Drug-Eluting Balloons

Introduction

Coronary angioplasty was introduced into clinical use by Andreas Grüntzig in 1977. In the field of coronary intervention, the most important advance has been the introduction of stents. Stenting overcomes the weaknesses of balloon angioplasty alone, which include acute recoil and dissection, and longer-term negative vessel remodeling, but not restenosis because of continued or increased neointimal proliferation with stents. Local intravascular drug delivery by drug-eluting stents (DESs) that elute paclitaxel, sirolimus, and their associated analogues have successfully addressed this cellular basis of restenosis in the coronary territory. However, stents cannot be implanted or may be suboptimal at coronary sites where neointimal proliferation may limit the long-term benefit of angioplasty, such as in small vessels and bifurcations. Moreover, DESs that use sirolimus and its analogues have not been found to be effective in the treatment of atherosclerotic disease of the femoropopliteal territory. In the coronary arteries, sometimes delayed or incomplete reendothelialization with the need for long-term dual-antiplatelet therapy (DAPT) to reduce the risk of late stent thrombosis can limit the use of this technology in certain patients at risk for hemorrhagic complications, or it can limit the need for planned surgery. Sustained drug release seems to be essential for stent-based local drug delivery because of the inhomogeneous drug distribution from DESs to the arterial wall, the time course of the inflammation related to the initial trauma of the procedure, and the provocation of neointimal hyperplasia due to the implanted prosthesis and any associated polymeric coating. About 75% to 85% of the stented vessel wall area is not covered by the stent struts, resulting in low tissue levels of the antiproliferative agent in these areas. Cell culture experiments indicate that low drug concentrations require much longer exposure times to achieve sufficient inhibition of cell proliferation than do higher concentrations. Therefore high drug concentrations on the stent struts, including a controlled and sustained release, are mandatory for stent-based local drug delivery, with the consequence of delayed and incomplete reendothelialization of the stent struts. Autopsy studies show that even beyond 40 months, some DESs can demonstrate incomplete endothelial coverage. Furthermore, the polymeric matrices on the stent that are meant to control the release kinetics of the antiproliferative drug can induce inflammation and thrombosis. On the other hand, incomplete suppression of neointimal hyperplasia at the stent margins or between the struts may limit the efficacy of DESs. Alternative approaches to overcome the limitations of DESs have included modifying the sustained drug release from stent struts to allow for earlier reendothelialization, using bioerodable polymers or nonpolymeric release mechanisms (such as surface-modified stent struts), and using thinner struts that require less coverage.

Antiproliferative taxanes, such as paclitaxel, seem to be suitable for the prevention of local intravascular restenosis because of their high lipophilicity and tight binding to various cell constituents compared with sirolimus and its analogues; this results in effective local retention at the site of delivery. The addition of a contrast agent surprisingly resulted in a solubility of taxanes far beyond the concentrations applied in previous investigations. In the porcine coronary model, the intracoronary bolus administration of a taxane–contrast medium formulation led to a significant reduction of neointimal formation after experimental coronary stent implantation despite the short application time. Paclitaxel in a contrast agent was better tolerated and led to higher local tissue concentrations than diluted Taxol, indicating the impact of additional compounds for local drug transfer. The surprising discovery was that sustained drug release is not a precondition for long-lasting restenosis inhibition. In 2001, the basic premise of a more lesion- than vessel-specific method of intramural drug delivery became embodied in the concept of a drug-coated balloon (DCB). By coating paclitaxel onto the surface of a conventional angioplasty balloon used to dilate the stenotic artery, an exclusively local effect could theoretically be achieved, with the drug transferred to the dilated segment as the balloon was inflated. In this way, an effective local drug concentration is achieved with very low systemic exposure. However, several properties of the balloon coating are crucial for ensuring effective drug delivery to the target site: (1) its form on the balloon surface; (2) the homogeneity of distribution along the surface of the balloon; (3) its stability during production, handling, and storage; (4) the degree of premature loss while transiting to the target vessel segment; (5) the ability to release during balloon expansion; (6) the transfer efficiency to the vessel wall; and (7) the amount of particulate material released to the distal circulation.

