- Email: [email protected]
Effect of Everolimus-Eluting Stents in Different Vessel Sizes (from the Pooled FUTURE I and II Trials)
Effect of Everolimus-Eluting Stents in Different Vessel Sizes (from the Pooled FUTURE I and II Trials) Yoshihiro Tsuchiya, MDa, Alexandra J. Lansky, MDa,*, Ricardo A. Costa, MDa, Roxana Mehran, MDa, Cody Pietras, BSca, Yoshihisa Shimada, MDb, Shinjo Sonoda, MDb, Ecaterina Cristea, MDa, Manuela Negoita, MDa, George D. Dangas, MD, PhDa, Jeffrey W. Moses, MDa, Martin B. Leon, MDa, Peter J. Fitzgerald, MD, PhDb, Ralf Müller, MDc, Hans Störger, MDd, Karl E. Hauptmann, MDe, and Eberhard Grube, MDc The everolimus-eluting stent (EES) has been shown to significantly decrease neointimal proliferation at 6 months compared with the bare metal stent (BMS) in patients with de novo coronary lesions. We report mid-term outcomes based on different vessel sizes in the combined FUTURE I and II trials. In the prospective, randomized, FUTURE I trial (single center) and expanded FUTURE II trial (multicenter), 106 patients (107 lesions) were randomized to EESs (n ⴝ 49 lesions) or BMSs (n ⴝ 58 lesions). Patients were categorized into 3 groups based on preprocedure reference diameter as assessed by quantitative coronary angiography (small vessel <2.75 mm, medium vessel 2.75 to 3.25 mm, and large vessel >3.25 mm). At 6-month follow-up, EESs decreased in-stent late lumen loss (decreased rate range of 78% to 94%), resulting in significantly larger minimum lumen area as assessed by intravascular ultrasound (increased range of 34% to 42%) compared with the BMS across all vessel sizes. There were no cases of in-stent restenosis with EESs at any vessel size but 8 cases with BMSs (5 in small vessels). No stent thrombosis, aneurysm formation, or late stent incomplete apposition was observed in any group. The EES appears to be effective for treatment of de novo coronary lesions in decreasing neointimal proliferation at 6-month follow-up compared with BMSs, regardless of vessel size. © 2006 Elsevier Inc. All rights reserved. (Am J Cardiol 2006;98:464 – 469) Everolimus (SDZ-RAD, C53H83NO14), an active immunosuppressive and antiproliferative compound of the same macrocyclic family as sirolimus, has been shown to decrease smooth muscle cell proliferation in human transplant allografts.1 The everolimus-eluting stent (EES) has been shown to safe, feasible, and efficient in the treatment of diseased native coronary vessels.2,3 We investigated the effect of EESs compared with bare metal stents (BMSs) in different vessel sizes. •••
From May to July 2002, 42 patients were prospectively randomized in a 2:1 ratio (EESs vs BMSs) in the first-inhuman, single-center, safety, and feasibility First Use To Underscore Restenosis reductions with Everolimus (FUTURE) I trial. The FUTURE II trial was the subsequent multicenter, feasibility trial that enrolled 64 patients between September and November 2002 using a reverse randomization scheme (1:2 ratio for EESs vs BMSs, respectively) to equalize the
