doi: 10.1161/01.CIR.0000082928.33891.B7
(Circulation. 2003;108:386.)
© 2003 American Heart Association, Inc.
Mini-Review: Expert Opinions |
Coronary Brachytherapy in the Drug-Eluting Stent Era
Don’t Bury It Alive
From the Division of Cardiology (R.W.), Washington Hospital Center, Washington DC, and Intervention Cardiology Center (J.W.), New York Presbyterian Hospital, New York, NY.
Correspondence to Ron Waksman, MD, Washington Hospital Center, 100 Irving St, NW, Suite 4B-1, Washington, DC 20010. E-mail ron.waksman{at}medstar.net
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Introduction |
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 Top Introduction Coronary Brachytherapy and Drug...Cost Effectiveness and...References |
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When vascular radiation was proposed as a therapy for restenosis prevention more than a decade ago,1 it was received with skepticism. After 20 years of failure to reduce the restenosis rate with various systemic pharmacological agents and devices, it seemed unlikely that intracoronary radiation therapy would successfully defeat this seemingly intractable clinical problem. Vascular biologists challenged the a priori effectiveness of the therapy on the basis of previous experiences with (external-beam) radiotherapy involving vascular structures, and pathologists predicted either delayed restenosis or aneurysm formation at the radiated site. Logistic problems were envisioned; would it be feasible to handle radioactive sources in the catheterization laboratory or accept the radiation oncology team as part of routine percutaneous coronary intervention (PCI)? A combination of dedicated radiation biologists, physicists, oncologists, and cardiologists persisted in demonstrating how this therapy could be safely and effectively utilized to reduce rates of restenosis. They proceeded to optimize intracoronary radiation therapy and make it a safe, feasible, effective, and clinically useful tool to reduce restenosis.
Today there are 3 radiation delivery systems approved for routine clinical use in the United States for the treatment of in-stent coronary restenosis (ISR), as follows: a 
-emitting system utilizing the radioisotope Ir192 and 2 ß-emitting systems utilizing P32 and Sr90/Y90 sources. The data supporting approval of these technologies for clinical use came from randomized clinical trials that demonstrated superiority of adjunctive intracoronary radiation therapy, or vascular brachytherapy (VBT), over conventional treatment for ISR.2–8 Subset analysis confirmed the benefit of VBT in ISR lesions of varying lengths and vessel diameters, native artery and aortocoronary saphenous vein graft targets, and/or the presence of diabetes.9,10 In 2002, nearly 50 000 brachytherapy procedures were performed for patients with ISR in >500 catheterization laboratories worldwide.
With experience, the application of VBT has become more refined. Limitations and complications of the technology, such as edge effect and late thrombosis, were largely overcome by improvements in technique and adjunctive therapy.11 Brachytherapy is associated with delayed healing after PCI. This was of particular importance when a new stent was placed in the radiated field. The delayed healing led to observation of delayed "subacute thrombosis." Antiplatelet therapy, using clopidogrel for 12 months, has been shown to effectively eliminate late stent thrombosis.12 Another problem identified in early studies was an excess of recurrences after brachytherapy treatments at the edges of the radiated field. The basis for this phenomenon is complex, involving both "geographical miss," in which there is mismatch between the radiated segment and the intervened arterial segment, and an appreciation of the importance of therapeutic doses to the entire area of intervention, not simply the original lesion. Animal studies had clearly demonstrated the ability of subtherapeutic doses to stimulate restenosis in an injured arterial segment.13 Wide therapeutic radiation margins, which bracket the segment of intervention and include at least 5-mm margins at each end, were shown to reduce the edge effect phenomenon.14 A therapeutic dose range was identified, and the 5-year follow-up data demonstrated longevity of efficacy despite some late catch-up phenomena without adverse events related to the radiation therapy.15 Since the release of coronary brachytherapy systems for general clinical use, the most recent postmarketing surveillance registry of 3695 patients treated with the Sr90/Y90 system for ISR has revealed a clinically driven target vessel revascularization rate of 3.8% at 6 months (Source, Novoste Corp [Norcross, Ga]), compared with historical rates of recurrence of 40% to 50% in patients with ISR. Interestingly, studies of the use of brachytherapy to prevent restenosis of de novo lesion PCI failed to show a difference between control and VBT groups. Although there are signals from small trials5,16,17 that VBT has the potential to reduce restenosis for de novo lesions (especially for nonstented ones), at this time the evidence does not support generalizing this technology for de novo PCI. If brachytherapy could be shown to prevent restenosis in de novo lesions, the use of VBT might be expanded to high-risk patient populations such as those with diabetes; those with small vessels; or those with peripheral vascular stenoses with unacceptably high restenosis rates, such as superficial femoral artery (SFA) lesions.
Recently the application of VBT has expanded beyond coronary circulation with the use of VBT for de novo SFA lesions. Initial studies demonstrated the utility of brachytherapy to prevent restenosis in SFA lesions.18,19 Whether VBT will be included as ancillary therapy for other noncoronary sites is under clinical investigation.
Finally, in recent months, the availability, efficiency, and logistics of VBT have been improved with the integration of the radiation oncology team in the dynamics of the catheterization laboratory environment, and by regulatory allowance for any authorized user (not limited to the radiation oncologist) to supervise and handle the radiation delivery system. With 3 to 5 minutes of dwell time with the ß systems, the overall procedure does not add more than 15 minutes to the intervention.
