ANNALS OF EMERGENCY MEDICINE
MARCH 2015
Systematic Review Snapshot TAKE-HOME MESSAGE In management of acute ischemic stroke, there is no evidence that endovascular therapy improves functional outcomes over that achieved with intravenous tissue plasminogen activator (tPA). METHODS
Does Endovascular Therapy Benefit Patients With Acute Ischemic Stroke? EBEM Commentators
DATA SOURCES The authors searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus from inception through February 2013, with no language restriction. References of eligible articles and conference proceedings were hand searched, and content experts were contacted to identify any additional studies. STUDY SELECTION Randomized trials of endovascular therapy versus standard care without it in patients with acute ischemic stroke were included. Two authors independently screened titles and abstracts and then conducted full-text review of articles that met the inclusion criteria. To be included in the meta-analysis, trials were required to report data necessary to calculate a risk estimate for allcause mortality, functional outcome, or symptomatic intracranial hemorrhage. DATA EXTRACTION AND SYNTHESIS Predesigned abstraction forms were used to extract data from individual studies. Trial authors were contacted
288 Annals of Emergency Medicine
Benton R. Hunter, MD Shradha V. Shardhul, MBBS, DEM Indiana University School of Medicine Department of Emergency Medicine Indianapolis, IN
Results Table. Pooled relative risk from 5 randomized trials comparing endovascular therapy with standard care. Outcome (90 Days) Mortality mRS* 1 mRS* 2 Symptomatic ICH
No. of Patients Randomized
Endovascular Therapy, n/N
Control, n/N
1,197 1,163 1,163 1,197
127/707 194/685 275/685 42/707
84/490 135/478 189/478 30/490
RR (95% CI) 0.98 1.02 1.02 0.99
(0.76–1.25) (0.84–1.23) (0.84–1.24) (0.62–1.58)
I2 0 1 21 0
RR, Relative risk; CI, confidence interval; mRS, modified Rankin Scale score; ICH, intracranial hemorrhage. *Definitions for mRS are available at http://en.wikipedia.org/wiki/Modified_Rankin_Scale.
Among the 1,255 potentially relevant articles identified by the search, 5 were eligible for meta-analysis. Because of the invasive nature of endovascular therapy, none of the included trials were blinded to participants (ie, none used a sham intervention), but 4 of 5 blinded the outcome assessors. There were considerable methodological differences between studies. Included studies performed endovascular therapy with catheter-directed intra-arterial tPA, mechanical thrombectomy, or both. The time from symptom onset to intervention ranged from less than 3 hours up to 8 hours. In 4 of the 5 trials, intravenous tPA was administered to all controls, whereas 1 trial allowed
“standard care” with or without intravenous tPA. Despite the clinical variation in protocols, there was minimal evidence of statistical heterogeneity among the results (Table).
Commentary As stroke centers increasingly adopt endovascular therapy, the benefit of doing so remains unproven. The pooled results of this meta-analysis showed no effect on mortality or functional outcomes with endovascular therapy compared with standard therapy, but the data based on randomized trials are limited. Five trials totaling 1,197 patients met the inclusion Volume 65, no. 3 : March 2015
Systematic Review Snapshot
for missing data. Study quality was assessed with the Jadad score, as well as the Cochrane Risk of Bias tool. A random-effects model was used to produce pooled relative risk estimates with 95% confidence intervals. Heterogeneity was reported with the I2 statistic and the Cochran Q statistic.