The aCardiovascular Research Foundation and Columbia University Medical Center, New York, New York; bStanford University Medical Center, Stanford, California; and the cHeart Center Siegburg, Siegburg, the d Red Cross Hospital Cardiology Center, Frankfurt, and eKrankenhaus der Barmherzigen Brüder, Trier, Germany. Manuscript received December 23, 2005; revised manuscript received and accepted February 9, 2006. * Corresponding author: Tel: 212-851-9320; fax: 212-851-9321. E-mail address: [email protected] (A.J. Lansky). 0002-9149/06/$ – see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2006.02.054
EES and BMS arms when the 2 studies were combined. Primary and secondary end points were major adverse cardiac events (composite of cardiac death, myocardial infarction, coronary artery bypass graft surgery to target vessel or any target lesion revascularization, and angiographic end points of late loss and binary restenosis at 6 months after stent implantation). Inclusion and exclusion criteria for the 2 studies have been previously described3 and were identical for the 2 trials except for the inclusion of diabetes (type 1 or 2) only in the FUTURE II trial. In brief, angiographic criteria included de novo coronary lesions, reference diameter 2.75 to 4.0 mm, lesion length ⬍18 mm (visually estimated), and preprocedure stenosis of 50% to 99%; total occlusions were excluded.3 For the purpose of this analysis, lesions were categorized into 3 groups according to baseline vessel size as assessed by quantitative coronary angiography. The EES platform is the S-Stent (Biosensors International, Singapore), a stainless steel, laser-cut, tubular stent. Everolimus is coated (197 g/cm2) onto the S-Stent with a bioabsorbable polymer (poly-L-lactic acid) in a 1:1 ratio, with ⬇70% drug release in 30 days and 85% in 90 days.2 The stent lengths were 14 and 18 mm, with diameters of 2.5, 3.0, 3.5, and 4.0 mm. All patients received aspirin (325 mg/day) and clopidogrel (300-mg loading dose immediately and 75 mg/day for 6 months). Heparin was given to achieve an activated clotting time of ⬎250 seconds. If a glycoprotein IIb/IIIa www.AJConline.org
Coronary Artery Disease/Effect of Everolimus Stent in Different Vessel Sizes
465
Table 1 Baseline characteristics Variable
Age (yrs) Men Hypertension Diabetes mellitus* Hyperlipidemia† Current smoker Previous myocardial infarction Previous coronary bypass Previous percutaneous coronary intervention Asymptomatic Stable angina pectoris Unstable angina pectoris Angina class III or IV§ Left ventricle ejection fraction ⬎50% No. of coronary arteries treated Left anterior descending Left circumflex Right Lesion type储 A B1 B2 C Lesion length (mm) Calcium (moderate/severe) Pre-TIMI grade 3 flow
Small (⬍2.75 mm)
Medium (2.75–3.25 mm)
Large (⬎3.25 mm)
EES (n ⫽ 12)
BMS (n ⫽ 25)
p Value
EES (n ⫽ 22)
BMS (n ⫽ 16)
p Value
EES (n ⫽ 14)
BMS (n ⫽ 17)
p Value
67.5 8 (66.7%) 6 (50%) 2 (15.4%) 8 (66.7%) 1 (8.3%) 3 (25%) 0 (0%) 2 (16.7%)
63.3 17 (68%) 18 (72%) 6 (24%) 21 (84%) 5 (20%) 6 (24%) 4 (16%) 12 (48%)
0.22 1.0 0.27 0.84 0.40 0.64 1.0 0.29 0.08
61.9 17 (77.3%) 20 (90.9%) 1 (4.6%) 16 (72.7%) 6 (27.3%) 3 (13.6%) 0 (0%) 7 (31.8%)
63.5 13 (81.3%) 14 (87.5%) 3 (18.8%) 14 (87.5%) 3 (18.8%) 3 (18.8%) 1 (6.3%) 4 (25%)
0.63 1.0 1.0 0.38 0.43 0.71 0.68 0.42 0.73
