The ‘paclitaxel evidence lifecycle’ and the case for faster, more innovative evaluation for PAD interventions

Weighing in on the fallout from the recent European Society for Vascular Surgery (ESVS) focused update on paclitaxel devices, Matt Popplewell (Leicester, UK), Thanos Saratzis (Leicester, UK) and Matthew Menard (Boston, USA) advocate a move towards newer research methodologies that aim to shorten the timeline between adoption of a new technology and the evidence to support its use. 

We read with interest the recent exchange between Schneider and colleagues and Wanhainen and colleagues over the 2026 ESVS focused update, which was highlighted at the recent ESVS annual meeting (6–9 October, Belgrade, Serbia) as a clash of opinions.^1–3 We feel that this is better read as the predictable endpoint of an evidence lifecycle that every healthcare intervention passes through. 

The use of paclitaxel-coated devices has probably been the most controversial debate of the 21st century in vascular surgery. Almost two decades ago, the THUNDER trial (2008) provided early proof of concept for this technology, demonstrating reduced restenosis after femoropopliteal drug-coated angioplasty.⁴ Industry-sponsored and funded pivotal trials then demonstrated superior patency and lower target-lesion revascularisation (TLR) for specific devices in selected groups.^5–7 Such devices gained regulatory approval and diffused rapidly into routine clinical practice globally. Controversially, a 2018 meta-analysis, which predominantly included reports of claudicants undergoing endovascular revascularisation, suggested a late mortality signal for participants receiving paclitaxel-coated treatments; later patient-level analysis did not confirm this.^8,9 Most recently, the large, pragmatic SWEDEPAD 2 randomised trial explored whether paclitaxel-based treatments improve quality of life in claudicants and found that they did not.¹⁰ 

This journey mirrors the stages of evaluating a healthcare intervention that are suggested in the IDEAL framework.¹¹ Each stage asks a different question. The two previous commentaries largely disagree about how much weight the latter stages should carry relative to the earlier ones. 

The earlier device trials and SWEDEPAD 2 sit at opposite ends of the explanatory–pragmatic continuum described by PRECIS-2.¹² Explanatory efficacy trials ask whether an intervention can work under controlled conditions. They use defined devices, lesions and patients, and are essential for establishing a biological effect and for device-specific regulatory decisions. Pragmatic effectiveness trials, however, ask whether such interventions ‘work’ in routine care, across heterogeneous patients, operators and devices, using outcomes that matter to patients. 

Neither answers the other’s question. Outcomes such as patency and TLR are intermediate outcomes, and improvements in such do not always reliably translate into patient benefit, as demonstrated in SWEDEPAD 2.¹³ Conversely, a pragmatic trial that pools many devices under one ‘paclitaxel strategy’ suggesting a class effect cannot prove that no single device is efficacious, and this may dilute the effect of better-performing platforms, as Schneider and colleagues suggest.¹ 

In our opinion, a mature evidence base needs both: efficacy trials to show which devices work and how, and effectiveness trials to show whether that translates into benefit for patients in routine practice. 

The central problem here is not that either side is wrong, but that the paclitaxel evidence lifecycle has taken 18 years to complete, from THUNDER in 2008 to a focused guideline update in 2026. Interestingly, in the UK, the National Institute for Health and Care Excellence (NICE) had recommended that when stenting is required, that bare-metal devices should be used. However, they are yet to comment on the use of paclitaxel devices following SWEDEPAD 2. A strong recommendation is upheld that supervised exercise therapy, smoking cessation and risk factor management should remain the mainstay of therapy for most patients.¹⁴ The Medicines and Healthcare products Regulatory Agency (MHRA) advises that paclitaxel devices can be used ‘where indicated’ in both claudication and chronic limb-threatening ischaemia (CLTI).¹⁵ These recommendations were also made prior to the publication of SWEDEPAD 2.  

Patients, clinicians and healthcare systems cannot afford evidence that arrives a generation after adoption. We believe that newer research methodologies could shorten this timeline such as registry-based randomised trials, platform and basket factorial multi-arm multi-stage trials (MAMS) and those that employ Bayesian adaptive or seamless designs.  

Such methodologies have been utilised in other fields; the large RECOVERY trial showed how quickly this approach can answer clinical questions at scale during the pandemic (factorial platform trial).¹⁶ The first iteration of this methodology in vascular surgery is due to start enrolment imminently, investigating multiple interventions to reduce surgical site infection following arterial groin exposure and major lower limb amputation (ROSSINI-Platform).¹⁷ 

These designs and methods need rigorous, transparent reporting, but they offer a route to answering efficacy and effectiveness questions faster or together, within years rather than decades.¹⁸ 

Finally, the guideline’s defenders argue for selective rather than routine use of paclitaxel-based devices, but the update, as well as other key guideline documents do not define who, or what should be selected.² Without criteria, ‘selective use’ risks becoming either routine use by another name or no use at all, depending on opinion. 

The identification of patients who might benefit from this technology needs to be investigated more thoroughly using the available trial data that we have. Defining these groups requires prespecified analyses of treatment-effect heterogeneity in existing trials, an individual-patient-data meta-analysis that pairs patency with patient-reported outcomes, and validated risk-prediction tools. Until then, selection should rest on shared decision-making that is explicit about uncertain benefit. Defining ‘selected patients’ is the natural final stage of this lifecycle, and one that we should now reach quickly. 