criteria for this meta-analysis. None of the trials attempted to blind participants, though 4 of the 5 blinded outcome assessors.1-4 Additionally, 2 of the 5 trials were stopped early.1,3 The largest trial planned to enroll 900 patients but was stopped early for futility after enrolling 656.1 The trial by Ciccone et al3 was stopped after enrolling 54 of a planned 350 patients to obtain funding for a larger expanded study.2 Outside of the blinding and premature stoppage, included studies had a low risk of bias. The authors of this systematic review examined multiple patient-centered outcomes (eg, mRS) and performed several sensitivity and subgroup analyses yet were unable to find a statistically significant benefit in any subgroup of patients or any iteration of endovascular therapy. The authors did observe that in the subgroup of patients with severe stroke, defined as National Institute of Health Stroke Scale (NIHSS) greater than or equal to 20, there appeared to be a trend toward better mRS with endovascular therapy (N¼271; 3 trials1-3). An adequately powered study would be required to confirm or refute this hypothesis. Almost all control patients in the included trials received intravenous tPA. A single trial4 allowed standard
Volume 65, no. 3 : March 2015
care with or without intravenous tPA, and 38 of the 54 controls (70%) in this trial did not receive intravenous tPA. The results of this trial, similar to the results of the other included trials, were negative. There is thus a paucity of data on endovascular therapy for patients who are not candidates for intravenous tPA. The authors hypothesize that time to recanalization may be a critical element for endovascular therapy success, but the most aggressive study,1 in which the intervention group received intravenous tPA before endovascular therapy within 3 hours, was stopped early for futility. An editorial published with the review suggests that more advanced neuroimaging may be the key to identifying patients who will preferentially benefit from endovascular therapy.5 Unfortunately, the only randomized trial to test this hypothesis reported negative results.4 It is conceivable that newergeneration devices will prove to be beneficial in future studies,6,7 though there is currently no evidence that one endovascular therapy device or strategy provides patient outcomes superior to that of another. Although none of the included trials suggested a benefit with endovascular therapy, none of them suggested harm either. Although current data have indicated no overall benefit, the search for a group of patients who may benefit from endovascular therapy is ongoing. Unfortunately, there does not appear to be a clear consensus on where to look (very early presenters, severe strokes, patients identified by advance neuroimaging, etc). Patients who are not candidates for intravenous tPA are essentially unstudied, and there
appears to be a trend toward improved outcomes with endovascular therapy in patients with NIHSS greater than or equal to 20. Enrollment for future studies should focus on which patients are likely to benefit from endovascular therapy and how to identify them. Editor’s Note: This is a clinical synopsis, a regular feature of the Annals’ Systematic Review Snapshots (SRS) series. The source for this systematic review snapshot is: Singh B, Parkaik AK, Prokop LJ, et al. Endovascular therapy for acute ischemic stroke: a systematic review and metaanalysis. Mayo Clin Proc. 2013;88:10561065. 1. Broderick JP, Palesch YY, Demchuk AM, et al. Endovascular therapy after intravenous t-PA versus t-PA alone for stroke. N Engl J Med. 2013;368:893-903. 2. Ciccone A, Valvassori L, Nichelatti M, et al. Endovascular treatment for acute ischemic stroke. N Engl J Med. 2013;368:904-913. 3. Ciccone A, Valvassori L, Ponzio M, et al. Intraarterial or intravenous thrombolysis for acute ischemic stroke? the SYNTHESIS pilot trial. J Neurointerv Surg. 2010;2:74-79. 4. Kidwell CS, Jahan R, Gornbein J, et al. A trial of imaging selection and endovascular treatment for ischemic stroke. N Engl J Med. 2013;368:914-923. 5. Liebeskind DS, Cucchiara B. The quest to prove endovascular stroke therapy: searching for the “sweet spot” in patient selection. Mayo Clin Proc. 2013;88: 1039-1041. 6. Saver J. Solitaire FR as Primary Treatment for Acute Ischemic Stroke (SWIFT PRIME). ClinicalTrials.gov Identifier: NCT01657461. 7. Alonso M. Efficacy and security of an endovascular treatment as first choice procedure compared with intravenous thrombolytic therapy treatment for patients with acute ischemic stroke within 4.5 hours after onset (FUN-TPA). ClinicalTrials.gov Identifier: NCT02164357.
Michael Brown, MD, MSc, Alan Jones, MD, and David Newman, MD, serve as editors of the SRS series.
