A Multicenter, Randomized, Dose-Finding Study of Gamma Intracoronary Radiation Therapy to Inhibit Recurrent Restenosis after Ste

Intracoronary radiation therapy (ICRT) for in-stent restenosis within bare metal stents substantially reduces the risk of recurrence.^1–3 However, target vessel failure remains a significant clinical problem for some patients. A higher delivered radiation dose may improve results by decreasing the surviving fraction of smooth muscle cells and improving adequate dosing across heterogeneous and eccentric lesions. However, a higher radiation dose may be associated with adverse events such as late thrombosis and aneurysm formation.^4,5 The major randomized clinical trials that established the efficacy of gamma ICRT for restenosis used doses ranging from 12 to 15 Gy at 2 mm from the source.^1–3 The U.S. Food and Drug Administration (FDA) currently approves a dose of 14 Gy. We hypothesized that a modestly higher dose would improve angiographic and clinical outcomes without increasing adverse events. The Scripps Coronary Radiation to Inhibit Proliferation Post Stenting (SCRIPPS)-IV Trial was a double-blind, randomized, clinical trial that evaluated the safety and efficacy of an increased dose of gamma radiation from 14 to 17 Gy in patients with in-stent restenosis. Methods The trial was approved by the institutional review boards at the two study sites. Informed consent was obtained from each patient before enrollment in the trial. Criteria for eligibility. Patients were enrolled between September, 2000 and February, 2002. Patients were eligible for the study if they had in-stent restenosis within a bare metal stent of more than 60% of the luminal diameter by visual assessment of the angiogram, and had symptoms of angina or studies suggesting coronary ischemia attributable to the target lesion. The lesion was required to be less than 81 mm in length and within a native vessel or saphenous vein graft measuring greater than 2.75 mm and less than 4.0 mm in diameter. Before randomization, intervention on the target lesion had to be considered successful by the operator (residual stenosis less than 30% of the luminal diameter). Patients were excluded if they were intolerant of aspirin or clopidogrel; had an acute myocardial infarction in the previous 48 hours (defined as serum creatine kinase greater than two times the upper limit of normal with an elevated CK-MB); the coronary revascularization procedure was unsuccessful; or the target lesion had angiographic evidence of thrombus. Procedure. The patients were given aspirin (325 mg) and intravenous heparin in a dose sufficient to maintain an activated clotting time greater than 300 seconds. The in-stent lesion was treated using high-pressure (> 14 atmospheres) balloon inflations with a balloon-to-artery ratio of 1 to 1.2:1. If by angiography or intravascular ultrasound, a less than 30% residual stenosis was not obtained after balloon dilatation or a significant dissection was noted, one or more FDA-approved stents were implanted within and/or overlapping the original stent. Immediately after successful intervention, patients were randomized to receive either a 14 Gy or 17 Gy dose of gamma radiation at 2 mm from the source. Randomization was stratified based on lesion length greater or less than 15 mm and location of the target lesion within a native coronary or saphenous vein graft. All patients and study personnel, except for the medical physicist and radiation safety officer at each center (who had no role in outcomes assessment), were blinded to the treatment assignment. Following randomization, a short, monorail, closed-ended, noncentered, 4 Fr dedicated radiation catheter (Cordis Corp., Miami, Florida) was inserted over the intracoronary guidewire. A 25 mm lead shield was placed between the patient and the control room before treatment. The radiation oncologist then inserted a 0.76 mm (0.03 inch) source wire (Best Industries, Springfield, Virginia) containing sealed sources of iridium-192 into the delivery catheter. The source wire contained multiple 3 mm seeds containing iridium-192 separated by a 1 mm space. Fluoroscopic positioning of the study ribbon was performed by both the radiation oncologist and the interventional cardiologist so that vessel margins of at least 4 mm at both ends of the target lesion were treated. The total length of the source ranged from 23 to 87 mm (6, 10, 14, 18, and 22 sources). The ribbon was kept in place for the appropriate time to deliver the prescribed dose as determined by the radiation oncologist and medical physicist. It was then removed by the radiation oncologist and placed