Analyses offer a deeper dive into BEST-CLI trial data

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Matthew Menard and Michael Conte

As the vascular community continues to digest key insights from the BEST-CLI randomized controlled trial (RCT), attendees of Plenary Session 3 at the Vascular Annual Meeting (VAM) 2023, taking place 8:00–9:30a.m. Thursday morning in Potomac A/B, will be offered a deep dive into the trial’s vast dataset in the form of two new secondary analyses.

BEST-CLI is the largest trial to date comparing revascularization treatment strategies in patients with chronic limb-threatening ischemia (CLTI). The primary results, reported to great interest by investigators in late 2022, showed that both surgical bypass and endovascular strategies are safe and effective, but in those with adequate single-segment great saphenous vein (GSV), it was found that surgery is likely to be the more effective revascularization strategy for a patient who is suitable for either of these approaches.

The two latest analyses, presented here at VAM, come from Matthew Menard, MD, comparing rates of clinical and hemodynamic failure as well as resolution of initial and prevention of recurrent CLTI following endovascular or open revascularization, and from Michael Conte, MD, focusing on reintervention-related endpoints.

“On Thursday, Dr Menard and I are presenting two of the pre-planned secondary endpoint analyses from the trial, which are important for the vascular community to further digest the impact of initial treatment selection on key clinical outcomes in CLTI patients,” Conte tells VS@VAM in an interview prior to taking to the podium.

“As with any large trial, primary publication can only get so much of the message across, and there is a lot more still planned in the coming months—including looking at subgroups of patients and other important secondary endpoints like these.”

Menard comments that the CLTI patient population is “complicated,” and each individual patient represents a unique treatment challenge, adding that there has been a great need for high-quality data to guide treatment decisions in the space.

“I think the vascular community has appreciated the effort it took to complete the trial and has welcomed the information,” he says.

“As we further unroll the many secondary analyses and additional outcomes, as well as the salient details on the patients that were enrolled into the trial and their anatomic profiles, I think the full impact of BEST-CLI will only continue to grow.”

In the analysis presented by Menard, clinical failure is defined as a composite of all-cause death, above ankle amputation, major reintervention, and degradation of wound, ischemia, and foot infection (WIfI), while hemodynamic failure comprises a composite of above-ankle amputation, major and minor reintervention to maintain index limb patency, failure to initially increase or a subsequent decrease in ankle brachial index of 0.15 or toe brachial index of 0.10, and radiographic evidence of treatment stenosis or occlusion.

The study’s time-to-event analyses were by intention-to-treat assignment in both trial cohorts—those with suitable single-segment GSV, and those lacking suitable single-segment GSV—using multivariate stratified Cox regression models.

Multivariate analysis

In the abstract published ahead of the presentation, it is reported that in the cohort of patients with suitable single-segment GSV there was a significant difference in time to clinical failure, hemodynamic failure, and resolution of presenting symptoms in favor of the open surgical approach.

Among those lacking suitable single-segment GSV, there was a significantly lower rate of hemodynamic failure, also favouring the open approach, and no significant difference in time to clinical failure or resolution of presenting symptoms. Multivariate analysis also reveals that assignment to open surgery was associated with significantly lower risk of clinical and hemodynamic failure in both cohorts, and a significantly higher likelihood of resolving initial and preventing recurrent CLTI symptoms in cohort 1, including after adjustment for key baseline patient covariates.

“My own belief is that there is much more to the story than how technically successful our initial revascularization effort is at restoring adequate perfusion to the ischemic foot,” Menard tells VS@ VAM, placing the findings firmly into context. “CLTI is quite analogous to cancer, and a hallmark of the disease is lingering wounds, persistent pain, and unfortunately, frequent recurrent symptoms.

“The current presentation suggests that for patients who were considered candidates for both open and endovascular treatment options, open surgical bypass is more effective at providing a sustained level of clinical and hemodynamic benefit. This result was seen in both patients that had a single segment of saphenous vein, which is the ideal surgical scenario, and those that did not.

“For those that did have optimal vein, the initial CLTI symptoms resolved more quickly, and the rate of recurrent symptoms over the course of the follow-up period was significantly lower.”

Conte, meanwhile, focuses his presentation on the reintervention-related study endpoints, looking at rates of both major reintervention, any reintervention and the composite of any reintervention, amputation or death, by intention-to-treat (ITT) assignment in both trial cohorts. The analysis also makes a comparison between treatment arms in each cohort using a stratified Cox model adjusted for prespecified baseline covariates.

“This analysis is really a deeper dive into the overall burden of reinterventions experienced by patients in the trial, and beyond the primary ITT comparisons we delve into what some of the predictive factors are for patients needing reinterventions,” says Conte of the aims of the study.

“We do not have anything quite like this existing in the literature—prospectively collected data in over 1,800 CLTI patients who were revascularized and followed for several years,” he comments.

“There are key observations that need to be brought to the forefront in terms of the nature of reinterventions, the cumulative number of reinterventions that were required, the timings of those reinterventions and how they differed between endo and open. This is important information for how to inform and follow CLTI patients in everyday practice, no matter what [approach] you pick.”

In the study’s abstract, the investigators report that in the trial’s cohort 1, assignment to initial open treatment was associated with a significantly reduced incidence of major limb reintervention, any reintervention, or the composite of any reintervention, amputation or death. The findings are similar in cohort 2 for major reintervention or any reintervention.

In both cohorts, limb reinterventions were notably higher for patients assigned to endovascular treatment, as opposed to open surgery.

“Secondary reinterventions in CLTI are common—and are more common with endovascular strategies compared to bypass with a good vein,” says Conte of the results. “Despite more than double the total number of major reinterventions, patients randomized to endo in BEST-CLI still experienced 27% more major amputations compared to those in the open arm with good vein.

“Thus, there are real downstream costs to these treatment failures, and not all limbs are recoverable by a secondary attempt. We should use the available evidence on patient risk, anatomic complexity, and severity of limb threat to select the best revascularization treatment up-front, and inform CLTI patients about these inherent trade-offs.

“It’s past time to end the tiresome “open-versus-endo” debate and embrace the complementary nature of these options for each individual patient.”

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