Surgery or Endovascular Therapy for Chronic Limb-Threatening Ischemia.

BACKGROUND: Patients with chronic limb-threatening ischemia (CLTI) require revascularization to improve limb perfusion and thereby limit the risk of amputation. It is uncertain whether an initial strategy of endovascular therapy or surgical revascularization for CLTI is superior for improving limb outcomes. METHODS: In this international, randomized trial, we enrolled 1830 patients with CLTI and infrainguinal peripheral artery disease in two parallel-cohort trials. Patients who had a single segment of great saphenous vein that could be used for surgery were assigned to cohort 1. Patients who needed an alternative bypass conduit were assigned to cohort 2. The primary outcome was a composite of a major adverse limb event - which was defined as amputation above the ankle or a major limb reintervention (a new bypass graft or graft revision, thrombectomy, or thrombolysis) - or death from any cause. RESULTS: In cohort 1, after a median follow-up of 2.7 years, a primary-outcome event occurred in 302 of 709 patients (42.6%) in the surgical group and in 408 of 711 patients (57.4%) in the endovascular group (hazard ratio, 0.68; 95% confidence interval [CI], 0.59 to 0.79; P<0.001). In cohort 2, a primary-outcome event occurred in 83 of 194 patients (42.8%) in the surgical group and in 95 of 199 patients (47.7%) in the endovascular group (hazard ratio, 0.79; 95% CI, 0.58 to 1.06; P = 0.12) after a median follow-up of 1.6 years. The incidence of adverse events was similar in the two groups in the two cohorts. CONCLUSIONS: Among patients with CLTI who had an adequate great saphenous vein for surgical revascularization (cohort 1), the incidence of a major adverse limb event or death was significantly lower in the surgical group than in the endovascular group. Among the patients who lacked an adequate saphenous vein conduit (cohort 2), the outcomes in the two groups were similar. (Funded by the National Heart, Lung, and Blood Institute; BEST-CLI ClinicalTrials.gov number, NCT02060630.).

Participation in a Chronic Limb Threatening Ischemia Randomized Trial Is Inversely Correlated With Regional Amputation Rate in Limb Threatening Ischemia Patients.

OBJECTIVE: The National Health Service demonstrated that regions of the United Kingdom with the highest number of patients enrolled in research studies had the lowest risk-adjusted mortality when patients were admitted to the hospital. Our goal was to investigate if this correlation was evident for patients with chronic limb threatening ischemia (CLI) treated in the United States (US). Accordingly, we examined correlations among sites participating in the Best Endovascular versus best Surgical Therapy in patients with Critical (BEST-CLI) trial, a multicenter, National Institute of Health-sponsored, international randomized controlled trial (RCT) comparing revascularization strategies in patients with CLI, and regional rates of major amputation from CLI. METHODS: We measured regional participation in the BEST-CLI trial by evaluating trial participation and enrollment rosters. To determine regional rates of lower limb amputation, we queried the Medicare database (2007-2016) for patients with concurrent peripheral arterial disease (PAD) and diabetes, then assessed how many had lower extremity amputations. Correlation of regional amputation rates with distribution of BEST-CLI sites in four US geographical regions was calculated using Pearson's correlation coefficients. Simple regression equations were used to calculate the significance of these correlation coefficients. RESULTS: Of 9,231,909 CLI patients, 342,406 underwent amputation in the Medicare dataset. Amputation rates per 1000 CLI patients differed by region (South 40.42, Midwest 40.12, West 34.81, Northeast 31.14). There were 116 US vascular centers, selected by volume and expertise that participated in BEST-CLI with the following distribution: South (n = 30, 26%), Midwest (n = 26, 22%), West (n = 29, 25%), and Northeast (n = 31, 27%). There was a negative correlation between the number of amputations per 1000 for Medicare CLI patients with diabetes and PAD and the number of BEST-CLI sites in the region which trended toward significance (Pearson R= -0.61, P = 0.39). CONCLUSIONS: Amputation rate among Medicare CLI patients is inversely correlated with US BEST-CLI site distribution. Higher participation in clinical research, especially within large RCTs, may be a marker of optimal PAD management.

Enrollment Obstacles in a Randomized Controlled Trial: A Performance Survey of Enrollment in BEST-CLI Sites.

BACKGROUND: Although randomized controlled trials (RCTs) provide the most reliable form of scientific evidence, they are challenging to complete because of a variety of enrollment obstacles. We evaluated obstacles in a large RCT by comparing survey results at high-performing sites (HPS) and low-performing sites (LPS). METHODS: The Best Endovascular versus Best Surgical Therapy in Patients with Critical Limb Ischemia (BEST-CLI) trial is a prospective, pragmatic, multicenter, and multispecialty RCT that will compare clinical outcomes, quality of life, and cost in patients with CLI randomized to surgical bypass or endovascular therapy. BEST-CLI aims to enroll 2100 patients at 160 sites in North America, Europe, and New Zealand. We surveyed the 30 HPS and 30 LPS to assess perceptions of enrollment obstacles. HPS were defined by enrollment of 0.5 subjects or more per month or more than 8 total subjects enrolled. LPS were defined by enrollment of 0.1 subjects per month or only 1 subject total. Responses were compared by site performance status. RESULTS: There were 22 of 30 (73%) HPS and 14 of 30 (47%) LPS that answered the survey (P = 0.06), including 17 investigators and 31 coordinators. The mean total enrollment and rate of enrollment at HPS and LPS were 12.5 subjects at 1.5 subjects/month and 1.0 subject at 0.1 subjects/month, respectively. The most common barrier to enrollment at HPS was difficulty convincing patients and their families to participate (36%), whereas at LPS both difficulty convincing patients and difficulty motivating investigators to enroll (29% each) were most frequently cited. At HPS, the most common obstacle to consenting patients for the trial was patient/family having strong preference toward revascularization strategy (32%) and at LPS it was patient/family not wanting to have treatment chosen at random (36%). At 55% of HPS and 43% of LPS, the trial team was reported as extremely collaborative (P = 0.73), whereas 68% of HPS and 64% of LPS reported having identified a trial champion on their team (P = 1). The most restrictive perceived enrollment criterion at HPS was prior index limb stenting with significant restenosis (32%), whereas at LPS it was excessive risk for surgical bypass (43%). Materials to aid enrollment were used equally at HPS and LPS: patient brochures at 59% HPS and 64% LPS (P = 1); investigator talking points at 45% of HPS and 36% of LPS (P = 0.73). CONCLUSIONS: Patient perceptions and investigator biases are significant challenges to enrollment in large RCTs. In the BEST-CLI trial, difficulty convincing patients and families to allow treatment randomization and difficulty in motivating investigators were major enrollment obstacles.