Objective. To investigate the safety and efficacy of a 60 mm transfer device, delivering 60 mm radiation source train, in the treatment of coronary lesions by b-brachytherapy employing the BetaCath™ system (Novoste, Norcross, Georgia). Methods and Results. As part of the REgistry NOvoste (RENO), the first large-scale registry of intracoronary b-radiation applied in routine clinical practice, forty-six centers registered 1,098 consecutive patients undergoing brachytherapy with the BetaCath system. Of these, 49 patients with 56 lesions were treated with a 60 mm transfer device/radiation source train (TD/RST) in at least 1 vessel, constituting the study population. With 75.4% in-stent restenosis (ISR), 3.6% graft lesions, long lesions (30.9 ± 14.7 mm) and 19% diabetes, the cohort had a high-risk for recurrence. The in-hospital major adverse cardiac event (MACE) rate was 4.1%. The 6-month follow-up revealed 2.0% death, 4.1% myocardial infarction, 8.2% target vessel revascularization, 12.2% MACE, 82.6% improved angina, 16.7% binary restenosis and 4.1% late thrombosis. The results were comparable to all other patients in the registry treated with standard source lengths of 30 mm and 40 mm, although much longer lesions were treated by the 60 mm device (18.4 ± 11.3 mm versus 30.9 ± 14.7 mm; p < 0.0001). In the ISR subgroup (mean lesion length, 32.03 ± 14.99 mm), the 6-month MACE rate was 12.8%, while the angiographic restenosis rate was 16.0% and the late thrombosis rate was 2.6%. Conclusion. b-brachytherapy with 60 mm TD/RST was safe, feasible and effective in this broad population of high-risk patients presenting in day-to-day practice. Its efficacy in long-segment ISR, where conventional interventional strategies have poor outcome rates, is particularly noteworthy.

       Intracoronary radiation, by virtue of its ability to inhibit intimal hyperplasia and constrictive vascular remodeling, reduces restenosis after percutaneous coronary interventions (PCI). Long lesions — longer than the available source length — have been treated by manual multisegmental irradiation or “pullback” method, in which the source is manually pulled back to cover the entire injury length. While the efficacy of manual pullback has been shown in several clinical studies,1–3 doubts have been raised on the precision with which this was achieved, as inaccuracies inadvertently occur in the form of overlaps and gaps.4 A 60 mm transfer device, delivering a 60 mm b-radiation source train in a 5 French catheter, was specially designed to avoid or to minimize the necessity of pullback during brachytherapy of long lesions. We report, for the first time, the results of this device in an unselected patient population comprising in-stent restenotic (ISR) and de novo lesions in both native coronary arteries and saphenous vein bypass grafts encountered in day-to-day clinical practice. We further compare the results of this device with those of the standard 30 mm and 40 mm source lengths employed in routine clinical practice.

