<h4>Background</h4>Carotid revascularisation, comprising either carotid endarterectomy or stenting, is offered to patients with carotid stenosis to prevent stroke based on the results of randomised trials conducted more than 30 years ago. Since then, medical therapy for stroke prevention has improved. We aimed to assess whether patients with asymptomatic and symptomatic carotid stenosis with a low or intermediate predicted risk of stroke, who received optimised medical therapy (OMT), would benefit from additional revascularisation.<h4>Methods</h4>The Second European Carotid Surgery Trial (ECST-2) is a multicentre randomised trial with blinded outcome adjudication, which was conducted at 30 centres with stroke and carotid revascularisation expertise in Europe and Canada. Patients aged 18 years or older with asymptomatic or symptomatic carotid stenosis of 50% or greater, and a 5-year predicted risk of ipsilateral stroke of less than 20% (estimated using the Carotid Artery Risk [CAR] score), were recruited. Patients were randomly assigned to either OMT alone or OMT plus revascularisation (1:1) using a web-based system. The primary outcome for this 2-year, interim analysis was a hierarchical outcome composite of: (1) periprocedural death, fatal stroke, or fatal myocardial infarction; (2) non-fatal stroke; (3) non-fatal myocardial infarction; or (4) new silent cerebral infarction on imaging. Analysis was by intention-to-treat using the win ratio-ie, each patient in the OMT alone group was compared as a pair with each patient in the OMT plus revascularisation group, with a win declared for the patient with a better outcome within the pair (a tie was declared if neither patient in the pair had a better outcome). The win ratio was calculated as the number of wins in the OMT alone group divided by the number of wins in the OMT plus revascularisation group. This trial is registered with the ISRCTN Registry (ISRCTN97744893) and is ongoing.<h4>Findings</h4>Between March 1, 2012, and Oct 31, 2019, 429 patients were randomly assigned to OMT alone (n=215) or OMT plus revascularisation (n=214). One patient allocated to OMT alone withdrew consent within 48 h and was not considered further. The median age of patients was 72 years (IQR 65-78); 296 (69%) were male and 133 (31%) female. No benefit was recorded in favour of either treatment group with respect to the primary hierarchical outcome assessed 2 years after randomisation, with 5228 (11·4%) wins for the OMT alone group, 5173 (11·3%) wins for the OMT plus revascularisation group, and 35 395 (77·3%) ties between groups (win ratio 1·01 [95% CI 0·60-1·70]; p=0·97). For OMT alone versus OMT plus revascularisation, four versus three patients had periprocedural death, fatal stroke, or fatal myocardial infarction; 11 versus 16 had non-fatal stroke; seven versus five had non-fatal myocardial infarction; and 12 versus seven had new silent cerebral infarction on imaging. One periprocedural death occurred in the OMT plus revascularisation group, which was attributed to decompensated aortic stenosis 1 week after carotid endarterectomy.<h4>Interpretation</h4>No evidence for a benefit of revascularisation in addition to OMT was found in the first 2 years following treatment for patients with asymptomatic or symptomatic carotid stenosis of 50% or greater with a low or intermediate predicted stroke risk (assessed by the CAR score). The results support treating patients with asymptomatic and low or intermediate risk symptomatic carotid stenosis with OMT alone until further data from the 5-year analysis of ECST-2 and other trials become available.<h4>Funding</h4>National Institute for Health and Care Research; Stroke Association; Swiss National Science Foundation; Dutch Organisation for Knowledge and Innovation in Health, Healthcare and Well-Being; Leeds Neurology Foundation.