Yvonne P. Clever

Long-Term Follow-Up After Treatment of Coronary In-Stent Restenosis With a Paclitaxel-Coated Balloon Catheter

OBJECTIVES This study presents long-term clinical follow-up, including binary restenosis rate and major adverse cardiovascular events, of the PACCOCATH-ISR (Treatment of In-Stent Restenosis by Paclitaxel Coated PTCA Balloons) I and II trial. BACKGROUND The PACCOCATH-ISR trial was a first-in-human study with a drug-coated balloon catheter and the first study for the treatment of coronary ISR with a drug-coated balloon. So, far no long-term follow-up data have been presented. METHODS This study enrolled 108 patients in a randomized, double-blinded multicenter trial on the efficacy and safety of a paclitaxel-coated balloon (3 μg/mm(2) balloon surface; PACCOCATH [Bayer AG, Germany]) compared with an uncoated balloon. The main inclusion criteria were a diameter stenosis of ≥ 70% and <30-mm length with a vessel diameter of 2.5 to 3.5 mm. The primary endpoint was angiographic late lumen loss in-segment after 6 months. Combined antiplatelet therapy was continued only for 1 month followed by treatment with aspirin alone. RESULTS During a follow-up of 5.4 ± 1.2 years, the clinical event rate was significantly reduced in patients treated with the drug-coated balloon (major adverse cardiovascular events: 59.3% vs. 27.8%, p = 0.009), which was mainly driven by the reduction of target lesion revascularization from 38.9% to 9.3% (p = 0.004). CONCLUSIONS Treatment of coronary ISR with paclitaxel-coated balloon catheters is safe and persistently reduces repeat revascularization during long-term follow-up. The initial results were sustained over the 5-year period. (Treatment of In-Stent Restenosis by Paclitaxel Coated PTCA Balloons [PACCOCATH ISR I]; NCT00106587. Treatment of In-Stent Restenosis by Paclitaxel Coated PTCA Balloons [PACCOCATH ISR II]; NCT00409981).

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 &mgr;g/mm2 and 3 overlapping applications of balloons coated with 3 times the regular dose of 3 &mgr;g/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 &mgr;g/mm2 in a coronary artery about 10% of drug remained on balloons, 20% to 30% was taken up into the vessel wall (∼200 &mgr;g). 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 &mgr;g/mm2; 2.0 ± 0.4 mm2 versus 1.7 ± 1.1 mm2 at 3 &mgr;g/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 &mgr;g/mm2. Except thrombotic events for the intentionally excessive dose, paclitaxel-coated balloons were well tolerated in the animal model.

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 &mgr;g/mm2) 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 &mgr;mol/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 &mgr;mol/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.

Paclitaxcel-coated balloon plus bare metal stent vs. sirolimus-eluting stent in de novo lesions: an IVUS study.

AIMS Restenosis after PCI and/or stent implantation is still one of the challenging problems in the field of interventional cardiology. Different approaches to prevent and to treat restenosis include the use of drug-eluting stents, which have shown to reduce restenosis. Another approach is the treatment with drug-coated balloons. This approach has been proven for different indications, e.g., in-stent restenosis and treatment of peripheral artery disease. METHODS AND RESULTS Patients from the PEPCAD III multicentre randomised trial in two study centres (Homburg and Hannover, Germany) were asked to participate in this intravascular ultrasound (IVUS) study at nine-month follow-up. At baseline (nine months before), patients were randomly assigned to receive either a paclitaxel-coated balloon (drug-coated balloon [DCB]) plus a premounted bare metal stent (DCB/BMS) or a sirolimus-eluting stent (drug-eluting stent [DES]) to treat de novo lesions. IVUS at follow-up was performed in order to analyse the restenosis for potential understanding of the mechanism leading to restenosis. IVUS data is available for 55 patients; 26 patients were treated with Cypher(®) DES (Cordis, Miami Lakes, FL, USA) and 29 patients with DCB/BMS. A focal malapposition of the stent was seen in six patients; four after DES and two after DCB/BMS. Stent expansion, calculated as symmetric expansion index, was equal for both groups (0.89 and 0.90). Mean stent area was also equal for both groups (6.25 ± 1.7 vs. 5.65 ± 1.5 mm(2), p=n.s.). The neointimal hyperplasia (calculated as stent area minus lumen area) was significantly different between both groups (0.69 ± 0.49 [DES] vs. 1.08 ± 0.53 mm(2) [DCB/BMS], p<0.01). This resulted in a significantly higher in-stent restenosis in the DCB/BMS group (19.7 vs. 11 %, p<0.01). There is no evidence of geographical mismatch. CONCLUSIONS First IVUS insights for the DCB/BMS showed a comparable, low incidence of malapposition for the combination of drug-coated balloon and premounted bare metal stent compared to the DES, and stent expansion was good and comparable to DES. However, at nine-month follow-up, the combination of drug-coated balloon and premounted bare metal stent showed higher in-stent restenosis compared to sirolimus DES. Geographical mismatch can be excluded as a reason for this result.

