Poor Outcome in Patients Treated with Brachytherapy for Diffuse In-Stent Restenosis. The Role of Additional Stenting Despite Pro

The recurrence of coronary in-stent restenosis has been significantly reduced by brachytherapy.^1–3 Patients treated with brachytherapy are characterized by poor outcomes in concomitant stent deployment, mainly because of late vessel thrombosis.^1,2,4 In the treatment of in-stent restenosis, additional stents may be required for either suboptimal results or residual flow-limiting dissections.^5,6 The risk of late vessel thrombosis has been overcome by prolongation of double antiplatelet therapy,⁷ however specific studies focusing on the influence of additional stenting on the recurrence of restenosis are lacking. The aim of our study was to evaluate the outcomes of patients with in-stent restenosis treated with brachytherapy and additional stenting, followed by prolonged antiplatelet therapy. Methods We analyzed 77 patients consecutively treated with beta radiation for in-stent restenosis at our institute. All of the lesions were in native coronary arteries. Based on the need to deploy additional stents during the index procedure, we identified 2 groups. Group 1 (G1) consisted of 62 patients (73 lesions) treated without additional stents, and Group 2 (G2) consisted of 15 patients (16 lesions) with one or more newly implanted stents. Percutaneous coronary intervention (PCI) was performed according to standard clinical practice. Additional stents were inserted for suboptimal angiographic results or flow-limiting dissections at the operator’s discretion. A bolus of 100 U/Kg of heparin was given in order to maintain ACT > 250 seconds. Before radiation, an adjunctive bolus of 40 U/Kg heparin was given to maintain an ACT > 300 seconds. Aspirin (100 mg) and ticlopidine (250 mg orally, twice daily) or clopidogrel (300 mg orally, loading dose of 75 mg orally, once daily) were started at least 48 hours before the procedure and continued for at least 12 months. All lesions were analyzed by quantitative coronary angiography (QCA) after intracoronary nitroglycerin administration. The analysis was carried out before and after the procedure and at follow-up. Written informed consent was obtained from all patients, with a radiation oncologist and medical physicist supervising all procedures. Clinical and angiographic follow-up was planned after 6 months, and further clinical follow-up at 12 months. Angiographic binary restenosis was defined as > 50% diameter stenosis at any site in the irradiated segment. Myocardial infarction (MI) was defined as a three-fold increase in levels of creatine kinase-MB isoform. The radiation delivery system (Beta-Cath™ System, Novoste, Norcross, Georgia) has been previously described.5 A pure beta emitter (90Sr/90Y) sealed in a “train” of miniature cylindrical sources was hydraulically delivered within a noncentered catheter at the site of coronary intervention. The prescribed dose to a distance of 2 mm from the centerline of the axis of the train source was 18.4 Gy in vessels with a diameter 4.0 mm. The full prescribed dose (the 90% isodose line) covered the 45 mm central part of the train of the 60 mm long source and the central 25 mm of the 40 mm long source. In order to properly irradiate segments longer than the central part of the source, a sequential manual pullback of the catheter was performed.8 Markers on the catheter and at the edges of the source enabled correct identification of the irradiated segment. Cineangiograms with a deflated balloon at the site of each inflation were obtained to define the injured segment. Irradiation encompassed the injured segment and at least 7 mm beyond the injured segment at each edge. An injured segment not receiving the full prescribed dose was defined as “geographic miss”. Statistical analysis. Data are shown as mean ± SD and/or as frequencies. Continuous variables were compared using the paired or unpaired Student’s t-test, while categorical variables were done using the c2 test and the Fisher’s exact test. P-values p Baseline results. The two groups were well matched for age, gender, risk factors, clinical history and extension of the disease. There were no significant differences in angiographic characteristics, number of recurrence and pattern of restenosis. Main clinical and angiographic characteristics of the two groups are summarized in Tables 1 and 2. In Group 1, 45 lesions were treated with balloon angioplasty, 24 with a cutting balloon and 4 with rotational atherectomy. Eleven patients received treatment in 2 vessels. In Group 2, all patients received 1 or more additional stents (16 lesions with 22 stents, or 1.46 stents/lesion). Therefore, the need for additional stenting accounted for 17.9% of the overall population. Before stenting, 11 lesions were treated with balloon angioplasty, and 5 with a cutting balloon. One patient received treatment in 2 vessels. Additional stents were implanted for a suboptimal angiographic result in 2 cases, and for dissection in 16 cases. One stent was deployed within the old stent (“stent-in-stent”), whereas the others were implanted in irradiated, nonstented portions of the vessel. Only 5 stents were deployed after brachytherapy. Among these, 3 were implanted because of threatened vessel closure after a dissection that was already present before catheter insertion and 2 for catheter-related