Evolution of angiographic restenosis rate and late lumen loss after intracoronary beta radiation for In-Stent restenotic lesions

Evolution of Angiographic Restenosis Rate and Late Lumen Loss After Intracoronary Beta Radiation for In-Stent Restenotic Lesions Thomas M. Schiele, MD, Barbara Po ¨ llinger, MD, Ralf Kantlehner, MD, Johannes Rieber, MD, Andreas Ko ¨ nig, MD, Vikto´ria Seelig, MD, Florian Kro ¨ tz, Hae-Young Sohn, MD, Uwe Siebert, MD, MPH, MSc, Eckhart Du¨hmke, MD, Karl Theisen, MD, and Volker Klauss, MD

MD,

The aim of this study was to investigate the time course of angiographic restenosis rate and late loss after successful percutaneous coronary intervention and vascular brachytherapy with ␤-irradiation using strontium-90/yttrium-90 in 98 patients who were prospectively enrolled into a quantitative angiographic and clinical follow-up protocol at 6, 12, and 24 months after the index procedure, regardless of their symptom status. Actuarial restenosis rates measured 11.2 ⴞ 5% at 6 months of follow-up, 24.5 ⴞ 5% at 12 months, and 28.5 ⴞ 6% at 24 months, respectively. Late loss of the stent segment during the first 6 months measured 0.38 ⴞ 0.40 mm (6 to 12 months: 0.25 ⴞ 0.38

mm; 12 to 24 months: 0.16 ⴞ 0.32 mm), of the injured segment 0.27 ⴞ 0.21 mm (6 to 12 months: 0.21 ⴞ 0.26 mm; 12 to 24 months: 0.13 ⴞ 0.24 mm), of the irradiated segment 0.18 ⴞ 0.29 mm (6 to 12 months: 0.19 ⴞ 0.31 mm; 12 to 24 months: 0.11 ⴞ 0.27 mm), and of the analysis segment 0.18 ⴞ 0.36 mm (6 to 12 months: 0.17 ⴞ 0.29 mm; 12 to 24 months: 0.11 ⴞ 0.20 mm). Restenosis after angioplasty and ␤-irradiation of in-stent restenotic lesions is not complete within 6 months but is sustained with a gradual decrease over 24 months. 䊚2004 by Excerpta Medica, Inc. (Am J Cardiol 2004;93:836 – 842)

epeat restenosis limits percutaneous coronary intervention (PCI) of in-stent restenosis (ISR). Its R incidence averages 50% regardless of the therapeutic

result of continuous low late loss has never been clearly demonstrated. The objective of this prospective study was to describe the time course of restenosis by determination of the statistically calculated restenosis rate using actuarial analysis and the angiographic late loss after VBT with strontium-90/yttrium-90 (Sr-90/Y-90) for ISR in 98 patients by quantitative coronary angiography at 6, 12, and 24 months.

modality used.1– 4 Restenosis usually develops within 3 to 5 months after the index procedure. Restenosis after 6 months is very rarely observed.5,6 Vascular brachytherapy (VBT) has been proven to effectively reduce the repeat ISR rate in randomized controlled trials.7–10 Yet follow-up intervals have been only 6 or 9 months, which may be too short because radiation might prolong the healing process after vascular injury. Long-term angiographic follow-up data have been published in only a few clinical studies.11,12 Sample sizes were small, contained only de novo lesions or both de novo and ISR lesions, and the follow-up intervals were 6 months and either 2 or 3 years, allowing no precise determination of the evolution of the restenotic process after VBT. Whether restenosis after VBT demonstrates a late catch-up phenomenon or whether late restenotic events are a From the Cardiology Division, Department of Medicine and the Department of Radiation Therapy and Radiation Oncology, Medizinische Klinik und Poliklinik–Innenstadt, University Hospital, Munich, Germany; the Institute of Physiology, University of Munich, Munich, Germany; and the Harvard Center for Risk Analysis, Harvard School of Public Health, Boston, Massachusetts. Manuscript received September 26, 2003; revised manuscript received and accepted December 5, 2003. Address for reprints: Thomas M. Schiele, MD, Kardiologie, Medizinische Poliklinik–Innenstadt, Klinikum der Universita¨t, Ziemssenstrasse 1, 80336 Munich, Germany. E-mail: Thomas.Schiele@ medinn.med.uni-muenchen.de.

