Drug-Coated Balloons: Drugs Beyond Paclitaxel?

BACKGROUND: Although controversially discussed, paclitaxel is the only clinically proven drug that inhibits restenosis when released from drug-coated balloons (DCBs). Limus drugs are currently being explored as alternatives. The aim of the preclinical studies was to investigate drug candidates beyond paclitaxel considered for balloon coating. METHODS: Drugs were tested with respect to dissolution in organic solvents, coating on balloons, and drug transfer to the vessel wall. Inhibition of neointimal proliferation was tested in the porcine model of coronary in-stent stenosis. Intravascular drug treatment was achieved by DCBs at the time of stent implantation. RESULTS: Coating had to be adjusted for each drug. Doses on the balloons ranged from 1.0 to 8.6 µg/mm2 balloon surface. Satisfactory amounts of drug ranging from 5% to 29% of initial doses were transferred into the vessel wall. Angiographic parameters such as late lumen loss (LLL) at 4 weeks did not show reduction of in-stent neointimal proliferation by treatment with arsenic trioxide (0.87 ± 0.44 mm), betamethasone dipropionate (1.00 ± 0.54 mm), bortezomib (1.74 ± 0.46 mm), green tea extract (1.24 ± 0.51 mm), fantolon, an epothilone (0.86 ± 0.61 mm), methotrexate (1.09 ± 0.72 mm), and thalidomide (1.59 ± 0.55 mm) compared to treatment with uncoated balloons (1.07 ± 0.60 mm), while coatings with paclitaxel reliably reduced in-stent stenosis (LLL = 0.36 ± 0.25 mm). CONCLUSIONS: Despite the proven antiproliferative and/or anti-inflammatory effect of the drugs, none of the coatings significantly reduced LLL compared to uncoated balloons and thus, based on the results presented here, none of the tested coatings may be considered a substitute for the paclitaxel-based coatings currently in clinical use.

Improvement of Outcome for Treatment of 'Restenosis-prone' Vascular Lesions? Potential Impact of the Paclitaxel dose on Late Lumen Loss in Porcine Peripheral Arteries.

PURPOSE: Clinical data indicate that the drug density on drug-coated balloons (DCBs) might have a role on treatment effect and durability. The aim of the current study was to investigate inhibition of neointimal formation and potential adverse effects after treatment with a novel double-dose DCB in swine. MATERIAL AND METHODS: A four-week study was performed in peripheral arteries of 12 domestic pigs after vessel injury and stent implantation. The novel double-dose DCB with 6-µg paclitaxel (Ptx)/mm2 balloon surface (1 × 6) was compared to a standard DCB with 3.5 µg Ptx/mm2 (3.5) and uncoated balloons (POBA). Potential adverse effects were stimulated by using three fully overlapping DCBs with 6 µg Ptx/mm2 each (3 × 6). Quantitative angiography, histomorphometry and histopathological analyses were performed. RESULTS: Higher paclitaxel doses per square millimeter of treated arteries were associated with reduced late lumen loss (LLL) in quantitative angiography 4 weeks after treatment (POBA: 0.91 ± 0.75 mm; 3.5: 0.45 ± 0.53 mm; 1 × 6: 0.21 ± 0.41 mm; 3 × 6: - 0.38 ± 0.65 mm). In histomorphometry, maximal neointimal thickness and neointimal area were the lowest for the 1 × 6 group (0.15 ± 0.06 mm/1.5 ± 0.4 mm2), followed by 3 × 6 (0.20 ± 0.07 mm/1.8 ± 0.4 mm2), 3.5 (0.22 ± 0.12 mm/2.2 ± 1.1 mm2) and POBA (0.30 ± 0.07 mm/3.2 ± 0.7 mm2). Downstream tissue showed histopathological changes in all groups including POBA, in larger number and different quality (e.g., edema, inflammation, vessel wall necrosis, vasculitis and perivasculitis) in the 3 × 6 group, which did not cause clinical or functional abnormalities throughout the study. CONCLUSION: Treatment with the double-dose DCB (6 µg Ptx/mm2) tended to increase inhibition of in-stent neointimal formation and to diminish LLL after peripheral intervention in the porcine model compared to a market-approved DCB with 3.5 µg Ptx/mm2.

