From the International Symposium on Endovascular Therapies (ISET) Meeting, held February 4-8, 2017.

Local drug delivery is rapidly emerging as the first line of therapy for the interventional treatment of superficial femoral artery (SFA) disease. Paclitaxel-coated balloon (PCB) technologies have shown to be superior to plain balloon angioplasty in maintaining long-term vessel patency among patients undergoing SFA intervention.¹ The pharmacokinetic behavior of PCBs is highly variable and largely depends on the size and solubility of the paclitaxel particles delivered to the vessel surface.² It has been hypothesized that the variability in paclitaxel tissue levels displayed by PCB technologies may impact the durability of long-term clinical results. 

Tissue pharmacokinetics modulates biological effect on restenosis and overall vessel patency. In the setting of PCB delivery, drug is passively retained on the surface of the vessel wall as a function of its particle size and solubility.² Paclitaxel transfer into the tissue is facilitated by concentration gradients and occurs in an uncontrolled fashion. Typically, arterial levels of paclitaxel rapidly decline 72 hours following balloon delivery and fall below therapeutic levels by 180 days.² First-in-human clinical studies using different PCB technologies demonstrate that PCB decreases angiographic restenosis by 40% to 50% by 6 months following initial delivery compared to PTA. However, randomized controlled studies suggest that the effect on restenosis and vessel patency declines after the first 12 months and appears to be technology dependent.³ 

Some of the target-lesion revascularization (TLR) events reported in PCB are focal and related to either excessive vascular recoil or dissections left behind occurring right after balloon dilation. Then, paclitaxel-eluting metallic stents promise to improve the clinical outcomes showed by PCB. A first-generation polymer-free paclitaxel stent (Zilver PTX; Cook Medical) showed higher 1-year primary patency rates (84.4%) compared to standard-of-care intervention, defined as percutaneous transluminal angioplasty and provisional Zilver bare-metal stent implantation (67.4%).⁴ Similar to what has been seen with PCB technologies, by 3 and 5 years, primary patency had declined to 71.5% and 66.4%, respectively. Finally, early clinical evidence from a study using a polymer-based paclitaxel-eluting stent suggests that sustained paclitaxel release achieved higher patency rates (primary patency of 95%), with low major adverse event rates (4%) driven by TLR events in 2 patients at 12-month follow-up. High patency rates corresponded with favorable clinical outcomes. These results were sustained through 1 year, with 81% exhibiting no symptoms (category 0), and 13% presenting with mild claudication (category 1). 

Sustainability of the therapeutic effect is important, because multiple clinical studies have shown that the restenotic process in peripheral vascular intervention peaks between 9 to 12 months and sustained therapeutic tissue drug levels are needed to prevent restenosis in this critical period of the healing response.⁵ Despite the encouraging 12-month patency results seen with all local drug delivery devices, a progressive loss of lumen patency is always seen and attributed to the highly variable pharmacokinetic profiles seen in all these technologies. Therefore, future generations of peripheral vascular technologies must focus on the development of drug delivery concepts capable of improving vessel patency by providing a more sustainable and controllable environment following device use. 

References

1. Rosenfield K, Jaff MR, White CJ, et al. Trial of a paclitaxel-coated balloon for femoropopliteal artery disease. N Engl J Med. 2015;373:145-153.
2. Granada JF, Stenoien M, Buszman PP, et al. Mechanisms of tissue uptake and retention of paclitaxel-coated balloons: impact on neointimal proliferation and healing. Open Heart. 2014;1:e000117.
3. Laird JR, Schneider PA, Tepe G, et al. Durability of treatment effect using a drug-coated balloon for femoropopliteal lesions: 24-month results of IN.PACT SFA. J Am Coll Cardiol. 2015;66:2329-2338.
4. Dake MD, Ansel GM, Jaff MR, et al. Durable clinical effectiveness with paclitaxel-eluting stents in the femoropopliteal artery: 5-year results of the Zilver PTX randomized trial. Circulation. 2016;133:1472-1483.
5. Cejna M, Thurnher S, Illiasch H, et al. PTA vs Palmaz stent placement in femoropopliteal artery obstructions: a multicenter prospective randomised study. J Vasc Intervent Radiol. 2001;12:23-31.