Serial Intravascular Ultrasound Assessment of the Efficacy of Intracoronary γ-Radiation Therapy for Preventing Recurrence in Very Long, Diffuse, In-Stent Restenosis Lesions
Background— The efficacy of coronary γ-irradiation in preventing recurrent in-stent restenosis (ISR) is well established. However, brachytherapy may be less effective in very long, diffuse ISR lesions.
Methods and Results— We used serial intravascular ultrasound (IVUS) to study patients with long, diffuse ISR lesions (length, 36 to 80 mm) who were enrolled in (1) Long WRIST (Washington Radiation In-Stent Restenosis Trial), a double-blind, placebo-controlled trial of intracoronary γ-irradiation (15 Gy at 2 mm from the source) and (2) high-dose (HD) Long WRIST, a registry that used a dose prescription of 18 Gy at 2 mm from the source. IVUS was performed using automated pullback (0.5 mm/s). Stent, lumen, and intimal hyperplasia were measured at 2-mm intervals. Complete postintervention and follow-up IVUS imaging was available in 30 irradiated and 34 placebo patients from Long WRIST and in 25 patients from HD Long WRIST. Stent length was longer in HD Long WRIST than in placebo or treated patients in Long WRIST (P=0.0064 and P=0.0125, respectively). Otherwise, baseline measurements were similar. At follow-up, the minimum lumen area was largest in the HD Long WRIST patients (4.0±1.4 mm2); areas were 2.9±1.0 mm2 in irradiated patients in Long WRIST and 1.9±1.1 mm2 in placebo patients in Long WRIST (P<0.005 for all comparisons).
Conclusions— Serial IVUS analysis shows that γ-irradiation reduces recurrent in-stent neointimal hyperplasia in long, diffuse ISR lesions; however, it is even more effective when given at a higher dose.
Received April 18, 2001; revision received June 21, 2001; accepted June 22, 2001.
Diffuse in-stent restenosis (ISR) is associated with higher recurrence rates, and treatment continues to be unsatisfactory.1–5 Although intracoronary radiation therapy is effective in preventing recurrence in both focal and diffuse ISR, the results of this therapy in diffuse lesions have been less impressive.6,7 The present study used serial (postirradiation and follow-up) intravascular ultrasound (IVUS) imaging to assess the efficacy of intracoronary γ-radiation (192Ir) in preventing recurrence after treatment for diffuse ISR.
The patients were enrolled in 2 studies of brachytherapy for diffuse ISR (length of lesions, 36 to 80 mm). These trials were (1) Long WRIST (Washington Radiation In-Stent Restenosis Trial), a double-blind, placebo-controlled trial of intracoronary γ-irradiation (15 Gy at 2 mm from the source; it included 60 irradiated and 61 placebo patients) and (2) high-dose (HD) Long WRIST, a registry that used a dose prescription of 18 Gy at 2 mm from the source (120 patients).
Primary interventional techniques, which included rotational atherectomy (SCIMED/Boston Scientific Corporation), excimer laser coronary angioplasty (Spectranetics), additional stent implantation, balloon angioplasty, or a combination of the above, were first performed at the discretion of the operator. After primary treatment, a 5-French, closed-end, noncentering catheter was used to deliver the 192Ir at the prescribed doses in both trials. Seed trains were 14 to 23 in number and covered a length of 55 to 91 mm. The dwell time averaged 20.0±3.3 minutes for Long WRIST and 25.6±3.8 minutes for HD Long WRIST (P=0.0001).
IVUS Imaging and Analysis
IVUS imaging was performed after the administration of 200 μg of intracoronary nitroglycerine using a single element (30 or 40 MHz), mechanically rotating transducer (SCIMED/Boston Scientific Corporation) and automated pullback (0.5 mm/s). Stent, lumen, and intimal hyperplasia (IH; stent minus lumen) and cross-sectional areas (CSA) were measured using computerized planimetry (Tape Measure, Indec Systems) according to standard protocols. Measurements were made every 2 mm of the stented length. Stent, lumen, and IH volumes were calculated using Simpson’s rule and normalized for stent length. These methods have been used extensively to analyze ISR, including the results of brachytherapy treatment.6–11 Complete postintervention and follow-up IVUS imaging was available in 30 irradiated and 34 placebo patients with from Long WRIST and in 25 patients from HD Long WRIST.
Statistical analysis was performed using Statview 4.5 (SAS Institute). Categorical variables are presented as frequencies, with comparison using χ2 statistics. Continuous variables are presented as mean±1SD and are compared using factorial ANOVA with post-hoc analysis using the Bonferroni correction for multiple comparisons, in which P<0.0125 is required for significance.