Novel Sirolimus–Coated Balloon Catheter In Vivo Evaluation in a Porcine Coronary Model

Background—Limus-eluting stents are dominating coronary interventions, although paclitaxel is the only drug on balloon catheters with proven inhibition of restenosis. Neointimal inhibition by limus-coated balloons has been shown in few animal studies, but data from randomized clinical trials are not available. The aim of the present preclinical studies was to achieve high and persistent sirolimus levels in the vessel wall after administration by a coated balloon. Methods and Results—Different coating formulations and doses were studied in the porcine coronary model to investigate sirolimus tissue levels at different time points as well as efficacy at 1 month using quantitative coronary angiography and histomorphometry. Loss of the selected coating in the valve, guiding catheter, and blood was low (2±14% of dose). Acute drug transfer to the vessel wall was 14.4±4.6% with the crystalline coating, whereas the amorphous coatings were less effective in this respect. Persistence of sirolimus in the vessel wall until 1 month was 40% to 50% of the transferred drug. At 1-month follow-up, a modest but significant reduction of neointimal growth was demonstrated in a dose range from 4 &mgr;g/mm2 to 2×7 &mgr;g/mm2, for example, maximum neointimal thickness of 0.38±0.13 versus 0.65±0.21 mm in the uncoated control group. Conclusions—Various sirolimus-coated balloons effectively reduce neointimal proliferation in the porcine coronary model but differ considerably in retention time in the vessel wall. It has to be determined if such a formulation with persistent high vessel concentration will result in a relevant clinical effect.

Paclitaxel and sirolimus differentially affect growth and motility of endothelial progenitor cells and coronary artery smooth muscle cells

AIMS EPC and hCASMC play an important role in the pathogenesis of restenosis and stent thrombosis. Drug-coated balloon catheters exert a local, short-term application of antiproliferative agents. This study investigates the time-dependent influence on growth and motility of paclitaxel and sirolimus alone and combined with the coating additive iopromide on EPC and hCASMC. METHODS AND RESULTS Treatment of cultured human EPC and hCASMC with paclitaxel and sirolimus 1.5 and 15 µM for three seconds, three minutes and 24 hours, alone or combined with iopromide 0.197 M, resulted in a concentration- and time- dependent inhibition of proliferation and of migration. Paclitaxel and sirolimus increase apoptosis in either cell type. However, the effects of paclitaxel and sirolimus differed between the cell types: short-term exposure with paclitaxel leads to stronger inhibition of cell-density and apoptosis of hCASMC compared to EPC. In comparison to paclitaxel, short-term incubation with sirolimus showed a more effective inhibition of cell-density and migration as well as increased apoptosis in EPC in contrast to hCASMC. The effects of paclitaxel and sirolimus were increased in combination with iopromide. Interestingly, the antiproliferative effect of the paclitaxel-iopromide formulation on hCASMC was more potent compared to its effect on EPC. Endothelialisation in a porcine coronary stent model was similar with drug-coated balloons and uncoated controls, whereas it was delayed with drug-eluting stents. CONCLUSION After short-term application, paclitaxel and sirolimus show differential, cell-specific effects on EPC and hCASMC. Iopromide used as a coating agent intensifies these effects.

Influence of a paclitaxel coated balloon in combination with a bare metal stent on restenosis and endothelial function: Comparison with a drug eluting stent and a bare metal stent

Different approaches of local intravascular drug delivery may influence endothelial and microvascular function. The aim of this trial was to study the influence of a paclitaxel coated balloon in combination with a bare metal stent (DCB + BMS) versus a bare metal stent (BMS) or a sirolimus‐eluting stent (DES) on coronary restenosis and endothelial function.

Inhibition of neo‐intimal hyperplasia in porcine coronary arteries utilizing a novel paclitaxel‐coated scoring balloon catheter

Objective: Scoring balloons are particularly useful in the acute treatment of fibro‐calcific, bifurcation and in‐stent restenosis lesions but have not been shown to affect the restenosis rate. Conventional balloons coated with paclitaxel have recently been shown to reduce restenosis rates in certain lesion subsets, but are associated with suboptimal acute results. A novel paclitaxel‐coated scoring balloon was developed to overcome these limitations. Design: AngioSculpt® scoring balloons (SB) were coated with paclitaxel admixed with a specific excipient. Setting and Interventions: Four in vitro and in vivo studies were performed: (a) loss of the drug during passage to the lesion, (b) transfer of the drug to the vessel wall; (c) inhibition of neo‐intimal proliferation in porcine coronary arteries as compared to uncoated SB and the Paccocath™, and (d) evaluation of the dose‐response to 1.5–12 μg of paclitaxel/mm2. Main outcome measures and Results: Drug loss during delivery to the lesion was 17% ± 8%, and transfer to the vessel wall was 9% ± 4% of dose on unused balloons. The paclitaxel‐coated SB resulted in a lower late lumen loss of 0.27 ± 0.24 mm compared to 1.4 ± 0.7 mm with the uncoated SB (P = 0.001). Histomorphometry revealed larger luminal areas of 6.8 ± 1.6 mm2 (paclitaxel‐coated SB) and 5.8 ± 1.7 mm2 (Paccocath) as compared to the uncoated SB (2.3 ± 1.5 mm2; P = 0.001). No coating related adverse effects were observed on follow‐up angiography or histologic examination at the treatment site or downstream myocardium. Conclusion: A novel paclitaxel‐coated SB leads to a significant inhibition of neointimal proliferation in the porcine coronary model.

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

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).

A novel drug‐coated scoring balloon for the treatment of coronary in‐stent restenosis: Results from the multi‐center randomized controlled PATENT‐C first in human trial

Scoring balloons produce excellent acute results in the treatment of in‐stent restenosis (ISR), fibro‐calcific and bifurcation lesions but have not been shown to affect the restenosis rate. A novel paclitaxel‐coated scoring balloon (SB) was developed and tested to overcome this limitation.