Long-Term Outcomes after Intracoronary Beta-Irradiation for In-Stent Restenosis in Bare-Metal Stents

Intracoronary brachytherapy using β- or γ-irradiation is effective in reducing angiographic restenosis as well as target vessel revascularization (TVR) in patients with in-stent restenosis (ISR) after bare-metal stent (BMS) implantation.^1–5 Today, however, the technique is rarely used due to important logistic demands, the occurrence of stent-edge restenosis, a certain need for late TVR (“late catch-up phenomenon”), and most importantly, the introduction of drug-eluting stents (DES).⁶ Total occlusion occurring between 6 and 12 months after the index procedure has been identified as a major drawback of brachytherapy.⁷ Most brachytherapy trials^1–5 including the two recently-published randomized comparisons of brachytherapy and DES^8,9 reported follow-up periods of 9–12 months with only a few long-term (i.e., > 1 year) observations.^5,10–16 This may have been too short to detect very late problems such as very late stent thrombosis (i.e., > 1 year), which have been observed after DES, but hardly after BMS implantation.^17-20 The aim of the present study, therefore, was to describe the long-term clinical outcomes of consecutive patients undergoing intracoronary brachytherapy using β-irradiation (β-BT) at our institution, to differentiate specifically between events occurring < 1 year versus > 1 year after the index procedure, and to address the question whether very late thrombotic events also occur after β-BT as recently described after DES implantation.^17,19

Materials and Methods
Patient population. Between 2001 and 2003, 83 consecutive patients underwent β-BT for ISR after BMS implantation at our institution. Patients with a lesion > 75% diameter stenosis by visual estimation and ischemic symptoms and/or objective evidence of ischemia were eligible. Patients with ostial lesions, recent myocardial infarction (MI) (≤ 3 days), intracoronary thrombus, contraindications to prolonged combined antiplatelet therapy, and chronic consuming illness were not treated with β-BT. Patients were followed in a prospectively conducted registry. Two patients left the country early after the index procedure and could not be followed. Accordingly, the present analysis is based on the data on 81 patients. β-brachytherapy procedure. Radiation treatment was performed by a team consisting of cardiologists, radiooncologists and radiation physicists. The β-radiation source was phosphorus-32 (32P). The system used for β-BT (Galileo Centering Catheter, Guidant Corp., Santa Clara, California) has been described previously in detail.^5,21 In brief, the system was composed of three components. The source wire was a 0.018 inch flexible nitinol wire, with the active 32P source encapsulated in the distal 27 mm of the wire. The centering balloon catheter was a double-lumen catheter with a short monorail distal tip for a rapid-exchange method of delivery and a 34 mm or 52 mm-long spiral balloon, with nominal diameters of 2.5, 3.0 and 3.5 mm, which centered the source within the lumen while allowing perfusion of sidebranches and the distal vessel. The source delivery unit provided safe storage of the active wire and automated delivery and retrieval. Patients received a dose of 20 Gy at 1 mm tissue depth. Depending on the length of the lesion to treat, one or two pullback procedures were performed to cover the entire lesion length. The irradiated segment always included the injured segment after balloon angioplasty and a safety margin (> 5 mm proximal and distal edge). Additional stent implantation was avoided whenever possible, but was performed in cases of major flow-limiting dissections. After the procedure, all patients were treated with oral aspirin (100 mg/d) long-term and with oral clopidogrel (75 mg/d after a loading dose of 300 mg) for 12 months.
Follow up. Myocardial perfusion imaging (MPI) with rest ²⁰¹Tl /stress (exercise/adenosine) ^99mTc sestamibi single-photon emission computed tomography and control angiography were planned for all patients after 6 months, but only a subset of patients agreed with these examinations. Decisions about repeat revascularization procedures were based on symptoms and MPI findings. Thereafter, patients were followed clinically. Data on long-term outcomes were obtained by chart review and phone calls to patients and general practitioners between December 20, 2006 and February 10, 2007, i.e., 5.2 (4.4–5.6) years after the index procedure. We assessed major adverse cardiac events (MACE), defined as target vessel revascularization (TVR), nonfatal MI and cardiac death occurring < 1 year and > 1 year after the index procedure. TVR was defined as revascularization of the target lesion or a segment outside of the target lesion, but within the same vessel. Stent thrombosis in the irradiated vessel was classified as “possible”, “probable” or “definite” according to the Academic Research Consortium (ARC) definition of stent thrombosis²² and was analyzed separately from MACE.
Statistical analysis. Continuous data are presented as mean ± standard deviation or median (interquartile range), as appropriate. Categorical data are shown as counts and percentages. Event-free survival was estimated with Kaplan-Meier curves. Multivariate Cox regression analysis was performed to identify independent predictors of MACE during the entire study period and < 1 year and > 1 year after the index procedure. The following variables were included in the model: age > 60 years, body mass index > 30 kg/m2, diabetes mellitus, multivessel disease, previous coronary artery bypass graft surgery, previous percutaneous coronary intervention (PCI) in a vessel other than the target vessel, PCI in a vessel other than the β-BT vessel during the index procedure, an irradiated vessel length > 32 mm (median value), a reference luminal diameter ≤ 3.0 mm, dissection at the brachytherapy site during the index procedure, stent implantation during the index procedure, as wells as treatment with a statin, beta-blocker, inhibitors of the renin-angiotensin-aldosterone system, calcium channel-blocker and nitrate. Variables with a p-value < 0.1 at the univariate analysis were included in the multivariate model (forward stepwise technique). The log rank test was used to compare the time-dependent occurrence of MACE in subgroups. Statistical analysis was performed using a commercially available software package (SPSS, Version 10.1, SPSS, Inc., Chicago, Illinois).