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©2004 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 93 April 1, 2004

METHODS

Study design and population: The study population consisted of 98 consecutive patients who had undergone successful PCI for ISR and VBT with Sr-90/ Y-90 and who were prospectively enrolled into an angiographic follow-up protocol at 6, 12, and 24 months, regardless of their symptomatic status. All patients gave written informed consent, and the ethics committee of our institution approved the protocol. Patients were eligible for inclusion in the study if they had angina pectoris or objective signs of myocardial ischemia and ISR of a native coronary artery with a diameter stenosis of 50% to 99% by visual assessment. Exclusion criteria were acute myocardial infarction within 3 months before the index procedure, contraindication to antiplatelet therapy, left ventricular ejection fraction ⬍30%, unprotected left main disease, presence of thrombus or intraluminal filling defect, anticipated difficulty with the follow-up procedures, estimated life expectancy ⬍5 years, pregnancy, and child-bearing potential or status after chest irradiation. 0002-9149/04/$–see front matter doi:10.1016/j.amjcard.2003.12.020

Angioplasty and brachytherapy procedure: After the baseline coronary angiography, PCI with the cutting balloon (Boston Scientific, Natick, Massachusetts) or a conventional balloon was performed according to standard practice using the femoral approach. A satisfactory initial acute result was a prerequisite for subsequent VBT using a monorailtype 5Fr delivery catheter (Novoste, Norcross, Georgia) to hydraulically deliver a source train of Sr-90/ Y-90 seeds with a length of either 40 or 60 mm. A manual stepping maneuver was performed in 18 patients. The dose, prescribed at 2 mm from the longitudinal axis of the source train, varied according to the angiographically determined reference diameter (2.7 to 3.35 mm: 18.4 Gy; 3.35 to 4.0 mm: 23.0 Gy; ⬎4.0 mm: 25.3 Gy). All balloon inflations and radiation sources were recorded. Meticulous care was taken to entirely cover the injured vessel segment by the radiation source to prevent overt geographic miss. Coronary angiography: Coronary angiography was performed after intracoronary administration of nitroglycerin 0.25 mg in 2 orthogonal projections using identical projection angles and table height throughout the entire procedure at baseline and at follow-up. Acetylsalicylic acid 100 mg/day was given indefinitely and clopidogrel 75 mg/day was administered for 6 months in all cases. The occurrence of angiographic restenosis and a patient’s refusal of further investigation determined the number of follow-up angiograms utilizable for quantitative coronary angiography. Patients with angiographic restenosis who required repeat intervention were excluded from angiographic analysis at subsequent follow-up because repeat interventions would have altered the correct determination of late loss over time. Quantitative coronary angiography was performed off-line in a blinded fashion using the validated Philips Digital Cardiac Imaging system (Philips, Eindhoven, The Netherlands).13 The minimum luminal diameter was determined by edge detection; the reference diameter was automatically calculated by the interpolated method. Minimum luminal diameter was defined as the mean of the smallest luminal diameter determined in the respective vessel segment analyzed. The mean reference diameter was obtained from averaging an apparently healthy coronary segment proximal and distal to the analysis segment. The percent diameter stenosis of each analyzed segment was calculated. The analyzed segment of the coronary artery was divided into 4 segments: the “stent segment,” containing the initial target lesion; the “injured segment,” including all parts of the vessel having been treated with balloon angioplasty; the “irradiated segment,” representing the vessel segment where the full radiation dose (excluding axial dose fall-off) was applied; and the “analysis segment,” containing the rest of the analyzed vessel, including the segments exposed to axial radiation dose fall-off. All segments were analyzed separately. Distal and proximal measurements of the respective segments were averaged. In each of the segments, late loss was defined as minimum luminal diameter after completion of the index procedure minus the minimum lumi-

