Treatment Effect of Intravenous Thrombolysis Bridging to Mechanical Thrombectomy on Vessel Occlusion Site
2021; Lippincott Williams & Wilkins; Volume: 53; Issue: 1 Linguagem: Inglês
10.1161/strokeaha.121.037603
ISSN1524-4628
Autores Tópico(s)Stroke Rehabilitation and Recovery
ResumoHomeStrokeVol. 53, No. 1Treatment Effect of Intravenous Thrombolysis Bridging to Mechanical Thrombectomy on Vessel Occlusion Site Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessEditorialPDF/EPUBTreatment Effect of Intravenous Thrombolysis Bridging to Mechanical Thrombectomy on Vessel Occlusion Site Thanh N. Nguyen, MD and Urs Fischer, MD, MSc Thanh N. NguyenThanh N. Nguyen Correspondence to: Thanh N. Nguyen, MD, Department of Neurology and Radiology, Boston Medical Center, Boston University School of Medicine, Boston, MA 02118, Email E-mail Address: [email protected] https://orcid.org/0000-0002-2810-1685 Department of Neurology and Radiology, Boston Medical Center, Boston University School of Medicine, MA (T.N.N.). and Urs FischerUrs Fischer Urs Fischer, MD, MSc, Department of Neurology, University Hospital Basel, University of Basel, Basel, Switzerland, Email E-mail Address: [email protected] https://orcid.org/0000-0003-0521-4051 Department of Neurology, University Hospital Bern, University of Bern, Switzerland (U.F.). Department of Neurology, University Hospital Basel, University of Basel, Switzerland (U.F.). Originally published17 Dec 2021https://doi.org/10.1161/STROKEAHA.121.037603Stroke. 2022;53:17–19This article is a commentary on the followingEffect of Occlusion Site on the Safety and Efficacy of Intravenous Alteplase Before Endovascular Thrombectomy: A Prespecified Subgroup Analysis of DIRECT-MTOther version(s) of this articleYou are viewing the most recent version of this article. Previous versions: December 17, 2021: Ahead of Print See related article, p 7Intravenous thrombolysis (IVT) has been the cornerstone of acute stroke therapy since the NINDS trial (National Institute of Neurological Disorders and Stroke) in 1995,1 with an expansion of indications over time.2–4 The emergence of several randomized clinical trials demonstrating a treatment effect of endovascular therapy (EVT) for large vessel occlusion (LVO) stroke was a watershed moment, raising the question of the role of IVT as adjunctive treatment to EVT for large vessel occlusion. These patients are of interest because they usually present with a major stroke and may harbor risk for intracerebral hemorrhage.5,6The controversy led to the pursuit of several randomized trials with mixed results in supporting (or refuting) the adjunctive benefit of IVT with EVT in the treatment of stroke with LVO. DIRECT MT (Direct Intraarterial Thrombectomy to Revascularize Acute Ischemic Stroke Patients With Large Vessel Occlusion Efficiently in Chinese Tertiary Hospitals)7 and DEVT (Direct Endovascular Treatment Versus Standard Bridging Therapy for Patients With Acute Stroke With Large Vessel Occlusion in the Anterior Circulation),8 both from China, were the only IVT/EVT bridging trials that proved noninferiority, however, with liberal noninferiority margins. SKIP (Direct Mechanical Thrombectomy in Acute LVO Stroke),9 conducted in Japan, was underpowered and did not show noninferiority. MR CLEAN-NO IV (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) failed to show superiority and noninferiority.10 Data of the SWIFT DIRECT (Solitaire With the Intention for Thrombectomy Plus Intravenous t-PA Versus DIRECT Solitaire Stent-Retriever Thrombectomy in Acute Anterior Circulation Stroke), DIRECT SAFE (DIRECT Endovascular Clot Retrieval Versus Standard Bridging Thrombolysis With Endovascular Clot Retrieval) trials and a pooled analysis of these trials are pending.11While we await the results of the pooled trial analysis of bridging therapy, the heterogeneity of treatment effect of IVT on patient subgroups in patients with LVO is of interest as we move toward tailored individual therapy and precision medicine in stroke.12 At a granular level, the efficacy of IVT for the treatment of acute ischemic stroke varies by clot location, composition, and burden of clot.13 IVT has been reported more efficacious in the treatment of distal compared with proximal vessel occlusion,14–16 drip-and-ship versus mothership patients,14 smaller compared with large clot burden13 and posterior versus anterior circulation.17,18In this issue of Stroke, Zhou et al19 performed a subanalysis of the DIRECT