Drug-eluting stents (DES) and drug-coated balloons (DCB) have gained huge presence in the toolbox of your everyday vascular specialist. So it was no surprise that controversy ensued after Katsanos et al released a meta-analysis in late 2018 demonstrating increased risk of death with the use of paclitaxel-coated balloons (PCBs) and stents in the femoral-popliteal arteries.1 Fast forward to the present, after a statement by the FDA and innumerable debates on the safety and efficacy of DESs and DCBs, Katsanos et al has again released a meta-analysis, “Risk of Death and Amputation with Use of Paclitaxel-Coated Balloons in the Infrapopliteal Arteries for Treatment of Critical Limb Ischemia: A Systematic Review and Meta-Analysis of Randomized Controlled Trials (RCTs)”.2 Below, we present a few questions, along with a review of their results.
Are There Any Issues With the Study Design?
Naturally, providers and patients were left with important questions after so much attention was brought to paclitaxel-coated devices; therefore, further investigation will continue to lead us to similar studies until a more comprehensive, prospective study can be completed. Many providers will be left desiring more statistical sense due to the lack of patient-centered data. More so, the meta-analysis possesses 8 RCTs but lacks compatibility between them due to different parameters and protocol, which forces additional statistical methods to create compatibility. The article also exhibits a poor allocation ratio (835:585, PCB:POBA) and lacks long-term follow-up. Lastly, amputation-free survival was deemed statistically significant, but its components (all cause death or major amputation) were not individually significant.2
Do Inflow Treatment, TLR, or Target Lesion Characteristics Affect AFS?
Do we know if and which patients were treated with a drug-coated device before infrapopliteal intervention? Was target lesion revascularization (TLR) carried out with DCB intervention? If paclitaxel dose plays a role in amputation-free survival (AFS), prior or additional treatment in the same limb with a drug-coated device must be considered and most of the included studies do not report these details.
Additionally, it is difficult to pass up on several features of the included retrospective studies. For example, the PCB arm of the IN.PACT DEEP trial exhibited impaired inflow to the target lesion in comparison to the lesions of the control arm.3 In the BIOLUX P-II trial, a 6-month angiographic follow-up was carried out which may have falsely increased the TLR rate due to the possible treatment of clinically asymptomatic restenosis.4
Finally, lesion characteristics play an essential role in drug delivery at the arterial wall. Asymmetric allocation of moderate or severely calcified lesions into the PCB arm may confound the results due to impaired drug deliver which was observed in the BIOLUX P-II trial.4 Further clarification and stratification on the aforementioned parameters will be beneficial in the future.
Did They Answer Questions About Paclitaxel Dosing?
Back in late 2018, many readers instantly compared paclitaxel’s usage in cancer patients to its usage in endovascular treatment for peripheral artery disease (PAD). On the contrary, the targeting of paclitaxel into the arterial wall with an endovascular device carries different kinetics in comparison to intravenous administration. Tissue retention of paclitaxel may have additional effects on arterial wall viability, wound healing, etc.2
PAD and CLI are complex processes that require a multidisciplinary approach, and a standard
protocol with comprehensive wound care should be implemented in future prospective trials. If not, poor or unexpected outcomes are inevitable, especially in multicentered studies like the IN.PACT DEEP trial where 23%-29% of wounds were self-cared.4 The level of CLI must also be considered, as there was an abundance of Rutherford category 5 lesions throughout the included trials.
Further investigation with a long-term, multicentered RCT comparing mortality with PCB and POBA use in the infrapopliteal arteries is obviously warranted, and hopefully will provide definitive answers in the near future. Until then, providers should be aware of the increased signal associated with paclitaxel-coated devices and appropriately inform their patients.
Disclosure: Dr Patel reports no conflicts of interest regarding the content herein. Dr Beasley reports he is a speaker/trainer for Abbott Vascular. BSCI (also, Medical Advisory Board), Cardinal Health/Cordis, Cook Medical, CR BARD/Becton Dickinson (also, Medical Advisory Board), CSI, Endologix, Inari Medical, Medtronic, Micro Medical Solutions, Philips/Volcano/Spectranetics, Penumbra, Terumo/Bolton, and WL Gore.
Address for correspondence: The authors can be contacted via Dr Robert Beasley at firstname.lastname@example.org.
1. Katsanos K, Spiliopoulos S, Kitrou P, Krokidis M, Karnabatidis D. 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 Dec 18; 7(24): e011245.
2. Katsanos K, Spiliopoulos S, Kitrou P, Krokidis M, Paraskevopoulos I, Karnabatidis D. Risk of death and amputation with use of paclitaxel-coated balloons in the infrapopliteal arteries for treatment of critical limb ischemia: a systematic review and meta-analysis of randomized controlled trials. J Vasc Interv Radiol. https://doi.org/10.1016/j.jvir.2019.11.015.
3. Zeller T, Baumgartner I, Scheinert D, et al. Drug-eluting balloon versus standard balloon angioplasty for infrapopliteal arterial revascularization in critical limb ischemia: 12-month results from the IN.PACT DEEP randomized trial. J Am Coll Cardiol. 2014;64(15):1568-1576.
4. Zeller T, Beschorner U, Pilger E, et al. Paclitaxel-coated balloon in infrapopliteal arteries: 12-month results from the BIOLUX P-II randomized trial (BIOTRONIK'S first in man study of the Passeo-18 LUX drug releasing PTA balloon catheter vs. the uncoated Passeo-18 PTA balloon catheter in subjects requiring revascularization of infrapopliteal arteries). JACC Cardiovasc Interv. 2015;8(12):1614-1622.