A novel paclitaxel coated balloon with increased drug transfer for treatment of complex vascular lesions.

BACKGROUND: Drug coated balloons (DCB) with paclitaxel (Ptx) dose of 2-3.5 µg/mm2 balloon surface inhibit restenosis with different effectiveness and duration of success. A clinical dose finding study is not known for any of the currently marketed products. The aim of the present preclinical trial was to investigate a novel DCB coated with 6 µg Ptx/mm2 in a porcine model. METHODS AND RESULTS: The current study investigated a DCB with a novel, modified iopromide based matrix with 6 µg Ptx/mm2. Drug transfer to the vessel wall of peripheral arteries was compared with a dose of 3 µg Ptx/mm2 and two fully overlapping DCB with 3 µg Ptx/mm2, each. Ptx concentration in the vessel wall after drug transfer was about twice as high for balloons with 6 µg/mm2 (1957±1472 µg/g) and two overlapping DCB with 3 µg Ptx/mm2, each (1287±619 µg/g) compared to a single balloon with 3 µg Ptx/mm2, (787±738 µg/g), with statistical significant differences for 1x6 µg/mm2 vs. 1x3 µg/mm2 (p = 0.017) but not for 2x3 µg/mm2 vs. 1x3 µg/mm2 (p = 0.184) and 1x6 µg/mm2 vs. 2x3 µg/mm2 (p = 0.178). The proportion of residual Ptx on balloon after treatment was similar for all groups between 6±1% and 10±3% of dose on balloon. CONCLUSION: The dose of 6 µg Ptx/mm2 was successfully as well as reproducibly coated on conventional balloon catheters. Increased Ptx on balloons resulted in increased drug concentration in the vessel wall. A single balloon with 6 µg Ptx/mm2 seems to provide double dose compared to 3 µg Ptx/mm2, facilitates the procedure, and may reduce medico-economic cost compared to the use of two standard DCB.

Efficacy and safety of a magnesium stearate paclitaxel coated balloon catheter in the porcine coronary model.

BACKGROUND: Local administration of growth-inhibiting substances such as paclitaxel or sirolimus could reduce the risk of restenosis. In the drug coated balloon (DCB) technology the coating and the applied dose seem to play a major role. The aim of the present preclinical studies was to investigate the efficacy and safety of a specific DCB with paclitaxel as active ingredient and magnesium stearate as excipient. METHODS: Evaluation of the coating, drug release and transfer was done ex vivo and in vivo on peripheral arteries. A porcine coronary stent model was chosen to provoke intimal thickening. Conventional uncoated balloons were compared with paclitaxel urea and paclitaxel magnesium stearate coated balloons. QCA and histomorphometry was performed on treated vessels. Three areas of the heart were histologically examined for pathological changes. RESULTS: QCA and histomorphometry revealed no differences in baseline data between treatment groups. All DCB groups showed a significant reduction of angiographic and histologic parameters describing neointimal formation 4 weeks after treatment (e.g. mean angiographic late lumen loss all coated 0.31 ± 0.18 mm versus 0.91 ± 0.37 mm in the uncoated balloon group). There were no device-related animal deaths or clinical abnormalities. In spite of very slight-to-slight microscopic findings limited to small arterial vessels in downstream tissue there was no change in left ventricular ejection fraction or angiographic presentation of small side branches of treated arteries. CONCLUSION: Paclitaxel DCB using stearate as excipient show a high efficacy in reducing neointima formation after experimental coronary intervention. No evidence of myocardial damage resulting from distal embolization was found.