MT trial to examine whether the occlusion site modifies the effect of IVT before EVT. The authors did not find a treatment-by-occlusion site interaction. Herein, we summarize the study findings, and critique the study's strengths and limitations.Summary of DIRECT MT Secondary AnalysisZhou et al present a prespecified secondary analysis of the DIRECT MT randomized clinical trial, evaluating the treatment effect of IVT (0.9 mg/kg) initiated within 4.5 hours of symptom onset and occlusion location involving the internal carotid artery, middle cerebral artery M1 or M2 segment. The primary outcome in this analysis was 90-day modified Rankin Scale. The trial was conducted at 41 sites in China, in patients presenting directly to an endovascular center. Of 658 randomized patients, 640 with baseline occlusion were included.There was no significant treatment-by-occlusion site interaction of IVT (compared with no IVT) for internal carotid artery (n=226), M1 (n=339), or M2 (n=75) occlusions, as relates to 90-day dichotomized modified Rankin Scale score outcomes. Overall, successful reperfusion (expanded Treatment in Cerebral Infarction score, ≥2b) before thrombectomy was less common in the thrombectomy only group (2.4% versus 7.0%). Symptomatic hemorrhage rates were no different between the 3 groups.Commentary of Zhou et al ArticleWe commend the DIRECT MT investigators for executing a trial pivoting on the question of adjunctive benefit of IVT to EVT in patients with LVO, at an important crossroad in the contemporary practice of acute stroke intervention. As expected, patients with more proximal occlusion had worse outcomes compared with patients with distal occlusion. However, expecting a potential beneficial treatment effect of IVT on more distal locations such as the M2 segment, it is a surprise that no IVT treatment effect by occlusion location was observed in this secondary analysis. Paradoxically, more benefit of direct EVT treatment compared with IVT bridging with EVT was observed in distal occlusions. Several reasons may explain these results.The study design of DIRECT MT enrolling patients presenting to an endovascular center and the efficiency in workflow is likely an important factor to account for these results. In DIRECT MT, the median time from door to IVT was 59 (IQR 45–78) minutes, whereas the median time from door to groin puncture was 85.5 (IQR 70–115) minutes. Delays incurred to IVT are most likely related to time to consent a patient in this randomized trial and IVT consent. These delays may have provided added lead time for the EVT teams to prepare, hence the short interval of 26 minutes between the beginning of IVT to groin puncture. As such, 86.5% had intravenous alteplase still running during the thrombectomy procedure. With the efficiency of the workflows in a mothership model in this study, there may not have been an adequate lapse of time between the IVT infusion to EVT procedure to state conclusively the lack of benefit of alteplase in the treatment of distal occlusions.16 In the CLOTBUST trial (Combined Lysis of Thrombus in Brain Ischemia Using Transcranial Ultrasound and Systemic TPA), only 18% of patients with MCA occlusion treated with IVT had complete recanalization at the 2-hour mark.20 While waiting for IVT response is generally not recommended in a mothership paradigm, 1- to 3- hour delays can be a reality in the drip and ship paradigm in which one may have more time to observe the IVT treatment effect.21Other factors that may explain the lack of treatment effect by occlusion site are the small sample size of the subgroups, particularly M2 occlusions, limiting statistical power. Furthermore, there was a small but nonsignificant increase in symptomatic hemorrhage in the bridging group for M1 (2.5%) and M2 (4.3%) occlusions, which may have explained worse outcomes in this cohort compared with the direct MT group.Overall, the unexpected observation is the lower rate of favorable 90-day functional outcomes in DIRECT MT compared with the HERMES cohort (modified Rankin Scale score 0–2, 36% versus 46%, respectively).22 This may be driven by a disproportionately higher rate of intracranial ICA occlusions in DIRECT MT compared with HERMES (35% versus 21%, respectively), the occlusion location of which is associated with worse outcome compared with more distally situated occlusions. Chinese ethnicity versus non-Asian ethnicity, higher number of patients with diabetes in DIRECT MT may also