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Intracoronary beta brachytherapy as a treatment option for high-risk refractory in-stent restenosis
Cardiovascular Radiation Medicine 5 (2004) 9 – 14
Intracoronary beta brachytherapy as a treatment option for high-risk refractory in-stent restenosis Compassionate use Susie Kim, Francis Q. Almeda *, Meechai Tessalee, R. Jeffrey Snell, Sandeep Nathan, Stephen Thew, Cam Nguyen, James C.H. Chu, Gary L. Schaer Rush University Medical Center, Rush Heart Institute, and Rush Medical College, Chicago, IL, USA Received 23 February 2004; received in revised form 31 March 2004; accepted 1 April 2004
Abstract
Background: Vascular (VBT) has clearly been shown in multiple clinical trials to decrease restenosis rates for in-stent restenosis (ISR). However, patients enrolled in these randomized clinical trials represent a select group, and the efficacy of VBT in patients with ISR who were excluded from these controlled trials due to more complex coronary anatomy requires further investigation. This study sought to define the angiographic and clinical profile and outcomes of these high-risk patients with ISR who were excluded from the randomized clinical trials and who received VBT using Strontium-90 (Sr90) using the Novoste Beta-Cathk System through a Compassionate Use Protocol (CUP). Methods: The study was designed as a single center, prospective, open label registry trial evaluating the use of VBT on complex instent restenotic lesions in patients who were excluded from the START and START 40 trials. In general, these patients included those with saphenous vein graft (SVG) lesions, long lesions (>35 mm), and patients with a history of more than three prior interventions. VBT using Sr-90 was delivered using the Novoste Beta-Cathk System after successful angioplasty. The predetermined primary endpoint was freedom from target vessel revascularization (TVR) at 8 months, one and two years. The secondary endpoint was a composite of death, myocardial infarction (MI) and TVR at 8 months, one year, and two years. Results: Between September 4, 1998 and December 6, 2000, 32 patients were treated with VBT under the UCP protocol. The mean duration of follow up was 15.3F8.3 months. There were 9 major cardiac events at eight months including one death, one acute myocardial infarction and 7 TVR. Excluding the one patient who died, 33 lesions were available for follow-up. The rate of TVR in this high-risk patient population was 21.1% (n = 7/33 lesions). The method of revascularization included one bypass surgery and 6 repeat percutaneous coronary interventions. Conclusions: This trial demonstrates that utilization of the Beta-Cathk System using Sr-90 for the treatment of ISR in a patient population excluded from the randomized clinical trials due to unfavorable lesions characteristics is feasible appears to be associated TVR rates that compare favorably with the event rates of patients enrolled in other trials enrolling lower-risk groups. D 2004 Elsevier Inc. All rights reserved.
1. Introduction While the initial results of human trials evaluating the efficacy of drug-eluting stents are highly promising, economic and technical considerations may render the delivery * Corresponding author. Ingalls Memorial Hospital, One Ingalls Drive, Harvey, IL 60426, USA. Tel.: +1-708-3312200; fax: +1-708-9158015. E-mail address: [email protected] (F.Q. Almeda). 1522-1865/04/$ – see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.carrad.2004.04.002
and deployment of these devices infeasible in a variety of clinical scenarios. In contemporary interventional practice, physicians are increasingly faced with patients with more complicated clinical histories and more difficult coronary lesions, and the optimal strategy for dealing with these problematic patients remains controversial. Vascular brachytherapy (VBT) has clearly been shown in multiple clinical trials to decrease restenosis rates for in-stent restenosis (ISR) [1,2]. However, patients enrolled in these
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randomized clinical trials represent a select group, and the efficacy of VBT in patients with ISR who were excluded from these controlled trials due to more complex coronary anatomy requires further investigation. In general, patients who were not eligible for randomization include those with saphenous vein graft (SVG) lesions, long lesions ( >35 mm), and patients with a history of more than three prior interventions. This study sought to define the angiographic and clinical profile and outcomes of these high-risk patients with ISR who were excluded from the randomized clinical trials and who received VBT using strontium-90 (Sr-90) using the Novoste Beta-Cath System through a compassionate use protocol (CUP).
2. Methods 2.1. Patient population The study was designed as a single-center, prospective, open-label registry trial evaluating the use of VBT on complex in-stent restenotic lesions. Between September 4, 1998, and December 6, 2000, 32 patients were referred to our center for VBT, but were excluded from the randomized trials due to disease complexity. At the time, VBT for ISR using the Novoste Beta-Cath System was not approved by the Food and Drug Administration (FDA) for the treatment of ISR, and thus VBT was administered as part of a CUP approved by the Rush Investigational Review Board (IRB), radiation safety committee, and Novoste Medical Board. 2.2. Criteria for eligibility Only patients who were excluded from ongoing trials (i.e., START/START 40 [1,3]) due to lesion complexity were considered for this trial. Patients were eligible for the registry if they had evidence of angina and signs of myocardial ischemia amenable to percutaneous transluminal coronary angioplasty (PTCA). The lesion could be in a native vessel or in a bypass graft, amenable to PTCA, and must have been treated twice previously with a minimum of two interventional methods. A single lesion in a single vessel or multiple lesions in different vessels were acceptable, but lesions must be more than 10 mm apart from each other. The specific lesion inclusion criteria included a reference lumen diameter of 2.5 – 4.0 mm, preintervention stenosis between 50% and 100%, and postintervention residual stenosis of V30%. The principle exclusion criteria for this trial were myocardial infarction within the preceding 72 h, inability to take antiplatelet medication, and conditions inhibiting the use of the Beta-Cath System (excessive coronary artery tortuosity or significant peripheral vascular disease). Women of child-bearing potential, unprotected left main disease, significant renal insufficiency (creatinine z2.0 mg/dl), and previous or current chest radiotherapy were also excluded.