Annals of Emergency Medicine 289
MARCH 2015
Systematic Review Snapshot TAKE-HOME MESSAGE In management of acute ischemic stroke, there is no evidence that endovascular therapy improves functional outcomes over that achieved with intravenous tissue plasminogen activator (tPA). METHODS
Does Endovascular Therapy Benefit Patients With Acute Ischemic Stroke? EBEM Commentators
DATA SOURCES The authors searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus from inception through February 2013, with no language restriction. References of eligible articles and conference proceedings were hand searched, and content experts were contacted to identify any additional studies. STUDY SELECTION Randomized trials of endovascular therapy versus standard care without it in patients with acute ischemic stroke were included. Two authors independently screened titles and abstracts and then conducted full-text review of articles that met the inclusion criteria. To be included in the meta-analysis, trials were required to report data necessary to calculate a risk estimate for allcause mortality, functional outcome, or symptomatic intracranial hemorrhage. DATA EXTRACTION AND SYNTHESIS Predesigned abstraction forms were used to extract data from individual studies. Trial authors were contacted
288 Annals of Emergency Medicine
Benton R. Hunter, MD Shradha V. Shardhul, MBBS, DEM Indiana University School of Medicine Department of Emergency Medicine Indianapolis, IN
Results Table. Pooled relative risk from 5 randomized trials comparing endovascular therapy with standard care. Outcome (90 Days) Mortality mRS* 1 mRS* 2 Symptomatic ICH
No. of Patients Randomized
Endovascular Therapy, n/N
Control, n/N
1,197 1,163 1,163 1,197
127/707 194/685 275/685 42/707
84/490 135/478 189/478 30/490
RR (95% CI) 0.98 1.02 1.02 0.99
(0.76–1.25) (0.84–1.23) (0.84–1.24) (0.62–1.58)
I2 0 1 21 0
RR, Relative risk; CI, confidence interval; mRS, modified Rankin Scale score; ICH, intracranial hemorrhage. *Definitions for mRS are available at http://en.wikipedia.org/wiki/Modified_Rankin_Scale.
Among the 1,255 potentially relevant articles identified by the search, 5 were eligible for meta-analysis. Because of the invasive nature of endovascular therapy, none of the included trials were blinded to participants (ie, none used a sham intervention), but 4 of 5 blinded the outcome assessors. There were considerable methodological differences between studies. Included studies performed endovascular therapy with catheter-directed intra-arterial tPA, mechanical thrombectomy, or both. The time from symptom onset to intervention ranged from less than 3 hours up to 8 hours. In 4 of the 5 trials, intravenous tPA was administered to all controls, whereas 1 trial allowed
“standard care” with or without intravenous tPA. Despite the clinical variation in protocols, there was minimal evidence of statistical heterogeneity among the results (Table).
Commentary As stroke centers increasingly adopt endovascular therapy, the benefit of doing so remains unproven. The pooled results of this meta-analysis showed no effect on mortality or functional outcomes with endovascular therapy compared with standard therapy, but the data based on randomized trials are limited. Five trials totaling 1,197 patients met the inclusion Volume 65, no. 3 : March 2015
Systematic Review Snapshot
for missing data. Study quality was assessed with the Jadad score, as well as the Cochrane Risk of Bias tool. A random-effects model was used to produce pooled relative risk estimates with 95% confidence intervals. Heterogeneity was reported with the I2 statistic and the Cochran Q statistic.
