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The Present State of Drug-Coated Balloons
Although the advent of drug-eluting stents has brought remarkable benefit to the treatment of atherosclerotic vascular disease, its advantages have been undermined, especially when used for off-label indications, such as stenting in bifurcation lesions, small vessels, acute MI, saphenous vein bypass grafts, left main disease and, recently, peripheral vascular disease. In addition, new concerns have arisen regarding the safety of these devices since clinical studies have shown increased risk of late stent thrombosis in patients receiving DES.
The limitations of current DES technology have strengthened interest in the use of drug-coated balloons (DCB), which have the advantage of distributing anti-proliferative drugs homogenously on the luminal surface rapidly, without the use of a polymer carrier or a rigid metallic frame. Clinical studies have shown early promise for the treatment of coronary and lower extremity vascular disease. The positive results will undoubtedly lead to more rapid expansion of clinical DCB use; however, at this point, it should be useful to pause for a better understanding of DCB, so that we look for the most appropriate use of this device.
DCB vs. DES
The early enthusiasm for DES was dampened quickly by a safety concern over the increased risk for late stent thrombosis that carries with it a higher mortality rate. Our autopsy studies have revealed delayed arterial healing, characterized by uncovered metal struts and poor re-endothelialization, as the primary substrate for this tragic event. In addition, excessive inflammatory reaction and fibrin deposition, likely from polymer usage on stents and/or the residual cytotoxic drug, have been documented at autopsy. DES restenosis, although uncommon, still occurs primarily in the presence of severe vessel injury, uneven stent expansion or metal stent fracture. Moreover, the accelerated neoatherosclerosis within the stented segment has been suggested as another potential mechanism of late adverse events with DES.
Taken together, drug-elution from the balloon surface is a rational idea that appears as an attractive alternative to local drug delivery via polymers on metal stent struts. Following the short contact of DCB to the vessel wall, only a drug and excipient is left behind, which is less likely to induce unfavorable responses to foreign materials and allows for complete restoration of the vessel to its original state with a functional endothelium. Another potential superiority of DCB over DES is its even and uniform drug deliverability to the diseased vessel wall, as focal gradient of drug concentration by non-uniform strut distribution triggers neointimal overgrowth in sirolimus-eluting stents.
Figure 1. Effects of drug-coated balloons at 28 days in non-atherosclerotic rabbit iliac arteries. Smooth muscle cell loss and proteoglycans/collagen deposition are seen (arrowheads).
Images: CVPath Institute; reprinted with permission
Drug Selection for DCB
Currently, paclitaxel is primarily used among DCB manufacturers because of its high-lipophilic property that allows for passive absorption through cell membrane and sustained effect within the treated vessel wall. On the other hand, -limus drugs (sirolimus and zotarolimus), which are much less lipophilic than paclitaxel, have also shown efficacy in suppression of neointimal growth in the limited number of animal models; however, to date, the data in humans are lacking. It seems that, unlike DES, the difference in drug property more directly influences the vascular responses, as the pharmacokinetics after balloon deflation are mainly dependent upon the drug itself and not the polymers.
Carrier Excipient for Coating
The most revolutionary invention in DCB technology is the adoption of carrier excipient to facilitate drug transfer to the vessel wall. Without the excipient, the drug (paclitaxel) forms crystalline lumps on the balloon surface, which prevents drug transfer and absorption during the short period of contact between the inflated balloon and the vessel wall. A clinical study of DCB, which applied microporous structure on the balloon surface for paclitaxel coating without an excipient, was halted before completion by investigators because of significant differences in outcomes compared with paclitaxel-eluting stents. A variety of carrier excipients, such as iopromide, urea, shellac and other materials under investigation, have been applied with the same concept to enhance drug delivery. However, the efficiency of drug transport and vascular response to each DCB are apparently diverse.
Further, in our histologic experience with animal models, DCB rarely demonstrate a circumferentially uniform drug effect on the intima-media thickness, as well as longitudinally, even with the use of an excipient (Figure 1), suggesting that there is still more room for the development of better excipients or other breakthroughs. Today, the best formulation remains unknown, as no head-to-head comparisons between different DCB have been made in clinical or preclinical studies.
Another advantage of excipient use is to avoid drug loss in the bloodstream since one of the biggest losses of the drug occurs during delivery of the balloon to its site of application on the vessel wall. It has been reported in an experimental model that at least 20% to 30% of the paclitaxel loaded on the balloon with iopromide or urea-mawtrix coating is absorbed in the blood. In preclinical studies, 5% to 10% of the histologic sections of myocardium or peripheral muscles show pathologic changes attributable to embolization from DCB (Figure 2). Although there is no clear evidence showing deterioration of myocardial function or decreased ejection fraction following DCB use in humans, it cannot be denied that a small scar in the myocardium could become an arrhythmogenic focus. The development of ancillary technology including a shielding technique (dedicated folding of the balloon) will reduce such risk.
Figure 2. Pathologic changes in swine myocardium following treatment with drug-coated balloons. Various histologic responses to embolization of drug and excipient are observed in subendocardial areas.
Clinical Perspective
Although the results from clinical trials with a limited number of patients appear promising, especially in peripheral artery disease, more efforts will be needed to improve the efficacy of DCB. In addition, discussion should be made regarding the application of DCB in the clinical setting. Currently, the European Society of Cardiology guidelines have given a Class IIa approval to DCB only for the treatment of restenosis in coronary arteries with bare-metal stents, although this has not been approved in the United States. Given that acute recoil and excessive dissections remain an intrinsic drawback of DCB, this application is rational and will be applied to in-DES restenosis as well. It is also speculated that the presence of a metal strut enhances drug retention when DCBs are utilized within stents.
Other indications of DCB are being investigated in niche lesion subsets (ie, small vessels, bifurcation, ACS, chronic total occlusion and PAD); however, the results are still controversial due to the lack of data from a large clinical trial. Moreover, the procedural strategy apparently needs optimization regarding inflation pressure and duration, artery-balloon ratio, and the pro and cons of adjunctive stenting with BMS or DES. It appears too early to hail DCB as the next revolution in PCI until ongoing clinical studies reveal its safety and efficacy.
Masataka Nakano, MD, is a cardiovascular research scholar at CVPath Institute in Gaithersburg, Md. Saami K. Yazdani, PhD, is an assistant professor at the University of South Alabama, Mobile. Renu Virmani, MD, is the president and medical director at CVPath Institute, and is a member of the Cardiology Today Intervention Editorial Board; she can be reached at CVPath Institute,19 Firstfield Road, Gaithersburg, MD 20878; email: rvirmani@cvpath.org.
Disclosure: Nakano and Yazdani report no relevant financial disclosures; Virmani is a consultant for Abbott Vascular, Lutonix, Medtronic CardioVascular and W. L. Gore.