nal diameter at the respective follow-up. Analysis of late loss per time interval (0 to 6,6 to 12,12 to 24 months) and late loss per month was performed. Loss index was defined as late loss divided by the acute gain. Acute gain was defined as the minimum luminal diameter after the completion of the index procedure minus minimum luminal diameter before PCI. Definitions: Overt geographic miss was considered present when the injured vessel segment obviously and unavoidably had not been fully covered by irradiation. Angiographic geographic miss was present when it had been detectable only while performing off-line quantitative coronary angiography after the index procedure. Technical success was considered present when at least 90% of the planned dose of radiation had been delivered and the final residual stenosis was ⬍30%. Binary restenosis was determined as ⬎50% diameter stenosis at follow-up. Acute myocardial infarction was defined as a creatine kinase increase greater than twice the upper limit of normal and/or new Q waves on the electrocardiogram. Deaths were classified as cardiac or noncardiac. Deaths of undetermined cause were considered to have been cardiac. A major adverse cardiac event was considered to have occurred if these were documented: death, myocardial infarction, or target vessel revascularization. Target lesion revascularization was defined as coronary angioplasty or surgical bypass due to symptomatic restenosis of the stented segment. Target vessel revascularization comprised all revascularization procedures of the entire vessel, therefore, including stenotic segments attributable to edge effect. Statistical analysis: Clinical and quantitative coronary angiography data were collected in a computerized database (FileMaker Pro 5.0; FileMaker, Santa Clara, California). Statistical analysis was performed by a dedicated software package (SPSS for Windows 10.0.7; SPSS Inc., Chicago, Illinois). All variables are presented as percent frequencies or as mean value ⫾ SD. Serial quantitative coronary angiographic data were compared using the multiple analysis of variance with Bonferroni’s correction for multiple comparisons. Actuarial restenosis rate was calculated by the Cutler-Ederer life-table method (statistically determined restenosis rate compensating for follow-up angiographic studies missing due to exclusion of patients who developed restenosis requiring repeat intervention or patient denial). Correlation coefficients of continuous variables were calculated with Pearson⬘s product-moment-correlation method. All tests were 2-tailed. A p value ⬍0.05 was considered significant.

RESULTS

Baseline clinical and angiographic characteristics:

Baseline clinical and angiographic characteristics of the study population are listed in Table 1. Patients revealed a high prevalence of cardiovascular risk factors, unstable angina pectoris and renal insufficiency. Notably, the prevalence of multivessel disease and lesion length were above average. Details of the angioplasty and brachytherapy procedures are listed in

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TABLE 1 Baseline Clinical and Angiographic Characteristics of the Study Population (n ⫽ 98) Age (yrs) Men Body mass index Unstable angina pectoris Cardiovascular risk factors Family history of ischemic heart disease Hypercholesterolemia Mean cholesterol level (mg/dl) Statin in medication Diabetes mellitus Systemic arterial hypertension Smoking Renal insufficiency (serum creatinine ⬎1.2 mg/dl) Patients on hemodialysis Extent of coronary artery disease (lesions with diameter stenosis ⬎50%) Single-vessel 2-vessel 3-vessel Left ventricular ejection fraction (%) No. of restenoses First Second Third Fourth Location of target lesion Left anterior descending coronary artery Left circumflex coronary artery Right coronary artery Lesion characteristics Ostial Total occlusion Reference luminal diameter ⬍2.5 mm Transplant vasculopathy Stent length ⬎10 mm Length of the stented segment (mm) Length of the injured segment (mm) Length of the irradiated segment (mm) Length of the analysis segment (mm)

63.8 ⫾ 10 79 (81%) 26.8 ⫾ 4 22 (22%) 56 (54%) 86 (88%) 179.5 ⫾ 36 90 (92%) 31 (32%) 85 (87%) 49 (50%) 41 (42%) 6 (6%)

