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An Integrated TAXUS IV, V, and VI Intravascular Ultrasound Analysis of the Predictors of Edge Restenosis After Bare Metal or Paclitaxel-Eluting Stents
An Integrated TAXUS IV, V, and VI Intravascular Ultrasound Analysis of the Predictors of Edge Restenosis After Bare Metal or Paclitaxel-Eluting Stents Jian Liu, MDa, Akiko Maehara, MDa,*, Gary S. Mintz, MDa, Neil J. Weissman, MDb, Alan Yu, MSc, Hong Wang, MSc, Lazar Mandinov, MDc, Jeffrey J. Popma, MDd, Stephen G. Ellis, MDe, Eberhard Grube, MDf, Keith D. Dawkins, MDc, and Gregg W. Stone, MDa We used intravascular ultrasound data after stent implantation from the TAXUS IV, V, and VI trials to determine predictors of angiographic stent edge restenosis. In the combined TAXUS IV, V, and VI trials, intravascular ultrasound was performed at implantation in 255 patients with bare metals stents (BMSs) and 276 patients with paclitaxel-eluting stents who underwent quantitative coronary angiography at 9 months. At follow-up, 6 BMSs (2.5%) had proximal edge and 6 BMSs (2.4%) had distal edge angiographic restenosis; 14 TAXUS stents (5.2%) had proximal edge and 1 TAXUS stent (0.4%) had distal edge angiographic restenosis. Although univariate analysis identified external elastic membrane, lumen areas, and plaque burden (external elastic membrane minus lumen/ external elastic membrane) as predictors of 9-month angiographic edge restenosis in the overall cohort and in BMS- and TAXUS-treated patients separately, only edge plaque burden was an independent predictor of 9-month angiographic edge restenosis. Receiver operator characteristic analysis showed that residual plaque burden, but not edge lumen area, was predictive of 9-month angiographic edge restenosis in BMS-treated patients (cutoff 47.7%, c ⴝ 0.70, p ⴝ 0.0244) and in TAXUS-treated patients (cutoff 47.1%, c ⴝ 0.69, p ⴝ 0.0137). In conclusion, residual edge plaque burden predicts stent edge restenosis after BMS or TAXUS stent implantation and the optimal plaque burden for stent edge landing zones are the same for BMSs and TAXUS stents, independent of vessel size and edge lumen dimensions. © 2009 Elsevier Inc. (Am J Cardiol 2009;103:501–506)
Stent edge restenosis can occur after implantation of bare metal stents (BMSs) or drug-eluting stents (DESs). Previous studies have suggested that stent edge plaque burden is a predictor of stent edge restenosis; therefore, stent edge restenosis can be minimized by stenting from “normal to normal.”1,2 However, reference segments are rarely normal; and the optimal criteria for stent edge landing zone plaque burden that would minimize edge restenosis have not been clearly established. The present analysis combined data from the TAXUS IV, V, and VI trials to evaluate the baseline (after stent implantation) intravascular ultrasound (IVUS) measurement of stent edge plaque burden as a predictor of stent edge binary angiographic restenosis at 9-month follow-up and to determine the optimum stent edge plaque burden that would minimize stent edge restenosis.
a
Cardiovascular Research Foundation/Columbia University Medical Center, New York, New York; bWashington Hospital Center, Washington, D.C.; cBoston Scientific Corporation, Natick, and dSt. Elizabeth Medical Center, Boston, Massachusetts; eCleveland Clinic, Cleveland, Ohio; and f Heart Center Siegburg, Siegburg, Germany. Manuscript received September 17, 2008; revised manuscript received and accepted October 7, 2008. Dr. Mintz, Dr. Weissman, Dr. Stone, and Dr. Popma are consultants or receive grant support from Boston Scientific Corporation, Natick, Massachusetts. *Corresponding author: Tel: 212-851-9371; fax: 212-851-9230. E-mail address: [email protected] (A. Maehara). 0002-9149/09/$ – see front matter © 2009 Elsevier Inc. doi:10.1016/j.amjcard.2008.10.010
Methods The TAXUS IV, V, and VI trials were prospective, double-blind, BMS-controlled trials in which patients with a single de novo native coronary artery lesion were randomly assigned to treatment with a paclitaxel-eluting TAXUS stent (Boston Scientific, Natick, Massachusetts) or an otherwise identical BMS (Boston Scientific).3–5 The TAXUS IV and V studies used the slow-release (commercially available) formulation, whereas TAXUS VI used the moderate-release (not commercially available) formulation that has 3 times higher in vivo paclitaxel release over time. Of the 2,918 patients enrolled in the 3 trials, the first 956 patients enrolled at prespecified IVUS sites underwent serial volumetric IVUS analysis and were included in the IVUS cohort: 268 from TAXUS IV, 509 from TAXUS V, and 179 from TAXUS VI. In this IVUS substudy the final cohort included 255 BMS- and 276 TAXUS-treated patients; the patients were excluded from the present analysis because (contrary to protocol) IVUS imaging did not include adequate proximal and/or distal stent edges and reference segments or did not have adequate angiographic follow-up. Coronary angiography was performed after intracoronary nitroglycerin before and after stent implantation and at 9-month follow-up. Per protocol, identical angiographic projections of the lesions were to be used at each time point; www.AJConline.org
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Table 1 Baseline clinical and lesion characteristics comparing TAXUS stent with bare metal stent
Table 2 Quantitative coronary angiographic findings comparing TAXUS stent with bare metal stent
Variable
Variable
Age (yrs) Men Diabetes mellitus Hypertension Hyperlipidemia* Smoker Previous myocardial infarction Unstable angina pectoris Treated coronary artery Left anterior descending Right Left circumflex Calcification AHA/ACC lesion type Type B2 Type C
TAXUS (n ⫽ 276)
BMS (n ⫽ 255)
p Value
62.2 ⫾ 10.3 22.5% (62/276) 28.3% (78/276) 26.6% (73/274) 69.0% (189/274) 24.5% (67/274) 33.0% (91/276)
61.8 ⫾ 10.5 32.2% (82/255) 25.5% (65/255) 30.6% (78/255) 71.7% (182/254) 19.0% (48/252) 33.7% (86/255)
0.67 0.0145 0.49 0.34 0.51 0.14 0.85
35.9% (99/276)
32.2% (82/255)
0.41
46.0% (127/276) 28.6% (79/276) 25.4% (70/276) 65.6% (181/276)
39.6% (101/255) 32.9% (84/255) 27.5% (70/255) 64.7% (165/255)
0.16 0.30 0.62 0.86
33.7% (93/276) 35.9% (99/276)
35.3% (90/255) 40.4% (103/255)
0.72 0.32
* Defined as medical treatment for hyperlipidemia. AHA/ACC ⫽ American Heart Association/American College Cardiology.
