Portal de Periódicos da CAPES

Society of Interventional Radiology Position Statement on Endovascular Acute Ischemic Stroke Interventions

2013; Elsevier BV; Volume: 24; Issue: 9 Linguagem: Inglês

10.1016/j.jvir.2013.05.050

1535-7732

David Sacks, John J. Connors, Carl M. Black,

Cerebrovascular and Carotid Artery Diseases

In February 2013, the world of stroke interventions changed. Three trials were presented at the 2013 International Stroke Conference and then published in the New England Journal of Medicine: Interventional Management of Stroke (IMS) III (1), Local Systemic Thrombolyis for Acute Ischemic Stroke (SYNTHESIS) Expansion (2Ciccone A. Valvassori L. Nichelatti M. et al.for the SYNTHESIS Expansion InvestigatorsEndovascular treatment for acute ischemic stroke.N Engl J Med. 2013; 368: 904-913Crossref PubMed Scopus (403) Google Scholar), and Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE) (3Kidwell C.S. Jahan R. Gornbein J. et al.for the MR RESCUE InvestigatorsA trial of imaging selection and endovascular treatment for ischemic stroke.N Engl J Med. 2013; 368: 914-923Crossref PubMed Scopus (1147) Google Scholar), each of which concluded that intraarterial (IA) ischemic stroke revascularization provided no significant benefit over intravenous (IV) thrombolysis with tissue plasminogen activator (tPA) or standard of care. In addition, MR RESCUE (3Kidwell C.S. Jahan R. Gornbein J. et al.for the MR RESCUE InvestigatorsA trial of imaging selection and endovascular treatment for ischemic stroke.N Engl J Med. 2013; 368: 914-923Crossref PubMed Scopus (1147) Google Scholar) concluded that the use of magnetic resonance (MR) imaging to select patients with a greater likelihood of benefit from IA treatment based on a “mismatch” between a “core” and a “penumbra” was unsuccessful. Based on these articles, the California Technology Assessment Forum concluded that IA “mechanical thrombectomy” is of unproven benefit (4California Technology Assessment Forum. Use of thrombectomy devices for the emergent treatment of acute ischemic stroke. Available at: www.ctaf.org/assessments/use-thrombectomy-devices-emergent-treatment-acute-ischemic-stroke. Accessed June 25, 2013.Google Scholar). These were not the results expected from these studies. Do these results reflect current practice? It is important to practice evidence-based medicine, but the evidence and associated conclusions must be reliable. It is worth looking at each of these trials in detail. In the National Institutes of Health (NIH)–sponsored IMS III trial (1Broderick J.P. Palesch Y.Y. Demchuk A.M. et al.for the Interventional Management of Stroke (IMS) III InvestigatorsEndovascular therapy after intravenous t-PA versus t-PA alone for stroke.N Engl J Med. 2013; 368: 893-903Crossref PubMed Scopus (1504) Google Scholar), patients were included if their ischemic stroke was severe enough to have an NIH Stroke Score (NIHSS) of at least 10, indicating a moderately severe stroke. Strokes of this severity have an approximately 80% likelihood of being caused by a large vessel occlusion in the internal carotid, vertebrobasilar, or proximal intracranial arterial circulation. Patients were randomized to receive IV tPA alone or IV tPA as a bridge to IA treatment. Of the 434 patients randomized to receive IA therapy, only 334 received IA treatment. As IMS III was a multiyear study, IA treatment initially represented IA thrombolysis but later included mechanical thrombectomy with the use of first-generation devices and then at the end of the study included second-generation devices such as stentrievers or large aspiration thrombectomy devices. The majority of patients who received endovascular treatment were treated with IA thrombolysis with only tPA. Overall, IA therapy provided no additional benefit over IV therapy alone. Good clinical outcomes (ie, modified Rankin scale [mRS] score of 0–2 at 90 d) occurred in 39% of patients who received IV treatment alone and 41% of those who received IV plus IA treatment. Limitations in this study (1Broderick J.P. Palesch Y.Y. Demchuk A.M. et al.for the Interventional Management of Stroke (IMS) III InvestigatorsEndovascular therapy after intravenous t-PA versus t-PA alone for stroke.N Engl J Med. 2013; 368: 893-903Crossref PubMed Scopus (1504) Google Scholar) include the following:1.The majority of the patients in the IV plus IA treatment arm did not receive standard US Food and Drug Administration–approved IV tPA treatment, but rather a nonstandard two-thirds IV dose infused for a duration of 40 minutes rather than the standard 60 minutes. This could adversely affect outcomes in the IA treatment group.2.The IA dose of tPA could be as much as the remaining third of the standard systemic IV tPA dose (ie, ≤ 30 mg IA tPA). There are no dose-ranging studies for catheter-directed IA tPA, but ultra-high catheter-directed doses of tPA have been shown to be less effective than lower doses (5Bookstein J.J. Bookstein F.L. Augmented experimental pulse-spray thrombolysis with tissue plasminogen activator, enabling dose reduction by one or more orders of magnitude.J Vasc Interv Radiol. 