Paclitaxel in the lower limbs: harm outweighs the benefit

Abstract

Of further significant concern, in the SWEDEPAD 2 trial at 5 years, all-cause mortality was significantly higher in the paclitaxel-coated group than in the uncoated group (HR 1·47 [95% CI 1·09 to 1·98]), echoing our original 2018 meta-analysis. 3 The authors employed a nationwide registry-based randomisation in Sweden and stratified between critical limb-threatening ischaemia and claudication with hard patient-centred endpoints, namely quality of life, major amputations, mortality, and limb re-interventions. 1,2 We applaud the registry-RCT design that leveraged the efficiency and data linkage of the existing Swedish registry infrastructure to produce the two largest randomised studies available to date in the peripheral arterial disease arena. In the BASIL-3 trial, neither paclitaxel-coated balloons (HR 0·84 [95% CI 0·61 to 1·16]), nor paclitaxel-coated stents (HR 0·83 [95% CI 0·60 to 1·15]) conferred any significant clinical benefit in time to major amputation or all-cause death. 4 The SWEDEPAD 2 trial also did not translate the well known anti-restenotic efficacy of paclitaxel into meaningful gains of quality of life. 2 We contend that quality of life is shaped by multiple factors, including, but not limited to, instrument (questionnaire) insensitivities, lifestyle adaptations, socioeconomic environment, psychological wellbeing, systemic progression of atherosclerosis, and other influences often unrelated to the treated limb. Alternative patient-reported functional outcomes, such as pain-free walking distance, have been proposed as more appropriate primary endpoints for claudication trials. 5 The SWEDEPAD 2 trial has once again showed a markedly elevated risk of all-cause mortality—approximately 1·5-fold—in paclitaxel-treated patients at 5 years. 2 Even though this mortality signal appears attenuated in very long-term follow-up, this likely reflects the well recognised statistical properties of hazard functions, in which early differences are progressively diluted over time. 6 Its absence in the SWEDEPAD 1 trial is plausibly explained by the natural history of critical limb-threatening ischaemia, in which multiple systemic comorbidities act as competing risks and might overshadow or mute any potential paclitaxel-related harm.