32 (33%) 22 (22%) 44 (45%) 61.5 ⫾ 11 1.4 ⫾ 1 73 (75%) 12 (12%) 5 (5%) 6 (6%) 41 (42%) 17 (17%) 40 (41%) 12 (12%) 4 (4%) 14 (14%) 5 (5%) 92 (94%) 31.6 ⫾ 18 38.4 ⫾ 20 51.9 ⫾ 51 59.6 ⫾ 44

TABLE 2 Characteristics of the Angioplasty and Irradiation Procedures (n ⫽ 98) Angioplasty device used Cutting balloon Conventional balloon High-speed rotational angioplasty Balloon diameter (mm) Balloon length (mm) Balloon-to-artery ratio No. of balloon inflations Maximum inflation pressure (atm) Prescribed radiation dose (Gy) Pullback maneuver performed Fractionation necessary Overt geographic miss Angiographic geographic miss

77 (79%) 20 (20%) 1 (1%) 3.3 ⫾ 1 12.7 ⫾ 5 1.15 ⫾ 1.1 3.6 ⫾ 2 13.1 ⫾ 5 21.3 ⫾ 2 18 (18%) 2 (2%) 3 (3%) 7 (7%)

Table 2. Most of the ISRs were treated in moderately aggressive fashion with the cutting balloon; pullback maneuvers were performed in 1/5 of cases, and geographic miss was rare. Clinical follow-up was obtained in all patients. Table 3 provides the incidence of clinical events during the entire follow-up period. Most repeat interventions were necessary during the first year of follow-up. 838 THE AMERICAN JOURNAL OF CARDIOLOGY姞

VOL. 93

Angiographic results: Actuarial analysis of the restenosis rate is depicted in Figure 1. At 6 months, the restenosis rate measured 15.3 ⫾ 3.9%, at 12 months 24.5 ⫾ 4.8%, and at 24 months 28.5 ⫾ 6.2%. Therefore, restenosis was not complete within the traditional 6 months of follow-up. It developed predominantly within the first year. During the second year, an additional yet smaller increase of restenosis rate occurred. Indexes as assessed by quantitative coronary angiography are listed in Table 4. During the first year, significant late loss was present. Late loss was most pronounced in the stented segment. Between 12 and 24 months of follow-up, there was a trend for significant increase of absolute late loss of the stented segment, but the per month late loss was very low. Correlation between the acute gain and subsequent late loss after PCI revealed to be only moderate at 6 months of follow-up (r ⫽ 0.478, p ⬍0.001), and, interestingly, showed increases at 12 (r ⫽ 0.554, p ⫽ 0.002) and 24 (r ⫽ 0.723, p ⬍0.001) months of follow-up.

DISCUSSION

Quantitative coronary angiography: Visual estimation of the severity of coronary lesions is associated with a wide range of intra- and interobserver variability.14 Percent diameter stenosis, although usually used in restenosis studies, has been reported to correlate only moderately with the true significance of the lesion.15 Therefore, a quantitative coronary angiographic analysis of the absolute dimensions of the vessels seemed to be appropriate for this trial evaluating the evolution of repeat ISR. Different definitions of restenosis have been previously proposed, and the rate of restenosis is strongly dependent on the definition of restenosis applied. Because it has been used in most contemporary trials, we chose a diameter stenosis of ⬎50% by quantitative coronary angiography as the definition of restenosis in our study. Quantitative analysis was performed with a system using a minimum cost algorithm extensively demonstrated to be very accurate, fast, and robust in routine clinical practice.13 Gradient field transform analysis, which has been shown to be superior to the minimum cost algorithm in very complex lesions with irregular borders, was deemed not to be necessary in this study due to the usually smooth configuration of ISR.16 Mechanisms of restenosis: The major determinant of the repeat restenotic process in ISR is neointima formation. VBT reduces the amount of neointima formation by 50% to 70%, revealing this to be the relevant mechanism in the treatment of ISR.7,9 In our study, the observed actuarial restenosis rates and the cumulative late loss compare, considering the higher-risk patient subset, very favorably with the results of published trials. Of special note, the mean length of the stented segment measured 31.6 mm and the analysis segment 59.6 mm. Yet, some observations require attention. In our study, the stented segment revealed the highest late loss of the entire vessel analyzed, whereas in the Scripps Coronary Radiation to Inhibit Proliferation APRIL 1, 2004