2000; 11: 299-303Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar), and it is possible that the IMS III protocol (1Broderick J.P. Palesch Y.Y. Demchuk A.M. et al.for the Interventional Management of Stroke (IMS) III InvestigatorsEndovascular therapy after intravenous t-PA versus t-PA alone for stroke.N Engl J Med. 2013; 368: 893-903Crossref PubMed Scopus (1504) Google Scholar) would therefore be less effective than a much lower local dose for IA therapy.3.Approximately two thirds of patients were treated with tPA alone in the endovascular group. Only five of 434 patients in the IA treatment arm were treated with a stentriever. IMS III (1Broderick J.P. Palesch Y.Y. Demchuk A.M. et al.for the Interventional Management of Stroke (IMS) III InvestigatorsEndovascular therapy after intravenous t-PA versus t-PA alone for stroke.N Engl J Med. 2013; 368: 893-903Crossref PubMed Scopus (1504) Google Scholar) is predominantly a trial of endovascular thrombolysis and not mechanical thrombectomy.4.The time to IA treatment in IMS III (1Broderick J.P. Palesch Y.Y. Demchuk A.M. et al.for the Interventional Management of Stroke (IMS) III InvestigatorsEndovascular therapy after intravenous t-PA versus t-PA alone for stroke.N Engl J Med. 2013; 368: 893-903Crossref PubMed Scopus (1504) Google Scholar) was 32 minutes longer than in IMS I and II (6Khatri P. Abruzzo T. Yeatts S.D. Nichols C. Broderick J.P. Tomsick T.A. IMS I and II InvestigatorsGood clinical outcome after ischemic stroke with successful revascularization is time-dependent.Neurology. 2009; 73: 1066-1072Crossref PubMed Scopus (409) Google Scholar). This could be a result of the increased use of “drip-and-ship” transfer of patients to centers that provided IA therapy. IMS I/II and IMS III data indicate that there is a 10% absolute reduction in good outcomes for every 30-minute delay in endovascular treatment (6Khatri P. Abruzzo T. Yeatts S.D. Nichols C. Broderick J.P. Tomsick T.A. IMS I and II InvestigatorsGood clinical outcome after ischemic stroke with successful revascularization is time-dependent.Neurology. 2009; 73: 1066-1072Crossref PubMed Scopus (409) Google Scholar, 7Khatri P, Mazighi M, Broderick JP, et al. Time to angiographic reperfusion is highly associated with good clinical outcomes in the Interventional Management of Stroke phase III (IMS III) trial. Presented at the 2013 International Stroke Conference of the American Heart Association; February 5–8, 2013; Honolulu, Hawaii. Abstract LB9.Google Scholar). In IMS III (1Broderick J.P. Palesch Y.Y. Demchuk A.M. et al.for the Interventional Management of Stroke (IMS) III InvestigatorsEndovascular therapy after intravenous t-PA versus t-PA alone for stroke.N Engl J Med. 2013; 368: 893-903Crossref PubMed Scopus (1504) Google Scholar), there was no clinical benefit of IA treatment following IV treatment when IA reperfusion started more than 5.5 hours after symptom onset. When patients were treated within 3 hours of symptom onset, good outcomes were obtained in nearly 70% of patients in the IA treatment group versus 39% of those in the IV treatment group in the IMS III trial (7Khatri P, Mazighi M, Broderick JP, et al. Time to angiographic reperfusion is highly associated with good clinical outcomes in the Interventional Management of Stroke phase III (IMS III) trial. Presented at the 2013 International Stroke Conference of the American Heart Association; February 5–8, 2013; Honolulu, Hawaii. Abstract LB9.Google Scholar). The negative effect of time was confirmed in a comparison of the Thrombectomy Revascularization of large Vessel Occlusions in Acute Ischemic Stroke (TREVO) and TREVO 2 trials (8Wahlgren N, Macho J, Killer M, Liebeskind D, Jansen O, for the TREVO investigators. Final results from the Trevo study (Thrombectomy Revascularization of large Vessel Occlusions in Acute Ischemic Stroke). Presented at the 2012 International Stroke Conference of the American Heart Association; February 1–3, 2012; New Orleans, La. Abstract LB2.Google Scholar, 9Nogueira R.G. Lutsep H.L. Jovin T.G. et al.for the TREVO 2 TrialistsTrevo versus Merci retrievers for thrombectomy revascularisation of large vessel occlusions in acute ischaemic stroke (TREVO 2): a randomised trial.Lancet. 2012; 380: 1231-1240Abstract Full Text Full Text PDF PubMed Scopus (935) Google Scholar). The TREVO trial (8Wahlgren N, Macho J, Killer M, Liebeskind D, Jansen O, for the TREVO investigators. Final results from the Trevo study (Thrombectomy Revascularization of large Vessel Occlusions in Acute Ischemic Stroke). Presented at the 2012 International Stroke Conference of the American Heart Association; February 1–3, 2012; New Orleans, La. Abstract LB2.Google Scholar) had a time from symptom onset to groin puncture of 3.5 hours and good clinical outcomes in 55% of patients. The TREVO 2 trial (9Nogueira R.G. Lutsep H.L. Jovin T.G. et al.for the TREVO 2 TrialistsTrevo versus Merci retrievers for thrombectomy revascularisation of large vessel occlusions in acute ischaemic stroke (TREVO 2): a randomised trial.Lancet. 2012; 380: 1231-1240Abstract Full Text Full Text PDF PubMed Scopus (935) Google Scholar) studied comparable patients but had a time to groin puncture of 4.4 hours and good clinical outcomes in 40% of patients. The delay to IA treatment is highly likely to have reduced the benefit from IA treatment below the anticipated benefit of IA therapy (10% expected effect size), leading to a negative trial result. It is more likely that the negative results of IMS III (1Broderick J.P. Palesch Y.Y. Demchuk A.M. et al.for the Interventional Management of Stroke (IMS) III InvestigatorsEndovascular therapy after intravenous t-PA versus t-PA alone for stroke.N Engl J Med. 2013; 368: 893-903Crossref PubMed Scopus (1504) Google Scholar) are caused by delays resulting from transfer of patients rather than an intrinsic lack of benefit of IA therapy itself.5.Patients who do not have a large vessel occlusion as the cause of their ischemic stroke have much better outcomes compared with those with a large vessel occlusion. Patients without large vessel occlusions include those with peripheral branch occlusions or lacunar infarcts, who tend to do well with IV tPA alone (10The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study GroupTissue plasminogen activator for acute ischemic stroke.N Engl J Med. 1995; 333: 1581-1587Crossref PubMed Scopus (10439) Google Scholar). By definition, thrombectomy cannot be performed unless there is a