Results

Patients. Baseline characteristics of the study population are provided in Table 1. Patients were relatively young with a relatively high rate of risk factors and single-, double- and triple-vessel disease in about one-third each. The target vessel treated most was the left anterior descending coronary artery followed by the right coronary artery, and 80% of patients had diffuse ISR (types III and IV²³).
Procedures. Characteristics of the index procedure are provided in Table 2. Target lesions were long and diffuse in all cases, as shown by the total irradiated length of 32 mm (32–54 mm). In 7% of patients, additional BMS implantation was required due to a suboptimal result after balloon dilatation and irradiation. In 26% of patients, PCI of another lesion was performed in the same session. There were no periprocedural complications.
Systematic follow up at 6 months. Because of early recurrence of symptoms, 5 patients underwent repeat angiography before the scheduled 6-months MPI and invasive follow up, resulting in TVR in 2 patients, revascularization of a vessel other than the target vessel in 2 other patients and no need for an intervention in 1 patient.
Among the remaining patients, MPI was performed in 60/76 (79%) patients 5.9 (5.0–6.3) months after the index procedure. Myocardial ischemia with a summed difference score of 3 4 was present in 19/60 (32%) patients undergoing MPI, which was identified as target vessel ischemia in 15 patients. Of these 15 patients, 13 underwent repeat angiography and TVR. Two patients with asymptomatic target vessel ischemia refused repeat angiography. Four patients with ischemia not attributable to the target vessel underwent repeat angiography and revascularization of a vessel other than the β-BT target vessel.
Overall, control angiography was carried out in 48/76 (63%) patients 5.9 (5.3–6.5) months after the index procedure. Target vessel obstruction > 50% was noted in 24/48 (50%) patients undergoing control angiography. Thirteen of these 24 patients had target vessel ischemia (as reported above) and underwent subsequent TVR. In 14 patients, there was an obstruction > 50% of a vessel other than the target vessel, either alone (n = 8) or in presence of a target vessel obstruction >50% (n = 6). Two of the latter patients underwent coronary artery bypass grafting, and 5 of the former patients (4 of them also reported above in the MPI followup) underwent PCI of a vessel other than the β-BT target vessel. In the remaining 7 patients, no intervention was performed, either due to the presence of chronic total occlusions in bypass grafts (n = 2) or a native vessel (n = 1) or the absence of ischemia (n = 4).