TABLE 3 Clinical Events and Symptomatic Status at Follow-up 6 mo Per Interval Clinical follow-up Death Myocardial infarction Angina pectoris Late total occlusion Target lesion revascularization Target vessel revascularization All major adverse cardiocascular events

1 3 15 4 9 13 17

12 mo Cumulative

98 (100%) (1.0%) 1 (1.0%) (3.1%) 3 (3.1%) (15.3%) 15 (15.3%) (4.1%) 4 (4.1%) (9.2%) 9 (9.2%) (13.3%) 13 (13.3%) (17.4%) 17 (17.4%)

FIGURE 1. Actuarial coronary restenosis rate in 98 consecutive patients. Restenosis rate is expressed as mean ⴞ SE. The numbers above the line represent the patients at risk at the end of each interval.

Post-Stenting and the Beta Energy Restenosis Trial investigations, the late loss at the nonstented segments was of greater proficiency. We may be able to explain these controversial findings. First, a comparably larger lesion length, as observed in our study, might be accompanied by a higher late loss due to reasons of probability. Second, only ISRs have been included in our study, therefore excluding positive remodeling as a confounder of lower late loss. In the Beta Energy Restenosis Trial, predominantly de novo lesions in nonstented vessels have been treated with sole balloon angioplasty, allowing for positive remodeling as a relevant mechanism for the preservation of vessel lumen. Third, the prevalence of geographic miss was very low in our series of patients, probably contributing to a comparably small late loss at the nonstented vessel segments. In the Scripps Coronary Radiation to Inhibit Proliferation Post-Stenting trial, the length of the radiation source was only slightly larger than the stent length, thus increasing the risk of geographic miss significantly. It has been previously shown that there is a positive correlation between the acute gain and the subsequent late loss after PCI.17 To explain this association, an interrelation between the barotrauma applied during the angioplasty procedure and the subsequent vascular response leading to the restenosis process has been assumed. To investigate whether a similar pattern was

Per Interval 0 2 7 1 4 7 9

Cumulative

97 (100%) (0%) 1 (1.0%) (2.0%) 5 (5.2%) (7.2%) 22 (22.7%) (1.0%) 5 (5.2%) (4.1%) 13 (13.4%) (7.2%) 20 (20.6%) (9.3%) 26 (26.8%)

24 mo Per Interval 0 0 7 0 2 3 3

Cumulative

97 (100%) (0%) 1 (1.0%) (0%) 5 (5.2%) (7.2%) 29 (30.0%) (0%) 5 (5.2%) (2.1%) 15 (15.5%) (3.1%) 23 (23.7%) (3.1%) 29 (30.0%)

