Long-term effects on vascular healing of bare metal stents delivered via paclitaxel-coated balloons in the porcine model of restenosis.

BACKGROUND: Clinical trials have consistently demonstrated benefits of paclitaxel-coated balloons (PCB) in particular clinical situations such as in-stent restenosis and peripheral vascular interventions. However, the long-term vascular effects of bare metal stents (BMS) delivered via PCB (PCB+BMS) are still unknown. The aim of this study was to assess the long-term effects of PCB+BMS on vascular healing and neointimal formation (NF). METHODS: A total of 208 stents: 56 BMS crimped on PCB, 50 BMS crimped on uncoated balloons (UCB+BMS), 52 Taxus and 50 Cypher stents were implanted in normal coronary arteries of 104 pigs using 1.2:1.0 stent-to-artery ratio. Follow-up occurred at 3, 7, 28, 90, and 180 days. Vascular effects were assessed based on angiographic and histological analysis. Endothelialization was evaluated using an anti von-Willebrand Factor stain. RESULTS: At 28 days, delivery of a BMS using a PCB led to a significant reduction in NF compared to the UCB+BMS and the Taxus stent (P < 0.01). Between 28 and 180 days, the progression of NF tended to be lower in the PCB+BMS compared to all DES groups. At 90 days, the PCB+BMS (2.56 ± 0.43) and the Taxus stents (2.60 ± 0.59) had a trend toward higher inflammatory scores compared to the UCB+BMS group (1.85 ± 1.13, P = 0.09). By 180 days, inflammation and NF had completely normalized between the groups. Expression of peristrut vWF was comparable among all tested groups at 28 days. CONCLUSION: The long-term pattern of vascular healing occurring following PCB+BMS deployment appears to be comparable to what has been reported with DES technologies.

Do pharmacokinetics explain persistent restenosis inhibition by a single dose of paclitaxel?

BACKGROUND: The purpose of this study was to investigate the elimination of paclitaxel from the arterial wall after a single short administration with a coated balloon. METHODS AND RESULTS: Slightly oversized paclitaxel-coated balloons (dose 3 or 9 µg/mm(2)) without or with premounted stents were inflated in nonatherosclerotic coronary arteries of either young domestic pigs or adult Goettingen minipigs. The paclitaxel content of plasma, arterial segments, and residual hearts (without treated arteries) was measured for up to 180 days using high-performance liquid chromatography/ultraviolet detection or mass spectrometry. Angiograms were evaluated for lumen narrowing. The paclitaxel concentration in plasma remained <10 ng/mL. In arteries of domestic pigs and minipigs treated with paclitaxel-coated balloons with premounted stents, 10%±5% or 21%±8% of dose, respectively, was initially detected and decreased to 3.5%±3.1% of dose (domestic pig) by Day 7. Within 6 months it fell with a half-life of 1.9 months to 0.40%±0.35%. After 3 months the concentration in the arterial wall was 17±11 µmol/L. Without a stent, drug transfer to the vessel wall was somewhat reduced and elimination faster. Immediately after treatment up to 26%±4% of dose was detected in the residual whole hearts. It dropped with a half-life of 45 days to 1.5%±0.6% of dose (0.3 µmol/L) within 6 months. CONCLUSIONS: After a single local administration with coated balloons, paclitaxel stays in the vessel wall of pigs long enough to explain persistent inhibition of neointimal proliferation. The pharmacokinetics of paclitaxel does, however, not exclude other reasons for sustained efficacy such as early blocking of processes initiating excessive and prolonged neointimal proliferation.

Dose response to Paclitaxel-coated balloon catheters in the porcine coronary overstretch and stent implantation model.