Preclinical Data

Using various coating procedures, Speck and colleagues coated conventional coronary balloon catheters with different doses of paclitaxel and studied their pharmacokinetics in a porcine coronary model. The paclitaxel dose was variable on the coated balloons, between 1.3 and 3 μg/mm , which corresponded to a total dose of approximately 220 to 650 μg of paclitaxel, depending on the balloon size. About 10% of the initial amount of paclitaxel on the balloon was lost while the catheter was being advanced to the lesion through the hemostatic valve and the guiding catheter, and about 80% of the dose was released during inflation. Most of the dose released at the target site was distributed as particulate distally in the bloodstream, with less than 20% being directly taken up into the vessel wall. In this way, paclitaxel-coated balloons deliver drug to the target site in a very short time, and the dosing is higher than that released by stents over the course of several weeks’ elution. At 5-week follow-up, the implantation of bare-metal stents (BMSs) premounted on paclitaxel-coated balloons was found to have caused a marked dose-dependent and statistically significant reduction in late lumen loss (LLL) and an equally impressive statistically significant increase in minimal lumen diameter (MLD) compared with controls. Quantitative coronary angiography revealed no edge effects or signs of malapposition or aneurysm. Histomorphometry showed a statistically significant increase in lumen diameter and lumen area and a corresponding decrease in maximal neointimal thickness and neointimal area in the vessels treated with paclitaxel-coated balloons (a reduction of neointimal area by 63% in the paclitaxel-coated balloon group vs. the uncoated balloon group). Furthermore, the drug was more evenly distributed on the vessel surface compared with that delivered by a DES. However, studies suggest that the amount of paclitaxel in the arterial tissue varies widely depending on the dose of drug on the balloon and particularly on the coating formulation. An adequate inhibition of neointimal proliferation was observed when balloons were coated with paclitaxel mixed with the contrast agent iopromide dissolved in acetone; the effect was markedly lower when ethyl acetate was used as a solvent without iopromide. The difference in efficacy of these two coating formulations may be primarily explained by the presence of the hydrophilic iodinated contrast medium in the case of the acetone version, thus suggesting that a proper solubilizing agent is important.

Paclitaxel admixed with a small amount of the hydrophilic contrast medium iopromide has also been registered under the name Paccocath (Charite University Hospital, Berlin, Germany). These balloons were standard angioplasty balloons coated with a more uniform paclitaxel dose of 3 μg/mm ² of balloon surface. The situation in the peripheral arteries is not directly comparable with that in the coronary arteries, and treatment is much more complex in several respects. Specifically, the incidence of restenosis in the superficial femoral artery (SFA) is considerably higher and can reach up to 50% within the first 6 months after intervention in longer lesions. Given the clinical need, it was very encouraging when Albrecht and colleagues developed early preclinical data that demonstrated local intraarterial administration of paclitaxel using DCBs or an admixture of paclitaxel and contrast medium could inhibit in-stent stenosis of peripheral arteries in the porcine overstretch model: in-stent stenosis in the control group was 38% (±20%, uncoated balloons). In the treatment groups, it was reduced: treatment group I used balloons coated with 330 μg paclitaxel, and in-stent stenosis was 18% (±22%); treatment group II used balloons coated with 480 μg paclitaxel, and the rate was 12% (±18%); and treatment group III used 6.4 mg paclitaxel dissolved in 50 mL iopromide 370 + 5 mL ethanol), and the rate was 18% (±20%; P < .05). Cremers and coworkers subsequently evaluated the effects of various inflation times (10, 60, and 2 × 60 seconds) on the efficacy of restenosis inhibition and the safety of different doses (5 μg; 2 × 5 μg paclitaxel/mm ² balloon surface) in pigs. Treatment with a DCB (5 μg paclitaxel/mm ² balloon surface with iopromide) for 10 seconds reduced the neointimal area to the same extent as contact with the vessel wall for 2 times 60 seconds (by 57% and 56%, respectively, compared with control). Furthermore, neointimal proliferation and all other parameters that characterize in-stent restenosis (ISR) were not further decreased by inflating two drug-coated balloons (each containing 5 μg paclitaxel/mm ² balloon surface) in the same vessel segment for 60 seconds each. These results suggest that balloons coated with the paclitaxel-iopromide formulation release most of the drug rapidly during the first seconds of inflation. Thus the initial contact of the coated balloon membrane with the vessel wall appears to produce the desired effect of inhibiting neointimal proliferation. The results of this study indicate that it may be sufficient to inflate the balloon for a few seconds only to achieve adequate protection from restenosis. The results also show that doses of up to 10 μg paclitaxel/mm ² balloon surface applied by the inflation of two DCBs does not appear to be linked with clinical toxicity, such as increasing the risk of thrombosis or aneurysm. In addition, persistence of detectable drug in the vessel has been demonstrated to at least 30 days.