large vessel thrombus. Current clinical practice reserves endovascular thrombectomy for patients who have a large vessel occlusion typically confirmed by preprocedural computed tomography (CT) or MR angiography. The IMS III trial (1Broderick J.P. Palesch Y.Y. Demchuk A.M. et al.for the Interventional Management of Stroke (IMS) III InvestigatorsEndovascular therapy after intravenous t-PA versus t-PA alone for stroke.N Engl J Med. 2013; 368: 893-903Crossref PubMed Scopus (1504) Google Scholar) selected patients by NIHSS values, expecting and finding that 20% of patients did not have a large vessel occlusion at catheter angiography and implying that a similar 20% of patients did not have a large vessel occlusion in the IV tPA group either. Such patients did not receive endovascular therapy but were still included in the intent-to-treat outcomes analysis for the IA and IV treatment arms. Including patients who were likely to do well regardless of treatment and who would never be considered for IA therapy dilutes the results for both arms and obscures the potential benefit for patients who receive arterial revascularization. This is analogous to having a trial of the effectiveness of penicillin when the selection criterion is “fever” rather than “bacterial infection.” The significance of this selection bias is confirmed in an analysis of the subset of patients who had a CT angiogram that confirmed the presence of a large vessel occlusion before randomization (11Demchuk A. IMS III: comparison of outcomes between IV and IV/IA treatment in baseline CTA confirmed ICA, M1, M2 and basilar occlusions. Presented at the 2013 International Stroke Conference of the American Heart Association; February 5–8, 2013; Honolulu, Hawaii.Google Scholar). When comparing those patients who would actually be treated with endovascular revascularization (ie, those who had a large vessel occlusion), IA treatment provided patients with statistically significant benefit over IV tPA alone. Specifically, clinical outcomes in patients with an mRS score of 0-1 (almost complete neurologic recovery) were 35% for IA treatment and 19.8% for IV treatment. This is a complete reversal of the conclusion of IMS III (1Broderick J.P. Palesch Y.Y. Demchuk A.M. et al.for the Interventional Management of Stroke (IMS) III InvestigatorsEndovascular therapy after intravenous t-PA versus t-PA alone for stroke.N Engl J Med. 2013; 368: 893-903Crossref PubMed Scopus (1504) Google Scholar) that IA therapy provides no benefit over IV therapy.6.Although the use of an inline arterial air filter was not “required” in endovascular cases in IMS III (1Broderick J.P. Palesch Y.Y. Demchuk A.M. et al.for the Interventional Management of Stroke (IMS) III InvestigatorsEndovascular therapy after intravenous t-PA versus t-PA alone for stroke.N Engl J Med. 2013; 368: 893-903Crossref PubMed Scopus (1504) Google Scholar), the use of air filters for intracerebral infusion is not uncommon. The actual incidence of use of such filters on the tubing used to infuse IA tPA is not recorded. Such filters have recently been found to absorb nearly all (99.9%) of the tPA (J.J.C., unpublished data, April 4, 2011). Most patients in the IMS III trial (1Broderick J.P. Palesch Y.Y. Demchuk A.M. et al.for the Interventional Management of Stroke (IMS) III InvestigatorsEndovascular therapy after intravenous t-PA versus t-PA alone for stroke.N Engl J Med. 2013; 368: 893-903Crossref PubMed Scopus (1504) Google Scholar) received IA tPA, but patients treated with filters would not have been receiving any therapeutic medication. In the absence of data on filter use, the effect on outcomes in this study is not known, but the effect could only be to reduce the likelihood of additional benefit from IA tPA treatment.7.Only 40% of patients in the endovascular arm showed Thrombolysis in Cerebral Infarction (TICI) 2b or 3 revascularization (ie, > 50% of affected territory), which are the categories with the highest rates of good outcomes (48% and 78%, respectively). These rates of revascularization in the IMS III trial (1Broderick J.P. Palesch Y.Y. Demchuk A.M. et al.for the Interventional Management of Stroke (IMS) III InvestigatorsEndovascular therapy after intravenous t-PA versus t-PA alone for stroke.N Engl J Med. 2013; 368: 893-903Crossref PubMed Scopus (1504) Google Scholar) are lower than those achieved in current routine clinical practice with use of the same contemporary technologies used in IMS III (1Broderick J.P. Palesch Y.Y. Demchuk A.M. et al.for the Interventional Management of Stroke (IMS) III InvestigatorsEndovascular therapy after intravenous t-PA versus t-PA alone for stroke.N Engl J Med. 2013; 368: 893-903Crossref PubMed Scopus (1504) Google Scholar). The national Interventional Stroke Therapy Outcomes Registry (INSTOR; www.strokeregistry.com) reports data from 136 patients treated with intraarterial therapy (as detailed later). Final TICI 2b-3 flow was reported in 74% of patients. For those patients compatible with IMS III selection criteria (ie, those with IV tPA administered within 3 h of symptom onset and endovascular treatment), INSTOR reports 56% good outcomes (ie, mRS score of 0–2 at 90 d). Registry data have limitations compared with data from trials, but the INSTOR data suggest that results from the IMS III trial (1Broderick J.P. Palesch Y.Y. Demchuk A.M. et al.for the Interventional Management of Stroke (IMS) III InvestigatorsEndovascular therapy after intravenous t-PA versus t-PA alone for stroke.N Engl J Med. 2013; 368: 893-903Crossref PubMed Scopus (1504) Google Scholar) do not meet angiographic or clinical outcomes achieved in routine clinical care. This may be a result of differences in operator skill or possibly bias in which patients were offered participation in the IMS III trial (1Broderick J.P. Palesch Y.Y. Demchuk A.M. et al.for the Interventional Management of Stroke (IMS) III InvestigatorsEndovascular therapy after intravenous t-PA versus t-PA alone for stroke.N Engl J Med. 2013; 368: 893-903Crossref PubMed Scopus (1504) Google Scholar). In the Italian SYNTHESIS Expansion trial (2Ciccone A. Valvassori L. Nichelatti M. et al.for the SYNTHESIS Expansion InvestigatorsEndovascular treatment for acute ischemic stroke.N Engl J Med. 2013; 368: 904-913Crossref PubMed Scopus (403) Google Scholar), patients were randomized to receive a systemic dose of IV tPA or systemic-dose IA catheter-directed tPA with the use of additional devices in some patients. IA therapy was assigned to 181 patients but provided no significant benefit over IV therapy. Excellent clinical outcomes (ie, mRS score of 0-1 at 90 d) occurred in 35% of the IV therapy group and 30% of the IA therapy group. Good clinical outcomes (ie, mRS score of 0–2 at 90 d) occurred in 46% of the IV therapy group and 42% of the IA therapy group. Limitations in this study include the following:1.The SYNTHESIS Expansion trial (2Ciccone A. Valvassori L. Nichelatti M. et al.for the SYNTHESIS Expansion InvestigatorsEndovascular treatment for acute ischemic stroke.N Engl J Med. 2013; 368: 904-913Crossref PubMed Scopus (403) Google Scholar) used an unusual design of IV tPA selection criteria and doses for IA tPA administration and obtaining results similar to those of IV tPA. There was no confirmation of large vessel clot in the IV therapy group. If there was no large vessel clot seen on cerebral angiography in the IA group, IA tPA was given anyway. This is not the standard of care in the United States. The authors do not report how often they found no large vessel clot at angiography.2.Only one third of patients were treated with a mechanical device and only one sixth were treated with a stentriever. Therefore, this was really a trial of systemic-dose tPA administered IV versus IA.3.As noted earlier, ultra-high catheter-directed doses of tPA have been shown to be less effective than lower doses (5Bookstein J.J. Bookstein F.L. Augmented experimental pulse-spray thrombolysis with tissue plasminogen activator, enabling dose reduction by one or more orders of magnitude.J Vasc Interv Radiol. 2000; 11: 299-303Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar), and it is possible that the SYNTHESIS IA protocol would therefore be less effective than a much smaller IA dose or even the same systemic dose given via IV administration.4.There was no exclusion based on a low NIHSS score. Patients with a lower NIHSS score are expected to do well regardless of type of treatment and tend to do very well with IV tPA alone or even placebo, as demonstrated in the European Cooperative Acute Stroke Study III (12Hacke W. Kaste M. Bluhmki E. et al.for the ECASS InvestigatorsThrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke.N Engl J Med. 2008; 359: 1317-1329Crossref PubMed Scopus (5290) Google Scholar), in which 62% of placebo-treated patients with an average NIHSS score of 11 had an mRS of 0–2 at 90 days. Indeed, many patients with a low NIHSS score may never be more disabled than an mRS of 1 or 2. SYNTHESIS Expansion (2Ciccone A. Valvassori L. Nichelatti M. et al.for the SYNTHESIS Expansion InvestigatorsEndovascular treatment for acute ischemic stroke.N Engl J Med. 2013; 368: 904-913Crossref PubMed Scopus (403) Google Scholar) does not report outcomes stratified by an NIHSS threshold, such as a score of 10 as used in the IMS III trial (1Broderick J.P. Palesch Y.Y. Demchuk A.M. et al.for the Interventional Management of Stroke (IMS) III InvestigatorsEndovascular therapy after intravenous t-PA versus t-PA alone for stroke.N Engl J Med. 2013; 368: 893-903Crossref PubMed Scopus (1504) Google Scholar).5.The outcomes reported for the endovascular treatment arm include 15 of 181 patients who did not receive IA treatment. The investigators provide no data whether these patients did well or poorly, but their inclusion is not appropriate in an analysis of outcomes from IA therapy. An analysis of patients actually treated as intended is needed.6.TICI revascularization scores were not reported. Patients who do not undergo revascularization do not have good outcomes. These are critical data that are not provided. Poor revascularization, if present, could be caused by ineffective results of very large amounts of tPA via IA administration. In the NIH-sponsored MR RESCUE trial (3Kidwell C.S. Jahan R. Gornbein J. et al.for the MR RESCUE InvestigatorsA trial of imaging selection and endovascular treatment for ischemic stroke.N Engl J Med. 2013; 368: 914-923Crossref PubMed Scopus (1147) Google Scholar), MR imaging was used to identify patients with and without a significant ischemic penumbra. Patients were randomized to receive standard of care (IV tPA if eligible or conservative treatment if not) or IA embolectomy with the use of first-generation devices. A total of 64 patients received IA treatment, 28 of whom (44%) received IV tPA. Not only was there a lack of benefit of IA compared with IV therapy, but there was no benefit in selecting patients for IA therapy based on the presence of ischemic penumbra. Good outcomes (ie, mRS score 0–2 at 90 d) occurred in 21% of the penumbra/embolectomy treatment group, 26% of the penumbra/standard of care group, 17% of the nonpenumbra/embolectomy group, and 10% of the nonpenumbra/standard of care group. The results of all study arms are similar to, or worse than, those for placebo reported in other IA stroke trials (13Furlan A. Higashida R. Wechsler L. 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: 2003-2011Crossref PubMed Scopus (2778) Google Scholar, 14Ogawa A. Mori E. Minematsu K. et al.Randomized trial of intraarterial infusion of urokinase within 6 hours of middle cerebral artery stroke: the middle cerebral artery embolism local fibrinolytic intervention trial (MELT) Japan.Stroke. 