Clinical follow up. The median follow up was 4.6 (3.9–5.4) years, and the observation period covered 360 patient years. MACE rates occurring < 1 year and > 1 year after the index procedure are presented in Table 3. During the entire observation period, 8.7% of patients died from cardiac causes, 18.5% suffered a nonfatal MI and 35.8% underwent TVR. The total MACE rate was 49.4%, and the total cardiac death/MI rate was 25.9%. Kaplan-Meier plots for MACE (Figure 1A) and TVR (Figure 1B) are provided in Figure 1. These plots illustrate that MACE, including TVR, continued to occur up to 5 years after the index procedure.
MACE < 1 year after the index procedure. Within the first year after the index procedure, 2 patients died from cardiac causes, 5 patients suffered a nonfatal MI with subsequent TVR (n = 2), revascularization of a vessel other than the target vessel (n = 2), or no revascularization (n = 1), and 14 patients underwent TVR unrelated to an acute event. Thirteen of these TVRs were performed during the scheduled 6-month follow up. The total MACE rate was 25.9% within the first year, and rates for cardiac death, nonfatal MI, cardiac death/MI and TVR were 2.5%, 6.2%, 8.7% and 19.8%, respectively.
MACE > 1 year after the index procedure. After the first year, 5 patients died from cardiac causes, 10 patients suffered a nonfatal MI with subsequent TVR (n = 5), revascularization of a vessel other than the target vessel (n = 4), or no revascularization (n = 1; coronary artery bypass grafting refused by the patient), and 8 patients underwent TVR unrelated to an MI. The average annual MACE rate after the first year was 5.5%, and the annual rates of cardiac death, nonfatal MI, cardiac death/MI and TVR were 1.5%, 2.9%, 4.1% and 3.8%, respectively.

Predictors of MACE. Only an irradiated length > 32 mm (median value) was significantly associated with the occurrence of MACE at the univariate and thus also the multivariate analysis (odds ratio [OR] 1.88, [1.01–3.52], 95% confidence interval [CI]; p = 0.047), whereas the presence of diabetes (OR [95%CI] 2.01 [0.99–4.04]; p = 0.051) and a reference luminal diameter ≤ 3.0 mm (OR [95% CI] 1.73 [0.88–3.41]; p = 0.11) were less strongly related to MACE. In Figure 2, MACE-free survival is compared in patients with irradiated lengths £ 32 mm and > 32 mm (Figure 2A) and patients with and without diabetes (Figure 2B). Patients with an irradiated length > 32 mm and those with diabetes were more likely to suffer MACE during the entire follow up period (in contrast to the Cox regression, the log rank test yielded a statistically significant difference for the occurrence of MACE in patients with compared to those without diabetes). When comparing predictors of MACE occurring < 1 year as opposed to > 1 year after the index procedure, an irradiated length > 32 mm was found to be the only predictor of MACE within the first year (OR [95%CI] 2.73 [1.10–6.78]; p = 0.03), whereas it was not significantly associated with the occurrence of MACE > 1 year (OR [95%CI] 0.90 [0.36–2.23]; p = 0.8). There was no significant association between diabetes and the occurrence of MACE < 1 year (OR [95%CI] 1.41 [0.52–3.84]; p = 0.51). In contrast, there was a trend towards an association between diabetes and the occurrence of MACE > 1 year (OR [95%CI] 2.49 [0.94–6.57]; p = 0.07). A reference luminal diameter £ 3.0 mm was not significantly associated with the occurrence of MACE < 1 year (OR [95%CI] 1.92 [0.77–4.75]; p = 0.16) or > 1 year (OR [95% CI] 1.24 [0.45–3.44]; p = 0.68) after the index procedure.
Occurrence, timing and circumstances of late thrombotic events. In Table 4, possible, probable, or definite stent thrombosis occurring < 1 year or > 1 year after the index procedure are displayed. Among the cardiac deaths occurring < 1 year after the index procedure, 1 patient died suddenly after worsening angina during the preceding days. Since an autopsy was not performed, the event was classified as possible late stent thrombosis. One patient died after aortic valve replacement, and thus it was not classified as stent thrombosis. Among the 4 patients suffering nonfatal MI within the first year after the index procedure, there was 1 patient presenting with electrocardiographic changes in the territory of the irradiated vessel, but coronary angiography performed the same day showed a good result after β-BT. It was hypothesized that a thrombus was dissolved under therapy with heparin and a glycoprotein IIb/IIIa inhibitor. Accordingly, the event was classified as probable late stent thrombosis.
Among the 5 cardiac deaths occurring > 1 year after the index procedure, 2 patients died suddenly, but autopsies were not performed. These deaths were classified as possible very late stent thrombosis. Two patients died from cardiogenic shock due to a large MI. In 1 of these 2 cases, emergency angiography revealed that the β-BT target vessel was the culprit lesion. Although there was no clear evidence for thrombosis, the event was classified as probable very late stent thrombosis. In the other case, an autopsy revealed an anterior wall MI, but the β-BT target vessel was the left circumflex artery, and thus the event was not classified as stent thrombosis. Among the 8 patients undergoing TVR not related to an acute event > 1 year after the index procedure, there was 1 patient with angiographic evidence of thrombosis within the irradiated segment, and thus it was classified as definite very late stent thrombosis, although the patient did not experience MI. From the data provided in Table 4, an annual event rate of 2.5% for the first year and 1.3% for the following 4 years can be calculated.
Noncardiac deaths. During the study period, 6 patients died from noncardiac causes including breast cancer (n = 2), colon cancer (n = 1), bladder cancer (n = 1), lung cancer (n = 1) and bleeding after abdominal surgery (n = 1). None of these cancers
were known prior to β-BT.