Since this initial research was published, several manufacturers have started commercializing or developing DCBs. Currently, paclitaxel is the drug of choice, the typical dosage being 3 μg/mm ² of balloon surface. The critical factor enabling successful drug transfer is the formulation used to coat the balloon. Current products range from those with no additive and very tight binding of the drug to the balloon membrane, to those applied in conjunction with contrast agents or other beneficial additives. A number of these developers have undertaken extensive research into this issue with the assumption that the formulation will be critical to successful product performance and adoption ( Table 17.1 ). The matrix coating of the SeQuent Please balloon catheter (B. Braun Melsungen AG, Germany) for percutaneous transluminal coronary angioplasty (PTCA) consists of a mixture of paclitaxel and iopromide, identical in composition to Paccocath. The preclinical data compare very well with the results from the Paccocath program. Buszman and colleagues reported histologic results showing the Cotavance coating (Bayer-Schering, Berlin, Germany), an iterative coating formula based on Paccocath, to be superior to an uncoated balloon in treating coronary artery and SFA lesions in pigs. In an additional pilot study, single or overlapping Cotavance balloons were compared with single nonoverlapping balloons coated with a contrast medium (iopromide) without paclitaxel in a healthy porcine iliofemoral stent model. Balloon angioplasty was followed by self-expandable BMS implantation. After 28 days, Cotavance balloons decreased neointimal proliferation in a dose-dependent manner when assessed by quantitative angiography (LLL with Cotavance single 1.5 ± 0.7 mm vs. Cotavance overlap 0.7 ± 0.6 mm compared with contrast-coated control 1.7 ± 0.4 mm). Unfortunately, this balloon is no longer produced, nor is it available for use.

FreePac (Medtronic Invatec, Italy) is a proprietary hydrophilic coating formulation in which urea serves as the matrix substance. Urea is a nontoxic, ubiquitous endogenous compound commonly used in pharmacy; it is meant to enhance the release of paclitaxel during the short time of contact with the vessel wall. In the porcine coronary model, similar amounts of paclitaxel were transferred to the vessel wall with the Paccocath coating (214 ± 106 μg paclitaxel) and the FreePac coating (175 ± 101 μg paclitaxel) 15 to 25 minutes after stent implantation. Twenty-eight days after balloon dilation, the original Paccocath coating caused the known strong inhibition of neointimal formation in the porcine coronary model (MLD: 2.7 ± 0.3 mm; LLL, 0.3 ± 0.2 mm). The FreePac coating was equally efficacious and equally well tolerated (MLD: 2.7 ± 0.2 mm; LLL, 0.4 ± 0.2 mm). The aim of another preclinical study was to determine the minimum effective dose and local toxicity at extremely high doses of the FreePac formulation. The balloons were coated with 1 to 9 μg paclitaxel/mm ² balloon surface. In the highest-dose group, three balloons, each coated with 9 μg paclitaxel/mm ² balloon surface, were expanded in the same vessel segment. FreePac paclitaxel-coated balloon catheters efficaciously inhibited neointimal proliferation starting with the lowest dose tested (1 μg/mm ² ) and were well tolerated up to 3 times the preferred dose of 3 μg/mm ² . Stent occlusions observed at the highest dose level and repeated treatment (3 × 9 μg/mm ² ) indicate that the limit of tolerance was reached.

As early as 2007, a paclitaxel-coated balloon catheter, Dior (Eurocor GmbH, Bonn, Germany), received approval in Europe (Conformité Européenne [CE] mark). A study of first-generation Dior balloon catheters reported a tissue paclitaxel concentration of the dilated segment in porcine arteries 1.5 hours after dilation of 1.82 μmol/L (±1.60), which decreased significantly to 0.73 (±0.27; P = .03), 0.62 (±0.34), and 0.44 μmol/L (±0.31) at 12, 24, and 48 hours, respectively. In a direct comparison with the Paccocath balloon, the roughened Dior balloon failed to produce statistically significant effects on angiographic measures of stenosis or morphometric parameters such as maximal neointimal thickness and luminal area. Use of the matrix-coated Paccocath balloon led to a highly significant ( P < .01) reduction in all parameters, indicating improved neointimal proliferation compared with both the uncoated control and Dior balloons at 28-day follow-up. Only about 50% of the drug coating was released from the roughened balloons during the recommended balloon inflation time of 45 to 60 seconds. In contrast, the iopromide matrix was found to release the full amount of the drug (4.5% ± 0.7 % of the total paclitaxel dose on balloons after the procedure), which may contribute to its superiority in inhibiting restenosis. The second-generation Dior II balloon is a coronary dilation balloon for human use with a paclitaxel coating of 3.0 μg/mm ² on the balloon surface, which is applied using a completely different coating technique: the drug is mixed with shellac composed of a network of hydroxy fatty acid esters and sesquiterpene acid esters with a molecular weight of about 1000. The 1:1 mixture of paclitaxel and shellac is coated onto regular balloon catheters. A balloon inflation time dependency study in the porcine model of coronary artery overstretch showed almost maximal tissue paclitaxel concentrations after balloon inflation times of 30 seconds and demonstrated release of 75% of the drug from the balloon surface, which resulted in an up to 20-fold higher tissue concentration compared with the first-generation Dior. Two weeks after overstretch injury, histomorphometry showed significantly smaller neointimal hyperplasia and neointimal thickness in the Dior group compared with the conventional uncoated balloon group. As a result, the area of the coronary artery lumen was larger in the Dior-treated arteries compared with those treated with the conventional balloon (1.20 ± 0.27 mm ² vs. 0.5 ± 0.22 mm ² , P < .001).