Paclitaxel-Coated Balloon vs Uncoated Balloon Angioplasty for Treatment of In-Stent Restenosis in the Superficial Femoral and Popliteal Arteries: The COPA CABANA Trial.

Purpose: To investigate the efficacy and sustainability of drug-coated balloon (DCB) treatment of femoropopliteal in-stent restenosis (ISR). Materials and Methods: An investigator-initiated, prospective, multicenter, 1:1 randomized study enrolled 88 patients for treatment of ISR with DCB (n=47; mean age 68.3±9.6 years; 26 men) or uncoated balloon (n=41; mean age 67.6±10.2 years; 26 men) angioplasty (ClinicalTrials.gov identifier NCT01594684). Additionally, the protocol provided for an observational arm composed of patients from either randomized arm who experienced recurrent ISR ≥30 days after the index treatment. Redo treatment consisted of 2 DCBs sequentially inflated at the same location (double dose therapy). The majority of patients (66, 78%) had Rutherford category 3 ischemia. The mean lesion length was 140 mm; a third (27, 31%) were total occlusions. The primary endpoint was angiographic late lumen loss (LLL) at 6 months evaluated by an independent core laboratory. Results: Twenty-two patients (7 DCB +15 uncoated) were treated for recurrence with fully overlapping double DCB angioplasty. Six-month LLL was lower after DCB (0.34±1.12 mm) treatment than after angioplasty with an uncoated balloon (1.58±1.10 mm, p<0.001). At the 12-month follow-up, target lesion revascularization (TLR) was performed in 18 (49%) of 37 patients in the uncoated group, 6 (14%) of 43 patients in the single-dose DCB group (p=0.001), and no patients from the recurrent ISR group. At ~2 years after treatment, a remarkable number (14/27, 52%) of TLRs were recorded in the single-dose DCB group. Conclusion: Treatment with DCBs resulted in significantly less 6-month LLL and fewer TLRs up to 24 months than treatment with uncoated balloons. The double dose for treating recurrent ISR did not cause recognizable adverse events or require TLR up to 24 months.

Correction to: Impact of Patient and Lesion Characteristics on Drug-Coated Balloon Angioplasty in the Femoropopliteal Artery: A Pooled Analysis of Four Randomized Controlled Multicenter Trials.

In their recently published pooled analysis of four drug-coated balloon (DCB) studies, which focused on the impact of patient and lesion characteristics on LLL at 6 months (Albrecht T et al. Cardiovasc Intervent Radiol. 2018 Dec 11. https://doi.org/10.1007/s00270-018-2137-3 ), the authors reported slightly inaccurate 2-year mortality rates.

Impact of Patient and Lesion Characteristics on Drug-Coated Balloon Angioplasty in the Femoropopliteal Artery: A Pooled Analysis of Four Randomized Controlled Multicenter Trials.

OBJECTIVES: The principal objective of this pooled analysis was to investigate various patient and lesion characteristics on late lumen loss (LLL) after drug-coated balloon (DCB) angioplasty. BACKGROUND: Four randomized controlled trials (THUNDER, FEMPAC, PACIFIER, CONSEQUENT) were pooled to investigate the influence of various patient and lesion characteristics on DCB angioplasty and on plain old balloon angioplasty (POBA) in patients with femoropopliteal artery disease. METHODS: Angiographic data from 355 patients were pooled to assess the impact of patient (demographics, cardiovascular risk factors, cardiovascular co-morbidities, Rutherford stages) and lesion-/procedure-related (location, occlusion, length, restenosis, calcification, subintimal crossing, post-dilatation, dissection, stenting) characteristics on LLL. Linear regression models were utilized with LLL as the dependent variable to determine the predictive value of cardiovascular and lesion-/procedure-related factors. RESULTS: Observational statistics revealed that LLL was lower in the DCB group as compared to POBA independent of all tested patient variables. LLL after DCB was also independent of most lesion and procedural characteristics except for lesion length and bailout stenting. LLL increased with lesion length in both treatment groups. Bailout stenting did not improve LLL in the DCB group but did so in the POBA group (0.74 ± 1.07 mm vs. 1.22 ± 1.36 mm, p = 0.043). CONCLUSIONS: DCB was superior to POBA for all tested patient subgroups and lesion subgroups. Our results suggest that all patients and lesions benefit to a similar degree from the use of DCB. DCB-PTA should therefore be preferred to POBA in all patients with steno-occlusive femoropopliteal lesions.