2.3. Procedural data Treatment of ISR was performed with various percutaneous coronary intervention (PCI) techniques. Highpressure balloon dilatations ( >12 atm), atheroablative technique (rotational atherectomy followed by PTCA), or cutting balloon angioplasty (Cutting Balloon) were used to treat this patient population. VBT using Sr-90 was delivered using the Novoste Beta-Cath System after successful angioplasty (defined as a < 30% residual stenosis). The source train is composed of 12 or 16 independent, cylindrical, sealed sources to equal 30- and 40-mm train lengths. The length of the train was selected according to the interventional injury length created during the intervention. A single-use, 5 Fr triple-lumen catheter was utilized to deliver the source train to the interventional injury site in the coronary artery. Positioning of the source train was confirmed visually under fluoroscopy by noting the location of the radiopaque inactive gold marker seeds at both ends of the source train. Care was given to ensure that 5-mm margins beyond the region of vessel injury were included. Intravenous heparin was administered to maintain an activated clotting time of 250 –300 s. Additional interventions were performed if clinically indicated (residual stenosis >30% or dissections) before removal of the guide wire and guiding catheter. Stents were placed if there was NHLBI C dissection of the coronary artery or significant residual stenosis (defined as > 30% residual stenosis). All patients received oral aspirin (325 mg daily) and oral clopidogrel (75 mg daily, for more than 48 h, or a 300-mg loading dose) before intervention. After the procedure, patients were instructed to continue oral aspirin (325 mg) indefinitely and oral clopidogrel (75 mg daily) for at least 6 months after VBT at the discretion of the cardiologist. 2.4. Dosimetry The prescription dose of the radiation was determined by the cardiologists’ visual estimate of the reference diameter. The dosing was as follows: 18.4 Gy at 2 mm for vessels 2.5 to < 3.35 mm, and 23.0 Gy at 2 mm for vessels 3.36 through 4.0 mm in diameter. The dwell times for each category of reference vessel diameter were specified on the calibration certificate. The length of the source train used for the procedure was determined by the interventional injury length created during the PCI. For interventional injury lengths V 20 mm, the 30-mm source train was used. Injury lengths of z 21 to V 30 mm necessitated the use of the 40-mm source train. Due to the complexity patient population, it was occasionally necessary to treat longer lesions, i.e., for interventional injury lengths > 30mm, with the ‘‘pull-back’’ technique (distal interventional injury length treated followed by the treatment of the proximal injury length with a one active source to one active source overlap).
S. Kim et al. / Cardiovascular Radiation Medicine 5 (2004) 9–14 Table 1 BASELINE demographics of study patients N = 32 Mean follow up, months (S.D.), range
15.3 ( F 8.3) 5 – 32 months 64.7 ( F 11.5) 22 (69) 10 (31) 27 (84) 14 (44) 29 (91) 19 (60) 12 (38) 19 (59) 3.8 ( F 2.2) 3.1 ( F 2.4) 1.44 (0.759) 22 (69%) 7 (22%) 3 (9%)
Age, years (S.D.) Male, n (%) Female, n (%) HTN, n (%) DM, n (%) Hyperlipidemia, n (%) Tobacco use, n (%) Family history CABG n (%) Mean no. of prior interventions (S.D.) Time (months) between repeat PTCA (mean F S.D.) No. of diseased native coronary arteries, n (%) 1 2 3
2.5. Study endpoints and follow-up The predetermined primary endpoint was freedom from target vessel revascularization (TVR) at 8 months, 1 year, and 2 years. The secondary endpoint was a composite of death, myocardial infarction (MI), and TVR at 8 months,
Table 2 Lesion characteristics and procedural variables N = 34 Location of target lesion n (%) LAD/diagonals 8 Left circumflex/OM 8 Right coronary artery 6 Ramus intermedius 1 SVG 11 Angiographic findings Reference diameter, mean (S.D.) 3.12 Preintervention diameter stenosis, mean (S.D.) 88% Postintervention diameter stenosis, mean (S.D.) 11.3% MLD preintervention 0.92 MLD postintervention 2.03 No. of previous target lesion procedures, mean (S.D.) 3.5 z4 interventions, n (%) 15 Sandwich or overlapping stents, n (%) 15 z3 layered stents, n (%) 2 SVG lesions, n (%) 11 Lesion length, mean(S.D.) 23.8 z35-mm-length lesion, n (%) 5 Device use, n (%) Balloon 33 Cutting balloon 4 Rotoblator 6 Additional stents 3 Treatment dose (Gy), mean(S.D.) 19.5 Dwell time, mean (range) 3.23 Pullbacks, n (%) 5 1, n (%) 3 2, n (%) 2
(24%) (24%) (17%) (3%) (32%)
11
1 year, and 2 years. Clinical follow-up was obtained by chart review or telephone survey. Procedural and follow-up angiographic data were reviewed by a blinded cardiologist using the QuantCor QCA System.