Patient, lesion, and procedural data were similar in all 3 groups (Table 1), with the following exceptions. There were more lesions in the left anterior descending artery in HD Long WRIST patients (P<0.0001). Excimer laser angioplasty was used more often and rotational atherectomy less often in HD Long WRIST patients (P<0.0001).
Mean Planar IVUS Measurements
Stent length was longer in HD Long WRIST than in placebo or treated patients in Long WRIST (P=0.0064 an P=0.0125, respectively). For this reason, volumes were normalized for stent length, and mean planar results are reported in Table 2.
Baseline measurements were similar in all 3 groups. At follow-up, mean lumen CSA was smaller in placebo than in Long WRIST or HD Long WRIST lesions (P=0.0019 and P<0.0001, respectively). Similarly, mean IH CSA was greater in placebo than in Long WRIST or HD Long WRIST patients (P=0.0011 and P=0.0003, respectively).
Minimum Lumen and Maximum IH Measurements
Baseline minimum lumen CSA was similar in all 3 groups. However, the follow-up minimum lumen CSA was smaller in placebo patients than in Long WRIST or HD Long WRIST patients (P=0.002 and P<0.0001, respectively), and the follow-up minimum lumen CSA was significantly smaller in Long WRIST compared with HD Long WRIST patients (P=0.0004).
Serial IVUS imaging in the Scripps Coronary Radiation to Inhibit Proliferation Post Stenting (SCRIPPS),6 WRIST,7 and Gamma-18 trials have documented the effectiveness of radiation in preventing IH reaccumulation in ISR. However, because of protocol limitations, ISR length (by IVUS) was only 22±8 mm in SCRIPPS, 27±11 mm in WRIST, and 32±13 mm in Gamma-1. The current study extends these previous observations to longer lesions in native coronary arteries. However, the current study also suggests that increasing the dose prescription can improve the efficacy of brachytherapy in this problematic lesion subset.
ISR presents in various angiographic patterns. Mehran et al4 classified ISR into focal (<10 mm in length), diffuse intra-stent (>10 mm confined to the stented segment), proliferative (>10 mm in length extending into contiguous reference segments), and total occlusions. Clinical recurrence increased from 19% to 35% to 50% to 83% according to this classification. These findings were confirmed in a report by Bossi et al.12 The factors responsible for diffuse ISR and its high recurrence rate are not known. However, some studies have suggested that smaller stent size and genetic factors may be responsible for this phenomenon.9,10,13 Smaller arteries with smaller stent sizes would have less tolerance for neointimal hyperplasia reaccumulation.
Efficacy of Brachytherapy in Diffuse ISR
Similarly, the reasons for the reduced efficacy of brachytherapy in diffuse ISR are not well understood. One possibility is that longer lesions have more aggressive neointimal proliferation. However, a subset analysis from SCRIPPS indicated that brachytherapy is more efficacious in diabetics,14 and diabetics are known to have more aggressive ISR and more in-stent IH than nondiabetics.15
A previous report from our laboratory offered an alternative explanation.9 Longer ISR lesions were associated with longer maximum source-to-target distances. Because source-to-target distances determine the dose delivered to the adventitia, focal areas within longer ISR lesions seemed to receive a lower dose. This resulted in more IH and a smaller follow-up minimum lumen CSA in the longer lesions. These findings support the importance of careful dosimetry, particularly in very long, diffuse ISR lesions. To be effective, a minimum dose must be delivered to the adventitia.16 The current serial IVUS analysis showed that the higher prescribed dose proved more effective, as reflected by a smaller increase in maximum IH CSA and a larger follow-up minimum lumen CSA; this occurred despite longer ISR lengths in the HD group. Centering the source within the lumen might also improve the dose delivered to the adventitia.9
Follow-up was limited to 6 months. The current findings only apply to γ-irradiation in the doses described, and the actual dose delivered to the adventitia was not calculated. Because of the lengths of the lesions, imaging of adjacent reference segments could not be performed routinely; therefore, edge effects could not be analyzed. Not all patients had serial IVUS imaging; in particular, 7 irradiated and 5 placebo patients in Long WRIST (10% of the total cohort) and 8 patients in HD Long WRIST (7% of the total cohort) had total occlusions at follow-up. Different interventional devices were used in each of the 3 groups.
Although patients in Long WRIST were randomized to placebo versus irradiation, HD Long WRIST was a registry. However, HD Long WRIST patients were similar to those in the other 2 groups.
Serial IVUS analysis showed that γ-irradiation reduces recurrent in-stent neointimal hyperplasia, even in long, diffuse ISR lesions. However, it is even more effective when given at a higher dose.
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Kornowski R, Mintz GS, Kent KM, et al. Increased restenosis in diabetes mellitus after coronary interventions is due to exaggerated intimal hyperplasia: a serial intravascular ultrasound study. Circulation. 1997; 95: 1366–1369.
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