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Meta-analysis of the Effects of Paclitaxel-Eluting Stents Versus Bare Metal Stents on Volumetric Intravascular Ultrasound in Patients With Versus Without Diabetes Mellitus†
Meta-analysis of the Effects of Paclitaxel-Eluting Stents Versus Bare Metal Stents on Volumetric Intravascular Ultrasound in Patients With Versus Without Diabetes Mellitus† Masashi Kimura, MDa, Gary S. Mintz, MDa,*, Neil J. Weissman, MDb, Keith D. Dawkins, MDc, Eberhard Grube, MDd, Stephen G. Ellis, MDe, Louis A. Cannon, MD, ARf, Zaki Masud, MDg, Lazar Mandinov, MDh, Donald Baim, MDh, and Gregg W. Stone, MDa Diabetes mellitus is a strong predictor of in-stent restenosis after bare-metal stent placement because of exaggerated intimal hyperplasia (IH). In this study, serial intravascular ultrasound was used to evaluate the effects of polymer-based, paclitaxel-eluting stents (PES) on in-stent neointima formation in patients with and without diabetes. A volumetric IVUS meta-analysis of 956 patients randomized to PES or bare-metal stents in the TAXUS IV (n ⴝ 268), TAXUS V (n ⴝ 509), and TAXUS VI (n ⴝ 179) trials was performed. Diabetes was present in 273 of the 956 patients (28.6%). Stent, luminal, and IH areas were measured every millimeter within the stent, and volumes, percentage IH (%IH), and neointima-free stent length were calculated. Patients with diabetes treated with bare-metal stents had greater IH volumes (78.9 vs 61.2 mm3, p ⴝ 0.0095) and %IH (34.9% vs 30.1%, p ⴝ 0.0186) compared with those without diabetes. However, patients with diabetes treated with PES had similar median IH volume (22.8 vs 16.3 mm3, p ⴝ 0.35) and median %IH (9.1% vs 9.2%, p ⴝ 0.27) compared with those without diabetes and significantly less IH volume and %IH than after bare-metal stent implantation (p <0.0001 for the 2 comparisons). In conclusion, serial volumetric IVUS analysis showed that treatment with PES neutralizes the propensity of patients with diabetes to develop greater IH, such that patients with and without diabetes treated with PES have similar vascular responses and restenosis rates. © 2008 Elsevier Inc. All rights reserved. (Am J Cardiol 2008;101: 1263–1268)
In patients with coronary artery disease, diabetes mellitus increases the risk for cardiac mortality approximately twofold to fourfold.1–3 Although acute outcomes after percutaneous coronary intervention are similar in patients with and without diabetes, those with diabetes have higher rates of restenosis and repeat revascularization due to excessive neointimal proliferation after nonstent4,5 and bare-metal a Columbia University Medical Center and The Cardiovascular Research Foundation, New York, New York; bCardiovascular Research Institute, Washington Hospital Center, Washington, District of Columbia; c Southampton University Hospital, Southampton, United Kingdom; dHerzzentrum, Siegburg, Germany; eCleveland Clinic Foundation, Cleveland, Ohio; fCardiac and Vascular Research Center of Northern Michigan, Petoskey, Michigan; gBuffalo General Hospital Buffalo, New York; and h Boston Scientific Corporation, Natick, Massachusetts. Manuscript received November 15, 2007; revised manuscript received and accepted December 19, 2007. This study was supported by Boston Scientific Corporation, Natick, Massachusetts. *Corresponding author: Tel: 212-851-9395; fax: 212-851-9399. E-mail address: [email protected] (G.S. Mintz). †
Conflict of interest: Drs. Weissman, Dawkins, Grube, Ellis, and Cannon have received research grants from Boston Scientific Corporation. Drs. Mintz, Ellis, and Cannon are on the speaker’s bureau of and have received honoraria from Boston Scientific Corporation. Drs. Ellis, Cannon, and Stone are consultants for and are on the advisory board of Boston Scientific Corporation. Drs. Mandinov and Baim have ownership interest or stock in and are employed at Boston Scientific Corporation. 0002-9149/08/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2007.12.025
stent interventions.6 – 8 Recent studies comparing polymeric paclitaxel-eluting stents (PES) with equivalent bare-metal stents have reported dramatic reductions in in-stent restenosis and target lesion and target vessel revascularization.9 –13 Intravascular ultrasound (IVUS) provides greater information about the extent of intimal hyperplasia (IH) than angiography; the major PES randomized TAXUS trials included substudies of patients who underwent postprocedural and follow-up IVUS imaging. We used volumetric IVUS data from the randomized TAXUS IV, TAXUS V, and TAXUS VI trials to evaluate the effects of polymer-based PES compared with bare-metal stents in patients with diabetes who underwent stent implantation. Methods Patient population and protocol: TAXUS IV, TAXUS V, and TAXUS VI were prospective, double-blind, controlled trials in which patients with single de novo native coronary artery lesions were randomly assigned to treatment with PES or otherwise identical bare-metal stents. The TAXUS IV and TAXUS V studies used the Taxus slow-release (commercially available) formulation (Boston Scientific Corporation, Natick, Massachusetts), whereas TAXUS VI used the Taxus moderate-release (not commercially available) formulation, which has 3 times higher in vivo drug release over time.14 The IVUS substudy data from these trials were analyzed at a single core laboratory (Medlantic Research Institute, Washington Hospital Center, Washington, District of Columbia), as described previously.10 –13 Of the 2,918 patients enrolled in the www.AJConline.org
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Table 1 Baseline and procedural characteristics Variable
Clinical characteristics Age (yrs) Women Diabetes requiring insulin Hypertension Hyperlipidemia Smoking Previous myocardial infarction Target coronary artery Left anterior descending Right coronary artery Left circumflex Angiographic features Lesion length (mm) Total length of study stent (mm) Type C lesions Procedural outcomes Overlapped stents Final balloon size (mm) Maximum inflation pressure (atm) Multiple stents Stent length/lesion length ratio
Patients Without Diabetes
Patients With Diabetes
p Value*
p Value†
0.89 0.0157 — 0.0079 0.0214 0.0276 1.0
0.89 0.62 0.60 0.45 0.68 0.61 0.90
BMS (n ⫽ 345)
PES (n ⫽ 338)
BMS (n ⫽ 137)
PES (n ⫽ 136)
62.4 ⫾ 10.5 27.8% — 61.2% 67.7% 23.6% 31.1%
62.9 ⫾ 10.5 23.4% — 66.0% 65.0% 25.2% 33.1%
63.0 ⫾ 10.7 38.0% 32.8 82.5% 73.7% 13.2% 34.1%
62.8 ⫾ 11.5 34.6% 29.4 78.7% 76.3% 15.7% 32.6%
41.5% 31.5% 25.4%
43.1% 30.8% 27.8%
44.9% 25.7% 29.4%
44.1% 26.5% 29.4%
0.61 0.37 0.74
1.0 1.0 1.0
16.37 ⫾ 8.97 26.17 ⫾ 11.51 35.6%
16.97 ⫾ 8.32 27.56 ⫾ 11.92 37.3%
16.45 ⫾ 8.32 27.91 ⫾ 12.80 39.7%
17.22 ⫾ 9.22 27.12 ⫾ 12.97 29.4%
0.77 0.72 0.11
0.47 0.61 0.11
25.7% 3.19 ⫾ 0.5 13.52 ⫾ 2.77 22.3% 1.80 ⫾ 0.88
27.3% 3.15 ⫾ 0.48 13.55 ⫾ 2.44 26.9% 1.80 ⫾ 0.76
36.3% 3.07 ⫾ 0.49 13.54 ⫾ 2.70 30.7% 1.89 ⫾ 0.91
33.3% 3.09 ⫾ 0.56 13.83 ⫾ 2.39 28.7% 1.73 ⫾ 0.71
0.29 0.27 0.26 0.73 0.35
0.77 0.73 0.35 0.79 0.10
Data are expressed as mean ⫾ SD. * Comparison for PES between patients with and without diabetes. † Comparison between PES and BMS in patients with diabetes. BMS ⫽ bare-metal stent.