in an adequately shielded container. If the patient had not previously been taking clopidogrel, a loading dose of 300 mg was administered during the procedure. Patients were discharged the following day on aspirin 325 mg/day indefinitely, and clopidogrel 75mg/day for 6 months. Patients who received new stents during the index radiation procedure were treated with clopidogrel 75 mg/day for 12 months in addition to aspirin 325 mg/day indefinitely. Quantitative angiographic analysis. Quantitative angiographic analysis was performed at baseline and 8-month follow up by a core laboratory (Cardiovascular Research Foundation, Lenox Hill Hospital, New York, New York) blinded to the treatment assignments, using a validated edge detection program (Cardiovascular Measurement System, Medis Medical Imaging Systems, Nuenen, The Netherlands). Angiographic analysis was performed on the stented area (“in-stent”) and also on that stented area plus the adjacent 5 mm of the nonstented area on each side of the stent, and any additional region covered by the radiation source wire during treatment (“in-lesion”). Reference vessel diameter (RVD), minimal luminal diameter (MLD), acute luminal gain (MLD immediately after the procedure minus the MLD before the procedure), binary restenosis (stenosis of greater than 50% of the luminal diameter), percent diameter stenosis, and late luminal loss (MLD immediately after the procedure minus the MLD at follow up) were measured. Endpoints. Clinical follow up was performed at 1 and 8 months. All patients were requested to return for repeat coronary angiography at 8 months. Revascularization was performed at the discretion of the operator. Data were analyzed on an intention-to-treat basis. The primary endpoint of the study was in-lesion late luminal loss at 8-month follow up as determined by quantitative coronary angiography. Based on the results of the GAMMA II trial,⁶ which treated a similar cohort of patients and found a late loss of 0.6 ± 0.77 mm, a sample size of 304 analyzable patients was estimated to provide an 80% power to demonstrate a late loss reduction of 0.2 mm (33% relative reduction) assuming an alpha error of 0.05. Secondary endpoints included binary restenosis, the need for target lesion revascularization (TLR) at 8 months, the need for target vessel revascularization (TVR) at 8 months, and a composite clinical endpoint of death, Q-wave and non-Q-wave myocardial infarction, stent thrombosis or TLR. Non-Q-wave myocardial infarction was defined as an elevation in the creatine kinase (CK) more than twice the upper limit of normal and the presence of MB iso-enzyme twice greater than the upper limit of normal. Late thrombosis was defined as stent thrombosis confirmed by angiography or suspected by clinical history occurring more than 30 days after ICRT. For the analysis of continuous data, two-tailed t-tests were used to assess differences between the two treatment groups. Results are expressed as means ± standard deviation. Categorical data were compared with the use of the Chi-squared or Fisher’s exact test. Multiple logistic regression analysis was used to assess the relationship between TVR and multiple clinical and angiographic variables, including prior percutaneous intervention, age, gender, smoking history, prior myocardial infarction, prior coronary bypass surgery, randomization to 14 Gy rather than 17 Gy, reference vessel diameter, minimal luminal diameter, diameter stenosis and lesion length. Results A total of 336 patients were enrolled in the study. Baseline clinical and angiographic characteristics of the treatment groups are shown in Table 1. The groups were well matched with the exception of a greater number of males and diabetic patients in the higher dose arm. Overall, the mean patient age was 63 years, diabetes was present in 35% of patients, the mean lesion length was 22.7 mm, and the mean number of previous procedures at the target lesion was 1.8. Procedural and in-hospital outcomes. There were no significant differences in in-hospital outcomes between the two groups. TVR occurred in 2 patients in the 14 Gy group and in 1 patient in the 17 Gy group. There were no myocardial infarctions. One cardiac death occurred in-hospital in the 17 Gy group due to acute intraprocedural coronary closure resulting in myocardial infarction and death. Follow-up. Eight-month angiographic follow up was obtained and analyzable in 224 patients (67% of enrolled patients). Patients undergoing angiographic follow up were more likely male (76.2% versus 67.3%; p = 0.07), had a greater number of previous interventions on the target lesion (1.9 ± 1.1 versus 1.6 ± 