Endovascular Therapy for Acute Ischemic Stroke: Time to Enter a New Era in Stroke Management Tareq Kass-Hout1, Krishna Amuluru1, Yazan Al-Derazi1, Paul Singh1-3, Charles J. Prestigiacomo1-3, Chirag D. Gandhi1-3
Endovascular thrombectomy in acute ischemic stroke (AIS) generated significant controversy regarding its role in achieving good clinical outcome. This was especially palpable as of February 2013 when 3 prospective randomized controlled trials (Interventional Management of Stroke [IMS III] (Ref 2), Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy [MR RESCUE] (Ref 6), and SYNTHESIS-Expansion (Ref 4)) were presented in the International Stroke Conference and simultaneously published in the New England Journal of Medicine —. None of these trials were able to demonstrate clinical outcome benefit of endovascular therapy versus medical management, which was the standard of care in AIS. Despite the significant design flaws in all of these trials (which was mostly due to slow patient enrollment, slow endovascular therapy delivery, older thrombectomy devices, and poor target lesion selection), the results of these trials had a significant effect on triaging and referral pattern of patients with emergent large vessel occlusion (ELVO) acute ischemic stroke. This motivated stroke investigators around the globe to conduct trials with improved design parameters to avoid the shortcomings reported in the preceding trials. Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) (1) was the first prospective randomized controlled trial to prove superiority of endovascular intervention to medical therapy in ELVO strokes. This trial was conducted in 16 centers in the Netherlands, included 500 patients, and compared endovascular therapies with medical management for patients with ELVO (233 assigned to intra-arterial [IA] treatment and 267 to usual care alone). Most patients in both groups received intravenous tissue plasminogen activator (IV tPA) (intervention arm, 87.1%; control arm, 90.6%) with similar reported times to treatment (intervention arm, 85 minutes; control arm, 87 minutes). Time to groin puncture in the intervention arm was 260 minutes. The mean age of treated patients was 65 years (range, 23e96 years), and newest stent-retriever technology was used in 190 of the 233 patients (81.5%) assigned to IA therapy. General demographics were similar between the 2 groups, with a median National Institutes of Health Stroke Scale score of 17 in the intervention group and 18 in the control group; 25.7% of the patients in the intervention group
WORLD NEUROSURGERY - [-]: ---, - 2015
had internal carotid artery occlusions compared with 29.3% in the control arm. Overall, in assessment of the primary outcome, there was an odds ratio of 1.67 (95% confidence interval 1.212.30) of better outcome as assessed by modified Rankin scale (mRs) 0e2 at 90 days in the intervention arm. There was also a shift in the distribution of the score of the mRs at 90 days in favor of the endovascular therapy. The shift toward better outcome in favor of endovascular therapy was consistent for all categories of the mRS, except for death. An absolute difference of 13.5 percentage points (95% confidence interval, 5.9e21.2) in the rate of functional independence (measured by mRS 0e2) in favor of endovascular therapy (32.6% vs. 19.1%) was found without a significant difference in the mortality rate between the 2 groups. Excellent recanalization rate measured as a Thrombolysis In Cerebral Ischemia 2b/3 was achieved in 58.7% of the intervention group. Likewise, absence of residual occlusion at 24 hours after therapy was achieved in 75% of the intervention group versus 33% in the medical group. Final infarct volume (49 mL in the intervention group vs. 79 mL in the medical group) was also significantly lower in the interventional arm. This clinical benefit persisted throughout all age groups and all predefined subgroups, except for patients presenting with a