A question from Manj Gohel (Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK) on what the Charing Cross (CX) audience should take back to their multidisciplinary team meetings from the first-time presentation of BASIL-2 led chief investigator Andrew Bradbury (University of Birmingham, Birmingham, UK) to deliver the stark message: a patient who needs a below-the-knee revascularisation with or without a femoropopliteal revascularisation is likely to do better if they are treated with a best endovascular-first strategy rather than a vein bypass-first approach.
In the BASIL-2 (Bypass versus angioplasty for severe ischaemia of the leg) trial of 345 patients with chronic limb-threatening ischaemia (CLTI), a best endovascular treatment-first revascularisation strategy was associated with better amputation-free survival than a vein bypass-first strategy in those who required an infrapopliteal repair—with or without a more proximal infrainguinal procedure. This result was largely driven by fewer deaths in the best endovascular treatment group. Bradbury presented this key finding at the 2023 CX International Symposium (25–27 April, London, UK). The results were simultaneously published in The Lancet.
“It all seems to be pointing towards attempting an endovascular procedure first and then if that does not work, doing something else—which could be more endovascular,” Bradbury said in response to Gohel. Alternatively, he added, this could be the point at which the vascular specialist switches over to a bypass approach. BASIL-2, however, “lends quite a lot of weight” to an endovascular-first revascularisation strategy, “with all the caveats that we have to consider”.
Bradbury, delivering the data for the first time during day one of CX 2023, revealed that 63% of patients randomised to a vein bypass-first strategy of treatment underwent a major amputation or died during follow-up, compared to just 53% of those allotted to a best endovascular-first approach—BASIL-2’s primary outcome measure (adjusted hazard ratio 1.35, 95% confidence interval [CI] 1.02–1.08, p=0.037).
“Essentially this means that, in this cohort, a vein bypass revascularisation strategy resulted in a 35% increased risk of amputation or death during the follow-up compared with a best endovascular-first revascularisation strategy,” Bradbury told the CX audience.
Median survival for the whole cohort was 3.8 years—3.3 years for the vein bypass group and 4.4 for the endovascular arm, he said. “The significant difference we have observed in favour of best endovascular therapy with amputation-free survival is very largely driven by the fact that there were more deaths in the vein bypass group—53% of vein bypass patients and 45% of best endovascular therapy patients,” Bradbury continued. “There is no significant difference of 30-day mortality but you can see that the median survival of the two groups is quite different.”
CLTI is the “severest manifestation” of peripheral arterial disease (PAD) and presents as ischaemic pain at rest or tissue loss, or both, the authors detail in The Lancet. Against this backdrop, Bradbury and colleagues were comparing effectiveness of a vein bypass-first with a best endovascular treatment-first revascularisation strategy in terms of preventing major amputation and death in patients with CLTI.
“It is important to emphasise that the best way of analysing this trial, which is the way our statistical colleagues have done it, is on the intention-to-treat population; however, for completeness they have done some sensitivity analyses, and this includes a per protocol analysis, which includes only patients who were adherent—that is, they received the allocated intervention they were randomised to,” Bradbury explained at CX. “They also performed an as-treated analysis, which is based upon the first revascularisation that the patient actually received following randomisation, and as you can see here they both trend towards reduced amputation-free survival in the vein bypass-first group.”
The BASIL-2 co-investigators, namely Catherine Moakes, Gareth Bate and Matthew Popplewell (all University of Birmingham, Birmingham, UK) and Lewis Meecham (University Hospital Cardiff, Cardiff, UK) also presented during the session on the journey from BASIL-1 to BASIL-2, a hypothesis-generating prospective cohort study, methodology, study limitations and future work, among other topics.
BASIL-2 was an open-label, pragmatic, multicentre, phase 3, randomised trial performed at 41 vascular surgery units in three countries: the United Kingdom (n=39), Sweden (n=1) and Denmark (n=1). The central site was the University of Birmingham. “Eligible patients were those who presented to hospital-based vascular surgery units with [CLTI] due to atherosclerotic disease and who required an infrapopliteal, with or without an additional more proximal infrainguinal, revascularisation procedure to restore limb perfusion,” they state in The Lancet.