3 trials, the first 956 patients enrolled at the prespecified IVUS sites had to undergo serial volumetric IVUS analysis and were included in the IVUS cohort: 268 from TAXUS IV, 509 from TAXUS V, and 179 from TAXUS VI. Of these 956 patients, 273 (28.6%) had diabetes, defined as treatment with oral hypoglycemic agents or insulin at the time of admission; 188 patients (68.9% of the diabetics [19.7% of the entire population]) received oral diabetic medications, and 85 patients (31.1% of the diabetics [8.9% of the entire population]) were treated with insulin. There were no significant differences between patients in the IVUS subgroup and patients not in the IVUS subgroup except that the IVUS subgroup had a higher frequency of diabetes (p ⫽ 0.043), more American Heart Association and American College of Cardiology type C lesions (p ⫽ 0.012), longer lesion lengths (p ⫽ 0.0012), and more patients treated with multiple stents (p ⬍0.0001). Quantitative angiographic analysis: Two or more angiographic projections of the stenosis after intracoronary nitroglycerin were acquired, with the repetition of identical angiographic projections of the lesion at the time of follow-up angiography. With the contrast-filled injection catheter as the calibration source, quantitative angiographic analysis was performed using a validated automated edge detection algorithm (MEDIS CMS; MEDIS Medical Imaging Systems, Leiden, The Netherlands) by a technician who was unaware of the clinical and IVUS findings and blinded to treatment arm.
IVUS imaging and analysis: Clinical sites were selected on the basis of their IVUS experience and volume and their willingness to enroll all of their patients in the IVUS substudy. Volumetric IVUS was performed immediately after stent implantation and at 9-month follow-up in all patients at the IVUS substudy sites of each trial until the prespecified enrollment numbers were obtained. IVUS imaging was performed after the intracoronary administration of nitroglycerin 0.1 to 0.2 mg using motorized pullback (0.5 mm/s) and contemporary commercial scanners. Images were continuously recorded throughout the stent and ⱖ5 mm distal and proximal to the stent. Images were recorded onto S-VHS videotape or onto compact discs or magneto-optical discs and analyzed at an independent core laboratory. All IVUS core laboratory analyses were performed by technicians who were blinded to treatment arm; the adequacy of the images was determined before unblinding the data for analysis. Using computerized planimetry (Tapemeasure; Indec Systems, Inc., Mountain View, California), stent and luminal areas (in square millimeters) were measured every millimeter within the stent (stent and luminal areas) and 5 mm proximal and distal to each stent edge (external elastic membrane and luminal areas). IH was calculated as stent area minus lumen area, and plaque area plus media was calculated as external elastic membrane area minus lumen area within the reference segments. Volumes and mean areas were calculated using Simpson’s rule. Percentage IH (%IH; IH divided by stent) and neointima-free
Table 2 Angiographic measurements Variable
p Value†
Patients With Diabetes
p Value‡
BMS
PES
BMS
PES
2.79 (343) (2.40, 2.78, 3.12) 0.88 (343) (0.63, 0.88, 1.11) 68.1 (343) (59.7, 68.4, 76.2)
2.76 (334) (2.44, 2.75, 3.05) 0.89 (334) (0.66, 0.84, 1.10) 67.9 (334) (60.9, 68.1, 74.7)
2.65 (136) (2.28, 2.58, 2.98) 0.83 (136) (0.58, 0.78, 1.04) 68.8 (136) (60.7, 69.1, 76.9)
2.69 (136) (2.30, 2.65, 3.07) 0.84 (136) (0.59, 0.79, 1.12) 68.7 (136) (59.0, 68.0, 77.5)
0.14 0.17* 0.47
0.56 0.80* 0.94
2.66 (341) (2.35, 2.63, 2.97) 2.25 (343) (1.85, 2.20, 2.63) 5.0 (341) (1.4, 6.3, 12.3) 20.6 (343) (13.7, 18.7, 26.6) 1.78 (341) (1.44, 1.74, 2.06) 1.39 (243) (1.02, 1.34, 1.73)
2.64 (333) (2.31, 2.64, 2.95) 2.23 (335) (1.90, 2.22, 2.53) 5.6 (333) (0.4, 6.6, 12.4) 20.8 (335) (13.6, 19.2, 26.8) 1.75 (332) (1.46, 1.71, 2.03) 1.35 (242) (1.05, 1.32, 1.62)
2.57 (134) (2.24, 2.55, 2.88) 2.10 (136) (1.70, 2.00, 2.58) 3.9 (134) (0.7, 3.6, 10.4) 22.4 (136) (14.3, 20.3, 28.9) 1.73 (134) (1.42, 1.68, 1.95) 1.25 (102) (0.98, 1.24, 1.55)
2.57 (135) (2.23, 2.54, 2.93) 2.13 (135) (1.70, 2.05, 2.47) 4.5 (135) (2.5, 4.9, 10.9) 21.5 (135) (14.6, 21.3, 28.1) 1.73 (135) (1.44, 1.67, 2.02) 1.31 (95) (0.88, 1.23. 1.68)
0.13 0.07 0.16* 0.34* 0.50* 0.18*
0.98 0.83* 0.59* 0.81* 0.95* 0.76*
1.76 (301) (1.26, 1.82, 2.26) 1.66 (301) (1.17, 1.74, 2.10) 0.90 (301) (0.48, 0.84, 1.30) 0.60 (301) (0.18, 0.52, 0.96) 36.2 (301) (21.1, 33.3, 51.7) 39.8 (301) (25.6, 35.9, 54.2)
2.22 (304) (1.93, 2.26, 2.63) 1.95 (306) (1.66, 2.03, 2.38) 0.43 (304) (0.05, 0.32, 0.68) 0.29 (306) (0.04, 0.19, 0.50) 19.6 (304) (7.3, 15.4, 26.9) 29.7 (306) (17.1, 24.3, 36.5)
1.52 (112) (0.91, 1.48, 2.09) 1.44 (112) (0.89, 1.44, 1.93) 1.05 (112) (0.52, 1.06, 1.57) 0.69 (112) (0.19, 0.62, 1.08) 43.6 (112) (26.9, 40.8, 62.3) 46.9 (112) (31.6, 44.0, 63.6)
2.09 (120) (1.68, 2.15, 2.62) 1.84 (120) (1.52, 1.87, 2.28) 0.48 (119) (0.06, 0.38, 0.72) 0.29 (119) (0.04, 0.13, 0.45) 22.5 (120) (7.9, 16.1, 32.2) 32.3 (120) (18.7, 26.3, 38.9)
0.07* 0.0363* 0.68* 0.51* 0.39* 0.29*
Data are expressed as mean (sample size) (25th percentile, median, 75th percentile). * Wilcoxon’s 2-sample test. † Comparison for PES between patients with and without diabetes. ‡ Comparison between PES and BMS in patients with diabetes. Abbreviation as in Table 1.
⬍0.0001 ⬍0.0001* ⬍0.0001* ⬍0.0001* ⬍0.0001* ⬍0.0001*
Coronary Artery Disease/TAXUS Diabetic Integrated Analysis
Preprocedure Reference vessel diameter (mm) Minimum luminal diameter (mm) Diameter stenosis (%) Postprocedure In-stent minimum luminal diameter (mm) Analysis segment minimum luminal diameter (mm) In-stent diameter stenosis (%) Analysis segment diameter stenosis (%) In-stent acute gain (mm) Analysis segment acute gain (mm) Follow-up In-stent minimum luminal diameter (mm) Analysis segment minimum luminal diameter (mm) In-stent late loss (mm) In-segment late loss (mm) In-stent diameter stenosis (%) In-segment diameter stenosis (%)
Patients Without Diabetes
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0.68 0.40 0.20 0.35 0.27 0.0383 0.01 Data are expressed as mean (sample size) (25th percentile, median, 75th percentile); p values for Wilcoxon’s 2-sample test. * Comparison for PES between patients with and without diabetes. † Comparison between PES and BMS in patients with diabetes. Abbreviation as in Table 1.