Drug Distribution and Basic Pharmacology of Paclitaxel/Resveratrol-Coated Balloon Catheters.

PURPOSE: To experimentally investigate a new homogenously paclitaxel/resveratrol-coated balloon catheter in terms of transport of the coating to the treated tissue and local effects including histology and functional tests. METHODS: Adherence of the coating to the balloon was explored by in vitro simulation of its passage to the lesion. Paclitaxel and resveratrol transfer to the vessel wall was investigated in porcine coronary and peripheral arteries. Matrix-assisted laser desorption/ionization (MALDI) was used for direct microscopic visualization of paclitaxel in arterial tissue. Inhibition of neointimal proliferation and tolerance of complete coating and resveratrol-only coating was investigated in pigs 4 weeks after treatment, and the effect of resveratrol on inflammation and healing after 3 and 7 days. RESULTS: Drug loss on the way to the lesion was < 10% of dose, while 65 ± 13% was detected at the site of balloon inflation. After treatment similar proportions of drug were detected in coronary and peripheral arteries, i.e., 7.4 ± 4.6% of dose or 125 ± 74 ng/mg tissue. MALDI showed circumferential deposition. Inhibition of neointimal proliferation by paclitaxel/resveratrol coating was significant (p = 0.001) whereas resveratrol-only coating did not inhibit neointimal proliferation. During the first week after treatment of peripheral arteries with resveratrol-only balloons, we observed nominally less inflammation and fibrin deposition along with a significant macrophage reduction and more pronounced re-endothelialization. No safety issues emerged including left ventricular ejection fraction for detection of potential distal embolization after high-dose treatment of coronary arteries. CONCLUSIONS: Paclitaxel/resveratrol-coated balloons were effective and safe in animal studies. Beyond acting as excipient resveratrol may contribute to vascular healing.

A novel constrained, paclitaxel-coated angioplasty balloon catheter.

AIMS: The study aimed to assess drug adherence, transfer to the vessel wall, tolerance and efficacy of a constrained angioplasty balloon coated with an excipient-enhanced paclitaxel coating (Chocolate coated balloon [CCB]) in the porcine model. METHODS AND RESULTS: Drug adherence was investigated in vitro. Drug transfer was evaluated in porcine arteries. A stent overstretch model was chosen to provoke intimal thickening in the efficacy and tolerance study. Conventional uncoated balloons were used as controls. CCB were coated with a nominal (3 µg/mm2) and high dose (two completely overlapping inflations each at 6 µg/mm2) of paclitaxel. Efficacy was assessed by histomorphometry and quantitative coronary angiography (QCA). Tolerance, including potential downstream effects, was assessed by myocardial function and histopathology. The CCB lost 6±12% of dose during in vitro simulated delivery to the lesion; drug transfer to the vessel wall was 14±4%. QCA and histomorphometry revealed no baseline differences between treatment groups. Thirty days after treatment, both doses of the CCB resulted in a 50% reduction in neointimal thickening of arteries relative to the uncoated balloon group. Maximum neointimal thickness was 1.12±0.36 mm for uncoated control specimens and 0.46±0.06 mm and 0.44±0.30 mm for the two CCB doses (3 and 2×6 µg/mm2), respectively. There were no device-related animal deaths or changes in left ventricular ejection fraction or device-specific myocardial histopathologies. There were no statistically significant differences between inflammatory scores among treatment groups. CONCLUSIONS: The results demonstrate efficacy and tolerance of a mechanically unique constrained angioplasty balloon within the tested dose range of the selected paclitaxel coating in the chosen porcine preclinical model.