0.8; p = 0.002), and a larger postprocedure lesion minimal luminal diameter (1.83 ± 0.44 versus 1.72 ± 0.47; p = 0.03) compared to patients who did not undergo follow up, while the frequency of diabetes mellitus (32.9% versus 38.4%; p = 0.33), the average lesion length (21.8 ± 13.0 mm versus 24.45 ± 15.0 mm; p = 0.13) and the mean reference vessel diameter (2.79 ± 0.47 mm versus 2.74 ± 0.49 mm; p = 0.29) were similar in both groups. Despite the lower-than-expected rate of follow-up angiography, indices of restenosis were lower in the 17 Gy dose group (Table 2). There was a strong trend toward a reduction in the primary endpoint of in-lesion late loss in the higher dose group (0.36 ± 0.63 mm versus 0.51 ± 0.64 mm; p = 0.09). The mean in-lesion minimal luminal diameter at follow up trended larger in the 17 Gy group compared to the 14 Gy group (1.48 ± 0.61 mm versus 1.32 ± 0.68 mm; p = 0.07). Angiographic restenosis within the stented area was observed in 37.5% of the patients in the 14 Gy group compared to 23.9% in the 17 Gy group (p = 0.03). In-lesion restenosis was lower in the higher-dose group, but the difference did not reach significance (36.4% versus 43.9%; p = 0.27). The higher dose significantly reduced the severity of recurrent restenosis, decreasing the incidence of total occlusion at follow up by 76% (2.7% versus 11.3%; p = 0.02). Two aneurysms were observed at angiographic follow up in the group receiving 14 Gy, while no new aneurysms were seen in the group receiving 17 Gy (p = NS). Clinical follow up at 8 months was completed in 99% of patients (Table 3). There were 3 episodes of late thrombosis (1.7%) in the low-dose group and 2 episodes (1.2%) in the high-dose group (p = NS). Significantly fewer patients in the 17 Gy group underwent TLR (15.2% versus 27.2%; p = 0.01) or TVR (21.3% versus 33.1%; p = 0.02). The composite clinical endpoint of death, myocardial infarction, stent thrombosis, or TLR was significantly reduced in the higher dose group (17.1% versus 28.4%; p = 0.02), driven primarily by decreased revascularization of the target lesion. By multivariate analysis, independent predictors of TLR at 8-month follow up were diabetes (odds ratio = 2.32; 95% CI, 1.25–4.32; p Discussion This prospective, double-blind, randomized study found that intracoronary gamma radiation therapy for in-stent restenosis with a dose of 17 Gy reduced recurrent restenosis at 8 months compared to 14 Gy, without increasing adverse events. The rate of repeat revascularization of the target lesion was reduced by 44%, and the rate of repeat revascularization of the target vessel was reduced by 36%. This is the first prospective, randomized clinical trial to demonstrate a dose-response relationship of gamma ICRT for the treatment of in-stent restenosis. The optimal dose of gamma ICRT for in-stent restenosis is unknown. We chose to study the impact of an approximately 20% increase in the radiation dose currently approved by the FDA. The target cell of ICRT is the smooth muscle cell residing within the media and intima, whose proliferation and extracellular matrix production is responsible for the neointimal hyperplasia that characterizes in-stent restenosis.⁷ A higher dose of radiation will decrease the surviving fraction of smooth muscle cells, potentially limiting this phenomenon, but may have adverse consequences such as vessel wall thinning and aneurysm formation.^4,5 The doses used in the clinical trials that established the efficacy of ICRT for restenosis were empiric: the doses used in radiation therapy to treat other benign diseases such as keloids, heterotopic bone formation, and Graves disease range between 8 and 20 Gy.⁸ In the SCRIPPS, GAMMA and WRIST randomized trials, the prescribed dose ranged from 12–15 Gy at 2 mm from the source (for vessels less than 4 mm in diameter). Although these trials demonstrated significant efficacy, recurrent restenosis still occurred in 17–32%, and major adverse cardiac events occurred in 15–28% of patients. If this proven range of radiation dose falls within the exponential growth portion of the sigmoid function that describes the therapeutic effect of radiation, even a modest escalation in dosage may lead to a significant improvement in outcomes. We hypothesized that an increase from 14 to 17 Gy would improve outcomes but remain within the therapeutic window for ICRT. Previous nonrandomized studies support the hypothesis that higher doses may safely improve clinical outcomes, particularly in patients at high risk for recurrent restenosis. The Long-WRIST High Dose Registry found a 39% relative reduction in clinical events in patients with long lesions (mean length 42 ± 8 mm) treated with 18 Gy compared to historical controls treated with 15 Gy.