Combined Vascular Brachytherapy and Stenting for the Treatment of In-Stent Restenosis.

In-stent restenosis (ISR) remains a therapeutic challenge in the current drug-eluting stent (DES) era. Vascular brachytherapy (VBT) is a therapeutic option for ISR, but data about the outcomes of combination therapy with VBT and stenting for ISR lesions are sparse. We retrospectively analyzed patients who presented with ISR at our institution from 2003 through 2017. Three treatment arms were compared: VBT alone, VBT plus bare-metal stent (BMS), and VBT plus DES. Clinical, procedural, and 1-year outcome data were collected. Follow-up was obtained by phone calls and clinic visits. The patient cohort included 461 patients (764 ISR lesions). Of these, 333 patients (533 lesions) were treated with VBT alone, 89 patients (158 lesions) with VBT plus BMS, and 39 patients (73 lesions) with VBT plus DES. There were no significant differences in baseline characteristics among the 3 groups except for more patients with a remote smoking history in the VBT plus BMS (43.8%) and VBT plus DES groups (56.4%), and more patients with history of peripheral vascular disease (39.5%) and congestive heart failure (27%) in the VBT plus DES group. The most common clinical presentation was unstable angina (64.6%). In the VBT plus DES group, 10.3% of patients presented with MI, versus 5.5% in the VBT alone group and 2.2% in the VBT plus BMS group. At 1-year follow-up, the VBT plus DES group had higher rates of target vessel revascularization-major adverse cardiovascular events (38.5%) than the VBT plus BMS (21.3%) and VBT alone (15.6%) groups (p = 0.002). In conclusion, in patients with ISR, combination therapy with VBT and stenting at the same setup is associated with worse outcomes at 12 months and, if possible, should be avoided.

Intravascular gamma radiation for in-stent restenosis in saphenous-vein bypass grafts.

BACKGROUND: Intracoronary radiation therapy is effective in reducing the recurrence of in-stent stenosis in native coronary arteries. We examined the effects of intravascular gamma radiation in patients with in-stent restenosis of saphenous-vein bypass grafts. METHODS: A total of 120 patients with in-stent restenosis in saphenous-vein grafts, the majority of whom had diffuse lesions, underwent balloon angioplasty, atherectomy, additional stenting, or a combination of these procedures. If the intervention was successful, the patients were randomly assigned in a double-blind fashion to intravascular treatment with a ribbon containing either iridium-192 or nonradioactive seeds. The prescribed dose, delivered at a distance of 2 mm from the source, was 14 to 15 Gy in vessels that were 2.5 to 4.0 mm in diameter and 18 Gy in vessels with a diameter that exceeded 4.0 mm. The primary end points were death from cardiac causes, Q-wave myocardial infarction, revascularization of the target vessel, and a composite of these events at 12 months. RESULTS: Revascularization and radiation therapy were successfully accomplished in all patients. At six months, the restenosis rate was lower in the 60 patients assigned to the iridium-192 group than in the 60 assigned to the placebo group (21 percent vs. 44 percent, P=0.005). At 12 months, the rate of revascularization of the target lesion was 70 percent lower in the iridium-192 group than in the placebo group (17 percent vs. 57 percent, P<0.001), and the rate of major cardiac events was 49 percent lower (32 percent vs. 63 percent, P<0.001). CONCLUSIONS: The results of our study support the use of gamma-radiation therapy for the treatment of in-stent restenosis in patients with bypass grafts.

Radioactive 133-Xenon gas-filled balloon to prevent restenosis: dosimetry, efficacy, and safety considerations.

BACKGROUND: Ionizing radiation administered intraluminally via catheter-based systems using solid beta and gamma sources or liquid-filled balloons has shown reduction in the neointima formation after injury in the porcine model. We propose a novel system that uses a 133-Xenon (133Xe) radioactive gas-filled balloon catheter system. METHODS AND RESULTS: Overstretch balloon injury was performed in the coronary arteries of 33 domestic pigs. A novel 133Xe radioactive gas-filled balloon (3.5/45 mm) was positioned to overlap the injured segment with margins. After vacuum was obtained in the balloon catheter, approximately 2.5 cc of 133Xe gas was injected to fill the balloon. Doses of 0, 7.5, 15, and 30 Gy were delivered to a distance of 0.25 mm from the balloon surface. The dwell time ranged from 1.0 to 4.0 minutes, depending on the dose. Localization of 133Xe in the balloon was verified by a gamma camera. The average activity in a 3.5/45-mm balloon was measured at 67.7+/-12.1 mCi, and the total diffusion loss of the injected dose was 0.26% per minute of the injected dose. Bedside radiation exposure measured between 2 and 6 mR/h, and the shallow dose equivalent was calculated as 0.037 mrem per treatment. Histomorphometric analysis at 2 weeks showed inhibition of the intimal area (intimal area corrected for medial fracture length [IA/FL]) in the irradiated segments of 0.26+/-0.08 with 30 Gy, 0.07+/-0.24 with 15 Gy, and 0.12+/-0.89 with 7.5 Gy versus 0.76+/-0.08 with control P<0.001. CONCLUSIONS: 133Xe gas-filled balloon is feasible and effective in the reduction of neointima formation in the porcine model and safe for use in coronary arteries.