207.5 (84) (125.0, 172.1, 271.3) 180.0 (84) (102.6, 147.0, 229.1) 5.4 (95) (3.5, 4.9, 7.2) 29.7 (84) (3.4, 22.8, 42.5) 13.7 (84) (3.0, 9.1, 22.7) 9.8 (59) (2.0, 8.0, 16.0) 39.1 (59) (8.3, 31.3, 64.7) 202.9 (208) (134.1, 184.3, 247.2) 178.3 (207) (120.8, 162.5, 216.6) 5.6 (256) (4.2, 5.5, 7.1) 25.2 (208) (3.5, 16.4, 37.2) 11.9 (208) (2.3, 9.2, 18.3) 12.1 (140) (5.0, 11.5, 16.0) 52.9 (140) (18.8, 51.8, 90.0) 206.0 (204) (126.8, 179.3, 264.2) 145.0 (204) (82.4, 126.5, 190.0) 4.8 (256) (2.8, 4.7, 6.2) 61.2 (204) (33.4, 48.4, 77.4) 30.1 (204) (21.0, 29.8, 38.3) 3.4 (129) (0.0, 0.0, 5.0) 14.3 (129) (0.0, 0.0, 21.7)
221.3 (70) (146.5, 199.6, 274.5) 142.6 (70) (86.0, 124.0, 176.3) 4.3 (89) (2.5, 3.8, 6.3) 78.9 (70) (37.6, 63.5, 106.4) 34.9 (70) (23.9, 35.2, 46.4) 2.6 (41) (0.0, 0.0, 4.0) 10.5 (41) (0.0, 0.0, 12.5)
207.3 (91) (126.0, 186.0, 274.0) 207.2 (91) (126.0, 185.7, 274.0) 6.5 (108) (4.6, 6.1, 7.9) 214.2 (81) (141.2, 179.2, 250.1) 215.6 (81) (148.1, 187.7, 252.5) 6.2 (104) (4.4, 5.8, 7.8) 211.0 (230) (134.3, 187.5, 266.8) 211.5 (229) (134.3, 187.2, 269.5) 6.5 (283) (4.9, 6.4, 7.9) 216.4 (231) (132.8, 189.7, 274.5) 216.5 (231) (132.8, 189.4, 274.2) 6.8 (293) (5.1, 6.6, 8.2)
BMS Table 3 Intravascular ultrasound measurements
Postprocedure Stent volume (mm3) Luminal volume (mm3) Minimum luminal area (mm2) Follow-up Stent volume (mm3) Luminal volume (mm3) Minimum luminal area (mm2) IH volume (mm3) %IH Neointima-free stent length (mm) % neointima-free stent length/stent length
PES PES
BMS
Patients With Diabetes Patients Without Diabetes
Results Baseline characteristics: Baseline demographics, angiographic features, and procedural outcomes are listed in Table 1. Patients with diabetes compared with those without diabetes treated with PES were more often women and more often had concomitant hypertension and hyperlipidemia. Among 273 patients with diabetes, there were no significant differences between the group treated with PES and the group treated with bare-metal stents. Angiographic analyses: Pre- and postprocedural angiographic results (Table 2) showed no significant differences among the 4 groups. At follow-up, patients with diabetes compared with those without diabetes treated with bare-metal stents had higher in-stent late loss (p ⫽ 0.0167), smaller instent minimal luminal diameters (p ⫽ 0.0019), and higher in-stent (p ⫽ 0.0026) and in-segment (p ⫽ 0.0013) percentage diameter stenosis. Patients with diabetes treated with PES rather than bare-metal stents had significantly less in-stent and in-segment late loss, reduced follow-up in-stent and in-segment percentage diameter stenosis, and lower in-stent and in-segment restenosis rates (Table 2). Moreover, there were no significant differences in late angiographic results between patients with and without diabetes treated with PES except for larger in-segment follow-up minimal luminal diameter in patients without diabetes.
0.75 0.72 0.35
p Value*
Statistical analysis: Individual patient data were integrated from the 3 TAXUS Express trials (TAXUS IV, TAXUS V de novo, and TAXUS VI) into 1 common database representing outcomes across 2 paclitaxel release formulations (slow and moderate release). For binary data, the homogeneity of the odds ratios across the 3 TAXUS Express studies was assessed using the Breslow-Day test, which tests the null hypothesis that the odds ratios of the treatment effect across studies are equal. If p ⬎0.05, then a treatment effect across studies was homogenous, justifying pooling of the results. If the Breslow-Day test indicated a treatment-by-study interaction, the quantitative interaction with treatment effect in the same direction, but of different magnitude, was investigated. If there was no evidence to contradict the assumption of homogeneity across different TAXUS Express studies, the treatment effect of PES over bare-metal stents from the pooled data was assessed using a 2-sided Fisher’s exact test. Categorical variables were compared using chi-square statistics and are summarized as frequencies and percentages. Continuous variables are presented as mean ⫾ 1 SD or medians. The analysis plan in this post hoc analysis was (1) to compare patients with diabetes treated with PES with patients with diabetes treated with bare-metal stents and (2) to compare patients with diabetes treated with PES with those without diabetes treated with PES. Variables were compared using 2-tailed, unpaired Student’s t tests. If parameters were not normally distributed per the Kolmogorov-Sminrnov test, Wilcoxon’s 2-sample test was used, and data are presented as medians and interquartile ranges. Differences were considered to be statistically significant when p ⬍0.05.
0.88 0.78 0.60
p Value†
stent length (in millimeters; determined as the length of each stent that was free of IVUS-detectable neointima) were also measured as previously described.15
0.22 0.0318 0.0038 ⬍0.0001 ⬍0.0001 ⬍0.0001 ⬍0.0001
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Table 4 Intravascular ultrasound measurements at stent edges Variable
Proximal edge ⌬ mean EEM area (mm2) ⌬ mean luminal area (mm2) ⌬ mean P&M area (mm2) Distal edge ⌬ mean EEM area (mm2) ⌬ mean luminal area (mm2) ⌬ mean P&M area (mm2)
Patients Without Diabetes
Patients With Diabetes
p Value*
p Value†
BMS
PES
BMS
PES
⫺0.64 ⫾ 2.04 ⫺1.09 ⫾ 1.87 0.47 ⫾ 1.63
⫺0.63 ⫾ 2.45 ⫺0.80 ⫾ 1.84 0.43 ⫾ 1.47
⫺0.75 ⫾ 1.83 ⫺0.50 ⫾ 1.38 0.21 ⫾ 1.38
⫺0.31 ⫾ 1.78 ⫺0.78 ⫾ 1.24 0.32 ⫾ 1.66
0.36 0.92 0.74
0.27 0.41 0.51
⫺0.77 ⫾ 1.81 ⫺0.82 ⫾ 1.69 0.03 ⫾ 1.07
⫺0.11 ⫾ 2.13 ⫺0.37 ⫾ 1.66 0.14 ⫾ 1.22
⫺0.57 ⫾ 1.57 ⫺0.84 ⫾ 1.23 0.25 ⫾ 0.94
⫺0.12 ⫾ 2.09 ⫺0.47 ⫾ 1.38 0.08 ⫾ 1.36
0.96 0.72 0.79
0.26 0.22 0.52
Data are expressed as mean ⫾ SD. * Comparison for PES between patients with and without diabetes. † Comparison between PES and BMS in patients with diabetes. EEM ⫽ external elastic membrane; P&M ⫽ plaque and media. Other abbreviation as in Table 1.
IVUS analyses: IVUS analyses are listed in Table 3. As with angiography, there were no significant differences in postrocedural measures between patients with and without diabetes treated with PES or in patients with diabetes treated with PES versus bare-metal stents. At 9-month follow-up, patients with diabetes treated with bare-metal stents had larger IH volumes (p ⫽ 0.0095) and %IH (p ⫽ 0.0186) compared with those without diabetes. Patients with diabetes treated with PES rather than bare-metal stents had significantly smaller IH volumes and less %IH, resulting in greater follow-up minimal luminal areas and luminal volumes, as well as longer neointima-free stent lengths in PES-treated patients with diabetes (Table 3). Moreover, in PES-treated patients, there were no significant differences in IH volume or %IH in patients with diabetes compared with those without diabetes, although those with diabetes did have shorter percentage neointima-free stent lengths than PES-treated patients without diabetes. At the 5-mm-long stent edges, there were no differences in changes from postprocedure to 9-month follow-up in mean external elastic membrane, luminal, or plaque plus media areas in patients with diabetes treated with PES compared with bare-metal stents or between patients with and without diabetes treated with PES (Table 4). Insulin-treated patients with diabetes: In the IVUS subset of 273 patients, 40 patients in the PES-treated group and 45 patients in the group treated with bare-metal stents had insulin-treated diabetes (29.4% vs 32.8%, p ⫽ 0.60). In patients treated with PES, insulin-treated patients with diabetes, compared with those not treated with insulin, showed no significant differences in IH volume (25.0 ⫾ 36.0 vs 31.3 ⫾ 32.9 mm3, p ⫽ 0.45), %IH (12.3 ⫾ 13.5% vs 14.1 ⫾ 12.1%, p ⫽ 0.57), and neointima-free stent lengths (9.9 ⫾ 9.1 vs 9.7 ⫾ 9.8 mm, p ⫽ 0.92). Insulin-treated patients with diabetes in the PES-treated group, compared to the group treated with baremetal stents, however, had significantly reduced IH volumes (25.0 ⫾ 36.0 vs 87.3 ⫾ 75.4 mm3, p ⫽ 0.001) and %IH (12.3 ⫾ 13.5% vs 36.1 ⫾ 15.9%, p ⫽ 0.001), resulting in greater minimal luminal areas (5.7 ⫾ 3.0 vs 3.9 ⫾ 1.9 mm2, p ⫽ 0.009) and longer neointima-free stent lengths (9.9 ⫾ 9.1 vs 3.1 ⫾ 5.9 mm, p ⫽ 0.008).
