The last several years have seen ongoing controversy and debate about the risks and benefits of paclitaxel-coated devices (PCDs) for patients with peripheral arterial disease (PAD). The latest contribution from Konstantinos Katsanos, MD, and colleagues raises questions about potential increased risk of amputation in patients treated with paclitaxel drug-coated balloons (DCB), particularly in the context of chronic limb-threatening ischemia (CLTI). Since the 2018 publication from the same first author highlighted a potential mortality risk, several large-scale observational studies, as well as a report from the SWEDEPAD registry, have shown no discernible mortality signal.
The issue remains somewhat unsettled, and the Food and Drug Administration (FDA) has not as yet changed its most recent guidance, urging some caution and a need for more long-term data.
From my perspective, the plausibility of potential adverse off-target effects of paclitaxel has always been greater in the treated limb rather than systemically. So, this publication should engender some appropriate caution and emphasize need for greater study given limitations in the data. It should also be put into perspective from the standpoint of both risk and benefit.
First, and most importantly, as yet there is no demonstration of clinical efficacy of drug-coated balloons (DCBs) in patients with CLTI. Clearly, patients with CLTI have ongoing major unmet needs for improved and more durable vascular interventions, but so far DCBs have not shown themselves to be the answer. One wonders if this observation is part of that explanation. The recent failure of Lutonix-BTK to meet its efficacy endpoint further highlights the disappointing impact of DCBs where they are needed most: in patients with CLTI and severe tibial disease.
The risk estimated by Katsanos is also very modest—i.e. less than three in 100 excess amputations—and is not controlled for important confounders such as limb severity (e.g. the wound, ischemia and foot infection [WIfI] stage). But in the absence of proven efficacy in CLTI, one should be quite cautious about any increased risk profile. Drug-eluting devices and their associated pharmacology are complex, and one should be cautious about lumping multiple unique devices, and certainly device classes, together. The potential embolization concern is legitimate but also likely to be device and formulation specific.
In the interim, we would advise caution in the use of DCBs in CLTI patients with advanced WIfI stage, larger wounds, or those needing reconstructive foot surgery. We will await the results of ongoing trials such as BEST-CLI (Best endovascular versus best surgical therapy in critical limb ischemia), BASIL-3, and SWEDEPAD to get more comprehensive data on both the risks and benefits of DCBs in CLTI.
Additionally, the paclitaxel controversies have spurred accelerated work to develop alternative drugs—for example limus agents—and delivery platforms that may yet prove to be the silver lining.
Furthermore, the amputation rate was only significantly different in the CLTI group, but not the claudicant group, and the overall amputation rate is much lower than would be expected in CLTI patients (about 4–7%)—which would correlate with only WIfI clinical stage 1, and perhaps stage 2, patients.
Unfortunately, we do not have any stratification of limb risk (WIfI) or runoff/ anatomy—e.g. the Global Limb Anatomic Staging System (GLASS)—so making any comparison of amputation risk without this and other information is difficult.
We also don’t have a good handle on the timing of the major amputations. If particulate embolization is the proposed mechanism, one would expect that to occur fairly early after intervention, but that is hard to ferret out.
Michael Conte, MD, is co-director of the UCSF Heart & Vascular Center and chief of the division of vascular and endovascular surgery in San Francisco. Joseph Mills, MD, is chief of the division of vascular surgery and endovascular therapy at Baylor College of Medicine in Houston.