existent for the development of late loss after PCI and VBT, we calculated correlation coefficients between acute gain and late loss at different follow-up points of time. Acute gain and subsequent late loss after PCI showed only a moderate correlation at 6 months of follow-up, whereas there was a stronger correlation at 12 and 24 months. This finding might be indicative of a gradual loss over time for VBT⬘s potential to equalize the influence of acute gain on late loss. Time course of restenosis: There is evidence that most instances of restenosis after conventional PCI occur within the first 6 months after the index procedure. Restenosis beyond 12 months of follow-up is seen very rarely. Serruys et al5 reported, in different groups of patients exhibiting comparable demographic and angiographic baseline characteristics, a peak of the restenotic process at 3 months of follow-up, with a restenosis rate of 3.6% after 1 month, 9.0% after 2 months, 23.7% after 3 months, and 13.2% at 4 months of follow-up after balloon angioplasty. Nobuyoshi et al6 reported a restenosis rate of 12.7% after 1 month, 43% after 3 months, 49.4% after 6 months, and 52.5% after 1 year of follow-up after balloon angioplasty in a longitudinal observation of 229 patients. In contrast, the Randomized Study with the Sirolimus-Eluting Bx Velocity Balloon-Expandable Stent trial showed a 0% restenosis rate after 6 months and only 9.7% after 18 months.18,19 The 2-year angiographic follow-up of the First-in-Man experience with the slow-release formulation of a sirolimus-eluting stent also showed virtually no late loss with a minimum luminal diameter of 2.67 mm after intervention, 2.69 mm at 4 months, 2.47 mm at 1 year, and 2.63 mm at 2 years. At 3 years of follow-up, there was no additional need for revascularization procedures indicating no significant additional late loss. Regarding the time course of restenosis after VBT, the findings from experimental data in several animal models remain controversial. Although it has been shown that ␤-irradiation effectively inhibited neointima formation in the short term after balloon overstretch injury of native porcine coronary arteries, an inhibitory effect sustained for 6 months after implantation of radioactive stents or ␤-irradiation after balloon-overstretch injury of native nonatheroslerotic porcine coronary arteries could not be demonstrated.20 –22 Most data from clinical studies cover a follow-up interval of 6 months, where a 50% decrease in

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840 THE AMERICAN JOURNAL OF CARDIOLOGY姞

TABLE 4 Angiographic Indexes of the Stented, Injured, Irradiated, and Analysis Segment at Baseline and at Follow-up Before PCI

VOL. 93 APRIL 1, 2004

Reference luminal diameter (mm) Stented segment Minimum luminal diameter (mm) Acute gain (mm) Late loss between groups, (mm) Loss per month between groups (mm) Cumulative late loss (mm) Loss index Net gain (mm) Diameter stenosis (%) Injured segment Minimum luminal diameter (mm) Late loss between groups (mm) Loss per month between groups (mm) Cumulative late loss (mm) Diameter stenosis (%) Irradiated segment Minimum luminal diameter (mm) Late loss between groups (mm) Loss per month between groups (mm) Cumulative late loss (mm) Diameter stenosis (%) Analysis segment (including dose fall-off) Minimum luminal diameter (mm) Late loss between groups (mm) Loss per month between groups (mm) Cumulative late loss (mm) Diameter stenosis (%) TVR ⫽ target vessel revascularization.