3. Results 3.1. Baseline demographics Baseline characteristics of this patient population are shown in Table 1. The majority of the patients were middle-aged males with multiple cardiac risk factors. There was a large percentage of diabetics (42%, n = 14), and 59% had previous coronary bypass surgery (n = 19). 3.2. Procedural success Procedural success, defined as < 30% residual stenosis upon completion of the PCI and delivery of the prescribed radiation treatment, was achieved in 31 (94%) of the patients. A total of 34 lesions were treated. The lesion characteristics and procedural variables are outlined (Table 2). In 2 patients, the device could not be advanced across the lesion, therefore no VBT was performed. The average dwell time was 3.23 min (range 3.1 – 4.2 min). The minimal luminal diameter of the vessel was compromised by multiple previously placed stents, which precluded advancement of the device. There were no complications related to the BetaCath System or the radiation exposure itself. These two patients are not included in the follow-up analysis. 3.3. Lesion characteristics The occurrence of specific lesion characteristics that resulted in the exclusion of the patients from the randomized trials are shown in Fig. 1. The average interval between
(F0.438) mm (8.63) (8.64) (F0.176) (F0.419) (1.31) (44%) (44%) (6%) (32%) (16.3) mm (15%) (97%) (12%) (18%) (9%) (F6.06) (3.1 – 4.2) min (15%) (9%) (6%)
Fig. 1. Occurrence of complex lesion characteristics. Target lesions with >3 previous interventions was 48% (n = 5), SVG targets 25% (n = 8), overlapping stents 48% (n = 15), > 3 layered stents was 7% (n = 2), and lesions > 25 mm in length were 19% (n = 6).
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Sixty-eight percent of patients (n = 21) had angiographic follow-up for restenosis. The rate of TVR was 18.2% (n = 6/33 lesions, excluding the one patient who expired). One patient (3%) had stenting of the target vessel >10 mm distal to the previously treated target lesion. One patient (3%) had angiographic evidence of edge effect due to geographic miss at 7 months [4,5]. The TVR within each category of complex lesions is shown in Fig. 2. The SVG lesions had a TVR of 9% (1/11 lesions).
4. Discussion
Fig. 2. TVR rates of complex lesion subsets.
interventions was 3.1 months (F 2.4 months). Two (6%) were excluded from other trials because they had multiple clinically significant lesions. One patient (3%) had been excluded from other trials only due to lesion length. 3.4. Clinical and angiographic outcomes The incidence of major cardiac events at 8 months was 29.0% (n = 9). This includes one death (3%) related to an acute MI of a nontarget vessel, one MI involving a nontarget vessel (3%), and seven TVRs (23%). Excluding the one patient who died, 33 lesions were available for follow-up. The rate of TVR in this high-risk patient population was 21.1% (n = 7/33 lesions). The method of revascularization includes one (3%) bypass surgery and six (18.2%) repeat PTCA. Three patients (10%) had acute myocardial infarctions (AMI) at 1 month of their procedure. None of these three patients were taking clopidogrel. The first patient was enrolled early in the trial before clopidogrel was routinely given after PTCA of ISR, the second patient stopped taking clopidogrel due to an urgent surgery for esophageal cancer, and the third patient was noncompliant.
The number of percutaneous interventions utilizing intracoronary stenting has increased exponentially over the past decade. As a result, ISR remains a problematic issue in contemporary interventional practice despite advances in medical therapy and percutaneous interventions [6– 9]. The results with drug-eluting stents are promising, but its efficacy for ISR has not been clearly established [10 – 13]. VBT is the only therapeutic modality for ISR that has been proven to be successful in reducing restenosis. Several trials have demonstrated favorable results utilizing both gamma and beta radiation therapy for treating de novo and ISR [14,15,17]. However, the efficacy of VBT in patients with ISR who had significant high-risk features, specifically those who were excluded from the randomized clinical trials due to unfavorable lesion characteristics, is unknown. This study sought to elucidate the angiographic and clinical outcomes of these patients with ISR who were treated with VBT who received Sr-90 under a CUP. The coronary lesions included in this study had characteristics that placed them at higher risk for recurrent restenosis (long lesions, multiple procedures, overlapping stents, and SVG). A major limitation of this study is the lack of a comparison group to serve as a control. Although historical controls may offer insight into the efficacy of VBT in this uniquely high-risk population, direct comparisons and conclusions cannot be made with certainty due to differences in trial design and selection bias.