pretreatment Alberta Stroke Program Early Computed Tomography Score of 0e4, which is indicative of a large core infarction at presentation. MR CLEAN (4), which focused on assessing safety of interventional therapies, demonstrated a low procedure-related complication rate including vessel perforation (0.9%), embolization in a new territory (8.6%), and vessel dissection (1.7%). Mortality rate at 30 days (interventional group 18.9% vs. medical group 18.4%) was similar between the 2 groups and this was persistent at 90 days. Similarly, symptomatic intracranial hemorrhage, defined as neurological deterioration (an increase of 4 points in the score on the National Institutes of Health Stroke Scale) and evidence of intracranial hemorrhage on imaging studies, was not significantly different between the 2 arms (interventional group 7.7% vs. medical group 6.4%). Despite a modest Thrombolysis In Cerebral Ischemia 2b/3 recanalization rate achieved in the endovascular arm in MR CLEAN (4), the trial showed consistent clinical benefit of IA therapy versus medical management. The differences in results
www.WORLDNEUROSURGERY.org
1
when compared to prior negative trials can be partially explained by better patient selection with pretreatment vessel imaging confirming ELVO. After the positive results from MR CLEAN (4), 2 other trials evaluating endovascular interventions— Endovascular Treatment for Small Core and Proximal Occlusion Ischemic Stroke (ESCAPE) (5) and Extending the Time for Thrombolysis in Emergency Neurological DeficitseIntra-Arterial (EXTEND IA) (3)—have been stopped after early interim analyses showed benefit in the intervention group. Both ESCAPE (5) and EXTEND IA (6) trials were presented in the International Stroke Conference in 2015 and were simultaneously published in the New England Journal of Medicine. In light of the preliminary reports of these 3 positive endovascular recanalization trials, the data safety monitoring committee of the Solitaire FR as Primary Treatment for Acute Ischemic Stroke (SWIFT PRIME) study,
REFERENCES 1. Berkhemer OA, Fransen PS, Beumer D, van den Berg LA, Lingsma HF, Yoo AJ, Schonewille WJ, Vos JA, Nederkoorn PJ, Wermer MJ, van Walderveen MA, Staals J, Hofmeijer J, van Oostayen JA, Lycklama à Nijeholt GJ, Boiten J, Brouwer PA, Emmer BJ, de Bruijn SF, van Dijk LC, Kappelle LJ, Lo RH, van Dijk EJ, de Vries J, de Kort PL, van Rooij WJ, van den Berg JS, van Hasselt BA, Aerden LA, Dallinga RJ, Visser MC, Bot JC, Vroomen PC, Eshghi O, Schreuder TH, Heijboer RJ, Keizer K, Tielbeek AV, den Hertog HM, Gerrits DG, van den Berg-Vos RM, Karas GB, Steyerberg EW, Flach HZ, Marquering HA, Sprengers ME, Jenniskens SF, Beenen LF, van den Berg R, Koudstaal PJ, van Zwam WH, Roos YB, van der Lugt A, van Oostenbrugge RJ, Majoie CB, Dippel DW; MR CLEAN Investigators: A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med 372:11-20, 2015. 2. Broderick JP, Palesch YY, Demchuk AM, Yeatts SD, Khatri P, Hill MD, Jauch EC, Jovin TG, Yan B, Silver FL, von Kummer R, Molina CA, Demaerschalk BM, Budzik R, Clark WM, Zaidat OO, Malisch TW, Goyal M, Schonewille WJ, Mazighi M, Engelter ST,
2
www.SCIENCEDIRECT.com
investigating a newer generation embolectomy technology, recommended a temporary halt in enrollment and the performance of an early interim analysis. Similar benefit of intervention was evident in the interim analysis of the SWIFT PRIME and was presented at the International Stroke Conference in 2015. The final results of the trial are to be published soon. The overwhelming positive results of all of these prospective trails confirm the superiority of endovascular therapy versus standard medical management and provide a Level 1, Class A evidence for such therapy in patients presenting with ELVO in the anterior circulation within 6 hours from the onset of symptoms. These new encouraging results in patients with AIS will require institutions to focus on optimizing rapid patient access to endovascular therapy.
