Long-Term Outcome of Percutaneous Coronary Interventions Following Failed Beta-Brachytherapy

ABSTRACT: Background. Recurrent restenosis following vascular brachytherapy (VBT) has been reported in up to one-third of the patients enrolled in clinical trials. The long-term outcome of repeat percutaneous intervention (PCI) after failed beta-brachytherapy is currently unknown. Methods. We retrospectively analyzed 97 consecutive patients undergoing percutaneous coronary reintervention after failed beta-brachytherapy at our institution (80.8% of all brachytherapy failures). Long-term incidence of major adverse cardiac events (MACE; death, myocardial infarction, target lesion revascularization) was assessed. Results. The procedure was successful in 90 patients (92.8%). A new stent was implanted in 72% of the procedures (sirolimus-eluting stent in 16.5%). After 3 years, survival was 94.3%, survival-free from myocardial infarction was 86.7% and MACE-free survival was 66.1%. No difference was observed in MACE-free survival between patients originally treated with brachytherapy for recurrent in-stent restenosis and patients receiving irradiation for de novo lesions (68.2% de novo group versus 61.2% ISR group; p = 0.6 by log rank test). Overall, a second target lesion revascularization was performed in 27 patients (27.8%) after an average of 11.2 ± 11.2 months; 21 patients (21.6%) had restenosis, and 6 (6.2%) developed late total vessel occlusion (related to acute myocardial infarction in 2 cases). Conclusion. Repeat PCI is the most common choice after failed brachytherapy. This strategy appears to be a reasonable therapeutic option for this complex iterative pathology.

Key words: brachytherapy, coronary angioplasty, restenosis

Ionizing radiation has been shown to reduce neointimal formation after balloon angioplasty through the reduction of vascular smooth muscle cell proliferation and positive vessel remodeling.¹ Although coronary vascular brachytherapy (VBT) for prevention of restenosis in de novo lesions is controversial,^2–4 it represents the gold standard treatment for diffuse in-stent restenosis (ISR).^5–9 However, in clinical trials, brachytherapy failure (angiographic restenosis and target lesion revascularization) has been reported in a consistent number of patients, with a slow but progressive increase over long-term follow-up.¹⁰ Although in this clinical setting bypass surgery may represent a more definitive choice of treatment, repeat percutaneous coronary intervention (PCI) remains an appealing strategy. Recently, two studies reported the outcome of repeat PCI in patients after failure of gamma-brachytherapy in the GAMMA¹¹ and the WRIST trials.¹² They showed that the pattern of recurrent restenosis was predominantly focal. In these studies, percutaneous reintervention was accomplished safely, but in up to one-third of the patients a repeat reintervention was necessary during follow-up. Beta-radiation, in contrast with gamma, has limited penetration and does not require modifications to the standard shielding used in the catheterization laboratory. As a result, beta-sources became the most widely used type of vascular brachytherapy. Nevertheless, there is no specific information in the literature regarding the outcome of patients who failed beta-brachytherapy. The process of restenosis after coronary irradiation is still not entirely understood, and a possible different vascular response to percutaneous treatment following beta- and gamma-radiation cannot be ruled out a priori. The aim of this study was therefore to assess the long-term clinical outcome of patients who underwent percutaneous revascularization for restenosis following intracoronary beta-brachytherapy with catheter-based techniques. Methods Patient population. We retrospectively analyzed the data from all patients treated with catheter-based beta-brachytherapy at our institution between April 29, 1997 and December 31, 2001 (n = 301). The majority of patients were enrolled in clinical studies, with designs and principal results published elsewhere (Table 1).^4,6,13–17 A total of 120 patients with the diagnosis of brachytherapy failure were identified (39.9% of the entire brachytherapy-treated population in the pre-defined period). Brachytherapy was originally administered for in-stent restenosis in 43 patients, and for de novo lesions in 77 patients. The subsequent management of these patients, including revascularization strategy (surgical or percutaneous), was decided conjointly by a team of interventional cardiologists and cardiac surgeons. Overall, eight asymptomatic patients (5.8%) with angiographic restenosis were treated conservatively, fifteen patients (12.5%) underwent bypass surgery, and the remaining 97 patients (80.8%) were treated with repeat percutaneous intervention and comprise the present analysis. Percutaneous reintervention procedure. All patients were pre-treated with aspirin (> 75 mg/day). Clopidogrel (75 mg/day or 300 mg as a loading bolus dose) was given to those in whom stent implantation was planned in advance. During the procedure, weight-adjusted heparin was administrated to achieve an activated clotting time of > 300 seconds. Final treatment strategy and medications were left to operator discretion. Definitions. Restenosis was defined as > 50% diameter stenosis by quantitative coronary analysis. At baseline, lesions were classified as: 1) restenosis in the irradiated segment; 2) edge-restenosis, defined as restenosis occurring in the 5 millimeters proximal or distal to the irradiated segment; or 3) late total occlusion, defined as total vessel occlusion angiographically documented at the irradiated site more than 30 days after the brachytherapy procedure. The percutaneous reintervention was considered successful when a good angiographic result was obtained in combination with TIMI flow 3. Major adverse cardiac events (MACE) were defined as death, nonfatal myocardial infarction and target lesion revascularization (either percutaneous or surgical). The diagnosis of myocardial infarction was based on an increased level of creatine kinase to greater than twice the upper limit of normal with an increased level of creatine kinase-MB isoform. For patients admitted to peripheral hospitals in the acute phase, the diagnosis of myocardial infarction was confirmed by the referring physician based on the same criteria. Target lesion revascularization was defined as any surgical or percutaneous reintervention due to restenosis within the irradiated segment or the 5 mm proximal or distal segments (edge restenosis). Target vessel revascularization was defined as any reintervention driven by lesions located in the treated vessel beyond the target lesion limits. Non-target vessel revascularization was defined as any reintervention in vessels other than the target vessel. Subacute thrombosis was defined as angiographically documented total occlusion 30 days after the percutaneous reintervention. Follow-up. Baseline clinical and procedural data were prospectively entered into a dedicated database. Information about reinterventions was obtained from an electronic database of hospital records. The Thoraxcentre is a tertiary cardiology center serving a group of 14 local hospitals, and is the only one with facilities for percutaneous interventions in the region of Rotterdam. As required by the local medical system organization, all baseline procedures were performed in this tertiary facility, as were the vast majority of reinterventions. Long-term survival status was assessed by written inquiries to the Municipal Civil Registries. Questionnaires were sent to all living patients focusing on the occurrence of adverse cardiac events such as myocardial infarction and repeat intervention (surgical and percutaneous). The referring physicians and institutions as well as the general practitioners were directly approached whenever necessary. The follow-up period was defined as the time between the first reintervention following failed brachytherapy and March 31, 2003. Complete follow-up was obtained for all patients. Statistical methods. Continuous variables are expressed as means ± standard deviations, and categorical variables are reported as numbers and relative percentages. Event-free survival rates were estimated according to the Kaplan-Meier method, and compared by the log-rank test. Results Baseline clinical and angiographic characteristics. Baseline characteristics of the 97 patients who failed brachytherapy and underwent a new PCI are described in Table 2. The average time from the brachytherapy procedure to this first TLR was 13.4 ± 13.4 months. In 11 patients (11.3%), irradiation was performed with a 32Phosphorus (32P) source, and in 86 (88.7%) with a 90Strontium/90Yttrium (90Sr/90Y) source. The average dose administered was 18.7 ± 5.5 Gy, and average source length was 35 ± 8 mm. Acute coronary syndrome was the presenting diagnosis in 36 patients (37.1%); of these, five (4.2%) had acute myocardial infarction due to late thrombosis (all had been treated and had received brachytherapy for de novo lesions, and 4 of them had received a new stent). Restenotic post-brachytherapy lesions were classified as restenosis within the irradiated segment in 55 patients (56.7%), edge-restenosis in 21 patients (21.6%) and late total occlusion in 21 patients (21.6%). During repeat PCI, procedural success was achieved in 90 patients (92.8%). There were seven procedural failures, all in patients with totally occluded vessels. A new stent was implanted in 65 cases (72.2%). Sixteen patients (16.5%) received a sirolimus-eluting stent during the reintervention. Follow-up. Figure 1 shows a flow chart with the design and principal results of the study. Total revascularization rate was 30.9% (30 patients). Repeat TLR was performed in 27 patients (27.8%); ten of these (10.3%) were treated with bypass surgery and a second percutaneous TLR was performed in the remaining 17 (17.7%). The average time from the first to the second TLR procedure was 11.2 ± 11.2 months. The clinical presentation at the time of the second TLR was stable angina in 17 patients (63.0%), unstable angina in seven (25.9%) and acute myocardial infarction in three (11.1%). All patients with acute myocardial infarction received a new stent during the first reintervention following brachytherapy (on an individual basis, the time elapsed from the brachytherapy procedure was 8.4, 11.5 and 28.1 months, whereas the time elapsed from the first reintervention post-brachytherapy was 4.4, 5.9 and 12.0 months). Angiographically, late total occlusion was documented