OBJECTIVE: There is little published information regarding the efficacy of paclitaxel-coated balloon catheters except for the iopromide-containing formulation, and less is known about the kind of toxicity at overdose. The aim of our study was to assess 2 different paclitaxel matrix formulations on angioplasty balloon catheters in vitro, with respect to pharmacokinetics, and efficacy and tolerance to determine the minimum effective dose and local toxicity at extremely high dose which is only achieved in experimental studies. METHODS AND MATERIALS: Adherence of coatings was tested in vitro in dry state and during passage through hemostatic valves, guiding catheters, and blood. Drug release, transfer to the vessel wall during coronary angioplasty, inhibition of neointimal proliferation, and tolerance were investigated in swine. Efficacy and tolerance of balloons were examined for doses ranging from 1 to 9 µg/mm2 and 3 overlapping applications of balloons coated with 3 times the regular dose of 3 µg/mm2. Paclitaxel concentrations were determined by high performance liquid chromatography, efficacy and tolerance by vital signs, clinical observation, quantitative coronary angiography, and histomorphometry 4 weeks after implanting premounted bare stents in coronary arteries applying 1:1.2 overstretch. RESULTS: Under worst-case conditions, drug loss on the way through the guiding catheter and blood was in the range of 30%. After inflation of balloons coated with the clinically tested dose of 3 µg/mm2 in a coronary artery about 10% of drug remained on balloons, 20% to 30% was taken up into the vessel wall (∼200 µg). Neointimal area on cross sections was 6.8 ± 2.2 mm2 (uncoated control); 3.1 ± 1.1 mm2 (iopromide-matrix) and 3.0 ± 0.5 mm2 (urea-matrix) at 1 µg/mm2; 2.0 ± 0.4 mm2 versus 1.7 ± 1.1 mm2 at 3 µg/mm2 with no further decrease at higher doses. Thrombotic occlusions were observed in 3 of 15 vessel segments treated with overlapping inflations of 3 high-dose balloons but without any signs of aneurysms. CONCLUSION: In the animal model, 2 paclitaxel matrix formulations were similar in respect of uptake in the vessel wall, and effective already at a dose of 1 µg/mm2. Except thrombotic events for the intentionally excessive dose, paclitaxel-coated balloons were well tolerated in the animal model.

Comparison of two different paclitaxel-coated balloon catheters in the porcine coronary restenosis model.

BACKGROUND: Drug-eluting balloon (DEB) catheters coated with paclitaxel in a water-soluble matrix have shown beneficial effects in the treatment and prevention of restenosis in the porcine coronary overstretch model and in clinical trials. Adherence of paclitaxel, same dose, on another recently introduced coated percutaneous coronary intervention (PCI) catheter (DIOR) is mediated by a roughened balloon surface. Only scarce experimental and clinical data has been published on the new coating method. The aim of the present study was to compare the safety and efficacy of the two coatings in the porcine model. METHODS AND RESULTS: Twenty-eight stainless steel stents were implanted in the left anterior descending and circumflex coronary arteries of 14 domestic pigs using either matrix-coated (n = 8), roughened DEB (n = 9), or uncoated PCI catheters, which served as control (n = 11). After 28 days, quantitative angiography and histomorphometry of the stented arteries were performed. Matrix-coated DEB led to a highly significant (P < 0.01) reduction of all parameters indicating neointimal proliferation compared to both, uncoated control and the roughened DEB; late lumen loss in-segment was 0.4 +/- 0.2, 1.9 +/- 0.5, and 1.4 +/- 0.5 mm, respectively. In contrast, the roughened DEB failed to produce statistically significant effects on angiographic measures of stenosis or morphometric parameters such as maximal neointimal thickness and luminal area, except for neointimal area (5.7 +/- 1.5 mm(2) in the control group, 4.1 +/- 1.7 mm(2) roughened DEB, P < 0.05 vs. control, and 2.5 +/- 0.8 mm(2) matrix-coated DEB, P < 0.01 vs. control). CONCLUSION: Inhibition of neointimal proliferation in the porcine coronary overstretch model by paclitaxel depends critically on the coating method.