion therapy for acute ischemic stroke,” said Dr. Broderick.

In the IMS III study, which was conducted at 58 centers in the United States, Canada, Australia, and Europe, 434 patients were randomized to endovascular therapy plus IV t-PA, and 222 were randomized to standard treatment with IV t-PA alone. Treatment began within three hours of stroke onset. Patients’ median age was approximately 68 (range, 23 to 89). More than half of patients were men, approximately 14% were black or Hispanic, and the median NIH Stroke Scale (NIHSS) score was 17. At the beginning of the study, only one thrombectomy device had been approved by the FDA. As the trial continued, the researchers used other devices as they were approved.

Time to Endovascular Therapy Did Not Affect Outcomes
The investigators observed no differences in the primary outcome (ie, mRS of 2 or less at 90 days) between patients with an NIHSS score of 20 or greater and patients with an NIHSS score of 19 or less. The neurologists had hypothesized that endovascular therapy would have greater efficacy in patients with severe strokes, because these patients “have the highest likelihood of occlusion in a major intracranial artery and the greatest volume of ischemic brain at risk.”

The researchers also had hypothesized that receiving endovascular therapy earlier rather than later would be associated with a greater benefit. Time of endovascular therapy was not a significant factor in outcomes, however.

Mortality at 90 days was 19.1% in the endovascular therapy group and 21.6% in the IV t-PA–alone group. Within 30 hours of t-PA initiation, 6.2% of subjects who received endovascular therapy and 5.9% of subjects who received t-PA alone had a symptomatic intracerebral hemorrhage. The differences in mortality at seven days and in the parenchymal hematoma rate also were not significantly different between the two groups. The rate of asymptomatic intracerebral hemorrhage, however, was significantly higher in the endovascular group.

Outcomes of combined therapy tended to be better in patients with strokes that involved larger artery occlusions and in patients with the shortest times from stroke onset to initiation of treatment. Because of the small patient population, however, the differences did not achieve statistical significance. These subgroups should be the focus of future clinical trials, said Dr. Broderick.

Endovascular Therapy Provided More Effective Recanalization Than t-PA
The predicted advantage of combined therapy was that IV t-PA could be started quickly in the emergency department, while endovascular therapy, which requires time to mobilize the interventional team, would increase the likelihood of early recanalization.

The study results provided further evidence that endovascular therapy is more effective than IV t-PA at achieving recanalization. The rate of partial or complete recanalization at 24 hours for an occlusion in the internal carotid artery was 81% in patients who received combined therapy, compared with 35% in patients who received IV t-PA alone. The higher recanalization rate among patients who received endovascular therapy did not entail a clinical benefit, however. This result may have occurred because recanalization occurred too late—after ischemia had turned into infarction, explained Dr. Broderick.

“IMS 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,” said Brian Silver, MD, Director of the Stroke Center at Brown University in Providence, Rhode Island, who was not involved in the trial.

“The most critical feature is to treat the patients as soon as possible when they arrive in the emergency department, perhaps within 90 minutes. That’s the best chance for recovery,” said Dr. Silver in an interview. “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,” he added.

The results of IMS III may not change neurologists’ clinical practice. “IMS III is by no means the final word on combined therapy,” said Thomas A. Tomsick, MD, in an interview. “In Cincinnati tomorrow, if a patient with a large NIHSS score shows up, and we’re treating him with IV t-PA at two 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,” he added. Dr. Tomsick is a Professor of Radiology at the University of Cincinnati.

Five endovascular devices were used in IMS III. As new devices were adopted in clinical practice, investigators allowed them to be used in the trial to keep it clinically relevant. But recruitment for the study was slow, because experience already had convinced many clinicians that combined therapy is better than t-PA alone. As a result, the endovascular therapies used most frequently in IMS III were not the devices most widely used in clinical practice today. Major new randomized trials that compare combined therapy using state-of-the-art, more effective stent clot retriever devices to IV t-PA alone are now under way, added Dr. Tomsick.

The Future of Endovascular Therapy
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,” noted Dr. Broderick in the New England Journal of Medicine.

No matter how future trials of combined therapy turn out, endovascular therapy is not going away because some patients are not eligible to receive t-PA, Dr. Broderick observed. “Roughly 5% of patients who undergo coronary artery bypass surgery have a stroke. If you have somebody with a big stroke two days after having his or her chest cracked, you can’t use t-PA. In that case, those endovascular devices are the way we can get up in there and get rid of the clot,” he explained.

The clinical implications of IMS III are that endovascular therapy remains unproven and IV t-PA should remain the first-line treatment for patients with acute ischemic stroke within 4.5 hours after stroke onset, said Marc I. Chimowitz, MD, in an editorial published online in the February 8

Although new clinical trials of more effective IV clot busters, such as tenecteplase, and next-generation endovascular devices are urgently needed to improve stroke outcomes, patient recruitment is likely to remain a challenge. This obstacle could be overcome if Medicare placed a moratorium on reimbursement for endovascular therapy of acute ischemic stroke, except as part of a randomized trial, according to Dr. Chimowitz, who is a Professor of Neurology at the Medical University of South Carolina in Charleston.

HONOLULU—Functional and safety outcomes were not significantly different between patients with acute ischemic stroke treated with IV t-PA and those treated with IV t-PA and endovascular therapy, said investigators at the 2013 International Stroke Conference.

In the Interventional Management of Stroke (IMS) III study, 40.8% of patients randomized to receive endovascular therapy plus IV t-PA had a modified Rankin Scale (mRS) score of 2 or lower at 90 days, compared with 38.7% of patients who received IV t-PA alone, said Joseph Broderick, MD, Chair of the Department of Neurology at the University of Cincinnati and lead investigator of IMS III. The difference between the groups was not statistically significant. Mortality and other safety outcomes also were not significantly different between the two groups of patients in the study, which was halted early because of futility after 656 of the planned 900 patients had been randomized. The study was published online ahead of print on February 7 in the New England Journal of Medicine.

