Judah Weinberger

Drug-Eluting Stents in Preclinical Studies: Recommended Evaluation From a Consensus Group

The arrival of drug-eluting stents raises important questions about preclinical evaluation of devices and the optimal means of predicting clinical safety and efficacy. The Interventional, Regulatory, Commercial, and Scientific communities have all asked for assistance in defining criteria for device evaluation. This document is an integrated view of requirements for evaluating drug-eluting stents in preclinical models. The suggested requirements encompass study design, experimental performance, and histopathologic evaluations, emphasizing safety and efficacy at multiple points in time. This is a consensus document assembled by clinical, academic, and industrial investigators engaged in preclinical interventional device evaluation. Suggested requirements might well serve as a standard but do not prescribe a single manner in which all devices should be evaluated. They instead motivate such an evaluation and describe how examinations might be performed. It is understood that methods will change and knowledge will evolve, in particular as corroboration is established with clinical data. The dynamic nature of this document allows for future modifications and additions. A drug-eluting stent presents or releases single or multiple bioactive agents into the blood stream. The drug can deposit in and/or affect blood vessels, cells, plaque, or tissues either adjacent to the stent or at a distance. Systemic drug concentrations may be avoided or desirable. It is assumed that drugs undergoing preclinical evaluation will have sound theoretical and practical reasons for biological success, and that the preclinical studies will help answer the magnitude and safety of effect when presented with or from the stent. It is likely that substantial empirical data already exists documenting the effects of these drugs on isolated cells in culture and even in vivo after systemic administration. Some drugs may already be in clinical use. Drug can be embedded and released from within (“matrix-type”) or surrounded by and released through (“reservoir-type”) polymer materials that coat …

Intracoronary irradiation: Dose response for the prevention of restenosis in swine

PURPOSE Restenosis after percutaneous transluminal coronary angioplasty represents, in part, a proliferative response of vascular smooth muscle at the site of injury. We have previously shown that high-dose radiation (20 Gy), delivered via an intracoronary 192Ir source, causes focal medial fibrosis and markedly impairs the restenosis process after balloon angioplasty in swine. This study sought to delineate the dose-response characteristics of this effect. METHODS AND MATERIALS Forty juvenile swine underwent coronary angiography; a segment of the left coronary artery was chosen as a target for balloon injury. In 30 swine, a 2 cm ribbon of 192Ir was positioned at the target segment and 20, 15, or 10 Gy were delivered to the vessel wall (10 animals/dose). Subsequently, overdilatation balloon angioplasty was performed at the irradiated segment. In 10 control swine, overdilatation balloon angioplasty was performed without previous irradiation. Thirty-eight animals survived until sacrifice at 30 +/- 3 days. Histopathological analysis was performed by a pathologist in a blinded manner. The area of maximal luminal compromise within the target segment was analyzed via computer-assisted planimetry. RESULTS Neointimal area was decreased by 71.4% at 20 Gy and by 58.3% at 15 Gy compared with control animals (p < 0.05 for both). A stimulatory effect on smooth muscle cell proliferation was noted at 10 Gy, with a 123% increase in neointimal area compared with controls (p < 0.05). Mean percent area stenosis was also reduced by 63% at 20 Gy and by 74.8% at 15 Gy compared with controls (p < 0.05 for both). CONCLUSIONS Intracoronary irradiation prior to overstretch balloon angioplasty markedly reduces neointima formation; this effect is dose dependent, with evidence of a significant stimulatory effect at 10 Gy. The effective therapeutic dose range for the prevention of restenosis in this model begins at approximately 15 Gy delivered to the vessel wall.