Discussion
The present study shows that patients treated with β-BT for ISR after BMS implantation carried a substantial risk of events not only occurring < 1 year, but also >1 year after the index procedure, and that among these events, there was a significant number of cardiac deaths. Our data suggest that events occurring < 1 year after the index procedure were related to the irradiated vessel length, whereas events occurring > 1 year after the index procedure tended to be related to the presence of diabetes. Notably, the rate of thrombotic events was twice as high within the first year compared to the following years (2.5 vs. 1.3%).
The risk of further events after β-BT for ISR is high if compared to BMS or DES implantation in de novo lesions^17,24 or interventions using DES for the treatment of ISR.^8,9 The overall event rate observed in the present study during the first 12 months (25.9%) was comparable to the target vessel failure rates of 21.6%⁸ and 19.6%⁹ after 9 months in the brachytherapy groups in two recent randomized comparisons between brachytherapy and DES. The irradiated length was similar in the latter two studies (lesion length up to 40 mm⁸ and 46 mm⁹, respectively, mean irradiated length 39.7 mm in one study⁸ and not given in the other study,⁹ but probably similar when regarding the very similar lesion lengths in the two studies) and in the present one (irradiated length up to 112 mm; median irradiated length 32 mm). Accordingly, 1-year results in the present population were comparable to those in recent randomized trials. Interestingly, data on the very late outcome after brachytherapy are sparse. In a registry of consecutive patients undergoing brachytherapy (γ-irradiation in 93%; follow-up period between 2 and 6 years), more than 50% of the events were found to occur after the first 12 months.¹¹ The average time to MACE in these patients was 14.6 months.¹¹ A 3-year follow-up study including 128 consecutive patients undergoing β-BT in Aachen found a target lesion revascularization (TLR) rate of 18% and a MACE rate of 19% at 6 months, and 28% and 37% at 36 months, respectively.¹⁴ Event rates after 1 year are not available from that study, and the follow up was shorter than in the present study (3 vs. 5 years). Nonetheless, a significant number of events occurring > 1 year becomes obvious also from this study. In Rotterdam, the largest study in the field followed 301 consecutive patients undergoing β-BT for both native lesions and restenosis, researchers reported a MACE rate (death, nonfatal MI, TVR) of 36% and a target lesion revascularization rate of 28% at 1 year, and 58% and 50% at 4 years.¹⁵ Thus, annual MACE and TLR rates of 7.3% and 7.3% after the first year can be calculated, which is higher than what was found in the present study (5.5% and 3.8%).
Important information on long-term outcomes after brachytherapy comes from the randomized Washington Radiation for In-Stent restenosis Trial (WRIST). In this study, 130 patients with ISR after previous BMS implantation in native coronary arteries or saphenous vein grafts underwent PCI and were randomized to brachytherapy using a g-source or placebo.¹⁶ After 6 months, patients undergoing brachytherapy had a lower MACE rate (19% vs. 63%). After 5 years, the MACE rate was still lower in the brachytherapy group (46% vs. 69%), but the difference between the brachytherapy and placebo groups was markedly reduced, which was due to a markedly higher late TVR rate (27% vs. 6%) in the brachytherapy group between 6 months and 5 years.¹⁶ From the data given in the publication, annual MACE and TVR rates of 6% for the period between the first 6 months and 6% for 5 years can be calculated, which was much higher than in the placebo group (1.3% and 1.3%).¹⁶ Since data after 1 year are not available, direct comparison with the present study is not possible. This observation of late TVR referred to as the “late catch-up phenomenon” has seriously challenged the application of brachytherapy in practice. The WRIST study differs from the present one in that γ-radiation was employed, whereas we used a β-emitting source. Similar to the WRIST study, a high MACE rate was not only found within the first year but also > 1 year after the index procedure also in the present study. Whereas MACE rates during the first year were driven by systematic MPI and angiographic follow up, there was a significant number of clinical events after the first year. Of note, these events continued to occur up to 5 years after the index procedure, and there was a high number of cardiac deaths > 1 year after the index procedure. Note that these cardiac deaths occurred 4.5 (3.8–5.0) years after the index procedure, which corresponds to an observation period that exceeds that of most other brachytherapy studies.