therefore, follow-up angiography with nonmatching projections was not analyzed. All quantitative coronary angiographic analyses were performed at a single core laboratory (Brigham and Women’s Hospital, Boston, Massachusetts) with the contrast-filled injection catheter as the calibration source using a validated automated edge-detection algorithm (Medis, CMS, Maastricht, The Netherlands) by a technician unaware of the clinical or IVUS findings who was blinded to the treatment arm. Minimal lumen diameter was measured within the stent (in-stent analysis) and within 5 mm proximal and distal to the stent (edge analysis) and used to calculate a diameter stenosis. Binary angiographic restenosis (in stent or proximal or distal edge) was the incidence of diameter stenosis ⱖ50% at qualifying angiographic follow-up. Substudy sites were selected based on IVUS experience, volume, and stated willingness to enroll all patients in the IVUS substudy until prespecified IVUS substudy enrollment numbers were obtained. IVUS imaging was performed after intracoronary administration of nitroglycerin 0.1 to 0.2 mg using motorized transducer pullback (0.5 mm/s) and contemporary, commercial scanners. Images were continuously recorded from distal to proximal including the stent and ⬎5-mm-long segments distal and proximal to the stent. All IVUS substudy data were analyzed at a single core laboratory (Medstar Research Institute, Washington Hospital Center, Washington, D.C.) by a technician unaware of the clinical or angiographic findings who was blinded to the treatment arm. With the use of computerized planimetry (TapeMeasure, Indec Systems, Mountain View, California), external elastic membrane, stent, and lumen borders were manually traced; stent, lumen, and plaque and media (external elastic membrane minus lumen) cross-sectional area and plaque burden (plaque/media divided by external elastic
TAXUS
BMS
Before procedure No. of subjects 276 255 Reference vessel diameter 2.79 ⫾ 0.49 2.81 ⫾ 0.54 (mm) Minimum lumen diameter 0.89 ⫾ 0.36 0.87 ⫾ 0.34 (mm) Diameter stenosis (%) 68.3 ⫾ 11.1 69.0 ⫾ 10.8 Lesion length (mm) 16.97 ⫾ 7.92 17.17 ⫾ 9.59 In stent at 9 mos No. of subjects 276 255 Minimum lumen diameter 2.24 ⫾ 0.64 1.71 ⫾ 0.67 (mm) Diameter stenosis (%) 18.8 ⫾ 19.6 38.5 ⫾ 21.2 Binary restenosis rate 9.4% (26/276) 31.8% (81/225) Late loss (mm) 0.42 ⫾ 0.55 0.97 ⫾ 0.57 Proximal edge at 9 mos No. of subjects 267 242 Minimum lumen diameter 2.57 ⫾ 0.71 2.58 ⫾ 0.66 (mm) Diameter stenosis (%) 15.3 ⫾ 16.4 15.1 ⫾ 14.2 Binary restenosis rate 5.2% 2.5% Late loss (mm) 0.24 ⫾ 0.50 0.27 ⫾ 0.46 Distal edge at 9 mos No. of subjects 274 254 Minimum lumen diameter 2.31 ⫾ 0.56 2.20 ⫾ 0.5 (mm) Diameter stenosis (%) 8.2 ⫾ 12.6 12.7 ⫾ 12.8 Binary restenosis rate 0.4% 2.4% Late loss (mm) 0.08 ⫾ 0.39 0.19 ⫾ 0.37
p Value
0.65 0.58 0.47 0.80
⬍0.0001 ⬍0.0001 ⬍0.0001 ⬍0.0001
0.87 0.90 0.12 0.43
0.0311 ⬍0.0001 0.06 0.0005
membrane) were calculated every millimeter within the stented segment and adjacent 5-mm proximal and distal stent edges. For the purposes of this analysis, proximal and distal edges were combined, and the 1-mm slices closest to either edge of the stent were analyzed. The present observations are based on post hoc analysis of the original quantitative data. Categorical variables were summarized as frequencies and percentages and compared using chi-square statistics. Continuous variables were presented as mean ⫾ 1 SD and compared using 2-tailed, unpaired t tests. Multivariate analysis was used to determine predictors of 9-month angiographic stent edge restenosis. (More patients were enrolled in angiographic than in IVUS studies; therefore, an angiographic end-point definition was used rather than an IVUS definition of edge restenosis.) All covariates were modeled univariately for each outcome and multivariately using a stepwise procedure in the logistic regression model. Receiver operator characteristic analysis was used to measure the ability of baseline (after stent implantation) IVUS variables to discriminate between stent edges that developed restenosis from stent edges that did not. Receiver operator characteristic curves plot the probability of detecting true signals (sensitivity) and false signals (1 ⫺ specificity) for an entire range of possible cutpoints. Acceptable discrimination is considered if area under the curve is ⱖ0.7, but ⬍0.8; excellent and outstanding discriminations are considered for an area under the curve ⱖ0.8,
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Table 3 Postprocedure intravascular ultrasound findings comparing TAXUS with bare metal stent Variable In stent after procedure Average lumen area (mm2) Average external elastic membrane area (mm2) Average plaque/media area (mm2) Minimum lumen area (mm2) Proximal 1-mm edge after procedure Lumen area (mm2) External elastic membrane area (mm2) Plaque/media area (mm2) Plaque burden (%) Distal 1-mm edge after procedure Lumen area (mm2) External elastic membrane area (mm2) Plaque/media area (mm2) Plaque burden (%)
TAXUS (n ⫽ 276)
BMS (n ⫽ 255)
p Value
7.83 ⫾ 2.39 (275) 14.94 ⫾ 4.88 (240) 7.15 ⫾ 2.94 (240) 6.36 ⫾ 2.08 (275)
8.12 ⫾ 2.43 (254) 15.43 ⫾ 4.80 (227) 7.39 ⫾ 2.85 (227) 6.56 ⫾ 2.15 (254)
0.17 0.28 0.38 0.30
8.31 ⫾ 3.10 (215) 15.89 ⫾ 4.94 (197) 7.48 ⫾ 2.98 (197) 46.74 ⫾ 10.86 (197)
8.94 ⫾ 3.16 (201) 16.55 ⫾ 4.91 (181) 7.80 ⫾ 2.99 (181) 46.88 ⫾ 10.69 (181)
0.0419 0.19 0.30 0.90
7.37 ⫾ 3.14 (248) 12.15 ⫾ 5.09 (240) 4.82 ⫾ 2.71 (240) 38.29 ⫾ 12.25 (240)
7.40 ⫾ 2.97 (232) 12.49 ⫾ 5.27 (227) 5.11 ⫾ 3.07 (227) 38.73 ⫾ 12.04 (227)
0.90 0.48 0.27 0.70
Figure 1. Receiver operator characteristic curves for stent edge plaque burden (top) and lumen area (bottom) as predictors of angiographic stent edge restenosis at 9 months.
but ⬍0.9 and ⱖ0.9, respectively. To determine the optimal cut-off value of IVUS measurements for predicting 9-month angiographic stent edge restenosis, the cross point of
sensitivity and specificity curves was used. Differences were considered to be statistically significant for p values ⬍0.05.
