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Background: Acute ischemic stroke with isolated posterior cerebral artery occlusion (iPCAO) lacks management evidence from randomized trials. We aimed to evaluate whether the association between endovascular treatment (EVT) and outcomes in iPCAO acute ischemic stroke is modified by initial stroke severity (baseline National Institutes of Health Stroke Scale [NIHSS]) and arterial occlusion site., Methods: Based on the multicenter, retrospective, case-control study of consecutive iPCAO acute ischemic stroke patients (PLATO study [Posterior Cerebral Artery Occlusion Stroke]), we assessed the heterogeneity of EVT outcomes compared with medical management (MM) for iPCAO, according to baseline NIHSS score (≤6 versus >6) and occlusion site (P1 versus P2), using multivariable regression modeling with interaction terms. The primary outcome was the favorable shift of 3-month modified Rankin Scale (mRS). Secondary outcomes included excellent outcome (mRS score 0-1), functional independence (mRS score 0-2), symptomatic intracranial hemorrhage, and mortality., Results: From 1344 patients assessed for eligibility, 1059 were included (median age, 74 years; 43.7% women; 41.3% had intravenous thrombolysis): 364 receiving EVT and 695 receiving MM. Baseline stroke severity did not modify the association of EVT with 3-month mRS distribution ( P interaction =0.312) but did with functional independence ( P interaction =0.010), with a similar trend on excellent outcome ( P interaction =0.069). EVT was associated with more favorable outcomes than MM in patients with baseline NIHSS score >6 (mRS score 0-1, 30.6% versus 17.7%; adjusted odds ratio [aOR], 2.01 [95% CI, 1.22-3.31]; mRS score 0 to 2, 46.1% versus 31.9%; aOR, 1.64 [95% CI, 1.08-2.51]) but not in those with NIHSS score ≤6 (mRS score 0-1, 43.8% versus 46.3%; aOR, 0.90 [95% CI, 0.49-1.64]; mRS score 0-2, 65.3% versus 74.3%; aOR, 0.55 [95% CI, 0.30-1.0]). EVT was associated with more symptomatic intracranial hemorrhage regardless of baseline NIHSS score ( P interaction =0.467), while the mortality increase was more pronounced in patients with NIHSS score ≤6 ( P interaction =0.044; NIHSS score ≤6: aOR, 7.95 [95% CI, 3.11-20.28]; NIHSS score >6: aOR, 1.98 [95% CI, 1.08-3.65]). Arterial occlusion site did not modify the association of EVT with outcomes compared with MM., Conclusions: Baseline clinical stroke severity, rather than the occlusion site, may be an important modifier of the association between EVT and outcomes in iPCAO. Only severely affected patients with iPCAO (NIHSS score >6) had more favorable disability outcomes with EVT than MM, despite increased mortality and symptomatic intracranial hemorrhage., Competing Interests: Disclosures Dr Dabus: consultancy for Cerenovus, Penumbra, Route 92, Medtronic, MicroVention, and Stryker; stock holdings in RIST and InNeuroCo. Dr Fifi: consultancy for Cerenovus, MicroVention, and Stryker; Data Safety Monitoring Board (DSMB) for MIVI; stock holdings in Imperative Care and Sim&Cure. Dr Fischer: research support from the Swiss National Science Foundation (SNF), Medtronic, Stryker, Rapid Medical, Penumbra, and Phenox; consultancies for Stryker and CSL Behring; is on the advisory board for Alexion/Portola, Boehringer Ingelheim, Biogen, and Acthera. Dr Haussen: consultancy for Vesalio, Cerenovus, Stryker, Brainomix, Poseydon Medical, and Chiesi USA; DSMB for Jacobs Institute; stock options in viz AI. Dr Herweh: consultancy for Brainomix; speaker with Stryker. Dr Jadhav: consulting with Basking Biosciences; stock options in Gravity Medical Technology; a patent for a novel stent retriever device licensed to Basking Biosciences; and Editor-in-Chief for the Stroke: Vascular and Interventional Neurology journal. Dr Kaesmacher: grants from the Swiss Academy of Medical Sciences/Bangerter Foundation, Swiss Stroke Society, and Clinical Trials Unit Bern. Dr Kaiser: grants from the