EDITORIAL COMMENT
Vascular brachytherapy and coronary stenting for de novo lesions
Love on the rocks*
Ron Waksman, MD, FACC ,*
Washington Hospital Center, Washington, DC, USA
* Reprints requests and correspondence: Dr. Ron Waksman, Washington Hospital Center, 110 Irving Street, NW, Suite 4B-1, Washington, DC 20010, USA.
ron.waksman{at}medstar.net
Although vascular brachytherapy (VBT) has proved to be effective and safe for the treatment of in-stent restenosis (1–8), its role in the treatment of de novo lesions remains unclear. The clinical trials that were designed to study the effectiveness of various beta radiations for the treatment of de novo coronary lesions reported mixed results. Although feasibility studies such as the Beta Energy Restenosis Trial (BERT) (9), which used 90Sr/Y, the Proliferation Reduction and Vascular Energy trial (10), which used P-32, and the Dose-Finding Study (11), which used a Y-90 emitter, suggested the efficacy and safety of beta radiation for the prevention of restenosis of de novo lesions, the pivotal BetaCath study failed to demonstrate efficacy and raised questions about the safety of using VBT, especially as adjunct therapy to the coronary stenting of de novo lesions (12).
The main pitfalls of the BetaCath study were its high incidence of late thrombosis, which was controlled with the administration of prolonged antiplatelet therapy, and the edge effect stenosis phenomenon, which was attributed to geographical miss and insufficient coverage of the injured margins with a sufficient radiation dose (12). As a result, beta-radiation therapy was abound for the prevention of restenosis for de novo lesions and was restricted for the prevention of the recurrence of in-stent restenosis.
During the last two years there have been several attempts to revisit and study the possibility of using VBT for the treatment of de novo lesions. These studies were inconclusive and had mixed results. The two studies presented in this issue of the Journal, by Serruys et al. (13) and Sabaté et al. (14), were designed to study the impact of VBT on stented coronary arteries and attempted to implement lessons from previous VBT studies with an emphasis on prolonged antiplatelet therapy—a minimum of six months—and the avoidance of geographical miss. Whereas the Beta-Radiation Investigation with Direct stenting and Galileo in Europe (BRIDGE) study was a multicentered study conducted on patients with single lesions  18 mm, the study by Sabaté et al. (14) was a single-center study that focused on diabetic patients.
The strength of these studies was that they were prospective, randomized, controlled trials that both chose a primary end point reflecting the impact of beta irradiation on neointimal proliferation at six months, either by angiographic intrastent late loss by quantitative coronary angiography in the BRIDGE study or by or intravascular ultrasound alone in the study by Sabaté et al. (14). Both studies had small patient cohorts and were underpowered to detect secondary end points such as clinical events. Nevertheless, both studies met their primary end points, although these were not translated to clinical utility. In both the BRIDGE study and the study by Sabaté et al. (14), a significant reduction in the neointimal volume was noted in the radiation group, which resulted in significantly lower late loss when compared with the controls. Furthermore, the absolute neointimal volume in the irradiated group of the Sabaté et al. (14) study was even lower when compared with the neointimal volume of the patients in the BRIDGE study, in which only 15% had diabetes. Thus, these results confirm observations from previous studies reporting that vascular radiation therapy continues to be an effective therapy in the diabetic populations as well (15).
The authors of the BRIDGE study claim that direct stenting and the use of glycoprotein IIb/IIIa blockers optimized all procedural steps with radiation therapy. To date, however, there are no reports supporting that these additional features do indeed optimize radiation therapy. In fact, direct stenting and the use of glycoprotein IIb/IIIa failed to affect restenosis rates with metallic stents and drug-eluting stents. In contrast, the key factors considered essential in improving the results of VBT are adequate dosimetry and radiation coverage with wide margins to avoid geographical miss (16,17) and prolonged antiplatelet therapy to prevent late thrombosis. Nevertheless, the execution of these features was far from optimal; in the BRIDGE study, 21% of vessels had documented geographical miss, suggesting misplacement of the source in relation to the stent position. This rate of geographical miss is unexpected because 32-mm sources are supposed to cover stents of 18 mm with no geographic miss.
The authors of the BRIDGE study disclosed that at least three patients from the radiation group had stent thrombosis related to premature clopidogrel withdrawal, which suggests that these patients were not under optimal management with antiplatelet therapy in relation to VBT. For patients undergoing VBT today, it is recommended that they be given clopidogrel for at least 6 months (preferably for 12 months) for cardiac event reduction (18).