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Results Baseline characteristics of the 531 patients used in this analysis are presented in Table 1 and are similar for TAXUS-treated and BMS-treated groups. Baseline angiographic data including reference vessel diameter, minimum lumen diameter, percent diameter stenosis, and lesion length were similar for the TAXUS and BMS groups (Table 2). At 9-month follow-up, patients in the TAXUS group compared with the BMS group had larger in-stent minimum lumen diameter (2.24 ⫾ 0.64 vs 1.71 ⫾ 0.67 mm, p ⬍0.0001), smaller in-stent diameter stenosis (18.8 ⫾ 19.6% vs 38.5 ⫾ 21.2%, p ⬍0.0001), less in-stent late loss (0.42 ⫾ 0.55 vs 0.97 ⫾ 0.57 mm, p ⬍0.0001), and a lower rate of binary in-stent restenosis (9.4% vs 31.8%, p ⬍0.0001). At 9-month follow-up there were no differences in diameter stenosis between the TAXUS and BMS groups at the proximal stent edge (Table 2). However, at the distal stent edge patients in the TAXUS group had smaller diameter stenosis compared with the BMS group (8.2 ⫾ 12.6% vs 12.7 ⫾ 12.8%, p ⬍0.0001). Binary angiographic restenosis at follow-up occurred in 2.5% of BMS proximal edges and in 5.2% of TAXUS stent proximal edges and in 2.4% of BMS distal edges and 0.4% TAXUS stent distal edges, with no statistically significant differences between the 2 stents (Table 2). A total of 27 angiographic edge restenoses occurred in patients receiving a BMS or TAXUS stent. Other than a smaller proximal edge lumen area in TAXUS stent-treated lesions, there were no differences in postprocedure IVUS findings between TAXUS- and BMStreated lesions (Table 3). However, when proximal and distal stent edges were combined, there were no differences in postprocedure edge lumen area (7.81 ⫾ 3.15 vs 8.13 ⫾ 3.16 mm2, p ⫽ 0.14) or edge plaque burden (42.1 ⫾ 12.4% vs 42.3 ⫾ 12.2%, p ⫽ 0.9) between TAXUS- and BMStreated lesions. IVUS measurements immediately after TAXUS or BMS implantation were available in 24 of 27 edges with 9-month angiographic restenosis. Comparing postprocedure IVUS findings in edges that did (n ⫽ 24) versus those that did not develop 9-month edge restenosis (n ⫽ 860), there was no significant difference in edge lumen area (7.12 ⫾ 2.96 vs 7.99 ⫾ 3.16 mm2, p ⫽ 0.19). However, lesions that did develop edge restenosis had a larger edge plaque burden after stent implantation than those with no restenosis at follow-up (50.3 ⫾ 13.3% vs 42.0 ⫾ 12.2%, p ⫽ 0.0012). Using univariate and multivariate logistic regression analyses, we tested postprocedure stent edge external elastic membrane, lumen areas, and plaque burden as predictors of 9-month angiographic edge restenosis in the overall cohort (combing TAXUS and BMS) and in TAXUS- and BMStreated lesions separately. In all 3 analyses only stent edge plaque burden (ratio of plaque/media to external elastic membrane area or percent external elastic membrane area occupied by plaque) predicted subsequent stent edge restenosis (odds ratio 1.06, 95% confidence interval 1.02 to 1.11, p ⫽ 0.0016, for TAXUS ⫹ BMS; odds ratio 1.07, 95% confidence interval 1.01 to 1.12, p ⫽ 0.0155, for TAXUS
alone; odds ratio 1.06, 95% confidence interval 1.00 to 1.13, p ⫽ 0.0421, for BMS alone). We performed receiver operator curve analysis of 9-month stent edge angiographic restenosis versus stent edge lumen area and stent edge plaque burden after stent implantation; edge plaque burden was moderately (and similarly) predictive of 9-month angiographic edge restenosis in BMS-treated patients (cutoff 47.7%, c ⫽ 0.70, p ⫽ 0.0244) and TAXUS-treated patients (cutoff 47.1%, c ⫽ 0.69, p ⫽ 0.0137; Figure 1). However, edge lumen area did not predict 9-month angiographic edge restenosis in BMStreated patients (p ⫽ 0.0629) or TAXUS-treated patients (p ⫽ 0.25; Figure 1). Discussion The major findings of this study follow. (1) Postimplantation stent edge plaque burden predicts stent edge restenosis after BMS or TAXUS implantation. (2) The optimal plaque burden criteria for stent edge landing zones are the same for BMSs and TAXUS stents, independent of vessel size and edge lumen dimensions. (3) Edge lumen area does not predict 9-month angiographic edge restenosis in BMStreated or TAXUS-treated patients. In the BMS era edge restenosis was not commonly appreciated or reported when stents were implanted in de novo lesions. Edge restenosis emerged as an important clinical problem in the brachytherapeutic era. Edge restenosis after radioactive stent implantation was 20% to 40% depending on the type of radioactive stent and the type of analysis.6,7 Edge restenosis also was a problem when brachytherapy was used to treat BMS restenosis. Geographic miss—a segment proximal or distal to the treated lesion subjected to injury during balloon inflation or new stent implantation, but not covered by the last seeds of the radiation source— was a contributing factor.8 Edge restenosis continued to be important in the DES era. Although there were no stent edge restenoses reported in RAVEL,9 in SIRIUS edge restenoses were more frequently observed at the proximal (5.5%) than at the distal (2.0%) edges of Cypher stents and in smaller vessels compared with larger vessels.10 In a smaller vessel cohort Schampaert et al11 reported a rate of Cypher stent edge restenosis of 2.3% in C-SIRIUS. In E-SIRIUS Schofer et al12 demonstrated that for Cypher stents proximal and distal stent edge restenosis rates were 2.1% and 1.3%, respectively. In TAXUS II proximal stent edge restenosis rates for TAXUS slow-release and moderate-release stents were 1.9% and 2.8%, respectively; distal edge restenosis rates were 1.9% and 0.9%, respectively.13 Most recently, in TAXUS IV, a subset of whose patients were included in the present analysis, Stone et al3 reported rates of proximal stent edge restenosis of 2.7% in TAXUS-treated patients and 3.4% in BMS-treated patients and rates of distal stent edge restenosis of 0.7% and 1.9%, respectively. Edge restenosis rates in the present study are in keeping with previous observations. Overall, 2.5% of BMSs and 5.2% of TAXUS stents had proximal edge restenosis, and 2.4% of BMS stents and 0.4% of TAXUS stents had distal edge restenosis. Combining proximal and distal stent edges,
Coronary Artery Disease/Stent Edge Plaque Burden and Restenosis
there were no differences between the 2 groups with respect to the frequency of stent edge restenosis. Stent edge angiographic restenosis can be due to a decrease in external elastic membrane (negative remodeling) and/or an increase in plaque from disease progression or intimal hyperplasia. Hoffmann et al1 reported that BMS edge restenosis was a combination of stent-induced intimal hyperplasia closest to the stent edge and progressively more negative remodeling at distances remote from the stent edge. The interaction between these 2 mechanisms was supported by an analysis from Weissman et al14 who also noted that the greatest lumen loss occurred within the first 2 mm from the proximal and distal edges of the stent and was primarily due to intimal hyperplasia. Mudra et al15 reported only intimal hyperplasia as the cause of restenosis within the first 3 mm of BMS edges. In brachytherapy studies edge restenosis was also the result of an increase in intimal hyperplasia except in patients with geographic miss in whom negative remodeling was shown to be important.16,17 The mechanism of edge restenosis after Cypher stent implantation has not been well studied. However, Serruys et al13 reported that for TAXUS-treated patients lumen loss within 2 mm of the stent edge