Paclitaxel DCBs Now Implicated in Death, Amputation in Below-the-Knee CLI

The same group of researchers who turned the endovascular community on its head last year by detecting a long-term signal of harm with treatment of paclitaxel-based devices for femoropopliteal artery disease are back with a fresh message. Now, in a new meta-analysis of critical limb ischemia (CLI) patients, they suggest that using paclitaxel-based drug-coated balloons (DCBs) below the knee also may increase the risk of amputations and death in the short term.

“It seems that there is a very similar signal of harm related to the use of paclitaxel-coated balloons in the infrapop vessels,” Konstantinos Katsanos, MD, PhD (Patras University Hospital, Rion, Greece), told TCTMD, referencing the similarities of the new work to his controversial meta-analysis from late 2018. “Instead of improving amputation-free survival, which is the main aim when we are treating CLI populations, we saw a detrimental effect with paclitaxel,” he emphasized.

Published online today in the Journal of Vascular and Interventional Radiology, the latest study by Katsanos and colleagues pooled eight RCTs totaling 1,420 patients—97% of whom had CLI—and five different DCBs. While treatment with a paclitaxel DCB reduced the incidence of TLR compared with uncoated balloons (RR 0.53; 95% CI 0.35-0.81), the paclitaxel-treated groups had lower amputation-free survival. The latter was driven by greater risks of all-cause death (OR 1.39; 95% CI 0.94-2.07) and major amputation (OR 1.63; 95% CI 0.92-2.90).

Poolability, Probability, and Paclitaxel

Of the eight RCTs in the meta-analysis, three had 6-month clinical follow-up and five had 1-year clinical follow-up.

Commenting on the study for TCTMD, Sahil A. Parikh, MD (NewYork-Presbyterian/Columbia University Irving Medical Center, New York, NY), said with varying devices, protocols, follow-up times, and wound care among the studies, “it's a little bit unclear to me that all the data are poolable.”

Similarly, Eric Secemsky, MD (Beth Israel Deaconess Medical Center, Boston, MA), called the conclusion that paclitaxel use in the lower legs is related to increased death and amputations “jumping the gun,” given that some of the included studies are unpublished and one, IN.PACT DEEP, used a device that was pulled from the market in 2013 due to concerns about amputations in the paclitaxel group.

In a statement, Laura Findeiss, MD (Emory University School of Medicine, Atlanta, GA), president of the Society of Interventional Radiology, which publishes the Journal of Vascular and Interventional Radiology, said that while the study raises questions about the management of CLI patients, “the lack of patient-level data and the inclusion of unpublished data sets in this analysis may weaken the strength of the conclusions.” Findeiss added that validation of the findings and further study of this issue is needed given the fact that CLI patients are a vulnerable population with few care options.

Katsanos and colleagues also performed dose-response analyses and found that amputation-free survival was significantly decreased with most 3.0 μ/mm2 or 3.5 μ/mm2 DCBs (HR 1.62; 95% CI 1.16-2.27). However, there was no impact on survival in the Lutonix BTK study of a 2.0 μ/mm2 device (HR 1.06; 95% CI, 0.48-2.34).

The researchers say the findings “add to the evidence underpinning some major safety concerns about use of paclitaxel in lower limb angioplasties.” They further contend that paclitaxel embolization beyond the target lesion may be responsible for the increase in amputations and deaths. 

To TCTMD, Parikh said the dose analysis as detailed in the paper appears to have been incorrectly performed, making the findings “more alarmist than real.” He also noted that although avoiding amputations is thought to save lives, it is impossible to know from this meta-analysis whether or not some amputations may have hastened death independent of treatment with paclitaxel or anything else. Due to the nature of the meta-analysis, the individual causes of deaths and clinical indications for amputation remain unknown.

“All the same criticisms that were leveled against the [2018 meta-analysis] could be applied to this paper,” Parikh observed. “It's actually kind of disappointing that the peer review process didn't insist that more rigor be applied. I don't think there's anything wrong with the approach of doing a meta-analysis, but I think the rigor of a meta-analysis now needs to be at a much higher level because the bar has been set much higher than in the past.” Over the course of 2019, multiple societies and the US Food and Drug Administration weighed in on the quality of the original Katsanos meta-analysis, dissecting its methodology and suggesting ways to strengthen future meta-analyses.

I would argue that this is a very pertinent study with regards [to] timing following our previous publication and how the whole of the evidence resonates together. Konstantinos Katsanos

To TCTMD, Katsanos said the RCTs were chosen based on strict criteria and using the evidence-based PICO tool (Patient, Intervention, Comparison, Outcome). As for the unpublished studies that were included, such as SINGA-PACLI, he maintained that it was presented in full at CIRSE 2019 and that it and all the other trials are fully disclosed on ClinicalTrials.gov. With regard to the short duration of follow-up Katsanos said it is actually extremely relevant to CLI patients, 50% of whom will die within 5 years. “One year of follow-up is quite reasonable when examining a CLI population,” he noted.

None of the devices in the meta-analysis are commercially available in the US and others are in various phases of testing in Europe and Asia. For those reasons, Katsanos said he does not expect the findings of the new meta-analysis to have as much of an impact on clinical practice as the 2018 meta-analysis. That bombshell study prompted a series of FDA alerts in 2019 and according to speakers at meetings throughout the year led to a decline in the use of paclitaxel-based devices in PAD. Instead, said Katsanos, this new study may be a catalyst for improving future design of trials and devices for use in the infrapopliteal arteries. It also may be important in encouraging the full disclosure of data that have been collected but not published, such as from the PICCOLO and EUROCANAL trials.

“You can argue that this may be a premature study,” he said. “But on the contrary, I would argue that this is a very pertinent study with regards [to] timing following our previous publication and how the whole of the evidence resonates together.”

Secemsky agreed that the study won’t change anything for now, adding: “It doesn't keep me from using drugs above the knee for a really complex disease where I'm concerned about aggressive restenosis in CLI. It just makes me want more information before I start using below-the-knee drug-based devices.”