65.2 13 (92.9%) 12 (85.7%) 2 (14.3%) 9 (64.3%) 3 (21.4%) 0 (0%) 1 (7.1%) 6 (42.9%)
63.5 13 (76.5%) 13 (76.5%) 3 (17.6%) 13 (76.5%) 3 (17.6%) 2 (11.8%) 1 (5.9%) 6 (35.3%)
0.53 0.34 0.66 0.81 0.70 1.0 0.49 1.0 0.72
2 (16.7%) 10 (83.3%) 0 (0%) 4 (33.3%) 9 (75%)
1 (4%) 22 (88%) 2 (8%) 8 (32%) 24 (96%)
0.24 1.0 1.0 1.0 0.09
4 (19%)‡ 13 (61.9%)‡ 4 (19%)‡ 5 (23.8%)‡ 19 (86.4%)
0 (0%) 13 (81.3%) 3 (18.8%) 7 (43.8%) 13 (81.3%)
0.12 0.28 1.0 0.29 0.68
1 (7.1%) 13 (92.9%) 0 (0%) 2 (14.3%) 12 (85.7%)
1 (5.9%) 16 (94.1%) 0 (0%) 1 (5.9%) 13 (76.5%)
1.0 1.0
13 8 (61.5%) 4 (30.8%) 1 (7.7%)
25 16 (64%) 7 (28%) 2 (8%)
1.0 1.0 1.0
22 10 (45.5%) 3 (13.6%) 9 (40.9%)
16 8 (50%) 2 (12.5%) 6 (37.5%)
1.0 1.0 1.0
14 7 (50%) 0 (0%) 7 (50%)
17 7 (41.2%) 3 (17.6%) 6 (35.3%)
0.26 0.29 0.71 1.0 0.92 1.0 1.0
6 (27.3%) 2 (12.5%) 6 (27.3%) 8 (50%) 6 (27.3%) 4 (25%) 4 (18.2%) 2 (12.5%) 9.71 ⫾ 3.26 11.78 ⫾ 3.51 4 (18.2%) 3 (18.8%) 20 (90.9%) 15 (93.8%)
5 (38.5%) 5 (20%) 3 (23.1%) 11 (44%) 4 (30.8%) 6 (24%) 1 (7.7%) 3 (12%) 10.53 ⫾ 3.32 10.27 ⫾ 3.86 1 (7.7%) 3 (12%) 12 (92.3%) 24 (96%)
0.43 0.19 1.0 1.0 0.07 1.0 1.0
1 (7.1%) 3 (17.6%) 8 (57.1%) 9 (52.9%) 5 (35.7%) 4 (23.5%) 0 (0%) 1 (5.9%) 10.05 ⫾ 2.66 10.53 ⫾ 3.26 3 (21.4%) 3 (17.6%) 13 (92.9%) 16 (94.1%)
0.58 0.66
0.72 0.23 0.48 0.61 1.0 0.69 1.0 0.66 1.0 1.0
* Diabetics enrolled in FUTURE 11 only. † Defined as total cholesterol level ⬎220 mg/dl and/or triglyceride level ⬎200 mg/dl. ‡ Available in 21 patients. § According to the Canadian Cardiovascular Society angina status classification. 储 According to the American College of Cardiology and American Heart Association classification. TIMI ⫽ Thrombolysis In Myocardial Infarction.
antagonist was administered (based on operator’s discretion), the activated clotting time was to be maintained at 225 to 300 seconds. Predilation of the target lesion was mandatory before stent placement, and multiple stent implantation was permitted. All cineangiograms and intravascular ultrasound images were analyzed at independent core laboratories that were blinded to the treatment protocol. After intracoronary nitrate administration, coronary angiograms were obtained in multiple views. Quantitative coronary angiography was performed using the CMS-GFT algorithm (MEDIS, Leiden, The Netherlands). Quantitative measurements of the target lesions were performed “in stent” (only the stented segment), “in segment” (stented segment plus 5-mm proximal and distal peristent zones), and in the 5-mm proximal and distal “peristent” areas immediately adjacent to the stent. Binary restenosis was defined as ⬎50% diameter stenosis, late lumen loss was the change in minimum lumen diameter from after the procedure to follow-up. Intravascular ultrasound images were acquired using automated pullback at 0.5 mm/s after