Drug-Eluting Stents in Preclinical Studies Updated Consensus Recommendations for Preclinical Evaluation

Coronary drug-eluting stents are commonplace in clinical practice with acceptable safety and efficacy. Preclinical evaluation of novel drug-eluting stent technologies has great importance for understanding safety and possibly efficacy of these technologies, and well-defined preclinical testing methods clearly benefit multiple communities within the developmental, testing, and clinical evaluation chain. An earlier consensus publication enjoyed widespread adoption but is in need of updating. This publication is an update, presenting an integrated view for testing drug-eluting technologies in preclinical models, including novel devices such as bioabsorbable coatings, totally bioabsorbable stents, bifurcation stents, and stent-free balloon-based drug delivery. This consensus document was produced by preclinical and translational scientists and investigators engaged in interventional technology community. The United States Food and Drug Administration (USFDA) recently issued a Draft Guidance for Industry Document for Drug-Eluting Stents. This expert consensus document is consistent with the Food and Drug Administration guidance. The dynamic nature of this field mandates future modifications and additions that will be added over time.

DOSIMETRIC CONSIDERATIONS FOR CATHETER-BASED BETA AND GAMMA EMITTERS IN THE THERAPY OF NEOINTIMAL HYPERPLASIA IN HUMAN CORONARY ARTERIES

PURPOSE Recent data indicate that intraluminal irradiation of coronary arteries following balloon angioplasty reduces proliferation of smooth muscle cells, neointima formation, and restenosis. We present calculations for various isotopes and geometries in an attempt to identify suitable source designs for such treatments. METHODS AND MATERIALS Analytical calculations of dose distributions and dose rates are presented for 192Ir, 125I, 103Pd, 32P, and 90Sr for use in intracoronary irradiation. The effects of source geometry and positioning accuracy are studied. RESULTS Accurate source centering, high dose rate, well-defined treatment volume, and radiation safety are all of concern; 15-20 Gy are required to a length of 2-3 cm of vessel wall (2-4 mm diameter). Dose must be confined to the region of the angioplasty, with reduced doses to normal tissues. Beta emitters have radiation safety advantages, but may not have suitable ranges for treating large diameter vessels. Gamma emitters deliver larger doses to normal tissues and to staff. Low energy x-ray emitters such as 125I and 103Pd reduce these risks but are not available at high enough activities. The feasibility of injecting a radioactive liquid directly into the angioplasty balloon is also explored. CONCLUSIONS Accurate source centering is found to be of great importance. If this can be accomplished, then high energy beta emitters such as 90Sr would be ideal sources. Otherwise, gamma emitters such as 192Ir may be optimal. A liquid beta source would have optimal geometry and dose distribution, but available sources, such as 32P are unsafe for use with available balloon catheters.

Intracoronary Radiation for Prevention of Restenosis Dose Perturbations Caused by Stents

BACKGROUND Intravascular irradiation with beta-emitters has been proposed for inhibition of restenosis in coronary arteries after balloon angioplasty or stent implantation. Previous studies have shown the effectiveness of gamma-radiation to prevent recurrent restenosis, even in the presence of an implanted stent. The limited range of beta-particles compared with gamma-radiation, however, opens the question of whether absorption and scattering of beta-particles by stent struts will cause significant perturbations in the uniformity and magnitude of the radiation dose, which may in turn compromise treatment. METHODS AND RESULTS Nine different stents were deployed with a balloon filled with a beta-emitting radioactive liquid. Dose distributions were measured with Gafchromic film. Stents varied significantly in their absorption of beta-particles. Some stents, constructed of fine meshed wires, produced minimal dose perturbations. Others, with thicker, high-atomic-number struts, induced cold spots in the dose distribution adjacent to the wires of </=35%. Average dose reduction varied from 4% to 14% in the presence of various stents. CONCLUSIONS Radiation strategy may have to be tailored to stent design. Stents that minimally perturb the dose distribution may be deployed before irradiation. Those that significantly alter the radiation dose might be better deployed after irradiation. Dose prescriptions may require modification if such perturbations prove clinically significant. Observed dose perturbations, however, decreased rapidly with increasing distance from the stent, which may mitigate the clinical impact of these findings. This, as well as the effects of stents on gamma-dose distributions, requires further investigation.