⁹ Our trial confirms the observations of that study in a randomized, prospective manner within a heterogeneous group of patients that reflect a “real-world” restenosis population. Importantly, the 8-month clinical event rates observed in the 14 Gy group (a TLR of 26.6% and TVR of 33.1%) are consistent with those of other clinical trials using a similarly prescribed dose. In GAMMA I, 9-month TLR was 24.4% and TVR was 31.3%.3 This strengthens our observation of additional efficacy at the higher 17 Gy dose. We observed that the higher dose led to a significant reduction in clinical events, while there was a strong trend toward benefit in the primary angiographic endpoint of late loss (p = 0.09). This paradox between clinical and angiographic outcomes is most likely explained by the nearly complete clinical follow up, but the less-than-expected angiographic follow up, thereby underpowering the study for the late loss endpoint. Angiographic follow up was performed in 75% of the patients required to provide the study with adequate power to detect a 33% reduction in late loss. Within this smaller group of patients, we observed a 30% reduction in late loss. Important predictors of restenosis, including diabetes mellitus, lesion length and reference vessel diameter, did not differ significantly between patients who underwent angiographic follow up and those who did not. The higher dose had a clear biologic effect, leading to a larger luminal diameter and smaller percent diameter stenosis at follow up. Our trial also demonstrated the safety of a prescribed dose of 17 Gy at 2 mm from the source. A higher dose of radiation may potentially lead to late adverse effects such as thrombosis, fibrosis, vessel wall thinning, and aneurysm formation.⁴ At 8-month follow up, the rates of early and late thrombosis were equivalent between the two dose groups and there was no difference in mortality. Late stent thrombosis (greater than 30 days postprocedure) occurred in only 1.5% of patients, and there were no episodes of early thrombosis. The low rate of thrombosis observed in our study further supports the findings of several previous studies that demonstrated the benefit of prolonged antiplatelet therapy after ICRT, especially after stenting.¹⁰ Recent data suggest a late “catch-up” phenomenon that may limit the long-term benefit of ICRT for the treatment of ISR.^11,12 Long-term follow up is required to determine whether this phenomenon is dose-related and can be mitigated by a higher prescribed dose. Drug-eluting stents have recently been shown to reduce the incidence of restenosis in native coronary arteries.^13,14 Nonrandomized, observational studies of drug-eluting stents to prevent recurrent in-stent restenosis show promise;^15–17 prospective, randomized clinical trials comparing the relative efficacy of drug-eluting stents and ICRT are ongoing. In light of our findings that an increased radiation dose can markedly improve clinical outcomes, it is imperative that sufficient doses be used in trials comparing drug-eluting stents to ICRT before the noninferiority or superiority of a new approach can be conclusively demonstrated. Moreover, the appropriate treatment for DES restenosis is unknown, and as increasingly complex, multivessel PCI is performed, the burden of DES restenosis will increase.^18,19 ICRT may represent a therapeutic option for such patients.²⁰ Our findings regarding the safety and improved efficacy of higher dosing for bare metal ISR should guide the appropriate dosing regimen used in clinical trials testing this strategy for DES ISR. Study limitations. The major limitation of this study was the lower-than-expected rate of angiographic follow up. Unfortunately, many of our patients had sustained multiple previous restenoses, and were reluctant to undergo another angiogram at 8 months if they were asymptomatic. Clinical follow up, however, was complete in 99% of the patients. Also, there were more patients with diabetes in the 17 Gy group; however, given the higher risk of recurrent stenosis in diabetic patients, this would tend to favor the 14 Gy group and underestimate the observed efficacy of the higher dose. Conclusions Compared to a dose of 14 Gy, gamma intracoronary radiation therapy with 17 Gy reduced recurrent restenosis within bare metal stents and substantially reduced clinical events at 8-month follow up, without increasing adverse events. Increasing the currently recommended dose prescription for the treatment of in-stent restenosis from 14 Gy to 17 Gy should be strongly considered.