intracoronary nitrate administration. Two-dimensional and volumetric intravascular ultrasound analyses were performed using planimetry software (TapeMeasure/EchoPlaque, Indec Systems, Mountain View, California). Vessel, stent, lumen, and neointimal volumes were analyzed in stent and in segment. To adjust for different stent lengths, volume index was calculated as volume data divided by stent length (vessel volume index, stent volume index, lumen volume index, and neointimal volume index). Percent neointimal volume was defined as neointimal volume index divided by stent volume index. Data are presented as mean ⫾ SD or frequency. Statistical analyses were performed with SAS software (SAS Institute, Cary, North Carolina). For comparisons of continuous variables, a 2-tailed, unpaired Student’s t test was used. Categorical data were compared by Fisher’s exact test. A p value ⬍0.05 was considered statistically significant. In total, 106 patients (107 lesions) were categorized into 3 groups according to baseline reference diameter (small ⬍2.75 mm, 12 patients with 13 lesions in the EES group, 25
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Table 2 Quantitative coronary angiographic and intravascular ultrasound results Variable
Medium (2.75–3.25 mm)
Large (⬎3.25 mm)
EES
BMS
p Value
EES
BMS
p Value
EES
BMS
p Value
13
25
—
22
16
—
14
17
—
2.49 ⫾ 0.20 0.75 ⫾ 0.34 70.1 ⫾ 12.8
2.51 ⫾ 0.17 0.85 ⫾ 0.35 66.0 ⫾ 15.4
0.76 0.41 0.41
3.01 ⫾ 0.13 1.12 ⫾ 0.36 62.7 ⫾ 12.0
3.01 ⫾ 0.14 1.08 ⫾ 0.44 63.8 ⫾ 14.8
0.94 0.76 0.79
3.50 ⫾ 0.25 1.34 ⫾ 0.37 61.5 ⫾ 10.9
3.61 ⫾ 0.31 1.31 ⫾ 0.48 63.5 ⫾ 13.6
0.30 0.83 0.66
2.70 ⫾ 0.25 ⫺5.1 ⫾ 14.6
2.68 ⫾ 0.30 ⫺4.5 ⫾ 11.2
0.84 0.88
2.90 ⫾ 0.27 3.2 ⫾ 9.9
2.91 ⫾ 0.36 4.5 ⫾ 14.3
0.91 0.75
3.38 ⫾ 0.33 4.0 ⫾ 8.5
3.16 ⫾ 0.33 11.6 ⫾ 9.5
0.07 0.03
2.11 ⫾ 0.23 18.4 ⫾ 8.8 12
1.98 ⫾ 0.34 23.0 ⫾ 12.2 19
0.24 0.23 —
2.50 ⫾ 0.22 16.5 ⫾ 7.2 21
2.33 ⫾ 0.44 23.9 ⫾ 14.3 15
0.15 0.07 —
2.87 ⫾ 0.44 18.6 ⫾ 10.2 13
2.68 ⫾ 0.45 25.2 ⫾ 12.1 13
0.23 0.11 —
2.50 ⫾ 0.20 1.9 ⫾ 9.3 0.19 ⫾ 0.22 0 (0%)
1.86 ⫾ 0.79 26.7 ⫾ 30.3 0.86 ⫾ 0.68 5 (26.3%)
0.003 0.003 0.0006 0.13
2.84 ⫾ 0.26 1.0 ⫾ 10.5 0.05 ⫾ 0.23 0 (0%)
2.01 ⫾ 0.64 31.1 ⫾ 22.1 0.90 ⫾ 0.44 2 (13.3%)
0.0002 0.0001 ⬍0.0001 0.17
3.25 ⫾ 0.40 6.7 ⫾ 12.0 0.14 ⫾ 0.29 0 (0%)
2.24 ⫾ 0.49 32.7 ⫾ 13.9 0.77 ⫾ 0.39 1 (7.7%)
⬍0.0001 ⬍0.0001 ⬍0.0001 1.0
1.97 ⫾ 0.43 22.7 ⫾ 16.6 0.12 ⫾ 0.36 1 (8.3%)
1.51 ⫾ 0.63 40.6 ⫾ 24.4 0.51 ⫾ 0.46 7 (36.8%)
0.03 0.03 0.002 0.11
2.35 ⫾ 0.28 18.2 ⫾ 9.7 0.15 ⫾ 0.24 0 (0%)
1.76 ⫾ 0.60 35.7 ⫾ 21.4 0.56 ⫾ 0.51 4 (26.7%)
0.002 0.002 0.009 0.02
2.62 ⫾ 0.67 29.6 ⫾ 15.2 0.22 ⫾ 0.50 1 (7.7%)
2.17 ⫾ 0.44 37.7 ⫾ 12.7 0.42 ⫾ 0.59 2 (15.4%)
0.051 0.04 0.37 1.0
2.41 ⫾ 0.40 0.00 ⫾ 0.24 0 (0%)
2.33 ⫾ 0.59 0.23 ⫾ 0.59 1 (5.3%)
0.68 0.14 1.0
2.75 ⫾ 0.32 0.18 ⫾ 0.36 0 (0%)
2.48 ⫾ 0.66 0.24 ⫾ 0.33 1 (6.7%)
0.16 0.62 0.42
3.07 ⫾ 0.90 0.35 ⫾ 0.78 1 (7.7%)
3.11 ⫾ 0.56 0.08 ⫾ 0.36 0 (0%)
0.89 0.37 1.0
2.03 ⫾ 0.44 0.11 ⫾ 0.38 1 (8.3%) 11 4.93 ⫾ 0.96 12.64 ⫾ 3.36 5.99 ⫾ 1.03 6.16 ⫾ 1.17 0.17 ⫾ 0.18 2.4 ⫾ 2.1
2.03 ⫾ 0.37 0.17 ⫾ 0.40 1 (5.3%) 16 3.66 ⫾ 1.14 14.06 ⫾ 3.51 5.24 ⫾ 1.42 6.75 ⫾ 1.52 1.51 ⫾ 1.12 21.6 ⫾ 15.0
0.97 0.70 1.0
2.56 ⫾ 0.42 0.14 ⫾ 0.34 0 (0%) 19 6.16 ⫾ 1.71 15.99 ⫾ 3.98 7.74 ⫾ 1.83 7.95 ⫾ 1.87 0.21 ⫾ 0.19 2.6 ⫾ 2.3
2.39 ⫾ 0.39 0.11 ⫾ 0.51 0 (0%) 13 4.35 ⫾ 1.45 17.18 ⫾ 2.11 5.66 ⫾ 1.80 7.68 ⫾ 1.54 2.02 ⫾ 1.13 27.0 ⫾ 15.0
0.22 0.84 —
2.84 ⫾ 0.49 0.07 ⫾ 0.40 0 (0%) 13 8.04 ⫾ 2.31 20.48 ⫾ 4.30 9.69 ⫾ 2.50 9.75 ⫾ 2.60 0.12 ⫾ 0.14 1.1 ⫾ 1.4
2.69 ⫾ 0.56 0.07 ⫾ 0.43 1 (7.7%) 11 6.01 ⫾ 1.39 21.02 ⫾ 4.11 7.92 ⫾ 2.17 9.64 ⫾ 1.91 1.72 ⫾ 1.15 18.4 ⫾ 11.7
