The impact of diabetes mellitus on the outcomes of revascularization for chronic limb-threatening ischemia in the BEST-CLI trial.

Several observational studies have demonstrated an association between diabetes mellitus (DM) and above-ankle amputation after lower extremity revascularization (LER). However, data from prospective randomized trials is lacking. This analysis compares the outcomes of patients with and without DM enrolled in the Best Endovascular vs Best Surgical Therapy in patients with Chronic Limb-Threatening Ischemia (BEST-CLI) trial. Baseline characteristics were compared between patients with and without DM in the BEST-CLI trial. Cox regression was used to determine the association between DM and major outcomes of major adverse limb events (MALE), reintervention, above-ankle amputation, and all-cause death. Among 1777 patients who underwent LER, 69.2% had DM. Compared with patients without DM, those with DM were significantly younger, less likely to be White, and more likely to be Hispanic. Patients with DM were more likely to have hypertension, hyperlipidemia, coronary artery disease, congestive heart failure, and renal disease and be on optimal medical therapy (antiplatelets and statins), whereas patients without DM were significantly more likely to be smokers and have chronic obstructive pulmonary disease. Patients with DM were significantly more likely to present with late Wound Ischemia foot Infection (WIfI) stages (3-4) (73.7% vs 45.9%; P < .001) that were driven predominantly by differences in wound and infection grade. Conversely, patients without DM had significantly lower ankle pressures and toe pressures and were significantly more likely to have WIfI ischemia grade 3 compared with patients with DM (60% vs 52.5%; P = .016). At 3 years, patients with DM exhibited higher rates of above-ankle amputation and all-cause death compared with patients without DM. Kaplan-Meier analysis demonstrated significantly higher MALE or all-cause death compared with patients without DM (3-year estimate: 53.5% vs 46.4%; P < .001). After adjusting for potential confounders, regression analysis demonstrated that DM was independently associated with increased above-ankle amputation (1.75 [1.22-2.51]), all-cause death (1.63 [1.31-2.03]), and MALE or all-cause death (1.24 [1.04-1.47]). Patients with DM undergoing LER for chronic limb-threatening ischemia experienced a greater incidence of MALE or all-cause death compared with patients without DM. The impact of DM seems to be mediated by more severe wounds and infections at the time of presentation, and a higher prevalence of cardiac and renal disease.

Ochoa Chaar CI ，Malas M ，Doros G ，Schermerhorn M ，Conte MS ，Alameddine D ，Siracuse JJ ，Yadavalli SD ，Dake MD ，Creager MA ，Tan TW ，Rosenfield K ，Menard MT ，Farber A ，Hamdan A ... -  《-》

Female patients have fewer limb amputations compared to male patients in the BEST-CLI trial.

Female patients are less likely to be diagnosed with and treated for peripheral artery disease. When treated, there are also reported sex disparities in short- and long-term outcomes. We designed this study to compare outcomes after open and endovascular revascularization in the Best Endovascular vs best Surgical Therapy in patients with Critical Limb Ischemia (BEST-CLI) trial between females and males, and to examine outcomes of each revascularization type in an all-female cohort. In a secondary analysis of cohorts 1 and 2 of the BEST-CLI Trial, patients with chronic limb-threatening ischemia (CLTI) undergoing open surgical bypass (with or without adequate conduit) and endovascular therapy were stratified by sex. In addition, in a female-only cohort, we evaluated differences in outcomes between treatment arm (combined all bypasses from cohorts 1 and 2 and compared with all endovascular treatment in cohorts 1 and 2). Outcomes included major amputation, reintervention, major adverse limb event (MALE, a composite of major amputation and reintervention), all-cause death, and composite outcome of MALE or all-cause death. Univariable and adjusted Cox regressions were used to assess outcome between males and females. Similar methods were used to assess differences in outcomes between treatment arm in females. Among 1830 patients, females were significantly underrepresented, comprising only 28% (n = 519) of the BEST-CLI cohort. Overall, the characteristics of females enrolled in the trial had some differences compared with males: females were more likely to have rest pain alone (72% vs 60%; P < .0001) and when presenting with an ischemic wound, were less likely to have a wound infection (38% vs 47%; P = .01). Females were less likely to have an adequate single-segment greater saphenous vein (SSGSV) available (82% vs 89%; P = .01). Controlled for baseline clinical factors, at 1 year, females had significantly lower rates of major limb amputation compared with males (hazard ratio [HR], 0.70; P = .023), which drove better amputation- and MALE-free survival rates. All-cause death at 1 year was not statistically different between sexes (11.8% vs 11.2%; P = .286). In the all-female cohort, results paralleled the overall trial; open surgical bypass (with any conduit) had significantly better outcomes compared with endovascular therapy. Specifically, among females undergoing endovascular therapy, the rate of major reintervention was particularly high compared with females undergoing open surgical bypass (24.8% vs 10.5%; P < .001). Despite being underrepresented in BEST-CLI, the primary results of the trial, namely, improved MALE-free survival with open surgical bypass with SSGSV, were mirrored in the all-female subset. Female patients enrolled in BEST-CLI had better amputation-free survival at 1 year compared with male patients. These findings suggest that in treating female patients with CLTI considered appropriate for both open and endovascular revascularization, surgical bypass with optimal conduit is the preferred treatment option and can potentially ameliorate poor limb preservation outcomes associated with sex.