Similarly, in the Sabaté et al. (14) study, most of the target vessel revascularization was an edge effect that occurred because of geographical miss. All late thrombosis events occurred as a result of clopidogrel withdrawal. Therefore, although the intent of these two studies was to treat patients with VBT under full optimization at every step, those steps were poorly executed and resulted in undesired events such as edge effect and late thrombosis.
The authors of both studies claim that despite the significant reduction of late loss in-stent, this result did not translate into clinical utility in terms of angiographic restenosis, target lesion, and vessel revascularization reduction. It is important to remember that these studies were not powered to detect differences in clinical events between the two treatments arms. However, the lack of any difference between the two groups and the late thrombosis that led to acute myocardial infarction events in the irradiated group raise a legitimate question: Can we marry stents and radiation for the prevention of restenosis of de novo lesions? The data from the present studies and previous studies, including the stented arm of the BetaCath study, indicate that the marriage between these two promising technologies is problematic and resembles a "love on the rocks" kind of relationship.
In an attempt to address this question and to resolve the edge effect, we preformed a series of preclinical studies in which stents were placed in porcine coronaries and were irradiated with different doses and different radiation margins. We reported that the edge effect can be eliminated when stents are placed in non-injured vessels and irradiated if the radiation margins are at least 15 mm in length from the injured segment and a higher dose of nearly 20% is prescribed (19). It is possible that the radiation margins used in the BRIDGE and Sabaté et al. (14) studies (<10 mm) were not sufficient to eliminate the edge effect.
The major complication in the presented studies was the presence of late thrombosis, which led to acute myocardial infarction and death. From other studies, we know that this complication can be controlled and nearly eliminated with prolonged antiplatelet therapy. In the stented arm of the BetaCath study, late thrombosis was eliminated with a prolonged antiplatelet therapy of at least 60 days, but the doses prescribed in the present studies were higher and therefore required a longer duration of the antiplatelet therapy, perhaps a minimum of 12 months.
In the Saphenous Vein Graft Beta Radiation to Prevent In-Stent Restenosis study (20), radiation was used in de novo saphenous vein graft lesions, the majority of which were stented and irradiated with adequate margins and prolonged antiplatelet therapy (a minimum of six months). A low recurrence rate and absence of late thrombosis were reported.
Nevertheless, with the introduction of drug-eluting stents, the strategy of stenting and radiation for the prevention of restenosis of de novo coronary lesions has become futile and may be valid only for insulin-requiring diabetic patients, who are reported to have higher rates of restenosis in the pivotal studies of drug-eluting stents (21). In contrast, radiation therapy was associated with the same results for diabetic patients as for non-diabetic patients, and its ability to reduce neointima formation after metallic stenting also was demonstrated in the study of diabetic patients by Sabaté et al. (14). Thus, only a comparison of drug-eluting stents to radiation therapy with bare metal stenting will determine which of the two approaches is preferable. If diabetic patients continue to experience restenosis with drug-eluting stents, this may merit a study to examine the safety of a combination therapy of VBT and drug-eluting stenting.
Therefore, with the dissemination of drug-eluting stents for the treatment of de novo lesions, the only role left for VBT in the treatment of de novo lesions remains as adjunct therapy for non-stented lesions. The data for the treatment of non-stented lesions with VBT are favorable and are reported in numerous studies, including BERT (9), the Dose-Finding Study (11), the balloon arm of the BetaCath study (12), and the Re-188 liquid-filled balloon study (22). All demonstrated that VBT resulted in acceptable outcomes when applied to de novo lesions. In these studies, the radiation arm performed better, with less restenosis and with the potential for favorable remodeling, when compared with the control arm. Even if we fix the edge effect and eliminate the late thrombosis phenomenon, it would be difficult to justify the use of VBT as adjunct therapy for stenting as an alternative to drug-eluting stents. However, with its ability to inhibit neointima formation, the role of VBT in the treatment of de novo lesions will be limited to the non-stented ones—whether pretreated with balloon or other non-stented devices.
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Footnotes
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Dr. Waksman is entitled to royalties from vascular brachytherapy devices used for the prevention of restenosis.
* editorials published in the journal of the american college of cardiology reflect the views of the authors and do not necessarily represent the views of jacc or the american college of cardiology. 
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References
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