Surgical Revascularization Versus Endovascular Therapy to Treat Chronic Limb-Threatening Ischemia: Perhaps Less Invasive Is Not Always Better

Abstract

Lower extremity peripheral arterial disease (PAD) negatively impacts the lives of many - it is estimated that up to 12 percent of adults worldwide suffer from lower extremity PAD in some form.1 Beyond the functional limitations caused by lower extremity PAD, like claudication and rest pain, PAD is associated with increased mortality when compared to persons without PAD.2 Chronic limb-threatening ischemia (CLTI) is a clinical syndrome of severe PAD paired with lower extremity rest pain, gangrene, and/or ulcerated wound of two or more weeks duration.3 By definition, those with CLTI are at high risk for lower extremity limb loss, and 12% of patients who undergo revascularization procedures for CLTI will require some form of above ankle amputation within 6 months of that intervention.4 Moreover, the mortality rates for persons with CLTI that do not undergo lower extremity revascularization is 20% within 24 months after diagnosis.5 Patients with CLTI require diligent treatment in attempt to mitigate the aforementioned undesirable outcomes. The most recent practice guidelines (with interdisciplinary society sponsorship, published in 2019) for management of CLTI (with a salvageable limb who is at “standard” surgical risk) recommend medical management for all patients, paired with revascularization intervention, via either an open surgical approach (for vascular bypass) or an endovascular approach.3 Given the considerable burden and detriment associated with CLTI, there is considerable value in building robust evidence to guide which treatments are offered and to whom. In December 2022, The New England Journal of Medicine published the results of the Best Endovascular versus Best Surgical Therapy in Patients with CLTI (BEST-CLI) trial, which offers updated evidence that may impact treatment options for persons with CLTI.6 The BEST-CLI Trial is an international, multi-center, prospective randomized (open label) controlled trial, with stated intent to “determine whether endovascular revascularization was superior to surgical revascularization in patients with CLTI caused by infrainguinal PAD who were judged to be suitable candidates for both approaches”.6 150 centers on 3 continents enrolled patients aged ≥18 years old and diagnosed with CLTI into the study. Each enrolled patient underwent pre-randomization evaluation with bilateral lower extremity duplex ultrasound to evaluate the characteristics of their great saphenous veins (GSV). The Trial was made up of two parallel-cohort studies: cohort 1, in which patients were found to have a viable segment of GSV that could be used for surgical bypass of the diseased arterial segment of the limb, and cohort 2, in which an alternative bypass conduit (e.g.: graft material) would be used for surgical bypass. Within each cohort, patients randomized to undergo surgical bypass were compared against patients randomized to undergo endovascular interventions for revascularization. The endovascular technique used was left to the discretion of the physician performing the procedure. The primary outcome was composite: death from any cause and/or major adverse limb events (defined as undergoing an above-ankle amputation on the operated limb or need for a major reintervention on the operated limb); “major reinterventions” were defined as a new bypass procedure, interposition graft revision, thrombolysis, or thrombectomy. Secondary outcomes evaluated included need for minor reinterventions in the index limb and major adverse cardiovascular event (defined as a composite of myocardial infarction, stroke, or death from any cause). Follow-up for data collection was done at 30 days following the procedure (or 30 days after randomization if the index procedure had not yet been performed), then at 3 months, 6 months, and then every 6 months thereafter for up to a total of 84 months after randomization.6 A total (between both cohorts) of 1847 eligible patients underwent randomization; 1434 patients had useable GSV and were assigned to cohort 1, and 396 patients required an alternative operative conduit and were assigned to cohort 2. The major patient characteristics (e.g.: age, race, medical comorbidities, relevant prescribed medications, etc.) among randomized patients did not show any statistically significant difference. In cohort 1, 718 patients were assigned to undergo surgery (and were included in the intention-to-treat analysis as such) and 716 were assigned to undergo endovascular intervention (and underwent intention-to-treat analysis as such). Cohort 2 saw 197 patients assigned to undergo surgery and 199 underwent endovascular intervention; the same numbers in each group underwent