Table 3 Clinical VBT trial comparison
N Type Control group MACE (%) Treated group MACE (%) Reduction (%) Control group TVR (%) Treated group TVR (%) Reduction (%) Control group TLR (%) Treated group TLR (%) Reduction (%)
START
START 40
GAMMA 1
GAMMA CUP
CUP
476 Beta/Sr-90 25.9 18.0 31 24.1 16.0 42 22.4 13.1 42
207 Beta/Sr-90 25.9 19.3 26 24.1 15.9 50 22.4 11.1 50
252 Gamma/Ir-192 43.8 28.2 36 47.9 33.6 42 42.1 24.4 42
100 Gamma/Ir-192
33 Beta/ Sr-90
22.2
29.0
N/A 18.2 N/A
N/A 21.1 N/A
10.1
18.2
S. Kim et al. / Cardiovascular Radiation Medicine 5 (2004) 9–14
Bearing these limitations in mind, we sought to review the outcomes of the previous trials in VBT for the treatment of ISR. Despite the complexity of the clinical history and coronary anatomy of the patients enrolled in this trial, this study suggests that the CUP group had outcomes that appeared similar compared to the treatment arms of other VBT trials (Table 3). The START trial [1] was pivotal in achieving FDA approval for beta radiation as a treatment for ISR. A total of 476 patients were enrolled and were randomized in a double-blind, placebo-controlled manner in 50 different sites around the world. START [1] and START 40[3] involved a well-defined study population, and patients with more than three interventions, overlapping stents, SVG lesions, multiple lesions, and long lesions were excluded. GAMMA 1 [15], using gamma rather than beta radiation, had higher rates of restenosis with a TVR of 33.6% in the treated group. Although the TVR was higher than START [1], it also was found to have favorable results with lower rates of MACE, TVR, and TLR when compared with its control. The exclusion criteria for GAMMA 1 [15] were not as limited as START [1] and START 40 [3]. GAMMA 1 [15] included long lesions and multiple procedures, but SVG lesions were excluded. Thus, this patient population was presumably at higher risk for restenosis than those of START [1] and START 40 [3]. There are limited published data addressing the use of beta radiation in complex lesions. There are some data involving use of gamma radiation [16] in a group of patients with at least two episodes of restenosis at the target lesion, more than one lesion, long (< 80 mm) lesions, and lesions in native coronary arteries or SVG. The actual numbers of lesions with each particular characteristic was not available for comparison. The result of this trial is listed in Table 3 as GAMMA CUP [16]. This trial, similar to the current study, did not have a control group for comparison, and the lesion characteristics were similar to the CUP group. Comparing the results of these the studies, START [1] and START 40 [3] had the lowest MACE, TVR, and TLR, although the START trials had strict limitations that GAMMA 1 [15], GAMMA CUP [16], or CUP did not have. GAMMA 1 [15], which included more aggressive lesions, had a TVR of 31%, the highest in this group. This supports the concept that the patient population studied is the major determinant of subsequent TVR rates. If we compare the TVR of the control group of START [1], START 40 [3], and GAMMA 1 [15], there is a definite increase in number of TVRs between START [1], START 40 [3], and GAMMA 1 [15], likely due to an increasing gradient of patient and lesion complexity. The TVR in CUP in this current study was lower than the event rate reported in GAMMA 1 [15]. As previously discussed, although the event rate in this current study compares favorably with other trials, direct comparisons and conclusions cannot be made with certainty due to differences in trial design and selection bias.
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The three patients in this study who had myocardial infarctions of their target vessels within 30 days of their procedure had discontinued the use of their clopidogrel. This has been previously shown to increase the risk of late total occlusions due to thrombosis. Thus, it is likely that the event rate in the CUP group would have been lower with prolonged antiplatelet therapy [18]. Although promising results have been obtained using drug-eluting stents for de novo coronary lesions, it is debatable whether these findings will be applicable to patients with ISR with more complex coronary lesions. This study supports the use of VBT in patient populations at the highest risk for recurrent restenosis, although the efficacy of VBT compared to drug-eluting stents in this specific group with highly complex coronary anatomy requires further study. In summary, VBT has been the only form of cardiovascular percutaneous revascularization proven to reduce the recurrent ISR. This trial demonstrates that utilization of the Beta-Cath System using Sr-90 for the treatment of ISR in a patient population excluded from the randomized clinical trials due to unfavorable lesion characteristics is feasible appears to be associated with TVR rates that compare favorably with the event rates of patients enrolled in other trials enrolling lower-risk groups.
References [1] Popma JJ, Suntharalingam M, Lansky AJ. Randomized trial of 90 Sr/ 90Y h-radiation versus placebo control for treatment of In-Stent Restenosis. Circulation 2002;106:1090 – 6. [2] Waksman R, Raizner A, Yeung A, Lansky AJ, Vandertie L. Use of localized intracoronary h-radiation in treatment of in-stent restenosis: the INHIBIT randomized controlled trial. Lancet 2002;359: 551 – 7. [3] Suntharalingam M, Laskey W, Lansky AJ, Waksman R, White L, Teirstein P, Massullo V, Rutherford B, Elman A, Kuntz RE, Popma JJ, Bonan R. Clinical and angiographic outcomes after use of 90 Sr/ 90Y h-radiation for the treatment of In-stent Restenosis: results from the stents and radiation theraphy 40 (START 40) registry. Int J Radiat Oncol Biol Phys 2002;52(4):1075 – 82. [4] Kim HS, et al. Edge stenosis and geographical miss following intracoronary gamma radiation therapy for in-stent restenosis. J Am Coll Cardiol 2001;37(4):1026 – 30. [5] Farb A, et al. Late arterial responses (6 and 12 months) after (32)P beta-emitting stent placement: sustained intimal suppression with incomplete healing. Circulation 2001;103(14):1912 – 9. [6] Casterella PJ, Teirstein PS. Prevention of coronary restenosis. Cardiol Rev 1999;7(4):219 – 31. [7] Baim DS, et al. Management of restenosis within the Palmaz – Schatz coronary stent (the US multicenter experience. The US Palmaz – Schatz Stent Investigators. Am J Cardiol 1993;71(4):364 – 6. [8] Baim DS, et al. Results of directional coronary atherectomy during multicenter preapproval testing. The US Directional Coronary Atherectomy Investigator Group. Am J Cardiol 1993;72(13):6E – 11E. [9] Mehran R, et al. Treatment of in-stent restenosis with excimer laser coronary angioplasty: mechanisms and results compared with PTCA alone. Circulation 1997;96(7):2183 – 9. [10] Holmes DR, Leon MB, Moses JW, Popma JJ, Culip D, Fitzgerald PJ, Brown C, Fischell T, Wong SC, Midei M, Snead D, Kuntz RE.
