Trends in Endovascular Therapy and Clinical Outcomes Within the Nationwide Get With The Guidelines-Stroke Registry

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1 Trends in Endovascular Therapy and Clinical Outcomes Within the Nationwide Get With The Guidelines-Stroke Registry Bijoy K. Menon, MD; Jeffrey L. Saver, MD; Mayank Goyal, MD; Raul Nogueira, MD; Shyam Prabhakaran, MD; Li Liang, PhD; Ying Xian, MD; Adrian F. Hernandez, MD; Gregg C. Fonarow, MD; Lee Schwamm, MD; Eric E. Smith, MD, MPH Background and Purpose We sought to determine hospital and patient characteristics associated with the use of endovascular therapy for acute ischemic stroke and to analyze trends in clinical outcome. Methods Data were from Get With The Guidelines-Stroke hospitals from April 1, 2003, to June 30, We looked at trends in number of hospitals providing endovascular therapy, the use of endovascular therapy in these hospitals and clinical outcomes. We analyzed hospital and patient characteristics associated with endovascular therapy use. Results Of 1087 hospitals, 454 provided endovascular therapy to 1 patient in the study period. From 2003 to 2012, proportion of hospitals providing endovascular therapy increased by 1.6% per year (from 12.9% to 28.9%; P<0.0001), with a modest drop to 23.4% in Utilization of endovascular therapy increased from 0.7% to 2% (P<0.001) with a modest drop to 1.9% in The overall rate of symptomatic intracerebral hemorrhage among endovascular therapy treated patients was 9.7%. In multivariable analyses, patient outcomes after endovascular therapy improved over time, with reductions in in-hospital mortality (29.6% in 2004 to 16.2% in 2013; P=0.002); and from late 2010, reduction in symptomatic intracerebral hemorrhage (11% in 2010 to 5% in 2013; P<0.0001), increased independent ambulation at discharge (24.5% in 2010 to 33% in 2013; P<0.0001) and discharge home (17.7% in 2010 to 26.1% in 2013; P<0.0001). Trends for these outcomes persist in the analyses adjusted for baseline National Institutes of Health Stroke Scale. Conclusion The use of endovascular therapy increased modestly nationally from 2003 to 2012 and decreased in Clinical outcomes improved notably from 2010 to 2013, coincident with more experience and newer thrombectomy devices. (Stroke. 2015;46: DOI: /STROKEAHA ) Key Words: endovascular procedures outcome assessment stroke Since the 1980s, when Zeumer et al 1 first reported on 5 patients with vertebrobasilar occlusions treated with local intra-arterial fibrinolysis, endovascular therapy has been a treatment option for patients with acute ischemic stroke. From 1999 to 2011, evidence was increasingly supporting the deployment of endovascular in advanced stroke centers across the globe. Encouraging, although not definitive, signals of benefit were observed in randomized trials of intra-arterial fibrinolysis, and first-generation neurothrombectomy devices were approved on the basis of multicenter nonrandomized cohort studies. 2 6 The publication in 2013 of 3 randomized clinical trials demonstrating no added advantage of endovascular therapy over current standard of care challenged the notion that intraarterial fibrinolysis and first-generation neurothrombectomy devices are effective at improving patient outcomes. 7 9 Advocates of endovascular therapy cited limitations of these trials, including low recanalization rates, prolonged time to endovascular intervention, broad imaging selection criteria, and lack of equipoise affecting patient enrollment as reasons why these trials failed to demonstrate any additional benefit in the endovascular arm Moreover, recently published randomized trials demonstrated that newer generation stent retrievers are better at achieving recanalization than first-generation mechanical devices and in the case of the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) trial, clinically effective and safe when administered within 6 hours of stroke symptom onset Received September 22, 2014; final revision received January 24, 2015; accepted January 29, From the Calgary Stroke Program, Department of Clinical Neurosciences, Hotchkiss Brain Institute (B.K.M., M.G., E.E.S.) and Department of Radiology (B.K.M., M.G., E.E.S.), University of Calgary, Calgary, Alberta, Canada; Department of Neurology (J.L.S.) and Division of Cardiology (G.C.F.), University of California, Los Angeles; Department of Neurology, Marcus Stroke and Neuroscience Center, Grady Memorial Hospital, Emory University