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Background and Aims: The clinical evolution of acute ischemic stroke patients with isolated proximal posterior cerebral artery (PCA) occlusion treated with medical management alone has been poorly described. We aimed to determine the clinical and radiological factors associated with poor functional outcome in this population., Methods: We conducted a multicenter international retrospective study of consecutive stroke patients with isolated occlusion of the first (P1) or second (P2) segment of PCA admitted within 6 h from symptoms onset in 26 stroke centers in France, Switzerland, and the United States, treated with the best medical management alone. Poor functional outcome was defined as a modified Rankin scale (mRS) ⩾2 at 3 months or no return to pre-stroke mRS. The associations between pretreatment variables and poor outcome were studied in univariable and then multivariable analyses, as well as the association between poor outcome and key follow-up radiological variables., Results: Overall, 585 patients were included. The median age was 74 years (interquartile range (IQR) = 63-83), median National Institutes of Health Stroke Scale (NIHSS) was 6 (3-10), 80% received intravenous thrombolysis (IVT), and 22% and 78% had P1 and P2 occlusions, respectively. Poor outcome occurred in 56% of patients. In multivariable analysis focusing on pretreatment variables, age (adjusted odds ratio (OR) = 1.12 per 5-year increase [95% confidence interval (CI) = 1.05-1.20]; p  = 0.001), NIHSS score (aOR = 1.12 per each point increase [1.08-1.18]; p  < 0.001), infarct volume (aOR = 1.16 per 5 mL increase [1.07-1.25]; p  < 0.001), and the lack of IVT use (aOR = 1.79 [1.10-2.94], p  = 0.020) were independently associated with poor outcome. Regarding 24-h follow-up radiological variables, complete recanalization (defined as no clot in the vascular tree at or beyond the primary occlusive lesion, aOR = 0.37 [95% CI = 0.21-0.65], p  < 0.001) and parenchymal hematoma occurrence (aOR = 2.37 [95% CI = 1.01-5.56], p  = 0.048) were independently associated with poor 3-month outcome., Conclusions: Poor outcome occurred in more than half of medically treated PCA-related acute stroke patients. Facilitating IVT use may improve functional outcome. Therapeutic approaches aimed at enhancing recanalization and reducing hemorrhagic transformation need to be studied in clinical trials., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr M.R.H. reports grants from Swiss National Science Foundation, SITEM Research Support Funds, and Swiss Heart Foundation, not directly related to this manuscript. Professor C.R. receives fees from OTR3 for her participation in a DSMB. Y.B. reports personal fees from BMS, Pfizer, Medtronic, Amgen, Servier, NovoNordisk, Novartis, and Laboratoire XO, outside the submitted work. Dr G.W.A. reports stock holdings in iSchemaView; compensation from Biogen, iSchemaView, and Genentech for consultant services. Dr G.T. reports lecture fees from Guerbert France and consultant services for AI-Stroke. Professor M.M. reports consulting fees from Acticor Biotech, and Boerhinger. Dr P.S. receives speaker fees from Acticor Biotech. Other authors have nothing to disclose.

Rationale: Oxygen is essential for cellular energy metabolism. Neurons are particularly vulnerable to hypoxia. Increasing oxygen supply shortly after stroke onset could preserve the ischemic penumbra until revascularization occurs., Aims: PROOF investigates the use of normobaric oxygen (NBO) therapy within 6 h of symptom onset/notice for brain-protective bridging until endovascular revascularization of acute intracranial anterior-circulation occlusion., Methods and Design: Randomized (1:1), standard treatment-controlled, open-label, blinded endpoint, multicenter adaptive phase IIb trial., Study Outcomes: Primary outcome is ischemic core growth (mL) from baseline to 24 h (intention-to-treat analysis). Secondary efficacy outcomes include change in NIHSS from baseline to 24 h, mRS at 90 days, cognitive and emotional function, and quality of life. Safety outcomes include mortality, intracranial hemorrhage, and respiratory failure. Exploratory analyses of imaging and blood biomarkers will be conducted., Sample Size: Using an adaptive design with interim analysis at 80 patients per arm, up to 456 participants (228 per arm) would be needed for 80% power (one-sided alpha 0.05) to detect a mean reduction of ischemic core growth by 6.68 mL, assuming 21.4 mL standard deviation., Discussion: By enrolling endovascular thrombectomy candidates in an early time window, the trial replicates insights from preclinical studies in which NBO showed beneficial effects, namely early initiation of near 100% inspired oxygen during short temporary ischemia. Primary outcome assessment at 24 h on follow-up imaging reduces variability due to withdrawal of care and early clinical confounders such as delayed extubation and aspiration pneumonia., Trial Registrations: ClinicalTrials.gov: NCT03500939; EudraCT: 2017-001355-31., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.