Paclitaxel-Coated Balloons: Investigation of Drug Transfer in Healthy and Atherosclerotic Arteries - First Experimental Results in Rabbits at Low Inflation Pressure.

PURPOSE: Beyond antiproliferative properties, paclitaxel exhibits anti-inflammatory activity, which might be beneficial in the local treatment of nonocclusive coronary artery disease. Paclitaxel release and tissue concentrations after paclitaxel-coated balloon treatment using different pressures have not been investigated so far. The aim of the study was to investigate in an atherosclerotic rabbit model whether drug transfer from paclitaxel-coated balloons into the vessel wall is affected by the presence of atherosclerotic lesions and to which extent it depends on the inflation pressure used. METHODS: Paclitaxel-coated balloons (3.5 µg/mm(2) paclitaxel) were inflated with pressures of 1, 2, or 6 atm (60s) in healthy (n = 39) and atherosclerotic (n = 22) arteries of New Zealand White Rabbits. Paclitaxel content in arterial walls (10 min after interventions) and paclitaxel remaining on balloons after treatment were analyzed using high-performance liquid chromatography. RESULTS: Median paclitaxel tissue concentrations were 829.3 µg/g (IQR 636.5-1487 µg/g) in healthy and 375.7 µg/g (IQR 169.8-771.6 µg/g) in atherosclerotic arteries (p = 0.0002). The paclitaxel tissue concentration was dependent on inflation pressure (1 atm vs. 2 atm vs. 6 atm) in atherosclerotic arteries (p = 0.0106) but not in healthy arteries (p ≥ 0.05). CONCLUSIONS: Atherosclerotic lesions impede the transfer of paclitaxel into arterial walls. Higher inflation pressures resulted in an increased paclitaxel transfer in atherosclerotic but not in healthy arteries. However, it is assumed that the tissue concentrations achieved with an inflation pressure of 2 atm are potentially effective in this model.

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 µg/mm(2) to 2×7 µg/mm(2), 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.

How does a drug-coated balloon work? Overview of coating techniques and their impact.

BACKGROUND: According to current understanding the drug-coated balloon (DCB) carries a sufficient dose of an effective antineoplastic agent, i.e. paclitaxel, to the target lesion. METHODS: Literature review and report on experimental studies simulating the access of coated balloons to the treatment site and studies in pigs. RESULTS: The drug adheres to the balloon membrane and is partially hidden below the folds which are wrapped around the shaft. Upon inflation solid paclitaxel particles are pushed into the vessel wall. Premature loss of paclitaxel and transfer to the vessel wall are controlled by the coating formulation which includes an inactive additive. Particles in the tissue dissolve slowly resulting in a terminal half-life of almost 2 months. The very low solubility of paclitaxel minimizes premature loss of the drug, dissolution, and elimination, while maximizing efficacy and tolerance are limited by the very low solubility of paclitaxel. From an exemplary DCB, approximately 10% of drug is lost before the target lesion is reached, 5-20% is transferred into the vessel wall and 10% remain on the balloon after withdrawal. The remainder of the drug is distributed in the general circulation. Inhibition of neointimal proliferation in animal models is reliable and as persistent as with drug-eluting stents. Histology reveals slight to moderate dose-dependent downstream effects without functional or clinical impairment. CONCLUSION: Paclitaxel continues to be the drug of choice, the dose varies between 2 and 3.5 µg/mm² balloon surface. Neither animal experiments nor clinical trials have demonstrated problems in vessel segments treated with overlapping balloons. Future developments are expected to improve efficacy in additional disease conditions (e.g., calcified vessels) and vessel territories.

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.

