In-stent restenosis: intracoronary ß-radiation at the crossroads

R Seabra-Gomes

Hospital de Santa Cruz, Institute do Corção, Av. Prof. Reynaldo Dos Santos, Carnaxide Linda-a-Velha, 2795 Lisbon, Portugal

E-mail address: seago{at}esoterica.pt

See doi:10.1016/S1095-668X(02)00617-6for thearticle to which this editorial refers.

In-stent restenosis, particularly of the diffuseand proliferative types, remains a major concern after percutaneous coronary interventions. Smooth muscle cells proliferation has been considered the main constituent of early restenotic plaques and there is evidence that late extracellular matrix production and chronic inflammation can also occur.1 The incidence of recurrent in-stent restenosis is known to be much higher than after initial stent placement and relates with longer lesion or stent length, smaller vessel diameter, saphenous vein grafts, presence of diabetes, etc.2

If vascular radiation is controversial for patients with de novo lesions,3 several randomized clinical trials of intracoronary brachytherapy for in-stent restenosis already published,4–9 have confirmed that this form of treatment is efficient in reducing recurrent restenosis, when compared with conventional mechanical percutaneous interventions. Both gamma and beta sources are effective. The results of the GAMMA I trial6 with 192Ir, theSTART trial9 with 90Sr/90Y and the INHIBIT trial7 with 32P, are all concordant. They have proventhat intracoronary brachytherapy was the firsteffective antiproliferative strategy for in-stentrestenosis.

The problems related with this form of treatment are also known. They are the generalization of the treatment requiring the cooperation of physicists and radiation oncologists, the possibility of late stent thrombosis related with the short- term duration of the double antiplatelet therapy (aspirin+ticlopidine/clopidogrel) plus the use ofadditional stents, and the edge failure. The fact that restenosis outside the stent is higher than within the stent, might be accounted for by the geographic miss at the time of treatment or by the edge effect of balloon or other forms of mechanical interventions before the application of radiation. This has lead to the suggestion to use longer radiation sources and it is now suggested that a safety margin of 10mm per vessel is used to minimize the geographic miss.10

Although in the United States gama radiation is more widely used, the European experience has been mainly with beta sources of radiation(strontium and iridium 90).11 The limitations of gamma use are the prolonged dwell times, the need of extensive shielding and the requirement forlaboratory personnel to leave the room during brachytherapy administration.

Urban et al., report in the current issue of the Journal12 the results of the RENO Registry. In 46 European centers, 1098 patients were treated with Sr/Y90intracoronary radiation using the BetaCathTM (Novoste) system, between 1999 and 2000. This makes it the biggest registry of beta radiation in clinical practice and in Europe, soon after efficacy demonstrated by clinical trials, thus allowing for the assessment of effectiveness, feasibility, learning curve and safety issues. Exclusion criteria, often used in trials (long lesions, chronic total occlusions, saphenous vein graft, multivessel procedures, etc.), were not applied in this Registry.

The main conclusion of the study reinforces the idea that the major current application of vascular brachytherapy is for the treatment of in-stentrestenosis.

In-stent restenosis accounted for 878 (77.7%) of the patients included in the RENO Registry. This allows a comparison with the 244 patients included in the radiation arm of the START trial,9 recently published, which was the first multicenter, randomized, placebo controlled trial, demonstrating that intracoronary brachytherapy with 90Sr/90Y beta-radiation reduced angiographic and clinical recurrence of in-stent restenosis.

Within the same age group (62 years), patients in the RENO had less diabetes (24 vs. 31%) and hypertension (64.1 vs. 72%) with slightly more hyperlipidemia (79.9 vs. 77%). In the START, there were more patients with unstable angina (74 vs. 24.8%) and prior myocardial infarction (47 vs. 37.9%), but less multivessel disease (37 vs. 49.4%). The mean reference diameter of the vessel with in-stentrestenosis was higher in the RENO (3.2±0.5 vs. 2.76±0.48mm) as well as the mean lesion length (19.4±12.3 vs. 16.3±7.2mm), with only 29% of the lesions in the START longer than 20mm. The main significant difference between the two studies was in the length of the beta source used. The 30-mm source was used in 14.7% of lesions in the RENO (vs. 94.9% in the START), the 40-mm source in 81.1% (vs. 5.04%) and the 60-mm source in 4.2% (vs. 0%). With very high technical success (96%) in the RENORegistry, the incidence of both in-Hospital MACE (1.7 vs. 2.5% in the START) and MACE at 6 months follow-up (17.7 vs. 19.1%), was similarly low, and the same was observed for target vessel revascularizations (by PCI 12.3 vs. 8.3% and by CABG 3.3 vs. 9.1%). With angiographic follow-up in 70.9% ofpatients of the RENO Registry, the restenosis rate (including 3.6% occlusions) was 23.7% (which compares well with the 14.2% in the stented segment, 18.2% in the injured segment, 24.4% in the irradiated segment and 28.8% in the analysis segment of the START Trial with 8 months angiographic follow-up in 83.2% of patients).

Therefore, with all limitations of a multicenter registry, the RENO study has confirmed the safety and efficacy of beta radiation for in-stent restenosis in clinical practice, with short- and medium-term results reproducible to thoseobtained in randomized trials. The SCRIPPS follow-up data with gamma radiation have already suggested that the efficacy of brachytherapy can be sustained over the period of 5 years.13

Why is then brachytherapy at the crossroads? The threat comes at the moment from drug-eluting stents. Recent published and reported data on the use of drug-eluting stents have shown a dramatic reduction of restenosis in normal size vessels (2.5–3.0mm) and relatively short lesions (<20mm).14–16 If these initial results would be confirmed, for those subsets of lesion or patient characteristics, where the problem of diffuse and recurrent in-stent restenosis is more accurate, then the need for future brachytherapy would be minimal.

The latest SIRIUS data recently presented,17 have shown in-stent restenosis of 5.3% andin-segment restenosis of 18.6% for vessels <2.5mm, with target lesion revascularization of 7.3%. For the worst cases of small vessels, diabetics and lesions longer than 15mm, the in-segment restenosis was reported to be of 23.7%.18 Therefore, the problem might not be solved yet.

As usual, many questions still remain to beanswered. Will all drug-eluting stents give identical results? Are drug-eluting stents the final word or newer uncoated stent technologies (such as cobalt–chromium stents) will become an alternativestrategy? Can we, or how safe would be, to use brachytherapy after drug-eluting stents? Should drug-eluting stents be the prefered option for in-stent restenosis? What will be in the future the recommended strategy for long lesions of small vessels in diabetic patients?

Finally, another problem, always present in the back of our minds, might become quite decisive, in the future. Should the economic issue influence our clinical decisions? The fact is that at the moment drug-eluting stents are initially quite expensive and brachytherapy is already an established, clinical and economic, alternative for in-stent restenosis.19 Prospective economic analysis is certainly needed, when it is expected that restenosis and targetvessel revascularization will be reduced with drug-eluting stents. For how long is the crossroads to be maintained, is a question whose answer shouldbe given in the shortest time possible.

References

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Related articles in EHJ:

A multicentre European registry of intraluminal coronary beta brachytherapy
P. Urban, P. Serruys, D. Baumgart, A. Colombo, S. Silber, E. Eeckhout, A. Gershlick, K. Wegscheider, L. Verhees, R. Bonan, and For the RENO investigators
EHJ 2003 24: 604-612. [Abstract] [Full Text]  




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