Effect of Intracoronary γ-Radiation Therapy on In-Stent Restenosis
An Intravascular Ultrasound Analysis from the Gamma-1 Study
Background—The aim of this study was to use serial volumetric intravascular ultrasound to evaluate the effect of γ-radiation on recurrent in-stent restenosis.
Methods and Results—After successful reintervention, patients were randomized to receive either 192Ir or placebo. Intravascular ultrasound studies with motorized pullback (0.5 mm/s) were performed immediately after irradiation and at 8-month follow-up in 70 patients. Paired volumetric analysis of the stented segment and of 5-mm proximal and distal reference segments was performed; this included measurements of the external elastic membrane, lumen, plaque and media (external elastic membrane minus lumen), stent, and intimal hyperplasia (stent minus lumen). Baseline proximal reference, stent, and distal reference measurements were similar in both groups. The changes in proximal and distal reference measurements of the external elastic membrane, plaque and media, and lumen areas were similar in both groups. However, the decrease in stented segment lumen volume was less in the 192Ir patients than the placebo patients (–25±34 mm3 versus –48±42 mm3; P=0.0225), and the increase in the volume of intimal hyperplasia in the stented segment was less in the 192Ir patients than in the placebo patients (28±37 mm3 versus 50±40 mm3; P=0.0352). When averaged over the length of the stented segment (32±13 mm versus 33±14 mm; P=0.9), the increase in mean area of intimal hyperplasia was 0.8±1.0 mm2 in the 192Ir group and 1.6±1.2 mm2 in the control group (P=0.0065). Late stent-vessel wall malapposition was noted in one placebo patient and no 192Ir patients.
Conclusions—γ-Radiation therapy can effectively prevent recurrent in-stent restenosis by inhibiting neointimal formation within the stent. At the stent edge, there were no significant differences between 192Ir and placebo patients.
In-stent restenosis (ISR) remains the major limitation of coronary stenting. The primary mechanism of ISR is neointimal hyperplasia.1 Despite aggressive interventional strategies to treat ISR, angiographic recurrence and late clinical outcomes have been disappointing.2 Recently, adjunct brachytherapy using 192Ir was shown to reduce recurrent ISR after primary catheter-based intervention.3 4 We report the results of the intravascular ultrasound (IVUS) substudy of Gamma-1, a multicenter, randomized, placebo control trial of γ-irradiation to reduce ISR.
After primary catheter-based intervention, 252 patients with ISR in a native coronary artery (angiographic reference, 2.75 to 4.00 mm) were randomized (double-blinded) to receive either 192Ir (Best Industries) or placebo. The following 4 of the 12 Gamma-1 sites were selected for the IVUS substudy: Washington Hospital Center, Scripps Clinic and Research Foundation, Cleveland Clinic Foundation, and Lennox Hill Hospital. These 4 centers enrolled 139 patients; paired (immediately after irradiation and at 8-month follow-up) IVUS images were available in 70 patients. No differences existed in baseline patient and lesion characteristics or primary treatment when comparing (1) patients in the IVUS substudy versus the total cohort and (2) treated versus untreated (placebo) patients in the IVUS substudy (including diabetes and frequency of diffuse or proliferative ISR5 ).
Sources were inserted into a noncentered, blind lumen catheter (Cordis). The ISR lesion was treated at the operator’s discretion using conventional techniques, which were typically balloon angioplasty, atheroblation (rotational atherectomy or excimer laser angioplasty), and/or additional stent implantation (>80% of the lesions in both groups were restented). Dosimetry was calculated as follows. A series of IVUS images after reintervention was analyzed. The distance from the center of the IVUS catheter to the external elastic membrane (EEM) was measured over the length of the stent, and maximum and minimum source-to-target distances were determined. The dwell time was calculated to deliver 800 cGy to the target farthest from the radiation source, provided no more than 3000 cGy was delivered to the target closest to the source. Source lengths included 6 seeds (23-mm ribbon) for lesions <15 mm, 10 seeds (39-mm ribbon) for lesions 15 to 30 mm, and 14 seeds (55-mm ribbon) for lesions 30 to 45 mm.
Paried IVUS Imaging and Analysis
IVUS imaging was performed after the administration of intracoronary nitroglycerine (150 to 200 μg) using a commercial scanner (SCIMED) consisting of a single-element, 30- or 40-MHz transducer mounted on the tip of a flexible shaft rotated at 1800 rpm within either a 3.2 or 2.6 F short monorail polyethylene imaging sheath. Motorized transducer pullback (0.5 mm/s) was performed to ensure a constant interval between slices, allowing accurate volumetric analysis. Ultrasound images were recorded on half-inch, high-resolution, s-VHS videotape for off-line analysis. According to validated and published protocols6 7 8 9 and using computerized planimetry (TapeMeasure, Indec Systems), the reference segment EEM, lumen, and plaque and media (P&M; EEM minus lumen) areas were measured every 1 mm over a 5-mm length adjacent to the stent edge. Stent, lumen, and intimal hyperplasia (IH; stent minus lumen) areas were measured every 1 mm within the stented segment. Mean reference and stent areas and stent volumes were calculated. Minimum lumen area (MLA) and maximum area stenosis (mean reference lumen minus MLA divided by mean reference lumen) were reported.
Continuous data are presented as mean±1SD. Statistical analysis was performed with Statview 4.5 (Abacus Concepts). Continuous variables were compared using paired or unpaired Student’s t tests or factorial ANOVA with post hoc comparisons using the Bonferroni correction.
