February 24, 2025

BEST-CLI Subanalysis Finds Better Limb Outcomes in Female Patients, Favorable Overall Outcomes With Open Surgical Approach

February 24, 2025—In a secondary analysis of the BEST-CLI trial, McGinigle et al found lower rates of major adverse limb events (MALE) and major limb amputations in female compared with male patients. Like the overall trial results, the female-only subcohort also had a lower risk of MALE with any open surgical bypass compared to endovascular therapy. The results were published in Journal of Vascular Surgery.¹

KEY FINDINGS

Female patients had fewer major limb amputations, better limb outcomes, and better amputation-free survival at 1 year compared with male patients.
Female patients who underwent open surgical bypass had significantly better outcomes than females who underwent endovascular therapy.

Investigators conducted a sex-stratified analysis using the data set from the primary BEST-CLI trial, which was a multisite, randomized controlled trial that included 1,830 patients with chronic limb-threatening ischemia (CLTI) who were randomized 1:1 to either open surgical bypass or endovascular therapy.² For this analysis, outcomes were the same as the primary trial (time to first major amputation, reintervention, all-cause death, MALE, and a composite outcome of MALE and all-cause death). Of note, because of small sample size, female cohorts 1 and 2 were combined, and the open group included female patients who underwent bypass with either single-segment greater saphenous vein (SSGSV) or alternative conduits.

Female patients comprised 28% (n = 519) of the BEST-CLI cohort. They were found to be more likely than male patients to present with rest pain (72% vs 60%; P < .0001) and noninfected wounds (38% vs 47%; P = .01) and were less likely to have adequate SSGSV (82% vs 89%; P = .01).

Controlling for these factors, compared with male patients, female patients had a 22% lower rate of MALE (hazard ratio [HR], 0.78; P = .027) and a 39% lower rate of major limb amputation at 1 year (HR, 0.7; P = .044), while all-cause death was similar between sexes (11.8% vs 11.2%).

In the all-female cohort analysis, significantly better outcomes were seen in females who underwent open surgical bypass versus those who underwent endovascular therapy. Specifically, the rate of reintervention was higher in those who underwent endovascular therapy versus open surgery (24.8% vs 10.5%; P < .001). Compared with female patients who underwent endovascular therapy, those who underwent open surgical revascularization had a 57% lower risk of MALE at 1 year (HR, 0.43; 95% CI, 0.26-0.66) and better overall 1-year survival (HR, 0.67; 95% CI, 0.50-0.89), but there was no difference in rates of major amputation (HR, 0.63; 95% CI, 0.34-1.16).

The investigators noted several limitations, including the underrepresentation of female patients in the primary BEST-CLI trial and the potential for selection bias, especially since the females enrolled in the trial were less likely to have severe and infected wounds, as may be encountered in general practice settings. Additionally, although it appears that open surgical bypass is the favorable revascularization approach in female patients who are eligible for either open or endovascular therapy, the study lacks power to determine the best treatments to achieve the best outcomes for females specifically. Nonetheless, with aggressive diagnosis and treatment of female patients with CLTI, any open surgical bypass for revascularization can potentially eliminate sex disparities noted in previously reported retrospective studies, added the investigators.

1. McGinigle KL, Doros G, Alabi O, et al. Female patients have fewer limb amputations compared to male patients in the BEST-CLI trial. J Vasc Surg. 2025;81:366-373.e1. doi: 10.1016/j.jvs.2024.09.031

2. Farber A, Menard MT, Conte MS, et al. Surgery or endovascular therapy for chronic limb-threatening ischemia. N Engl J Med. 2022;387:2305-2316. doi: 10.1056/NEJMoa2207899

ENDOVASCULAR TODAY ASKS…

Lead study investigator Katharine McGinigle, MD, MPH, with University of North Carolina at Chapel Hill, discusses the study’s findings, their applicability in practice, and areas for future study.

Registry data have shown negative sex disparities in the diagnosis, treatment, and outcomes of females with peripheral artery disease (PAD) compared to males, but these differences were not seen in the BEST-CLI data. What might explain this, and how can this be further explored?

To answer this, we’ll separate out diagnosis and outcomes. For the diagnosis of PAD and/or CLTI, I think there were disparities in the patients who were ultimately enrolled in the trial. Because PAD is equally prevalent between genders and more prevalent in elderly females than males, the poor representation of females in the trial is likely reflective of the overall underdiagnosis and lack of aggressive treatment of the condition in females. However, for the female patients who did make it into the trial, the care provided by the multidisciplinary limb preservation teams at each of the 160 sites clearly worked well. It is reassuring to see that the historically reported technical complications, serious adverse events, and graft failures were not observed. In fact, once diagnosed and properly cared for with the aggressive treatment provided by these PAD teams, females did better than anticipated!

How have the findings from this analysis informed your approach to your female CLTI patients, and how does that differ from your male patients? What do these findings reveal regarding the main differences between male and female CLTI patients?

The BEST-CLI trial overall has influenced my approach to all patients with CLTI. I am a very aggressive endovascular surgeon, but now I always get vein mapping on new patients with CLTI and am more likely to perform a vein bypass compared to earlier in my career. The clinical operational patterns and financial incentives are not yet aligned with the approach, but I really think it is the best thing for the patient. This sex-stratified study, specifically, has made me feel more optimistic about setting preoperative expectations in female patients. After so many retrospective studies telling us that no matter what we do, females will have worse outcomes, it is nice to know that aggressive, multidisciplinary care similar to what was championed at the BEST-CLI trial sites actually does a decent job with limb preservation.

How might a future prospective study, whether randomized or registry/database-oriented, explore your findings further?

To be honest, there is so much that we don’t know about treating CLTI. Large studies like BEST-CLI and all the smaller industry-sponsored device trials predominantly enrolled males who do not have severe chronic kidney disease. Unfortunately, the regulatory environment disincentivizes including all the heterogenous patient populations that are regularly seen in our clinics.

In the basic science labs (hopefully not all in male mice, as is common), there needs to be intense study of biologic differences between males, premenopausal, and postmenopausal females with specific, targeted drug development to prevent and treat atherosclerosis. In the translational space, there needs to be bespoke device development for patients with small arteries (who are disproportionately female). In the clinical trial space, we need specific trials that help us understand what the best medical and surgical treatment combinations for pre- and postmenopausal females are. Female patients, in fact, want to be able to choose between multiple treatment options and know what their actual expected outcomes are based on those choices. Just telling them they may do relatively better or worse than a male patient isn’t helpful. Finally, in the population health and health services research space, we need to study the sex-specific barriers to the diagnosis and treatment of PAD in females and then create systems and/or policies to correct those problems.

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