Five-Year Clinical Follow Up after Intracoronary Radiation for the Prevention of In-Stent Restenosis

Intracoronary radiation therapy (IRT), utilizing both gamma- and beta-emitting radiation sources, was until recently the only effective method for the prevention of recurrent in-stent restenosis (ISR) and the need for additional revascularization procedures in patients with ISR.^1–6 Recent analyses of large randomized, controlled studies have shown that during long-term follow up there is a significant decline in the benefit of IRT. The increasing number of patients with poor long-term outcomes after IRT is mainly due to late restenosis, i.e., the “catch-up phenomenon”, and late stent thrombosis.^7–10 We assessed the long-term outcomes of “real-world” patients who were treated with IRT for the prevention of ISR and the clinical and angiographic characteristics implicated in IRT failure. Methods Patient population. After the introduction of IRT as a viable and effective treatment modality for ISR, we initiated a prospective registry of the clinical and angiographic characteristics of all patients with ISR treated with IRT at our institution between March 1999 and January 2004. During this period, baseline clinical characteristics and risk factors were collected for 132 patients on admission and recorded in a registry, constituting the largest experience in our country. Patient-based data regarding complications were collected during the procedure and during the periprocedural period. Lesion-based angiographic data were documented during the interventional procedure. Patient-based data concerning the procedural outcomes on a short-term basis were documented at 1 month, 3 months, 6 months and at 1-year follow up. On a long-term basis, all surviving patients were clinically followed up every 6 months until January 2005. Patients who were not available for follow up were contacted by telephone, and all events were source-documented. Ultimately, patients were divided for the present analysis into two groups: successful IRT and failed IRT, defined as any patient who had a major adverse cardiac event, i.e., died, had a myocardial infarction, target vessel revascularization (TVR), target lesion revascularization (TLR) or coronary artery bypass graft surgery (CABG) following IRT. Patients with occluded vessels treated conservatively were also included in this group. Procedural technique. Radiation treatment was performed by a team comprised of a cardiologist, oncologist and physicist within a shielded laboratory on a total of 148 lesions. For patients receiving g-radiation, an Iridium192 (Ir192) source train was delivered into a noncentering, end-lumen catheter using the Checkmate™ System (Cordis Corp., Miami, Florida). The catheter was loaded with 10 or 14 Ir192 seeds and was used to cover a total vessel segment of 39 mm and 55 mm, respectively. The Ir192 seeds were left in place for 20–45 minutes to administer a prescribed dose of 14 Gray (Gy) at 2.0 mm from the center of the source. Patients receiving b-radiation were administered yttrium90 (Y90) by delivering a pure b-emitter source using the Beta-Cath™ System (Novoste Corp., Norcross, Georgia). The Y90 b-emitter source was left in place in order to administer 20.6 Gy to a distance 1.0 mm from the surface of the inflated balloon. The physicist repeatedly measured radiation exposure inside and outside of the catheterization laboratory during the procedure according to standard guidelines. Quantitative coronary analysis (QCA), using standard morphological criteria from the index procedure, was performed at our core laboratory by a fully dedicated technician using the Cardiovascular Angiography Analysis System II (CAAS II) from Pie Medical Imaging (Maastricht, the Netherlands). Definitions. Failed IRT was defined as any procedure that resulted in a patient who died or had a myocardial infarction, underwent target lesion revascularization, target vessel revascularization or coronary artery bypass graft surgery. Major adverse cardiac events were defined as the combined endpoint of all of the individual endpoints. Myocardial infarction was acknowledged when patients had a periprocedural elevation in CK-MB >/= 2 times the normal level. TLR included coronary angioplasty or CABG of the target vessel due to the presence of a stenosis that was >/= 50% of the luminal diameter of the irradiated target lesion. A revascularization procedure within the same vessel, but outside the target lesion, was considered as TVR; this included, but was not limited to, TLR and coronary artery bypass surgery. Clinical restenosis was defined as the recurrence of angina pectoris and/or positive myocardial perfusion imaging for ischemia in the target vessel territory. During follow up, target lesion restenosis was described as a recurrent stenosis that involved >/= 50% of the luminal diameter of the stent and/or the area 5 mm proximal and/or 5 mm distal to the stent margin, thus the target area where the radiation seeds were located during IRT. Diffuse ISR was, by definition, a recurrent stenotic lesion >/= 50% and > 10 mm in length. Focal ISR was defined as a recurrent stenotic lesion >/= 50% of the luminal diameter and 10 mm within the stent, pattern III comprises lesions that are > 10 mm extending outside the stent and pattern IV is a totally occluded stent.