0.46 0.99 1.0
0.006 0.31 0.15 0.29 0.0002 0.0001
0.004 0.32 0.005 0.68 ⬍0.0001 ⬍0.0001
0.02 0.76 0.09 0.91 0.002 0.056
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No. of lesions Quantitative angiography Preprocedure Reference diameter (mm) Minimum lumen diameter (mm) Diameter stenosis (%) Final In stent Minimum lumen diameter (mm) Diameter stenosis (%) In segment Minimum lumen diameter (mm) Diameter stenosis (%) No. of lesions at follow-up In stent Minimum lumen diameter (mm) Diameter stenosis (%) Late loss (mm) Binary restenosis In segment Minimum lumen diameter (mm) Diameter stenosis (%) Late loss (mm) Binary restenosis Proximal edge Minimum lumen diameter (mm) Late loss (mm) Binary restenosis Distal edge Minimum lumen diameter (mm) Late loss (mm) Binary restenosis No. of quantitative intravascular ultrasounds Minimum lumen area (mm2) Vessel volume index (mm3/mm) Lumen volume index (mm3/mm) Stent volume index (mm3/mm) Neointimal volume index (mm3/mm) Neointimal volume (%)
Small (⬍2.75 mm)
Coronary Artery Disease/Effect of Everolimus Stent in Different Vessel Sizes
467
Figure 1. Cumulative frequency distribution curves for (A) small vessels (⬍2.75 mm), (B) medium vessels (2.75 to 3.25 mm), and (C) large vessels (⬎3.25 mm) for EESs (solid line) versus BMSs (dashed line) at baseline (crosses), after procedure (open circles), and at follow-up (solid circles). Mean minimum lumen diameter in the EES group was significantly larger than that in the BMS group at 6-month follow-up in all vessel sizes (p ⬍0.005).
lesions in the BMS group; medium 2.75 to 3.25 mm, 22 lesions in the EES group, 16 lesions in the BMS group; large ⬎3.25 mm, 14 lesions in the EES group, 17 lesions in the BMS group). Baseline clinical and lesion characteristics were similar across groups regardless of vessel size (Table 1). Diabetics represented 10.4% of the EES group versus 20.7% of the BMS group and did not differ across subgroups regardless of vessel size. All patients had successful stent implantations without increased creatine kinase or creatine kinase-MB levels and were discharged without complications. Thirteen asymptomatic patients refused angiographic follow-up (2 in the EES group and 11 in the BMS group); 1 patient in the EES group had a noncardiac death on the 138th day of follow-up. Therefore, 92 patients (86.8% of initial cohort) had followup angiograms at 6 months. Angiographic data are presented in Table 2. At 6-month follow-up, EES patients had larger in-stent and in-segment minimum lumen diameters with significantly lower in-stent late loss regardless of vessel size. Cumulative frequency distribution curves for instent minimum lumen diameter according to vessel size demonstrated the consistent benefit of EESs across all vessel sizes (Figure 1). The EES group had no in-stent restenosis and 4.3% (2 of 46) had in-segment restenosis (1 at the distal edge in the small-vessel group and 1 at the proximal edge in the large-vessel group). In contrast, the BMS group
Figure 2. (A) In-stent and (B) in-segment binary restenosis rates at 6-month follow-up for EESs (white bars) versus BMSs (black bars).