Discussion Until the present study, no published IVUS study has examined effects of PES compared with bare-metal stents in patients with diabetes. In our study involving 273 patients with diabetes and 683 patients without diabetes, diabetes was a strong predictor of angiographic and IVUS measures of in-stent restenosis. In addition, we observed that patients with diabetes treated with PES rather than bare-metal stents had significantly smaller IH volumes and less %IH, resulting in greater minimal luminal areas and luminal volumes at follow-up. One of the most notable findings of the present study is that the quantitative IVUS outcomes were virtually identical for patients with and without diabetes treated with PES; in essence, the use of PES neutralized the adverse impact of diabetes on producing excess neointimal proliferation, as seen in previous studies.16,17 In the Sirolimus-Eluting Stent in Coronary Lesions (SIRIUS)17 and Sirolimus-Eluting vs Uncoated Stents for Prevention of Restenosis in Small Coronary Arteries (SES-SMART)18 trials, IH was similarly inhibited in insulin-treated and non-insulin-treated patients with diabetes who received sirolimus-eluting stents. Likewise, in insulintreated patients in TAXUS IV, PES significantly reduced angiographic restenosis by 82%, similar to patients without diabetes.16 The only previous IVUS study comparing insulin-treated and non-insulin-treated patients with diabetes after sirolimus-eluting stent implantation19 reported that IH was similarly inhibited in the 2 groups with sirolimus-eluting stents but that the relative reduction in IH volume was greater in the insulin-treated group. In the present study in patients receiving PES, insulin-treated patients with diabetes showed no significant differences in IH volume and %IH compared with non-insulintreated patients with diabetes. In a subanalysis of SIRIUS,17 patients with diabetes had higher rates of proximal (8.4%) and distal-edge (4.8%) restenosis. Explanations included balloon injury in nonstented zones (geographic miss) or incomplete lesion coverage by the stent, as suggested by a larger postintervention plaque burden at the restenotic edge.20 In the present study,
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there were no deleterious edge effects between lesions treated with PES and bare-metal stents in patients with diabetes or between patients with and without diabetes treated with PES. In the TAXUS II study, PES-treated lesions had an increase in edge external elastic membrane and less luminal loss compared with edges in patients treated with bare-metal stents.21 Paclitaxel has multiple known actions on smooth-muscle migration—the prevention of microtubule depolymerization,22 the modulation of cell mitogenesis downstream23–25—that may allow it to attenuate smooth-muscle-cell proliferation through the alternate Akt-dependent signaling pathway, even in the presence of insulin receptor downregulation and reduced stimulation through the mammalian target of rapamycin pathway in the diabetic restenotic cascade.20 This is consistent with the observation that the antimigratory effects of paclitaxel are not attenuated, even under high-glucose conditions.26 The TAXUS II trial was excluded from this analysis because TAXUS II was analyzed at a different core laboratory. There was some heterogeneity within the pooled groups (e.g., doses and release kinetics of paclitaxel, stent platforms), and the study inclusion and exclusion criteria resulted in the exclusion of the most complex patients with diabetes (e.g., those with multivessel and diffuse disease). Although the present study represents the largest IVUS series in PES-treated patients with diabetes, the number of patients in the insulin-requiring group was still relatively small. Complete serial IVUS data were not available in all patients enrolled. As with all IVUS studies, complete IVUS follow-up was not obtained, because IVUS follow-up is frequently not performed in severely obstructive vessels and in patients with adverse cardiac events. 1. Kannel WB, McGee DL. Diabetes and glucose tolerance as risk factors for cardiovascular disease: the Framingham study. Diabetes Care 1979;2:120 –126. 2. Pyorala K, Laakso M, Uusitupa M. Diabetes and atherosclerosis: an epidemiologic view. Diabetes Metab Rev 1987;3:463–524. 3. Stamler J, Vaccaro O, Neaton JD, Wentworth D. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care 1993;16:434 – 444. 4. Stein B, Weintraub WS, Gebhart SP, Cohen-Bernstein CL, Grosswald R, Liberman HA, Douglas JS Jr, Morris DC, King SB III. Influence of diabetes mellitus on early and late outcome after percutaneous transluminal coronary angioplasty. Circulation 1995;91:979 –989. 5. Van Belle E, Ketelers R, Bauters C, Perie M, Abolmaali K, Richard F, Lablanche JM, McFadden EP, Bertrand ME. Patency of percutaneous transluminal coronary angioplasty sites at 6-month angiographic follow-up: A key determinant of survival in diabetics after coronary balloon angioplasty. Circulation 2001;103:1218 –1224. 6. West NE, Ruygrok PN, Disco CM, Webster MW, Lindeboom WK, O’Neill WW, Mercado NF, Serruys PW. Clinical and angiographic predictors of restenosis after stent deployment in diabetic patients. Circulation 2004;109:867– 873. 7. Carrozza JP Jr, Kuntz RE, Fishman RF, Baim DS. Restenosis after arterial injury caused by coronary stenting in patients with diabetes mellitus. Ann Intern Med 1993;118:344 –349. 8. Cutlip DE, Chauhan MS, Baim DS, Ho KK, Popma JJ, Carrozza JP, Cohen DJ, Kuntz RE. Clinical restenosis after coronary stenting: perspectives from multicenter clinical trials. J Am Coll Cardiol 2002; 40:2082–2089. 9. Colombo A, Drzewiecki J, Banning A, Grube E, Hauptmann K, Silber S, Dudek D, Fort S, Schiele F, Zmudka K, et al. Randomized study to assess the effectiveness of slow- and moderate-release polymer-based paclitaxeleluting stents for coronary artery lesions. Circulation 2003;108:788 –794. 10. Stone GW, Ellis SG, Cox DA, Hermiller J, O’Shaughnessy C, Mann JT, Turco M, Caputo R, Bergin P, Greenberg J, et al. One-year clinical
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results with the slow-release, polymer-based, paclitaxel-eluting TAXUS stent: the TAXUS-IV trial. Circulation 2004;109:1942–1947. Stone GW, Ellis SG, Cox DA, Hermiller J, O’Shaughnessy C, Mann JT, Turco M, Caputo R, Bergin P, Greenberg J, et al. A polymer-based, paclitaxel-eluting stent in patients with coronary artery disease. N Engl J Med 2004;350:221–231. Stone GW, Ellis SG, Cannon L, Mann JT, Greenberg JD, Spriggs D, O’Shaughnessy CD, DeMaio S, Hall P, Popma JJ, et al. 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. Dawkins KD, Grube E, Guagliumi G, Banning AP, Zmudka K, Colombo A, Thuesen L, Hauptman K, Marco J, Wijns W, et al. 