BACKGROUND: 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. METHODS AND RESULTS: SB were coated with paclitaxel admixed with a specific excipient. Patients at four clinical sites in Germany and one in Brazil with ISR of coronary bare metal stent (BMS) were randomized 1:1 to treatment with either a drug-coated or uncoated SB. Baseline and 6-month follow-up quantitative coronary angiography was performed by an independent blinded core lab and all patients will be evaluated clinically for up to one year. The primary endpoint was angiographic in-segment late lumen loss (LLL). Secondary endpoints included the rate of clinically driven target lesion revascularization (TLR), composite of major adverse cardiovascular events (MACE), stent thrombosis and other variables. Sixty-one patients were randomized (28 uncoated and 33 drug-coated SB); mean age 65 years, males 72%, and presence of diabetes 39%. At 6-month angiography, in-segment LLL was 0.48 ± 0.51 mm in the uncoated SB group versus 0.17 ± 0.40 mm in the drug-coated SB group (P = 0.01; ITT analysis). The rate of binary restenosis was 41% in the uncoated SB group versus 7% in the drug-coated SB group (P = 0.004). The MACE rate was 32% with the uncoated SB vs. 6% in the drug-coated SB group (P = 0.016). This difference was primarily due to the reduced need for clinically driven TLR in the coated SB group (3% vs. 32% P = 0.004). CONCLUSIONS: A novel paclitaxel-coated coronary SB has been developed and successfully used in a first-in-human randomized controlled trial [ClinicalTrials.gov Identifier: NCT01495533]. © 2015 Wiley Periodicals, Inc.

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 instentrestenosis (ISR), fibro-calcific and bifurcation lesions but have not been shown toaffect the restenosis rate. A novel paclitaxel-coated scoring balloon (SB) was developedand tested to overcome this limitation. Methods and Results: SB were coatedwith paclitaxel admixed with a specific excipient. Patients at four clinical sites inGermany and one in Brazil with ISR of coronary bare metal stent (BMS) were randomized1:1 to treatment with either a drug-coated or uncoated SB. Baseline and 6-monthfollow-up quantitative coronary angiography was performed by an independent blindedcore lab and all patients will be evaluated clinically for up to one year. The primaryendpoint was angiographic in-segment late lumen loss (LLL). Secondary endpoints included the rate of clinically driven target lesion revascularization (TLR), composite ofmajor adverse cardiovascular events (MACE), stent thrombosis and other variables.Sixty-one patients were randomized (28 uncoated and 33 drug-coated SB); mean age65 years, males 72%, and presence of diabetes 39%. At 6-month angiography, insegmentLLL was 0.48 6 0.51 mm in the uncoated SB group versus 0.17 6 0.40 mm inthe drug-coated SB group (P 5 0.01; ITT analysis). The rate of binary restenosis was41% in the uncoated SB group versus 7% in the drug-coated SB group (P 5 0.004). TheMACE rate was 32% with the uncoated SB vs. 6% in the drug-coated SB group(P 5 0.016). This difference was primarily due to the reduced need for clinically drivenTLR in the coated SB group (3% vs. 32% P 5 0.004). Conclusions: A novel paclitaxelcoatedcoronary SB has been developed and successfully used in a first-in-human randomized controlled trial...

Angioplasty of femoral-popliteal arteries with drug-coated balloons: 5-year follow-up of the THUNDER trial.