1. Teirstein PS, Massullo V, Jani S, et al. N Engl J Med 1997;336:1697–1703. 2. Waksman R, White RL, Chan RC, et al. Intracoronary gamma-radiation therapy after angioplasty inhibits recurrence in patients with in-stent restenosis. Circulation 2000;101:2165–2171. 3. Leon MB, Teirstein PS, Moses JW, et al. Localized intracoronary gamma-radiation therapy to inhibit the recurrence of restenosis after stenting. N Engl J Med 2001;344:250–256. 4. Gillette EL, Powers BE, McChesney SL, et al. Response of aorta and branch arteries to experimental intraoperative irradiation. Int J Radiat Oncol Biol Phys 1989;17:1247–1255. 5. Giap H, Massullo V, Teirstein PS, Tripuraneni P. Theoretical assessment of late cardiac complications from endovascular brachytherapy for restenosis prevention. Cardiovasc Radiat Med 1999;1:233–238. 6. Wong SC, Teirstein PS, Moses JW. Nine-month clinical outcomes after intravascular radiation therapy for in-stent restenosis: A report from the GAMMA-II registry. Am J Cardiol 2000;86:8A. 7. Virmani R, Farb A. Pathology of in-stent restenosis. Curr Opin Lipidol 1999;10:499–506. 8. Meyer JL. The radiation therapy of benign diseases: Current indications and techniques. In: Front Radiat Ther Oncol Basel: Karger, 2001. 9. Waksman R, Cheneau E, Ajani AE, et al. Intracoronary radiation therapy improves the clinical and angiographic outcomes of diffuse in-stent restenotic lesions: Results of the Washington Radiation for In-Stent Restenosis Trial for Long Lesions (Long WRIST) Studies. Circulation 2003;107:1744–1749. 10. Waksman R, Ajani AE, White RL, et al. Prolonged antiplatelet therapy to prevent late thrombosis after intracoronary gamma-radiation in patients with in-stent restenosis: Washington Radiation for In-Stent Restenosis Trial plus 6 months of clopidogrel (WRIST PLUS). Circulation 2001;103:2332–2335. 11. Waksman R, Ajani AE, White RL, et al. Five-year follow-up after intracoronary gamma radiation therapy for in-stent restenosis. Circulation 2004;109:340–344. 12 Leon MB, Teirstein PS, Moses JW, et al. Declining long-term efficacy of vascular brachytherapy for in-stent restenosis: 5-year follow-up from the GAMMA I Randomized Trial (AHA Abstr). Circulation(Supplement) 2004. 13. Moses JW, Leon MB, Popma JJ, et al. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med 2003;349:1315–1323. 14. Stone GW, Ellis SG, Cox DA, et al. A polymer-based, paclitaxel-eluting stent in patients with coronary artery disease. N Engl J Med 2004;350:221–231. 15. Sousa JE, Costa MA, Abizaid A, et al. Sirolimus-eluting stent for the treatment of in-stent restenosis: A quantitative coronary angiography and three-dimensional intravascular ultrasound study. Circulation 2003;107:24–27. 16. Tanabe K, Serruys PW, Grube E, et al. TAXUS III Trial: In-stent restenosis treated with stent-based delivery of paclitaxel incorporated in a slow-release polymer formulation. Circulation 2003;107:559–564. 17. Degertekin M, Regar E, Tanabe K, et al. Sirolimus-eluting stent for treatment of complex in-stent restenosis: The first clinical experience. J Am Coll Cardiol 2003;41:184–189. 18. Orlic D, Bonizzoni E, Stankovic G, et al. Treatment of multivessel coronary artery disease with sirolimus-eluting stent implantation: Immediate and mid-term results. J Am Coll Cardiol 2004;43:1154–1160. 19. Briguori C, Colombo A, Airoldi F, et al. Sirolimus-eluting stent implantation in diabetic patients with multivessel coronary artery disease. Am Heart J 2005;150:807–813. 20. Ortolani P, Marzocchi A, Aquilina M, et al. 32P brachytherapy in the treatment of complex Cypher in-stent restenosis. J Intervent Cardiol 2005;18:205–211.