was limited because positive vessel remodeling (increase in external elastic membrane) compensated for intimal hyperplasia, a phenomenon seen in slow-release and moderate-release TAXUS stents, but not in BMSs. There is accumulating evidence that plaque burden at the edge of the stent predicts edge restenosis after BMS or DES implantation. Hoffmann et al1 demonstrated that the dominant periprocedural predictor of BMS edge restenosis was stent edge plaque burden. Using data from SIRIUS, Sakurai et al2 demonstrated that a larger stent edge plaque burden and a step-up index (ratio of stent edge to reference minimum lumen area) predicted edge stenosis after Cypher stent implantation. Costa et al18 extended the concept of geographic miss to DESs; injured or diseased segments not covered by Cypher stents occurred frequently and was associated with increased risk of 1-year target vessel revascularization and myocardial infarction. However, these studies did not establish the plaque burden that best separated edge restenosis from no edge restenosis. Similarly, in the present study edge plaque burden, but not edge lumen dimensions, was predictive of 9-month angiographic edge restenosis in BMS-treated or TAXUStreated patients. Postintervention stent edge plaque burden was determined by preintervention plaque burden and plaque shift during stent implantation.19,20 Ahmed et al20 showed axial redistribution of plaque away from the center of the lesion toward the reference segments to increase postintervention stent edge plaque burden. However, Prati et al21 reported that the magnitude of reference segment plaque increase after stenting was slight (3.0 mm3/5 mm in the proximal reference segment and 1.7 mm3/5 mm in the distal reference segment). Thus, the major contribution to postintervention stent edge plaque burden was the preintervention plaque burden and not plaque shift. This study is a post hoc analysis of previous multicenter randomized, controlled, prospective TAXUS trials. Most patients had relatively simple de novo coronary lesions and low-risk profiles. We included slow-release and moderate-
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release TAXUS stents, although statistical analysis did not show any difference between these 2 formulations of the TAXUS stent. The results for edge restenosis after TAXUS implantation are heavily dominated by the proximal edge; further studies will be needed to understand better the plaque burden that can be tolerated at the proximal edge versus that at the distal edge. These data may not apply to other DESs. 1. Hoffmann R, Mintz GS, Kent KM, Satler LF, Pichard AD, Popma JJ, Leon MB. Serial intravascular ultrasound predictors of restenosis at the margins of Palmaz-Schatz stents. Am J Cardiol 1997;79:951–953. 2. Sakurai R, Ako J, Morino Y, Sonoda S, Kaneda H, Terashima M, Hassan AH, Leon MB, Moses JW, Popma JJ, et al; SIRIUS Trial Investigators. Predictors of edge stenosis following sirolimus-eluting stent deployment (a quantitative intravascular ultrasound analysis from the SIRIUS trial). Am J Cardiol 2005;96:1251–1253. 3. 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; TAXUS-IV Investigators. A polymer-based, paclitaxel-eluting stent in patients with coronary artery disease. N Engl J Med 2004;350:221– 231. 4. Stone GW, Ellis SG, Cannon L, Mann JT, Greenberg JD, Spriggs D, O’Shaughnessy CD, DeMaio S, Hall P, Popma JJ, Koglin J, Russell ME; TAXUS V Investigators. Comparison of a polymer-based paclitaxel-eluting stent with a bare metal stent in patients with complex coronary artery disease: a randomized controlled trial. JAMA 2005; 294:1215–1223. 5. Dawkins KD, Grube E, Guagliumi G, Banning AP, Zmudka K, Colombo A, Thuesen L, Hauptman K, Marco J, Wijns W, et al; TAXUS VI Investigators. Clinical efficacy of polymer-based paclitaxel-eluting stents in the treatment of complex, long coronary artery lesions from a multicenter, randomized trial: support for the use of drug-eluting stents in contemporary clinical practice. Circulation 2005;112:3306 – 3313. 6. Albiero R, Nishida T, Adamian M, Amato A, Vaghetti M, Corvaja N, Di Mario C, Colombo A. Edge restenosis after implantation of high activity 32P radioactive -emitting stents. Circulation 2000;101: 2454 –2457. 7. Wardeh AJ, Albiero R, Kay IP, Knook AH, Wijns W, Kozuma K, Nishida T, Ferrero V, Levendag PC, van Der Giessen WJ, Colombo A, Serruys PW. Angiographical follow-up after radioactive “Cold Ends” stent implantation: a multicenter trial. Circulation 2002;105:550 –553. 8. Kim HS, Waksman R, Cottin Y, Kollum M, Bhargava B, Mehran R, Chan RC, Mintz GS. Edge stenosis and geographical miss following intracoronary gamma radiation therapy for in-stent restenosis. J Am Coll Cardiol 2001;37:1026 –1030. 9. Morice MC, Serruys PW, Sousa JE, Fajadet J, Ban Hayashi E, Perin M, Colombo A, Schuler G, Barragan P, Guagliumi G, Molnàr F, Falotico R; RAVEL Study Group. Randomized study with the sirolimus-coated Bx velocity balloon-expandable stent in the treatment of patients with de novo native coronary artery lesions. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med 2002;346:1773–1780. 10. Popma JJ, Leon MB, Moses JW, Holmes DR Jr, Cox N, Fitzpatrick M, Douglas J, Lambert C, Mooney M, Yakubov S, Kuntz RE; SIRIUS Investigators. Quantitative assessment of angiographic restenosis after sirolimus-eluting stent implantation in native coronary arteries. Circulation 2004;110:3773–3780. 11. Schampaert E, Cohen EA, Schlüter M, Reeves F, Traboulsi M, Title LM, Kuntz RE, Popma JJ; C-SIRIUS Investigators. The Canadian study of the sirolimus-eluting stent in the treatment of patients with long de novo lesions in small native coronary arteries (C-SIRIUS). J Am Coll Cardiol 2004;43:1110 –1115. 12. Schofer J, Schlüter M, Gershlick AH, Wijns W, Garcia E, Schampaert E, Breithardt G; E-SIRIUS Investigators. Sirolimus-eluting stents for treatment of patients with long atherosclerotic lesions in small coronary arteries: double-blind, randomised controlled trial (E-SIRIUS). Lancet 2003;362:1093–1099. 13. Serruys PW, Degertekin M, Tanabe K, Russell ME, Guagliumi G, Webb J, Hamburger J, Rutsch W, Kaiser C, Whitbourn R, et al; TAXUS II Study Group. Vascular responses at proximal and distal
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The American Journal of Cardiology (www.AJConline.org) edges of paclitaxel-eluting stents: serial intravascular ultrasound analysis from the TAXUS II trial. Circulation 2004;109:627– 633. Weissman NJ, Wilensky RL, Tanguay JF, Bartorelli AL, Moses J, Williams DO, Bailey S, Martin JL, Canos MR, Rudra H, et al. Extent and distribution of in-stent intimal hyperplasia and edge effect in a non-radiation stent population. Am J Cardiol 2001;88:248 –252. Mudra H, Regar E, Klauss V, Werner F, Henneke KH, Sbarouni E, Theisen K. Serial follow-up after optimized ultrasound-guided deployment of Palmaz-Schatz stents. In-stent neointimal proliferation without significant reference segment response. Circulation 1997;95:363–370. Ahmed JM, Mintz GS, Waksman R, Lansky AJ, Mehran R, Wu H, Weissman NJ, Pichard AD, Satler LF, Kent KM, Leon MB. Serial intravascular ultrasound analysis of edge recurrence after intracoronary gamma radiation treatment of native artery in-stent restenosis lesions. Am J Cardiol 2001;87:1145–1149. Meerkin D, Tardif JC, Crocker IR, Arsenault A, Joyal M, Lucier G, King SB III, Williams DO, Serruys PW, Bonan R. Effects of intracoronary beta-radiation therapy after coronary angioplasty: an intravascular ultrasound study. Circulation 1999;99:1660 –1665.