2007; 38: 2633-2639Crossref PubMed Scopus (420) Google Scholar). Limitations of the MR RESCUE trial include the following:1.This trial compared embolectomy versus standard of care, with outcomes stratified by the presence of penumbra. Penumbra was defined as an infarct core less than 90 cm3 and core/total ischemic tissue volume less than 70% (ie, mismatch ≥ 30%). The trial failed to distinguish groups with or without penumbra. Table 1 of the article (3Kidwell C.S. Jahan R. Gornbein J. et al.for the MR RESCUE InvestigatorsA trial of imaging selection and endovascular treatment for ischemic stroke.N Engl J Med. 2013; 368: 914-923Crossref PubMed Scopus (1147) Google Scholar) shows that the no-penumbra group actually had a median mismatch of 50%. There was no separation based on the presence or absence of penumbra: the groups were actually separated on the basis of core infarct size.2.Revascularization was assessed at 7 days. Seven days is a clinically irrelevant time frame in which to assess revascularization, which must occur within minutes to hours to provide benefit.3.Angiographic revascularization was poor: TICI 2a flow was achieved in 40% of cases, but only 27% reached TICI 2b or 3 flow. These outcomes are even worse than those of IMS III (1Broderick J.P. Palesch Y.Y. Demchuk A.M. et al.for the Interventional Management of Stroke (IMS) III InvestigatorsEndovascular therapy after intravenous t-PA versus t-PA alone for stroke.N Engl J Med. 2013; 368: 893-903Crossref PubMed Scopus (1504) Google Scholar) and far worse than clinical practice documented in INSTOR data with the use of similar techniques as noted earlier. The poor outcomes support the possibility of lack of operator skills or patient selection bias. Anecdotally, patient selection bias has been confirmed with some physicians participating in MR RESCUE (Carpenter J, personal communication, April 8, 2013).4.Good outcomes were reported in only 21% of patients treated with penumbra and embolectomy (3Kidwell C.S. Jahan R. Gornbein J. et al.for the MR RESCUE InvestigatorsA trial of imaging selection and endovascular treatment for ischemic stroke.N Engl J Med. 2013; 368: 914-923Crossref PubMed Scopus (1147) Google Scholar). This is half the expected rate based on comparisons with other IA studies, including the IMS III trial (1Broderick J.P. Palesch Y.Y. Demchuk A.M. et al.for the Interventional Management of Stroke (IMS) III InvestigatorsEndovascular therapy after intravenous t-PA versus t-PA alone for stroke.N Engl J Med. 2013; 368: 893-903Crossref PubMed Scopus (1504) Google Scholar) and SYNTHESIS Expansion (2Ciccone A. Valvassori L. Nichelatti M. et al.for the SYNTHESIS Expansion InvestigatorsEndovascular treatment for acute ischemic stroke.N Engl J Med. 2013; 368: 904-913Crossref PubMed Scopus (403) Google Scholar). This likely reflects low technical success of catheter-based revascularization.5.In the penumbra groups, patients treated with embolectomy had more infarct growth than seen with standard of care (27 cm3 vs 7 cm3). For patients receiving standard of care, there was almost no infarct growth in the penumbra group (7 cm3) but extensive infarct growth in the no-penumbra group (84 cm3). These results are counterintuitive and suggest that the conclusion of no embolectomy benefit is unfounded. Although the California Technology Assessment Forum concluded that mechanical thrombectomy was of unproven benefit based on the results of these three trials (1Broderick J.P. Palesch Y.Y. Demchuk A.M. et al.for the Interventional Management of Stroke (IMS) III InvestigatorsEndovascular therapy after intravenous t-PA versus t-PA alone for stroke.N Engl J Med. 2013; 368: 893-903Crossref PubMed Scopus (1504) Google Scholar, 2Ciccone A. Valvassori L. Nichelatti M. et al.for the SYNTHESIS Expansion InvestigatorsEndovascular treatment for acute ischemic stroke.N Engl J Med. 2013; 368: 904-913Crossref PubMed Scopus (403) Google Scholar, 3Kidwell C.S. Jahan R. Gornbein J. et al.for the MR RESCUE InvestigatorsA trial of imaging selection and endovascular treatment for ischemic stroke.N Engl J Med. 2013; 368: 914-923Crossref PubMed Scopus (1147) Google Scholar), it is critical to note that these were actually not trials of mechanical thrombectomy. The IMS III (1Broderick J.P. Palesch Y.Y. Demchuk A.M. et al.for the Interventional Management of Stroke (IMS) III InvestigatorsEndovascular therapy after intravenous t-PA versus t-PA alone for stroke.N Engl J Med. 2013; 368: 893-903Crossref PubMed Scopus (1504) Google Scholar) and SYNTHESIS Expansion (2Ciccone A. Valvassori L. Nichelatti M. et al.for the SYNTHESIS Expansion InvestigatorsEndovascular treatment for acute ischemic stroke.N Engl J Med. 2013; 368: 904-913Crossref PubMed Scopus (403) Google Scholar) trials used IA infusion of tPA at unproven doses. Although the MR RESCUE trial (3Kidwell C.S. Jahan R. Gornbein J. et al.for the MR RESCUE InvestigatorsA trial of imaging selection and endovascular treatment for ischemic stroke.N Engl J Med. 2013; 368: 914-923Crossref PubMed Scopus (1147) Google Scholar) included the use of thrombectomy devices, the conclusions of this trial are suspect as a result of limitations of the first-generation devices or operator failure. Three studies with negative findings, however limited, still carry academic credibility, even though the flaws are significant enough to mask beneficial effects of endovascular treatment. What evidence is there that beneficial effects are truly being masked? The Prolyse in Acute Cerebral Thromboembolism II trial (13Furlan A. Higashida R. Wechsler L. 