Given the observation of late stent thrombosis after DES placement^17,19 we tried to assess late and very late thrombotic events after β-BT. Using the recently-proposed ARC classification,²² we identified stent thrombosis of any probability in 7% of the study group during the entire follow-up period. The annual event rate during the first year was twice as high as in the following four years (2.5% vs. 1.3%), but events occurred up to 5 years after the index procedure. In WRIST, there was a trend toward higher rates of thrombotic events in the brachytherapy group both at 6 months (8% vs. 3%) and at 5 years (12% vs. 6%), but late thrombotic events did not occur after 3 years.¹⁶ After implantation, the stent thrombosis rates during the first year of BMS, sirolimus-eluting stents and paclitaxel-eluting stents were described by one study to be 0.7%, 0.6% and 0.7%.²⁵ However, most of these interventions were performed in de novo lesions,²⁵ thus these data cannot be compared to those from interventions for ISR. In another registry, the rate of stent thrombosis after DES implantation was 1.7% within the first year (1.2% within the first 30 days and 0.5% thereafter), and 0.6% thereafter.¹⁹
The length of the irradiated segment was identified as the single independent predictor of the occurrence of MACE during the entire follow-up period, but especially during the first year, indicating that events occurring < 1 year after the index procedure were strongly related to the β-BT procedure. This may indicate that the mechanism underlying this relationship might be ongoing luminal loss with the development of late ISR within the irradiated segment¹⁴ and thrombotic events due to radiationinduced endothelial damage and delayed reendothelialization, as previously proposed by Togni and colleagues.²⁶
In contrast to the irradiated vessel length, diabetes was related to MACE occurring > 1 year after the index procedure (although the association was only of borderline significance). The presence of diabetes might be a surrogate for rapid disease progression. This hypothesis is somewhat supported by a relevant number of revascularization procedures for vessels other than the target vessel, not only within the first year, but also at > 1 year. In previous studies, unstable angina before the index procedure, hypercholesterolemia and previous intervention in the β-BT segment were identified as independent predictors of short-term MACE,¹⁵ and a lower radiation dose¹⁵ and a lower minimal lumen diameter14 were independently associated with TLR during follow up. Interestingly, diabetes was recently identified as an independent predictor of late and very late stent thrombosis after DES implantation.¹⁹ Current guidelines recommend that “antiplatelet therapy with both aspirin and a thienopyridine be continued for at least 6–12 months after brachytherapy”²⁷, thereby implying that prolonged (> 12 months) dual-antiplatelet therapy might be considered. However, to the best of our knowledge, there are no data on the impact of such an approach on long-term outcomes after intracoronary brachytherapy. Given our observation that disease progression is an important issue (as indicated by the fact that diabetes was the only predictor of MACE > 1 year), aggressive secondary prevention including optimal treatment of diabetes (glucose-lowering drugs, statins) might be the most important therapeutic consequence.
A surprising finding of the present study was the manifestation of 5 fatal cancers during late follow up, which had not been known when patients underwent β-BT. However, given the short range of b−radiation, β-BT can be expected to deliver radiation very locally and should not be associated with radiation damage to other organs. Thus, the observation of cancer deaths during follow up might be a chance finding and hardly indicates a relationship between β-BT and the occurrence of cancer.
Study limitations. The present study is limited by the observational nature and inherent limitations of a registry, as well as the comparatively small sample size. However, the long follow-up period covering 360 patient years and the analysis of late stent thrombosis as well as cardiac and noncardiac deaths may add new aspects to this field.

Conclusions
Patients undergoing intracoronary brachytherapy for in-stent restenosis in BMS carry a substantial risk of MACE occurring both within and beyond the first year after the index procedure, including thrombotic events and cardiac deaths. Accordingly, although the technique is only very rarely applied in current practice, the brachytherapy period has left a population of “vulnerable” patients who need careful monitoring over a prolonged period.

Acknowledgement.
We wish to thank Werner Estlinbaum, MD, and Jean-Luc Crevoisier, MD, for their assistance with the follow-up data collection.

References

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