The Figure⇓ shows the postintervention versus follow-up IVUS analysis of the proximal reference, stented, and distal vessel segments. Both 192Ir and placebo groups experienced a decrease in proximal and distal reference lumen areas that was more the result of a decrease in EEM area than an increase in P&M area. Changes in proximal reference measurements were similar to changes in distal reference measurements in both groups; however, all of the changes were small.
The Figure⇑ also shows that in both the 192Ir and placebo groups there was a decrease in lumen area within the stented segment that was almost entirely the result of an increase in IH area. In control patients, there was a larger decrease in stent lumen area compared with both proximal reference (P=0.0202) and distal reference (P=0.0115) vessel segments. Conversely, in 192Ir patients, the decrease in stent lumen area was similar to the decrease in proximal reference and distal reference lumen areas (P=0.9 for both comparisons).
The Table⇓ shows the IVUS analysis of the 192Ir versus the placebo group. Baseline proximal reference, stented segment, and distal reference measurements were similar in the 2 groups. The changes in proximal and distal reference segment EEM, P&M, and lumen areas were also similar. However, the decrease in stented segment lumen volume and the increase in stented segment IH volume was less in 192Ir patients compared with placebo patients. When averaged over the length of the stent, the increase in IH area was 0.8±1.0 mm2 in the 192Ir group and 1.6±1.2 mm2 in the control group (P=0.0065).
The Table⇑ also shows the IVUS MLA and area stenosis. Baseline measurements were similar between the 2 groups. The follow-up MLA was larger, the area stenosis was smaller, and the change in MLA was less in the 192Ir patients compared with placebo patients.
Late malapposition (not present postintervention) was noted in one placebo patient and no 192Ir patients.
The current study demonstrated a reduction in late lumen loss and neointimal hyperplasia in patients with ISR treated with γ-radiation. These data are consistent with the results of the Scripps Coronary Radiation to Inhibit Proliferation Post-Stenting (SCRIPPS) Trial.3 In the SCRIPPS trial, ΔIH volume measured 45.1 mm3 in control patients and 15.5 mm3 in 192Ir patients (P=0.01). When normalized for ISR length, ΔIH area in the 192Ir group in the SCRIPPS study measured 0.7 mm2 (identical to the current study) and 2.2 mm2 in controls (greater than in the current study). Nevertheless, there were several differences between the SCRIPPS trial and the current study. (1) SCRIPPS included vein graft lesions; the current study did not. (2) Mean lesion length was shorter in SCRIPPS. Lesion length is a predictor for recurrence after conventional therapies and brachytherapy. (3) Only 62% of the patients in SCRIPPS had ISR. Previous ISR is a risk factor for recurrence after conventional therapies.5 (4) A total of 27% of the 192Ir group and 41% of the control group in SCRIPPS were diabetic. Diabetes may be a risk factor for recurrence after conventional therapies.
The data in the current study are also consistent with the result of the Washington Radiation for In-Stent Restenosis Trial (WRIST). In WRIST, ΔIH volume measured 55.0 mm3 in control patients and 3.1 mm3 in treated patients (P<0.0001). There were also several differences between WRIST and the current study. (1) WRIST included vein graft lesions. (2) WRIST used a fixed dose prescription.4 (3) A total of 39% of the 192Ir group and 45% of the control group in SCRIPPS were diabetic.
The current study also indicated an absence of edge effect after γ-radiation. Changes in segments 5 mm proximal and distal to the stent were similar in the γ-radiation and control groups. Edge effects have been most noticeable with the 32P-emitting stent.10 11 IVUS studies of edge restenosis with the 32P-emitting stent have indicated that this is predominately the result of exaggerated neointimal hyperplasia.
IVUS End Points in Brachytherapy Studies
Most current brachytherapy studies include IVUS analysis or at least an IVUS substudy. In SCRIPPS, only 65% of the 55 patients had paired (postintervention and follow-up) IVUS; nevertheless, IVUS end points were markedly positive. Similarly, in Gamma-1, only 28% of the 252 patients had paired IVUS imaging; however, the IVUS end points were still positive. Because of the sensitivity of this modality, IVUS end points may require fewer patients to be enrolled; however, this may be offset by attrition from inadequate IVUS studies or lack of follow-up IVUS.
Serial (postintervention and follow-up) IVUS imaging was performed in only a subset of the 252 patients enrolled in the Gamma-1 trial. Total occlusions were typically not imaged at follow-up; these could represent exaggerated neointimal hyperplasia or late stent thrombosis. It has been suggested that IVUS can underestimate neointimal volume, especially in subtotal lesions.
γ-Radiation significantly reduces recurrent ISR by inhibiting neointimal tissue growth within the stent; it does not have a significant impact on the adjacent reference segments.
Supported by Cordis.
J. Giorgianni is an employee of Cordis. Dr Teirstein receives research funding from Cordis, Guidant, Boston Scientific, Novoste, and Isostent; he also serves as a consultant to Guidant and Cordis. He owns patents on radiation devices and may receive royalties on the sale of these devices. Dr Waksman is a consultant to Guidant, Nucletron, and Radiance; Dr Tripuraneni is a consultant to Best, Cordis, Novoste, Guidant, and Nucletron; and Dr Jani is a consultant to Cordis and Best.
- Received August 17, 2000.
- Revision received October 11, 2000.
- Accepted October 16, 2000.
- Copyright © 2000 by American Heart Association
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