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Analysis of 1-year clinical outcomes in the SIRIUS trial: a randomized trial of a sirolimus-eluting stent versus a standard stent inpatients at high risk for coronary restenosis. Circulation 2004;109: 634 – 40. [11] Stone GW, Ellis SG, Cox DA, Hermiller J, O’Shaughnessy C, Mann JT, Turco M, Caputo R, Bergin P, Greenberg J, Popma JJ, Russell ME. One-year clinical results with the slow-release, polymer-based, pacitaxel-eluting TAXUS stent: the TAXUS-IV trial. Circulation 2004;109:1942 – 7. [12] Abizaid A, Costa MA, Blanchard D, Albertal M, Eltchainoff H, Guagliumi G, Geert-Jan L, Abizaid AS, Sousa AG, Wuelfert E, Wietze L, Sousa JE, Serruys PW, Morice MC. Sirolimus-eluting stents inhibit neointimal hyperplasia in diabetic patients. Insights from the RAVEL trial. Eur Heart J 2004;25:107 – 12. [13] Hong MK, Mintz GS, Lee CW, Song JM, Han KH, Kang DH, Song JK, Kim JJ, Weissman NJ, Fearnot NE, Park SW, Park SJ. Pacilataxel coating reduces in-stent intimal hyperplasia in human coronary arteries: a serial volumetric intravascular ultrasound analysis from the
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Asian Pacilataxel-Eluting Stent Clinical Trial (ASPECT). Circulation 2003;107:517 – 20. Teirstein PS, et al. Three-year clinical and angiographic follow-up after intracoronary radiation: results of a randomized clinical trial. Circulation 2000;101(4):360 – 5. Leon MB, et al. Localized intracoronary gamma-radiation therapy to inhibit the recurrence of restenosis after stenting. N Engl J Med 2001; 344(4):250 – 6. Waksman R, et al. Clinical outcome of intracoronary gamma radiation therapy for patients with refractory in-stent restenosis: compassionate use. In American Heart Association, Anaheim, CA, 2001. Castagna MT, et al. Comparative efficacy of gamma-irradiation for treatment of in-stent restenosis in saphenous vein graft versus native coronary artery in-stent restenosis: an intravascular ultrasound study. Circulation 2001;104(25):3020 – 2. Waksman R, et al. Late total occlusion after intracoronary brachytherapy for patients with in-stent restenosis. J Am Coll Cardiol 2000; 36(1):65 – 8.
Intracoronary beta brachytherapy as a treatment option for high-risk refractory in-stent restenosis Compassionate use Susie Kim, Francis Q. Almeda *, Meechai Tessalee, R. Jeffrey Snell, Sandeep Nathan, Stephen Thew, Cam Nguyen, James C.H. Chu, Gary L. Schaer Rush University Medical Center, Rush Heart Institute, and Rush Medical College, Chicago, IL, USA Received 23 February 2004; received in revised form 31 March 2004; accepted 1 April 2004
Abstract
Background: Vascular (VBT) has clearly been shown in multiple clinical trials to decrease restenosis rates for in-stent restenosis (ISR). However, patients enrolled in these randomized clinical trials represent a select group, and the efficacy of VBT in patients with ISR who were excluded from these controlled trials due to more complex coronary anatomy requires further investigation. This study sought to define the angiographic and clinical profile and outcomes of these high-risk patients with ISR who were excluded from the randomized clinical trials and who received VBT using Strontium-90 (Sr90) using the Novoste Beta-Cathk System through a Compassionate Use Protocol (CUP). Methods: The study was designed as a single center, prospective, open label registry trial evaluating the use of VBT on complex instent restenotic lesions in patients who were excluded from the START and START 40 trials. In general, these patients included those with saphenous vein graft (SVG) lesions, long lesions (>35 mm), and patients with a history of more than three prior interventions. VBT using Sr-90 was delivered using the Novoste Beta-Cathk System after successful angioplasty. The predetermined primary endpoint was freedom from target vessel revascularization (TVR) at 8 months, one and two years. The secondary endpoint was a composite of death, myocardial infarction (MI) and TVR at 8 months, one year, and two years. Results: Between September 4, 1998 and December 6, 2000, 32 patients were treated with VBT under the UCP protocol. The mean duration of follow up was 15.3F8.3 months. There were 9 major cardiac events at eight months including one death, one acute myocardial infarction and 7 TVR. Excluding the one patient who died, 33 lesions were available for follow-up. The rate of TVR in this high-risk patient population was 21.1% (n = 7/33 lesions). The method of revascularization included one bypass surgery and 6 repeat percutaneous coronary interventions. Conclusions: This trial demonstrates that utilization of the Beta-Cathk System using Sr-90 for the treatment of ISR in a patient population excluded from the randomized clinical trials due to unfavorable lesions characteristics is feasible appears to be associated TVR rates that compare favorably with the event rates of patients enrolled in other trials enrolling lower-risk groups. D 2004 Elsevier Inc. All rights reserved.