criteria for this meta-analysis. None of the trials attempted to blind participants, though 4 of the 5 blinded outcome assessors.1-4 Additionally, 2 of the 5 trials were stopped early.1,3 The largest trial planned to enroll 900 patients but was stopped early for futility after enrolling 656.1 The trial by Ciccone et al3 was stopped after enrolling 54 of a planned 350 patients to obtain funding for a larger expanded study.2 Outside of the blinding and premature stoppage, included studies had a low risk of bias. The authors of this systematic review examined multiple patient-centered outcomes (eg, mRS) and performed several sensitivity and subgroup analyses yet were unable to find a statistically significant benefit in any subgroup of patients or any iteration of endovascular therapy. The authors did observe that in the subgroup of patients with severe stroke, defined as National Institute of Health Stroke Scale (NIHSS) greater than or equal to 20, there appeared to be a trend toward better mRS with endovascular therapy (N¼271; 3 trials1-3). An adequately powered study would be required to confirm or refute this hypothesis. Almost all control patients in the included trials received intravenous tPA. A single trial4 allowed standard
Volume 65, no. 3 : March 2015
care with or without intravenous tPA, and 38 of the 54 controls (70%) in this trial did not receive intravenous tPA. The results of this trial, similar to the results of the other included trials, were negative. There is thus a paucity of data on endovascular therapy for patients who are not candidates for intravenous tPA. The authors hypothesize that time to recanalization may be a critical element for endovascular therapy success, but the most aggressive study,1 in which the intervention group received intravenous tPA before endovascular therapy within 3 hours, was stopped early for futility. An editorial published with the review suggests that more advanced neuroimaging may be the key to identifying patients who will preferentially benefit from endovascular therapy.5 Unfortunately, the only randomized trial to test this hypothesis reported negative results.4 It is conceivable that newergeneration devices will prove to be beneficial in future studies,6,7 though there is currently no evidence that one endovascular therapy device or strategy provides patient outcomes superior to that of another. Although none of the included trials suggested a benefit with endovascular therapy, none of them suggested harm either. Although current data have indicated no overall benefit, the search for a group of patients who may benefit from endovascular therapy is ongoing. Unfortunately, there does not appear to be a clear consensus on where to look (very early presenters, severe strokes, patients identified by advance neuroimaging, etc). Patients who are not candidates for intravenous tPA are essentially unstudied, and there
appears to be a trend toward improved outcomes with endovascular therapy in patients with NIHSS greater than or equal to 20. Enrollment for future studies should focus on which patients are likely to benefit from endovascular therapy and how to identify them. Editor’s Note: This is a clinical synopsis, a regular feature of the Annals’ Systematic Review Snapshots (SRS) series. The source for this systematic review snapshot is: Singh B, Parkaik AK, Prokop LJ, et al. Endovascular therapy for acute ischemic stroke: a systematic review and metaanalysis. Mayo Clin Proc. 2013;88:10561065. 1. Broderick JP, Palesch YY, Demchuk AM, et al. Endovascular therapy after intravenous t-PA versus t-PA alone for stroke. N Engl J Med. 2013;368:893-903. 2. Ciccone A, Valvassori L, Nichelatti M, et al. Endovascular treatment for acute ischemic stroke. N Engl J Med. 2013;368:904-913. 3. Ciccone A, Valvassori L, Ponzio M, et al. Intraarterial or intravenous thrombolysis for acute ischemic stroke? the SYNTHESIS pilot trial. J Neurointerv Surg. 2010;2:74-79. 4. Kidwell CS, Jahan R, Gornbein J, et al. A trial of imaging selection and endovascular treatment for ischemic stroke. N Engl J Med. 2013;368:914-923. 5. Liebeskind DS, Cucchiara B. The quest to prove endovascular stroke therapy: searching for the “sweet spot” in patient selection. Mayo Clin Proc. 2013;88: 1039-1041. 6. Saver J. Solitaire FR as Primary Treatment for Acute Ischemic Stroke (SWIFT PRIME). ClinicalTrials.gov Identifier: NCT01657461. 7. Alonso M. Efficacy and security of an endovascular treatment as first choice procedure compared with intravenous thrombolytic therapy treatment for patients with acute ischemic stroke within 4.5 hours after onset (FUN-TPA). ClinicalTrials.gov Identifier: NCT02164357.
Michael Brown, MD, MSc, Alan Jones, MD, and David Newman, MD, serve as editors of the SRS series.
Annals of Emergency Medicine 289
