BEST-CLI, BASIL-2 and Beyond: Bridging the Gap Between Our Daily Clinical Practice and Research Realities

The clinical realities of big trials such as BEST-CLI and BASIL-2 were dissected this morning in a session that explored strategic visions for the future of below-the-knee interventions. Tatsuya Nakama, Director, Department of Cardiology, Tokyo Bay Medical Center, Japan, spoke to LINC Today to offer a review of some of the concepts he discussed, emphasizing an overarching analogy: Why drive a sports car up a mountain when an off-road vehicle is much more suitable?

Based on the findings from the BEST-CLI and BASIL-2 trials, what are some of your key ‘takeaways’ on the outcomes of infrainguinal versus infrapopliteal revascularization in the management of chronic limb-threatening ischemia (CLTI)?

The conflicting results of these 2 randomized trials clarified an already well-known fact. Bypass surgery with autogenous veins demonstrated a higher rate of freedom from major reintervention (9.2% vs 23.5%; hazard ratio [HR]: 0.35, 95%; confidence interval [CI]: 0.27–0.47) and a higher rate of freedom from major amputations (10.4% vs 14.9%; HR: 0.73; 95% CI: 0.54–0.98) in the BEST-CLI trial,¹ whereas in the BASIL-2 trial, it showed a significantly higher rate of major amputation or death (63% vs 53%; HR: 1.35; 95% CI: 1.02–1.80; p = 0.037), and superiority of the endovascular therapy (EVT) was proven.²

The favorable outcomes of EVT in the BASIL-2 trial were primarily due to a lower rate of all-cause death (53% vs 45%; HR: 1.37; 95% CI: 1.00–1.87).² These findings simply proved scientifically what was already known about the benefits of the 2 revascularization methods, offering no new information to clinicians. Moreover, the results highlight the heterogeneity among real-world CLTI patients. A key takeaway from these studies is that randomized controlled trials (RCTs) have not been the most appropriate method for establishing the best revascularization method for the CLTI patient.

Through these experiences, it raises the question of what proportion of CLTI patients treated in daily clinical practice would actually be eligible for inclusion in an RCT? Understanding this topic is crucial when utilizing the results of these RCTs in daily clinical practice.

In an interesting report by Hata et al., the eligibility of 352 CLTI patients (average age 72 ± 10 years, male 63.9%, diabetes 63.1%, hemodialysis 55.8%) for Cohort 1 of the BEST-CLI trial was retrospectively analyzed. It was found that: 1) 87.5% were at standard surgical risk (perioperative and 2-year mortality rate < 5%); 2) 76.1% had an adequate distal anastomosis site (IM grade P1 or 0); and 3) 46.3% had a usable great saphenous vein of more than 3.0 mm. In conclusion, only 32.7% (n = 115) of patients met all these criteria.³ Furthermore, when this 32.7% of patients were assessed for appropriate revascularization methods based on GLASS stage (anatomical complexity) and WIfI clinical stage (limb severity), only 8.8% (n = 31) were deemed suitable for surgical bypass first (intermediate was 13.1%).³ While the BEST-CLI study undoubtedly provides high-level evidence, its direct application to clinical practice is challenging. Distal bypass surgery using veins is an effective treatment, but it is a limited option suitable for only 8.8% of patients.

Moreover, it is rare for endovascular treatments to demonstrate superiority over surgery in hard endpoints such as all-cause death, as seen in the BASIL-2 trial. Therefore, the clinical value of EVT for CLTI has increased through these 2 RCTs. It may be inferior in terms of the incidence of major reinterventions but shows superiority in hard endpoints such as survival and amputation-free survival. 

The trials highlighted high mortality rates among CLTI patients, regardless of the revascularization strategy. Does this emphasize the need for optimized risk factor modification?

Very high mortality rates were observed in BEST-CLI (33.0% [bypass group] vs 37.6% [EVT group]; HR: 0.98; 95% CI: 0.82–1.17) and BASIL-2 (53% [bypass group] vs 45% [EVT group]; HR: 1.37; 95% CI: 1.00–1.87). As this all-cause death accounted for approximately 80% of the serious adverse events during the observation period, these results reflect the severe fragility of the CLTI patient population. Both bypass surgery and EVT primarily aim to improve limb outcomes and do not directly extend life. To enhance outcomes for CLTI patients, it is crucial to address how to reduce overall mortality, even though it would be challenging for these target populations.

Cardiovascular events, particularly coronary artery disease, are common causes of death among CLTI patients. Past studies show that rigorous application of guideline-dedicated medical therapy (GDMT) and proper management of cardiovascular risk factors can improve outcomes.³ Therefore, risk reduction through diligent application of GDMT is essential for improving prognosis, and should be considered paramount in revascularization strategies. Currently, the evidence for pharmacological treatment in CLTI/peripheral arterial disease patients is sparse, highlighting the need for well-designed, large-scale studies to eliminate the significant impact caused by mortality rates in CLTI research.

In terms of patient selection, would you agree that the optimal treatment approach for CLTI varies depending on patients’ characteristics, comorbidities, anatomical considerations, and disease severities?

Definitely. In the target populations for CLTI, as previously mentioned, only a small fraction are suitable for the design of randomized trials. It is impossible to choose the ‘best’ revascularization method using only the data from RCTs. Tailor-made treatment would be mandatory. Therefore, the revascularization strategy should be determined based on discussions that consider patient background, comorbidities, anatomical severity, wound severity, and the availability of autogenous veins.

