Comparative Efficacy of γ-Irradiation for Treatment of In-Stent Restenosis in Saphenous Vein Graft Versus Native Coronary Artery In-Stent Restenosis
An Intravascular Ultrasound Study
Background— We used serial volumetric (post-irradiation and follow-up) intravascular ultrasound (IVUS) to compare the effectiveness of γ-irradiation (192Ir) in saphenous vein graft (SVG) versus native coronary artery in-stent restenosis (ISR).
Methods and Results— The study population consisted of 47 patients with native coronary artery ISR from WRIST (Washington Radiation for In-Stent Restenosis Trial) and 31 patients with SVG ISR (12 from the WRIST and 19 from SVGWRIST). After irradiation and at 6-month follow-up, stent, lumen, and intimal hyperplasia (IH, stent minus lumen) areas were measured every 1 mm. ISR length was similar in the 2 groups (29±12 versus 29±14 mm, P=0.9). Post-intervention measurements of stent (280±154 versus 324±270 mm3, P=0.4), lumen (184±91 versus 214±172 mm3, P=0.3), and IH (96±77 versus 109±119 mm3, P=0.5) volumes were similar in the 2 groups. The post-intervention minimum lumen cross sectional areas tended to be smaller in native artery ISR lesions (4.7±1.7 versus 5.4±1.6 mm2, P=0.11). During follow-up, there was a slight increase in IH volume (9±38 mm3) in native artery ISR lesions and a slight decrease in IH volume in SVG ISR lesions (−9±32 mm3, P=0.0463). There was also a slight decrease in minimum lumen area in the native artery ISR lesions versus a slight increase in minimum lumen area in the SVG ISR lesions (−0.8±1.7 versus 0.2±1.1, P=0.0087). As a result, the follow-up minimum lumen area in native artery lesions was smaller than in SVG ISR lesions (4.1±2.1 mm2 versus 5.6±2.2 mm2, P=0.0067).
Conclusion— γ-Irradiation with 192Ir brachytherapy appears to be as effective in SVGs as it is in native artery ISR lesions.
Received September 20, 2001; revision received October 26, 2001; accepted October 29, 2001.
Although stenting has reduced restenosis compared with conventional balloon angioplasty, in-stent restenosis (ISR) is still an important clinical issue.1–2 Recently, intracoronary brachytherapy has emerged as a promising alternative for preventing recurrent ISR.3–6 However, these studies primarily addressed native artery ISR, and no previous study has compared the efficacy of brachytherapy in saphenous vein graft (SVG) versus native coronary artery ISR.
The objective of this volumetric serial (post-irradiation and follow-up) intravascular ultrasound (IVUS) study was to compare the effectiveness of γ-irradiation (192Ir) in SVG versus coronary artery ISR. Patients were selected from the active arms of 2 randomized, placebo-control clinical trials: Washington Radiation In-Stent Restenosis Trial (WRIST, which included both native artery and SVG lesions) and Saphenous Vein Graft WRIST (SVG WRIST, which enrolled only patients with SVG ISR). The same dose prescription (15Gy at 2 mm from the source) was used in both trials.
The active (treated) arms of WRIST enrolled 50 native artery and 15 SVG ISR lesions; the active arm of SVGWRIST enrolled 60 patients. The current study population consisted of 47 patients with native coronary artery ISR from WRIST and 31 patients with SVG ISR (19 from the SVGWRIST and 12 from the WRIST). This includes all of the patients who had complete serial (post-irradiation and follow-up) IVUS imaging. All patients were treated with γ radiation (192Ir, 15 Gy at 2 mm from the source except for 3 SVG patients that received 15 Gy at 2.4 mm from the source).
The ISR lesions were initially treated with rotational atherectomy, excimer laser angioplasty, additional stent implantation, conventional balloon angioplasty, or a combination at the discretion of the primary operator. Afterward, a 5 F closed-end non-centering catheter was used to deliver the active source. Source length was selected according to ISR lesion length: 6 seeds (23-mm ribbon) were used 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. The dwell time was similar in both groups: 22.4±4.1 minutes for SVG ISR and 21.8±3.3 minutes for native artery ISR (P=0.5).
Angiographic analysis was performed using an automated edge detection algorithm (CMS-GFT, MEDIS) according to previously described methods.7 Reference diameters were selected from user-defined segments proximal and distal to the lesion. The minimum lumen diameter (MLD) and diameter stenosis (DS) were measured from the worst view. Lesion lengths were measured in the view with the least amount of foreshortening.