School of Medicine, Atlanta, GA (R.N.); Department of Neurology, Northwestern University, Evanston, IL (S.P.); Duke Clinical Research Institute, Duke University, Durham, NC (L.L., Y.X., A.F.H.); and Department of Neurology, Massachusetts General Hospital, Boston, MA (L.S.). Guest Editor for this article was Markku Kaste, MD, PhD. Presented in part at the International Stroke Conference of the American Heart Association, Nashville, TN, February 11 13, The online-only Data Supplement is available with this article at /-/DC1. Correspondence to Bijoy K. Menon, MD, 1079 A, 29th St NW, Calgary, Alberta, Canada T3H4J2. Bijoy.Menon@Albertahealthservices.ca 2015 American Heart Association, Inc. Stroke is available at DOI: /STROKEAHA

2 990 Stroke April 2015 Clinical outcomes with endovascular therapy are potentially influenced by hospital size, work-flow processes, availability of stroke units, rapid access to care, optimal poststroke therapy and patient demographics In this study, we used data from the Get With The Guidelines (GWTG)-Stroke registry to determine secular trends in endovascular therapy use and hospital discharge outcomes during the past decade. We also analyze hospital and patient-level characteristics associated with the use of this therapy and resultant clinical outcomes. Methods GWTG-Stroke is a voluntary quality improvement initiative whose details have been described previously. 20,21 We analyzed data submitted to GWTG-Stroke during the time period April 1, 2003, to June 30, The study population, hospital-, and patient-level variables analyzed are described in the online-only Data Supplement. The use of endovascular therapy for acute ischemic stroke was recorded but not the type of therapy (eg, whether intra-arterial fibrinolysis, mechanical clot retrieval, angioplasty, stenting, alone or in combination). Clinical outcomes studied included symptomatic intracerebral hemorrhage (sich), in-hospital mortality, length of hospital stay, and ambulatory status at discharge. 21 Statistical Analysis Data were summarized using standard descriptive statistics. Trends over time in the number of hospitals providing endovascular therapy and in the use of endovascular therapy in these hospitals were reported as proportions. Hospital-level characteristics were compared between hospitals providing endovascular therapy and those not. Multivariable logistic regression was used to identify hospital-level variables that are independently associated with hospitals that provide endovascular therapy. Hospitals with bed size or teaching status missing (n=10) were excluded from this analysis. Patient-level characteristics were compared between patients receiving endovascular therapy and those not as above. Using multivariable logistic regression and a generalized estimating equations approach with exchangeable working correlation matrix that takes into account within hospital clustering of patient-level data, patientlevel variables associated with the use of endovascular therapy were identified. Missing data on most variables were <5%, except for arrival mode, the use of antihypertensives and the use of antidiabetic medications before admission (10% missing). A simple imputation to dominant level was used for these variables. Whenever data were missing on hospital variables, these were excluded from analysis. Because vital signs, laboratory data, anticoagulation, and antiplatelet use before admission had >45% missing, these variables were excluded from analysis. In patients receiving endovascular therapy, time from stroke symptom onset to hospital arrival was included in the multivariable analysis identifying patient- and hospital-level variables associated with various clinical outcomes. The primary multivariable analysis was restricted to patients with baseline National Institutes of Health Stroke Scale (NIHSS) data available. A sensitivity analysis that did not include NIHSS in the model was also done. Finally, we analyzed trends over time for prespecified clinical outcomes in patients receiving endovascular therapy. Unadjusted data showed a significant improvement in many clinical outcomes from the fourth quarter of 2010 (31st quarter of total time interval from April 1, 2003, to June 30, 2013). To identify patient- and hospitallevel variables associated with the prespecified clinical outcomes and to identify risk adjusted trends over time in these outcomes in patients receiving endovascular therapy, we used multivariable