3.1 Paclitaxel: Friend or Mortal Foe?

These proceedings summarize the educational activity of the 16th Biennial Meeting of the International Andreas Gruentzig Society held January 31-February 3, 2022 in Punta Cana, Dominican Republic

Faculty Disclosures     Vendor Acknowledgments

2022 IAGS Summary Document

Statement of the problem or issue

The antimitotic drug paclitaxel is a promising therapy for preventing hyperplasia and cellular proliferation in the treatment of atherosclerotic disease of both superficial femoral arteries (SFA) and popliteal arteries. However, over time, certain misconceptions arose about its safety over the longer term, especially its possible effects on mortality at 5 years.¹ Because of this, the FDA has been cautious in its consideration of paclitaxel-coated balloons for treatment and prevention of restenosis.²

These longer-term safety issues have led to a redirection of interest away from other secondary antiproliferative agents, such as the limus family of drugs, which might be used to improve current treatments below the knee (BTK) and especially with tibial artery atherosclerotic disease. It is unclear whether these other agents would be as safe and effective as paclitaxel. Although we can debate whether paclitaxel itself is associated with increased mortality or not, at least we can agree that paclitaxel is effective. Will we face the same questions 5 years from now with the limus family of agents?

Paclitaxel is one of the more favorable agents when attached to an excipient for transportation into the body and then into the vessel media. However, embolization is still a major issue because just as paclitaxel can be easily attached to an excipient, it can just as easily be detached. The amount of paclitaxel that can be used is limited by the length of the atherosclerotic lesions. This is appropriate for now, but what if drug-coated balloon treatment becomes mainstream therapy? How will we resolve this dose issue? There is also discordance in the concentrations of the drug placed onto current commercially available balloons. There is disagreement on the value of low-dose vs high-dose concentrations. How can we resolve those concerns?

Gaps in knowledge

Previously, the trend in thinking was that tibial arteries are similar to coronary arteries. But let’s stop for a second and think about that: coronary arteries have an inner endothelial layer, surrounded by a media consisting of 3 to 5 layers of smooth muscle cells, and then an adventitia with an outer elastic membrane. However, the tibial arteries are dramatically different from coronary arteries in multiple ways and we should never compare the two. Tibial arteries have dual smooth muscle cell layers. The first is a proliferative-type smooth muscle cell layer and the second is a secretion-type smooth muscle cell layer.

When you see a hyperplastic response to balloon angioplasty in tibial arteries, think of the “beast” of a thick, hyperproliferative dormant layer that is awakened by the significant radial force applied by the balloon. This radial force triggers an over-reactive response to the point of possible complete obliteration of the tibial lumen. This aggressive hyperproliferative response appears to happen more commonly in the distal tibial arteries rather than in the proximal tibial arteries. We don’t yet know why this occurs.

The secretory smooth muscle cells are triggered by unknown factors, many are which are still hypothetical at present. However, diabetes and renal disease seem to be most common factors of the ones known. There is a theory that these 2 conditions, diabetes and renal disease, can lead to formation of calcifications, starting with a phenomenon known as calcium dust phosphate formation. This process can continue until we see the ever-famous medial calcium accumulation. Eventually, this secretory medial layer can transform into osteocytes, with osteophytes and actual bone formation occurring within the medial layer of the vessel. The individual variation in severity of this medial calcification seems to be consistent with the chronicity of the other comorbidities, but as the process unfolds it leads ultimately to the lack of any utility from paclitaxel treatment at this point. It was demonstrated in the DEBELLUM study that paclitaxel cannot penetrate this type of tissue.^3,4

Possible solutions and future directions

The reality is this: if you treat these vessels every day, you quickly learn that plain old balloon angioplasty alone is more detrimental than helpful in the treatment of these peripheral vessels. On the other hand, atherectomy of various types may alter the medial wall barrier and possibly provide for better uptake of paclitaxel into the newly fractured channels leading into the subadventitial areas.

A method is needed for circumferential barrier penetration with drug delivery on both sides of the barrier wall: this would lead to inhibition of the proliferative smooth muscle cells of the media and at the same time inhibit the signals for hyperplasia that are coming from the subadventitia. Currently there are devices in development and under study that show promise in enhancing delivery of the paclitaxel (or other) drug. If calcium is not present in the media, then a 1:1 ratio of balloon-to-artery will provide the best preparation for these vessels prior to drug-eluting balloon delivery.

References

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;7(24):e011245. doi:10.1161/JAHA.118.011245

2. Farb A, Malone M, Maisel WH. Drug-coated devices for peripheral arterial disease. N Engl J Med. 2021;384(2):99-101. doi:10.1056/NEJMp2031360

3. Fanelli F, Cannavale A, Corona M, Lucatelli P, Wlderk A, Salvatori FM. The “DEBELLUM”— lower limb multilevel treatment with drug eluting balloon—randomized trial: 1-year results. J Cardiovasc Surg (Torino). 2014;55(2):207-216.

4. Fanelli F, Cannavale A, Gazzetti M, et al. Calcium burden assessment and impact on drug-eluting balloons in peripheral arterial disease. Cardiovasc Intervent Radiol. 2014;37(4):898-907. doi:10.1007/s00270-014-0904-3