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. Kamath KR, Barry JJ, Miller KM. The Taxus drug-eluting stent: a new paradigm in controlled drug delivery. Adv Drug Deliv Rev 2006;58: 412– 436. Mintz GS, Hong MK, Raizner AE, Lee CW, Kim JJ, Escolar E, Fearnot NE, Park SW, Park SJ, Weissman NJ. Intravascular ultrasound assessment of neointima distribution and the length of stent that was free of intravascular ultrasound-detectable intimal hyperplasia in paclitaxel-eluting stents. Am J Cardiol 2005;95:107–109. Hermiller JB, Raizner A, Cannon L, Gurbel PA, Kutcher MA, Wong SC, Russell ME, Ellis SG, Mehran R, Stone GW. Outcomes with the polymerbased paclitaxel-eluting TAXUS stent in patients with diabetes mellitus: the TAXUS-IV trial. J Am Coll Cardiol 2005;45:1172–1179. Moussa I, Leon MB, Baim DS, O’Neill WW, Popma JJ, Buchbinder M, Midwall J, Simonton CA, Keim E, Wang P, et al. Impact of sirolimuseluting stents on outcome in diabetic patients: a SIRIUS (SirolimusCoated Bx Velocity Balloon-Expandable Stent in the Treatment of Patients With de Novo Coronary Artery Lesions) substudy. Circulation 2004;109:2273–2278. Ortolani P, Ardissino D, Cavallini C, Bramucci E, Indolfi C, Aquilina M, Marzocchi A. Effect of sirolimus-eluting stent in diabetic patients with small coronary arteries (a SES-SMART substudy). Am J Cardiol 2005; 96:1393–1398. Jimenez-Quevedo P, Sabate M, Angiolillo DJ, Costa MA, Alfonso F, Gomez-Hospital JA, Hernandez-Antolin R, Banuelos C, Goicolea J, Fernandez-Aviles F, et al. Vascular effects of sirolimus-eluting versus bare-metal stents in diabetic patients: three-dimensional ultrasound results of the Diabetes and Sirolimus-Eluting Stent (DIABETES) trial. J Am Coll Cardiol 2006;47:2172–2179. Sakurai R, Ako J, Morino Y, Sonoda S, Kaneda H, Terashima M, Hassan AH, Leon MB, Moses JW, Popma JJ, et al. 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. Serruys PW, Degertekin M, Tanabe K, Russell ME, Guagliumi G, Webb J, Hamburger J, Rutsch W, Kaiser C, Whitbourn R, et al. Vascular responses at proximal and distal edges of paclitaxel-eluting stents: serial intravascular ultrasound analysis from the TAXUS II trial. Circulation 2004;109:627– 633. Axel DI, Kunert W, Goggelmann C, Oberhoff M, Herdeg C, Kuttner A, Wild DH, Brehm BR, Riessen R, Koveker G, Karsch KR. Paclitaxel inhibits arterial smooth muscle cell proliferation and migration in vitro and in vivo using local drug delivery. Circulation 1997;96:636 – 645. Le Roith D, Zick Y. Recent advances in our understanding of insulin action and insulin resistance. Diabetes Care 2001;24:588 –597. Mitsuuchi Y, Johnson SW, Selvakumaran M, Williams SJ, Hamilton TC, Testa JR. The phosphatidylinositol 3-kinase/AKT signal transduction pathway plays a critical role in the expression of p21WAF1/CIP1/ SDI1 induced by cisplatin and paclitaxel. Cancer Res 2000;60: 5390 –5394. Virkamaki A, Ueki K, Kahn CR. Protein-protein interaction in insulin signaling and the molecular mechanisms of insulin resistance. J Clin Invest 1999;103:931–943. Patterson C, Mapera S, Li HH, Madamanchi N, Hilliard E, Lineberger R, Herrmann R, Charles P. Comparative effects of paclitaxel and rapamycin on smooth muscle migration and survival: role of AKT-dependent signaling. Arterioscler Thromb Vasc Biol 2006;26:1473–1480.
In patients with coronary artery disease, diabetes mellitus increases the risk for cardiac mortality approximately twofold to fourfold.1–3 Although acute outcomes after percutaneous coronary intervention are similar in patients with and without diabetes, those with diabetes have higher rates of restenosis and repeat revascularization due to excessive neointimal proliferation after nonstent4,5 and bare-metal a Columbia University Medical Center and The Cardiovascular Research Foundation, New York, New York; bCardiovascular Research Institute, Washington Hospital Center, Washington, District of Columbia; c Southampton University Hospital, Southampton, United Kingdom; dHerzzentrum, Siegburg, Germany; eCleveland Clinic Foundation, Cleveland, Ohio; fCardiac and Vascular Research Center of Northern Michigan, Petoskey, Michigan; gBuffalo General Hospital Buffalo, New York; and h Boston Scientific Corporation, Natick, Massachusetts. Manuscript received November 15, 2007; revised manuscript received and accepted December 19, 2007. This study was supported by Boston Scientific Corporation, Natick, Massachusetts. *Corresponding author: Tel: 212-851-9395; fax: 212-851-9399. E-mail address: [email protected] (G.S. Mintz). †
Conflict of interest: Drs. Weissman, Dawkins, Grube, Ellis, and Cannon have received research grants from Boston Scientific Corporation. Drs. Mintz, Ellis, and Cannon are on the speaker’s bureau of and have received honoraria from Boston Scientific Corporation. Drs. Ellis, Cannon, and Stone are consultants for and are on the advisory board of Boston Scientific Corporation. Drs. Mandinov and Baim have ownership interest or stock in and are employed at Boston Scientific Corporation. 0002-9149/08/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2007.12.025
stent interventions.6 – 8 Recent studies comparing polymeric paclitaxel-eluting stents (PES) with equivalent bare-metal stents have reported dramatic reductions in in-stent restenosis and target lesion and target vessel revascularization.9 –13 Intravascular ultrasound (IVUS) provides greater information about the extent of intimal hyperplasia (IH) than angiography; the major PES randomized TAXUS trials included substudies of patients who underwent postprocedural and follow-up IVUS imaging. We used volumetric IVUS data from the randomized TAXUS IV, TAXUS V, and TAXUS VI trials to evaluate the effects of polymer-based PES compared with bare-metal stents in patients with diabetes who underwent stent implantation. Methods Patient population and protocol: TAXUS IV, TAXUS V, and TAXUS VI were prospective, double-blind, controlled trials in which patients with single de novo native coronary artery lesions were randomly assigned to treatment with PES or otherwise identical bare-metal stents. The TAXUS IV and TAXUS V studies used the Taxus slow-release (commercially available) formulation (Boston Scientific Corporation, Natick, Massachusetts), whereas TAXUS VI used the Taxus moderate-release (not commercially available) formulation, which has 3 times higher in vivo drug release over time.14 The IVUS substudy data from these trials were analyzed at a single core laboratory (Medlantic Research Institute, Washington Hospital Center, Washington, District of Columbia), as described previously.10 –13 Of the 2,918 patients enrolled in the www.AJConline.org
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Table 1 Baseline and procedural characteristics Variable
Clinical characteristics Age (yrs) Women Diabetes requiring insulin Hypertension Hyperlipidemia Smoking Previous myocardial infarction Target coronary artery Left anterior descending Right coronary artery Left circumflex Angiographic features Lesion length (mm) Total length of study stent (mm) Type C lesions Procedural outcomes Overlapped stents Final balloon size (mm) Maximum inflation pressure (atm) Multiple stents Stent length/lesion length ratio
Patients Without Diabetes
Patients With Diabetes
p Value*
p Value†
0.89 0.0157 — 0.0079 0.0214 0.0276 1.0
0.89 0.62 0.60 0.45 0.68 0.61 0.90
BMS (n ⫽ 345)
PES (n ⫽ 338)
BMS (n ⫽ 137)
PES (n ⫽ 136)
62.4 ⫾ 10.5 27.8% — 61.2% 67.7% 23.6% 31.1%
62.9 ⫾ 10.5 23.4% — 66.0% 65.0% 25.2% 33.1%
63.0 ⫾ 10.7 38.0% 32.8 82.5% 73.7% 13.2% 34.1%
62.8 ⫾ 11.5 34.6% 29.4 78.7% 76.3% 15.7% 32.6%
41.5% 31.5% 25.4%
43.1% 30.8% 27.8%
44.9% 25.7% 29.4%
44.1% 26.5% 29.4%
0.61 0.37 0.74
1.0 1.0 1.0
16.37 ⫾ 8.97 26.17 ⫾ 11.51 35.6%
16.97 ⫾ 8.32 27.56 ⫾ 11.92 37.3%
16.45 ⫾ 8.32 27.91 ⫾ 12.80 39.7%
17.22 ⫾ 9.22 27.12 ⫾ 12.97 29.4%
0.77 0.72 0.11
0.47 0.61 0.11
25.7% 3.19 ⫾ 0.5 13.52 ⫾ 2.77 22.3% 1.80 ⫾ 0.88
27.3% 3.15 ⫾ 0.48 13.55 ⫾ 2.44 26.9% 1.80 ⫾ 0.76
36.3% 3.07 ⫾ 0.49 13.54 ⫾ 2.70 30.7% 1.89 ⫾ 0.91
33.3% 3.09 ⫾ 0.56 13.83 ⫾ 2.39 28.7% 1.73 ⫾ 0.71
0.29 0.27 0.26 0.73 0.35
0.77 0.73 0.35 0.79 0.10
Data are expressed as mean ⫾ SD. * Comparison for PES between patients with and without diabetes. † Comparison between PES and BMS in patients with diabetes. BMS ⫽ bare-metal stent.