had 17% (8 of 47) in-stent and 27.7% (13 of 47) in-segment restenoses, with higher binary restenosis observed in smaller vessels (Figure 2). EESs significantly decreased
468
The American Journal of Cardiology (www.AJConline.org)
Figure 3. Mean ⫾ SD (lines above bars) in-stent and in-segment late lumen losses for EESs (white bars) versus BMSs (black bars).
in-stent late loss (lower rate range of 78% to 94%) compared with BMSs and decreased in-segment late loss across all vessel sizes (Figure 3). Quantitative intravascular ultrasound analysis at 6 months showed that EESs produced a significantly larger minimum lumen area compared with BMSs in all vessel sizes. For volumetric analysis, EESs showed a decreased volume in neointimal formation as assessed by neointimal volume index (lower rate range of 89% to 93%) and percent neointimal volume compared with BMSs (Table 2). Overall, there was a trend for decreased 6-month major adverse cardiac events in the EES group compared with the BMS group (6.4% vs 15.1%, respectively, p ⫽ 0.17). In the EES group, small- and large-vessel groups had 1 target lesion revascularization each, with 1 target vessel revascularization by bypass surgery in the large-vessel group. The BMS group had 4 target lesion revascularizations in the smallvessel group, 3 target lesion revascularizations in the mediumvessel group, and a non–Q-wave myocardial infarction in the large-vessel group. There was a single noncardiac death in the EES group on day 138 of follow-up. There was no stent thrombosis or aneurysm formation at 6-month follow-up in either group. Incomplete stent apposition was observed in 9.8% of the EES group and 4.9% in the BMS group after the procedure (p ⫽ 0.68), and no late (or acquired) incomplete stent apposition was observed at follow-up. •••
Vessel diameter is an established predictor of angiographic restenosis after catheter-based intervention, with a higher rate of restenosis in smaller vessels.4 Several studies have attempted to demonstrate the efficacy of stenting versus balloon angioplasty in small vessels (SISA, BESMART, and ISAR-SMART trials) and have demonstrated conflicting results.5–7 In the present study, in-stent restenosis rates of the control BMS group approximately tripled from the largestdiameter vessels to the smallest-diameter vessels (26.3% to 7.7%; Figure 2), whereas late loss increased only slightly (from 0.77 to 0.86 mm). This is attributed to the disproportionately larger amount of neointimal tissue compared with vessel caliber in smaller vessels.4 Dramatic decreases in neointimal proliferation with EESs were consistent across all vessel sizes (78% to 94% decrease in late loss as assessed by quantitative coronary angiography and 89% to 93% volume decrease in neointimal volume index as assessed by intravascular ultrasound compared with BMSs). In consequence, no in-stent restenosis was observed even in the small vessels. The inverse tendency between vessel size and angiographic restenosis rate was not found in the EES group. The mechanism of action of EESs has been described in detail.2 Everolimus and sirolimus are similar in pharmacology, potency, and structure but differ in solubility, with everolimus being more lipophilic than sirolimus.8 The effi-
Coronary Artery Disease/Effect of Everolimus Stent in Different Vessel Sizes
cacy of sirolimus-eluting stents in small vessels has been reported.9 However, the effect of different solubilities on treatment effect in different vessel sizes is unknown. In this present study, we found no significant decrease in late loss at the distal and proximal edges of the stent regardless of vessel size. There was no significant treatment effect in the peristent areas, implying that the benefit of everolimus is localized to the stent. The study included only 106 patients, thus limiting its power to demonstrate significant restenosis and clinical differences in the subgroups. In addition, the relatively lower angiographic follow-up rate in the BMS group may have introduced a possible bias; however, the present study supports the feasibility, safety, and likely efficacy of EESs in all vessel sizes.
