The Beta-Particle—Emitting Radioisotope Stent (Isostent): Animal Studies and Planned Clinical Trials

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Abstract

Radiation delivered by intravascular stent is an appealing approach to prevent neointimal hyperplasia, since it nonselectively kills dividing cells. In particular, beta-particle—itting radioisotope stents may prove to be an ideal means of local irradiation in that 95% of the dose is delivered within 4 mm of the stent edge and the dose drops off rapidly to < 1/1,000 of the original dose at 5 months postimplantation. In the in vitro smooth muscle cell model, one can observe a zone of growth inhibition around radioactive stent wires that averages about 6 mm at very-low-activity levels (0.006 μCi/cm of wire). In vivo studies in animal models, including porcine iliac and coronary arteries and rabbit iliac arteries, have shown the effectiveness of radioisotope stents in inhibiting neointimal proliferation. Proliferating endothelial cells appear to be relatively radioresistant. A computer model was employed to look at the radiation dose delivered as a function of distance from the stent. With very-low-activity stents, presumably, DNA of the smooth muscle cells is damaged as they migrate through the “electron fence” on the way to the neolumen, diminishing the population of myofibroblasts and reducing hyperplasia. Catheter-based radiation therapies may disable these cells before they migrate, although such an approach may not inhibit early recoil or late contraction. Based on the characteristics of beta emissions (i.e., rapid drop-off, minimal leaching), radioisotope stents containing phosphorus-32 appear to be safe. A randomized triple-blind clinical trial is planned to assess restenosis at 6 months in native coronary arteries treated with radioisotope stents.

Section snippets

CONCEPT OF BETA-PARTICLE RADIOISOTOPE STENT

Rationale for intravascular irradiation: Despite the favorable lumen geometry created by stents, proliferating cells can migrate through these devices and lead to restenosis. Radiation is an appealing concept for preventing neointimal hyperplasia because it nonselectively kills dividing cells, whether they are malignant or benign. In addition, radiation has been shown to prevent keloid formation, which in many ways is similar to restenosis in that it results from the finite proliferation (in

ARTERIAL EFFECTS OF RADIOISOTOPE STENTING

Fig. 1 shows a human coronary artery 7 months after stent implantation. In this case, stents had been used as a palliative treatment prior to retransplantation. Thus, we were able to examine a series of Palmaz-Schatz stents (Johnson & Johnson Interventional Systems, Warren, NJ) at 3 weeks, 3 months, and 7 months following implantation in human coronary arteries. Despite relatively modest injury, with virtually no wires through the internal elastic lamina, there is a profound neointimal

INHIBITION OF NEOINTIMAL HYPERPLASIA: POTENTIAL MECHANISMS

We believe that the inhibition of neointimal proliferation seen with very-low-activity stents (0.1–1.0 μCi) may be caused in large part by the thinning of the proliferating smooth muscle cell population as these cells pass through the “electron fence” at the plane of the stent wires. In addition, there is evidence that very low levels of beta-particle irradiation may inhibit smooth muscle cell migration. At low activity levels (3–25 μCi)—although not ultra-low doses, such as those we have used

SAFETY FEATURES OF RADIOISOTOPE STENTS

Since essentially no radiation is delivered beyond the adventitia owing to the rapid drop-off in beta-particle emission, the use of radioisotope stents should be safe. The total body dose to the patient is <1/10,000 of the fluoroscopy dose scatter delivered during routine angioplasty. Prior to implantation, the stent is encased in a lucite/plastic shield, which blocks the electrons and protects the interventionalist from exposure to any measurable radiation.

Since the beta particles are

CLINICAL TRIAL

Finally, we are planning a clinical trial, the Isostent for Restenosis Intervention Study (IRIS), to begin in the summer of 1996. Our proposed plan for phase 1 is an initial trial involving 3 centers and 30 patients using a 1-μCi Palmaz-Schatz stent. In phase 2, we expect to enroll approximately 1,200 patients in a randomized, controlled, triple-blind (to patient, physician, and core labs) trial. This trial will likely include a larger dose/activity range and will compare clinical,

CONCLUSIONS

Based on in vitro studies, very-low-dose beta-particle irradiation emitted from a stent wire appears to inhibit vascular smooth muscle cell growth and/or migration. Endothelial cells, in contrast, appear relatively radioresistant. In vivo studies in porcine iliac and coronary vessels and rabbit iliac vessels have demonstrated marked, dose-dependent inhibition of neointimal hyperplasia after placement of radioisotope (32P) stents. We continue to conduct in vivo testing, looking at dose-response

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