logistic regression and the generalized estimating equations approach as above; calendar time was evaluated for nonlinearity in the association with the binary outcomes by fitting a restricted cubic spline. The spline fit is plotted for predicted outcomes by calendar time from April 2003 to June 2013 with confidence bounds using the mean of covariates for all other covariates; for mortality and LOS (log transformed), a single linear relationship is assessed (P=0.45 for nonlinearity test for mortality and 0.74 for LOS). For other outcomes, data and plot suggested calendar time included in these models as a continuous variable using 2 pieces of splines with a single cut point at the 31st quarter. All P values are 2 sided, with P<0.05 considered statistically significant. Analyses were performed using SAS software (version 9.2; SAS Institute, Cary, NC). Results Of 1087 hospitals, 454 (41.8%) provided endovascular therapy to 1 patient during the study period. After excluding 28 hospitals without full calendar year data, 99 of 1059 (9.4%) hospitals provided continuous endovascular therapy. In hospitals providing any endovascular therapy, 9506 (1.6%) of patients with ischemic stroke received endovascular therapy, including 6296 (1.1%) patients receiving endovascular therapy alone and 3210 (0.5%) receiving both endovascular therapy and intravenous tissue-type plasminogen activator (tpa). By comparison, of (8.0%) of patients with ischemic stroke in these hospitals received intravenous tpa alone without endovascular therapy. At hospitals continuously providing endovascular therapy (n=99), the median annual number of patients receiving endovascular therapy was 6 (interquartile range, ), whereas the median percentage of patients with acute ischemic stroke receiving endovascular therapy was 2.6% (interquartile range, 1.6% 4.4%). An increase over time in the proportion of hospitals providing endovascular therapy was noted from 2003 to 2012, increasing at 1.6% per year (P<0.0001), with a modest drop in 2013 after the reporting of neutral randomized trials (Figure 1). Similarly, the proportion of patients treated with endovascular therapy at hospitals providing this therapy increased from 0.7% to 2% from 2003 to 2012 (P<0.001), with a modest drop in Hospital-level characteristics associated with endovascular therapy are shown Table I in the online-only Data Supplement (univariate analysis) and Table 1 (multivariable analysis, adjusted for NIHSS). On multivariable analysis, at hospital level, larger teaching hospitals in urban areas treating more patients with ischemic stroke per year and with higher annual intravenous tpa administration rates were more likely to administer endovascular therapy. No geographic or race ethnic patient mix differences in the likelihood of hospitals offering endovascular therapy were noted. Hospitals that treat more women were less likely to offer endovascular therapy. In analysis of characteristics associated with hospitals offering endovascular therapy continuously, independent associations were with higher annual ischemic stroke rate, higher annual intravenous tpa administration rate, and higher proportion of non-hispanic white patients. Patient-level characteristics associated with endovascular therapy are shown in Table I in the online-only Data Supplement (univariate analysis) and Table 1 (multivariable analysis, adjusted for NIHSS). On multivariable analysis, patients who were offered endovascular therapy were more likely to be younger and not have a history of previous stroke/ transient ischemic attack. Patients arriving during on-hours were more likely to receive endovascular therapy than those arriving during off-hours. Patients transported by Emergency

3 Menon et al Secular Trends With IA Therapy 991 Figure 1. Temporal trends in the use of endovascular therapy within hospitals participating in Get With The Guidelines- Stroke (GTWG-Stroke) during the past decade. A, The proportion of hospitals within GWTG-Stroke providing endovascular therapy. B, The proportion of patients with acute ischemic stroke being treated with endovascular therapy in the hospitals providing endovascular therapy. Medical Services (EMS) were also more likely to receive endovascular therapy. Other patient-level variables associated with the use of endovascular therapy include history of atrial fibrillation, having a prosthetic heart valve, history of coronary artery disease/myocardial infarction, history of carotid