Methods
       Patient population. Between April 1999 and September 2000, the REgistry NOvoste (RENO), the first large-scale (post-marketing surveillance) registry of b-brachytherapy applied in routine clinical practice, included 1,098 consecutive patients treated by the BetaCath™ System (Novoste, Norcross, Georgia) in 46 European centers. The methodology and results of the registry are published elsewhere.5,6 Three radiation source train lengths (30 mm, 40 mm and 60 mm) delivered in a 5 Fr catheter were used to treat the patients.The decision to use a particular source length was mainly based on operator perception, as there were no fixed guidelines given by the registry. The study group of the present analysis consisted of 49 patients with 56 lesions who were treated with the 60 mm transfer device/radiation source train (TD/RST) in at least 1 vessel. The pre-brachytherapy interventional procedure, as well as pre- and post-brachytherapy protocols, including the administration of antiplatelet regimen, were according to the practices prevalent at the individual participating centers. Table 1 represents the demographic and clinical profile of the study group and its comparison with all other registry patients. The latter were rather similar, except that they were somewhat older and had a relatively lower incidence of prior myocardial infarction (MI) and hyperlipidemia. ISR was the overwhelming indication for treatment in both groups. As expected, much longer lesions were treated with the 60 mm TD/RST.
       Procedural variables. The procedural data are summarized in Table 2. Technical success, pertaining to the radiation procedure after conventional intervention, was seen in 96% patients, thus underlining the practical feasibility of the procedure in long lesions. Despite long source length, pullback was still used in one-fifth of patients, thereby underscoring the extensive lesion lengths treated. New stents were deployed in about one-third of the instances at the time of the procedure. A comparison of the procedural data in the study group with all other registry patients showed a significantly greater dwell time and a higher administered radiation dose in the former. More cutting balloons were used in the study patients.
       Endpoints. The clinical endpoints were: 1) in-hospital death, MI, composite of death or MI, and total major adverse cardiac events (MACE); and 2) 6-month follow-up, including in-hospital death, MI, composite of death or MI, and total MACE. MI was defined as a documented creatine kinase rise of more than 2 times normal in the post-intervention phase, and by the presence of at least 2 of the following: pain; rise in creatine kinase; or electrocardiographic changes after discharge. The angiographic endpoint was the 6-month angiographic binary restenosis (defined as 50% stenosis relative to the reference luminal diameter) rate. A surrogate composite endpoint for late thrombotic target vessel occlusion was defined as the occurrence of 1 or more of the following beyond the first 30 days post-brachytherapy: documented angiographic total occlusion within the irradiated segment; acute MI in any location (only when MI was documented not to have occurred in the territory of the target vessel, was it not counted as part of the surrogate endpoint); and cardiac death. All reported events were reviewed by a Critical Event Committee.
       Statistical analysis. Discrete variables are provided as counts and percentages (in brackets). Continuous variables are expressed as means ± standard deviations. The p-values correspond to likelihood ratio Chi-square tests (counts) or two-sided Mann-Whitney U tests (continuous variables) for group comparisons, with the sampling unit being patients or lesions, as applicable. Since there was more than 1 vessel treated per patient, p-values for lesion characteristics (Table 1), procedural variables (Table 2) and results (Tables 3, 4 and 5) relate to the first vessel only, in order to fulfill required independence assumptions. The values in Tables 1 (lesion characteristics) and 2, as well in the majority of instances in the text, refer to lesions as sampling units, while Tables 1 (other than lesion characteristics), 3, 4 and 5 have patients as sampling units.

Results
       Clinical and angiographic outcome. The in-hospital events, 6-month follow-up clinical events including the in-hospital events, and follow-up angiographic events are summarized in Table 3. Though brachytherapy with 60 mm TD/RST was safe (2 non-fatal MIs), the in-hospital incidence of MI and death or MI was higher in the study group compared to all other registry patients.

Figure 1

Six-month angiographic follow-up after brachytherapy with the BetaCath™ System. Upper panel: a long-segment in-stent restenosis in the right coronary artery (RCA) before balloon angioplasty, and a 60 mm radiation source train within the RCA after adequate balloon predilatation. Lower panel: the final intervention result, and the 6-month follow-up showing persistence of a good angiographic result.

       Clinical follow-up was obtained in all patients. Considering the complex high-risk study group, the clinical event rate was low and improvement in angina occurred in the vast majority of patients. There was no statistical difference in the incidence of clinical events in the study group versus all other registry patients.
       While the clinical follow-up was obligatory, angiography at 6 months was recommended but not mandatory. The angiographic follow-up rate was a little under 70% in the study group, while the binary restenosis rate was an acceptable 16.7%. Angiographic follow-up rate, binary restenosis rate and the surrogate composite endpoint of late thrombotic target vessel occlusion were comparable in the two groups. The component of cardiac death in the late thrombosis endpoint was higher in the 60 mm TD/RST group, but this was based on 1 follow-up cardiac death only.
       Subgroup analyses according to nature of presenting lesion, ISR versus de novo lesions, and according to placement of new stents (Table 4). Compared to ISR, in the de novo group more new stents were implanted (76.9% versus 23.3%; p = 0.002) and the incidence of pullback was higher (38.5% versus 14.0%; p = 0.039). The technique was safe and effective in both subgroups, with similar rates of clinical and angiographic events. Similarly, placement of a new stent did not significantly alter the clinical and angiographic endpoints in the subgroups.
       ISR: Patients treated with 60 mm TD/RST versus all other registry patients (Table 5). Significantly longer ISR lesions were treated by the 60 mm TD/RST compared to all other registry patients treated with standard source lengths (32.02 ± 14.99 mm versus 18.88 ± 11.85 mm; p < 0.0001). Just like the overall study group, ISR patients treated with the 60 mm device were relatively younger (59.0 ± 9.4 years versus 62.3 ± 10.4 years; p = 0.037) and had a higher incidence of prior MI (56.4% versus 37.1%; p = 0.015). While the mean dwell time was greater in these patients (4.2 ± 1.2 min/sec versus 4.1 ± 1.4 min/sec; p = 0.025), the mean dose delivered was higher (20.6 ± 3.0 Gy versus 18.9 ± 3.1 Gy; p = 0.001), and more cutting balloons were used. The overall in-hospital MACE rate was low and comparable in the 2 groups, though the incidence of non-fatal MI was higher in the 60 mm patients. Despite much longer lesion lengths treated, the 6-month follow-up revealed an encouragingly low clinical and angiographic event rate in the study patients. The follow-up results were comparable in the two groups.