Time course of stent endothelialization after intravascular radiation therapy in rabbit iliac arteries.

BACKGROUND: Late total occlusion after vascular brachytherapy (VBT) continues to be a serious complication. Delayed reendothelialization was suggested as a pivotal cause, but the time course for complete healing is unknown. METHODS AND RESULTS: Seventy-two rabbit iliac arteries underwent stent implantation and were treated with gamma-radiation using 192Ir. The prescribed doses were 0 Gy (controls, n=24 arteries), 15 Gy (n=24), or 30 Gy (n=24) at 2 mm. Animals were killed at 1 month (n=24), 3 months (n=24), or 6 months (n=24) and were analyzed for histomorphometry or scanning electron microscopy. Intimal area was reduced after VBT at 3 months with 15 and 30 Gy (0.66+/-0.07 and 0.66+/-0.04 mm2, respectively) compared with controls (1.01+/-0.11 mm2, P<0.05) and at 6 months with 30 Gy (0.75+/-0.09 versus 1.28+/-0.26 mm2 in controls, P<0.01). Intimal area was similar at 6 months between 15 Gy and controls. At 1 month, 92+/-4% of the control stented segment was covered with endothelial cells, whereas only 37+/-4% and 37+/-8% was covered in the 15- and 30-Gy arteries, respectively. Similarly, at 3 and 6 months, there was a difference in the extent of reendothelialized areas (at 3 months, 95+/-2%, 32+/-12%, and 29+/-13%; and at 6 months, 98+/-2%, 40+/-8%, and 35+/-12% in control, 15-Gy, and 30-Gy arteries, respectively). Excess platelets and leukocytes were seen in irradiated arteries without complete coverage of endothelium. CONCLUSIONS: Reendothelialization after VBT is not completed at 6 months after VBT. Special care with prolonged antiplatelet therapy should be considered beyond that time point.

The outcome of percutaneous coronary intervention in patients with in-stent restenosis who failed intracoronary radiation therapy.

OBJECTIVES: This study reports the outcome of patients who failed intracoronary radiation therapy (IRT) for the treatment of in-stent restenosis (ISR). BACKGROUND: Intracoronary radiation therapy has demonstrated a reduction in the recurrence rate of restenosis for patients with ISR. However, 10% to 30% of these patients require repeat intervention to the irradiated site. METHODS: Of 961 patients who were assigned to gamma or beta radiation for the treatment of diffuse ISR, we evaluated the outcome of 282 (29%) consecutive patients who failed IRT and compared them with the 679 (71%) patients who had successful IRT. For patients who failed radiation, the mean time to the first target vessel revascularization (TVR) was 173 +/- 127 days after the index procedure and the total duration of follow-up was 494 +/- 304 days. RESULTS: Patients who failed IRT were younger (60 +/- 10 vs. 63 +/- 11 years, p = 0.002) and had a higher incidence of restenting (51% vs. 41%, p = 0.003). The majority (55%) of the restenotic lesions after IRT failure were focal (< or =10 mm), with a mean lesion length of 11.9 +/- 1.9 mm. Of the 257 patients who had subsequent TVR after failed IRT, 68 (26%) underwent coronary artery bypass grafting and 189 (74%) underwent percutaneous coronary intervention using balloon in 61%, restenting in 26%, atheroablation in 11%, and the cutting balloon in 2% of cases. At six months, 6% of patients died, 1% had Q-wave MI, 17% had repeat TVR, and the overall rate of major adverse cardiac events was 21%. CONCLUSIONS: The predominant angiographic pattern of lesions in patients who failed IRT is focal restenosis, with these lesions responding well to conventional revascularization methods.

Effectiveness of radioactive tungsten source in the prevention of restenosis in stented porcine coronary arteries.

