Drug-Coated Balloons for Treatment of Infrapopliteal Peripheral Artery Disease: Where Do We Stand?

Endovascular intervention (EVI) for peripheral artery disease (PAD) affecting the infrapopliteal arteries has been a target for several innovations. After applying plain old balloon angioplasty (POBA) only, the use of drug-eluting stents (DES), scoring balloons, and atherectomy devices have improved the outcome of patients with infrapopliteal PAD. Initially introduced for coronary in-stent restenosis, drug-coated balloon (DCB) technology has been expanded to the femoropopliteal arteries. The favorable patency rate associated with the utilization of DCB in femoropopliteal arteries led to the extension of its use in infrapopliteal segments. Several randomized trials of DCB showed a positive or neutral effect on surrogate endpoints, e.g. binary restenosis or target lesion revascularization (TLR). However, one trial demonstrated a concerning trend towards higher amputation rates in patients assigned to DCB compared to POBA.¹ Katsanos et al pooled study-level data from those trials and investigated the outcomes of infrapopliteal PAD treated by DCB vs POBA.² Among 339 eligible studies, only 8 met the inclusion criteria. A total of 1420 patients were included: 835 in the DCB arm and 585 in the POBA arm. Despite the inclusion of mainly critical limb ischemia (CLI) patients, the trials were reasonably heterogeneous concerning the design, devices used, paclitaxel doses, various excipients, and follow-up period. The primary efficacy outcome was amputation-free survival (AFS), which was significantly worse in the DCB compared to POBA arm (13.7% vs 9.4%) with no heterogeneity (I²=0). Furthermore, both individual endpoints of major amputation and all-cause death, although not significant, were also not in favor of DCB vs POBA. Only TLR was highly significantly favorable in patients from the DCB compared to POBA arm (11.8% vs. 25.6%) with significant heterogeneity (I²=69%).

The authors should be commended for providing this critical analysis. However, several issues have to be considered while interpreting the results of this analysis. First, any study level meta-analysis will be characterized by the same biases and weaknesses of the trials from which it is derived. Therefore pooling data on a study level will not minimize but rather amplify the inherent weaknesses of the included trials. Second, the diverging outcomes of AFS vs TLR with the use of DCB vs POBA raises concerns regarding the issue of competing events. In a highly morbid patient population, death or amputation due to severe tissue loss or ulceration might have affected the lower rate of TLR in DCB vs POBA. Most of the included trials did not stratify patients according to wound severity, which might have led to an unbalanced treatment assignment. Additionally, in one of the included trials, which added the highest weight (>30%) to the outcome of AFS, had an unbalanced treatment assignment with regards to patients with previous target limb revascularization and previous coronary artery disease.¹ Furthermore, unlike hard endpoints such as major amputation or death, TLR is rather a soft event, and a summary of considerations of several clinical and imaging determinants. Furthermore, the decision for TLR involves several disciplines (vascular medicine and surgery, interventional radiology, and cardiology and podiatry) participating in the care of patients with CLI. Each might have a different approach as to whether a TLR is needed or not. Third, similar to a previous meta-analysis³ by the same group, the authors have no reasonable biological explanation for these findings in DCB compared to POBA. Unlike the late (>2 years) risk of morality associated with the use of paclitaxel-coated devices in femoropopliteal arteries3, death or major amputation occurred early after treatment with DCB in infrapopliteal arteries (<1 year), which might be explained by the inclusion of more morbid patients in this analysis. Fourth, the definition of the endpoint of amputation was not unified, and event adjudication by an independent clinical event committee was not performed in some of the included trials. Fifth, in a population of CLI, with repeatedly occurring events, trials using time-to-first-event analysis might miss subsequent more deleterious events. Therefore, similar to the primary endpoint selected for this meta-analysis, future trials on patients with CLI should be powered for major amputation and death rather than for soft endpoints like TLR, binary restenosis, or primary patency. Perhaps using a standardized endpoint definition⁴ in future trials will add to the improvement of the generalizability of clinical trials.

The reader is now left with the following question: how shall we approach patients with CLI in light of the findings of this meta-analysis? Certainly, CLI, which involves more calcified infrapopliteal lesions, might deserve a more advanced EVI approach, including advanced imaging, e.g., intravascular ultrasound, atherotomy, or atherectomy for debulking and possibly facilitation of paclitaxel diffusion from the DCB to the lesion. Furthermore, the role non-paclitaxel drug-eluting stents has to be re-emphasized and perhaps re-analyzed in an updated network meta-analytical approach. Last but not least, the role of surgical revascularization in this patient population should not be neglected. The Best Endovascular vs. Best Surgical Therapy in Patients With Critical Limb Ischemia (BEST-CLI) trial⁵ is currently in the enrollment stage and results are awaited with high interest.  

Disclosure: Dr Farhan and Dr Kamran report no conflicts of interest regarding the content herein. Dr Krishnan reports he is a consultant to Medtronic, Philips, BD, and Abbott. He is the co-national principal investigator for the ILLUMENATE study.

Address for correspondence: Dr Prakash Krishnan can be contacted at prakash.krishnan@mountsinai.org.

References
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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.    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.
4.    Patel MR, Conte MS, Cutlip DE, Dib N, Geraghty P, Gray W, Hiatt WR, et al. Evaluation and treatment of patients with lower extremity peripheral artery disease: consensus definitions from Peripheral Academic Research Consortium (PARC). J Am Coll Cardiol. 2015;65:931-941.
5.    Menard MT, Farber A, Assmann SF, Choudhry NK, Conte MS, Creager MA, et al. Design and rationale of the Best Endovascular Versus Best Surgical Therapy for Patients With Critical Limb Ischemia (BEST-CLI) trial. J Am Heart Assoc. 2016 Jul 8; 5(7). pii: e003219. doi: 10.1161/JAHA.116.003219.