Elutax (Aachen Resonance, Germany) uses pure paclitaxel without a matrix coated on a structured balloon surface, and preclinical data on the Moxy paclitaxel-coated balloon catheter (Lutonix Inc., New Hope, MN) were recently published. It has a paclitaxel dose of 2 μg/mm ² using polysorbate and sorbitol as excipients, resulting in paclitaxel tissue concentrations of 58.8 ng/mg at 1 hour and 0.3 ng/mg at 30 days. The treated arteries showed a long-term dose-dependent drug effect.

Pantera Lux (Biotronik AG, Berlin, Germany) uses butyryl-trihexyl citrate (BTHC) as a carrier for paclitaxel. BTHC is used in different medical devices and cosmetics and is approved for blood contact in blood bags. The same excipient is used with lower paclitaxel doses for the Danubio (Minvasys, Paris, France) and the Ranger DCB (Boston Scientific, Marlborough, MA).

A different, alternative mode of local drug delivery into the target artery segment has been developed using the Genie balloon (Acrostak Corp., Winterthur, Switzerland). Paclitaxel is delivered by a system consisting of a balloon with a distal and proximal occlusive segment and a central segment that allows transfer of paclitaxel to the vessel wall by infusion of paclitaxel solution into the vascular chamber created between the balloons. Preclinical investigations in the coronary arteries of pigs demonstrated that the administration via Genie of 10 μM paclitaxel (Taxol, diluted paclitaxel in a mixture of 50% cremophor and 50% ethanol [2.9 ± 1.6 mL 10 μM paclitaxel in this study equals 24.8 ± 13.7 μg paclitaxel]) markedly reduced LLL (0.9 ± 0.1 mm) compared with controls (2.2 ± 0.2 mm, P < .001). The histologic examination showed a statistically significant increase in the lumen area (5.2 ± 1.0 mm ² ) and a corresponding decrease in maximal neointimal thickness (0.1 ± 0.01 mm) and neointimal area (1.0 ± 0.1 mm ² ) in the stented artery treated with paclitaxel versus the control group (3.0 ± 0.3 mm ² , 0.3 ± 0.04 mm, 2.4 ± 0.2 mm ² ). These preclinical results suggest that a solid form (crystalline or amorphous) of paclitaxel is not a requisite for effectiveness.

Preclinical data with a paclitaxel-coated scoring balloon (AngioScore, Fremont, CA) showed increased luminal areas of 6.8 (±1.6) mm ² compared with uncoated scoring balloons (2.3 ± 1.5 mm ² ; P = .001). This concept of drug-coated specialty balloons dedicated to plaque modification may allow for better initial lumen gain and a reduced risk of dissections, leading to less stent usage.

Paclitaxel is a suitable drug for balloon coating due to its irreversible binding to the microtubes resulting in long persistence in the vascular cells and favorable cell-specific effects. Sirolimus and its analogues reversibly bind to FKBP 12, forming a complex with the mammalian target of rapamycin (mTOR), thus blocking cell cycle progression at the juncture of the G1 and S phases. In the case of DES, sirolimus must be released for a period of several weeks for effective inhibition of neointimal proliferation.

Balloon-based delivery of sirolimus should also include some kind of delayed release technology to overcome this reversible binding. Few studies have indicated neointimal inhibition by limus-coated balloons in animals, especially for zotarolimus. Different sirolimus coatings on balloons showed a rapid decrease of tissue concentration. In contrast, a crystalline sirolimus coating was associated with persistent vessel concentrations of up to 50% of the initial concentration at 1 month. First clinical evidence was reported from 50 patients with ISR treated with sirolimus in a liquid formulation delivered by a porous balloon (Sirolimus Angioplasty Balloon for Coronary In-Stent Restenosis [SABRE] trial). In this patient population, in-segment LLL at 6 months was 0.31 ± 0.52 mm.