Clinical trials in chronic limb-threatening ischaemia

More than 230 million people across the world have peripheral arterial disease (PAD) and up to 10 per cent have chronic limb-threatening ischemia (CLTI)1. Although management of CLTI includes medical therapy and limb-related soft tissue treatment, prompt revascularization to improve distal limb perfusion is of paramount importance2,3. Without such revascularization, above-ankle amputation rates approach 25 per cent at 1 year4. Revascularization strategies include open surgical operations, percutaneous endovascular procedures, and hybrid combinations of the two2. Bypass surgery has been the traditional operation for CLTI and infrainguinal PAD, its most common anatomical variant. With the development of minimally invasive techniques, endovascular therapy, using a variety of procedures including angioplasty, atherectomy, stents, and drug-eluting technologies, has developed into a commonly applied revascularization strategy. The availability of both open and endovascular treatments, an ever-increasing development of novel endovascular technologies, and an appetite for minimally invasive procedures has led to significant variability in the application of these revascularization approaches in CLTI5. Equipoise in choice of revascularization techniques among vascular specialists has been underscored by lack of good comparative effectiveness literature to guide treatment6. Until recently, the BASIL (Bypass versus Angioplasty in Severe Ischaemia of the Leg) trial was the only RCT in this field. Conducted in the UK, it compared surgical bypass with endovascular therapy, and found no significant difference in the primary outcome of amputation-free survival between 452 enrolled patients. However, there was a trend towards improved primary outcome in the surgical arm of patients who survived more than 2 years7. Given the paucity of level 1 comparative effectiveness literature, the National Heart Lung and Blood Institute (NHLBI) funded the BEST-CLI (Best Endovascular versus Best Surgical Therapy for Patients with Critical Limb Ischaemia) trial (NCT02060630). This prospective, randomized, multicentre, multispecialty, open-label, superiority, pragmatic clinical trial aimed to compare clinical effectiveness, functional outcomes, and costs in patients with CLTI and infrainguinal PAD who were candidates for both open vascular surgery and endovascular therapy. Prospective patients were evaluated using non-invasive studies to corroborate that they had severe ischaemia, and underwent ultrasonography of the great saphenous vein and imaging studies of leg arteries. An investigator credentialled in open surgery had to agree with one credentialled in endovascular therapy that any given patient was a candidate for the trial. Because the results of bypass are strongly influenced by the choice of conduit, and single-segment great saphenous vein (SSGSV) was judged to be the best conduit for bypass, patients were placed into two cohorts. Cohort 1 included patients with SSGSV, whereas patients in cohort 2 randomized to surgery would be treated using alternative conduits including prosthetic grafts. These cohorts were analysed in separate, parallel trials and not pooled. The authors chose to stratify the cohorts by clinical presentation (rest pain alone versus tissue loss) and anatomy (presence versus absence of significant tibial disease), in order to balance randomization across these important variables8. Amputation-free survival was the primary endpoint of BASIL, whereas BEST-CLI used major adverse event limb event (MALE) or all-cause death; MALE included above-ankle amputation and first major reintervention (surgical bypass, thrombectomy, thrombolysis). MALE was developed by the Society for Vascular Surgery Objective Performance Guideline working group and accepted by the NHLBI as a superior endpoint for comparison of revascularization strategies9. Some 1434 patients were enrolled in cohort 1 of BEST-CLI, and followed for a median of 2.7 years; 72, 20.3, and 66 per cent of these patients had diabetes, ischaemic rest pain alone, and significant tibial occlusive disease respectively. Although use of optimal medical therapy was low at baseline, at 30 days after revascularization, 75.2, 82.9, and 36.3 per cent of patients were on at least one statin, at least one antiplatelet agent, and dual antiplatelet therapy respectively. With a HR of 0.68, surgical bypass was associated with a 32 per cent reduction in MALE or all-cause death. This finding was driven by significantly more first major reinterventions in the endovascular arm. There was a significant 27 per cent reduction in above-ankle amputations in the surgery arm, and no difference in periprocedural death or major cardiovascular events at 30 days or for the duration of the trial. In cohort 2, there was no difference in the primary outcome between treatment arms among 396 patients10. Accomplished by more than 1000 investigators from the fields of vascular surgery, interventional radiology, and interventional cardiology, across 150 sites (of which two-thirds were multidisciplinary), BEST-CLI is a landmark undertaking. It provides level 1 evidence that significantly advances the evidence base for CLTI treatment. Its findings can be distilled into a number of salient conclusions. Both endovascular therapy and infrainguinal bypass are effective and safe. Bypass with adequate saphenous vein is a more effective strategy for patients deemed suitable for both open and endovascular approaches. As such, patients who are candidates for limb salvage should undergo an evaluation of surgical risk and conduit availability. Bypass with adequate saphenous vein should be offered as a first-line treatment option for suitable candidates with CLTI, as part of a fully informed, shared decision-making process with patients. Finally, an endovascular-first approach to all patients with CLTI is not supported by level 1 evidence. BEST-CLI data show that open and endovascular revascularization have complementary roles in the treatment of CLTI. BEST-CLI had a number of limitations that need to be acknowledged. Owing to its pragmatic design, there was possible selection bias in enrolment and intervention. Equipoise and eligibility were determined locally and were likely variable. There was heterogeneity in the use of endovascular techniques. It is likely that cohort 2 was underpowered. Finally, anatomical complexity has yet to be evaluated10. Efforts are under way to fully unpack the treasure trove of CLTI data generated by BEST-CLI. Reinterventions in the trial need to be better delineated and understood. Use of optimal medical therapy during the trial and its predictors need to be elucidated. Details of endovascular therapy by patient and anatomical level need to be described. Finally, quality of life, cost-effectiveness, technical failure modes, secondary interventions, and disparities need to be evaluated and reported. Although in-depth analysis of BEST-CLI is being pursued, the results of BASIL 2 and BASIL 3 are also eagerly awaited by the CLTI research community. These trials will provide more clarity and help vascular physicians take better care of their patients with CLTI. Equally important, BEST-CLI and the BASIL family of trials will hopefully inform the next series of relevant clinical and scientific questions that will produce an even more robust evidence base to guide optimal treatment of these patients. BEST-CLI was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health (award numbers U01HL107407, U01HL107352, and U01HL115662). The following entities also provided funding to the BEST-CLI trial during the follow-up interval (2019–2021). Physician Societies: Vascular InterVentional Advances, Society for Vascular Surgery, New England Society for Vascular Surgery, Western Vascular Society, Eastern Vascular Society, Midwest Vascular Surgery Society, Southern Association of Vascular Surgeons, Canadian Society for Vascular Surgery, Society for Clinical Vascular Surgery, Society of Interventional Radiology, Vascular and Endovascular Surgery Society, Society for Vascular Medicine. Industry sources: Janssen, Gore, Becton Dickinson and Company, Medtronic, Cook, Boston Scientific, Abbott, Cordis, Cardiovascular Systems Inc. As of 1 September 2022, ongoing BEST-CLI research has been funded primarily by the Novo Nordisk Foundation. This submission is not based on a previous communication to a society or a meeting. However, the results of BEST-CLI were published in the New England Journal of Medicine and presented to the American Heart Association in Chicago, Illinois, USA, November 2022, and those results have also been discussed in numerous press releases and other press coverage. The authors declare no conflict of interest.

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