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While findings from the DAWN and DEFUSE3 trials support late thrombectomy, rapid intervention remains the preferred goal.
HILTON HEAD, SC—Although two recent studies demonstrated that endovascular thrombectomy is effective up to 24 hours after acute stroke onset in patients with large vessel occlusions, the findings do not diminish the urgency of rapid intervention. According to one expert who spoke at the 41st Annual Contemporary Clinical Neurology Symposium, findings from studies of late thrombectomy are important to the management of only a small group of acute stroke patients and do nothing to alter the premise that time is brain. For better outcomes, “we need to get more patients into therapy more quickly. If we optimize our systems of care, we can achieve that,” said Michael Froehler, MD, PhD, Director of the Cerebrovascular Program at Vanderbilt University Medical Center in Nashville. 
Two Trials of Late Thrombectomy
In an analysis of the significance of these two studies as well as of other advances in stroke management, Dr. Froehler explained that rapid intervention is always the goal. The data from these multicenter trials, DAWN and DEFUSE3, were published earlier this year. Both randomized studies compared
The primary end points of the two trials differed, but the advantage of endovascular thrombectomy was comparable at 90 days when examining a modified Rankin score (mRS). A good outcome, defined as an mRS of 2 or less, was achieved with late endovascular thrombectomy in 49% and 45% of patients in DAWN and DEFUSE3, respectively, versus 13% and 17% of those treated with standard care. According to Dr. Froehler, these results were a surprise, because the effect size was greater in these two late treatment trials when compared with that of early endovascular thrombectomy (46% vs 27%) in a five-trial meta-analysis by Goyal et al published in 2016.
Entry criteria of these late endovascular thrombectomy trials are critical for understanding the results and their clinical significance, according to Dr. Froehler. He explained that both DAWN and DEFUSE3 were designed to enroll patients with salvageable tissue. Selection criteria such as a small infarct volume on imaging assessed with RAPID software ensured a “good collateral” patient population, Dr. Froehler said. Unlike the majority of patients with rapidly advancing infarcts, “good collateral patients hang on to salvageable brain for much longer,” Dr. Froehler explained.
The results of DAWN and DEFUSE3 thus are relevant to a small subpopulation of stroke patients. According to Dr. Froehler, only about 3% of acute stroke patients would meet entry criteria for DAWN or DEFUSE3, and only about 1.1% would meet the criteria for both.
“Unfortunately, the vast majority of patients we are seeing in real life are not going to be eligible for thrombectomy in the six- to 24-hour window,” Dr. Froehler emphasized. As a result, the data from DAWN and DEFUSE3, “do not change the importance of time” as the key factor in achieving good outcomes in patients with acute stroke.
Time Is Still Brain
The standard of care for management of acute stroke is IV t-PA within 4.5 hours, whether or not endovascular thrombectomy is offered, according to Dr. Froehler, but he cited data from the SWIFT PRIME trial, which employed endovascular thrombectomy after t-PA, to emphasize that the earlier the treatment, the better the outcome. In SWIFT PRIME, which was stopped early because of efficacy, the greater overall rate of good outcome (mRS ≤ 2) in the endovascular thrombectomy/t-PA versus t-PA alone groups were impressive (60% vs 35%), but time mattered. “Of those treated within 2.5 hours, 91% went home essentially normal,” according to Dr. Froehler.
Returning to his message that early reperfusion is the critical predictor of a good outcome, Dr. Froehler noted that an estimated 1.9 million neurons die for every minute of ischemia. In one analysis he cited, good outcomes dropped by 10% between 2.5 and 3.5 hours and then 20% for every hour thereafter.
One approach to accelerating time to appropriate therapy is optimizing triage strategies, particularly when patients who will benefit from endovascular thrombectomy will require transfer to a center that offers this intervention. Of triage strategies, Dr. Froehler singled out the 10-point ASPECTS scoring system, which is based on a CT scan. If the score is low, endovascular thrombectomy is not an option. Higher scores, particularly 6 or greater, can be a reason to consider and accelerate the time to transfer, which may mean the difference for a full recovery.
