Peripheral arterial disease (PAD) is primarily caused by atherosclerosis, has a prevalence of 3% to 10% in the general population, and is particularly common in individuals who smoke or have diabetes. A subset of patients with PAD have chronic critical limb ischemia (CLI), marked by intractable foot pain at rest and/or the presence of ischemic ulcerations or necrotic tissue. The annual incidence of CLI has been estimated at 220 to 3500 per 1,000,000 people; its prevalence is approximately 1% of the adult population and up to 10% of patients with PAD have or may develop CLI. The economic impact of CLI in the United States is significant, with annual health-care costs estimated to be greater than $4 billion. The cornerstone of CLI treatment is revascularization to relieve ischemic pain, heal wounds to preserve a functional limb, maintain ambulatory status, and prevent major limb amputation. Across the United States, there is great variability in both amputation and revascularization rates among patients with CLI.
Currently, a diverse group of practitioners – including interventional cardiologists, interventional radiologists, vascular medicine specialists, and vascular surgeons – provides treatment for patients with CLI. The decision to recommend surgical or endovascular revascularization varies among these physicians and is based on a range of patient factors (eg, disease pattern, availability of autogenous conduit, and comorbidities), physician factors (eg, training, surgical and endovascular skill sets, access to appropriate procedural facilities, patterns of referrals, and treatment biases), and other considerations.
Lack of treatment uniformity is highlighted by the marked variability in choice of revascularization strategy. Physicians generally agree that patients who are considered poor candidates for surgery may benefit from endovascular revascularization. However, uncertainty remains about which therapy is most appropriate for patients who have infrainguinal PAD and are candidates for both endovascular and open surgical approaches. Some have argued for an endovascular-first approach in such patients. However, data from both clinical trials and registries suggest that the outcomes of bypass procedures performed after a failed endovascular intervention may be disadvantaged compared with bypass performed as first-line therapy. Lack of consensus regarding the optimal treatment of CLI stems, in part, from disparate individual physician biases in the absence of high-quality data. Although there are many studies comparing management strategies for CLI, most have major limitations arising from their retrospective nature, incomplete control for indication, potential confounders, bias, and incomplete follow-up.
The BEST-CLI (Best Endovascular vs Best Surgical Therapy for Patients With Critical Limb Ischemia) trial, currently being conducted in North America, is a comparative-effectiveness, prospective, multicenter, multidisciplinary, pragmatic, open-label, superiority randomized controlled trial that will compare outcomes of best open surgical and best endovascular revascularization strategies in patients with CLI and infrainguinal PAD. The trial includes a clinical coordinating center with co-principal investigators Alik Farber, MD, Matthew Menard, MD, and Kenneth Rosenfield, MD, and a data coordinating center located at New England Research Institutes, Inc. The trial is sponsored by the United States National Heart, Lung, and Blood Institute. It aims to enroll 2100 patients to assess treatment efficacy, functional outcomes, resource utilization, and total costs between currently practiced open surgical and endovascular revascularization strategies in candidates for both procedures.
The BEST-CLI trial consists of two distinct, independently powered cohorts that will be analyzed separately. The first cohort includes patients who have adequate autogenous single-segment great saphenous vein (SSGSV), while the second includes those without SSGSV who will likely need an alternate conduit if randomized to bypass. The trial is pragmatic in that the specifics of how to best perform the treatment strategy assigned through randomization is left up to the treating physician. All commercially available endovascular therapies are allowed, as are all bypass techniques and conduit types. The primary endpoint is major adverse limb event (MALE)-free survival. This novel and clinically relevant aggregate endpoint includes all major repeated vascular procedures on the index limb, including above-ankle amputation and major reinterventions, and thus captures the therapeutic goals of treatment for CLI, including preservation of a functional limb and avoidance of major reinterventions that adversely affect quality of life.
The BEST-CLI leadership encourages sites to embrace a multidisciplinary team approach, whenever possible, to provide comprehensive, patient-centric care within the trial. Interventional radiologists, interventional cardiologists, interventional vascular medicine specialists, and vascular surgeons who treat patients with CLI are encouraged to work together and, as such, 78% of sites have multidisciplinary participation. Study teams, termed CLI teams, are also encouraged to engage non-operating caregivers, including podiatrists, vascular medicine specialists, wound management specialists, nurse practitioners, and physician assistants. This team approach fosters constructive information exchange and education among all investigators/caregivers and likely sharpens attention on important additional aspects of care, such as optimal medical therapy and wound management, that are not directly related to the index procedure.
At the time of this publication, the BEST-CLI trial has enrolled 775 patients at nearly 140 academic medical centers, private practice groups, and hospitals in the United States and Canada. There is balanced geographic distribution of sites, with 25% in the East, 20% in the South, 22% in the Midwest, 26% in the West, and 7% in Canada. The trial will be complemented by a robust companion CLI registry, sponsored by VIVA Physicians, which is in the process of being organized. This registry aims to enroll 5000 patients at BEST-CLI sites and will significantly expand our CLI management knowledge base. The BEST-CLI trial is a timely and critically needed trial that will significantly impact clinical practice by defining an evidence-based standard of care for patients with CLI.