Catheter-based revascularization strategies have rapidly evolved in the past few years and are the standard of care for patients with lower extremity peripheral artery disease (PAD). Even though PAD in general refers to involvement of any noncoronary vessel, the majority of lesions are located in the femoropopliteal tract.¹ Historically surgical intervention was the treatment of choice for patients with lifestyle-limiting claudication, critical limb ischemia (CLI) or acute limb ischemia, but with the advent of endovascular technology, the landscape of therapeutic strategies have changed. There is significantly less morbidity and faster recovery times with endovascular therapies especially in patients with multiple medical
comorbidities. However, one of the major criticisms of endovascular therapy has been a poor long-term patency rate especially for infrainguinal vasculature. However, most of this evidence comes from the percutaneous transluminal angioplasty (PTA) and bare-metal stent (BMS) era. The evolution of drug-coated therapy aimed at increasing the long-term patency rates of endovascular interventions. Most of the innovations in the PAD arena for the past 5 years were in the development of an “ideal” drug-coated therapy to mimic the success of these therapies in the coronary vasculature. One could argue that this milestone is yet to be achieved, but nevertheless the explosion of cardiovascular technologies in this area cannot be ignored. The objective of this chapter is to provide a basic understanding of the drug-coated technologies in the PAD world and their current clinical implications.

Even though the initial success rates of endovascular revascularization in the femoropopliteal territory have improved with betterment of dedicated devices,² the long-term patency remains suboptimal.³ Restenosis after endovascular therapy for PAD has been the major limitation for BMSs and PTA.⁴ It is important to understand the mechanism of restenosis to expand the horizon of interventional therapies and to improve its durability. There are not a lot of pathophysiologic studies examining the mechanism of restenosis in PAD, but one can extrapolate the work done in the coronary realm. It is well recognized that the principal mechanism of restenosis is by neointimal hyperplasia.⁵ The mechanical injury from angioplasty or stent implantation incites a fibroproliferative reaction initially involving the smooth muscle cells, followed by accumulation of extracellular matrix that results in neointimal thickening and eventually restenosis.^5,6 This process has been the Achilles’ heel of endovascular therapy in general. Moreover in the PAD arena, femoropopliteal (FP) territory has increased biomechanical stress that results in higher in-stent restenosis with BMSs.⁷ Apart from patient centric factors, there are numerous anatomic factors in PAD that predicts in-stent restenosis and hence worse long-term outcomes. CLI is usually associated with diffuse long segment FP lesions, below knee disease, or multilevel stenoses that portend higher restenosis rates.^8,9 The constant search for endovascular therapies with better long-term outcomes by reducing restenosis have resulted in the evolution of drug-coated therapies including drug-eluting stents (DESs) and drug-coated balloons (DCBs).

It is important to have a basic understanding of the drugs used to coat the stents and balloons for better therapeutic decisions. The ideal drug would have a long tissue retention time, wide therapeutic window, and lipophilic nature to increase tissue concentration. Traditionally there have been two classes of drugs that satisfied these criteria and have been used in the treatment of CAD. These include the Rapamycin (-limus) family and paclitaxel. In PAD, paclitaxel is more commonly used. Rapamycin is a macrolide antibiotic that binds to the cellular FK-binding protein to inhibit the mammalian target of rapamycin (mTOR). This in turn inhibits the protein complexes responsible for progression of cells from G1 to S phase hence blocking smooth muscle cell migration and proliferation.¹⁰ However, rapamycin does
not cause cell death. Paclitaxel on the other hand binds to the β-subunit of tubulin heterodimer inhibiting the protein kinase essential for microtubule depolymerization. This results in the unstable microtubules that inhibit cell proliferation and mitosis.¹¹ Higher doses of paclitaxel can result in cell death. The manner in which these drugs are incorporated into the stent platform and balloons is uniquely different and explains the rationale of their current clinical use.