Joachim Herz Foundation. Dr Kuramatsu: grants from Alexion Pharmaceuticals, Bayer Healthcare, Sanofi Pasteur, and Biogen Idec. Dr Marto: consulting and speaker fees from Amicus Therapeutics and Boehringer Ingelheim. Dr Michel: grants from the University of Lausanne and SNF. Dr Möhlenbruch: grants from Medtronic, Stryker, and MicroVention. Dr Mokin: stock holdings in BrainQ, Serenity Medical, Synchron, and Bendit Technology; consulting at MicroVention, Medtronic, and Johnson & Johnson. Dr Nagel: consultancy for Brainomix; speaker at Boehringer Ingelheim and Pfizer. Dr Nguyen: Associate Editor of Stroke, advisory board at Aruna Bio and Brainomix. Dr Nogueira: consultancy for Biogen, Brainomix, Corindus, Cerenovus, Stryker, Medtronic, Ceretrieve, Anaconda Biomed, Vesalio, Imperative Care, NeuroVasc Technologies, viz AI, Genentech, Prolong Pharmaceuticals, Perfuze, Phenox, and RapidPulse; stock options in viz AI, Vesalio, Perfuze, Corindus, Brainomix, and Ceretrieve; grants from Cerenovus and Stryker. Dr Nolte: research support and compensation from Novartis, AstraZeneca, Deutsches Zentrum für Herz-Kreislaufforschung, and Deutsches Zentrum für Neurodegenerative Erkrankungen; consultancy for Alexion, Daiichi Sankyo, Novartis, AstraZeneca, Bayer Healthcare, Pfizer, Alexion, and Bristol Myers Squibb. S. Poli: research grants from BMS/Pfizer, Boehringer Ingelheim, Daiichi Sankyo, German Federal Joint Committee Innovation Fund, and German Federal Ministry of Education and Research, Helena Laboratories and Werfen as well as speakers’ honoraria/consulting fees from Alexion, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb/Pfizer, Daiichi Sankyo, Portola, and Werfen (all outside of the submitted work). Dr Psychogios: grants from Penumbra, Rapid Medical, Medtronic, Phenox, Bangerter-Rhyner Stiftung, SNF, Siemens Healthineers, and Stryker Neurovascular; travel support from Medtronic, Siemens Healthineers, Phenox, Penumbra, and Stryker; consultancy for Siemens Healthineers. Dr Puetz: lecturer for Daiichi Sankyo. Dr Ribo: consultancy for Medtronic MiniMed, Cerenovus, AptaTargets, Stryker, and Philips; stock holdings in Methinks, Nora, and Anaconda Biomed. Dr Ringleb: travel support from Bayer and Bristol Myers Squibb; consultancy for Daiichi Sankyo Company and Boehringer Ingelheim. Dr Romoli: research grants from the Italian Stroke Association; consultancy for CSL Behring. Dr Sheth: consultancy for Imperative Care, viz AI, and Penumbra; compensation from Motif Neurosciences (other services); grants from the National Institutes of Health. Dr Siddiqui: ownership stake in Integra Lifesciences and Medtronic; consultancy for Cordis, Rapid Medical, MicroVention, Medtronic Vascular, Vassol, IRRAS USA, Boston Scientific, Amnis Therapeutics, Minnetronix Neuro, Canon Medical Systems USA, Cardinal Health 200, Johnson & Johnson–Latin America, Corindus, Penumbra, Apellis Pharmaceuticals, W.L. Gore & Associates, Stryker Corporation, and viz AI; stock holdings in E8, Spinnaker Medical, Endostream Medical, Cerebrotech Medical Systems, Adona Medical, Bend IT Technologies, Whisper Medical, Neurotechnology Investors, Collavidence, Instylla, Q’Appel Medical, Serenity Medical, Borvo Medical, NeuroRadial Technologies, Sense Diagnostics, Tulavi Therapeutics, Synchron, Neurolutions, Viseon, BlinkTBI, Radical Catheter Technologies, and Truvic Medical; stock options in viz AI, StimMed, Three Rivers Medical, Silk Road Medical, Imperative Care, CVAid Ltd, Cerevatech Medical, InspireMD, PerFlow Medical; security holdings in Vastrax, Launch NY, QAS.ai, VICIS, Inc, Neurovascular Diagnostics, Cognition Medical, and SongBird Therapy. Dr Strbian: Assistant Editor of Stroke, Editorial Board of European Stroke Journal, advisory board at Boehringer Ingelheim, Alexion/AstraZeneca, and Bristol Myers Squibb/Janssen; research support from Boehringer Ingelheim; consultancies for Orion, Herantis Pharma, and CSL Behring. The other authors report no conflicts.