Bradbury and colleagues randomly assigned participants 1:1 to receive either vein bypass or best endovascular treatment as their first revascularisation procedure through a secure online randomisation system. The Lancet paper details that participants were excluded if they had ischaemic pain or tissue loss considered not to be primarily due to atherosclerotic PAD. Most vein bypasses used the great saphenous vein and originated from the common or superficial femoral arteries, the authors communicate, while most endovascular interventions comprised plain balloon angioplasty with selective use of plain or drug-eluting stents.
Patients were followed up for a minimum of two years, Bradbury et al write, with data collected locally at participating centres. In England, Wales and Sweden, the authors note, centralised databases were used to collect information on amputations and deaths. They add that data were analysed centrally at the Birmingham Clinical Trials Unit.
The primary outcome of amputation-free survival was defined as time to first major (above the ankle) amputation or death from any cause measured in the intention-to-treat population. Safety was assessed by monitoring serious adverse events up to 30 days after first revascularisation.
Between 22 July 2014 and 30 November 2020, the triallists enrolled and randomised 345 patients with CLTI—65 (19%) women and 280 (81%) men with a median age of 72.5 years (62.7–79.3). The patients were randomly assigned to either the vein bypass group (172 [50%]) or the best endovascular treatment group (173 [50%]).
Bradbury detailed at CX that major amputation or death occurred in 108 (63%) of 172 patients in the vein bypass group and 92 (53%) of 173 patients in the best endovascular treatment group. The relevant mortality numbers were 91 (63%) among the vein bypass group and 77 (53%) in the endovascular arm.
In both groups, the authors write, the most common causes of morbidity and death— including that occurring within 30 days of their first revascularisation—were cardiovascular (61 deaths in the vein bypass group and 49 in the best endovascular treatment group) and respiratory events (25 deaths in the vein bypass group and 23 in the best endovascular treatment group). They add that the number of cardiovascular and respiratory deaths were not mutually exclusive.
In the discussion section of their paper, Bradbury et al consider how their findings compare to those from the BEST-CLI trial, which were presented for the first time last November. “At first glance,” they remark, “our results appear to conflict with the BEST-CLI trial”. However, they note that there were “many differences” between the two trials, including the primary endpoint. “Our clinical experience suggests that few patients with [CLTI] are deemed suitable and have an optimal vein for infrapopliteal bypass,” Bradbury and colleagues comment, adding that future work is required to determine whether the patients enrolled in BASIL-2 are more like the patients with a non-optimal vein in the BEST-CLI trial.
During the panel discussion following the BASIL-2 presentations at CX, Andres Schanzer (UMass Memorial Health, Worcester, USA) asked Bradbury and colleagues to cast the findings against the backdrop of BEST-CLI. Moakes, who was the statistician for BASIL-2, explained that the team are planning to conduct an individual patient data meta-analysis to answer questions around any relevant differences between the two trials.
“A trial of two strategies”
Also during the discussion, the panel touched on the evolving landscape of endovascular treatment, with moderator Andrew Holden (Auckland City Hospital, Auckland, New Zealand) asking Bradbury and colleagues whether they had noted a significant change in endovascular practice in the period between BASIL-2 and its eponymous predecessor.
Bradbury noted in his interpretation of the data that “there is a much greater willingness now that if you do an endo[vascular], and you are not happy with it, the interventional radiologists will go back and have another go, whereas what we tended to see, I think, in BASIL-1, was that if endo[vascular] did not work, [treatment would] quickly go over to bypass. I think that is the difference.”
Moderator Dittmar Böckler (Heidelberg University Hospital, Heidelberg, Germany) urged the audience to keep in mind the various options that remain open when undertaking an endovascular-first approach. Greenhalgh underscored the point. “It also came out with BEST-CLI that the quality of the vein is important,” he said. “It is very, very crucial that whatever you do first, it does not have to be the last word.”
Böckler said vascular specialists “need to learn from this trial which patient deserves which treatment”. It is not a case of surgery versus endovascular therapy, but rather a case of learning from the data, he added. Bradbury concurred. “It is a trial of two strategies,” he said. “That was what BASIL-1 was. It is quite a difficult concept to get across. We are not comparing a vein bypass with an endovascular treatment. We are in a sense—but what we are saying is, ‘What do you do first?’ If you have got equipoise, if you are really on the fence, and you do not know which to do, this trial suggests fairly strongly, I would suggest, that in this subgroup of patients, that you should go endo[vascular] first.”