Reevaluating t-PA
“When you look at what t-PA has done for patients with large vessel occlusion, it is noteworthy, but it is not that great,” cautioned Dr. Froehler in making a case for endovascular thrombectomy in eligible patients. He called recanalization rates with IV t-PA in those with the largest clots “pretty low,” showing that the majority of patients achieve either partial or no recanalization with this treatment alone.
In fact, the therapeutic margin is “rather narrow” for t-PA overall, according to Dr. Froehler, citing data from 12 trials with alteplase. He noted that a review of the original publications reveals that only two of the investigating teams characterized their results as positive. Although almost all the others discussed risk-to-benefit ratios without labeling the findings positive or negative, he believes clinician should be aware of the limitations of these data.
For the newer thrombolytic tenecteplase, which was included as an alternative to alteplase in the most recent American Heart Association/American Stroke Association guidelines, Dr. Froehler said the evidence is even more limited, particularly regarding the optimal dose. In the recently published guidelines, the recommended dose was 0.4 mg/kg , even though this dose has been associated with intracranial hemorrhage in at least one clinical study. Lower doses such as 0.25 mg/kg may be a safer alternative, but Dr. Froehler recommended caution. “I do not think there is evidence that we should be transitioning to tenecteplase now,” he said, concluding that more data regarding the most appropriate dose are needed.
Patients with acute stroke can anticipate a favorable outcome with current therapies, but the urgency of reperfusion remains unchanged despite advances. Dr. Froehler concluded, “We must now work toward optimizing stroke systems of care for endovascular thrombectomy” to increase the proportion of patients who benefit.
Dr. Froehler disclosed financial relationships with Balt USA, Control Medical, EndoPhys, Genentech, Medtronic, Microvention, NeurVana, Penumbra, Stryker, and Viz.ai.
Suggested Reading
Albers GW, Marks MP, Kemp S, et al. Thrombectomy for stroke at 6 to 16 hours with selection by perfusion imaging. N Engl J Med. 2018;378(8):708-718.
Goyal M, Menon BK, van Zwam WH, et al. Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials. Lancet. 2016;387(10029):1723-1731.
Nogueira RG, Jadhav AP, Haussen DC, et al. Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct. N Engl J Med. 2018;378(1):11-21.
Powers WJ, Rabinstein AA, Ackerson T, et al. 2018 Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2018;49(3):e46-e110.
Saver JL, Goyal M, Bonafe A, et al. Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke. N Engl J Med. 2015;372(24):2285-2295.
While findings from the DAWN and DEFUSE3 trials support late thrombectomy, rapid intervention remains the preferred goal.
While findings from the DAWN and DEFUSE3 trials support late thrombectomy, rapid intervention remains the preferred goal.
HILTON HEAD, SC—Although two recent studies demonstrated that endovascular thrombectomy is effective up to 24 hours after acute stroke onset in patients with large vessel occlusions, the findings do not diminish the urgency of rapid intervention. According to one expert who spoke at the 41st Annual Contemporary Clinical Neurology Symposium, findings from studies of late thrombectomy are important to the management of only a small group of acute stroke patients and do nothing to alter the premise that time is brain. For better outcomes, “we need to get more patients into therapy more quickly. If we optimize our systems of care, we can achieve that,” said Michael Froehler, MD, PhD, Director of the Cerebrovascular Program at Vanderbilt University Medical Center in Nashville.