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: 2003-2011Crossref PubMed Scopus (2778) Google Scholar), the Middle Cerebral Artery Embolism Local Fibrinolytic Intervention Trial (14Ogawa A. Mori E. Minematsu K. et al.Randomized trial of intraarterial infusion of urokinase within 6 hours of middle cerebral artery stroke: the middle cerebral artery embolism local fibrinolytic intervention trial (MELT) Japan.Stroke. 2007; 38: 2633-2639Crossref PubMed Scopus (420) Google Scholar), and two metaanalyses (15Lee M. Hong K.S. Saver J.L. Efficacy of intra-arterial fibrinolysis for acute ischemic stroke: meta-analysis of randomized controlled trials.Stroke. 2010; 41: 932-937Crossref PubMed Scopus (127) Google Scholar, 16Fields J. Khatri P. Nesbit G. Meta-analysis of randomized intra-arterial thrombolytic trials for the treatment of acute stroke due to middle cerebral artery occlusion.J Neurointerv Surg. 2011; 3: 151-155Crossref PubMed Scopus (36) Google Scholar) demonstrated that recanalization via IA thrombolysis, when performed safely, quickly, and effectively, is superior to placebo. Based on the IA thrombolysis results from these trials, thrombolysis with urokinase-type fibrinolytic agents is better than standard of care for those patients not eligible for IV tPA. There are no subsequent randomized trials that demonstrate that IA thrombolysis with the use of tPA is superior to IV tPA. There are trials that demonstrate that first-generation mechanical thrombectomy devices recanalize and have clinical outcomes comparable to those of IA lysis in similar patients (17Josephson S.A. Saver J.L. Smith W.S. Comparison of mechanical embolectomy and intraarterial thrombolysis in acute ischemic stroke within the MCA: MERCI and Multi MERCI compared to PROACT II.Neurocrit Care. 2009; 10: 43-49Crossref PubMed Scopus (53) Google Scholar). There are randomized trials and large case series (9Nogueira R.G. Lutsep H.L. Jovin T.G. et al.for the TREVO 2 TrialistsTrevo versus Merci retrievers for thrombectomy revascularisation of large vessel occlusions in acute ischaemic stroke (TREVO 2): a randomised trial.Lancet. 2012; 380: 1231-1240Abstract Full Text Full Text PDF PubMed Scopus (935) Google Scholar, 18Saver J.L. Jahan R. Levy E.I. et al.for the SWIFT TrialistsSolitaire flow restoration device versus the Merci Retriever in patients with acute ischaemic stroke (SWIFT): a randomised, parallel-group, non-inferiority trial.Lancet. 2012; 380: 1241-1249Abstract Full Text Full Text PDF PubMed Scopus (1097) Google Scholar, 19Frei D. Gerber J. Turk A. et al.The SPEED study: initial clinical evaluation of the Penumbra novel 054 reperfusion catheter.J Neurointerv Surg. 2013; 5: i74-i76Crossref PubMed Scopus (31) Google Scholar, 20Davalos A. Pereira M. Chapot R. Bonafe A. Andersson T. Gralla J. Solitaire GroupRetrospective multicenter study of Solitaire FR for revascularization in the treatment of acute ischemic stroke.Stroke. 2012; 43: 2699-2705Crossref PubMed Scopus (151) Google Scholar) that confirm that second-generation thrombectomy devices are associated with much higher rates of recanalization and revascularization compared with first-generation devices (89%–96% vs 67%–77%), with rapid treatment times (36 min vs 52 min) and better rates of good clinical outcomes (36%–40% vs 22%–28%). There are no trials yet that demonstrate superior outcomes from treatment with second-generation devices versus standard of care, and the good clinical outcomes reported (approximately 40%) are similar to those from earlier trials (13Furlan A. Higashida R. Wechsler L. 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: 2003-2011Crossref PubMed Scopus (2778) Google Scholar, 14Ogawa A. Mori E. Minematsu K. et al.Randomized trial of intraarterial infusion of urokinase within 6 hours of middle cerebral artery stroke: the middle cerebral artery embolism local fibrinolytic intervention trial (MELT) Japan.Stroke. 2007; 38: 2633-2639Crossref PubMed Scopus (420) Google Scholar), the IMS III trial (1Broderick J.P. Palesch Y.Y. Demchuk A.M. et al.for the Interventional Management of Stroke (IMS) III InvestigatorsEndovascular therapy after intravenous t-PA versus t-PA alone for stroke.N Engl J Med. 2013; 368: 893-903Crossref PubMed Scopus (1504) Google Scholar), and SYNTHESIS Expansion (2Ciccone A. Valvassori L. Nichelatti M. et al.for the SYNTHESIS Expansion InvestigatorsEndovascular treatment for acute ischemic stroke.N Engl J Med. 2013; 368: 904-913Crossref PubMed Scopus (403) Google Scholar), albeit in different patient populations. However, two recent nonrandomized controlled trials (21Roubec M. Kuliha M. Prochazka V. et al.A controlled trial of revascularization in acute stroke.Radiology. 2013; 266: 871-878Crossref PubMed Scopus (13) Google Scholar, 22Rangaraju S. Owada K. Noorian A.R. et al.Comparison of final infarct volumes in patients who received endovascular therapy or intravenous thrombolysis for acute intracranial large-vessel occlusions.JAMA Neurol. 2013; 13: 1-6Google Scholar) compared stroke outcomes between hospitals that differed in access to endovascular stroke interventions. The first study (21Roubec M. Kuliha M. Prochazka V. et al.A controlled trial of revascularization in acute stroke.Radiology. 2013; 266: 871-878Crossref PubMed Scopus (13) Google Scholar) compared two geographical locations, one of which had access to IA stroke interventions with the use of stents and the other of which had no access to IA interventions. Patients who received IV tPA but did not show a response were nearly three times more likely to have a good clinical outcome if they subsequently were able to receive IA treatment (44% vs 15%). Patients with contraindications to IV tPA were almost six times more likely to have a good clinical outcome if able to receive IA treatment (45% vs 8%) (21Roubec M. Kuliha M. Prochazka V. et al.A controlled trial of revascularization in acute stroke.Radiology. 