Discussion
       With 75.4% ISR, 3.6% graft lesions, long lesions (30.9 ± 14.7 mm), 30% unstable angina, and 19% diabetes, our study group had a high risk for recurrence. Yet b-brachytherapy with 60 mm TD/RST was feasible with high procedural success rates, safe with low in-hospital MACE, and effective with favorable clinical and angiographic mid-term outcomes (Figure 1). No study has directly compared the results of various source lengths. We therefore sought to compare the results of 60 mm TD/RST with those of standard source lengths of 30 and 40 mm (Table 3).
       The in-hospital results were comparable except for a higher incidence of non-fatal MI with the 60 mm TD/RST. While the latter could be a quirk due to the small sample size, it might as well be due to a higher probability of sidebranch compromise and peripheral embolization as a consequence of treatment on long lesions rather than an effect of longer source length per se. Further, the thrombotic propensity did not seem to increase after treatment with 60 mm TD/RST, as was evidenced by a similar rate of late target vessel thrombosis and total occlusions at follow-up angiograms. There were no increases in acute procedural complications like dissections requiring new stents or ischemia caused by placement of a longer device for a greater dwell time within the vessel and the procedure could be successfully completed in 96.4% of patients.
       The 6-month follow-up also revealed a comparable efficacy, although much longer lesions were treated by the 60 mm TD/RST. Lesion length is a predictor of restenosis irrespective of the conventional interventional strategy used.7 For lesions with a mean length of over 30 mm in an especially high-risk subset, the overall MACE rate of 12.2% and angiographic restenosis rate of 16.7% are very encouraging. The results of conventional interventional strategies are particularly bad in long, diffuse ISR (35–50% target lesion revascularization rate),8 and several studies have identified ISR length as a risk factor for recurrence.9–11 Even in this high-risk cohort, treatment with 60 mm TD/RST yielded similar MACE and restenosis rates.
       Since brachytherapy has a definite niche in the treatment of ISR, we compared the results of the 60 mm TD/RST with the standard 30 and 40 mm source lengths in the treatment of patients presenting with these lesions (Table 5). Here also, the results were comparable in the 2 groups despite the fact that much longer lesions were treated with the device under investigation.
While manual pullback has been reported to be safe and effective with 30 and 40 mm source length,1–3 the same appears to be true with 60 mm source lengths. Though this question was not addressed directly, the salutary results in our patients despite one-fifth undergoing manual pullback do suggest the feasibility of this method in treating very long lesions with 60 mm TD/RST.
       Although new stent implantation has been cited as a risk factor for late thrombosis after brachytherapy,12–14 we did not see such an adverse interaction in our study. This is probably related to the small sample size followed for an intermediate duration. Very late thrombosis is reported to occur on prolonged follow-up.12 A surrogate composite endpoint, consisting of death, MI and total occlusions at angiographic follow-up, was used to define late thrombosis and it is likely that the late thrombosis rate in our study is exaggerated; late total occlusions may not always occur because of late thrombosis. Moreover, the registry recommended combined antiplatelet treatment with aspirin and clopidogrel for a minimum of 3 months and it is possible that the prolonged antiplatelet treatment for 6 months or 1 year, as is the current trend, may have decreased the rates further.
       Significantly greater use of cutting balloons was observed in the study group. Since the use of these balloons was solely left to the discretion of the individual operators, it is likely that an attempt to have an optimal angioplasty result in a much more complex lesion type might have been the main motivational factor in their use. While it is difficult to say what contribution the greater use of these balloons might have had in improving the overall results in the study cohort, cutting balloon use was an independent predictor of a lower MACE rate in the overall RENO analysis.5 This may perhaps be due to lower chances of balloon slippage and geographical miss as a result of their use during lesion dilatation.
       The radiation dose was significantly higher with the 60 mm TD/RST and this might have contributed to its efficacy. Attrition of the efficacy of intracoronary gamma radiation has been described in long lesions, and serial intravascular ultrasound analysis has shown decreased dose delivery to the adventitia as one of the contributory mechanisms.15 The dosimetric considerations may be much more important with b-radiation due to its steeper depth-dose fall-off curve.
       Conclusion. Brachytherapy with the BetaCath™ Novoste system using a 60 mm TD/RST is safe, feasible, effective and convenient in a mixed population of high-risk patients presenting in “real world” clinical practice. Its efficacy in long, diffuse ISR is particularly appealing since conventional interventional strategies have worse outcomes in these lesions.
       Study limitations. This report is a sub-analysis of a registry, with both its weaknesses and strengths. While a control group is necessary to evaluate a new treatment strategy in true perspective, selection bias may not completely reflect day-to-day clinical practice. The sample size is relatively small and underpowered conclusions from such subgroup analyses must be interpreted with caution. The 6-month follow-up might still be inadequate and not truly be reflective of the long-term clinical course, as reocclusion/thrombosis are known to occur as delayed phenomena beyond 6-month so called “late late thrombosis.”12