3 trials, the first 956 patients enrolled at the prespecified IVUS sites had to undergo serial volumetric IVUS analysis and were included in the IVUS cohort: 268 from TAXUS IV, 509 from TAXUS V, and 179 from TAXUS VI. Of these 956 patients, 273 (28.6%) had diabetes, defined as treatment with oral hypoglycemic agents or insulin at the time of admission; 188 patients (68.9% of the diabetics [19.7% of the entire population]) received oral diabetic medications, and 85 patients (31.1% of the diabetics [8.9% of the entire population]) were treated with insulin. There were no significant differences between patients in the IVUS subgroup and patients not in the IVUS subgroup except that the IVUS subgroup had a higher frequency of diabetes (p ⫽ 0.043), more American Heart Association and American College of Cardiology type C lesions (p ⫽ 0.012), longer lesion lengths (p ⫽ 0.0012), and more patients treated with multiple stents (p ⬍0.0001). Quantitative angiographic analysis: Two or more angiographic projections of the stenosis after intracoronary nitroglycerin were acquired, with the repetition of identical angiographic projections of the lesion at the time of follow-up angiography. With the contrast-filled injection catheter as the calibration source, quantitative angiographic analysis was performed using a validated automated edge detection algorithm (MEDIS CMS; MEDIS Medical Imaging Systems, Leiden, The Netherlands) by a technician who was unaware of the clinical and IVUS findings and blinded to treatment arm.
IVUS imaging and analysis: Clinical sites were selected on the basis of their IVUS experience and volume and their willingness to enroll all of their patients in the IVUS substudy. Volumetric IVUS was performed immediately after stent implantation and at 9-month follow-up in all patients at the IVUS substudy sites of each trial until the prespecified enrollment numbers were obtained. IVUS imaging was performed after the intracoronary administration of nitroglycerin 0.1 to 0.2 mg using motorized pullback (0.5 mm/s) and contemporary commercial scanners. Images were continuously recorded throughout the stent and ⱖ5 mm distal and proximal to the stent. Images were recorded onto S-VHS videotape or onto compact discs or magneto-optical discs and analyzed at an independent core laboratory. All IVUS core laboratory analyses were performed by technicians who were blinded to treatment arm; the adequacy of the images was determined before unblinding the data for analysis. Using computerized planimetry (Tapemeasure; Indec Systems, Inc., Mountain View, California), stent and luminal areas (in square millimeters) were measured every millimeter within the stent (stent and luminal areas) and 5 mm proximal and distal to each stent edge (external elastic membrane and luminal areas). IH was calculated as stent area minus lumen area, and plaque area plus media was calculated as external elastic membrane area minus lumen area within the reference segments. Volumes and mean areas were calculated using Simpson’s rule. Percentage IH (%IH; IH divided by stent) and neointima-free
Table 2 Angiographic measurements Variable
p Value†
Patients With Diabetes
p Value‡
BMS
PES
BMS
PES
2.79 (343) (2.40, 2.78, 3.12) 0.88 (343) (0.63, 0.88, 1.11) 68.1 (343) (59.7, 68.4, 76.2)
2.76 (334) (2.44, 2.75, 3.05) 0.89 (334) (0.66, 0.84, 1.10) 67.9 (334) (60.9, 68.1, 74.7)
2.65 (136) (2.28, 2.58, 2.98) 0.83 (136) (0.58, 0.78, 1.04) 68.8 (136) (60.7, 69.1, 76.9)
2.69 (136) (2.30, 2.65, 3.07) 0.84 (136) (0.59, 0.79, 1.12) 68.7 (136) (59.0, 68.0, 77.5)
0.14 0.17* 0.47
0.56 0.80* 0.94
2.66 (341) (2.35, 2.63, 2.97) 2.25 (343) (1.85, 2.20, 2.63) 5.0 (341) (1.4, 6.3, 12.3) 20.6 (343) (13.7, 18.7, 26.6) 1.78 (341) (1.44, 1.74, 2.06) 1.39 (243) (1.02, 1.34, 1.73)
2.64 (333) (2.31, 2.64, 2.95) 2.23 (335) (1.90, 2.22, 2.53) 5.6 (333) (0.4, 6.6, 12.4) 20.8 (335) (13.6, 19.2, 26.8) 1.75 (332) (1.46, 1.71, 2.03) 1.35 (242) (1.05, 1.32, 1.62)
2.57 (134) (2.24, 2.55, 2.88) 2.10 (136) (1.70, 2.00, 2.58) 3.9 (134) (0.7, 3.6, 10.4) 22.4 (136) (14.3, 20.3, 28.9) 1.73 (134) (1.42, 1.68, 1.95) 1.25 (102) (0.98, 1.24, 1.55)
2.57 (135) (2.23, 2.54, 2.93) 2.13 (135) (1.70, 2.05, 2.47) 4.5 (135) (2.5, 4.9, 10.9) 21.5 (135) (14.6, 21.3, 28.1) 1.73 (135) (1.44, 1.67, 2.02) 1.31 (95) (0.88, 1.23. 1.68)
0.13 0.07 0.16* 0.34* 0.50* 0.18*
0.98 0.83* 0.59* 0.81* 0.95* 0.76*
1.76 (301) (1.26, 1.82, 2.26) 1.66 (301) (1.17, 1.74, 2.10) 0.90 (301) (0.48, 0.84, 1.30) 0.60 (301) (0.18, 0.52, 0.96) 36.2 (301) (21.1, 33.3, 51.7) 39.8 (301) (25.6, 35.9, 54.2)
2.22 (304) (1.93, 2.26, 2.63) 1.95 (306) (1.66, 2.03, 2.38) 0.43 (304) (0.05, 0.32, 0.68) 0.29 (306) (0.04, 0.19, 0.50) 19.6 (304) (7.3, 15.4, 26.9) 29.7 (306) (17.1, 24.3, 36.5)
1.52 (112) (0.91, 1.48, 2.09) 1.44 (112) (0.89, 1.44, 1.93) 1.05 (112) (0.52, 1.06, 1.57) 0.69 (112) (0.19, 0.62, 1.08) 43.6 (112) (26.9, 40.8, 62.3) 46.9 (112) (31.6, 44.0, 63.6)
2.09 (120) (1.68, 2.15, 2.62) 1.84 (120) (1.52, 1.87, 2.28) 0.48 (119) (0.06, 0.38, 0.72) 0.29 (119) (0.04, 0.13, 0.45) 22.5 (120) (7.9, 16.1, 32.2) 32.3 (120) (18.7, 26.3, 38.9)
0.07* 0.0363* 0.68* 0.51* 0.39* 0.29*
Data are expressed as mean (sample size) (25th percentile, median, 75th percentile). * Wilcoxon’s 2-sample test. † Comparison for PES between patients with and without diabetes. ‡ Comparison between PES and BMS in patients with diabetes. Abbreviation as in Table 1.