Two Trials of Late Thrombectomy
In an analysis of the significance of these two studies as well as of other advances in stroke management, Dr. Froehler explained that rapid intervention is always the goal. The data from these multicenter trials, DAWN and DEFUSE3, were published earlier this year. Both randomized studies compared
The primary end points of the two trials differed, but the advantage of endovascular thrombectomy was comparable at 90 days when examining a modified Rankin score (mRS). A good outcome, defined as an mRS of 2 or less, was achieved with late endovascular thrombectomy in 49% and 45% of patients in DAWN and DEFUSE3, respectively, versus 13% and 17% of those treated with standard care. According to Dr. Froehler, these results were a surprise, because the effect size was greater in these two late treatment trials when compared with that of early endovascular thrombectomy (46% vs 27%) in a five-trial meta-analysis by Goyal et al published in 2016.
Entry criteria of these late endovascular thrombectomy trials are critical for understanding the results and their clinical significance, according to Dr. Froehler. He explained that both DAWN and DEFUSE3 were designed to enroll patients with salvageable tissue. Selection criteria such as a small infarct volume on imaging assessed with RAPID software ensured a “good collateral” patient population, Dr. Froehler said. Unlike the majority of patients with rapidly advancing infarcts, “good collateral patients hang on to salvageable brain for much longer,” Dr. Froehler explained.
The results of DAWN and DEFUSE3 thus are relevant to a small subpopulation of stroke patients. According to Dr. Froehler, only about 3% of acute stroke patients would meet entry criteria for DAWN or DEFUSE3, and only about 1.1% would meet the criteria for both.
“Unfortunately, the vast majority of patients we are seeing in real life are not going to be eligible for thrombectomy in the six- to 24-hour window,” Dr. Froehler emphasized. As a result, the data from DAWN and DEFUSE3, “do not change the importance of time” as the key factor in achieving good outcomes in patients with acute stroke.
Time Is Still Brain
The standard of care for management of acute stroke is IV t-PA within 4.5 hours, whether or not endovascular thrombectomy is offered, according to Dr. Froehler, but he cited data from the SWIFT PRIME trial, which employed endovascular thrombectomy after t-PA, to emphasize that the earlier the treatment, the better the outcome. In SWIFT PRIME, which was stopped early because of efficacy, the greater overall rate of good outcome (mRS ≤ 2) in the endovascular thrombectomy/t-PA versus t-PA alone groups were impressive (60% vs 35%), but time mattered. “Of those treated within 2.5 hours, 91% went home essentially normal,” according to Dr. Froehler.
Returning to his message that early reperfusion is the critical predictor of a good outcome, Dr. Froehler noted that an estimated 1.9 million neurons die for every minute of ischemia. In one analysis he cited, good outcomes dropped by 10% between 2.5 and 3.5 hours and then 20% for every hour thereafter.
One approach to accelerating time to appropriate therapy is optimizing triage strategies, particularly when patients who will benefit from endovascular thrombectomy will require transfer to a center that offers this intervention. Of triage strategies, Dr. Froehler singled out the 10-point ASPECTS scoring system, which is based on a CT scan. If the score is low, endovascular thrombectomy is not an option. Higher scores, particularly 6 or greater, can be a reason to consider and accelerate the time to transfer, which may mean the difference for a full recovery.
Reevaluating t-PA
“When you look at what t-PA has done for patients with large vessel occlusion, it is noteworthy, but it is not that great,” cautioned Dr. Froehler in making a case for endovascular thrombectomy in eligible patients. He called recanalization rates with IV t-PA in those with the largest clots “pretty low,” showing that the majority of patients achieve either partial or no recanalization with this treatment alone.
In fact, the therapeutic margin is “rather narrow” for t-PA overall, according to Dr. Froehler, citing data from 12 trials with alteplase. He noted that a review of the original publications reveals that only two of the investigating teams characterized their results as positive. Although almost all the others discussed risk-to-benefit ratios without labeling the findings positive or negative, he believes clinician should be aware of the limitations of these data.
For the newer thrombolytic tenecteplase, which was included as an alternative to alteplase in the most recent American Heart Association/American Stroke Association guidelines, Dr. Froehler said the evidence is even more limited, particularly regarding the optimal dose. In the recently published guidelines, the recommended dose was 0.4 mg/kg , even though this dose has been associated with intracranial hemorrhage in at least one clinical study. Lower doses such as 0.25 mg/kg may be a safer alternative, but Dr. Froehler recommended caution. “I do not think there is evidence that we should be transitioning to tenecteplase now,” he said, concluding that more data regarding the most appropriate dose are needed.
