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BACKGROUND AND OBJECTIVES: Patients with multimorbidity are under-represented in clinical trials. Inclusion in stroke trials is often limited by exclusion based on pre-morbid disability, concerns about worse post-stroke outcomes in acute treatment trials, and a possibly increased proportion of haemorrhagic vs ischaemic stroke in prevention trials. Multimorbidity is associated with increased mortality after stroke, but it is unclear whether this is driven by increased stroke severity, or is confounded by particular stroke subtypes or premorbid disability. We aimed to determine the independent association of multimorbidity with stroke severity taking account of these main potential confounders. METHODS: In a population-based incidence study (Oxford Vascular Study; 2002-2017), pre-stroke multimorbidity (Charlson Comorbidity Index-CCI; unweighted/weighted) in all first-in-study strokes was related to post-acute severity (≈24 hours; NIH Stroke Scale-NIHSS), stroke subtype (haemorrhagic vs ischaemic; Trial of Org 10172 in Acute Stroke Treatment-TOAST), and pre-morbid disability (modified Rankin score/mRS≥2) using age/sex-adjusted logistic and linear regression models, and to 90-day mortality using Cox proportional hazard models. RESULTS: Among 2492 patients (mean/SD age=74.5/13.9; 1216/48.8% male; 2160/86.7% ischaemic strokes; mean/SD NIHSS=5.7/7.1), 1402/56.2% had at least one CCI comorbidity, and 700/28.1% had multimorbidity. Although multimorbidity was strongly related to pre-morbid mRS≥2 (aOR for per CCI comorbidity=1.42, 1.31-1.54, p<0.001) and comorbidity burden was crudely associated with increased severity of ischaemic stroke (OR per comorbidity: 1.12, 1.01-1.23 for NIHSS 5-9, p=0.027; 1.15, 1.06-1.26, for NIHSS≥10; p=0.001), no association with severity remained after stratification by TOAST subtype (aOR=1.02, 0.90-1.14, p=0.78 for NIHSS 5-9 vs 0-4: 0.99, 0.91-1.07, p=0.75 for NIHSS≥10vs0-4), or within any individual subtype. The proportion of intracerebral haemorrhage versus ischaemic stroke was lower in patients with multimorbidity (aOR per comorbidity=0.80, 0.70-0.92, p<0.001), and multimorbidity was only weakly associated with 90-day mortality after adjustment for age, sex, severity, and pre-morbid disability (aHR per comorbidity=1.09, 1.04-1.14, p<0.001). Results were unchanged using the weighted CCI. DISCUSSION: Multimorbidity is common in patients with stroke and is strongly related to pre-morbid disability, but is not independently associated with increased ischaemic stroke severity. Greater inclusion of patients with multimorbidity is unlikely therefore to undermine the effectiveness of interventions in clinical trials, but would increase external validity.

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