However, the low rate of stroke on medical therapy in patients with 50% to 69% high periprocedural risk, which does not vary by degree of stenosis,368 and lack of demonstrated benefit of PTAS in well-designed RCTs performed in a higher-risk population do not support the use of PTAS. 10. A large multicenter RCT comparing extracranial- intracranial arterial bypass with medical therapy in 1377 patients with recent minor stroke or TIA included patients with 70% intracranial middle cerebral artery (n=109) or ICA (n=149) stenosis and found higher rates of stroke in patients with ICAS treated with extracranial-intracranial arterial bypass than in those in the medical group.361 Knowledge Gaps and Future Research Despite numerous advances in ICAS treatment over the past several decades, the recurrent stroke risk remains high. Further investigation into the following should be prioritized: Studying new therapies in well-designed clinical trials, including novel antithrombotic regimens (eg, direct thrombin inhibitors), improved endovascular treatments (eg, submaximal balloon angioplasty), indirect bypass, and ischemic preconditioning. Determining the interaction between hemodynamic function or collateral flow and treatments (eg, BP management and endovascular therapy). Developing and using surrogate markers of stroke risk (eg, plaque characteristics) or high-risk prognostic fea- tures (eg, diabetes) that may lead to new therapies or improve patient selection for future therapeutic trials. Genetic variants that relate to ICAS (eg, ring finger protein 213) and whether such variants affect the rate of stroke recurrence or treatment responses. 5.1.2. Extracranial Large Artery Atherosclerosis 5.1.2.1. Extracranial Carotid Stenosis Recommendations for Extracranial Carotid Stenosis Referenced studies that support recommendations are summarized in online Data Supplement 28. 