18. Costa MA, Angiolillo DJ, Tannenbaum M, Driesman M, Chu A, Patterson J, Kuehl W, Battaglia J, Dabbons S, Shamoon F, et al; STLLR Investigators. Impact of stent deployment procedural factors on long-term effectiveness and safety of sirolimus-eluting stents (Final Results of the Multicenter Prospective STLLR Trial). Am J Cardiol 2008;101:1704 –1711. 19. Alfonso F, García P, Pimentel G, Hernández R, Sabaté M, Escaned J, Bañuelos C, Fernández C, Macaya C; Intravascular ultrasound study. Predictors and implications of residual plaque burden after coronary stenting: an intravascular ultrasound study. Am Heart J 2003;145:254 – 261. 20. Ahmed JM, Mintz GS, Weissman NJ, Lansky AJ, Pichard AD, Satler LF, Kent KM. Mechanism of lumen enlargement during intracoronary stent implantation: an intravascular ultrasound study. Circulation 2000;102:7–10. 21. Prati F, Pawlowski T, Gil R, Labellarte A, Gziut A, Caradonna E, Manzoli A, Pappalardo A, Burzotta F, Boccanelli A. Stenting of culprit lesions in unstable angina leads to a marked reduction in plaque burden: a major role of plaque embolization? A serial intravascular ultrasound study. Circulation 2003;107:2320 –2325.
Stent edge restenosis can occur after implantation of bare metal stents (BMSs) or drug-eluting stents (DESs). Previous studies have suggested that stent edge plaque burden is a predictor of stent edge restenosis; therefore, stent edge restenosis can be minimized by stenting from “normal to normal.”1,2 However, reference segments are rarely normal; and the optimal criteria for stent edge landing zone plaque burden that would minimize edge restenosis have not been clearly established. The present analysis combined data from the TAXUS IV, V, and VI trials to evaluate the baseline (after stent implantation) intravascular ultrasound (IVUS) measurement of stent edge plaque burden as a predictor of stent edge binary angiographic restenosis at 9-month follow-up and to determine the optimum stent edge plaque burden that would minimize stent edge restenosis.
a
Cardiovascular Research Foundation/Columbia University Medical Center, New York, New York; bWashington Hospital Center, Washington, D.C.; cBoston Scientific Corporation, Natick, and dSt. Elizabeth Medical Center, Boston, Massachusetts; eCleveland Clinic, Cleveland, Ohio; and f Heart Center Siegburg, Siegburg, Germany. Manuscript received September 17, 2008; revised manuscript received and accepted October 7, 2008. Dr. Mintz, Dr. Weissman, Dr. Stone, and Dr. Popma are consultants or receive grant support from Boston Scientific Corporation, Natick, Massachusetts. *Corresponding author: Tel: 212-851-9371; fax: 212-851-9230. E-mail address: [email protected] (A. Maehara). 0002-9149/09/$ – see front matter © 2009 Elsevier Inc. doi:10.1016/j.amjcard.2008.10.010
Methods The TAXUS IV, V, and VI trials were prospective, double-blind, BMS-controlled trials in which patients with a single de novo native coronary artery lesion were randomly assigned to treatment with a paclitaxel-eluting TAXUS stent (Boston Scientific, Natick, Massachusetts) or an otherwise identical BMS (Boston Scientific).3–5 The TAXUS IV and V studies used the slow-release (commercially available) formulation, whereas TAXUS VI used the moderate-release (not commercially available) formulation that has 3 times higher in vivo paclitaxel release over time. Of the 2,918 patients enrolled in the 3 trials, the first 956 patients enrolled at prespecified IVUS sites underwent serial volumetric IVUS analysis and were included in the IVUS cohort: 268 from TAXUS IV, 509 from TAXUS V, and 179 from TAXUS VI. In this IVUS substudy the final cohort included 255 BMS- and 276 TAXUS-treated patients; the patients were excluded from the present analysis because (contrary to protocol) IVUS imaging did not include adequate proximal and/or distal stent edges and reference segments or did not have adequate angiographic follow-up. Coronary angiography was performed after intracoronary nitroglycerin before and after stent implantation and at 9-month follow-up. Per protocol, identical angiographic projections of the lesions were to be used at each time point; www.AJConline.org
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Table 1 Baseline clinical and lesion characteristics comparing TAXUS stent with bare metal stent
Table 2 Quantitative coronary angiographic findings comparing TAXUS stent with bare metal stent
Variable
Variable
Age (yrs) Men Diabetes mellitus Hypertension Hyperlipidemia* Smoker Previous myocardial infarction Unstable angina pectoris Treated coronary artery Left anterior descending Right Left circumflex Calcification AHA/ACC lesion type Type B2 Type C
TAXUS (n ⫽ 276)
BMS (n ⫽ 255)
p Value
62.2 ⫾ 10.3 22.5% (62/276) 28.3% (78/276) 26.6% (73/274) 69.0% (189/274) 24.5% (67/274) 33.0% (91/276)
61.8 ⫾ 10.5 32.2% (82/255) 25.5% (65/255) 30.6% (78/255) 71.7% (182/254) 19.0% (48/252) 33.7% (86/255)
0.67 0.0145 0.49 0.34 0.51 0.14 0.85
35.9% (99/276)
32.2% (82/255)
0.41
46.0% (127/276) 28.6% (79/276) 25.4% (70/276) 65.6% (181/276)
39.6% (101/255) 32.9% (84/255) 27.5% (70/255) 64.7% (165/255)
0.16 0.30 0.62 0.86
33.7% (93/276) 35.9% (99/276)
35.3% (90/255) 40.4% (103/255)
0.72 0.32
* Defined as medical treatment for hyperlipidemia. AHA/ACC ⫽ American Heart Association/American College Cardiology.