Acknowledgment: The investigators thank Yingbo Na, BSc, for statistical assistance. 1. Eisen HJ, Tuzcu EM, Dorent R, Kobashigawa J, Mancini D, Valantinevon Kaeppler HA, Starling RC, Sorensen K, Hummel M, Lind JM, et al. Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients. N Engl J Med 2003;349:847– 858. 2. Grube E, Sonoda S, Ikeno F, Honda Y, Kar S, Chan C, Gerckens U, Lansky AJ, Fitzgerald PJ. Six- and twelve-month results from first human experience using everolimus-eluting stents with bioabsorbable polymer. Circulation 2004;109:2168 –2171.
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3. Costa RA, Lansky AJ, Mintz GS, Mehran R, Tsuchiya Y, Negoita M, Gilutz Y, Nikolsky E, Fahy M, Pop R, et al. Angiographic results of the first human experience with everolimus-eluting stents for the treatment of coronary lesions (the FUTURE I trial). Am J Cardiol 2005;95:113– 116. 4. Kuntz RE, Gibson CM, Nobuyoshi M, Baim DS. Generalized model of restenosis after conventional balloon angioplasty, stenting and directional atherectomy. J Am Coll Cardiol 1993;21:15–25. 5. Koning R, Eltchaninoff H, Commeau P, Khalife K, Gilard M, Lipiecki J, Coste P, Bedossa M, Lefevre T, Brunel P, et al. Stent placement compared with balloon angioplasty for small coronary arteries: inhospital and 6-month clinical and angiographic results. Circulation 2001;104:1604 –1608. 6. Doucet S, Schalij MJ, Vrolix MC, Hilton D, Chenu P, de Bruyne B, Udayachalerm W, Seth A, Bilodeau L, Reiber JH, et al. Stent placement to prevent restenosis after angioplasty in small coronary arteries. Circulation 2001;104:2029 –2033. 7. Kastrati A, Schomig A, Dirschinger J, Mehilli J, Dotzer F, von Welser N, Neumann FJ. A randomized trial comparing stenting with balloon angioplasty in small vessels in patients with symptomatic coronary artery disease. ISAR-SMART Study Investigators Intracoronary Stenting or Angioplasty for Restenosis Reduction in Small Arteries. Circulation 2000;102:2593–2598. 8. Schuler W, Sedrani R, Cottens S, Haberlin B, Schulz M, Schuurman HJ, Zenke G, Zerwes HG, Schreier MH. SDZ RAD, a new rapamycin derivative: pharmacological properties in vitro and in vivo. Transplantation 1997;64:36 – 42. 9. Regar E, Serruys PW, Bode C, Holubarsch C, Guermonprez JL, Wijns W, Bartorelli A, Constantini C, Degertekin M, Tanabe K, et al. Angiographic findings of the multicenter Randomized Study With the Sirolimus-Eluting Bx Velocity Balloon-Expandable Stent (RAVEL): sirolimus-eluting stents inhibit restenosis irrespective of the vessel size. Circulation 2002;106:1949 –1956.
From May to July 2002, 42 patients were prospectively randomized in a 2:1 ratio (EESs vs BMSs) in the first-inhuman, single-center, safety, and feasibility First Use To Underscore Restenosis reductions with Everolimus (FUTURE) I trial. The FUTURE II trial was the subsequent multicenter, feasibility trial that enrolled 64 patients between September and November 2002 using a reverse randomization scheme (1:2 ratio for EESs vs BMSs, respectively) to equalize the
The aCardiovascular Research Foundation and Columbia University Medical Center, New York, New York; bStanford University Medical Center, Stanford, California; and the cHeart Center Siegburg, Siegburg, the d Red Cross Hospital Cardiology Center, Frankfurt, and eKrankenhaus der Barmherzigen Brüder, Trier, Germany. Manuscript received December 23, 2005; revised manuscript received and accepted February 9, 2006. * Corresponding author: Tel: 212-851-9320; fax: 212-851-9321. E-mail address: [email protected] (A.J. Lansky). 0002-9149/06/$ – see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2006.02.054