intention-to-treat analysis. Technical procedural success for cohort 1 was reported in 98% of the surgical group and in 85% of the endovascular group; in cohort 2, 100% technical success was reported in the surgical group and in 81% of the endovascular group.6 In cohort 1 (surgical bypass with SVG versus endovascular intervention), the primary outcome of death or major adverse limb event during the 84 month follow up period occurred in 302 of 709 (42.6%) of the surgical group patients, and in 408 of 711 (57.4%) of those in the endovascular group (hazard ratio 0.68; 95% confidence interval 0.59-0.79; p<0.001). In cohort 2 (surgical bypass with artificial conduit versus endovascular intervention), the primary outcome occurred in 83 of 194 (42.8%) of the surgical patients, and in 95 of 199 (47.7%) of the endovascular patients (hazard ratio 0.79; 95% confidence interval 0.29-0.76; p=0.12).6 Prior to BEST-CLI, the Bypass versus Angioplasty for Severe Ischemia of the Leg (BASIL) trial, published in 2005, offered the most robust information on outcomes between revascularization therapies in CTLI. BASIL trial reported on amputation-free survival between patients with CLTI who underwent surgical intervention or endovascular intervention, and found that there was no statistically significant difference between the two groups over the 3 year follow-up period.7 Notably, a subsequent analysis of the BASIL patient group extended over a five year follow-up period found that in those patients who underwent surgical intervention and survived for 2 years after the initial randomization had a significantly higher overall survival at five years than the endovascular intervention group; the amputation-free survival rate between the two groups did not reach statistical significance, however.8 It is imperative to underscore that the BASIL study did not differentiate between the use of SVG and prosthetic graft material; the equipoise implied in BASIL must be considered in this context, and begged the question as to whether there is a benefit to surgery when SVG is used versus when prosthetic material is used for bypass.7 In opposition to BASIL, the BEST-CLI trial found statistically significant difference between the two groups studied in cohort 1, in which the SVG was used for surgical bypass. The benefit conferred to patients undergoing surgery in cohort 1 is impressive, to say the least, as the surgical group had almost 33% fewer occurrences of the primary outcome. On close inspection of the Kaplan-Meier curves representing the primary outcome for cohort 1 of this BEST-CLI study, it is notable that the surgical intervention group separated itself from the endovascular intervention group almost immediately, suggesting that patient benefit (from surgical intervention) begins very early after the treatment is rendered. But it must be noted: the primary outcome in BEST-CLI is, again, a composite outcome, which includes the occurrence of death or major limb event; “major limb event” was defined by need for an above-ankle amputation, or major intervention (i.e.: new bypass procedure, interposition graft revision, thrombolysis, or thrombectomy). When the composite outcome is broken down into the component events, the statistical difference is only seen in “major reintervention” – the outcome data showed no difference in outcomes between the surgical or endovascular groups when evaluated by death or need for above-ankle amputation.6,9 Surgical bypass for CLTI, it may be inferred, may not save the life of the patient with CLTI, but it may confer immediate, impressive benefit from post-intervention complications.6 The above-noted BASIL trial studies were published in 2005 and 2010, respectively. From the dates of those studies to present time, a considerable increase in the number of offered endovascular interventions for peripheral arterial disease (PAD) has occurred - a study of the SVS Vascular Quality Initiative found that in 2010, less than 40% of therapeutic interventions for PAD were endovascular, and in 2019, over 80% were endovascular.10 Despite this increase in practice pattern, it is notable that the defined technical failure rate for surgical intervention was over 16% in the BEST-CLI study (total across both cohorts); this failure rate is almost certainly multifactorial, and highlights the complexity of vascular anatomy, PAD pathophysiology, and the challenges that remain for endovascular therapies. Moreover, the comparatively high technical failure rate in the endovascular arm (when compared to surgical failure rates) likely has a significant role in the aforementioned near-immediate separation in the Kaplan-Meier curves that illustrate the primary outcome in cohort 1 of this study. Patients in cohort 2 - those who were deemed to not have a suitable GSV conduit for bypass