“There appears to be heightened risk of major amputation after use of paclitaxel-coated balloons [PCBs] in the peripheral arteries,” findings from a systematic review and meta-analysis of randomized controlled trials (RCTs) published in the European Journal of Vascular and Endovascular Surgery (EJVES) this week suggest. However, the authors clarify that the level of evidence is graded moderate, not high, due to scarce events in some studies.
And, leading physicians propose that the methodology used needs to be carefully considered and scrutinized before these conclusions are accepted.
Clarifying at the outset that he is not an expert on statistical methodology, globally recognized leader in the development of new less-invasive procedures, Barry T. Katzen, MD, founder and medical director of Miami Cardiac & Vascular Institute and the president of the CLI Global Society, tells Vascular Specialist: “As a physician engaged in multidisciplinary limb salvage with a view to improving quality of life by preventing amputations and death due to critical limb ischemia, the conclusions from this meta-analysis are of concern, of course, and need to be taken seriously. However, I have in parallel questions about the complex methodologies used in this paper to arrive at a finding that prospective randomized controlled trials have not demonstrated. From a practical point of view, before accepting the conclusion regarding the risk of paclitaxel drug-coated balloon use, there needs to be a significant discussion and analysis of the methodologies employed in this paper. This needs to be undertaken by appropriate statistical experts before these findings change practice, if they do so at all.”
This latest meta-analysis, authored by Konstantinos Katsanos, MD, of Patras University Hospital, Rion, Greece, and colleagues with co-authors from France, Germany, Finland and The Netherlands, drills down on the long-term risk of major amputation alone associated with use of PCBs in the lower limbs. The findings point to a significantly higher long-term risk of major limb loss using these devices in the femoropopliteal and/or infrapopliteal arteries.
Anna Maria Belli, MD, a former consultant radiologist and Professor of Interventional Radiology at St. George’s Hospital and Medical School in London, England, a past president of the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) and proponent of evidence-based trials, comments: “It is essential that we have publications such as this interrogating data on new technologies in an unbiased way. There is a natural tendency to believe new technologies will provide better results than old ones. It is only by pooling results from published trials that enough numbers are amassed to detect trends which might be missed by individual trials. Katsanos and colleagues are to be commended for highlighting the increased risk of amputation with PCBs and, as they say, this now needs to be confirmed or refuted by further investigations.”
Commenting on the publication in EJVES, Younes Jahangiri, MD, statistical editor of the Journal of Vascular and Interventional Radiology, says: “The manuscript has used a robust search strategy and meta-analysis techniques. Nevertheless, there are a considerable number of back-calculations and imputations that have been performed for data generation, which might not necessarily fit with real-world data. Additionally, exclusion of studies with no events in both arms, especially if the studies were of high quality and adequate follow-up, might have led to overestimation of the crude risk in both groups and potentially to the statistical significance of between-group differences. Although the meta-analysis itself suggests an alarming signal in a heavily computational way, confirmation of accuracy and adequacy of the signal would still require real-world targeted data.”
The harm signals suggested for paclitaxel devices from previous meta-analyses have not been substantiated by a wealth of real-world datasets that have shown no long-term safety concerns, and instead suggested increased benefits with the use of paclitaxel-coated devices. Importantly, an interim mortality analysis of the SWEDEPAD registry randomized trial did not confirm a heightened mortality risk in cases of paclitaxel treatment, as noted in the EJVES paper.
As reported in EJVES, the investigators performed a literature search last updated on Feb. 20, 2021, to analyze 21 RCTs with 3,760 lower limbs treated nearly equally for intermittent claudication (52%) and chronic limb threatening ischemia (CLTI; 48%). The median follow-up period was two years. Authors report 87 major amputations in 2,216 limbs in the paclitaxel arm (4% crude risk) compared with 41 major amputations in the 1,544 limbs in the control arm (2.7% crude risk). The risk of major amputation was significantly higher for paclitaxel-coated balloons with a hazard ratio (HR) of 1.66 (95% CI 1.14–2.42; p=0.008, one stage stratified Cox model). The observed amputation risk played out equally across femoropopliteal (p=0.055) and infrapopliteal (p=0.055) arteries. The number needed to harm was 35 for CLTI. In this systematic review and meta-analysis, authors suggest the summary effect demonstrated a 66% higher relative risk of major amputation in the limbs treated with PCBs, and call for further investigations.
Further, Katsanos and colleagues write that there was good evidence of a significant non-linear dose relationship with accelerated risk per cumulative paclitaxel dose (chi square model p=0.007). The results were also stable across sensitivity analyses (clarified as pertaining to different models and subgroups, based on anatomy and clinical indication and excluding unpublished trials).
Ziv Haskal, MD, of the University of Virginia, Charlottesville, Virginia, the former editor (2011–2020) of the Journal of Vascular and Interventional Radiology (JVIR) tells Vascular Specialist: “Dr. Katsanos and the research team stand, again, to shake-up the PCB planet with a suggested finding of worse amputation—the same goal paclitaxel was intended to make better, and with a dose-dependent effect. Unsurprisingly, it is a rigorous and clear-headed analysis. But there are interpolations, intercalations and imputations, likely to bring out critics, with force. This may be a curtain raiser, but the main play is yet to unfold.”