Anderson C, Spilker J, Carrozzella J, Ryckborst KJ, Janis LS, Martin RH, Foster LD, Tomsick TA; Interventional Management of Stroke (IMS) III Investigators: Endovascular therapy after intravenous t-PA versus t-PA alone for stroke. N Engl J Med 368:893-903, 2013. 3. Campbell BC, Mitchell PJ, Kleinig TJ, Dewey HM, Churilov L, Yassi N, Yan B, Dowling RJ, Parsons MW, Oxley TJ, Wu TY, Brooks M, Simpson MA, Miteff F, Levi CR, Krause M, Harrington TJ, Faulder KC, Steinfort BS, Priglinger M, Ang T, Scroop R, Barber PA, McGuinness B, Wijeratne T, Phan TG, Chong W, Chandra RV, Bladin CF, Badve M, Rice H, de Villiers L, Ma H, Desmond PM, Donnan GA, Davis SM; EXTEND-IA Investigators: Endovascular therapy for ischemic stroke with perfusion-imaging selection. N Engl J Med 372:1009-1018, 2015. 4. Ciccone A, Valvassori L, Nichelatti M, Sgoifo A, Ponzio M, Sterzi R, Boccardi E; SYNTHESIS Expansion Investigators: Endovascular treatment for acute ischemic stroke. N Engl J Med 368: 904-913, 2013. 5. Goyal M, Demchuk AM, Menon BK, Eesa M, Rempel JL, Thornton J, Roy D, Jovin TG, Willinsky RA, Sapkota BL, Dowlatshahi D, Frei DF,
Kamal NR, Montanera WJ, Poppe AY, Ryckborst KJ, Silver FL, Shuaib A, Tampieri D, Williams D, Bang OY, Baxter BW, Burns PA, Choe H, Heo JH, Holmstedt CA, Jankowitz B, Kelly M, Linares G, Mandzia JL, Shankar J, Sohn SI, Swartz RH, Barber PA, Coutts SB, Smith EE, Morrish WF, Weill A, Subramaniam S, Mitha AP, Wong JH, Lowerison MW, Sajobi TT, Hill MD; ESCAPE Trial Investigators: Randomized assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med 372 (11):1019-1030, 2015. 6. Kidwell CS, Jahan R, Gornbein J, Alger JR, Nenov V, Ajani Z, Feng L, Meyer BC, Olson S, Schwamm LH, Yoo AJ, Marshall RS, Meyers PM, Yavagal DR, Wintermark M, Guzy J, Starkman S, Saver JL; MR RESCUE Investigators: A trial of imaging selection and endovascular treatment for ischemic stroke. N Engl J Med 368:914-923, 2014.
From the Departments of 1Neurosurgery, 2Neurology, and 3 Radiology, Rutgers UniversityeNJ Medical School, Newark, New Jersey, USA 1878-8750/$ - see front matter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.wneu.2015.03.043
- [-]: ---, - 2015
WORLD NEUROSURGERY
Endovascular thrombectomy in acute ischemic stroke (AIS) generated significant controversy regarding its role in achieving good clinical outcome. This was especially palpable as of February 2013 when 3 prospective randomized controlled trials (Interventional Management of Stroke [IMS III] (Ref 2), Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy [MR RESCUE] (Ref 6), and SYNTHESIS-Expansion (Ref 4)) were presented in the International Stroke Conference and simultaneously published in the New England Journal of Medicine —. None of these trials were able to demonstrate clinical outcome benefit of endovascular therapy versus medical management, which was the standard of care in AIS. Despite the significant design flaws in all of these trials (which was mostly due to slow patient enrollment, slow endovascular therapy delivery, older thrombectomy devices, and poor target lesion selection), the results of these trials had a significant effect on triaging and referral pattern of patients with emergent large vessel occlusion (ELVO) acute ischemic stroke. This motivated stroke investigators around the globe to conduct trials with improved design parameters to avoid the shortcomings reported in the preceding trials. Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) (1) was the first prospective randomized controlled trial to prove superiority of endovascular intervention to medical therapy in ELVO strokes. This trial was conducted in 16 centers in the Netherlands, included 500 patients, and compared endovascular therapies with medical management for patients with ELVO (233 assigned to intra-arterial [IA] treatment and 267 to usual care alone). Most patients in both groups received intravenous tissue plasminogen activator (IV tPA) (intervention arm, 87.1%; control arm, 90.6%) with similar reported times to treatment (intervention arm, 85 minutes; control arm, 87 minutes). Time to groin puncture in the intervention arm was 260 minutes. The mean age of treated patients was 65 years (range, 23e96 years), and newest stent-retriever technology was used in 190 of the 233 patients (81.5%) assigned to IA therapy. General demographics were similar between the 2 groups, with a median National Institutes of Health Stroke Scale score of 17 in the intervention group and 18 in the control group; 25.7% of the patients in the intervention group
WORLD NEUROSURGERY - [-]: ---, - 2015