therefore, follow-up angiography with nonmatching projections was not analyzed. All quantitative coronary angiographic analyses were performed at a single core laboratory (Brigham and Women’s Hospital, Boston, Massachusetts) with the contrast-filled injection catheter as the calibration source using a validated automated edge-detection algorithm (Medis, CMS, Maastricht, The Netherlands) by a technician unaware of the clinical or IVUS findings who was blinded to the treatment arm. Minimal lumen diameter was measured within the stent (in-stent analysis) and within 5 mm proximal and distal to the stent (edge analysis) and used to calculate a diameter stenosis. Binary angiographic restenosis (in stent or proximal or distal edge) was the incidence of diameter stenosis ⱖ50% at qualifying angiographic follow-up. Substudy sites were selected based on IVUS experience, volume, and stated willingness to enroll all patients in the IVUS substudy until prespecified IVUS substudy enrollment numbers were obtained. IVUS imaging was performed after intracoronary administration of nitroglycerin 0.1 to 0.2 mg using motorized transducer pullback (0.5 mm/s) and contemporary, commercial scanners. Images were continuously recorded from distal to proximal including the stent and ⬎5-mm-long segments distal and proximal to the stent. All IVUS substudy data were analyzed at a single core laboratory (Medstar Research Institute, Washington Hospital Center, Washington, D.C.) by a technician unaware of the clinical or angiographic findings who was blinded to the treatment arm. With the use of computerized planimetry (TapeMeasure, Indec Systems, Mountain View, California), external elastic membrane, stent, and lumen borders were manually traced; stent, lumen, and plaque and media (external elastic membrane minus lumen) cross-sectional area and plaque burden (plaque/media divided by external elastic
TAXUS
BMS
Before procedure No. of subjects 276 255 Reference vessel diameter 2.79 ⫾ 0.49 2.81 ⫾ 0.54 (mm) Minimum lumen diameter 0.89 ⫾ 0.36 0.87 ⫾ 0.34 (mm) Diameter stenosis (%) 68.3 ⫾ 11.1 69.0 ⫾ 10.8 Lesion length (mm) 16.97 ⫾ 7.92 17.17 ⫾ 9.59 In stent at 9 mos No. of subjects 276 255 Minimum lumen diameter 2.24 ⫾ 0.64 1.71 ⫾ 0.67 (mm) Diameter stenosis (%) 18.8 ⫾ 19.6 38.5 ⫾ 21.2 Binary restenosis rate 9.4% (26/276) 31.8% (81/225) Late loss (mm) 0.42 ⫾ 0.55 0.97 ⫾ 0.57 Proximal edge at 9 mos No. of subjects 267 242 Minimum lumen diameter 2.57 ⫾ 0.71 2.58 ⫾ 0.66 (mm) Diameter stenosis (%) 15.3 ⫾ 16.4 15.1 ⫾ 14.2 Binary restenosis rate 5.2% 2.5% Late loss (mm) 0.24 ⫾ 0.50 0.27 ⫾ 0.46 Distal edge at 9 mos No. of subjects 274 254 Minimum lumen diameter 2.31 ⫾ 0.56 2.20 ⫾ 0.5 (mm) Diameter stenosis (%) 8.2 ⫾ 12.6 12.7 ⫾ 12.8 Binary restenosis rate 0.4% 2.4% Late loss (mm) 0.08 ⫾ 0.39 0.19 ⫾ 0.37
p Value
0.65 0.58 0.47 0.80
⬍0.0001 ⬍0.0001 ⬍0.0001 ⬍0.0001
0.87 0.90 0.12 0.43
0.0311 ⬍0.0001 0.06 0.0005
membrane) were calculated every millimeter within the stented segment and adjacent 5-mm proximal and distal stent edges. For the purposes of this analysis, proximal and distal edges were combined, and the 1-mm slices closest to either edge of the stent were analyzed. The present observations are based on post hoc analysis of the original quantitative data. Categorical variables were summarized as frequencies and percentages and compared using chi-square statistics. Continuous variables were presented as mean ⫾ 1 SD and compared using 2-tailed, unpaired t tests. Multivariate analysis was used to determine predictors of 9-month angiographic stent edge restenosis. (More patients were enrolled in angiographic than in IVUS studies; therefore, an angiographic end-point definition was used rather than an IVUS definition of edge restenosis.) All covariates were modeled univariately for each outcome and multivariately using a stepwise procedure in the logistic regression model. Receiver operator characteristic analysis was used to measure the ability of baseline (after stent implantation) IVUS variables to discriminate between stent edges that developed restenosis from stent edges that did not. Receiver operator characteristic curves plot the probability of detecting true signals (sensitivity) and false signals (1 ⫺ specificity) for an entire range of possible cutpoints. Acceptable discrimination is considered if area under the curve is ⱖ0.7, but ⬍0.8; excellent and outstanding discriminations are considered for an area under the curve ⱖ0.8,
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Table 3 Postprocedure intravascular ultrasound findings comparing TAXUS with bare metal stent Variable In stent after procedure Average lumen area (mm2) Average external elastic membrane area (mm2) Average plaque/media area (mm2) Minimum lumen area (mm2) Proximal 1-mm edge after procedure Lumen area (mm2) External elastic membrane area (mm2) Plaque/media area (mm2) Plaque burden (%) Distal 1-mm edge after procedure Lumen area (mm2) External elastic membrane area (mm2) Plaque/media area (mm2) Plaque burden (%)
TAXUS (n ⫽ 276)
BMS (n ⫽ 255)
p Value
7.83 ⫾ 2.39 (275) 14.94 ⫾ 4.88 (240) 7.15 ⫾ 2.94 (240) 6.36 ⫾ 2.08 (275)
8.12 ⫾ 2.43 (254) 15.43 ⫾ 4.80 (227) 7.39 ⫾ 2.85 (227) 6.56 ⫾ 2.15 (254)
0.17 0.28 0.38 0.30
8.31 ⫾ 3.10 (215) 15.89 ⫾ 4.94 (197) 7.48 ⫾ 2.98 (197) 46.74 ⫾ 10.86 (197)
8.94 ⫾ 3.16 (201) 16.55 ⫾ 4.91 (181) 7.80 ⫾ 2.99 (181) 46.88 ⫾ 10.69 (181)
0.0419 0.19 0.30 0.90
7.37 ⫾ 3.14 (248) 12.15 ⫾ 5.09 (240) 4.82 ⫾ 2.71 (240) 38.29 ⫾ 12.25 (240)
7.40 ⫾ 2.97 (232) 12.49 ⫾ 5.27 (227) 5.11 ⫾ 3.07 (227) 38.73 ⫾ 12.04 (227)
0.90 0.48 0.27 0.70
Figure 1. Receiver operator characteristic curves for stent edge plaque burden (top) and lumen area (bottom) as predictors of angiographic stent edge restenosis at 9 months.
but ⬍0.9 and ⱖ0.9, respectively. To determine the optimal cut-off value of IVUS measurements for predicting 9-month angiographic stent edge restenosis, the cross point of
sensitivity and specificity curves was used. Differences were considered to be statistically significant for p values ⬍0.05.