dissection. Postprocedural minimal luminal diameter (MLD) was 2.32 ± 0.7 mm with a residual diameter stenosis (DS) of 14 ± 10 % in G1 and 2.67 ± 0 .7 mm with a DS 6 ± 5% in G2 (p = ns). The mean dwell time of irradiation was 201 ± 60 seconds, and 213 ± 70 seconds in G1 and G2, respectively (p = ns).Pullback was performed in 14 lesions (19.2%) in G1, and in 8 lesions in G2 (50%) (p p = ns versus G1): 5 at the proximal, 1 at the distal and 2 at both proximal and distal edges. Follow-up. Six- and 12-month clinical follow-up was achieved in 100% of cases in both groups. At 6 months, 30 patients (48.3%) in G1 and 7 patients (46.6%; p = ns versus G1) in G2 were still experiencing angina. MI occurred in 2 patients (3.2%) in G1, and in 1 patient (6.6%; p = ns versus G1) in G2. No further adverse events were observed at 12 months. Prolonged antiplatelet therapy was well tolerated in all patients. Only 1 patient in G2 discontinued therapy due to gastric bleeding and experienced a subsequent Q-wave MI. Angiographic follow-up was obtained in 98% of patients after 7.8 ± 1.9 months in G1, and in 100% of patients after 7.2 ± 2.7 months in G2 (p = ns). Mean minimal lumen diameter (MLD) was 1.81 ± 0.99 mm in G1 and 1.25 ± 1.0 mm in G2 (p p = 0.02) (Figure 1). The 2 groups did not differ for the occurrence of late total occlusion (8 in G1, and 2 in G2). The site of restenosis was in the old stent in 7 (9.6%) lesions in G1, and 1 (6.2%) lesion in G2 (p = ns), at the proximal edge in 9 (12.3%) lesions in G1, in 2 (12.5%) lesions in G2 (p = ns), and at the distal edge in 7 (9.6%) lesions in G1 and in 1 (6.2%) lesion in G2 (p = ns). The higher recurrence rate observed in G2 was due to the restenosis detected in the additional stent (6/16; 37.5%; p = 0.02 versus each other site of restenosis in both G1 and G2) (Figure 2). Restenosis recurred in 4 of 11 lesions treated with additional stents before radiation delivery, and in 2 of 5 receiving stents after radiation delivery. In G1, restenosis developed in 7 (30.4%) segments in which geographic miss had also occurred. No geographic miss was evident in the other 16 restenotic lesions. In G2, restenosis was observed in 3 (30%) segments with a geographic miss (p = ns versus G1), and an additional stent had been implanted in only 1 of them. In the other 7 restenotic segments, geographic miss did not occur. In order to further support our observation, we performed a univariate analysis on the overall population to evaluate independent negative prognostic factors for restenosis. We included in the analysis the primary coronary risk factors (hypertension, diabetes, smoke habit, hyperlipidemia), the number of diseased vessels, the main angiographic characteristics (lesion length, reference vessel diameter, preprocedural and postprocedural MLD), the need for catheter pullback, geographic miss and additional stents. Significant univariate predictors of restenosis (that is diabetes, the number of diseased vessels, lesion length, preprocedural MLD, geographic miss and additional stenting) were entered in a multivariate analysis. The use of additional stents was found to be the only significant independent negative prognostic factor for the recurrence of restenosis. Discussion This study shows how additional stenting still remains a negative prognostic factor when associated with brachytherapy, also when it is followed by proper prolonged combined antiplatelet therapy. Previous studies analyzing the impact of additional stenting on brachytherapy mainly highlighted the danger of late vessel thrombosis. These concerns in the treatment of de novo lesions (whereby rates of stent deployment are high) led to a restricted clinical use of brachytherapy only for the treatment of in-stent restenosis^9–10 where the need of additional stenting not as great. However, other potential negative effects of additional stenting and brachytherapy are less studied and may have been underestimated in most reports focusing on the risk of late vessel thombosis. In the early studies of brachytherapy, the worst outcomes observed when additional stents were deployed were related to different mechanisms: 1) late in-stent thrombosis. This has been explained by both late malapposition and a delay in endothelialization of the struts of stent;^6,11 2) attenuation of radiation by the struts of the stent¹² that would lead to an inadequate dose absorbtion of radiation by the adventitia, considered the target for successful brachytherapy;¹³ 3) geographic miss: the presence of an injured segment not fully irradiated. All the injured segments should be homogeneously covered by full doses of radiation in order to freeze the proliferative stimulus, especially because there is evidence to suggest that low doses of radiation may promote, rather than inhibit, cell proliferation.^5,8,14 In addition, poor outcomes have been observed when a stent was deployed within an incompletely irradiated segment.⁹ In our population, we failed to find specific relationships among each of these mechanisms and the recurrence of restenosis in the group receiving additional stents. First, we did not observe a high prevalence of late vessel occlusion in either group. This result further highlights the benefit of prolonging double antiplatelet therapy after vessel irradiation.