It Keeps on Glowing
Stents are now used routinely for catheter-based coronary revascularization procedures. Early clinical trials of stents demonstrated reduced rates of angiographic restenosis compared with balloon angioplasty alone.1 2 3 In a registry analysis of 1403 patients, 64% of whom were treated with stents, the need for repeat revascularization was 39% less than in a similar cohort having coronary intervention in the prestent era.4 In addition to enhancing the durability of coronary angioplasty, stents appear to improve its safety. As stent usage has increased further, the rates of abrupt artery closure and complex dissection associated with catheter-based interventions have declined progressively from 2% to 1% and from 11% to 5%, respectively.5 Stents have also expanded the pool of patients suitable for nonsurgical revascularization. Lesions that are treated currently are longer and are located in more tortuous and smaller arteries.
Although stents substantially reduce the relative risk for lesion recurrence, the absolute chance of experiencing restenosis is still significant. Furthermore, when restenosis occurs within a stent, conventional treatments are of limited value, as repeat in-stent restenosis is observed in 54% to 66% of patients.6 7 8 There have been many attempts to improve on these results by placing a new stent within the original stent and supplementing repeat balloon angioplasty with excimer laser, high-speed rotational atherectomy and directional atherectomy. None of these strategies, however, have proved particularly successful.
Studies using intracoronary ultrasound have demonstrated that in-stent restenosis is due to neointimal tissue proliferation.9 Considering that radiation has been effective in the treatment of other hyperplastic disorders, both benign and malignant, investigators speculated that locally applied radiation might be useful for the treatment of restenosis, especially in-stent restenosis. Accordingly, intracoronary brachytherapy, using both β- and γ-emitting sources, has been evaluated intensively.6 7 8 10 11 12 Several randomized clinical trials have focused on in-stent restenosis. Data are available from 3 studies that used 192Ir.6 7 8 The results are remarkably consistent and demonstrate impressive benefit, with treatment effects in the range of 50% to 60%. β-Sources have also been evaluated for in-stent restenosis, as well as for de novo and restenotic lesions not previously stented.10 11 12 Preliminary observational results are similarly encouraging.
Although we have had considerable experience with intracoronary brachytherapy in the short-term, our knowledge of late patient outcome is limited. Natural questions relate to the sustained effectiveness of intracoronary brachytherapy and its safety. Does brachytherapy provide permanent protection against restenosis, or is the process merely delayed? Is intracoronary brachytherapy harmful? Will it result in myocardial damage and dysfunction with eventual heart failure? Will we see pericardial disease? Does brachytherapy accelerate atherosclerosis in neighboring coronary arteries? Do treated arteries undergo degeneration or expansion or form aneurysms?13 In this issue of Circulation, Teirstein and coauthors14 add important information to help answer these questions. They report the 3-year clinical and coronary angiographic outcome of patients enrolled in a trial that initially established the benefits of intracoronary brachytherapy in treating restenosis.
Several aspects of the Teirstein report are worth noting. First, the study was composed of patients with restenosis; some had been treated previously with a stent. Thus, the results of the trial apply to a mixed group of patients presenting with restenosis rather than just to a specific subset. Some had in-stent restenosis, and some did not.
For these patients, the cumulative 3-year rate of target-lesion revascularization was substantially lower among those receiving brachytherapy (15.4%) than among those treated by conventional techniques (48.3%). The restenosis rate for radiated patients having follow-up coronary angiography was 33.3% compared with 63.6% for controls. This independent, parallel assessment further validates treatment effectiveness. Also, when target-lesion revascularization occurred in either group, it nearly always occurred within the first 6 months. Thus, the effectiveness of intracoronary brachytherapy was sustained over the 3-year period. There was no evidence of delayed restenosis in treated patients. Importantly, the benefits of radiation remained substantial even when restenosis at the edges of the original lesions was classified as a treatment failure.
Second, adverse clinical events suggestive of serious myocardial or arterial damage from radiation were not identified. Review of hospitalizations for cardiac causes did not reveal the development of excessive heart failure or pericarditis. Furthermore, follow-up coronary angiography did not detect any coronary aneurysms or pseudoaneurysms among treated patients.
Third, there was considerable revascularization for lesions other than the original restenotic lesions. It is not likely that radiation was responsible for these events, because the rates of nonindex lesion revascularization were similar in both the radiated and control groups. More likely is the explanation that coronary artery disease is a progressive illness, and measures to attenuate disease progression are required as adjuncts to revascularizations.15
Fourth, a 0.37-mm decline in the mean value of minimal lumen diameter was observed in 17 irradiated patients but not in 10 control subjects. The significance of this observation is unclear. Both the magnitude of this change and the size of the group in which it was observed were small. Additional observations from larger patient cohorts will be needed for clarification.
Although this report helps to address several important questions about intracoronary brachytherapy, the small number of patients in the trial, the form of brachytherapy used, and the types of patients enrolled leave many additional, important questions unanswered. For example, we need to know more about each specific patient subgroup, including those who receive brachytherapy with or without a prior stent and with or without a new stent. Late stent thrombosis has been described recently. This condition, often presenting as unstable angina or acute myocardial infarction, appears to be strongly associated with the use of radiation, a fresh stent, and discontinuation of antiplatelet therapy. We fully expect to overcome this disorder and need to demonstrate this accomplishment convincingly. Because β-radiation is more “user friendly” and likely to be adopted with enthusiasm, we need to learn about its long-term effects. Finally, how long is long term? Given the 5 to 15 years that may be required to detect certain cardiac effects of radiation,16 we need to extend our observations after intracoronary brachytherapy beyond 3 years.
We appreciate the efforts of Teirstein and colleagues in the field of coronary brachytherapy for their initial and continued research. These efforts have clearly demonstrated that intracoronary brachytherapy can reduce the incidence of restenosis in both the short and long term and that it is of particular value to patients with in-stent restenosis for whom there is no effective catheter-based alternative. Although we are reassured by the safety data available through 3 years of follow-up, we encourage continued surveillance by early investigators to further augment our understanding of this very important and potent therapy.
The authors wish to thank Arlene S. Grant for assisting in the preparation of this manuscript.
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
- Copyright © 2000 by American Heart Association
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