2013; 266: 871-878Crossref PubMed Scopus (13) Google Scholar). The second study (22Rangaraju S. Owada K. Noorian A.R. et al.Comparison of final infarct volumes in patients who received endovascular therapy or intravenous thrombolysis for acute intracranial large-vessel occlusions.JAMA Neurol. 2013; 13: 1-6Google Scholar) compared outcomes between two hospitals in the same city that differed in the use of IA interventions. Among comparable patients, those patients with moderate or severe strokes treated with IA revascularization had final infarct volumes one third the size of patients treated with IV tPA or no reperfusion therapy (46 cm3 vs 149 cm3). Acceptable or good clinical outcomes were also much better in patients treated with IA interventions (42% vs 17% for moderate strokes, 27% vs 4% for severe strokes) (22Rangaraju S. Owada K. Noorian A.R. et al.Comparison of final infarct volumes in patients who received endovascular therapy or intravenous thrombolysis for acute intracranial large-vessel occlusions.JAMA Neurol. 2013; 13: 1-6Google Scholar). Other randomized trials are in process, but results will not be available immediately. Even if these trials show significant benefit from IA treatment, it will be necessary to demonstrate that good results are generalizable outside of the trial setting. Reporting of results of IA stroke treatment is required per the recently published Multisociety Consensus Quality Improvement Guidelines (23Sacks D. Black C.M. Cognard C. et al.Multisociety consensus quality improvement guidelines for intraarterial catheter-directed treatment of acute ischemic stroke.J Vasc Interv Radiol. 2013; 24: 151-163Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar), has been mandated in multiple society statements, and is similar to Food and Drug Administration requirements for postapproval studies for other medical devices (24US Food and Drug Administration. Post-approval studies. Available at: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMA/pma_pas.cfm. Accessed April 1, 2013.Google Scholar). As noted earlier, at this time, the results of INSTOR demonstrate outcomes superior to any of the three recent trials (1Broderick J.P. Palesch Y.Y. Demchuk A.M. et al.for the Interventional Management of Stroke (IMS) III InvestigatorsEndovascular therapy after intravenous t-PA versus t-PA alone for stroke.N Engl J Med. 2013; 368: 893-903Crossref PubMed Scopus (1504) Google Scholar, 2Ciccone A. Valvassori L. Nichelatti M. et al.for the SYNTHESIS Expansion InvestigatorsEndovascular treatment for acute ischemic stroke.N Engl J Med. 2013; 368: 904-913Crossref PubMed Scopus (403) Google Scholar, 3Kidwell C.S. Jahan R. Gornbein J. et al.for the MR RESCUE InvestigatorsA trial of imaging selection and endovascular treatment for ischemic stroke.N Engl J Med. 2013; 368: 914-923Crossref PubMed Scopus (1147) Google Scholar), albeit with relatively small numbers of patients. Physicians who provide IA therapy should meet the training requirements of their respective societies (25Connors III, J.J. Sacks D. Black C.M. et al.Training guidelines for intra-arterial catheter-directed treatment of acute ischemic stroke: a statement from a Special Writing Group of the Society of Interventional Radiology.J Vasc Interv Radiol. 2009; 20: 1507-1522Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar, 26Meyers P.M. Schumacher H.C. Alexander M.J. et al.Performance and training standards for endovascular acute ischemic stroke treatment.J Neurointerv Surg. 2009; 1: 10-12Crossref PubMed Scopus (25) Google Scholar). Adequate training is critical for selecting appropriate patients to treat and performing a procedure with technical excellence (27Sacks D. Connors III, J.J. Commentary: intraarterial stroke revascularization training guidelines.J Vasc Interv Radiol. 2009; 20: 1523-1526Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar). Facilities that provide IA therapy should meet the benchmarks described in the Multisociety Consensus Quality Improvement Guidelines (23Sacks D. Black C.M. Cognard C. et al.Multisociety consensus quality improvement guidelines for intraarterial catheter-directed treatment of acute ischemic stroke.J Vasc Interv Radiol. 2013; 24: 151-163Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar). It is particularly important that facilities that participate in trials of IA therapy meet these guideline metrics. Currently, compliance with these metrics is voluntary, but should become mandatory if these guidelines are incorporated into the requirements to become a comprehensive stroke center. Where do we go from here? Should hospitals stop offering IA therapy to any patients, or to patients who have received IV tPA? Should hospitals continue to offer IA treatment only if patients are part of a trial? Should patients no longer receive drip-and-ship treatment in which IV tPA is administered locally and the patient is then transferred to a tertiary center for IA revascularization? Should practice continue as before with no change (28Von Kummer R. Gerber J. IMS-3, SYNTHESIS, and MR RESCUE: no disaster, but down to Earth.Clin Neuroradiol. 