stenosis, absence of history of diabetes mellitus, peripheral vascular disease, hypertension, and smoker, use of statins, no use of diabetic medications before admission and nonfemale and nonblack ethnicity. In sensitivity analyses for all patients, the model remained the same with the following exceptions; male sex, history of carotid stenosis, and absence of history of peripheral vascular disease were not associated with the use of endovascular therapy, whereas history of heart failure was, and the magnitude of association with EMS arrival was increased. Clinical outcomes in patients receiving endovascular therapy are described in Table 2. Functional and safety outcomes did not differ among patients receiving combined intravenous tpa and endovascular therapy and patients receiving endovascular therapy alone. Variables associated with in-hospital mortality among patients offered endovascular therapy are shown in Table II in the online-only Data Supplement and included older age, history of coronary artery disease or previous myocardial infarction, history of diabetes mellitus, history of heart failure, EMS arrival, and no statin before admission. Mortality was also lower in hospitals that offered more endovascular therapy but higher in hospitals that offered more intravenous tpa therapy. Mortality was lower in the Midwest compared with that in the Northeast. Variables associated with discharge home among patients offered endovascular therapy are shown in Table II in the online-only Data Supplement and included younger age, male sex, nonblack race, absence of history of diabetes mellitus and hypertension, arriving during work hours rather than during off-hours and not brought to hospital by EMS. Discharge home was more likely in hospitals that offered more endovascular therapy. Variables associated with patients who ambulate independently at discharge and those associated with longer length of stay in hospital among patients offered endovascular therapy are described in Table II in the online-only Data Supplement. Adding NIHSS at baseline into the models resulted in that variable being a significant predictor of all outcomes. The association of on-hours versus off-hours admission on discharge home, ambulatory status, and mortality reduced significantly when adjusted for baseline NIHSS (Table III in the online-only Data Supplement).

4 992 Stroke April 2015 Table 1. Multivariable Models of Hospital and Patient Characteristics Associated With Use of Endovascular Therapy for Individual Patients (Only Significant Variables Reported) Odds Ratio (95% CI) P Value Model 1: hospital-level characteristics No. of beds (per 50 U) 1.07 ( ) <0.001 Rural (vs urban) 0.42 ( ) 0.03 Academic hospital 2.18 ( ) <0.001 Annual ischemic stroke cases: ( ) <0.001 (vs 0 100) Annual ischemic stroke cases: ( ) <0.001 (vs 0 100) Annual IV tpa cases: 20 (vs 0 10) 3.86 ( ) <0.001 Annual IV tpa cases: (vs 0 10) 1.86 ( ) <0.001 % Women (per 0.5 U) 0.10 ( ) 0.01 Model 2: patient-level characteristics in hospitals providing endovascular therapy Demographics Age (per 10 y) 0.76 ( ) <0.001 Baseline NIHSS (per 5 U increase) 1.53 ( ) <0.001 Sex (women) 0.95 ( ) Black (vs white) 0.70 ( ) <0.001 Medical history Atrial fibrillation/flutter 1.36 ( ) <0.001 Prosthetic heart valve 1.23 ( ) Previous stroke/tia 0.66 ( ) <0.001 Coronary artery disease/previous MI 1.05 ( ) 0.02 Carotid stenosis 1.14 (1.03 1,25) <0.01 Diabetes mellitus 0.87 ( ) <0.001 Peripheral vascular disease 0.92 ( ) 0.04 Hypertension 0.9 ( ) <0.001 Smoking 0.83 ( ) <0.001 Workflow Arrived at off-hours 0.83 ( ) <0.001 EMS from home/scene 2.04 ( ) <0.001 Medication history Statins 1.13 ( ) <0.001 Diabetic medications 0.90 ( ) <0.001 CI indicates confidence interval; EMS, Emergency Medical Services; IV tpa, intravenous tissue-type plasminogen activator; MI, myocardial infarction; NIHSS, National Institutes of Health; and TIA, transient ischemic attack. Changes in functional and safety outcomes over time are shown in Figure 2. In multivariable analyses, patient outcomes after endovascular therapy improved over time, with reductions in in-hospital mortality from 29.6% in 2004 to 16.2% in 2013 (odds ratio, 0.95; 95% confidence interval, ; P=0.002); and from late 2010 forward, reduction in sich from 11% in 2010 to 5% in 2013 (odds ratio, 0.71 per year, 95% confidence interval, ; P<0.0001) and increases in independent ambulation at discharge from 24.5% in 2010 to 33% in 2013 (odds ratio, 1.28 per year; 95% confidence