1. Introduction While the initial results of human trials evaluating the efficacy of drug-eluting stents are highly promising, economic and technical considerations may render the delivery * Corresponding author. Ingalls Memorial Hospital, One Ingalls Drive, Harvey, IL 60426, USA. Tel.: +1-708-3312200; fax: +1-708-9158015. E-mail address: [email protected] (F.Q. Almeda). 1522-1865/04/$ – see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.carrad.2004.04.002
and deployment of these devices infeasible in a variety of clinical scenarios. In contemporary interventional practice, physicians are increasingly faced with patients with more complicated clinical histories and more difficult coronary lesions, and the optimal strategy for dealing with these problematic patients remains controversial. Vascular brachytherapy (VBT) has clearly been shown in multiple clinical trials to decrease restenosis rates for in-stent restenosis (ISR) [1,2]. However, patients enrolled in these
10
S. Kim et al. / Cardiovascular Radiation Medicine 5 (2004) 9–14
randomized clinical trials represent a select group, and the efficacy of VBT in patients with ISR who were excluded from these controlled trials due to more complex coronary anatomy requires further investigation. In general, patients who were not eligible for randomization include those with saphenous vein graft (SVG) lesions, long lesions ( >35 mm), and patients with a history of more than three prior interventions. This study sought to define the angiographic and clinical profile and outcomes of these high-risk patients with ISR who were excluded from the randomized clinical trials and who received VBT using strontium-90 (Sr-90) using the Novoste Beta-Cath System through a compassionate use protocol (CUP).
2. Methods 2.1. Patient population The study was designed as a single-center, prospective, open-label registry trial evaluating the use of VBT on complex in-stent restenotic lesions. Between September 4, 1998, and December 6, 2000, 32 patients were referred to our center for VBT, but were excluded from the randomized trials due to disease complexity. At the time, VBT for ISR using the Novoste Beta-Cath System was not approved by the Food and Drug Administration (FDA) for the treatment of ISR, and thus VBT was administered as part of a CUP approved by the Rush Investigational Review Board (IRB), radiation safety committee, and Novoste Medical Board. 2.2. Criteria for eligibility Only patients who were excluded from ongoing trials (i.e., START/START 40 [1,3]) due to lesion complexity were considered for this trial. Patients were eligible for the registry if they had evidence of angina and signs of myocardial ischemia amenable to percutaneous transluminal coronary angioplasty (PTCA). The lesion could be in a native vessel or in a bypass graft, amenable to PTCA, and must have been treated twice previously with a minimum of two interventional methods. A single lesion in a single vessel or multiple lesions in different vessels were acceptable, but lesions must be more than 10 mm apart from each other. The specific lesion inclusion criteria included a reference lumen diameter of 2.5 – 4.0 mm, preintervention stenosis between 50% and 100%, and postintervention residual stenosis of V30%. The principle exclusion criteria for this trial were myocardial infarction within the preceding 72 h, inability to take antiplatelet medication, and conditions inhibiting the use of the Beta-Cath System (excessive coronary artery tortuosity or significant peripheral vascular disease). Women of child-bearing potential, unprotected left main disease, significant renal insufficiency (creatinine z2.0 mg/dl), and previous or current chest radiotherapy were also excluded.
2.3. Procedural data Treatment of ISR was performed with various percutaneous coronary intervention (PCI) techniques. Highpressure balloon dilatations ( >12 atm), atheroablative technique (rotational atherectomy followed by PTCA), or cutting balloon angioplasty (Cutting Balloon) were used to treat this patient population. VBT using Sr-90 was delivered using the Novoste Beta-Cath System after successful angioplasty (defined as a < 30% residual stenosis). The source train is composed of 12 or 16 independent, cylindrical, sealed sources to equal 30- and 40-mm train lengths. The length of the train was selected according to the interventional injury length created during the intervention. A single-use, 5 Fr triple-lumen catheter was utilized to deliver the source train to the interventional injury site in the coronary artery. Positioning of the source train was confirmed visually under fluoroscopy by noting the location of the radiopaque inactive gold marker seeds at both ends of the source train. Care was given to ensure that 5-mm margins beyond the region of vessel injury were included. Intravenous heparin was administered to maintain an activated clotting time of 250 –300 s. Additional interventions were performed if clinically indicated (residual stenosis >30% or dissections) before removal of the guide wire and guiding catheter. Stents were placed if there was NHLBI C dissection of the coronary artery or significant residual stenosis (defined as > 30% residual stenosis). All patients received oral aspirin (325 mg daily) and oral clopidogrel (75 mg daily, for more than 48 h, or a 300-mg loading dose) before intervention. After the procedure, patients were instructed to continue oral aspirin (325 mg) indefinitely and oral clopidogrel (75 mg daily) for at least 6 months after VBT at the discretion of the cardiologist. 2.4. Dosimetry The prescription dose of the radiation was determined by the cardiologists’ visual estimate of the reference diameter. The dosing was as follows: 18.4 Gy at 2 mm for vessels 2.5 to < 3.35 mm, and 23.0 Gy at 2 mm for vessels 3.36 through 4.0 mm in diameter. The dwell times for each category of reference vessel diameter were specified on the calibration certificate. The length of the source train used for the procedure was determined by the interventional injury length created during the PCI. For interventional injury lengths V 20 mm, the 30-mm source train was used. Injury lengths of z 21 to V 30 mm necessitated the use of the 40-mm source train. Due to the complexity patient population, it was occasionally necessary to treat longer lesions, i.e., for interventional injury lengths > 30mm, with the ‘‘pull-back’’ technique (distal interventional injury length treated followed by the treatment of the proximal injury length with a one active source to one active source overlap).