Dosimetry of a radioactive coronary balloon dilitation catheter for treatment of neointimal hyperplasia

Recent reports suggest that intraluminal irradiation of coronary arteries in conjunction with balloon angioplasty reduces proliferation of smooth muscle cells and neointima formation, thereby inhibiting restenosis. One possible irradiation technique is to inflate the balloon dilitation catheter with a radioactive solution. This has advantages over other proposed irradiation procedures, in that accurate source positioning and uniform dose to the vessel wall are assured. Several high-energy beta-minus emitters may be suitable for this application. We present experimental measurements and analytical calculations of the dose distribution around a 3-mm-diam by 20-mm-long balloon filled with 90Y-chloride solution. The dose rate at the surface of the balloon is approximately 0.14 cGy/s per mCi/ml (3.78 x 10(-11) Gy/s per Bq/ml), with the dose decreasing to 53% at 0.5 mm, and < 5% at 3.5-mm radial distance. 90Y and other possible isotopes are currently available at specific concentrations > or = 50 mCi/ml (1.85 x 10(9) Bq/ml), which enables the delivery of 20 Gy in less than 5 min. The dosimetric and radiation safety advantages of this system warrant further feasibility studies. Issues of concern include incorporating the beta-emitter into a suitable chemical form, and assessing organ and whole body doses in the (< 1 in 10(3)) event of balloon failure.

Preclinical Evaluation of Drug-Eluting Stents for Peripheral Applications Recommendations From an Expert Consensus Group

Drug-eluting stents implanted in the coronary arteries substantially improve long-term outcomes for restenosis. The utility of the stents in peripheral atherosclerosis is under evaluation. Drug-eluting stent evaluation with coronary arteries appears to be an excellent method for evaluating human safety end points. Predicting clinical efficacy remains unclear, however. Because drug-eluting stents are undergoing development for human peripheral arteries, safety and efficacy questions arise in much the same context as they did for the coronary arteries. As they did with the coronary arteries, the clinical, scientific, regulatory, and commercial communities are seeking acceptable criteria for peripheral device evaluation. Substantial differences in stent requirements and biological effects for bare metal peripheral stents depend on implant site. Different anatomic locations under evaluation include femoral, renal, and neurologic arterial stents, and other peripheral applications such as outflow veins of dialysis arteriovenous fistulae are being evaluated. Peripheral in-stent restenosis is less of a problem in carotid and aortoiliac stents and in iliac veins and in the cavae. In general, the benefit:risk ratio for drug-eluting stents may be less for peripheral stents. It is for this reason that peripheral stent performance should be evaluated carefully. This document presents an integrated recommendation set for evaluating drug-eluting stents in peripheral vessels with preclinical models. The recommendations encompass study design, experimental performance, and histopathologic evaluations and emphasize the need to evaluate safety and efficacy at multiple points in time. The present document is a consensus of clinical, academic, and commercial groups—all experts in the evaluation of preclinical investigational or interventional devices. Because preclinical peripheral studies are less well understood than are coronary models, the recommendations do not prescribe a single method for device evaluation; they instead provide broad suggestions for evaluation. Peripheral vascular knowledge will increase as correlations of preclinical with clinical data become available. Future versions of this …

Dosimetry study of Re-188 liquid balloon for intravascular brachytherapy using polymer gel dosimeters and laser-beam optical CT scanner.