Patients with acute stroke can anticipate a favorable outcome with current therapies, but the urgency of reperfusion remains unchanged despite advances. Dr. Froehler concluded, “We must now work toward optimizing stroke systems of care for endovascular thrombectomy” to increase the proportion of patients who benefit.
Dr. Froehler disclosed financial relationships with Balt USA, Control Medical, EndoPhys, Genentech, Medtronic, Microvention, NeurVana, Penumbra, Stryker, and Viz.ai.
Suggested Reading
Albers GW, Marks MP, Kemp S, et al. Thrombectomy for stroke at 6 to 16 hours with selection by perfusion imaging. N Engl J Med. 2018;378(8):708-718.
Goyal M, Menon BK, van Zwam WH, et al. Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials. Lancet. 2016;387(10029):1723-1731.
Nogueira RG, Jadhav AP, Haussen DC, et al. Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct. N Engl J Med. 2018;378(1):11-21.
Powers WJ, Rabinstein AA, Ackerson T, et al. 2018 Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2018;49(3):e46-e110.
Saver JL, Goyal M, Bonafe A, et al. Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke. N Engl J Med. 2015;372(24):2285-2295.
HILTON HEAD, SC—Although two recent studies demonstrated that endovascular thrombectomy is effective up to 24 hours after acute stroke onset in patients with large vessel occlusions, the findings do not diminish the urgency of rapid intervention. According to one expert who spoke at the 41st Annual Contemporary Clinical Neurology Symposium, findings from studies of late thrombectomy are important to the management of only a small group of acute stroke patients and do nothing to alter the premise that time is brain. For better outcomes, “we need to get more patients into therapy more quickly. If we optimize our systems of care, we can achieve that,” said Michael Froehler, MD, PhD, Director of the Cerebrovascular Program at Vanderbilt University Medical Center in Nashville.
Two Trials of Late Thrombectomy
In an analysis of the significance of these two studies as well as of other advances in stroke management, Dr. Froehler explained that rapid intervention is always the goal. The data from these multicenter trials, DAWN and DEFUSE3, were published earlier this year. Both randomized studies compared
The primary end points of the two trials differed, but the advantage of endovascular thrombectomy was comparable at 90 days when examining a modified Rankin score (mRS). A good outcome, defined as an mRS of 2 or less, was achieved with late endovascular thrombectomy in 49% and 45% of patients in DAWN and DEFUSE3, respectively, versus 13% and 17% of those treated with standard care. According to Dr. Froehler, these results were a surprise, because the effect size was greater in these two late treatment trials when compared with that of early endovascular thrombectomy (46% vs 27%) in a five-trial meta-analysis by Goyal et al published in 2016.
Entry criteria of these late endovascular thrombectomy trials are critical for understanding the results and their clinical significance, according to Dr. Froehler. He explained that both DAWN and DEFUSE3 were designed to enroll patients with salvageable tissue. Selection criteria such as a small infarct volume on imaging assessed with RAPID software ensured a “good collateral” patient population, Dr. Froehler said. Unlike the majority of patients with rapidly advancing infarcts, “good collateral patients hang on to salvageable brain for much longer,” Dr. Froehler explained.
The results of DAWN and DEFUSE3 thus are relevant to a small subpopulation of stroke patients. According to Dr. Froehler, only about 3% of acute stroke patients would meet entry criteria for DAWN or DEFUSE3, and only about 1.1% would meet the criteria for both.
“Unfortunately, the vast majority of patients we are seeing in real life are not going to be eligible for thrombectomy in the six- to 24-hour window,” Dr. Froehler emphasized. As a result, the data from DAWN and DEFUSE3, “do not change the importance of time” as the key factor in achieving good outcomes in patients with acute stroke.