PURPOSE: Intracoronary radiation has shown the potential to inhibit neointimal proliferation in porcine models of restenosis. The objective of this study was to determine whether intracoronary radiation using a new coiled wire of tungsten-188 ((188)W), a pure beta emitter (half-life 69.4 days) is safe. In addition, a dose of 0 Gy, 18 Gy, or 25 Gy prescribed to 2 mm from the center of the source and delivered intraluminally is sufficient to prevent restenosis and free from adverse effects. METHODS AND MATERIALS: Ten domestic swine underwent 13-mm stent implantation (SI) into two arteries, left anterior descending plus either the left circumflex or right coronary artery. After SI, a closed-end lumen radiation catheter was inserted to the treated artery and a 40-mm coiled (188)W source was manually delivered to cover the stented segment and its margins. A total of 20 arteries were randomized to treatment with a radiation dose of 0, 18 Gy, or 25 Gy delivered to 2 mm depth from the center of the source. Four weeks after the procedure, the swine underwent angiography and intravascular ultrasound using automated pullback at 0.5 mm/s. before being killed and the arteries perfusion fixed. Histopathologic and histomorphometric analyses were performed at 28 days after injury and radiation. RESULTS: Irradiation with (188)W at a dose of 25 Gy after SI significantly inhibited neointima formation (intimal area: 1.05 +/- 0.64 vs. 2.75 +/- 0.99 mm(2), p < 0.01) and at an 18 Gy dose of radiation (intimal area: 1.73 +/- 0.49 vs. 2.75 +/- 0.99 mm(2)), as compared to controls. One artery receiving 18 Gy and two arteries receiving 25 Gy were totally occluded at follow-up due to thrombus formation but no edge stenosis was observed in any of the irradiated arteries. CONCLUSIONS: Intracoronary radiation therapy using a new coiled wire of (188)W source delivered after SI appeared to be safe and well tolerated. The radiation doses demonstrated efficacy in reducing neointima formation in the porcine coronary stent injury model.

Real-world clinical practice of intracoronary radiation therapy as compared to investigational trials.

Intracoronary radiation therapy (IRT) is well established in clinical practice as an effective treatment for in-stent restenosis. We aimed to determine if the 6-month clinical outcome of patients treated postapproval for marketing [commercial radiation (CR)] is equivalent to those patients enrolled in the Washington Radiation for In-Stent Restenosis Trials [Gamma WRIST and Beta WRIST; investigational radiation (IR)]. The 6-month clinical outcome of 110 consecutive patients with 125 lesions who received IRT (gamma, (192)Ir, 15-18 Gy, n = 6; or beta, (32)P, 20 Gy, n = 20; or (90)Sr/Y, 18.4-23.0 Gy, n = 99) in CR was compared with the 6-month clinical outcome of 117 patients with 117 lesions who received IRT ((192)Ir, 15 Gy, n = 65, in Gamma WRIST; and (90)Y, 20.6 Gy, n = 52, in Beta WRIST) in IR. Patients in CR were treated with wider radiation margins. The CR received antiplatelet therapy for at least 6 months and the IR for 1 month. The baseline characteristics of both groups were similar. Use of atheroablation devices was less in CR than IR (15.2% vs. 32.8%, respectively; P = 0.001). The overall major adverse cardiac events (death, Q-wave myocardial infarction, and target vessel revascularization; 18.2% vs. 29.1% in IR; P = 0.05) were significantly lower in the CR when compared with patients in the IR. The real-world clinical practice of IRT demonstrates lower events and better clinical outcomes. This is most likely a result of implementation of the lessons learned from the clinical trials such as optimizing the dosimetry by using a higher dose, treating wider margins to minimize edge effect, and administering prolonged antiplatelet therapy to abolish late thrombosis.

Low-energy X-radiation for prevention of restenosis results in localized inhibition of V79 fibroblast cell proliferation.

Local delivery of high-energy ionizing radiation by using 3 or 3 emitters to injured vessels demonstrated inhibition of cell proliferation (CP) and neointima formation. Low-energy ('soft') X-radiation (LEXR) offers logistic and safety advantages over the use of disposable radioisotopes. This study evaluated the efficacy of LEXR in penetration and inhibition of CP at doses similar to those prescribed for the use of radioisotopes for prevention of restenosis. Serial measurements in an ion chamber detected the attenuation of LEXR using potentials of 17 and 40 kV at a distance of 17 cm of air through 0-10 mm depths of serum-containing tissue culture medium. The effect of inhibition on CP was determined by exposing V79 fibroblasts to a potential of 17 kV in order to deliver a prescribed dose of 13 Gy at a dose rate of 2.17 Gy/min to the surface of the cells. Complete inhibition of CP at a height of 0.00 mm occurred with 13 Gy; however, a 50% attenuation of the dose was measured at a medium depth of 1.22 mm and was associated with a reduction of 60% of the CP. LEXR demonstrated an ability to inhibit CP at doses equivalent to those used in techniques involving 3 and 3 irradiation. Under such conditions, the dose gradient is too high, especially for large vessels. However, a catheter-based LEXR that could be inserted into the artery with the capability of varying effective energy would be ideal for intravascular applications.

Radiation-induced atherosclerotic plaque progression in a hypercholesterolemic rabbit: a prospective vulnerable plaque model?