After PCI vs 6 mo

p Value

6 mo vs 12 mo Without 6 mo TVR

p Value

12 mo vs 24 mo Without 6 ⫹ 12 mo TVR

p Value

3.11 ⫾ 0.56

3.12 ⫾ 0.74

3.18 ⫾ 0.53

0.282

3.21 ⫾ 0.54

3.21 ⫾ 0.58

0.879

3.22 ⫾ 0.71

3.20 ⫾ 0.64

0.617

0.73 ⫾ 0.58 2.14 ⫾ 0.79

2.87 ⫾ 0.63

2.49 ⫾ 0.74

⬍0.001

2.54 ⫾ 1.15

2.29 ⫾ 1.03

⬍0.001

2.37 ⫾ 0.88

2.21 ⫾ 0.77

0.105

0.40 0.32 0.78 26.9

⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001

0.25 ⫾ 0.38 0.08 0.58 0.27 1.56 20.9 ⫾ 17.2 28.7

0.99 0.35 0.83 15.1

0.570 0.873 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001

0.16 ⫾ 0.32 0.01 0.66 0.31 1.48 26.3 ⫾ 27.3 31.0

0.78 0.28 0.86 21.5

0.034 ⬍0.001 0.454 0.102 0.082 0.076

2.86 ⫾ 0.60 2.59 ⫾ 0.59 0.27 ⫾ 0.21 0.045 0.27 ⫾ 0.21 8.3 ⫾ 10.8 18.6 ⫾ 16.9

⬍0.001 ⬍0.001 0.002 ⬍0.001 ⬍0.001

2.64 ⫾ 0.78 2.43 ⫾ 0.70 0.21 ⫾ 0.26 0.035 0.43 ⫾ 0.35 17.8 ⫾ 16.1 24.3 ⫾ 20.3

⬍0.001 0.913 0.042 ⬍0.001 ⬍0.001

2.48 ⫾ 0.54 2.35 ⫾ 0.50 0.13 ⫾ 0.24 0.011 0.51 ⫾ 0.40 23.0 ⫾ 21.5 26.6 ⫾ 20.6

0.106 0.055 0.082 0.555 0.123

2.85 ⫾ 0.72 2.67 ⫾ 0.69 0.18 ⫾ 0.29 0.03 0.18 ⫾ 0.29 8.7 ⫾ 10.2 16.0 ⫾ 13.8

0.032 ⬍0.001 0.003 0.001 0.025

2.73 ⫾ 0.77 2.54 ⫾ 0.76 0.19 ⫾ 0.31 0.032 0.31 ⫾ 0.32 15.0 ⫾ 15.0 20.9 ⫾ 16.8

0.006 0.835 0.123 0.001 0.003

2.59 ⫾ 0.81 2.48 ⫾ 0.61 0.11 ⫾ 0.27 0.009 0.37 ⫾ 0.23 19.6 ⫾ 17.3 22.5 ⫾ 16.0

0.234 0.067 0.067 0.532 0.301

2.83 ⫾ 0.81 2.65 ⫾ 0.76 0.18 ⫾ 0.36 0.03 0.18 ⫾ 0.36 9.3 ⫾ 15.6 16.7 ⫾ 16.0

0.027

2.71 ⫾ 0.87 2.54 ⫾ 0.66 0.17 ⫾ 0.29 0.28 0.29 ⫾ 0.41 15.6 ⫾ 22.2 20.9 ⫾ 24.3

0.023

2.58 ⫾ 0.66 2.47 ⫾ 0.55 0.11 ⫾ 0.20 0.009 0.36 ⫾ 0.28 19.9 ⫾ 16.2 22.8 ⫾ 18.2

0.256

76.5 ⫾ 17.0

0.38 ⫾ 0.40 0.06 0.38 0.18 1.76 8.0 ⫾ 14.2 21.7

⫾ ⫾ ⫾ ⫾

0.021

⫾ ⫾ ⫾ ⫾

0.034

⫾ ⫾ ⫾ ⫾

0.298

restenosis rate has been demonstrated consistently in numerous studies.7–10 In contrast, the long-term outcome has not been studied extensively. Teirstein et al11 reported a decrease of mean minimum luminal diameter from 2.49 ⫾ 0.81 to 2.12 ⫾ 0.73 mm between 6 and 36 months of follow-up, comparing well with the late loss between 6 and 24 months observed in our study. Therefore, the overall late loss after the first 6 months of follow-up might be regarded as similar despite different types of radiation and clinical settings. Yet, because additional intervals have not been studied, the time course of restenosis during the 6 and 36 months of follow-up has not been highlighted. Our study showed that significant additional late loss occurred between 6 and 12 months, whereas there were no significant changes between 12 and 24 months of follow-up. Meerkin et al12 reported a very small late loss of only 0.04 ⫾ 0.56 mm between 6 and 24 months of follow-up, demonstrating a sustained negative late loss of ⫺0.31 ⫾ 0.53 mm. This finding, controversial compared with the results of the Scripps Coronary Radiation to Inhibit Proliferation Post-Stenting trial and our study, is likely due to positive remodeling after VBT of de novo lesions, a mechanism not applicable to ISR. Several mechanisms may be involved to explain the observed findings. First, a complete inhibition of restenosis would require eradication of proliferative properties or death of the entire cell population. Yet it has been demonstrated previously that radiation doses currently applied would not be sufficient to accomplish this. In a contemporary clinical setting, approximately 10% of irradiated clonogenic cells will survive and maintain their integrity and ability to divide and migrate.23 Notably, complete inhibition of restenosis has not been shown in any of the clinical VBT trials.7–10 Second, it has been proposed that the proliferative properties and time kinetics of the surviving fraction of clonogenic smooth muscle cells might be comparable with those of nonirradiated cells. Consequently, restenosis after VBT probably follows a qualitative pattern comparable with nonirriadiated tissue, yet takes its origin from a smaller number of proliferating cells, resulting in a regularly timed process of restenosis with a reduced absolute amount of neointimal hyperplasia.23 Optimal timing of angiographic restudy in patients after VBT: Whether angiographic restudy is useful in

