Drug-eluting technologies, such as balloons coated with paclitaxel (DCB), are now the gold standard treatment for patients presenting with symptomatic peripheral artery disease (PAD) in the femoropopliteal region. DCBs have shown better clinical outcomes against uncoated balloons (PTA) for the treatment of femoropopliteal disease in large multicentre trials.1-3 After the introduction of the first DCB (Lutonix’s 0.035 over-the-wire DCB) there have been several entrants into the market. However, multiple clinical and pre-clinical studies have illustrated there are differences in performance and safety between the different products.4
DCBs are unlike drug-eluting stents (DES) which are routinely used for the treatment of coronary artery disease and rely on drug delivery from polymers to deliver the drug over 60–90 days. For the most part, DES effectively deliver the drug to the target arterial wall site while minimising its delivery to other non-target beds. DCBs, on the other hand, rely on drug delivery to the arterial wall site during the inflation time of the balloon (generally 90 seconds). During balloon inflation the excipient coating delivers crystalline paclitaxel, but more importantly facilitates the persistence of the drug at the site of the target tissue where it is needed to help prevent restenosis. However, it has been reported that the excipient and drug may embolise to non-target organs during the process of inflation. The potential consequences of these emboli remain uncertain, but it is logical to believe that this is an unwanted consequence because of the known tissue damaging effects of paclitaxel. Case reports have documented the occurrence of pannicilitus occurring weeks after use of the IN.PACT Admiral DCB (Medtronic).5
The most commonly-used drug for DCB is paclitaxel, a cytotoxic drug which has lipophilic properties, allowing passive absorption through cell membranes and sustained drug effect at the target site. The various DCB technologies differ in their design with regards to excipient coatings and drug form (amorphous vs. crystalline, including the size of the crytals). Drug delivery to the luminal surface is facilitated by different carrier excipients such as iopromide, urea, or polysorbate/ sorbitol. Each DCB technology should be evaluated separately. There are now three US Food and Drug Administration (FDA)-approved DCBs:
- The Lutonix 035 DCB is a lowdose (2mg/mm2) paclitaxel-coated balloon with a polysorbate/sorbitol carrier;
- The IN.PACT Admiral DCB is loaded with a higher concentration of paclitaxel (3.5mg/mm2) and uses a urea-based excipient;
- The Stellarex DCB (Spectranetics) is a low-dose (2mg/mm2) paclitaxel- coated balloon with a polyethylene glycol carrier.
The Ranger DCB (Boston Scientific) also contains low-dose (2mg/mm2) paclitaxel with a acetyl-tributyl citrate 2 carrier and is undergoing human trials for FDA approval. These design features can produce differences in effective drug delivery to target tissues and to non-target tissues. Of course the ideal DCB technology should effectively deliver drug to the target site (eg. superficial femoral artery) while minimising occurrence of downstream emboli. Such differences in DCB technology are difficult to detect in the clinic where patients involved in clinical trials are highly selected and where the clinical tests used to assess patient outcome are unable to discern whether such emboli have occurred. The porcine preclinical model allows for histologic examination of treated femoral arteries and associated downstream non-target territories to determine the local tissue reaction in the treated artery wall and embolic safety characteristics. In a previously-published study, the Lutonix 035 and the IN.PACT Admiral were tested and compared for target vessel changes and downstream embolic events. Femoral artery target tissue effects such as medial proteoglycan score and smooth muscle cell loss score were statistically significantly greater in the IN.PACT DCB at 90 days follow-up after overlapping balloon (3x dose) inflations, and, moreover, were accompanied by more downstream embolic debris and higher paclitaxel levels in downstream tissues.6
More recently, I presented (at VIVA 2017, 11–14 September, Las Vegas, USA) the results of another head-to-head preclinical study examining IN.PACT, Stellarex, and Ranger at triple doses in the same model at 28 days. For all DCBs tested, similar drug vasculature effect was seen at the target treatment (ie. superficial femoral artery) site. However, the percentage of sections with downstream vascular changes in arterioles were highest for IN.PACT, followed by Stellarex and least in Ranger. Embolic crystalline material was also observed in all cohorts and followed a similar trend. Drug analysis however, showed similar paclitaxel concentrations in non-target coronary band tissue but higher levels in downstream skeletal muscle for IN.PACT versus the other two DCBs.
All DCBs tested exhibited downstream effects of paclitaxel drug and/ or downstream emboli though differences between different DCBs were seen. The findings of embolic debris from DCB coatings is of potential importance and may be further compounded in patients with claudication and more complex critical limb ischaemia with limited flow reserve. Further work is needed to better understand the potential significance of these findings for patients.
Aloke V Finn is the medical director at CVPath Institute, Gaithersburg, and associate professor of Medicine at the University of Maryland School of Medicine, Baltimore, USA
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- Kolodgie FD, Pacheco E, Yahagi K, et al. J Vasc Interv Radiol 2016;27:1676–1685:e1672.