McGinigle KL ，Doros G ，Alabi O ，Brooke BS ，Vouyouka A ，Hiramoto J ，Charlton-Ouw K ，Strong MB ，Rosenfield K ，Menard MT ，Farber A ，Giles KA ... -  《-》

Advanced Wound, Ischemia, and Foot Infection stage is associated with poor outcomes in the BEST-CLI trial.

Wound, Ischemia, and foot Infection (WIfI) staging was established to provide objective classification in patients with chronic limb-threatening ischemia (CLTI) and to predict 1-year major amputation risk. Our goal was to validate WIfI staging using data from the Best Endovascular vs Best Surgical Therapy in Patients with CLTI (BEST-CLI) trial. Data from the BEST-CLI Trial, a prospective randomized trial comparing surgical revascularization (OPEN) and endovascular revascularization (ENDO), were used to assess the association of WIfI stage on long-term outcomes in an intention-to-treat analysis. Patients were prospectively allocated to two cohorts, which included patients with and without adequate single-segment greater saphenous vein, respectively. The primary outcome of this analysis was major amputation. There were 1568 patients analyzed, representing 86% of the entire trial population; of these 35.5%, 29.6%, and 34.9% were categorized as WIfI stage 4, WIfI stage 3, and WIfI stage 1/2, respectively. There were 1223 patients (606 OPEN, 617 ENDO) and 345 patients (OPEN 172, ENDO 173) in cohorts 1 and 2, respectively. On unadjusted Kaplan-Meier analysis, WIfI clinical stages 4 and 3, compared with WIfI stage 1/2, were associated with higher rates of major amputation (21.4%, 16.2% vs 10.7%), death (33.5%, 35.7% vs 24.6%), amputation/death (44.9%, 44.5% vs 31.3%), major adverse limb events (MALEs)/death (34.4%, 33.9% vs 29.5%), and reintervention/amputation/death (69.9% vs 69% vs 60.4%) (P < .05 for all) at 3 years. On risk-adjusted analysis, compared with WIfI stage 1/2, major amputation was associated with WIfI stage 4 (hazard ratio [HR], 2.06; 95% confidence interval [CI], 1.44-2.96; P < .001) and WIfI stage 3 (HR, 1.62; 95% CI, 1.1-2.37; P = .013) stages. Death was associated with WIfI stage 4 (HR, 1.3; 95% CI, 1.03-1.63; P = .027) and WIfI stage 3 (HR, 1.42; 95% CI, 1.13-1.79; P = .003). MALE/death was associated with WIfI stage 4 (HR, 1.29; 95% CI, 1.02-1.63; P = .036. Reintervention amputation/death was associated with WIfI stage 4 (HR, 1.28; 95% CI, 1.09-1.50; P = .03) and WIfI stage 3 (HR, 1.22, 99% CI 1.03-1.43) ; P = .018). When examining OPEN vs ENDO revascularization by each WIfI stage, OPEN intervention was favored in cohort 1 for MALE/death for each stage. In BEST-CLI, WIfI stage was strongly associated with major amputations, death, and MALEs/death after revascularization for CLTI. Cohort 1 patients, with an adequate preoperative single segment greater saphenous vein, had lower MALE/death with OPEN intervention across all WIfI stages. This validation of WIfI score in a prospective multicenter trial reinforces its importance in shared-decision making, informed consent, and prognostication.

Siracuse JJ ，Farber A ，Menard MT ，Rosenfield K ，Conte MS ，Schanzer A ，Doros G ，Motaganahalli R ，Laskowski IJ ，Barshes NR ，Genovese EA ，Strong MB ，Mills JL ... -  《-》

Surgery or endovascular therapy for patients with chronic limb-threatening ischemia requiring infrapopliteal interventions.

