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Original Contribution
Adjunctive Therapy: Angiographic and Intravascular Ultrasound Findings of the Late Catch-Up Phenomenon after Intracoronary Beta-
September 2005
Feasibility and short- and mid-term safety of catheter-based intravascular brachytherapy (IVBT) has been demonstrated in several clinical trials.1–4 Moreover, randomized studies using IVBT (beta or gamma) have reported a significant reduction of restenosis, as well as intrastent neointimal proliferation in patients with in-stent restenosis (ISR) lesions.5–7 Although the overall clinical benefit of IVBT has been sustained in long-term follow-up, it is important to note that there are few data regarding significant angiographic and intravascular ultrasonic in-stent lumen deterioration beyond the habitual 6-month analysis after the index radiation procedure, or so-called “late catch-up process” in the treatment of ISR. The aim of the present study is to compare the angiographic and intravascular ultrasound (IVUS) outcomes of patients with ISR treated with balloon angioplasty followed by IVBT at 6 and 12 months.
Methods
Between August 2001 and February 2002, a total of 25 consecutive patients with native vessel stent restenosis were scheduled to undergo balloon angioplasty followed by catheter-based intracoronary beta-radiation using the Beta-Cath System™ (Novoste Corporation, Norcross, Georgia) with 90 Sr/90 gamma source. All of them had completed angiographic and IVUS assessment at 6- and 12-month follow-up.
Patients were included in this study if they had a single in-stent restenotic lesion up to 24 mm in length and followed with successful conventional angioplasty. Impaired left ventricular function (Procedure and radiation system. In-stent restenosis lesions treated with IVBT were initially dilated by conventional balloon angioplasty followed by placement of a 5 French closed-end noncentering catheter to deliver the active source. The prescribed doses at 2 mm from the source axis were 18.4 Gy for vessels 2.75–3.35 mm, and 23 Gy for vessels > 3.36 mm. The source train of the Beta-Cath system consisted of a series of 16 independent cylindrical seeds that contained pure beta-emitting 90 Sr/90 g, bordered by 2 gold markers (40 mm in length). The length of the full irradiated segment (100% isodose) was 35 mm.8 A detailed description of the intracoronary radiation procedure has been reported.8
Pre-interventional medication included nonenteric aspirin (325 mg) and intravenous heparin (10,000 to 15,000 IU) in order to keep the activated clotting time to > 300 seconds during the procedure. Postinterventional medication consisted of long-term aspirin and antiplatelet therapy (clopidogrel 75 mg daily after a loading dose of 300 mg on the day of the procedure) for 6 months.
Quantitative measurements. Quantitative coronary angiography (QCA) and IVUS imaging were performed before, immediately after the procedure, and at 6 and 12 months. All data were analyzed at the Institute Dante Pazzanese core lab (São Paulo, Brazil). As described previously, 2 coronary segments were analyzed using QCA: 1) in-stent segment, and 2) in-lesion segment.9 In-stent segment was defined as the entire restenotic bare metal stent length. The in-lesion segment was defined as in-stent plus 5 mm long proximal and distal reference segments, or to the nearest side branch if the side branch was 10–13
As mentioned above, only 35 mm of the source length irradiates 100% isodose. Thus, any edge-stent segment traumatized by balloon inflation outside these source boundaries is considered geographical miss.4 To identify those areas with geographical miss, the following steps were followed: during the procedure, all balloon inflations were filmed in the same projection, as was the radiation source position. This approach allowed for the correct matching of the cine films in the off-line analysis. By using the QCA-CMS‚ version 5.1 (MEDIS, Medical Imaging Sistems Inc., AJ Leiden, The Netherlands), either of the cine loops showing balloon inflation and the radiation delivery catheter place (equidistant from the center of in-stent injured segment, with a margin of at least 7 mm proximally and distally) may be displayed simultaneously on the screen. By selecting those frames in the same part of the cardiac cycle, we were able to define whether the radiation power source length (35 mm) completely covered the injured segment.
Statistical analysis. All statistical analysis was performed with commercially available software (SPSS 9.0, SPSS Inc. Chicago, Illinois). Continuous variables are expressed as mean ± standard deviation. Comparisons between postintervention, 6-month and 12-month measurements were performed with a paired two-tailed Student’s t-test. Categorical data are presented as frequencies and compared using chi-square statistics. A p-value Results
The clinical characteristics of the 25 patients studied are shown in Table 1. Eight (32%) patients were diabetics, and 9 patients presented with unstable angina. The mean time of development ISR was 7 ± 2 months post bare metal stent implantation. Adjunctive pharmacotherapy pre-procedure, at 6 and 12-month follow-up, are summarized in Table 2. Lesion and procedural characteristics are described in Table 3. The average length of restenotic segment and stent segment was 18.7 ± 4.2 mm and 21.3 ± 3.3 mm, respectively. Two (8%) patients had total occlusion lesions, and 72% (18/25) showed a diffuse-proliferative pattern according to the previously reported classification.14 Complete intracoronary irradiation was feasible (> 90% prescribed dose) in all patients, resulting in a success rate of 100%. The mean prescribed dose was 20.7 ± 2.3 Gy, with a dwell time of 3.8 ± 2.1 minutes. Complete coverage with a safety margin of at least 7 mm proximal and distal to the injured segment was able to be achieved in 23/25 lesions, resulting in 2 cases of geographical miss.