⬍0.0001 ⬍0.0001* ⬍0.0001* ⬍0.0001* ⬍0.0001* ⬍0.0001*
Coronary Artery Disease/TAXUS Diabetic Integrated Analysis
Preprocedure Reference vessel diameter (mm) Minimum luminal diameter (mm) Diameter stenosis (%) Postprocedure In-stent minimum luminal diameter (mm) Analysis segment minimum luminal diameter (mm) In-stent diameter stenosis (%) Analysis segment diameter stenosis (%) In-stent acute gain (mm) Analysis segment acute gain (mm) Follow-up In-stent minimum luminal diameter (mm) Analysis segment minimum luminal diameter (mm) In-stent late loss (mm) In-segment late loss (mm) In-stent diameter stenosis (%) In-segment diameter stenosis (%)
Patients Without Diabetes
1265
0.68 0.40 0.20 0.35 0.27 0.0383 0.01 Data are expressed as mean (sample size) (25th percentile, median, 75th percentile); p values for Wilcoxon’s 2-sample test. * Comparison for PES between patients with and without diabetes. † Comparison between PES and BMS in patients with diabetes. Abbreviation as in Table 1.
207.5 (84) (125.0, 172.1, 271.3) 180.0 (84) (102.6, 147.0, 229.1) 5.4 (95) (3.5, 4.9, 7.2) 29.7 (84) (3.4, 22.8, 42.5) 13.7 (84) (3.0, 9.1, 22.7) 9.8 (59) (2.0, 8.0, 16.0) 39.1 (59) (8.3, 31.3, 64.7) 202.9 (208) (134.1, 184.3, 247.2) 178.3 (207) (120.8, 162.5, 216.6) 5.6 (256) (4.2, 5.5, 7.1) 25.2 (208) (3.5, 16.4, 37.2) 11.9 (208) (2.3, 9.2, 18.3) 12.1 (140) (5.0, 11.5, 16.0) 52.9 (140) (18.8, 51.8, 90.0) 206.0 (204) (126.8, 179.3, 264.2) 145.0 (204) (82.4, 126.5, 190.0) 4.8 (256) (2.8, 4.7, 6.2) 61.2 (204) (33.4, 48.4, 77.4) 30.1 (204) (21.0, 29.8, 38.3) 3.4 (129) (0.0, 0.0, 5.0) 14.3 (129) (0.0, 0.0, 21.7)
221.3 (70) (146.5, 199.6, 274.5) 142.6 (70) (86.0, 124.0, 176.3) 4.3 (89) (2.5, 3.8, 6.3) 78.9 (70) (37.6, 63.5, 106.4) 34.9 (70) (23.9, 35.2, 46.4) 2.6 (41) (0.0, 0.0, 4.0) 10.5 (41) (0.0, 0.0, 12.5)
207.3 (91) (126.0, 186.0, 274.0) 207.2 (91) (126.0, 185.7, 274.0) 6.5 (108) (4.6, 6.1, 7.9) 214.2 (81) (141.2, 179.2, 250.1) 215.6 (81) (148.1, 187.7, 252.5) 6.2 (104) (4.4, 5.8, 7.8) 211.0 (230) (134.3, 187.5, 266.8) 211.5 (229) (134.3, 187.2, 269.5) 6.5 (283) (4.9, 6.4, 7.9) 216.4 (231) (132.8, 189.7, 274.5) 216.5 (231) (132.8, 189.4, 274.2) 6.8 (293) (5.1, 6.6, 8.2)
BMS Table 3 Intravascular ultrasound measurements
Postprocedure Stent volume (mm3) Luminal volume (mm3) Minimum luminal area (mm2) Follow-up Stent volume (mm3) Luminal volume (mm3) Minimum luminal area (mm2) IH volume (mm3) %IH Neointima-free stent length (mm) % neointima-free stent length/stent length
PES PES
BMS
Patients With Diabetes Patients Without Diabetes
Results Baseline characteristics: Baseline demographics, angiographic features, and procedural outcomes are listed in Table 1. Patients with diabetes compared with those without diabetes treated with PES were more often women and more often had concomitant hypertension and hyperlipidemia. Among 273 patients with diabetes, there were no significant differences between the group treated with PES and the group treated with bare-metal stents. Angiographic analyses: Pre- and postprocedural angiographic results (Table 2) showed no significant differences among the 4 groups. At follow-up, patients with diabetes compared with those without diabetes treated with bare-metal stents had higher in-stent late loss (p ⫽ 0.0167), smaller instent minimal luminal diameters (p ⫽ 0.0019), and higher in-stent (p ⫽ 0.0026) and in-segment (p ⫽ 0.0013) percentage diameter stenosis. Patients with diabetes treated with PES rather than bare-metal stents had significantly less in-stent and in-segment late loss, reduced follow-up in-stent and in-segment percentage diameter stenosis, and lower in-stent and in-segment restenosis rates (Table 2). Moreover, there were no significant differences in late angiographic results between patients with and without diabetes treated with PES except for larger in-segment follow-up minimal luminal diameter in patients without diabetes.
0.75 0.72 0.35
p Value*
Statistical analysis: Individual patient data were integrated from the 3 TAXUS Express trials (TAXUS IV, TAXUS V de novo, and TAXUS VI) into 1 common database representing outcomes across 2 paclitaxel release formulations (slow and moderate release). For binary data, the homogeneity of the odds ratios across the 3 TAXUS Express studies was assessed using the Breslow-Day test, which tests the null hypothesis that the odds ratios of the treatment effect across studies are equal. If p ⬎0.05, then a treatment effect across studies was homogenous, justifying pooling of the results. If the Breslow-Day test indicated a treatment-by-study interaction, the quantitative interaction with treatment effect in the same direction, but of different magnitude, was investigated. If there was no evidence to contradict the assumption of homogeneity across different TAXUS Express studies, the treatment effect of PES over bare-metal stents from the pooled data was assessed using a 2-sided Fisher’s exact test. Categorical variables were compared using chi-square statistics and are summarized as frequencies and percentages. Continuous variables are presented as mean ⫾ 1 SD or medians. The analysis plan in this post hoc analysis was (1) to compare patients with diabetes treated with PES with patients with diabetes treated with bare-metal stents and (2) to compare patients with diabetes treated with PES with those without diabetes treated with PES. Variables were compared using 2-tailed, unpaired Student’s t tests. If parameters were not normally distributed per the Kolmogorov-Sminrnov test, Wilcoxon’s 2-sample test was used, and data are presented as medians and interquartile ranges. Differences were considered to be statistically significant when p ⬍0.05.
0.88 0.78 0.60
p Value†
stent length (in millimeters; determined as the length of each stent that was free of IVUS-detectable neointima) were also measured as previously described.15
0.22 0.0318 0.0038 ⬍0.0001 ⬍0.0001 ⬍0.0001 ⬍0.0001
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Variable
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Coronary Artery Disease/TAXUS Diabetic Integrated Analysis
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Table 4 Intravascular ultrasound measurements at stent edges Variable
Proximal edge ⌬ mean EEM area (mm2) ⌬ mean luminal area (mm2) ⌬ mean P&M area (mm2) Distal edge ⌬ mean EEM area (mm2) ⌬ mean luminal area (mm2) ⌬ mean P&M area (mm2)
Patients Without Diabetes
Patients With Diabetes
p Value*
p Value†
BMS
PES
BMS
PES
⫺0.64 ⫾ 2.04 ⫺1.09 ⫾ 1.87 0.47 ⫾ 1.63
⫺0.63 ⫾ 2.45 ⫺0.80 ⫾ 1.84 0.43 ⫾ 1.47
⫺0.75 ⫾ 1.83 ⫺0.50 ⫾ 1.38 0.21 ⫾ 1.38
⫺0.31 ⫾ 1.78 ⫺0.78 ⫾ 1.24 0.32 ⫾ 1.66
0.36 0.92 0.74
0.27 0.41 0.51
⫺0.77 ⫾ 1.81 ⫺0.82 ⫾ 1.69 0.03 ⫾ 1.07
⫺0.11 ⫾ 2.13 ⫺0.37 ⫾ 1.66 0.14 ⫾ 1.22
⫺0.57 ⫾ 1.57 ⫺0.84 ⫾ 1.23 0.25 ⫾ 0.94
⫺0.12 ⫾ 2.09 ⫺0.47 ⫾ 1.38 0.08 ⫾ 1.36
0.96 0.72 0.79
0.26 0.22 0.52
Data are expressed as mean ⫾ SD. * Comparison for PES between patients with and without diabetes. † Comparison between PES and BMS in patients with diabetes. EEM ⫽ external elastic membrane; P&M ⫽ plaque and media. Other abbreviation as in Table 1.