¹¹ Geographical miss occurred when the radiation source did not fully cover the injured segment. Statistical analysis. The X2 analysis was used to assess the differences between percentages of categorical outcomes. For continuous variables, comparisons between the two groups were made with the unpaired two-tailed Student’s t-test. Results were expressed as the mean ± 1 standard deviation (SD). A p-value Results Between March 1999 and January 2004, a total of 148 intracoronary radiation procedures were performed at our institution in 132 patients, consisting of the largest experience in the country. Of the 132 patients, 123 were treated with gamma-radiation and 9 with beta-radiation. Patients were not analyzed according to the type of radiation received. Only 1 patient, categorized as a failure, received both types of radiation. A total of 65 (49%) patients were classified in the failed IRT group, while 67 (51%) were defined as successful throughout the entire follow-up period. The average time to major adverse cardiac events in the failure group was 14.6 ± 15 months. Baseline clinical characteristics (patient-based) of both groups were identical and are shown in Table 1. The angiographic characteristics (lesion-based) are shown in Table 2. There was a significantly higher number of patients with multivessel disease and with total occlusions in the failure group (p = 0.01). In the failure group, 6 patients received radiation of 2 different lesions, whereas in the successful group, 8 patients received radiation in at least 2 different lesions, 1 receiving radiation to 3 lesions. The average time to a major adverse cardiac event or last follow up of all patients was 30 ± 22 months. Short- and long-term outcomes are documented in Table 3. The distribution of events is shown in Figure 1. The preferred method of revascularization was percutaneous reintervention, which was performed in 71% of patients. Only one-third of the patients were referred for CABG. ST-segment elevation myocardial infarction was infrequent during the procedure and occurred equally between the two groups, 1.5% in the successful group and 1.5% in the failure group, (p = NS). Vessel dissection during the index procedure was a more frequent complication, occurring in 7 patients overall: 3 successful patients (4%) and 4 nonsuccessful patients (6%) (p = NS). Abrupt vessel closure occurred in 2 patients, both of whom were classified as procedural failures. At 1-month follow up, 4 patients (3% of total) were categorized as having a major adverse cardiac event, 1 patient suffered congestive heart failure and 1 other patient developed pulmonary edema, both of whom eventually failed IRT. At the 3-month follow up point, 14 patients developed complications, all of which were classified as major adverse cardiac events (11% of total, 22% of those eventually becoming failures) (Figure 1). During long-term follow up (> 1 year), 56 procedures (42% of total, 85% of failure) underwent TLR, TVR or CABG. Furthermore, 61 patients (46% of total, 92% of failure) either died or underwent a revascularization procedure during the follow-up period, while 16 patients (24% of failure) who had failed IRT either had a myocardial infarction or died during the follow-up period (Table 3). There were 2 non-TLR procedures, 1 in each of the groups. Three patients in the successful IRT group had non-TVR, and 1 in the failure IRT group. Prior to radiation, 6% of the successful IRT patients and 17% of failures had a completely occluded artery with TIMI flow of 0 or 1. The IRT failure group tended to have a higher number of previous restenotic lesions within the target vessel (1.65 ± 1.0 versus 1.39 ± 0.65; p = NS). Patients with failed IRT were treated with an average number of 1.55 ± 0.75 prior stents, while the successful group received an average number of 1.42 ± .80 prior stents (p = NS). Stent characteristics from preceding interventions did not vary between the groups. The average prior stent diameter overall was 2.9 ± 0.36 mm, with an average length of 23.8 ± 12.6 mm. The average size of the balloon used for the angioplasty procedure was similar in both groups, at 2.97 ± 0.47 mm, with a balloon length that was insignificantly longer in the successful group (23.2 ± 11.2 mm versus 21.3 ± 6.3 mm in the IRT failure group). The use of glycoprotein IIb/IIIa inhibitors was evenly distributed between the two groups (45% for the successful group and 48% for the failures). A new stent was deployed following IRT in a minority of patients, 12 (18%) of the successful IRT patients and in 18 (28%) of the failed IRT patients (p = 0.25). The average new stent diameter in the successful group was 3.0 ± 0.58 mm and 2.9 ± 0.32 mm in the failure group. The average new stent length was 13.6 ± 6.3 mm in the successful IRT patients, and 17.7 ± 8.8 mm in those who failed (p = 0.2). After the initial stent placement, the successful IRT group received radiation therapy at a later time interval (276 ± 381 days versus 202 ± 163 days). The average radiation time was similar in both groups (20.1 ± 3.4 minutes), with similar number of Ir192 seeds (11.5 ± 1.9 in the