account for 90-day functional outcome differences between these 2 cohorts. Intracranial atherosclerosis, which was considered the cause of stroke in 8% (EVT) versus 6% (bridging arm) of DIRECT MT patients, may be another factor to explain the discrepancy in outcomes compared with HERMES.Future DirectionsIn the interim, tenecteplase has emerged as a potent thrombolytic with higher rates of early reperfusion compared with alteplase in patients with large vessel occlusion and without increased risk of hemorrhage.23 Its adoption would be of particular interest in primary stroke centers where delays to LVO access are common. Studies are ongoing to address whether tenecteplase bridging to thrombectomy can further improve outcomes (https://www.clinicaltrials.gov; Unique identifier: BRIDGE TNK NCT04733742).Further studies of whether bridging with IVT may confer benefit in the event of failed EVT or in the treatment of distal emboli after MT are of interest. In patients with tandem occlusion, another question is whether IVT should be skipped in the event a patient may require acute stenting with antiplatelet therapy. In addition to evaluating the treatment effect of IVT by location of occlusion, we look forward to the answers to these questions in the other trials, comparing bridging thrombolysis with direct thrombectomy as well as in the pooled analysis of the bridging randomized trials.Disclosures Dr Nguyen reported research support from Medtronic and the Society of Vascular and Interventional Neurology. Dr Fischer reported research support from Medtronic (SWIFT DIRECT), serving as consultant for Medtronic, Stryker, CSL Behring, and participating in an advisory board for Alexion/Portola outside the submitted work.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.For Disclosures, see page 19.Correspondence to: Thanh N. Nguyen, MD, Department of Neurology and Radiology, Boston Medical Center, Boston University School of Medicine, Boston, MA 02118, Email thanh.[email protected]orgUrs Fischer, MD, MSc, Department of Neurology, University Hospital Basel, University of Basel, Basel, Switzerland, Email urs.[email protected]chReferences1. National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group.Tissue plasminogen activator for acute ischemic stroke.N Engl J Med. 1995; 333:1581–1587.CrossrefMedlineGoogle Scholar2. Hacke W, Kaste M, Bluhmki E, Brozman M, Dávalos A, Guidetti D, Larrue V, Lees KR, Medeghri Z, Machnig Tet al.; ECASS Investigators.Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke.N Engl J Med. 2008; 359:1317–1329. doi: 10.1056/NEJMoa0804656CrossrefMedlineGoogle Scholar3. 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Campbell BCV, Mitchell PJ, Churilov L, Yassi N, Kleinig TJ, Dowling RJ, Yan B, Bush SJ, Dewey HM, Thijs Vet al.; EXTEND-IA TNK Investigators.Tenecteplase versus alteplase before thrombectomy for ischemic stroke.N Engl J Med. 2018; 378:1573–1582. doi: 10.1056/NEJMoa1716405CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited ByMasoud H, de Havenon A, Castonguay A, Asif K, Nguyen T, Mehta B, Abdalkader M, Gutierrez S, Leslie‐Mazwi T, Mansour O, Ma A, Czap A, Kenmuir C, Sheth S, Novakovic‐White R, Nour M, Jadhav A, Janardhan V, Hassan A, Liebeskind D, Malik A and Zaidat O (2022) 2022 Brief Practice Update on Intravenous Thrombolysis Before Thrombectomy in Patients With Large Vessel Occlusion Acute Ischemic Stroke: A Statement from Society of Vascular and Interventional Neurology Guidelines and Practice Standards (GAPS) Committee, Stroke: Vascular and Interventional Neurology, 2:4, Online publication date: 1-Jul-2022. Honig A, Hallevi H, Simaan N, Sacagiu T, Seyman E, Filioglo A, Gomori M, Rotschild O, Jonas-Kimchi T, Sadeh U, Horev A, Leker R, Cohen J and Molad J (2022) Safety and Efficacy of Intravenous Alteplase before Endovascular Thrombectomy: A Pooled Analysis with Focus on the Elderly, Journal of Clinical Medicine, 10.3390/jcm11133681, 11:13, (3681) Related articlesEffect of Occlusion Site on the Safety and Efficacy of Intravenous Alteplase Before Endovascular Thrombectomy: A Prespecified Subgroup Analysis of DIRECT-MTYu Zhou, et al. Stroke. 2022;53:7-16 January 2022Vol 53, Issue 1Article InformationMetrics © 2021 American Heart Association, Inc.https://doi.org/10.1161/STROKEAHA.121.037603PMID: 34915740 Originally publishedDecember 17, 2021 PDF download Advertisement SubjectsCerebrovascular ProceduresIschemic Stroke
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