interval, ; P<0.0001) and being discharged home from 17.7% in 2010 to 26.1% in 2013 (odds ratio, 1.31 per year; 95% confidence interval, ; P<0.0001). Table 2. Clinical Outcomes Among All Patients Who Received Endovascular Therapy Stratified by Whether They Received IV tpa Variable Received IV Total (n=7025) tpa (n=2890) Not Received IV tpa (n=4135) P Value sich<36 h (%) In-hospital mortality (%) Length of stay, d, 7 (4 11) 7 (4 11) 7 (4 11) 0.68 median (IQR) Length of stay 4 d, % Discharge home, % Ambulate independently, % Able to ambulate independently or with assistance, % IQR indicates interquartile range; IV tpa, intravenous tissue-type plasminogen activator; and sich, symptomatic intracerebral hemorrhage. Discussion We analyzed trends in the use and outcomes of endovascular therapy from 2003 to 2013 using data from patients with acute ischemic stroke and 1087 hospitals participating in a large US-based registry. We find that 2 of every 5 participating hospitals have provided endovascular therapy in the past decade; however, only 1 of every 10 hospitals provided endovascular therapy in every participating year. Among hospitals that provide continuous endovascular therapy, only 25% treat 10 patients per year. We also note increasing use of endovascular therapy from 2003 to 2012 with a mild decrement in 2013, after neutral trials of first-generation interventions were published. 7 9 The overall rate of sich in patients receiving endovascular therapy was 9.7%, whereas overall in-hospital mortality rate was 19.4%. We also found that every second patient stayed in hospital for at least a week, 1 of every 5 patients was discharged home, 1 of every 4 patients was able to ambulate independently, whereas 2 of every 3 patients were able to ambulate with assistance. These clinical outcome rates are similar to those reported for acute ischemic stroke endovascular therapy patients in US Nationwide Inpatient Sample data for the years 2004 to Our results also show substantial reduction in adverse outcomes over time. The rate of sich in patients receiving endovascular therapy declined from 1 in 7 to 1 in 20 over the study period. The risk-adjusted rate of in-hospital mortality declined from 1 in 3 to 1 in 7. The sich and in-hospital mortality rates in the final 2 years of the observation period ( ) are 3 absolute percentage points lower than those reported in the endovascular arm of the Interventional Management of Stroke III trial. 10 This decline in mortality was accompanied in the latter study years ( ) by an increase in the proportion of patients being discharged home after endovascular therapy, suggesting that increasing survival did not come at the cost of increasing disability. This time period coincides with increasing use of new mechanical devices like the Penumbra aspiration system (Food and Drug Administration cleared in 2008)

5 Menon et al Secular Trends With IA Therapy 993 Figure 2. Clinical outcomes with endovascular therapy during the past decade. The solid curve illustrates the relationship between outcomes and calendar time adjusted for patient and hospital characteristics. The dashed lines indicate the confidence intervals of predicted outcomes. The Penumbra aspiration system (1) received Food and Drug Administration (FDA) approval in January 2008, the Penumbra Pivotal Study (2) was published in July 2009, FDA approval for the first stentriever device (3) was in March 2012, Interventional Management of Stroke (IMS) III trial stopped recruitment (4) in April 2012, the SWIFT and TREVO-2 stentriever studies were published (5) in August 2012, whereas the IMS-3, SYNTHESIS, and MR RESCUE trials were published (6) February MR RESCUE indicates Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy; sich, symptomatic intracerebral hemorrhage; SWIFT, SOLITAIRE FR With the Intention for Thrombectomy Study; SYNTHESIS, Intra-Arterial Versus Systemic Thrombolysis for Acute Ischemic Stroke (SYNTHESIS EXP); and TREVO-2, Thrombectomy Revascularization of Large Vessel Occlusions in Acute Ischemic Stroke 2 Study. and stentrievers (Food and Drug Administration cleared in 2012) for endovascular therapy. These mechanical devices have higher recanalization rates than previous generation devices, achieve recanalization faster, and have lower complication rates. 