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.

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.

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.

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...

The pharmacokinetic profile, tolerability and safety of the iodinated, non-ionic, dimeric contrast medium Iosimenol 340 injection in healthy human subjects.

BACKGROUND: Iosimenol 340 injection is a new isotonic iodinated contrast medium for X-ray angiography. PURPOSE: To investigate the pharmacokinetics and biotransformation, tolerability, and safety of Iosimenol 340 in healthy human subjects. MATERIAL AND METHODS: Twenty-four subjects were enrolled and randomized to receive either Iosimenol 340 (0.5, 1.5 or 3.0 mL/kg) or placebo (0.9% saline). In each dosing group, six subjects received Iosimenol 340 and two subjects received placebo. Safety was assessed by physical examination, vital signs, electrocardiography, and laboratory tests. Adverse events were recorded throughout the study up to 14 days after dosing. Blood samples were collected from 10 min before until 48 h after the start of dosing and urine samples were collected from 15 min before until 96 h after the start of dosing. Iosimenol was quantified in plasma and urine by measuring iodine concentrations with X-ray fluorescence. High-performance liquid chromatography was used to assess iosimenol biotransformation. RESULTS: Mean half-lives (mean ± standard deviation [SD]) of iosimenol were 0.17 ± 0.08 h (10.2 ± 4.8 min) and 2.01 ± 0.32 h for distribution and terminal elimination phases, respectively. The apparent volume of distribution was 0.27 ± 0.05 L/kg, indicating distribution to the extracellular fluid volume. Iosimenol was excreted within 24 h without any sign of metabolic transformation. Thirty-two adverse events were observed in 14 subjects. All were mild or moderate, and were transient in nature. CONCLUSION: Iosimenol was not metabolized, had a distribution volume corresponding to the extracellular space, and was rapidly excreted through the kidneys by glomerular filtration. The area under the plasma concentration curve and the peak plasma concentration was proportional to dose, while clearance was independent of dose. Iosimenol 340 was well tolerated.

Intra-arterial and intravenous applications of Iosimenol 340 injection, a new non-ionic, dimeric, iso-osmolar radiographic contrast medium: phase 2 experience.

BACKGROUND: Iosimenol 340 injection is a new, dimeric, iso-osmolar, iodinated contrast medium for X-ray angiography. PURPOSE: To compare the safety and efficacy of iosimenol injection to iodixanol injection in two randomized, controlled phase 2 trials. MATERIAL AND METHODS: One hundred and forty-four adult patients were enrolled in the two trials, one for evaluation during arteriography and the other for evaluation during computed tomography. Safety was compared by assessing adverse events, vital signs, ECGs, and laboratory parameters. Efficacy was assessed as X-ray attenuation in the computed tomography (CT) trial and as the quality of contrast enhancement in the arteriography trial. RESULTS: There were no statistically significant differences in terms of safety or efficacy between the two contrast media. Both were well tolerated upon intravenous as well as intra-arterial injection. The most common adverse event was a feeling of warmth (observed in 35.1% of the patients with Iosimenol injection and 44.3% with iodixanol injection). CONCLUSION: Iosimenol upon intravenous as well as upon intra-arterial injection exhibits a safety profile and shows an efficacy similar to that of iodixanol.

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.

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.

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).

Inhibition of neointimal proliferation after bare metal stent implantation with low-pressure drug delivery using a paclitaxel-coated balloon in porcine coronary arteries.

A variety of mechanical and laser-based methods remove or shift atherosclerotic plaques and reopen the artery to its original lumen. Subsequent treatment with drug-coated balloons (DCB) may smooth the vessel wall but does not require high-pressure inflation. We investigated the efficacy of paclitaxel-coated balloons inflated with only 2 atm after bare metal stent implantation in coronary arteries of 24 pigs. Angiography and histomorphometry was performed on day 28. DCB inflated with 2 atm caused similar reduction of late lumen loss (LLL) as high-pressure inflation with 12 atm (0.89 ± 0.58 vs. 0.72 ± 0.39 mm, p = 0.34). Both DCB treatments significantly (p < 0.01) reduced LLL versus uncoated balloons (1.50 ± 0.51 mm). Treatment with low-pressure DCB resulted in less maximal intimal thickness (0.45 ± 0.15 vs. 0.67 ± 0.25 mm) and neointimal area (2.93 ± 0.73 vs. 3.82 ± 1.27 mm(2)) than treatment with uncoated balloons (p < 0.05). In conclusion, low-pressure treatment with DCB was similarly effective as high-pressure treatment justifying clinical trials in vessels which will benefit from inhibition of neointimal proliferation but may not tolerate high inflation pressure.

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.