S. Kim et al. / Cardiovascular Radiation Medicine 5 (2004) 9–14 Table 1 BASELINE demographics of study patients N = 32 Mean follow up, months (S.D.), range
15.3 ( F 8.3) 5 – 32 months 64.7 ( F 11.5) 22 (69) 10 (31) 27 (84) 14 (44) 29 (91) 19 (60) 12 (38) 19 (59) 3.8 ( F 2.2) 3.1 ( F 2.4) 1.44 (0.759) 22 (69%) 7 (22%) 3 (9%)
Age, years (S.D.) Male, n (%) Female, n (%) HTN, n (%) DM, n (%) Hyperlipidemia, n (%) Tobacco use, n (%) Family history CABG n (%) Mean no. of prior interventions (S.D.) Time (months) between repeat PTCA (mean F S.D.) No. of diseased native coronary arteries, n (%) 1 2 3
2.5. Study endpoints and follow-up The predetermined primary endpoint was freedom from target vessel revascularization (TVR) at 8 months, 1 year, and 2 years. The secondary endpoint was a composite of death, myocardial infarction (MI), and TVR at 8 months,
Table 2 Lesion characteristics and procedural variables N = 34 Location of target lesion n (%) LAD/diagonals 8 Left circumflex/OM 8 Right coronary artery 6 Ramus intermedius 1 SVG 11 Angiographic findings Reference diameter, mean (S.D.) 3.12 Preintervention diameter stenosis, mean (S.D.) 88% Postintervention diameter stenosis, mean (S.D.) 11.3% MLD preintervention 0.92 MLD postintervention 2.03 No. of previous target lesion procedures, mean (S.D.) 3.5 z4 interventions, n (%) 15 Sandwich or overlapping stents, n (%) 15 z3 layered stents, n (%) 2 SVG lesions, n (%) 11 Lesion length, mean(S.D.) 23.8 z35-mm-length lesion, n (%) 5 Device use, n (%) Balloon 33 Cutting balloon 4 Rotoblator 6 Additional stents 3 Treatment dose (Gy), mean(S.D.) 19.5 Dwell time, mean (range) 3.23 Pullbacks, n (%) 5 1, n (%) 3 2, n (%) 2
(24%) (24%) (17%) (3%) (32%)
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1 year, and 2 years. Clinical follow-up was obtained by chart review or telephone survey. Procedural and follow-up angiographic data were reviewed by a blinded cardiologist using the QuantCor QCA System.
3. Results 3.1. Baseline demographics Baseline characteristics of this patient population are shown in Table 1. The majority of the patients were middle-aged males with multiple cardiac risk factors. There was a large percentage of diabetics (42%, n = 14), and 59% had previous coronary bypass surgery (n = 19). 3.2. Procedural success Procedural success, defined as < 30% residual stenosis upon completion of the PCI and delivery of the prescribed radiation treatment, was achieved in 31 (94%) of the patients. A total of 34 lesions were treated. The lesion characteristics and procedural variables are outlined (Table 2). In 2 patients, the device could not be advanced across the lesion, therefore no VBT was performed. The average dwell time was 3.23 min (range 3.1 – 4.2 min). The minimal luminal diameter of the vessel was compromised by multiple previously placed stents, which precluded advancement of the device. There were no complications related to the BetaCath System or the radiation exposure itself. These two patients are not included in the follow-up analysis. 3.3. Lesion characteristics The occurrence of specific lesion characteristics that resulted in the exclusion of the patients from the randomized trials are shown in Fig. 1. The average interval between
(F0.438) mm (8.63) (8.64) (F0.176) (F0.419) (1.31) (44%) (44%) (6%) (32%) (16.3) mm (15%) (97%) (12%) (18%) (9%) (F6.06) (3.1 – 4.2) min (15%) (9%) (6%)
Fig. 1. Occurrence of complex lesion characteristics. Target lesions with >3 previous interventions was 48% (n = 5), SVG targets 25% (n = 8), overlapping stents 48% (n = 15), > 3 layered stents was 7% (n = 2), and lesions > 25 mm in length were 19% (n = 6).
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S. Kim et al. / Cardiovascular Radiation Medicine 5 (2004) 9–14
Sixty-eight percent of patients (n = 21) had angiographic follow-up for restenosis. The rate of TVR was 18.2% (n = 6/33 lesions, excluding the one patient who expired). One patient (3%) had stenting of the target vessel >10 mm distal to the previously treated target lesion. One patient (3%) had angiographic evidence of edge effect due to geographic miss at 7 months [4,5]. The TVR within each category of complex lesions is shown in Fig. 2. The SVG lesions had a TVR of 9% (1/11 lesions).
4. Discussion
Fig. 2. TVR rates of complex lesion subsets.
interventions was 3.1 months (F 2.4 months). Two (6%) were excluded from other trials because they had multiple clinically significant lesions. One patient (3%) had been excluded from other trials only due to lesion length. 3.4. Clinical and angiographic outcomes The incidence of major cardiac events at 8 months was 29.0% (n = 9). This includes one death (3%) related to an acute MI of a nontarget vessel, one MI involving a nontarget vessel (3%), and seven TVRs (23%). Excluding the one patient who died, 33 lesions were available for follow-up. The rate of TVR in this high-risk patient population was 21.1% (n = 7/33 lesions). The method of revascularization includes one (3%) bypass surgery and six (18.2%) repeat PTCA. Three patients (10%) had acute myocardial infarctions (AMI) at 1 month of their procedure. None of these three patients were taking clopidogrel. The first patient was enrolled early in the trial before clopidogrel was routinely given after PTCA of ISR, the second patient stopped taking clopidogrel due to an urgent surgery for esophageal cancer, and the third patient was noncompliant.