The recent publication of randomized trials comparing open bypass surgery to endovascular therapy in patients with chronic limb-threatening ischemia, namely, Best Endovascular vs Best Surgical Therapy in Patients with Critical Limb Ischemia (BEST-CLI) and Bypass versus Angioplasty in Severe Ischaemia of the Leg-2 (BASIL-2), has resulted in potentially contradictory findings. The trials differed significantly with respect to anatomical disease patterns and primary end points. We performed an analysis of patients in BEST-CLI with significant infrapopliteal disease undergoing open tibial bypass or endovascular tibial interventions to formulate a relevant comparator with the outcomes reported from BASIL-2. The study population consisted of patients in BEST-CLI with adequate single segment saphenous vein conduit randomized to open bypass or endovascular intervention (cohort 1) who additionally had significant infrapopliteal disease and underwent tibial level intervention. The primary outcome was major adverse limb event (MALE) or all-cause death. MALE included any major limb amputation or major reintervention. Outcomes were evaluated using Cox proportional regression models. The analyzed subgroup included a total of 665 patients with 326 in the open tibial bypass group and 339 in the tibial endovascular intervention group. The primary outcome of MALE or all-cause death at 3 years was significantly lower in the surgical group at 48.5% compared with 56.7% in the endovascular group (P = .0018). Mortality was similar between groups (35.5% open vs 35.8% endovascular; P = .94), whereas MALE events were lower in the surgical group (23.3% vs 35.0%; P<.0001). This difference included a lower rate of major reinterventions in the surgical group (10.9%) compared with the endovascular group (20.2%; P = .0006). Freedom from above ankle amputation or all-cause death was similar between treatment arms at 43.6% in the surgical group compared with 45.3% the endovascular group (P = .30); however, there were fewer above ankle amputations in the surgical group (13.5%) compared with the endovascular group (19.3%; P = .0205). Perioperative (30-day) death rates were similar between treatment groups (2.5% open vs 2.4% endovascular; P = .93), as was 30-day major adverse cardiovascular events (5.3% open vs 2.7% endovascular; P = .12). Among patients with suitable single segment great saphenous vein who underwent infrapopliteal revascularization for chronic limb-threatening ischemia, open bypass surgery was associated with a lower incidence of MALE or death and fewer major amputation compared with endovascular intervention. Amputation-free survival was similar between the groups. Further investigations into differences in comorbidities, anatomical extent, and lesion complexity are needed to explain differences between the BEST-CLI and BASIL-2 reported outcomes.

Giles KA ，Farber A ，Menard MT ，Conte MS ，Nolan BW ，Siracuse JJ ，Strong MB ，Doros G ，Venermo M ，Azene E ，Rosenfield K ，Powell RJ ... -  《-》

Outcomes of chronic limb-threatening ischemia revascularization in patients with chronic kidney disease in the BEST-CLI trial.

Chronic limb-threatening ischemia (CLTI) in patients with chronic kidney disease (CKD) has a high risk of poor outcomes. We aimed to compare the outcomes of lower extremity revascularization in patients with CLTI stratified by CKD severity in patients enrolled in the prospective, randomized Best Endovascular vs Best Surgical Therapy in Patients with CLTI (BEST-CLI) trial. The BEST-CLI trial dataset was queried to categorize patients into three groups according to CKD stage. Group A includes non-CKD and CKD stages <3; group B includes stage 3 and stage 4 CKD patients; and group C includes stage 5 CKD and dialysis-dependent patients. Furthermore, spline modeling was performed across the range of estimated glomerular filtration rate (eGFR, mL/min/1.73 m2) observed in study participants to identify a threshold eGFR that impacted the primary trial outcomes: major adverse limb events (MALEs; defined as above-ankle amputation or major reintervention) or all-cause mortality, by surgical or endovascular revascularization (as-treated analysis). Kaplan-Meier and multivariate Cox regression analyses were used to assess association of CKD risk groups with the outcomes. A total of 1797 patients were included. Group C patients had double the risk of amputation (hazard ratio [HR], 2.13; P < .001), MALE, or all-cause mortality (HR, 2.05; P < .001) and more than triple the risk of all-cause mortality (HR, 3.40; P < .001) compared with group A. In dialysis-dependent patients, endovascular therapy was associated with better survival, but twice the risk of reintervention compared with surgical revascularization. According to spline model analysis, hazard of MALE or all-cause mortality increased sharply at eGFR <30. The hazard ratios for eGFR <30 vs ≥60 were 2.03 (95% confidence interval [CI], 1.68-2.43; P < .001) and 3.46 (95% CI, 2.80-4.27; P < .001) for MALE and mortality, respectively. At eGFR <30, there was no difference in the primary outcome by treatment received (surgical or endovascular revascularization). The progressive nature of renal impairment in patients with CLTI threatens their survival and limb salvage and may reduce the relative benefit of open vs endovascular revascularization seen in the overall BEST-CLI trial population. In dialysis-dependent patients, endovascular therapy was associated with lower mortality but increased reintervention rate.

Malas MB ，Hamouda M ，Farber A ，Menard MT ，Conte MS ，Rosenfield K ，Strong MB ，Doros G ，Powell RJ ，Mena-Hurtado C ，Gasper W ，Schermerhorn ML ，Allievi S ，Smolderen KG ，Dake MD ，Rymer JA ，Tuttle KR ... -  《-》