IVUS analyses: IVUS analyses are listed in Table 3. As with angiography, there were no significant differences in postrocedural measures between patients with and without diabetes treated with PES or in patients with diabetes treated with PES versus bare-metal stents. At 9-month follow-up, patients with diabetes treated with bare-metal stents had larger IH volumes (p ⫽ 0.0095) and %IH (p ⫽ 0.0186) compared with those without diabetes. Patients with diabetes treated with PES rather than bare-metal stents had significantly smaller IH volumes and less %IH, resulting in greater follow-up minimal luminal areas and luminal volumes, as well as longer neointima-free stent lengths in PES-treated patients with diabetes (Table 3). Moreover, in PES-treated patients, there were no significant differences in IH volume or %IH in patients with diabetes compared with those without diabetes, although those with diabetes did have shorter percentage neointima-free stent lengths than PES-treated patients without diabetes. At the 5-mm-long stent edges, there were no differences in changes from postprocedure to 9-month follow-up in mean external elastic membrane, luminal, or plaque plus media areas in patients with diabetes treated with PES compared with bare-metal stents or between patients with and without diabetes treated with PES (Table 4). Insulin-treated patients with diabetes: In the IVUS subset of 273 patients, 40 patients in the PES-treated group and 45 patients in the group treated with bare-metal stents had insulin-treated diabetes (29.4% vs 32.8%, p ⫽ 0.60). In patients treated with PES, insulin-treated patients with diabetes, compared with those not treated with insulin, showed no significant differences in IH volume (25.0 ⫾ 36.0 vs 31.3 ⫾ 32.9 mm3, p ⫽ 0.45), %IH (12.3 ⫾ 13.5% vs 14.1 ⫾ 12.1%, p ⫽ 0.57), and neointima-free stent lengths (9.9 ⫾ 9.1 vs 9.7 ⫾ 9.8 mm, p ⫽ 0.92). Insulin-treated patients with diabetes in the PES-treated group, compared to the group treated with baremetal stents, however, had significantly reduced IH volumes (25.0 ⫾ 36.0 vs 87.3 ⫾ 75.4 mm3, p ⫽ 0.001) and %IH (12.3 ⫾ 13.5% vs 36.1 ⫾ 15.9%, p ⫽ 0.001), resulting in greater minimal luminal areas (5.7 ⫾ 3.0 vs 3.9 ⫾ 1.9 mm2, p ⫽ 0.009) and longer neointima-free stent lengths (9.9 ⫾ 9.1 vs 3.1 ⫾ 5.9 mm, p ⫽ 0.008).
Discussion Until the present study, no published IVUS study has examined effects of PES compared with bare-metal stents in patients with diabetes. In our study involving 273 patients with diabetes and 683 patients without diabetes, diabetes was a strong predictor of angiographic and IVUS measures of in-stent restenosis. In addition, we observed that patients with diabetes treated with PES rather than bare-metal stents had significantly smaller IH volumes and less %IH, resulting in greater minimal luminal areas and luminal volumes at follow-up. One of the most notable findings of the present study is that the quantitative IVUS outcomes were virtually identical for patients with and without diabetes treated with PES; in essence, the use of PES neutralized the adverse impact of diabetes on producing excess neointimal proliferation, as seen in previous studies.16,17 In the Sirolimus-Eluting Stent in Coronary Lesions (SIRIUS)17 and Sirolimus-Eluting vs Uncoated Stents for Prevention of Restenosis in Small Coronary Arteries (SES-SMART)18 trials, IH was similarly inhibited in insulin-treated and non-insulin-treated patients with diabetes who received sirolimus-eluting stents. Likewise, in insulintreated patients in TAXUS IV, PES significantly reduced angiographic restenosis by 82%, similar to patients without diabetes.16 The only previous IVUS study comparing insulin-treated and non-insulin-treated patients with diabetes after sirolimus-eluting stent implantation19 reported that IH was similarly inhibited in the 2 groups with sirolimus-eluting stents but that the relative reduction in IH volume was greater in the insulin-treated group. In the present study in patients receiving PES, insulin-treated patients with diabetes showed no significant differences in IH volume and %IH compared with non-insulintreated patients with diabetes. In a subanalysis of SIRIUS,17 patients with diabetes had higher rates of proximal (8.4%) and distal-edge (4.8%) restenosis. Explanations included balloon injury in nonstented zones (geographic miss) or incomplete lesion coverage by the stent, as suggested by a larger postintervention plaque burden at the restenotic edge.20 In the present study,
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there were no deleterious edge effects between lesions treated with PES and bare-metal stents in patients with diabetes or between patients with and without diabetes treated with PES. In the TAXUS II study, PES-treated lesions had an increase in edge external elastic membrane and less luminal loss compared with edges in patients treated with bare-metal stents.21 Paclitaxel has multiple known actions on smooth-muscle migration—the prevention of microtubule depolymerization,22 the modulation of cell mitogenesis downstream23–25—that may allow it to attenuate smooth-muscle-cell proliferation through the alternate Akt-dependent signaling pathway, even in the presence of insulin receptor downregulation and reduced stimulation through the mammalian target of rapamycin pathway in the diabetic restenotic cascade.20 This is consistent with the observation that the antimigratory effects of paclitaxel are not attenuated, even under high-glucose conditions.26 The TAXUS II trial was excluded from this analysis because TAXUS II was analyzed at a different core laboratory. There was some heterogeneity within the pooled groups (e.g., doses and release kinetics of paclitaxel, stent platforms), and the study inclusion and exclusion criteria resulted in the exclusion of the most complex patients with diabetes (e.g., those with multivessel and diffuse disease). Although the present study represents the largest IVUS series in PES-treated patients with diabetes, the number of patients in the insulin-requiring group was still relatively small. Complete serial IVUS data were not available in all patients enrolled. As with all IVUS studies, complete IVUS follow-up was not obtained, because IVUS follow-up is frequently not performed in severely obstructive vessels and in patients with adverse cardiac events. 1. Kannel WB, McGee DL. Diabetes and glucose tolerance as risk factors for cardiovascular disease: the Framingham study. Diabetes Care 1979;2:120 –126. 2. Pyorala K, Laakso M, Uusitupa M. Diabetes and atherosclerosis: an epidemiologic view. Diabetes Metab Rev 1987;3:463–524. 3. Stamler J, Vaccaro O, Neaton JD, Wentworth D. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care 1993;16:434 – 444. 4. Stein B, Weintraub WS, Gebhart SP, Cohen-Bernstein CL, Grosswald R, Liberman HA, Douglas JS Jr, Morris DC, King SB III. Influence of diabetes mellitus on early and late outcome after percutaneous transluminal coronary angioplasty. Circulation 1995;91:979 –989. 5. Van Belle E, Ketelers R, Bauters C, Perie M, Abolmaali K, Richard F, Lablanche JM, McFadden EP, Bertrand ME. Patency of percutaneous transluminal coronary angioplasty sites at 6-month angiographic follow-up: A key determinant of survival in diabetics after coronary balloon angioplasty. Circulation 2001;103:1218 –1224. 6. West NE, Ruygrok PN, Disco CM, Webster MW, Lindeboom WK, O’Neill WW, Mercado NF, Serruys PW. Clinical and angiographic predictors of restenosis after stent deployment in diabetic patients. Circulation 2004;109:867– 873. 7. Carrozza JP Jr, Kuntz RE, Fishman RF, Baim DS. Restenosis after arterial injury caused by coronary stenting in patients with diabetes mellitus. Ann Intern Med 1993;118:344 –349. 8. Cutlip DE, Chauhan MS, Baim DS, Ho KK, Popma JJ, Carrozza JP, Cohen DJ, Kuntz RE. Clinical restenosis after coronary stenting: perspectives from multicenter clinical trials. J Am Coll Cardiol 2002; 40:2082–2089. 9. Colombo A, Drzewiecki J, Banning A, Grube E, Hauptmann K, Silber S, Dudek D, Fort S, Schiele F, Zmudka K, et al. Randomized study to assess the effectiveness of slow- and moderate-release polymer-based paclitaxeleluting stents for coronary artery lesions. Circulation 2003;108:788 –794. 10. Stone GW, Ellis SG, Cox DA, Hermiller J, O’Shaughnessy C, Mann JT, Turco M, Caputo R, Bergin P, Greenberg J, et al. One-year clinical
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