References 

1. Schneider P, Zeller T, van den Berg J, et al. How should the new claudication guideline be interpreted? Vascular News. 23 September 2026.
2. Wanhainen A, Boyle J, Venermo M, et al. Why the ESVS focused update on claudication recommends selective use of paclitaxel-coated devices. Vascular News. 5 October 2026. 
3. Nordanstig J, Hinchliffe R, Lejay A, et al. Editor’s choice – Focused update on paclitaxel coated technologies, from the 2024 European Society for Vascular Surgery (ESVS) guidelines on the management of asymptomatic peripheral arterial disease and intermittent claudication. Eur J Vasc Endovasc Surg. 2026;71(6):923–927. 
4. Tepe G, Zeller T, Albrecht T, et al. Local delivery of paclitaxel to inhibit restenosis during angioplasty of the leg. N Engl J Med. 2008;358(7):689–699. 
5. Rosenfield K, Jaff MR, White CJ, et al. Trial of a paclitaxel-coated balloon for femoropopliteal artery disease. N Engl J Med. 2015;373(2):145–153. 
6. Laird JR, Schneider PA, Tepe G, et al. Durability of treatment effect using a drug-coated balloon for femoropopliteal lesions: 24-month results of IN.PACT SFA. J Am Coll Cardiol. 2015;66(21):2329–2338. 
7. Dake MD, Ansel GM, Jaff MR, et al. Durable clinical effectiveness with paclitaxel-eluting stents in the femoropopliteal artery: 5-year results of the Zilver PTX randomized trial. Circulation. 2016;133(15):1472–1483. 
8. Katsanos K, Spiliopoulos S, Kitrou P, et al. Risk of death following application of paclitaxel-coated balloons and stents in the femoropopliteal artery of the leg: a systematic review and meta-analysis of randomized controlled trials. J Am Heart Assoc. 2018;7(24):e011245. 
9. Parikh SA, Schneider PA, Mullin CM, et al. Mortality in randomised controlled trials using paclitaxel-coated devices for femoropopliteal interventional procedures: an updated patient-level meta-analysis. Lancet. 2023;402(10415):1848–1856. 
10. Nordanstig J, James S, Andersson M, et al. Paclitaxel-coated versus uncoated devices for infrainguinal endovascular revascularisation in patients with intermittent claudication (SWEDEPAD 2): a multicentre, participant-masked, registry-based, randomised controlled trial. Lancet. 2025;406(10508):1115–1127. 
11. McCulloch P, Altman DG, Campbell WB, et al. No surgical innovation without evaluation: the IDEAL recommendations. Lancet. 2009;374(9695):1105–1112. 
12. Loudon K, Treweek S, Sullivan F, et al. The PRECIS-2 tool: designing trials that are fit for purpose. BMJ. 2015;350:h2147. 
13. Fleming TR, DeMets DL. Surrogate end points in clinical trials: are we being misled? Ann Intern Med. 1996;125(7):605–613. 
14. National Institute for Health and Care Excellence. Peripheral arterial disease: diagnosis and management. Clinical guideline [CG147]. London: NICE; 2012 (updated 2020). 
15. Medicines and Healthcare products Regulatory Agency. Paclitaxel-coated devices (PCD) used in the treatment of peripheral arterial disease: update to previous MHRA guidance on use. Device Safety Information DSI/2024/001. London: MHRA; February 2024.  
16. RECOVERY Collaborative Group. Dexamethasone in hospitalized patients with Covid-19. N Engl J Med. 2021;384(8):693–704. 
17. The ROSSINI-Platform Investigators Collaborating Group. ROSSINI-Platform – Reduction of surgical site infection with a platform trial utilising a ‘Basket-MAMS’ design – application acceleration award. NIHR Open Res. 2024;4:76. 
18. Dimairo M, Pallmann P, Wason J, et al. The Adaptive designs CONSORT Extension (ACE) statement: a checklist with explanation and elaboration guideline for reporting randomised trials that use an adaptive design. BMJ. 2020;369:m115. 

Matt Popplewell is associate professor of vascular surgery at the University of Leicester (Leicester, UK); Thanos Saratzis is the National Institute for Health Research (NIHR) professor of vascular surgery and professor of vascular surgery at the University of Leicester (Leicester, UK); and Matthew Menard is a vascular surgeon at Brigham and Women’s Hospital (Boston, USA). 

The authors have declared the following disclosures: 

Matt Popplewell: investigator in the BASIL-3 trial; educational grant from LeMaitre Vascular. 

Thanos Saratzis: funded in full by the NIHR; research support (external research funding) by Shockwave (Johnson and Johnson), Abbott Medical, Cook Medical, Boston Scientific, and Angiodroid; honoraria/travel support from Shockwave Medical; educational grants from Cook Medical, Cordis, Boston Scientific, Philips; treasurer of the ESVS (no direct conflicts).   

Matthew Menard: grant support from Novo Nordisk Foundation; education grant support from Gore Medical; scientific Advisory Board: Regeneron, Novartis, Dialybrid. 

Read Peter Schneider, Thomas Zeller and colleagues’ comment piece here.

Read Anders Wanhainen and colleagues’ comment piece here.