Angiographic analysis. The in-stent and in-lesion MLD increased significantly after intervention (both = p IVUS in-stent volumetric analysis. As a result of the primary treatment modality (balloon dilatation), the percent IH volume obstruction was approximately 27% immediately after the procedure (Table 5). At 6-month follow-up, a slight recurrent IH volume was found (increase in IH volume of 6.8 ± 13.3 mm3; p = 0.2), associated with a nonsignificant in-stent lumen volume reduction (from 114.6 ± 30.3 to 108.4 ± 28.7 mm3; p = 0.2). Moreover, an increase of percent IH volume obstruction was observed at 6 months, without reaching statistical significance (D % IH volume obstruction = +4.7 ± 7.5%; p = 0.1). At 12-month follow-up, significant IH growth was observed (+11.2 ± 0.48 mm3; p = 0.03), resulting in a considerable in-stent lumen volume loss (D in-stent lumen volume = -10.8 ± 15.8 mm3; p = 0.04) (Table 5). Furthermore, the change in IH volume beyond 6 months was significantly higher (+17.8 ± 37.6 mm3; p = 0.0001), which correlated with a significant increase in percent IH volume obstruction (Table 5). There were no cases of late incomplete stent apposition or aneurysm formation.
IVUS volumetric analysis at the stent borders. At 6-months, IVUS edge analysis revealed that the lumen volumes at the proximal and distal edges decreased significantly (8.1 ± 2.5 to 5.2 ± 1.8 mm2, and 6.5 ± 1.7 to 4.4 ± 1.9 mm2, respectively; all p = 0.001), while no further reduction was observed at 12 months (Figure 2). This was consisted with the early angiographic edge recurrence. There was a strong linear relationship between the changes in lumen versus P&M volumes at the proximal edge (r = 0.67; p = 0.001), but not at the distal edge (r = -0.18; p = 0.34). Conversely, there was a significant linear relationship between the changes in lumen versus external elastic membrane volumes at the distal edge (r = 0.45; p = 0.02), but not at the proximal edge (r = -0.16; p = 0.4).
Discussion
In the current study, the use of intracoronary brachytherapy with beta-radiation for the treatment of ISR lesions suggests that it is associated with a significant in-stent lumen loss primarily due to neointimal tissue proliferation beyond 6 months of angiographic and volumetric IVUS follow-up assessments (Figure 3).
Angiographic and IVUS follow-up studies15–17 in patients undergoing catheter-based radiation therapy have reported the development of edge effect lumen loss at the segments adjacent to the treated site. Although this phenomenon is not completely understood, it has been related to the combination of balloon-induced injury and low-dose radiation or so-called “geographical miss”,8,15 resulting in plaque growth and vessel negative remodeling. In an attempt to reduce the incidence of geographical miss, longer radiation sources (? 40 mm) are currently recommended. In the present study, despite observing low geographical miss rates (8%; 2/25 patients), edge effects were observed in 4 patients (16%), 2 of them without geographical miss. It is possible that exposure to low-dose radiation or so-called “dose fall-off”16 alone contributed to edge lumen deterioration.
Intravascular ultrasound analysis showed that the growth of intimal hyperplasia was mild at 6-month follow-up; a result similar to that was found in other beta-radiation IVBT studies.18,19 Furthermore, previous IVBT reports with radioactive stent or catheter-based gamma-radiation therapy6,20 have described effective suppression of in-stent neointimal growth at 6 months, but significant late catch-up beyond this period. This phenomenon was also observed in the current study, characterized by significant neointimal tissue growth inside the stent, translated as a delayed overall increase in the angiographic restenosis rate (from 16% at 6 months to 32% at 12 months). The clinical impact of this phenomenon does not affect the long-term efficacy and longevity of the intracoronary radiation therapy (only gamma-radiation reports) when compared with the conventional therapeutic approach.6,21
One of the processes that could explain the delayed in-stent lumen loss is an inadequate radiation therapeutic dose range.22 Compared with gamma-radiation, beta-radiation has a smaller depth of penetration, minimizing the exposure to radiation for patients and operators, and thus requiring less radioprotection. However, the rapid decrease in the dose of beta-radiation within 2–5 mm of depth is related to a less homogeneous release of the dose.8,22 In our series, the therapeutic dose range was higher (> 18 Gy), which is related to better clinical long-term outcomes when compared to patients treated with lower-dose ranges.23 In addition, the “shield effect” produced by the stent struts could be associated with an attenuation > 15% in the radiation dose.24 On the other hand, when comparing the results of IVUS analysis in two large studies, beta-radiation showed a similar efficacy to gamma-radiation in preventing reaccumulation of neointimal hyperplasia within the stented segment at short-term follow-up.24 Of note, 80% of our patients had a more aggressive pattern of ISR (diffuse-proliferative or total occlusion) at the index procedure. Whether these high-risk ISR patients might influence our late angiographic findings remains to be determined.
Finally, at the present, the application of IVBT has become more sophisticated. Consequently, the historical limitations and complications of this technology such as late thrombosis (controlled with prolonged antiplatelet therapy) and edge effect (controlled with long radiation margins) were mostly overcome by enhancements in technique and adjunctive therapy;25 nevertheless, delayed restenosis appears to be a more important and potentially clinically relevant limitation.
Limitations. The current study consisted of an initial series of consecutive patients with ISR treated at our facility, with a late angiographic and IVUS follow-up assessment limited to 12 months. In addition, the current analysis does not include the totality of the patients treated with IVBT, only those with complete (postintervention, 6- and 12-month follow-up) angiographic and IVUS assessments. Due to the relatively reduced number of patients assessed and to the design of the study (nonrandomized, without control group, only a beta-radiation source with a single source length, and with exclusion of more complex cases), the results reported here should not be extrapolated to all cases of ISR lesions.
Conclusion
This preliminary study suggests that intracoronary beta-radiation for the treatment of ISR was associated with significant luminal deterioration (late catch-up) within the stents between 6 and 12 months due an important late progression of in-stent intimal hyperplasia.
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