Contemporary Chronic Limb-Threatening Ischemia Care in the United States—Part 2: Designing Clinical Device Trials

Head-to-head research comparing invasive revascularization strategies for chronic limb-threatening ischemia (CLTI) is sparse, partly due to challenges in conducting randomized controlled trials in the CLTI space. These include the expense of head-to-head trials, optimizing patient selection criteria for real-world applicability, and identifying optimal study end points. The Vascular InterVentional Advances (VIVA) Foundation, a 501(c)(3) not-for-profit organization, convened a Vascular Leaders Forum to initiate an open, multispecialty collaborative discussion of these challenges and ways to optimize the design of medical device trials in CLTI. This article summarizes the current landscape of clinical studies of CLTI revascularization strategies and options for designing comparative trials proposed by representatives from vascular surgery, interventional cardiology, interventional radiology, vascular medicine, podiatry, the U.S. Food and Drug Administration, and a medical device manufacturer. Four broad areas to optimize comparative trials of CLTI interventions were identified. First, primary end points should be carefully chosen with attention to clinical, patient-centric, imaging, and hierarchical considerations; standardization; and inclusion of guideline-directed medical therapy. Second, broader eligibility criteria can expand and hasten enrollment and are important for gathering evidence on outcomes in medically complex patients often encountered in real-world practice. Third, extending the primary end point timing to 12 months with additional follow-up out to 24 to 60 months would accommodate a longer period of device evaluation and the ability to enrich clinical end-point rates. Finally, innovative pragmatic trial designs and statistical methodologies are needed to conduct comprehensive, cost effective, relevant trials with sufficient statistical power and without prohibitively large sample sizes and study durations.