when undergoing surgery - did not appear to have the robust outcome benefit from surgical bypass that was reported in cohort 1, in which the surgical bypass was completed with the autologous GSV. The reason that the comparative outcomes benefit was not noted in cohort 2 is probably multifactorial. It is plausible that the non-GSV conduit used for surgical bypass is inferior to the use of GSV. But one must also consider that cohort 2 had two important study-based limitations: 1) the pre-determined enrollment number of 480 patients was not met, which leaves the study open to error in statistical analysis, and 2) although the plan at the outset of the trial was to ensure at least 24 months of post-randomization patient follow-up, this was achieved in cohort 1 but not cohort 2, which may hamper the interpretation of outcomes data through that follow-up period.6 Because of the aforementioned methodological limitations, the relevance and applicability of the cohort 2 is severely hampered. The importance of minimally invasive interventions in medicine – including endovascular therapies in arterial disease - have been a crucial advancement in patient care, often allowing acceptable clinical outcomes with less pain, less physiological stress, and faster hospital discharge.11 While the concept that “less is more” makes good, general theoretical sense, BEST-CLI serves to remind us that the details are important: while some patients with CLTI may have comorbidities that preclude a surgical approach to limb revascularization, those who are deemed appropriate surgical candidates and have a viable saphenous vein for arterial bypass may be better served over the short- and long-term by open surgery. References Fowkes FG, Rudan D, Rudan I, et al. Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: a systematic review and analysis. Lancet. 2013;382(9901):1329-1340. Vaartjes I, de Borst GJ, Reitsma JB, et al. Long-term survival after initial hospital admission for peripheral arterial disease in the lower extremities. BMC Cardiovasc Disord. 2009;9:43 Conte MS, Bradbury AW, Kolh P, et al. Global vascular guidelines on the management of chronic limb-threatening ischemia [published correction appears in J Vasc Surg. 2019 Aug;70(2):662]. J Vasc Surg. 2019;69(6S):3S-125S.e40 Baubeta Fridh E, Andersson M, Thuresson M, et al. Amputation rates, mortality, and pre-operative comorbidities in patients revascularised for intermittent claudication or critical limb ischaemia: A population based study. Eur J Vasc Endovasc Surg. 2017;54(4):480-486. Verwer MC, Wijnand JGJ, Teraa M, et al. Long term survival and limb salvage in patients with non-revascularisable chronic limb threatening ischaemia. Eur J Vasc Endovasc Surg. 2021;62(2):225-232. Farber A, Menard MT, Conte MS, et al. Surgery or Endovascular Therapy for Chronic Limb-Threatening Ischemia. N Engl J Med. 2022;387(25):2305-2316. Adam DJ, Beard JD, Cleveland T, et al. Bypass versus angioplasty in severe ischaemia of the leg (BASIL): multicentre, randomised controlled trial. Lancet 2005;366:1925-34 Bradbury AW, Adam DJ, Bell J, et al. Bypass versus angioplasty in severe ischaemia of the leg (BASIL) trial: An intention-to-treat analysis of amputation-free and overall survival in patients randomized to a bypass surgery-first or a balloon angioplasty-first revascularization strategy [published correction appears in J Vasc Surg. 2010 Dec;52(6):1751 Ramachandran M, Sen I, Tallarita T, et al. Outcomes in the management of chronic limb-threatening ischemia – Analysis of the BEST-CLI trial. J Cardiothorac Vasc Anesth. 2023 Apr;37(4):632-636 Li B, Rizkallah P, Eisenberg N, Forbes TL, Roche-Nagle G. Rates of intervention for claudication versus chronic limb-threatening ischemia in Canada and United States. Ann Vasc Surg. 2022;82:131-143 Pascarella L, Maen AH. Minimally invasive management of severe aortoiliac occlusive disease. 2018 May;28(5):562-568 Conflict of interest Drs. Kaplan and Augoustides: I am submitting a free-standing editorial (requested by Dr. Augoustides), entitled “Surgical Revascularization versus Endovascular Therapy to treat Chronic Limb Threatening Ischemia: Perhaps Less Invasive Isn't Always Better”, related to the BEST-CLI Trial (Farber A, Menard MT, Conte MS, et al. Surgery or Endovascular Therapy for Chronic Limb-Threatening Ischemia. N Engl J Med. 2022;387(25):2305-2316), an important manuscript published in New England Journal of Medicine, describing the outcomes of interventions for chronic limb-threatening ischemia in patients with peripheral arterial disease. I confirm I have no conflict of interest associated with this editorial submission. Dean A. Healy confirms no conflict of interest associated with this editorial submission. Bart Chess confirms no conflict of interest associated with this editorial submission.