had internal carotid artery occlusions compared with 29.3% in the control arm. Overall, in assessment of the primary outcome, there was an odds ratio of 1.67 (95% confidence interval 1.212.30) of better outcome as assessed by modified Rankin scale (mRs) 0e2 at 90 days in the intervention arm. There was also a shift in the distribution of the score of the mRs at 90 days in favor of the endovascular therapy. The shift toward better outcome in favor of endovascular therapy was consistent for all categories of the mRS, except for death. An absolute difference of 13.5 percentage points (95% confidence interval, 5.9e21.2) in the rate of functional independence (measured by mRS 0e2) in favor of endovascular therapy (32.6% vs. 19.1%) was found without a significant difference in the mortality rate between the 2 groups. Excellent recanalization rate measured as a Thrombolysis In Cerebral Ischemia 2b/3 was achieved in 58.7% of the intervention group. Likewise, absence of residual occlusion at 24 hours after therapy was achieved in 75% of the intervention group versus 33% in the medical group. Final infarct volume (49 mL in the intervention group vs. 79 mL in the medical group) was also significantly lower in the interventional arm. This clinical benefit persisted throughout all age groups and all predefined subgroups, except for patients presenting with a pretreatment Alberta Stroke Program Early Computed Tomography Score of 0e4, which is indicative of a large core infarction at presentation. MR CLEAN (4), which focused on assessing safety of interventional therapies, demonstrated a low procedure-related complication rate including vessel perforation (0.9%), embolization in a new territory (8.6%), and vessel dissection (1.7%). Mortality rate at 30 days (interventional group 18.9% vs. medical group 18.4%) was similar between the 2 groups and this was persistent at 90 days. Similarly, symptomatic intracranial hemorrhage, defined as neurological deterioration (an increase of 4 points in the score on the National Institutes of Health Stroke Scale) and evidence of intracranial hemorrhage on imaging studies, was not significantly different between the 2 arms (interventional group 7.7% vs. medical group 6.4%). Despite a modest Thrombolysis In Cerebral Ischemia 2b/3 recanalization rate achieved in the endovascular arm in MR CLEAN (4), the trial showed consistent clinical benefit of IA therapy versus medical management. The differences in results
www.WORLDNEUROSURGERY.org
1
when compared to prior negative trials can be partially explained by better patient selection with pretreatment vessel imaging confirming ELVO. After the positive results from MR CLEAN (4), 2 other trials evaluating endovascular interventions— Endovascular Treatment for Small Core and Proximal Occlusion Ischemic Stroke (ESCAPE) (5) and Extending the Time for Thrombolysis in Emergency Neurological DeficitseIntra-Arterial (EXTEND IA) (3)—have been stopped after early interim analyses showed benefit in the intervention group. Both ESCAPE (5) and EXTEND IA (6) trials were presented in the International Stroke Conference in 2015 and were simultaneously published in the New England Journal of Medicine. In light of the preliminary reports of these 3 positive endovascular recanalization trials, the data safety monitoring committee of the Solitaire FR as Primary Treatment for Acute Ischemic Stroke (SWIFT PRIME) study,
REFERENCES 1. Berkhemer OA, Fransen PS, Beumer D, van den Berg LA, Lingsma HF, Yoo AJ, Schonewille WJ, Vos JA, Nederkoorn PJ, Wermer MJ, van Walderveen MA, Staals J, Hofmeijer J, van Oostayen JA, Lycklama à Nijeholt GJ, Boiten J, Brouwer PA, Emmer BJ, de Bruijn SF, van Dijk LC, Kappelle LJ, Lo RH, van Dijk EJ, de Vries J, de Kort PL, van Rooij WJ, van den Berg JS, van Hasselt BA, Aerden LA, Dallinga RJ, Visser MC, Bot JC, Vroomen PC, Eshghi O, Schreuder TH, Heijboer RJ, Keizer K, Tielbeek AV, den Hertog HM, Gerrits DG, van den Berg-Vos RM, Karas GB, Steyerberg EW, Flach HZ, Marquering HA, Sprengers ME, Jenniskens SF, Beenen LF, van den Berg R, Koudstaal PJ, van Zwam WH, Roos YB, van der Lugt A, van Oostenbrugge RJ, Majoie CB, Dippel DW; MR CLEAN Investigators: A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med 372:11-20, 2015. 2. Broderick JP, Palesch YY, Demchuk AM, Yeatts SD, Khatri P, Hill MD, Jauch EC, Jovin TG, Yan B, Silver FL, von Kummer R, Molina CA, Demaerschalk BM, Budzik R, Clark WM, Zaidat OO, Malisch TW, Goyal M, Schonewille WJ, Mazighi M, Engelter ST,
2
www.SCIENCEDIRECT.com
investigating a newer generation embolectomy technology, recommended a temporary halt in enrollment and the performance of an early interim analysis. Similar benefit of intervention was evident in the interim analysis of the SWIFT PRIME and was presented at the International Stroke Conference in 2015. The final results of the trial are to be published soon. The overwhelming positive results of all of these prospective trails confirm the superiority of endovascular therapy versus standard medical management and provide a Level 1, Class A evidence for such therapy in patients presenting with ELVO in the anterior circulation within 6 hours from the onset of symptoms. These new encouraging results in patients with AIS will require institutions to focus on optimizing rapid patient access to endovascular therapy.