IVUS Imaging and Analysis
After administration of 200 μg of intracoronary (or intragraft) nitroglycerin, IVUS imaging was performed using a commercial scanner (SCIMED/Boston Scientific). This system used 30 or 40 MHz transducers mounted on the tip of a flexible shaft, rotated at 1800 rpm within a 3.2 or 2.6 F monorail sheath, and withdrawn mechanically at a pullback speed of 0.5 mm/sec. The IVUS images were recorded on s-VHS 0.5-inch tape for off-line analysis. IVUS imaging were performed immediately after irradiation and 6 months later. IVUS measurements were made every 1 mm of ISR length and included stent, lumen, and intimal hyperplasia (IH, stent minus lumen) cross sectional areas (CSA). Volumes were calculated using Simpson’s rule. The minimum lumen CSA was determined.
Statistical analysis was performed using Statview 4.5 (SAS Institute). Continuous variables are presented as mean±1 SD and compared using unpaired Student’s t test. Categorical variables are presented as frequencies and compared using chi-square statistics.
Baseline patient characteristics and the primary devices used to treat the ISR lesions prior to irradiation are shown in Table 1. The percentage of men was greater in the SVG ISR group. Recurrent ISR was more common in the SVG ISR group. SVG lesions were more frequently treated with excimer laser angioplasty whereas native arteries were more frequently treated with rotational atherectomy; however, additional stent use was similar in both groups.
Table 2 shows the quantitative angiographic results. Lesion lengths were similar. SVGs were larger; baseline MLDs were similar; and, therefore, the baseline DS was more severe in SVG ISR lesions. Final MLDs were larger in SVG lesions, but the final DS was similar in the 2 groups. There was a tendency for less late loss (0.07±0.62 mm versus 0.31±0.55 mm, P=0.13) and a larger follow-up DS in SVG lesions.
Post-Intervention IVUS Results
Table 3 shows the baseline (post-irradiation) IVUS measurements. ISR length was similar in the 2 groups. Post-intervention measurements of stent, lumen, and IH volumes were similar in the 2 groups. The post-intervention minimum lumen CSA tended to be smaller in native artery ISR lesions (P=0.11).
Follow-up IVUS Results
Table 3 shows both the follow-up and serial (post-irradiation versus follow-up) IVUS measurements. There was a slight increase in IH volume in native artery ISR lesions and a slight decrease in IH volume in SVG ISR lesions (P=0.0463). Half of each group had a decrease in IH volume at follow-up.
There was a slight decrease in minimum lumen area in the native artery ISR lesions versus a slight increase in minimum lumen area in the SVG ISR lesions (P=0.0087). As a result, the follow-up minimum lumen area in native artery lesions was significantly smaller than in SVG ISR lesions (4.1±2.1 mm2 versus 5.6±2.2 mm2, P=0.0067).
The current study indicates that, if anything, SVG ISR lesions are slightly more radiosensitive than native artery ISR lesions. On average, IVUS showed mild regression in IH volume and late lumen gain in SVG ISR lesions (versus a slight increase in IH volume and a slight decrease in lumen area in native artery ISR lesions). However, the volumetric IVUS changes from after irradiation to follow-up were minimal in both groups. The IVUS findings were substantiated by the angiographic results with a tendency toward less late loss and a larger follow-up diameter stenosis in SVG ISR lesions. Therefore, it appears that brachytherapy “freezes” the result after primary treatment of ISR—whether in native arteries or vein grafts.
Radiation is thought to inactivate cells that are going to proliferate, migrate, and synthesize matrix after the angioplasty.8–10 Animal studies have shown that the main source of the neointima is medial smooth muscle cells11–13; however, when the existing neointima caused by the first injury is injured again (the double-injury model), cell proliferation also occurs in the intima.14 Thus, in ISR lesions, the target layer may be both the intima and the media. In the present study, there were more previous episodes of ISR in the SVG lesion population.
Our study included only patients who had serial IVUS analysis and, therefore, does not include all patients enrolled in the WRIST studies. Follow-up was limited to 6 months. Only the stented segments were analyzed, not the edges. However, the IVUS analysis from γ-1 did not show an edge effect after γ irradiation of native artery ISR lesions.5 Although excimer laser angioplasty was used more frequently in SVG ISR lesions and rotational atherectomy was used more frequently in native artery ISR lesions, both devices achieve a similar result when used to treat diffuse ISR lesions.15
γ-Irradiation with 192Ir brachytherapy appears to be as efficacious in SVGs as it is in native artery ISR lesions.
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