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Coronary Brachytherapy and Drug-Eluting Stents |
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TopIntroductionCoronary Brachytherapy and Drug...Cost Effectiveness and...References |
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VBT was never intended to be the sole therapy for restenosis prevention, but it did convincingly demonstrate the ability of radiation to prevent neointima generation inside a stented artery. The postulated mechanisms for this effect included cell cycle arrest, inhibition of cell migration, interference with elaboration of extracellular matrix, and possibly positive vascular remodeling. This recognition led to development of drug-eluting stents (DES) using agents trying to locally mimic the effects of VBT. Preclinical studies with DES in the porcine stented model demonstrated "radiation-like" results. Later, results from the clinical trials of Sousa et al20 and RAVEL (RAndomized study with the sirolimus-eluting BX VELocity balloon-expandable stent [Cypher])21 created the unrealistic expectations of attaining 0% restenosis.
When studied in larger patient populations and in more complex lesion subsets, the rate of target vessel failure (death, myocardial infarction, or target vessel revascularization) was reported at 8.6% overall. Although this failure rate is statistically significantly lower than that of controls (21%), questions have been raised concerning a predisposition of the underlying stent platform to stimulate neointimal hyperplasia and thus increase the apparent benefit of the drug. The SIRIUS study (a multicenter randomized double-blind study of the SIRolImUS-coated BX Velocity stent) was designed to assess the safety and effectiveness of the sirolimus-eluting BX Velocity stent in reducing target vessel failure in de novo native coronary artery lesions compared with the uncoated BX Velocity stent. In the sirolimus-eluting-stent arm, the study showed restenosis rates of up to 18% in diabetic patients (35% in those with insulin dependence) and 16% in patients with small vessels and diffuse lesions.22 A recent registry of patients with bifurcation lesions disclosed a restenosis rate of up to 31% in this difficult subset of lesions.23 So far, except for sirolimus and taxol,20–22,24 all other stent-based compounds studied, including Taxene, actinomycin D, tacrolimus, dexamethasone, and batimastat, have failed to show efficacy to significantly reduce restenosis in clinical trials. In the first 140 patients treated with the Cypher (Cordis, Inc) stent in Milan, the rate of death was 2.9%, of Q-wave MI was 2.1%, and of target vessel failure was 17.9%, suggesting that high rates of restenosis will remain with the use of DES.25
To date, all published studies of sirolimus-eluting stents or Taxol stents have been in patients with de novo lesions in native coronary arteries. Anecdotal reports of the use of sirolimus stents to treat previously intervened arteries have observed 6-month major events in more than one third of the patients treated. What are the consequences of treating restenotic lesions with DES? Does the restenotic tissue represent a different substrate for the local diffusion of the drug? Moreover, what effect does previous irradiation have on drug eluted from the stent? This is likely to be agent specific. Is there a higher risk for late aneurysm formation? Late stent malapposition (erosion or separation of the endoluminal vessel surface from the stent struts) was increased by at least 10% in patients who received the sirolimus DES but appears to be without accompanying adverse clinical events. A critical issue to be studied is the safety of treating DES-associated restenosis with VBT. Will the previous drug alter the dose response to VBT? Further, will VBT degrade or alter the nonresorbable polymer? The drug is usually eluted over 2 to 4 weeks and is likely not present >12 weeks after DES deployment. Thus, the nonresorbable polymer is the most likely substance to be altered by VBT. What modification of dose and VBT technique will need to be implemented to safely treat the failures of this latest class of devices? It is important to understand that local therapies, be they physical or pharmacological, are likely to be associated with biological modifications affecting responses of the arterial segment for long periods of time.
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Cost Effectiveness and Alternatives |
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TopIntroductionCoronary Brachytherapy and Drug...Cost Effectiveness and...References |
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In Europe, 12 months after approval of the sirolimus-eluting stent, its clinical penetration rate ranges between 5% and 10% of PCI procedures. It is clear that economic considerations will limit initial penetration of DES to treat de novo PCI. Thus, restenosis both from existing bare-metal stents and from DES will continue to be a feature of clinical care for the foreseeable future. Although there is a good understanding today of the treatment options for bare-metal ISR, a similar treatment strategy has not been articulated or studied for DES restenosis.
So far, the efficacy of DES for the treatment of ISR has had mixed results. Comparative studies of DES versus VBT for this indication are warranted. Even if DES is as effective as VBT for ISR, scenarios exist in which one therapy may be preferable. For example, long segments of ISR, a "full metal jacket" of restenosis might prove problematic for restenting with DES.
Lastly, VBT remains a proven method of restenosis prevention for the treatment of ISR, and its role in treating DES restenosis remains to be studied. VBT will likely remain a treatment for DES failure in the peri-stent zones, although more clinical investigation is necessary to delineate efficacy and safety in this situation. As long as restenosis remains a clinical problem, it is likely that VBT will be an important modality for its treatment; so for the time being, don’t bury it alive.
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Footnotes |
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The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
Dr Waksman serves as a consultant to Guidant Corp and is entitled to royalties from Emory University related to inventions in the radiation field.
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References |
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TopIntroductionCoronary Brachytherapy and Drug...Cost Effectiveness and...References |
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1. Wiedermann JG, Marboe C, Weinberger J, et al. Intracoronary irradiation markedly reduces restenosis after balloon angioplasty in a porcine model. J Am Coll Cardiol. 1994; 23: 1491–1498.[Abstract]
2. Teirstein PS, Massullo V, Jani S, et al. Catheter-based radiotherapy to inhibit restenosis after coronary stenting. N Engl J Med. 1997; 336: 1697–1703.
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4. Leon MB, Teirstein PS, Moses JW, et al. Localized intracoronary -radiation therapy to inhibit the recurrence of restenosis after stenting. N Engl J Med. 2001; 344: 250–256.
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