Time Is Still Brain
The standard of care for management of acute stroke is IV t-PA within 4.5 hours, whether or not endovascular thrombectomy is offered, according to Dr. Froehler, but he cited data from the SWIFT PRIME trial, which employed endovascular thrombectomy after t-PA, to emphasize that the earlier the treatment, the better the outcome. In SWIFT PRIME, which was stopped early because of efficacy, the greater overall rate of good outcome (mRS ≤ 2) in the endovascular thrombectomy/t-PA versus t-PA alone groups were impressive (60% vs 35%), but time mattered. “Of those treated within 2.5 hours, 91% went home essentially normal,” according to Dr. Froehler.
Returning to his message that early reperfusion is the critical predictor of a good outcome, Dr. Froehler noted that an estimated 1.9 million neurons die for every minute of ischemia. In one analysis he cited, good outcomes dropped by 10% between 2.5 and 3.5 hours and then 20% for every hour thereafter.
One approach to accelerating time to appropriate therapy is optimizing triage strategies, particularly when patients who will benefit from endovascular thrombectomy will require transfer to a center that offers this intervention. Of triage strategies, Dr. Froehler singled out the 10-point ASPECTS scoring system, which is based on a CT scan. If the score is low, endovascular thrombectomy is not an option. Higher scores, particularly 6 or greater, can be a reason to consider and accelerate the time to transfer, which may mean the difference for a full recovery.
Reevaluating t-PA
“When you look at what t-PA has done for patients with large vessel occlusion, it is noteworthy, but it is not that great,” cautioned Dr. Froehler in making a case for endovascular thrombectomy in eligible patients. He called recanalization rates with IV t-PA in those with the largest clots “pretty low,” showing that the majority of patients achieve either partial or no recanalization with this treatment alone.
In fact, the therapeutic margin is “rather narrow” for t-PA overall, according to Dr. Froehler, citing data from 12 trials with alteplase. He noted that a review of the original publications reveals that only two of the investigating teams characterized their results as positive. Although almost all the others discussed risk-to-benefit ratios without labeling the findings positive or negative, he believes clinician should be aware of the limitations of these data.
For the newer thrombolytic tenecteplase, which was included as an alternative to alteplase in the most recent American Heart Association/American Stroke Association guidelines, Dr. Froehler said the evidence is even more limited, particularly regarding the optimal dose. In the recently published guidelines, the recommended dose was 0.4 mg/kg , even though this dose has been associated with intracranial hemorrhage in at least one clinical study. Lower doses such as 0.25 mg/kg may be a safer alternative, but Dr. Froehler recommended caution. “I do not think there is evidence that we should be transitioning to tenecteplase now,” he said, concluding that more data regarding the most appropriate dose are needed.
Patients with acute stroke can anticipate a favorable outcome with current therapies, but the urgency of reperfusion remains unchanged despite advances. Dr. Froehler concluded, “We must now work toward optimizing stroke systems of care for endovascular thrombectomy” to increase the proportion of patients who benefit.
Dr. Froehler disclosed financial relationships with Balt USA, Control Medical, EndoPhys, Genentech, Medtronic, Microvention, NeurVana, Penumbra, Stryker, and Viz.ai.
Suggested Reading
Albers GW, Marks MP, Kemp S, et al. Thrombectomy for stroke at 6 to 16 hours with selection by perfusion imaging. N Engl J Med. 2018;378(8):708-718.
Goyal M, Menon BK, van Zwam WH, et al. Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials. Lancet. 2016;387(10029):1723-1731.
Nogueira RG, Jadhav AP, Haussen DC, et al. Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct. N Engl J Med. 2018;378(1):11-21.
Powers WJ, Rabinstein AA, Ackerson T, et al. 2018 Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2018;49(3):e46-e110.
Saver JL, Goyal M, Bonafe A, et al. Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke. N Engl J Med. 2015;372(24):2285-2295.