in six patients. In two of these, the late total occlusion was associated with an acute myocardial infarction (one of them was still on combined antiplatelet regimen). At three years, the cumulative survival rate was 94.3%, survival free of myocardial infarction was 86.7% and survival free of MACE was 66.1% (Figure 2). When the patients originally treated with brachytherapy for recurrent ISR were compared to patients receiving irradiation for de novo lesions, the MACE-free survival rate was similar (68.2% de novo group versus 61.2% ISR group; p = 0.6 by log rank test) (Figure 3). Sirolimus-eluting stent subgroup. Among the sixteen patients treated with sirolimus-eluting stents, three (18.7%) underwent a second clinically-driven TLR, one patient (6.2%) died of progressive congestive heart failure (pre-existing) and two more patients (12.5%) had angiographic restenosis found at elective angiographic control. No further reinterventions were done because they were asymptomatic. Overall, a failure of sirolimus-eluting stents was clearly documented in five patients (31.2%). Discussion In this study, we report the outcome of a consecutive series of patients treated with PCI after recurrent restenosis following catheter-delivered coronary beta-irradiation. In this setting, a percutaneous strategy appeared feasible, with a high rate of procedural success and low peri-procedural risk. Moreover, considering the complexity of these patients, the long-term outcome could be considered acceptable. Indeed, our results are similar to those previously described for reinterventions after failed gamma-brachytherapy for ISR, where a long-term incidence of MACE of 42.2% and a revascularization rate of 33.3% were reported.¹¹ Defining the outcome after reinterventions following vascular brachytherapy failure is of great importance. In fact, although brachytherapy is considered the best therapeutic option for patients with complex in-stent restenosis,^5–9 up to one-third of these patients will subsequently develop recurrent restenosis and need reintervention.^11,12 Geographical miss,¹⁸ late stent thrombosis,¹⁹ late total occlusion,²⁰ delayed restenosis²¹ and persistent dissections²² are well documented phenomena. Most are intrinsically related to the radiation’s effects and cannot be completely avoided, despite technical improvements and the increased experience of the operators using this therapeutic modality. Moreover, the risk of late thrombosis following brachytherapy has been reduced, but not abolished, by prolonged antiplatelet therapy.^23,24 In this scenario, a definitive intervention would be desirable, especially considering these patients had already suffered a number of recurrent failures. Notably, repeat PCI was the most common choice at our institution, with 80.8% of the patients who failed brachytherapy treated with this modality. This is consistent with a previous report from the WRIST trial.¹² Possible explanations for this choice include the high-risk baseline profile of many patients (who were therefore deemed unsuitable for coronary artery bypass graft surgery), coronary anatomy unfavorable for bypass surgery (for example, small vessel diameter), absence of disease in the left anterior descending coronary artery and patient preference. In our study, twenty-four percent of the patients had a previous coronary bypass operation. Coronary bypass reinterventions are associated with an operative mortality distinctly higher than the mortality of first-time operations, and carry a higher risk of perioperative complications, including reoperation for bleeding, perioperative myocardial infarction, and neurological and pulmonary problems.²⁵ Our study confirms that the risk of late vessel occlusion after reintervention for failed brachytherapy remains in a sizable proportion (6.2%). In one-third of these cases, this led to an acute myocardial infarction. This was especially true for patients in whom a new stent was implanted. Although this phenomenon is well known when a new stent is implanted at the time of irradiation, it has not been described after a subsequent reintervention. The most likely explanations are long-term endothelial dysfunction and delayed vascular healing, two established drawbacks of vessel irradiation.²⁶ DES may have a role in the management of patients who have failed brachytherapy. However, preliminary results suggest that sirolimus-eluting stents, which have been proven to be very effective in other clinical settings,^27–29 seem to have a reduced efficacy for recurrent restenosis after failed brachytherapy.³⁰ Thus, although more extensive evaluation is necessary, it seems unlikely that drug-eluting stents could further improve the results in this “biologically modified” environment. Conclusion. The results of the present study suggest that patients treated with coronary brachytherapy have a consistent risk for repeat interventions at the irradiated segment in the long-term. Percutaneous reintervention is the most common choice. With this strategy, rates of MACE and further reinterventions are contained, although not negligible, with a residual risk of vessel occlusion, especially when a new stent is implanted. Percutaneous reintervention appears to be a reasonable therapeutic option for this complex iatrogenic pathology.