The importance of a multidisciplinary approach in managing complex cases of CLTI has been mentioned before in light of these results. Could you share your insights on this aspect?

Patients with CLTI are often frail, fragile, and heterogeneous, making it challenging to apply a uniform treatment approach. Treatment strategies should be decided based on a comprehensive understanding of not only the primary disease state of CLTI, but also comorbidities, activities of daily living (ADL), and the social contexts including patient’s families. Collecting such extensive information is beyond the capacity of physicians alone and often requires knowledge that physicians may lack. Therefore, discussions involving a multidisciplinary team are essential.

Additionally, the approach to treatment should not solely focus on delivering the best medical treatment, but also consider the patient’s advance care planning (ACP). Patients with CLTI are at the end-stage of arteriosclerotic disease and often near the end of life. Understanding the desires and thoughts of such patients and their families about how they wish to conclude their lives cannot be fully assessed by health care providers alone. There is a need for patient-centered decision-making and support that involves appropriate ACP (aka shared decision-making). In this context, the EVT, which is less invasive and requires shorter hospital stays, may play a significant role as part of the best clinical practice offered to these patients.

Based on your clinical experience, how have the findings from the BEST-CLI and BASIL-2 trials (among others) influenced your approach to treating patients with CLTI? Have you adopted any new strategies or modified existing ones in light of these results?

As has been the practice, it is essential to continue discussing the best treatment strategies individually and within multidisciplinary teams, based on the diverse information available about each patient. Of course, through the BEST-CLI trial, we re-understand the effectiveness of vein bypass surgery. Therefore, for patients with high ADL and adequate surgical tolerance, properly assessing the availability of usable veins and evaluating the potential for long-term patency with vein bypasses are crucial for fostering fair and informed discussions.

What were some of the key limitations of the trials that should be highlighted (e.g. sex, ethnicity)?

The design of RCTs itself is a limitation in these 2 studies. RCTs are designed for patient populations where any treatment option is appropriate, and the selection of either would not pose a problem. However, such a trial design is nonsensical for CLTI patients due to their significant heterogeneity. This situation is like debating whether to bring a luxurious 2-seater sports car to an unpaved mountain path or to enjoy a high-clearance off-road vehicle on a racing circuit. Wise experts already recognize how futile and unreasonable such debates are. The value of these options lies not in choosing one over the other but in sharing and using each appropriately. Vein bypass and EVT should complement rather than conflict with each other.

What do you perceive as the biggest challenges in implementing the lessons learned from the BEST-CLI and BASIL-2 trials into everyday clinical practice, and how can these challenges be overcome? Is this the ‘bridging the gap’ between research and reality that you will be focusing on?

Indeed, attempting to bridge the gap between patients enrolled in studies and those in the real world is a contradictory and impractical endeavor. The information necessary to resolve clinical challenges is not merely the superiority or inferiority of treatments discussed among a mere 8.8% of patients,³ but rather the real outcomes and facts of treatments deliberated and applied in daily clinical settings. For challenging patient groups like those with CLTI, there is a need for more aggressive utilization of real-world data and well-designed registries. A system must be established to accumulate and utilize detailed data not only from groups who received revascularization, but also from those treated conservatively without vascular reconstruction or those who underwent primary amputation.

Is there a need for further RCTs to integrate the lessons learned from these studies? What specific areas of research do you believe are most crucial for advancing the management of CLTI?

BASIL, BEST-CLI, and BASIL-2 have thoroughly discussed what the best solutions are for the patient groups eligible for these studies. Moving forward, we need data to assist in treatment choices for the majority of patients in real-world settings, who often present more complex challenges and are not suited for RCT designs. Such data must come from the use of registries and real-world data.

The next step in improving outcomes for CLTI might focus on reducing mortality, which is a major challenge in CLTI studies. Just as statin administration has shown dramatic effects in reducing cardiovascular events, and the recent emergence of the ‘Fantastic Four’ cardioprotective medications has dramatically changed the medical therapy of heart failure, new treatments and medications might be the next game changers for the management of CLTI. 

Well-designed prospective studies and RCTs to evaluate guideline-dedicated medical therapy are necessary to further discuss the best strategy for both existing and new medications.

Any final thoughts for the LINC Today audience?

Patients with CLTI are at the end-stage of arterial occlusive disease, making their treatment complex. What is required of we clinicians is the ‘clinical sense’ to discern the best solution and provide it to our patients, utilizing the toolbox of evidence and experience accumulated over the past 2 decades. Design of clinical trials/studies to build evidence is crucial, of course, but the ability to translate this evidence into clinical practice is arguably even more important for a clinician. Shouldn’t we avoid making proposals that would leave us struggling, like suggesting driving a luxury sports car on an unpaved road?

References

1. Farber A, Menard MT, Conte MS, et al. BEST-CLI Investigators. Surgery or endovascular therapy for chronic limb-threatening ischemia. N Engl J Med. 2022; 387: 2305–2316.

2. Bradbury AW, Moakes CA, Popplewell M, et al. BASIL-2 Investigators. A vein bypass first versus a best endovascular treatment first revascularization strategy for patients with chronic limb threatening ischaemia who required an infra-popliteal, with or without an additional more proximal infra-inguinal revascularization procedure to restore limb perfusion (BASIL-2): an open-label, randomised, multicentre, phase 3 trial. Lancet. 2023;401:1798–1809.

3. Hata Y, Iida O, Okamoto S, et al. Japanese real-world population with chronic limb-threatening ischemia who meet the criteria of the BEST-CLI trial. Vasc Med. 2024;29: 64–66.