6,13,14 Our results raise the possibility that increasing use of newer mechanical devices has resulted in better clinical outcome although other changes in practice such as better patient selection, more technical expertise, better periprocedural care, and improved healthcare systems may also explain some or all of the improvement in clinical outcomes in recent years. 7 9 We are unable to analyze outcomes according to recanalization method or devices directly because the device type is not captured in the GWTG data set. Of note, however, our analysis was risk adjusted, thus correcting for any baseline differences in stroke severity of patients treated over time. Endovascular therapy was provided inconsistently and to only a small minority of patients (1.6%) in the hospitals included in this study. Even among hospitals that consistently provided endovascular therapy, only a median of 2.6% patients was treated. More patients received endovascular therapy alone (1.1%) than combined intravenous tpa and endovascular therapy (0.5%). A potential reason for higher use of endovascular therapy alone versus combined therapy could be physician preference to offer this therapy to patients with disabling stroke whenever intravenous tpa is contraindicated. In addition, patients from remote areas reaching a comprehensive stroke center beyond time window for intravenous tpa administration may also be offered endovascular therapy alone. Nonetheless, the observation that the proportion of patients given endovascular therapy is still increasing, with disparities by geographic location, age, sex and race, suggests that endovascular therapy is still incompletely adopted in ischemic stroke practice. Our findings contrast with a study of endovascular therapy using data from the Nationwide Inpatient Sample that showed even lower adoption of acute ischemic stroke endovascular therapy (0.1% in 2004 to 0.6%

6 994 Stroke April 2015 in 2009). 22 Higher adoption rates in hospitals in our study could be because these hospitals have committed to quality improvement in stroke care through the GWTG-Stroke program. These hospitals, therefore, may not be representative of all US hospitals. We find that larger teaching hospitals in urban areas use endovascular therapy more than smaller, nonteaching hospitals in rural areas. We also find that hospitals using more endovascular therapy show better clinical outcomes and lower mortality rates than hospitals that use this therapy infrequently. These hospitals may be larger, more organized, and have more trained personnel operating 24/7 hours. There is increasing evidence that organized, dedicated, high-volume stroke centers improve patient outcomes. 23,24 A centralized model of endovascular care with a high-volume dedicated hub hospital receiving patients could help in maintaining case volumes, expertise and efficient in-hospital systems, reducing door to recanalization times, thereby further improving patient outcomes. 25 Patients arriving at endovascular hospitals during offhours were less likely to be offered this therapy; in addition, patients offered endovascular therapy during off-hours were less likely to be discharged home or ambulate independently. This association of off-hour admission weakens when analysis is adjusted for baseline NIHSS. An association of offhour admission with poorer outcomes has been demonstrated before in patients with strokes albeit not with endovascular therapy; many observers think that this effect to be because of differences in quality of care and delay in administering therapy. 26,27 Considerable weakening of this association in our study when adjusting for baseline stroke severity suggests that patients presenting during off-hours may have more severe strokes, a diurnal pattern well described in patients with myocardial infarction. 28 Our study found differences in the use of endovascular therapy based on age, sex, and race/ethnicity. Older patients, women, and nonwhite patients were less likely to be offered this therapy; interestingly, if offered this therapy, these same patients were less likely to do well clinically. Data on insurance were only collected since 2008; hence, we did not analyze differences in the use of endovascular therapy because of availability of insurance. Our results support previous literature on this topic. 29 Age, sex, and race ethnic differences could be because of differences in access, in education and awareness, and also to differences in stroke pathophysiology. Our study has limitations. Patients and hospitals may not be entirely representative of the US population. Nonetheless, the demographics of the GWTG-Stroke patient population are similar to the overall demographics of all US patients with stroke. 