successful group and 11.4 ± 1.9 in the IRT failure group). There was a higher rate of geographical miss in the IRT failure group (16.9% versus 10.4% in the successful IRT group; p = 0.19). In the successful IRT group, 4 patients had a probable geographical miss, while in the failure group, 5 patients were categorized as having a probable miss. There were 9 definite geographical misses, 3 in the successful IRT and 6 in the IRT failure group. By multivariate analysis for independent predictors of IRT failure, none of the variables included in the model showed a correlation with IRT failure. Discussion The results of this long-term follow up of patients treated with IRT indicate that despite initial satisfactory results, the long-term outcomes of these patients is marred by a high percentage of major adverse cardiac events. Half of all patients who underwent IRT at our institution had a major adverse cardiac event, including 55 patients (41.6%) who required repeat coronary revascularization. At 1-year follow up, slightly less than half (43%) of those patients in the failure group had a major adverse cardiac event. In those who failed IRT, the average time to develop a major adverse cardiac event occurred after 14.6 ± 15 months, supporting the notion of a “late catch-up phenomenon”. At the time that IRT was introduced this factor was not known, and when patients underwent cardiac catheterization after 6–8 months, restenosis rates were significantly lower when compared to patients in the control arm, with a decrease in recurrent ISR between 50% and 70% when brachytherapy was compared with conventional therapy.^2–5 Intracoronary radiation tended to delay the neointimal proliferation associated with ISR, rather than prevent it. Almost half of all patients (42%) underwent a revascularization procedure, and 16 patients (12%) either had a myocardial infarction or died during the follow-up period. Furthermore, 45 patients (34%) experienced a myocardial infarction or underwent TLR during the follow-up period. These results are in concordance with previous reports that have shown that there is some attrition in efficacy over time.^13–15 However, contrary to previous reports¹⁶ that have shown better results in patients treated with commercially-available systems (not as part of an investigational trial), there was a higher rate of major adverse cardiovascular events in our patients when compared to published series. Interestingly, 17% of patients in the failed radiation group had a geographical miss compared to only 10% in the successful arm. Although numerically higher, it did not achieve statistical significance, but may have played an important role in the clinical outcomes. Late stent thrombosis is known to be a potentially fatal complication of intracoronary radiation, especially after implantation of a new stent at the irradiated site.¹⁷ The administration of prolonged dual antiplatelet therapy has significantly reduced this dreaded complication. In the present study, 8 patients had a myocardial infarction and an additional 8 patients died during the follow-up period, which may be attributed to stent thrombosis. Angiographic follow up may have revealed a higher percentage of late stent thrombosis in our series. Although drug-eluting stents and pharmacological advances have significantly reduced the incidence of ISR,^18,19 intracoronary brachytherapy continues to be the gold-standard treatment for ISR, and is a level-II A indication for the treatment of ISR.²⁰ None of the usual predictors of ISR,²¹ such as diabetes, total vessel occlusion, vessel diameter and post-/preprocedural lesion length were independent predictors of IRT failure in our study, although the small number of patients in each arm is a limitation. The earlier need for radiological intervention in the failure group may be indicative of a more aggressive disease state, as there were a significantly higher percentage of patients with multivessel disease, lower TIMI scores, lower ejection fraction and more previous coronary interventions in these patients. It is noteworthy to mention, that geographical miss was more common in the IRT failure group, possibly contributing to a worse prognosis and outcome. In January of 2004, with the advent of drug-eluting stents, the supply of the IRT catheters ended and the intracoronary brachytherapy program was terminated at our institution, but follow up was performed accordingly. Study limitations. This study has several potential limitations. The sample itself is representative only of a small number of patients. Angiographic follow up was not routinely done and was clinically driven. We can presume that a higher number of patients had silent restenosis. In addition, although both gamma- and beta-radiation were used in this study, only a small percentage were treated with beta-radiation; thus, patients were not analyzed according to the type of radiation received. Furthermore, this was a nonrandomized, noncontrolled, prospective registry, therefore the results and conclusions are subject to survivorship bias and the limitations inherent to all such reports, but it provides an accurate account of the real outcome after intracoronary radiation performed under the best conditions.

