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Published on: September 22, 2020
Understanding objective performance goals for critical limb ischemia trials
1Division of Vascular and Endovascular Surgery, University of California, San Francisco, 400 Parnassus Avenue, Suite A-581, San Francisco, CA 94143, USA. michael.conte@ucsfmedctr.org
Insights
Objective performance goals (OPGs) were established for critical limb ischemia (CLI) to standardize clinical trials for new revascularization devices. These benchmarks aid in assessing device safety and efficacy for limb salvage in CLI patients.
Area of Science:
- Vascular Surgery
- Clinical Trial Design
- Peripheral Arterial Disease Research
Background:
- Critical limb ischemia (CLI) is the advanced stage of peripheral arterial disease, leading to high limb loss and mortality rates.
- Surgical bypass is the standard for limb salvage, but less-invasive endovascular therapies lack robust efficacy data for CLI.
- Clinical trials for CLI are complex due to undefined cohorts and endpoints, hindering device development.
Purpose of the Study:
- To establish objective performance goals (OPGs) for critical limb ischemia (CLI) to serve as therapeutic benchmarks.
- To facilitate the premarket assessment of new revascularization devices for CLI.
- To define key endpoints and high-risk subgroups for future CLI clinical trials.
Main Methods:
- Analyzed data from three large randomized controlled trials of surgical bypass for CLI.
- Defined a major adverse limb event (MALE) as a composite endpoint including amputation or major vascular reintervention.
- Developed risk-adjusted OPGs for specific high-risk CLI subgroups based on clinical, anatomical, and conduit characteristics.
Main Results:
- Established nine safety and efficacy measures for CLI device assessment, using surgical bypass as the comparator.
- Suggested freedom from perioperative death or MALE (MALE + POD) as a primary efficacy endpoint, with a 76.9% success rate in surgical bypass controls at 1 year.
- Defined high-risk subgroups (e.g., age >80, tissue loss, infrapopliteal disease, poor vein quality) with corresponding risk-adjusted OPGs.
Conclusions:
- The developed OPGs provide new benchmarks for evaluating revascularization therapies in CLI.
- These benchmarks are expected to streamline clinical trial design and accelerate the development of novel devices for CLI.
- Standardized endpoints and performance goals are crucial for advancing limb salvage in critical limb ischemia.
Abstract:
Critical limb ischemia (CLI), the most advanced form of peripheral arterial disease, is associated with a high rate of limb loss and substantial mortality. Revascularization remains the cornerstone of limb salvage in the CLI patient, and surgical bypass is the established standard. Endovascular therapies, such as angioplasty, atherectomy, and stenting offer a less-invasive option, but evidence of efficacy is lacking, and no devices are currently approved specifically for CLI. Design and execution of clinical trials in the CLI population are challenging, in part because of the lack of consensus on cohort definitions and relevant endpoints. Recently, the Society for Vascular Surgery undertook an initiative to define therapeutic benchmarks, objective performance goals (OPGs), for CLI. Using surgical bypass with autogenous vein as the standard for comparison, OPGs were developed for nine safety and efficacy measures that could be utilized in the premarket assessment of new devices in CLI. Data from three large randomized controlled trials of surgical bypass for CLI were analyzed. We defined a major adverse limb event (MALE) as a key endpoint for revascularization therapies in CLI--inclusive of amputation (transtibial or above) or any major vascular reintervention (thrombectomy, thrombolysis, or major surgical procedure [new bypass graft, jump/interposition graft revision]) in the index limb. Freedom from perioperative (30-day) death or any MALE (MALE + POD) was suggested as the primary efficacy endpoint for a single-arm trial design in CLI, with an observed rate of 76.9% for the surgical bypass controls at 1 year. Specific high-risk subgroups were also defined from the surgical dataset--based on clinical (age older than 80 years and tissue loss), arterial anatomy (infrapopliteal disease), and conduit quality (inadequate saphenous vein) characteristics. Risk-adjusted OPG were developed for these subgroups of interest. These OPGs define a new set of benchmarks for assessing the performance of revascularization therapies in CLI, and should facilitate clinical trial design and device development in this arena.
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