1. Moustapha A, Salloum J, Saikia S, et al. Combined cutting balloon angioplasty and intracoronary beta radiation for treatment of in-stent restenosis: Clinical outcomes and effect of pullback radiation for long lesions. Cathet Cardiovasc Interv 2002;57:325–329.
2. Waksman R, Raizner AE, Yeung AC, et al. Use of localised intracoronary beta radiation in treatment of in-stent restenosis: The INHIBIT randomised controlled trial. Lancet 2002;359:551–557.
3. Crocker I, Joyal M, Fox T, et al. Treatment of long, diffuse, in-stent restenotic lesions with beta radiation using strontium 90 and sequential positioning “pullback” technique: Procedural details and clinical outcomes. J Invas Cardiol 2001;13:782–787.
4. Coen VL, Marijnissen JP, Ligthart JM, et al. Inaccuracy in manual multisegmental irradiation in coronary arteries. Radiother Oncol 2002;63:89–95.
5. Urban P, Serruys P, Baumgart D, et al. Clinical application of intracoronary beta brachytherapy using Sr/Y90 source trains. The European surveillance registry with the Novoste Beta-Cath system. Eur Heart J 2003;24:604–612.
6. Jain D, Geist V, Lorenzen HP, et al. Intracoronary beta-brachytherapy in chronic total occlusions: A subgroup analysis from the RENO registry. Cathet Cardiovasc Interv 2003;58:322–329.
7. Goldberg SL, Loussararian A, De Gregorio J, et al. Predictors of diffuse and aggressive intra-stent restenosis. J Am Coll Cardiol 2001;37:1019–1025.
8. Mehran R, Dangas G, Abizaid AS, et al. Angiographic patterns of in-stent restenosis: Classification and implications for long-term outcome. Circulation 1999;100:1872–1878.
9. Mehran R, Mintz GS, Satler LF, et al. Treatment of in-stent restenosis with excimer laser coronary angioplasty: Mechanisms and results compared with PTCA alone. Circulation 1997;96:2183–2189.
10. vom Dahl J, Radke PW, Haager PK, et al. Clinical and angiographic predictors of recurrent restenosis after percutaneous transluminal rotational atherectomy for treatment of diffuse in-stent restenosis. Am J Cardiol 1999;83:862–867.
11. Bossi I, Klersy C, Black AJ, et al. In-stent restenosis: Long-term outcome and predictors of subsequent target lesion revascularization after repeat balloon angioplasty. J Am Coll Cardiol 2000;35:1569–1576.
12. Waksman R. Late thrombosis after radiation. Sitting on a time bomb. Circulation 1999;100:780–782.
13. Costa MA, Sabat M, van der Giessen WJ, et al. Late coronary occlusion after intracoronary brachytherapy. Circulation 1999;100:789–792.
14. Waksman R, Bhargava B, Mintz GS, et al. Late total occlusion after intracoronary brachytherapy for patients with in-stent restenosis. J Am Coll Cardiol 2000;36:65–68.
15. Ahmed JM, Mintz GS, Waksman R, et al. Serial intravascular ultrasound analysis of the impact of lesion length on the efficacy of intracoronary gamma-irradiation for preventing recurrent in-stent restenosis. Circulation 2001;103:188–191.