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Results Baseline characteristics of the 531 patients used in this analysis are presented in Table 1 and are similar for TAXUS-treated and BMS-treated groups. Baseline angiographic data including reference vessel diameter, minimum lumen diameter, percent diameter stenosis, and lesion length were similar for the TAXUS and BMS groups (Table 2). At 9-month follow-up, patients in the TAXUS group compared with the BMS group had larger in-stent minimum lumen diameter (2.24 ⫾ 0.64 vs 1.71 ⫾ 0.67 mm, p ⬍0.0001), smaller in-stent diameter stenosis (18.8 ⫾ 19.6% vs 38.5 ⫾ 21.2%, p ⬍0.0001), less in-stent late loss (0.42 ⫾ 0.55 vs 0.97 ⫾ 0.57 mm, p ⬍0.0001), and a lower rate of binary in-stent restenosis (9.4% vs 31.8%, p ⬍0.0001). At 9-month follow-up there were no differences in diameter stenosis between the TAXUS and BMS groups at the proximal stent edge (Table 2). However, at the distal stent edge patients in the TAXUS group had smaller diameter stenosis compared with the BMS group (8.2 ⫾ 12.6% vs 12.7 ⫾ 12.8%, p ⬍0.0001). Binary angiographic restenosis at follow-up occurred in 2.5% of BMS proximal edges and in 5.2% of TAXUS stent proximal edges and in 2.4% of BMS distal edges and 0.4% TAXUS stent distal edges, with no statistically significant differences between the 2 stents (Table 2). A total of 27 angiographic edge restenoses occurred in patients receiving a BMS or TAXUS stent. Other than a smaller proximal edge lumen area in TAXUS stent-treated lesions, there were no differences in postprocedure IVUS findings between TAXUS- and BMStreated lesions (Table 3). However, when proximal and distal stent edges were combined, there were no differences in postprocedure edge lumen area (7.81 ⫾ 3.15 vs 8.13 ⫾ 3.16 mm2, p ⫽ 0.14) or edge plaque burden (42.1 ⫾ 12.4% vs 42.3 ⫾ 12.2%, p ⫽ 0.9) between TAXUS- and BMStreated lesions. IVUS measurements immediately after TAXUS or BMS implantation were available in 24 of 27 edges with 9-month angiographic restenosis. Comparing postprocedure IVUS findings in edges that did (n ⫽ 24) versus those that did not develop 9-month edge restenosis (n ⫽ 860), there was no significant difference in edge lumen area (7.12 ⫾ 2.96 vs 7.99 ⫾ 3.16 mm2, p ⫽ 0.19). However, lesions that did develop edge restenosis had a larger edge plaque burden after stent implantation than those with no restenosis at follow-up (50.3 ⫾ 13.3% vs 42.0 ⫾ 12.2%, p ⫽ 0.0012). Using univariate and multivariate logistic regression analyses, we tested postprocedure stent edge external elastic membrane, lumen areas, and plaque burden as predictors of 9-month angiographic edge restenosis in the overall cohort (combing TAXUS and BMS) and in TAXUS- and BMStreated lesions separately. In all 3 analyses only stent edge plaque burden (ratio of plaque/media to external elastic membrane area or percent external elastic membrane area occupied by plaque) predicted subsequent stent edge restenosis (odds ratio 1.06, 95% confidence interval 1.02 to 1.11, p ⫽ 0.0016, for TAXUS ⫹ BMS; odds ratio 1.07, 95% confidence interval 1.01 to 1.12, p ⫽ 0.0155, for TAXUS
alone; odds ratio 1.06, 95% confidence interval 1.00 to 1.13, p ⫽ 0.0421, for BMS alone). We performed receiver operator curve analysis of 9-month stent edge angiographic restenosis versus stent edge lumen area and stent edge plaque burden after stent implantation; edge plaque burden was moderately (and similarly) predictive of 9-month angiographic edge restenosis in BMS-treated patients (cutoff 47.7%, c ⫽ 0.70, p ⫽ 0.0244) and TAXUS-treated patients (cutoff 47.1%, c ⫽ 0.69, p ⫽ 0.0137; Figure 1). However, edge lumen area did not predict 9-month angiographic edge restenosis in BMStreated patients (p ⫽ 0.0629) or TAXUS-treated patients (p ⫽ 0.25; Figure 1). Discussion The major findings of this study follow. (1) Postimplantation stent edge plaque burden predicts stent edge restenosis after BMS or TAXUS implantation. (2) The optimal plaque burden criteria for stent edge landing zones are the same for BMSs and TAXUS stents, independent of vessel size and edge lumen dimensions. (3) Edge lumen area does not predict 9-month angiographic edge restenosis in BMStreated or TAXUS-treated patients. In the BMS era edge restenosis was not commonly appreciated or reported when stents were implanted in de novo lesions. Edge restenosis emerged as an important clinical problem in the brachytherapeutic era. Edge restenosis after radioactive stent implantation was 20% to 40% depending on the type of radioactive stent and the type of analysis.6,7 Edge restenosis also was a problem when brachytherapy was used to treat BMS restenosis. Geographic miss—a segment proximal or distal to the treated lesion subjected to injury during balloon inflation or new stent implantation, but not covered by the last seeds of the radiation source— was a contributing factor.8 Edge restenosis continued to be important in the DES era. Although there were no stent edge restenoses reported in RAVEL,9 in SIRIUS edge restenoses were more frequently observed at the proximal (5.5%) than at the distal (2.0%) edges of Cypher stents and in smaller vessels compared with larger vessels.10 In a smaller vessel cohort Schampaert et al11 reported a rate of Cypher stent edge restenosis of 2.3% in C-SIRIUS. In E-SIRIUS Schofer et al12 demonstrated that for Cypher stents proximal and distal stent edge restenosis rates were 2.1% and 1.3%, respectively. In TAXUS II proximal stent edge restenosis rates for TAXUS slow-release and moderate-release stents were 1.9% and 2.8%, respectively; distal edge restenosis rates were 1.9% and 0.9%, respectively.13 Most recently, in TAXUS IV, a subset of whose patients were included in the present analysis, Stone et al3 reported rates of proximal stent edge restenosis of 2.7% in TAXUS-treated patients and 3.4% in BMS-treated patients and rates of distal stent edge restenosis of 0.7% and 1.9%, respectively. Edge restenosis rates in the present study are in keeping with previous observations. Overall, 2.5% of BMSs and 5.2% of TAXUS stents had proximal edge restenosis, and 2.4% of BMS stents and 0.4% of TAXUS stents had distal edge restenosis. Combining proximal and distal stent edges,
Coronary Artery Disease/Stent Edge Plaque Burden and Restenosis