2013; 23: 1-3Crossref PubMed Scopus (11) Google Scholar)? At a minimum, 100% of patients treated should have data entered in a trial or have their processes and outcomes data tracked and submitted to a national registry capable of continuously providing process analysis and outcomes results to the treating institution. Based on the three recent trials with negative results (1Broderick J.P. Palesch Y.Y. Demchuk A.M. et al.for the Interventional Management of Stroke (IMS) III InvestigatorsEndovascular therapy after intravenous t-PA versus t-PA alone for stroke.N Engl J Med. 2013; 368: 893-903Crossref PubMed Scopus (1504) Google Scholar, 2Ciccone A. Valvassori L. Nichelatti M. et al.for the SYNTHESIS Expansion InvestigatorsEndovascular treatment for acute ischemic stroke.N Engl J Med. 2013; 368: 904-913Crossref PubMed Scopus (403) Google Scholar, 3Kidwell C.S. Jahan R. Gornbein J. et al.for the MR RESCUE InvestigatorsA trial of imaging selection and endovascular treatment for ischemic stroke.N Engl J Med. 2013; 368: 914-923Crossref PubMed Scopus (1147) Google Scholar), it is appropriate for each hospital to assess its response based on review of the literature, local needs, expertise, and outcomes. Every facility that offers IA interventions needs to do the utmost to reduce door–to–arterial revascularization times. For facilities that rely on multimodality imaging (CT angiography, CT perfusion, MR imaging, MR angiography, MR perfusion), these studies should be performed rapidly and at the same time as the initial screening noncontrast head CT or MR imaging study (29Leifer D. Bravata D.M. Connors III, J.J. et al.Metrics for measuring quality of care in comprehensive stroke centers: detailed follow-up to Brain Attack Coalition comprehensive stroke center recommendations: a statement for healthcare professionals from the American Heart Association/American Stroke Association.Stroke. 2011; 42: 849-877Crossref PubMed Scopus (145) Google Scholar) so as not to delay IV or IA revascularization treatment (23Sacks D. Black C.M. Cognard C. et al.Multisociety consensus quality improvement guidelines for intraarterial catheter-directed treatment of acute ischemic stroke.J Vasc Interv Radiol. 2013; 24: 151-163Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar, 29Leifer D. Bravata D.M. Connors III, J.J. et al.Metrics for measuring quality of care in comprehensive stroke centers: detailed follow-up to Brain Attack Coalition comprehensive stroke center recommendations: a statement for healthcare professionals from the American Heart Association/American Stroke Association.Stroke. 2011; 42: 849-877Crossref PubMed Scopus (145) Google Scholar, 30Salottolo K.M. Fanale C.V. Leonard K.A. Frei D.F. Bar-Or D. Multimodal imaging does not delay intravenous thrombolytic therapy in acute stroke.AJNR Am J Neuroradiol. 2011; 32: 864-868Crossref PubMed Scopus (29) Google Scholar). IA therapy must be provided more rapidly than the times reported in the IMS III trial (1Broderick J.P. Palesch Y.Y. Demchuk A.M. et al.for the Interventional Management of Stroke (IMS) III InvestigatorsEndovascular therapy after intravenous t-PA versus t-PA alone for stroke.N Engl J Med. 2013; 368: 893-903Crossref PubMed Scopus (1504) Google Scholar) and SYNTHESIS Expansion (2Ciccone A. Valvassori L. Nichelatti M. et al.for the SYNTHESIS Expansion InvestigatorsEndovascular treatment for acute ischemic stroke.N Engl J Med. 2013; 368: 904-913Crossref PubMed Scopus (403) Google Scholar). The IMS III trial (1Broderick J.P. Palesch Y.Y. Demchuk A.M. et al.for the Interventional Management of Stroke (IMS) III InvestigatorsEndovascular therapy after intravenous t-PA versus t-PA alone for stroke.N Engl J Med. 2013; 368: 893-903Crossref PubMed Scopus (1504) Google Scholar) had a delay from IV therapy to arterial puncture of 86 minutes, with an expected absolute loss of good outcomes of 30% of patients as a result of the delay. SYNTHESIS Expansion (2Ciccone A. Valvassori L. Nichelatti M. et al.for the SYNTHESIS Expansion InvestigatorsEndovascular treatment for acute ischemic stroke.N Engl J Med. 2013; 368: 904-913Crossref PubMed Scopus (403) Google Scholar) had a delay of 80 minutes from randomization to start of arterial therapy. The Multisociety Consensus Quality Improvement Guidelines (23Sacks D. Black C.M. Cognard C. et al.Multisociety consensus quality improvement guidelines for intraarterial catheter-directed treatment of acute ischemic stroke.J Vasc Interv Radiol. 2013; 24: 151-163Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar) state that at least 75% of patients should have a door-to-puncture time of less than 2 hours. At the current time, informed consent with patients and families should include an honest discussion of the negative and positive published and local results. Every physician involved in the care of patients with acute ischemic stroke should pay attention to these three recent articles and their inherent limitations. Many physicians who provide stroke interventions will continue to provide this care, but it is necessary to prove that such interventions are beneficial to patients through better designed studies, tracking of procedural and clinical outcomes of every patient treated, reporting of results to a national trial or registry, obtaining adequate training and continuing medical education, and compliance with quality standards. The position of the Society of Interventional Radiology (SIR) differs from the conclusions of California Technology Assessment Forum. SIR believes that:1.IA stroke revascularization is beneficial to patients in whom IV tPA fails or who are not eligible for IV tPA.2.Patients with a large vessel occlusion who are treated rapidly (even with first-generation techniques) have improved outcomes compared those treated with IV tPA alone.3.Second-generation mechanical thrombectomy devices are the most effective therapy for large vessel occlusions.4.Randomized trials of second-generation mechanical thrombectomy devices compared with IV tPA alone need to be performed.5.Participation in research is critically important, but reimbursement for IA stroke revascularization should not be restricted to clinical trials.6.All IA cases should be contributed to a trial or national registry, including 90-day clinical outcomes. Reimbursement should be restricted to those facilities that participate in a trial or submit data to a national registry.