⁷ Second, even though the limited number of observations do not allow one to draw any definitive conclusion, it appears that attenuation by the struts cannot be considered as a significant contributor to brachytherapy failure. When a stent was deployed before brachytherapy, attenuation by the struts that may influence adventitial irradiation should contribute to recurrent restenosis in both the new and the old stents. However, significant hyperplasia developed predominantly in the new stent. Paradoxically, in a few cases of deployment of a new stent after radiation, when dose attenuation could not have occurred, we actually observed low rates of restenosis. Third, there were no differences in the occurrence of geographic miss between the two groups. In order to avoid the fall-off of radiation detectable at the edges of the source, we kept a distance of at least 7 mm beyond the injured segment by each side, as recommended by all radiation protocols. We deployed additional stents within the segment covered by the edges of the source, obtaining full irradiation of the stented segments. It has been observed that after stenting, the extension of reactive modification seems to involve a very long segment of the vessel, encompassing up to 10 mm beyond each stent edge.¹⁵ Furthermore, even though newer stents with thinner struts, biocompatible materials and different geometries have been developed, a chronic inflammatory response can be detected for months in the area of contact between the vessel wall and the struts of the stent.^16–17 There is a tendency towards negative vessel remodeling, mostly beyond the edge of the implanted stent.¹⁵ Therefore, the conventional 7 mm beyond each edge might not be enough to irradiate properly all of the vessel portion truly involved in the healing process after stent deployment. In a recent experiment in animals, it has been observed how additional stenting limits the efficacy of brachytherapy because of negative remodeling at the site of irradiation at the edge of the source, and how this effect could be minimized by extending the radiation margins from 10–14.5 mm beyond the edges.18 An in vivo comparison between the conventional radiation protocol and a procedure with more extensive irradiation would be necessary to test this hypothesis and to evaluate its real clinical benefit. However, more extensive coronary irradiation, as described in the animal model, have not been adequately tested in patients and raise concerns regarding long-term side effects. Limited data from the WRIST trial on irradiation of large non-injured/non-stented segments, however, seem to be favorable.¹⁹ The overall restenosis rates observed in our population (37%) are high in comparison to those observed in larger studies with brachytherapy. Binary restenosis rates ranged from 22% in the WRIST2 and in the PREVENT20 studies, up to 32.4% in the INHIBIT study,¹ and 34.1% in the Beta WRIST study.³ These studies employed different radiation sources and protocols. In our population, we used beta radiation with a delivery protocol similar to that used in the START trial,²¹ where additional stenting in 19.8% of cases (similarly to our population) was associated with a restenosis rate of 28.8%. The differences in restenosis rates might be explained by the characteristics of the lesions which were longer, with smaller MLDs, and more likely at the second and third recurrence in our population. In fact, unfavorable characteristics of the treated lesions may influence results of brachytherapy as observed in the LONG WRIST study, which reported restenosis rates of 45%.²² Our study suggests that association with brachytherapy should be discouraged when planning treatment of lesions that may require additional stenting, The TROPICAL trial involving rapamycin-eluting stents for in-stent restenosis, reported a recurrence rate of only 9.7% at 9 months.²³ Favorable results have also been observed with paclitaxel-eluting stents.²⁴ Although direct, randomized comparisons with brachytherapy have not been carried out, the use of drug-eluting stents is most promising in this difficult subset of patients. Study limitations. The main limitation of our study is the small sample size, in particular, the small number of patients receiving additional stents. After the results of the first reports on brachytherapy in which provisional stenting was required in up to 60% of cases,^2,3,16,20 it was explicitly advised to avoid additional stenting during brachytherapy procedures. In our population, we restricted stenting to bail-out conditions, obtaining a very narrow number of patients to be considered for the analysis. Although statistical considerations are strongly limited by the magnitude of the observations, our data strengthen a well-known concept (the negative prognostic impact of additional stenting with brachytherapy), while showing evidence of a different mechanism for failure. Longer follow-up periods will be necessary to further support our results. In fact, there is evidence to suggest a decreased effectiveness of brachytherapy on restenosis rates over time.^25,26 Conclusion In conclusion, our data suggest that the association of brachytherapy and new stent implantation in patients with in-stent restenosis may be limited by high rates of recurrence of hyperplasia within a newly implanted stent. Additional stenting may adversely affect the outcome of brachytherapy beyond the heightened risk of late vessel thrombosis.

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