30 We had data on stroke onset to hospital arrival time but did not have details on other interval times within the endovascular workflow, or what drugs or devices were used. We also did not have data on the modified Rankin Scale as an outcome measure. Nonetheless, we report on measures of functional independence like ambulatory status and mortality that have correlated well with the modified Rankin Scale. In summary, we note limited use of endovascular therapy for patients with acute ischemic stroke in hospitals capable of offering this therapy. Our results also show that the use increased, albeit mildly, from 2003 to 2012 and then most recently mildly declined with the presentation of 3 neutral randomized clinical trials of early generation technology. 7 9 Our data also suggest more recent improvement in clinical outcomes in patients receiving endovascular therapy, coincident with the introduction and dissemination of later generation mechanical devices, and possibly associated with increased expertise among physicians and hospital systems in taking care of these patients. Results of recent randomized trials of these new devices will, however, be critical in providing the evidence needed to justify reorganizing and further improving stroke systems of care. 15 Sources of Funding The American Heart Association and the American Stroke Association fund Get With The Guidelines-Stroke. The program is also supported, in part, by unrestricted educational grants to the American Heart Association by Pfizer, Inc., New York, NY, and the Merck-Schering Plough Partnership (North Wales, PA), who did not participate in the design, analysis, article preparation or approval. Disclosures Dr Fonarow is an employee of University of California, Los Angeles, which holds a patent on retriever devices for stroke. He also receives research support from Patient-Centered Outcomes Research Institute. Dr Saver is an employee of the University of California, Regents, which receives funding for his services as a scientific consultant on trial design and conduct to Covidien, CoAxia, Stryker, BrainsGate, Genervon, St. Jude Medical, and Grifols. He has served as an unpaid site investigator in multicenter trials run by Lundbeck and Covidien for which the UC Regents received payments on the basis of clinical trial contracts for the number of subjects enrolled. The University of California has patent rights in retrieval devices for stroke. Dr Schwamm reports serving on the International steering committee of the Desmoteplase in Acute Ischemic Stroke (DIAS) 3 and 4 trials (Lundbeck), the Data Safety Monitoring Board for the 3-dimensional (3D) separator trial (Penumbra) and as Principal Investigator of the National Institute of Neurological Disorders and Stroke funded A Study of Intravenous Thrombolysis With Alteplase in MRI-Selected Patients (MR WITNESS) trial of extended window thrombolysis for which Genentech provides alteplase free of charge and supplemental per patient site payments. Dr Noguiera reports the following disclosures: Stryker Neurovascular (Trevo-2 and Trevo and Medical Management Versus Medical Management Alone in Wake Up and Late Presenting Strokes [DAWN] Trials Principal Investigatorboth modest), Covidien (SWIFT and SWIFT Prime Trials Steering Committee both modest; Solitaire FR Thrombectomy for Acute Revascularisation [STAR] Trial Angiographic Core Laboratory significant), Penumbra (3D Separator Trial Executive Committee no payment), Rapid Medical (Stroke Trial Data Safety Monitoring Board modest), Editor-In-Chief Interventional Neurology (no payment). A.F. Hernandez reports receiving research support from Astra Zeneca, BMS and Portola. The other authors report no conflicts. References 1. Zeumer H, Hacke W, Ringelstein EB. Local intraarterial thrombolysis in vertebrobasilar thromboembolic disease. AJNR Am J Neuroradiol. 1983;4: del Zoppo GJ, Higashida RT, Furlan AJ, Pessin MS, Rowley HA, Gent M. PROACT: a phase II randomized trial of recombinant pro-urokinase by direct arterial delivery in acute middle cerebral artery stroke. PROACT Investigators. Prolyse in Acute Cerebral Thromboembolism. Stroke. 1998;29: Furlan A, Higashida R, Wechsler L, Gent M, Rowley H, Kase C, et al. Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. Prolyse in Acute Cerebral Thromboembolism. JAMA. 1999;282:

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