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Original Contribution
Beta Radiation in Lesions > 15 mm: A START Subgroup
November 2003
While stents have reduced the risk of restenosis,1–3 they induce neointimal hyperplasia,4 and rates of in-stent restenosis following intervention may be as high as 60%,5 particularly in long lesions.6 Studies of gamma-radiation therapy following treatment for in-stent restenosis have demonstrated considerable reduction in the incidence of clinical and angiographic restenosis as compared with placebo.7–11 Late thrombosis has been a problem, and while its origin is poorly understood, it appears to be linked to the short duration of ticlopidine therapy, placement of new stents or the use of multiple coronary stents.12–15
Beta-radiation yields less tissue penetration than gamma sources and may offer practical advantages over gamma radiation.13,16 Recently, the Stents and Radiation Therapy (START) trial (n = 476) compared the safety and effectiveness of intracoronary beta radiation using a 90Strontium/90Yttrium (90Sr/90Y) isotope with a 28-year half-life and a placebo control following successful percutaneous intervention in patients with in-stent restenosis.17 Beta radiation reduced binary stent restenosis by 66% [from 41.2% with placebo to 14.2% in radiation-treated patients (p 15 mm were treated with intracoronary 90Sr/90Y beta radiation or placebo.
Methods
Patients and materials. In the START trial, which has been described in detail elsewhere,17 a total of 476 patients from 50 centers in North America and Europe were randomized to intracoronary 90Sr/90Y or a placebo. Patients were eligible if they were over 18 years of age and had a single target site of stent restenosis in a native vessel with a diameter of 2.7–4.0 mm, with lesion lengths treatable with a 20 mm balloon.
In this subgroup of the START trial, data were analyzed from a total of 239 patients with lesions > 15 mm. All patients in the START trial were pretreated with 325 mg aspirin before the procedure and received intracoronary treatment with 90Sr/90Y or placebo using the 30 mm source train incorporated in the Beta-Cath™ System (Novoste Corporation, Norcross, Georgia). The patient, interventional cardiologist, radiation oncologist and cardiac catheterization staff were blinded to the treatment assignment. Following successful treatment, patients received aspirin (325 mg QD) for the duration of the study. If a new stent was placed within the in-stent restenosis site, patients enrolled from September 1998 until November 1999 received 325 mg aspirin QD for the duration of the trial and 250 mg ticlopidine BID for 14 days after the procedure. Due to the finding of significant target lesion thrombosis when beta radiation was used in a different trial, after November 1999, patients who received new stents were treated with 325 mg aspirin QD and 250 mg ticlopidine BID or 75 mg clopidogrel for at least 60 days post-procedure.12–15
Angiography. All cineangiograms were forwarded to a central angiographic core laboratory for analysis by observers blinded to treatment assignment and clinical outcome. Quantitative angiographic analysis was performed using a validated, automated edge detection algorithm [CMS-GFT, Medis (Leiden, The Netherlands)].13,17,18 The percent diameter stenosis (%DS) was determined by the mean reference diameter minus the minimum luminal diameter (MLD), divided by the mean reference vessel diameter. The post-procedure MLD minus the follow-up MLD determined late loss. Binary angiographic restenosis was defined as > 50% diameter stenosis at 8 months.
Clinical endpoints. The occurrence of major clinical events was recorded throughout the 8-month study period. The primary efficacy endpoint was target vessel failure (TVF), a combined clinical endpoint that comprised death, myocardial infarction, and all clinically driven repeat target vessel revascularization (TVR). The occurrence of TVR was determined as clinically driven repeat revascularization due to > 50% stenosis within the treated vessel on follow-up angiography. Target lesion revascularization (TLR) was defined as clinically driven repeat revascularization due to > 50% stenosis within 5 mm of the analyzed segment. The primary safety endpoint was major adverse cardiac events (MACE), defined as a composite of death, myocardial infarction, emergent coronary artery bypass grafting (CABG) and TVR. Secondary efficacy endpoints included angiographic binary restenosis (> 50%), follow-up MLD and late lumen loss.
Statistical analysis. Binary variables are presented as rates, and continuous variables are presented as mean values ± standard deviations. Binary variables were compared using Chi-square analysis and continuous variables were computed using the Student’s t-test. A two-sided p-value 15 mm; we chose to evaluate the results of these longer lesions, which typically are associated with higher rates of restenosis than those 15 mm revealed significant reductions in MACE and TVF in a population that is thought to be particularly susceptible to in-stent restenosis, and are similar to those seen in the original START trial.17 Although geographical miss was not evaluated in the START trial or this subgroup, restenosis rates were not significantly different between patients with or without geographical miss in the original START trial, and there were no significant differences between the START and placebo groups in mean percent stenosis at the proximal or distal edges of the source train.17 Such results agree with a more recent study that has demonstrated infrequent occurrence of edge restenosis.21 Although a relationship between the occurrence of geographic miss and angiographic or clinical restenosis could not be identified, edge effect and geographic miss were not specifically evaluated in this study. The failure to identify a relationship between the geographic miss and restenosis may be due to the fact that the effective radiation length of 25 mm for the 30 mm source (accounting for the dose fall-off at the edges of the radiation source) was sufficient to adequately cover the margins in most injured zones. Additional studies are needed to understand the relationship between radiation doses at the edge of the treatment zone and late restenosis.17
In this subgroup analysis, there was no stent thrombosis (0–240 days). Although this small group is not sufficient to make any statements regarding the risk of in-stent thrombosis in beta treatment of in-stent restenosis, the overall START group also did not have any stent thrombosis. Late stent thrombosis may be a consequence of radiation-induced delayed endothelialization over stent struts,10 the use of a new stent within the target in-stent restenosis lesion or short-term dosing of antiplatelet therapies in radiation trials.12,13 However, more than 70% of patients in this subset received fewer than 60 days of adjunctive antiplatelet therapy. This is in variance to the Gamma I trial, where thrombosis occurred in patients treated with radiotherapy, but these were primarily patients that received new stents and none of the patients were on ticlopidine at the time the thrombotic event occurred.13
Study limitations. Currently, only 8-month follow-up data are available. Although the initial results of the START trial and this subgroup are encouraging, longer clinical and angiographic follow-up are planned to assess whether or not in-stent restenosis is prevented or simply delayed with beta radiation. Lesion lengths in this analysis were moderate, but not excessively long. This may influence the beneficial results of beta radiation therapy for this subset. Whether this can be expanded to lesions spanning several stents (> 30 mm) is unknown, but it is worth studying with either longer treatment trains or utilizing a pull-back technique.23 Plaque debulking devices, particularly rotational atherectomy, were used in more than 50% of patients (with similar frequency in both groups) and further analysis on the clinical utility of these devices, with or without adjunctive radiation therapy, is warranted.
Conclusion. In a subgroup of patients with lesions > 15 mm from the START trial, the clinical and angiographic data suggest that intracoronary beta radiation may prevent early recurrent restenosis in long lesions and reduce major complications and the need for revascularization. Additional studies will be required to evaluate whether these reductions persist in mid- to long-term follow-up and to determine whether or not late stent thrombosis can continue to be minimized.
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