patients with a high risk for restenosis is under controversial discussion. Most reports suggest a lack of clear relation between symptomatic status and angiographic restenosis; the incidence of restenosis in asymptomatic patients varies from 4 to 17%.6 Angiographic restenosis might go undetected by patients who will not develop anginal symptoms due to neuropathy in diabetes mellitus or denervation after orthotopic heart transplantation, and might be of prognostic significance in patients with multivessel disease. In our study, half of the patients with angiographic restenosis presented without symptoms. In conjunction with the observed prolongation of the restenotic process after VBT, routine control angiog-

raphy not after 6 months but after 1 year after the index procedure might be recommended in high-risk patient subsets. Study limitations: Because the population studied was prone to a high rate of restenosis and major cardiovascular events, the results of our study cannot be generalized in a quantitative point of view. Especially regarding the length of the vessel segment analyzed and the very high prevalence of cardiovascular risk factors and co-morbidity, the cohort might not be representative. Furthermore the discussion of the time course and mechanisms of restenosis, in the light of lacking data for ISR, merely covered native restenosis. Nevertheless, because pathophysiologic and histologic characteristics of native and in-stent restenotic lesions show remarkable similarities, the pattern and time course of restenosis rate and late loss may be similar in various patient populations and restenosis subsets. Most of the ISRs were treated with the cutting balloon, but conventional balloon angioplasty was also frequently used. Whether the angioplasty device used has specific consequences for the acute and late outcome after VBT is under controversial discussion. In studies without adjunctive VBT, some investigators have shown the superiority of cutting balloon over conventional balloon angioplasty whereas others did not.24,25 The influence of the device used for angioplasty in VBT studies has not been prospectively investigated. In a retrospective analysis of the multicenter European Registry of Intraluminal Coronary Beta Brachytherapy, the use of the cutting balloon seemed to be associated with a lower target lesion and an especially lower revascularization rate. This has been explained by a lower risk for geographic miss due to missing balloon slippage when a cutting balloon was used.26 In our study, no significant differences could be demonstrated by using either the cutting or a conventional balloon (data not shown). The radiation dose applied, depending on the angiographically determined reference diameter, was 18.4, 23.0, or 25.3 Gy. Dose prescriptions have been made according to the recommendations of the manufacturer, which have been derived from experimental and clinical data in an empirical fashion only. Therefore, in light of limited evidence regarding the actual target tissue and correct absolute doses, the radiation doses applied might have been suboptimal. The natural progression of the underlying coronary artery disease might have influenced the evolution of angiographic restenosis rate and late loss. We did not systematically investigate this topic by analyzing the remaining coronary arteries. Yet, because the reference luminal diameter did not show any changes, the potential influence might be negligible. 1. Bauters C, Banos JL, Van Belle E, Mc Fadden EP, Lablanche JM, Bertrand

ME. Six-month angiographic outcome after successful repeat percutaneous intervention for in-stent restenosis. Circulation 1998;97:318 –321. 2. Mahdi NA, Pathan AZ, Harrell L, Leon MN, Lopez J, Butte A, Ferrell M, Gold HK, Palacios IF. Directional coronary atherectomy for the treatment of PalmazSchatz in-stent restenosis. Am J Cardiol 1998;82:1345–1351.

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3. Mehran R, Dangas G, Mintz GS, Waksman R, Abizaid A, Satler LF, Pichard

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