Anderson C, Spilker J, Carrozzella J, Ryckborst KJ, Janis LS, Martin RH, Foster LD, Tomsick TA; Interventional Management of Stroke (IMS) III Investigators: Endovascular therapy after intravenous t-PA versus t-PA alone for stroke. N Engl J Med 368:893-903, 2013. 3. Campbell BC, Mitchell PJ, Kleinig TJ, Dewey HM, Churilov L, Yassi N, Yan B, Dowling RJ, Parsons MW, Oxley TJ, Wu TY, Brooks M, Simpson MA, Miteff F, Levi CR, Krause M, Harrington TJ, Faulder KC, Steinfort BS, Priglinger M, Ang T, Scroop R, Barber PA, McGuinness B, Wijeratne T, Phan TG, Chong W, Chandra RV, Bladin CF, Badve M, Rice H, de Villiers L, Ma H, Desmond PM, Donnan GA, Davis SM; EXTEND-IA Investigators: Endovascular therapy for ischemic stroke with perfusion-imaging selection. N Engl J Med 372:1009-1018, 2015. 4. Ciccone A, Valvassori L, Nichelatti M, Sgoifo A, Ponzio M, Sterzi R, Boccardi E; SYNTHESIS Expansion Investigators: Endovascular treatment for acute ischemic stroke. N Engl J Med 368: 904-913, 2013. 5. Goyal M, Demchuk AM, Menon BK, Eesa M, Rempel JL, Thornton J, Roy D, Jovin TG, Willinsky RA, Sapkota BL, Dowlatshahi D, Frei DF,
Kamal NR, Montanera WJ, Poppe AY, Ryckborst KJ, Silver FL, Shuaib A, Tampieri D, Williams D, Bang OY, Baxter BW, Burns PA, Choe H, Heo JH, Holmstedt CA, Jankowitz B, Kelly M, Linares G, Mandzia JL, Shankar J, Sohn SI, Swartz RH, Barber PA, Coutts SB, Smith EE, Morrish WF, Weill A, Subramaniam S, Mitha AP, Wong JH, Lowerison MW, Sajobi TT, Hill MD; ESCAPE Trial Investigators: Randomized assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med 372 (11):1019-1030, 2015. 6. Kidwell CS, Jahan R, Gornbein J, Alger JR, Nenov V, Ajani Z, Feng L, Meyer BC, Olson S, Schwamm LH, Yoo AJ, Marshall RS, Meyers PM, Yavagal DR, Wintermark M, Guzy J, Starkman S, Saver JL; MR RESCUE Investigators: A trial of imaging selection and endovascular treatment for ischemic stroke. N Engl J Med 368:914-923, 2014.
From the Departments of 1Neurosurgery, 2Neurology, and 3 Radiology, Rutgers UniversityeNJ Medical School, Newark, New Jersey, USA 1878-8750/$ - see front matter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.wneu.2015.03.043
- [-]: ---, - 2015
WORLD NEUROSURGERY