OBJECTIVES: The purpose of this study was to evaluate the 5-year follow-up (FU) data of the THUNDER (Local Taxan With Short Time Contact for Reduction of Restenosis in Distal Arteries). BACKGROUND: The THUNDER trial was the first study to investigate the treatment of femoropopliteal arteries with a paclitaxel-coated balloon (PCB). METHODS: In 154 patients, femoropopliteal arteries were treated with PCB, with angioplasty with paclitaxel in contrast medium, or no paclitaxel (control). The primary endpoint was 6-month late lumen loss (LLL). Secondary endpoints included freedom from target lesion revascularization (TLR), binary restenosis rate, and amputation. The 5-year FU compares outcomes in patients treated with PCB and control subjects. Additionally, LLL at 6 months and TLR up to 5-year FU were analyzed in terms of sex and lesion length. RESULTS: Over the 5-year period, the cumulative number of patients with TLR remained significantly lower in the PCB group (21%) than in the control group (56%, p = 0.0005). In the small group of patients with angiographic and duplex sonographic follow-up, PCB was associated with a lower rate of binary restenosis (17% vs. 54%; p = 0.04). No signs of aneurysm formation or constrictive fibrosis were detected. Whereas LLL at 6-month FU did not differ between men and women in the PCB group, the TLR rate was lower in men than in women at 5-year FU. A benefit of PCB treatment in terms of LLL and TLR was seen independent of lesion length. CONCLUSIONS: The reduced TLR rate following PCB treatment was maintained over the 5-year FU period. No signs of drug-related local vessel abnormalities were detected. (Thunder Trial-Local Taxan With Short Time Contact for Reduction of Restenosis in Distal Arteries [THUNDER]; NCT00156624).

Paclitaxel-coated balloon catheter versus paclitaxel-coated stent for the treatment of coronary in-stent restenosis: the three-year results of the PEPCAD II ISR study.

AIMS: Treatment of bare metal in-stent restenosis with the paclitaxel-coated balloon catheter based on the PACCOCATH® technology has yielded superior six-month angiographic and one-year clinical results compared to a paclitaxel-eluting stent. The three-year clinical follow-up is presented. METHODS AND RESULTS: One hundred and thirty-one patients with coronary bare metal in-stent restenosis (>70%, length: <22 mm, vessel diameter: 2.5-3.5 mm) were randomly treated with the paclitaxel-coated balloon (DCB) (3 µg/mm²) or a paclitaxel-eluting stent (DES). Clinical follow-up information was requested from the patients and from their physicians. Quantitative angiographic and demographic baseline data were statistically not different between the groups. Per intention-to-treat analysis at 12 months, the lesion-related rates of major adverse cardiac events were 7.6% and 16.9% (p=0.11) while at 36 months the respective numbers were 9.1% and 18.5% (p=0.14). These differences were primarily due to reduced target lesion revascularisation (TLR) in DCB 4/66 (6.2%) compared to DES patients 10/65 (15.4%) (p=0.10). From 12 to 36 months, 1/65 (1.5%) DCB patients experienced a myocardial infarction while neither TLR nor death occurred in any study patient in either group during that period. CONCLUSIONS: The six-month superiority of the paclitaxel-coated balloon compared to the paclitaxel-eluting stent in the treatment of bare metal coronary in-stent restenosis persisted throughout the three-year clinical follow-up period indicating stability of the lesions treated. (ClinicalTrials.gov Identifier: NCT00393315).

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.

AIMS: 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. METHODS AND RESULTS: This prospective trial included 77 patients with coronary de novo lesions. The patients were assigned to either one of the treatment groups. After 9 months, patients underwent angiographic follow-up including invasive measurement of coronary endothelial function. After 9 months, late lumen loss in-stent was highest in the BMS group (0.85 ± 0.73 mm), lower in DCB + BMS (0.36 ± 0.46 mm); and lowest in the DES group (0.25 ± 0.34 mm; P = 0.001 [ANOVA]). When compared to the BMS group, in-segment late lumen loss was significantly reduced in the DCB + BMS group (0.27 ± 0.43 mm vs. 0.60 ± 0.55 mm, P = 0.029) and the DES group (0.28 ± 0.40 mm, P = 0.045). Coronary flow reserve was significantly higher with the DCB + BMS treatment (3.16 ± 0.97 vs. 2.42 ± 0.99 [BMS], P = 0.036) whereas the increase in the DES group did not reach the significance level (3.06 ± 1.39, P = 0.144 vs. BMS). Parameters of endothelial function like intracoronary flow velocity and vessel diameter distal to the stented area showed similar patterns of response to adenosine, acetylcholine, and nitro in all groups. CONCLUSION: DES and the combination of DCB + BMS showed a significant reduction of late lumen loss as compared to a BMS alone. Furthermore, both types of local drug delivery were not associated with a deterioration of microvascular function at 9 months [ClinicalTrials.gov Identifier: NCT00473499].