Comparing Two Reperfusion Therapies
Because of the lack of randomized clinical trial data, it was uncertain whether endovascular therapy, including endovascular pharmacologic thrombolysis and stent retrievers, alone or combined with IV t-PA is a more effective treatment for acute stroke than IV t-PA alone, “the only proven reperfusion therapy for acute ischemic stroke,” said Dr. Broderick.

In the IMS III study, which was conducted at 58 centers in the United States, Canada, Australia, and Europe, 434 patients were randomized to endovascular therapy plus IV t-PA, and 222 were randomized to standard treatment with IV t-PA alone. Treatment began within three hours of stroke onset. Patients’ median age was approximately 68 (range, 23 to 89). More than half of patients were men, approximately 14% were black or Hispanic, and the median NIH Stroke Scale (NIHSS) score was 17. At the beginning of the study, only one thrombectomy device had been approved by the FDA. As the trial continued, the researchers used other devices as they were approved.

Time to Endovascular Therapy Did Not Affect Outcomes
The investigators observed no differences in the primary outcome (ie, mRS of 2 or less at 90 days) between patients with an NIHSS score of 20 or greater and patients with an NIHSS score of 19 or less. The neurologists had hypothesized that endovascular therapy would have greater efficacy in patients with severe strokes, because these patients “have the highest likelihood of occlusion in a major intracranial artery and the greatest volume of ischemic brain at risk.”

The researchers also had hypothesized that receiving endovascular therapy earlier rather than later would be associated with a greater benefit. Time of endovascular therapy was not a significant factor in outcomes, however.

Mortality at 90 days was 19.1% in the endovascular therapy group and 21.6% in the IV t-PA–alone group. Within 30 hours of t-PA initiation, 6.2% of subjects who received endovascular therapy and 5.9% of subjects who received t-PA alone had a symptomatic intracerebral hemorrhage. The differences in mortality at seven days and in the parenchymal hematoma rate also were not significantly different between the two groups. The rate of asymptomatic intracerebral hemorrhage, however, was significantly higher in the endovascular group.

Outcomes of combined therapy tended to be better in patients with strokes that involved larger artery occlusions and in patients with the shortest times from stroke onset to initiation of treatment. Because of the small patient population, however, the differences did not achieve statistical significance. These subgroups should be the focus of future clinical trials, said Dr. Broderick.

Endovascular Therapy Provided More Effective Recanalization Than t-PA
The predicted advantage of combined therapy was that IV t-PA could be started quickly in the emergency department, while endovascular therapy, which requires time to mobilize the interventional team, would increase the likelihood of early recanalization.

The study results provided further evidence that endovascular therapy is more effective than IV t-PA at achieving recanalization. The rate of partial or complete recanalization at 24 hours for an occlusion in the internal carotid artery was 81% in patients who received combined therapy, compared with 35% in patients who received IV t-PA alone. The higher recanalization rate among patients who received endovascular therapy did not entail a clinical benefit, however. This result may have occurred because recanalization occurred too late—after ischemia had turned into infarction, explained Dr. Broderick.

“IMS 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,” said Brian Silver, MD, Director of the Stroke Center at Brown University in Providence, Rhode Island, who was not involved in the trial.

“The most critical feature is to treat the patients as soon as possible when they arrive in the emergency department, perhaps within 90 minutes. That’s the best chance for recovery,” said Dr. Silver in an interview. “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,” he added.

The results of IMS III may not change neurologists’ clinical practice. “IMS III is by no means the final word on combined therapy,” said Thomas A. Tomsick, MD, in an interview. “In Cincinnati tomorrow, if a patient with a large NIHSS score shows up, and we’re treating him with IV t-PA at two 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,” he added. Dr. Tomsick is a Professor of Radiology at the University of Cincinnati.

Five endovascular devices were used in IMS III. As new devices were adopted in clinical practice, investigators allowed them to be used in the trial to keep it clinically relevant. But recruitment for the study was slow, because experience already had convinced many clinicians that combined therapy is better than t-PA alone. As a result, the endovascular therapies used most frequently in IMS III were not the devices most widely used in clinical practice today. Major new randomized trials that compare combined therapy using state-of-the-art, more effective stent clot retriever devices to IV t-PA alone are now under way, added Dr. Tomsick.

The Future of Endovascular Therapy
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,” noted Dr. Broderick in the New England Journal of Medicine.

No matter how future trials of combined therapy turn out, endovascular therapy is not going away because some patients are not eligible to receive t-PA, Dr. Broderick observed. “Roughly 5% of patients who undergo coronary artery bypass surgery have a stroke. If you have somebody with a big stroke two days after having his or her chest cracked, you can’t use t-PA. In that case, those endovascular devices are the way we can get up in there and get rid of the clot,” he explained.

The clinical implications of IMS III are that endovascular therapy remains unproven and IV t-PA should remain the first-line treatment for patients with acute ischemic stroke within 4.5 hours after stroke onset, said Marc I. Chimowitz, MD, in an editorial published online in the February 8

Although new clinical trials of more effective IV clot busters, such as tenecteplase, and next-generation endovascular devices are urgently needed to improve stroke outcomes, patient recruitment is likely to remain a challenge. This obstacle could be overcome if Medicare placed a moratorium on reimbursement for endovascular therapy of acute ischemic stroke, except as part of a randomized trial, according to Dr. Chimowitz, who is a Professor of Neurology at the Medical University of South Carolina in Charleston.