PURPOSE: Human observations provide rich soil for making hypotheses, but good animal models are essential for understanding the disease and to test treatment modalities. Currently, there is no standard animal model of vulnerable plaque; therefore, the purpose of this study is to develop a pathophysiologically relevant vulnerable plaque model. METHODS: New Zealand White rabbits were fed with 1% hypercholesterolemic (HC) diet for 7 days, followed by balloon denudation of both the iliac arteries, and continued on 1% HC diet. Four weeks later, in 12 rabbits one of the iliac arteries was radiated (192-Ir, 15 Gy), and in five rabbits both the iliac arteries were sham treated. Following that, rabbits were fed with 0.15% HC diet. Four weeks later, arteries were processed for histomorphometry or immunohistochemistry. RESULTS: Serum cholesterol levels were similar in all the groups. In radiated arteries, plaque area was significantly larger (32% larger then in sham). Macrophage-positive area in radiated arteries was 2.4 times greater than the macrophage-positive area in the nonradiated arteries. The area positive for macrophages is also positive for metalloproteinases (MMP)-1. The extent of alpha-actin positive area was significantly less (2.3-fold) in radiated arteries. CONCLUSION: The atherosclerotic plaque developed in the current model is predominantly composed of macrophages expressing metalloproteinases with few smooth muscle cells (SMC)--a characteristic of vulnerable plaque. The animal model presented in this study can elucidate at least part of the mechanism of plaque vulnerability and could be used to test treatment modalities to test plaque stability.

Dose volume histogram assessment of late stent malapposition after intravascular brachytherapy.

PURPOSE: Positive remodeling and decreased neointima proliferation are among the causes for Late Stent Malapposition (LSM). It was our interest to investigate a possible relationship between dose and incidence of LSM. METHODS: Index and follow up IVUS examinations of 238 patients (152 treated with Intravascular Brachytherapy (IVBT), 86 control) enrolled in IVBT trials were reviewed to identify patients with LSM. 7.2% of patients treated with IVBT and 2.3% of patients in the control group were found to have LSM on their 6-month follow-up IVUS. Using the index IVUS study. Dose Volume Histograms (DVH) were constructed for a segment of the adventitia comprising an arc deep to the area where LSM is present at follow up. For control, two areas: an arc deep to complete apposition (Control 1) and a segment within the stent but 5 mm apart from the LSM (Control 2). Volumes were defined by IVUS images that were 1 mm apart and the media-adventitial contour was taken to be 0.5 mm thick from the border. RESULTS: DVH of 90% and 50% adventitial volume of LSM area received a significantly (p < .05) higher dose compared to both controls. Calculated are 12 LSM sites in 9 patients and 9 control sites. At all 12 sites Mean Cross Sectional Area of External Elastic Membrane (EEM CSA) was significantly larger in the LSM group at follow up compared to index (p-.001). CONCLUSIONS: DVH analysis showed a positive correlation between radiation dose to the adventitia and incidence of LSM. The myofibroblasts in the adventitia are known to be the target for irradiation. Proliferation of myofibroblasts leads to neointima formation. LSM may be due to the higher dosages delivered to 50% and 90% of the adventitia volume (LSM area) which may have led to profound neointima suppression. In turn the neointima could not compensate positive remodeling reflected by an increase in EEM CSA.

Safety and efficacy of manual stepping and overlapping of beta-emitter for diffuse in-stent restenosis lesions.

BACKGROUND: The effects of overlapping beta-emitter sources on the treatment of in-stent restenosis (ISR) lesions as a result of manual stepping are unknown. METHODS AND RESULTS: In the BETA WRIST (Beta Washington Radiation for In-stent Restenosis Trial), 17 out of the 50 patients who received radiation treatment had diffuse ISR in native coronaries that required manual stepping of the beta-emitter (90Y) source in order to cover the lesion and the edges. Fourteen of those patients received radiation with an overlap of up to 3 mm in the middle of the stented segment. The prescribed dose was 20.6 Gy to a distance of 1.0 mm from the surface of the inflated balloon, and the calculated dose to the vessel wall at the overlapped area did not exceed 75 Gy. There was no difference in late total occlusion (7.1% vs. 9.0%, P=NS) and target lesion revascularization (28.5% vs. 27.2%, P=NS) between patients with stepping and those without stepping. At 6 months, there was no evidence of perforation or aneurysm at the overlapped segments. Quantitative coronary angiographic (QCA) analysis revealed significantly reduced late loss in the overlapped segment compared to the adjacent segment (P=.04). Serial (postradiation vs. follow-up) IVUS measurement showed larger mean lumen cross-sectional area (CSA) (P=.0035) and smaller mean intimal hyperplasia (IH) CSA (P=.0010) in the overlapped segment compared to the adjacent segment. CONCLUSION: Manual stepping of beta-emitter source with a short overlapped segment is safe for diffuse ISR. Further increase in lumen dimension and reduction in IH formation are observed at the overlapped segment.