The number of percutaneous interventions utilizing intracoronary stenting has increased exponentially over the past decade. As a result, ISR remains a problematic issue in contemporary interventional practice despite advances in medical therapy and percutaneous interventions [6– 9]. The results with drug-eluting stents are promising, but its efficacy for ISR has not been clearly established [10 – 13]. VBT is the only therapeutic modality for ISR that has been proven to be successful in reducing restenosis. Several trials have demonstrated favorable results utilizing both gamma and beta radiation therapy for treating de novo and ISR [14,15,17]. However, the efficacy of VBT in patients with ISR who had significant high-risk features, specifically those who were excluded from the randomized clinical trials due to unfavorable lesion characteristics, is unknown. This study sought to elucidate the angiographic and clinical outcomes of these patients with ISR who were treated with VBT who received Sr-90 under a CUP. The coronary lesions included in this study had characteristics that placed them at higher risk for recurrent restenosis (long lesions, multiple procedures, overlapping stents, and SVG). A major limitation of this study is the lack of a comparison group to serve as a control. Although historical controls may offer insight into the efficacy of VBT in this uniquely high-risk population, direct comparisons and conclusions cannot be made with certainty due to differences in trial design and selection bias.
Table 3 Clinical VBT trial comparison
N Type Control group MACE (%) Treated group MACE (%) Reduction (%) Control group TVR (%) Treated group TVR (%) Reduction (%) Control group TLR (%) Treated group TLR (%) Reduction (%)
START
START 40
GAMMA 1
GAMMA CUP
CUP
476 Beta/Sr-90 25.9 18.0 31 24.1 16.0 42 22.4 13.1 42
207 Beta/Sr-90 25.9 19.3 26 24.1 15.9 50 22.4 11.1 50
252 Gamma/Ir-192 43.8 28.2 36 47.9 33.6 42 42.1 24.4 42
100 Gamma/Ir-192
33 Beta/ Sr-90
22.2
29.0
N/A 18.2 N/A
N/A 21.1 N/A
10.1
18.2
S. Kim et al. / Cardiovascular Radiation Medicine 5 (2004) 9–14
Bearing these limitations in mind, we sought to review the outcomes of the previous trials in VBT for the treatment of ISR. Despite the complexity of the clinical history and coronary anatomy of the patients enrolled in this trial, this study suggests that the CUP group had outcomes that appeared similar compared to the treatment arms of other VBT trials (Table 3). The START trial [1] was pivotal in achieving FDA approval for beta radiation as a treatment for ISR. A total of 476 patients were enrolled and were randomized in a double-blind, placebo-controlled manner in 50 different sites around the world. START [1] and START 40[3] involved a well-defined study population, and patients with more than three interventions, overlapping stents, SVG lesions, multiple lesions, and long lesions were excluded. GAMMA 1 [15], using gamma rather than beta radiation, had higher rates of restenosis with a TVR of 33.6% in the treated group. Although the TVR was higher than START [1], it also was found to have favorable results with lower rates of MACE, TVR, and TLR when compared with its control. The exclusion criteria for GAMMA 1 [15] were not as limited as START [1] and START 40 [3]. GAMMA 1 [15] included long lesions and multiple procedures, but SVG lesions were excluded. Thus, this patient population was presumably at higher risk for restenosis than those of START [1] and START 40 [3]. There are limited published data addressing the use of beta radiation in complex lesions. There are some data involving use of gamma radiation [16] in a group of patients with at least two episodes of restenosis at the target lesion, more than one lesion, long (< 80 mm) lesions, and lesions in native coronary arteries or SVG. The actual numbers of lesions with each particular characteristic was not available for comparison. The result of this trial is listed in Table 3 as GAMMA CUP [16]. This trial, similar to the current study, did not have a control group for comparison, and the lesion characteristics were similar to the CUP group. Comparing the results of these the studies, START [1] and START 40 [3] had the lowest MACE, TVR, and TLR, although the START trials had strict limitations that GAMMA 1 [15], GAMMA CUP [16], or CUP did not have. GAMMA 1 [15], which included more aggressive lesions, had a TVR of 31%, the highest in this group. This supports the concept that the patient population studied is the major determinant of subsequent TVR rates. If we compare the TVR of the control group of START [1], START 40 [3], and GAMMA 1 [15], there is a definite increase in number of TVRs between START [1], START 40 [3], and GAMMA 1 [15], likely due to an increasing gradient of patient and lesion complexity. The TVR in CUP in this current study was lower than the event rate reported in GAMMA 1 [15]. As previously discussed, although the event rate in this current study compares favorably with other trials, direct comparisons and conclusions cannot be made with certainty due to differences in trial design and selection bias.
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The three patients in this study who had myocardial infarctions of their target vessels within 30 days of their procedure had discontinued the use of their clopidogrel. This has been previously shown to increase the risk of late total occlusions due to thrombosis. Thus, it is likely that the event rate in the CUP group would have been lower with prolonged antiplatelet therapy [18]. Although promising results have been obtained using drug-eluting stents for de novo coronary lesions, it is debatable whether these findings will be applicable to patients with ISR with more complex coronary lesions. This study supports the use of VBT in patient populations at the highest risk for recurrent restenosis, although the efficacy of VBT compared to drug-eluting stents in this specific group with highly complex coronary anatomy requires further study. In summary, VBT has been the only form of cardiovascular percutaneous revascularization proven to reduce the recurrent ISR. This trial demonstrates that utilization of the Beta-Cath System using Sr-90 for the treatment of ISR in a patient population excluded from the randomized clinical trials due to unfavorable lesion characteristics is feasible appears to be associated with TVR rates that compare favorably with the event rates of patients enrolled in other trials enrolling lower-risk groups.
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