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/mm(2) . 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 mm(2) (paclitaxel-coated SB) and 5.8 ± 1.7 mm(2) (Paccocath) as compared to the uncoated SB (2.3 ± 1.5 mm(2) ; 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.

Compassionate use of a paclitaxel coated balloon in patients with refractory recurrent coronary in-stent restenosis.

OBJECTIVE: Treatment of coronary in-stent restenosis (ISR) remains a challenge in interventional cardiology, especially after drug eluting stent (DES)-ISR. Drug coated balloons (DCB) provide a new therapeutic option in the treatment of ISR. In patients with multiple layers of stents due to refractory ISR and exclusion criteria for revascularization by coronary artery bypass grafting, DCB may be a last therapy option. This paper presents DCB therapy as compassionate use treatment before the balloons were available in Europe. PATIENTS: Compassionate use of DCB was approved by the local ethical committee. Fifteen patients with refractory ISR in 28 lesions were prospectively enrolled between 12/2006 and 04/2009. The frequency of prior ISR was 3.0 ± 1.1. Nine patients presented with coronary three-vessel disease and six patients with one- or two-vessel disease. Thirteen patients had DES-ISR, two patients with contraindication for prolonged dual anti-platelet therapy repeated BMS-ISR. Two or three layers of metal were present in eleven patients. Four patients had prior coronary artery bypass grafting. RESULTS: All lesions were treated with DCB (SeQuent™ Please, B.Braun, Germany). Angiographic follow-up was obtained in 14 patients. Clinical follow-up was available in all patients after 3.2 ± 0.8 years (maximum 4.8 years). Target lesion revascularization was done in 2 of 28 lesions (7.1 %), one patient with ischemic cardiomyopathy died after 1.5 years. No further MACE occurred. CONCLUSION: DCB appear to be safe and clinically useful in the treatment of ISR. DCB is a new promising option for high-risk patients with refractory ISR.

High-grade, non-flow-limiting dissections do not negatively impact long-term outcome after paclitaxel-coated balloon angioplasty: an additional analysis from the THUNDER study.

PURPOSE: To investigate the impact of using paclitaxel-coated balloons (PCB) on outcome after post-angioplasty dissection in femoropopliteal arteries. METHODS: The angiograms obtained in the THUNDER study (ClinicalTrials.gov identifier NCT00156624) were analyzed to compare degrees of dissection and angiographic parameters between the control (uncoated balloons, n=43) and treatment (PCBs, n=43) groups before and after the intervention and at 6-month follow-up. Furthermore, target lesion revascularizations (TLR) were documented up to 2 years. RESULTS: In each group, 24 (56%) patients had a dissection after the intervention. At the 6-month follow-up, patients with dissection of any grade after treatment with PCBs had significantly less late lumen loss (0.4 mm) than patients with dissection after treatment with uncoated balloons (1.9 mm, p=0.001) and a lower degree of stenosis (20% vs. 51%, respectively; p=0.003). Patients with severe dissection (grades C, D, or E) especially seemed to benefit from the PCBs, with late lumen loss of 0.4 mm vs. 2.4 mm for controls (p=0.05). The binary restenosis rate was also markedly lower in the PCB group (20%) than in the uncoated group (55%, p=0.02). In the 2-year follow-up, TLR was performed in 56% of patients in the control group compared to 10% of patients in the PCB group (p=0.002). CONCLUSION: The results of this subgroup analysis suggest that patients with dissection following treatment with a paclitaxel-coated balloon have a very acceptable outcome and stent implantation is not necessary as long as the dissection does not result in acute flow limitation.