Angioplasty balloons inflated with a solution of the beta-emitter Re-188 have been used for intravascular brachytherapy to prevent restenosis. Coronary stents are in extensive clinical use for the treatment of de novo atherosclerotic stenoses. In this study, the effect of an interposed stent on the dose distribution has been measured for Re-188 balloon sources using the proprietary BANG polymer gel dosimeters and He-Ne laser-beam optical CT scanner. In polymer gels, after ionizing radiation is absorbed, free-radical chain-polymerization of soluble acrylic monomers occurs to form an insoluble polymer. The BANG polymer gel dosimeters used in these measurements allow high resolution, precise, and accurate three-dimensional determination of dosimetry from a given source. Re-188 liquid balloons, with or without an interposed metallic stent, were positioned inside thin walled tubes placed in such a polymer dosimeter to deliver a prescribed dose (e.g., 15 Gy at 0.5 mm). After removing the balloon source, each irradiated sample was mounted in the optical scanner for scanning, utilizing a single compressed He-Ne laser beam and a single photodiode. In the absence of a stent, doses at points along the balloon axis, at radial distance 0.5 mm from the balloon surface and at least 2.5 mm from the balloon ends, are within 90% of the maximum dose. This uniformity of axial dose is independent of the balloon diameter and length. Dose rate and dose uniformity for intravascular brachytherapy with Re-188 balloon are altered by the presence of stent. The dose reduction by the stent is rather constant (13%-15%) at different radial distances. However, dose inhomogeneity caused by the stent decreases rapidly with radial distance.

Radioactive beta-emitting solution-filled balloon treatment prevents porcine coronary restenosis.

PURPOSE Intracoronary gamma or beta radiation from centrally located sources at the time of overstretch balloon injury inhibits neointimal proliferation. In an effort to deliver homogeneous, centered radiation fields in a technically straightforward fashion, we studied the effects of a beta-emitting solution used as a balloon inflation fluid to deliver radiation at the time of coronary injury. METHODS Twenty-one coronary arteries in 13 juvenile swine underwent irradiation (control and 11 or 25 Gy media dose). Radiation was delivered using a perfusion balloon inflated with an Re-188 solution. Subsequently, overdilatation percutaneous transluminal coronary angioplasty was performed at the pretreated segment. Histopathologic and histomorphometric analysis was performed at 30 days after injury on the entire irradiated artery. RESULTS Balloon overdilation was associated with significant vascular injury and marked neointimal proliferation in control and low-dose (11 Gy)-treated arteries. High-dose radiation (25 Gy) significantly inhibited neointima formation compared with controls (neointimal area: 0.49 +/- 0.29 mm2 vs. 1.51 +/- 0.22 mm2, respectively; p = 0.02) and low-dose radiation (neointimal area 1.75 +/- 0.54 mm2, p > 0.1 compared with controls). CONCLUSIONS Liquid Re-188 is an effective beta-emitting vehicle to deliver intracoronary radiation and prevent restenosis in this model. Intracoronary radiation treatment using aqueous radioisotope sources is technically straightforward and provides the optimally achievable radiation dose distribution.

Intracoronary radiation using radioisotope solution-filled balloons

A substantial body of experimental evidence suggests that local application of radiation at sites of angioplasty or stent implantation prevents neointima formation. Recent initial clinical studies report a significant reduction in clinical restenosis rates when gamma emitting radiation sources are used to treat the site of coronary intervention. Because of the energy of therapeutic gamma sources and the shielding requirements, it would be far preferable to deliver ionizing radiation using a local beta emitter.This report discusses a number of the physical, biological, and technical parameters involved in radiation from a balloon angioplasty catheter filled with a beta emitting radioisotope solution.ZusammenfassungZahlreiche experimentelle Untersuchungen haben gezeigt, daß die Anwendung von Strahlung nach einer Angioplastie oder Stentimplantation die Neointimabildung verhindert. Kürzlich durchgeführte klinische Untersuchungen berichten über eine signifikante Reduktion der klinischen Restenoserate, wenn die Koronarstenosen nach einer PTCA einer Gammastrahlung ausgesetzt werden. Aufgrund notwendiger Umbaumaßnahmen für die Verwendung von Gammastrahlen werden Betastrahlen bevorzugt.Die vorliegende Arbeit diskutiert eine Vielzahl von physikalischen, biologischen und technischen Paramametern, die die Verwendung eines mit einer radioaktiven Substanz gefüllten PTCA-Ballonkatheters mit sich bringen.