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Results of Intracoronary b-Brachytherapy Administered by 60 mm Transfer Device/Radiation Source Train: A Subgroup Analysis from
July 2004
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.
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 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
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