there were no differences between the 2 groups with respect to the frequency of stent edge restenosis. Stent edge angiographic restenosis can be due to a decrease in external elastic membrane (negative remodeling) and/or an increase in plaque from disease progression or intimal hyperplasia. Hoffmann et al1 reported that BMS edge restenosis was a combination of stent-induced intimal hyperplasia closest to the stent edge and progressively more negative remodeling at distances remote from the stent edge. The interaction between these 2 mechanisms was supported by an analysis from Weissman et al14 who also noted that the greatest lumen loss occurred within the first 2 mm from the proximal and distal edges of the stent and was primarily due to intimal hyperplasia. Mudra et al15 reported only intimal hyperplasia as the cause of restenosis within the first 3 mm of BMS edges. In brachytherapy studies edge restenosis was also the result of an increase in intimal hyperplasia except in patients with geographic miss in whom negative remodeling was shown to be important.16,17 The mechanism of edge restenosis after Cypher stent implantation has not been well studied. However, Serruys et al13 reported that for TAXUS-treated patients lumen loss within 2 mm of the stent edge was limited because positive vessel remodeling (increase in external elastic membrane) compensated for intimal hyperplasia, a phenomenon seen in slow-release and moderate-release TAXUS stents, but not in BMSs. There is accumulating evidence that plaque burden at the edge of the stent predicts edge restenosis after BMS or DES implantation. Hoffmann et al1 demonstrated that the dominant periprocedural predictor of BMS edge restenosis was stent edge plaque burden. Using data from SIRIUS, Sakurai et al2 demonstrated that a larger stent edge plaque burden and a step-up index (ratio of stent edge to reference minimum lumen area) predicted edge stenosis after Cypher stent implantation. Costa et al18 extended the concept of geographic miss to DESs; injured or diseased segments not covered by Cypher stents occurred frequently and was associated with increased risk of 1-year target vessel revascularization and myocardial infarction. However, these studies did not establish the plaque burden that best separated edge restenosis from no edge restenosis. Similarly, in the present study edge plaque burden, but not edge lumen dimensions, was predictive of 9-month angiographic edge restenosis in BMS-treated or TAXUStreated patients. Postintervention stent edge plaque burden was determined by preintervention plaque burden and plaque shift during stent implantation.19,20 Ahmed et al20 showed axial redistribution of plaque away from the center of the lesion toward the reference segments to increase postintervention stent edge plaque burden. However, Prati et al21 reported that the magnitude of reference segment plaque increase after stenting was slight (3.0 mm3/5 mm in the proximal reference segment and 1.7 mm3/5 mm in the distal reference segment). Thus, the major contribution to postintervention stent edge plaque burden was the preintervention plaque burden and not plaque shift. This study is a post hoc analysis of previous multicenter randomized, controlled, prospective TAXUS trials. Most patients had relatively simple de novo coronary lesions and low-risk profiles. We included slow-release and moderate-
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release TAXUS stents, although statistical analysis did not show any difference between these 2 formulations of the TAXUS stent. The results for edge restenosis after TAXUS implantation are heavily dominated by the proximal edge; further studies will be needed to understand better the plaque burden that can be tolerated at the proximal edge versus that at the distal edge. These data may not apply to other DESs. 1. Hoffmann R, Mintz GS, Kent KM, Satler LF, Pichard AD, Popma JJ, Leon MB. Serial intravascular ultrasound predictors of restenosis at the margins of Palmaz-Schatz stents. Am J Cardiol 1997;79:951–953. 2. Sakurai R, Ako J, Morino Y, Sonoda S, Kaneda H, Terashima M, Hassan AH, Leon MB, Moses JW, Popma JJ, et al; SIRIUS Trial Investigators. Predictors of edge stenosis following sirolimus-eluting stent deployment (a quantitative intravascular ultrasound analysis from the SIRIUS trial). Am J Cardiol 2005;96:1251–1253. 3. 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; TAXUS-IV Investigators. A polymer-based, paclitaxel-eluting stent in patients with coronary artery disease. N Engl J Med 2004;350:221– 231. 4. Stone GW, Ellis SG, Cannon L, Mann JT, Greenberg JD, Spriggs D, O’Shaughnessy CD, DeMaio S, Hall P, Popma JJ, Koglin J, Russell ME; TAXUS V Investigators. Comparison of a polymer-based paclitaxel-eluting stent with a bare metal stent in patients with complex coronary artery disease: a randomized controlled trial. JAMA 2005; 294:1215–1223. 5. Dawkins KD, Grube E, Guagliumi G, Banning AP, Zmudka K, Colombo A, Thuesen L, Hauptman K, Marco J, Wijns W, et al; TAXUS VI Investigators. Clinical efficacy of polymer-based paclitaxel-eluting stents in the treatment of complex, long coronary artery lesions from a multicenter, randomized trial: support for the use of drug-eluting stents in contemporary clinical practice. Circulation 2005;112:3306 – 3313. 6. Albiero R, Nishida T, Adamian M, Amato A, Vaghetti M, Corvaja N, Di Mario C, Colombo A. Edge restenosis after implantation of high activity 32P radioactive -emitting stents. Circulation 2000;101: 2454 –2457. 7. Wardeh AJ, Albiero R, Kay IP, Knook AH, Wijns W, Kozuma K, Nishida T, Ferrero V, Levendag PC, van Der Giessen WJ, Colombo A, Serruys PW. Angiographical follow-up after radioactive “Cold Ends” stent implantation: a multicenter trial. Circulation 2002;105:550 –553. 8. Kim HS, Waksman R, Cottin Y, Kollum M, Bhargava B, Mehran R, Chan RC, Mintz GS. Edge stenosis and geographical miss following intracoronary gamma radiation therapy for in-stent restenosis. J Am Coll Cardiol 2001;37:1026 –1030. 9. Morice MC, Serruys PW, Sousa JE, Fajadet J, Ban Hayashi E, Perin M, Colombo A, Schuler G, Barragan P, Guagliumi G, Molnàr F, Falotico R; RAVEL Study Group. Randomized study with the sirolimus-coated Bx velocity balloon-expandable stent in the treatment of patients with de novo native coronary artery lesions. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med 2002;346:1773–1780. 10. Popma JJ, Leon MB, Moses JW, Holmes DR Jr, Cox N, Fitzpatrick M, Douglas J, Lambert C, Mooney M, Yakubov S, Kuntz RE; SIRIUS Investigators. Quantitative assessment of angiographic restenosis after sirolimus-eluting stent implantation in native coronary arteries. Circulation 2004;110:3773–3780. 11. Schampaert E, Cohen EA, Schlüter M, Reeves F, Traboulsi M, Title LM, Kuntz RE, Popma JJ; C-SIRIUS Investigators. The Canadian study of the sirolimus-eluting stent in the treatment of patients with long de novo lesions in small native coronary arteries (C-SIRIUS). J Am Coll Cardiol 2004;43:1110 –1115. 12. Schofer J, Schlüter M, Gershlick AH, Wijns W, Garcia E, Schampaert E, Breithardt G; E-SIRIUS Investigators. Sirolimus-eluting stents for treatment of patients with long atherosclerotic lesions in small coronary arteries: double-blind, randomised controlled trial (E-SIRIUS). Lancet 2003;362:1093–1099. 13. Serruys PW, Degertekin M, Tanabe K, Russell ME, Guagliumi G, Webb J, Hamburger J, Rutsch W, Kaiser C, Whitbourn R, et al; TAXUS II Study Group. Vascular responses at proximal and distal
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