References 1. Condado JA, Waksman R, Gurdiel O, et al. Long-term angiographic and clinical outcome after percutaneous transluminal coronary angioplasty and intracoronary radiation therapy in humans. Circulation 1997;96:727–732. 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. 3. Waksman R, White RL, Chan RC, et al. Intracoronary g-radiation therapy after angioplasty inhibits recurrence in patients with in-stent restenosis. Circulation 2000;101:2165–2171. 4. 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. 5. Gruberg L, Waksman R, Ajani AE, et al. The effect of intracoronary radiation for the treatment of recurrent in-stent restenosis in patients with diabetes mellitus. J Am Coll Cardiol 2002;39:1930–1936. 6. Gruberg L, Waksman R, Ajani AE, et al. The effect of intracoronary radiation for the treatment of recurrent in-stent restenosis in patients with chronic renal failure. J Am Coll Cardiol 2001;38:1049–1053. 7. Grise MA, Massullo V, Jani S, et al. Five-year clinical follow-up after intracoronary radiation: Results of a randomized clinical trial. Circulation 2002;105:2737–2740. 8. 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-1 randomized trial. Circulation 2004;110(Suppl):III-405. 9. Limpijankit T, Mehran R, Mintz GS, et al. Long-term follow-up of patients after gamma intracoronary brachytherapy failure (from GAMMA-I, GAMMA-II, and SCRIPPS-III). Am J Cardiol 2003;92:315–318. 10. Condado JA, Waksman R, Saucedo JF, et al. Five-year clinical and angiographic follow-up after intracoronary iridium-192 radiation therapy. Cardiovasc Radiat Med 2002;3:74–81. 11. Mehran R, Dangas G, Abizaid A, et al. Angiographic patterns of in-stent restenosis: Classification and implications for long-term outcome. Circulation 1999;100:1872–1878. 12. Gruberg L, Beyar R. Intracoronary radiation for in-stent restenosis in long lesions: Too much, too little, too late? J Invasive Cardiol 2003;15:644–645. 13. Waksman R, Ajani A, White L, et al. Two-year follow-up after beta and gamma intracoronary radiation therapy for patients with diffuse in-stent restenosis. Am J Cardiol 2001;88:425–428. 14. Ajani A, Waksman R, Cheneau E, et al. The outcome of percutaneous coronary intervention in patients with in-stent restenosis who failed intracoronary radiation therapy. J Am Coll Cardiol 2003;41:551–556. 15. Grise MA, Massullo V, Jani S, et al. Five-year clinical follow-up after intracoronary radiation: Results of a randomized clinical trial. Circulation 2002;105:2737–2740. 16. Rha SW, Kuchulakanti PK, Pakala R, et al. Real-world clinical practice of intracoronary radiation therapy as compared to investigational trials. Catheter Cardiovasc Interv 2005;64:61–66. 17. Waksman R. Late thrombosis after radiation: Sitting on a time bomb. Circulation 1999;100:780–782. 18. Saia F, Lemos P, Sianos G, et al. Effectiveness of sirolimus-eluting stent implantation for recurrent in-stent restenosis after brachytherapy. Am J Cardiol 2003;92;200–202. 19. Saia F, Lemos P, Hoye A, et al. Clinical outcomes for sirolimus-eluting stent implantation and vascular brachytherapy for the treatment of in-stent restenosis. Catheter Cardiovasc Interv 2004;62:283–288. 20. Smith SC Jr, Feldman TE, Hirshfeld JW Jr, et al., American College of Cardiology/American Heart Association Task Force on Practice Guidelines; American College of Cardiology/American Heart Association/Society for Cardiovascular Angiography and Interventions Wri ting Committee to Update the 2001 Guidelines for Percutaneous Coronary Intervention ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention — Summary article: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to Update the 2001 Guidelines for Percutaneous Coronary Intervention). Circulation 2006;113:156–175. 21. Almeda F, Chua D, Nathan S, et al. Correlates of failure following treatment with sr-90 beta irradiation for in-stent restenosis. Catheter Cardiovasc Interv 2003;59:176–183.