EES and BMS arms when the 2 studies were combined. Primary and secondary end points were major adverse cardiac events (composite of cardiac death, myocardial infarction, coronary artery bypass graft surgery to target vessel or any target lesion revascularization, and angiographic end points of late loss and binary restenosis at 6 months after stent implantation). Inclusion and exclusion criteria for the 2 studies have been previously described3 and were identical for the 2 trials except for the inclusion of diabetes (type 1 or 2) only in the FUTURE II trial. In brief, angiographic criteria included de novo coronary lesions, reference diameter 2.75 to 4.0 mm, lesion length ⬍18 mm (visually estimated), and preprocedure stenosis of 50% to 99%; total occlusions were excluded.3 For the purpose of this analysis, lesions were categorized into 3 groups according to baseline vessel size as assessed by quantitative coronary angiography. The EES platform is the S-Stent (Biosensors International, Singapore), a stainless steel, laser-cut, tubular stent. Everolimus is coated (197 g/cm2) onto the S-Stent with a bioabsorbable polymer (poly-L-lactic acid) in a 1:1 ratio, with ⬇70% drug release in 30 days and 85% in 90 days.2 The stent lengths were 14 and 18 mm, with diameters of 2.5, 3.0, 3.5, and 4.0 mm. All patients received aspirin (325 mg/day) and clopidogrel (300-mg loading dose immediately and 75 mg/day for 6 months). Heparin was given to achieve an activated clotting time of ⬎250 seconds. If a glycoprotein IIb/IIIa www.AJConline.org
Coronary Artery Disease/Effect of Everolimus Stent in Different Vessel Sizes
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Table 1 Baseline characteristics Variable
Age (yrs) Men Hypertension Diabetes mellitus* Hyperlipidemia† Current smoker Previous myocardial infarction Previous coronary bypass Previous percutaneous coronary intervention Asymptomatic Stable angina pectoris Unstable angina pectoris Angina class III or IV§ Left ventricle ejection fraction ⬎50% No. of coronary arteries treated Left anterior descending Left circumflex Right Lesion type储 A B1 B2 C Lesion length (mm) Calcium (moderate/severe) Pre-TIMI grade 3 flow
Small (⬍2.75 mm)
Medium (2.75–3.25 mm)
Large (⬎3.25 mm)
EES (n ⫽ 12)
BMS (n ⫽ 25)
p Value
EES (n ⫽ 22)
BMS (n ⫽ 16)
p Value
EES (n ⫽ 14)
BMS (n ⫽ 17)
p Value
67.5 8 (66.7%) 6 (50%) 2 (15.4%) 8 (66.7%) 1 (8.3%) 3 (25%) 0 (0%) 2 (16.7%)
63.3 17 (68%) 18 (72%) 6 (24%) 21 (84%) 5 (20%) 6 (24%) 4 (16%) 12 (48%)
0.22 1.0 0.27 0.84 0.40 0.64 1.0 0.29 0.08
61.9 17 (77.3%) 20 (90.9%) 1 (4.6%) 16 (72.7%) 6 (27.3%) 3 (13.6%) 0 (0%) 7 (31.8%)
63.5 13 (81.3%) 14 (87.5%) 3 (18.8%) 14 (87.5%) 3 (18.8%) 3 (18.8%) 1 (6.3%) 4 (25%)
0.63 1.0 1.0 0.38 0.43 0.71 0.68 0.42 0.73
65.2 13 (92.9%) 12 (85.7%) 2 (14.3%) 9 (64.3%) 3 (21.4%) 0 (0%) 1 (7.1%) 6 (42.9%)
63.5 13 (76.5%) 13 (76.5%) 3 (17.6%) 13 (76.5%) 3 (17.6%) 2 (11.8%) 1 (5.9%) 6 (35.3%)
0.53 0.34 0.66 0.81 0.70 1.0 0.49 1.0 0.72
2 (16.7%) 10 (83.3%) 0 (0%) 4 (33.3%) 9 (75%)
1 (4%) 22 (88%) 2 (8%) 8 (32%) 24 (96%)
0.24 1.0 1.0 1.0 0.09
4 (19%)‡ 13 (61.9%)‡ 4 (19%)‡ 5 (23.8%)‡ 19 (86.4%)
0 (0%) 13 (81.3%) 3 (18.8%) 7 (43.8%) 13 (81.3%)
0.12 0.28 1.0 0.29 0.68
1 (7.1%) 13 (92.9%) 0 (0%) 2 (14.3%) 12 (85.7%)
1 (5.9%) 16 (94.1%) 0 (0%) 1 (5.9%) 13 (76.5%)
1.0 1.0
13 8 (61.5%) 4 (30.8%) 1 (7.7%)
25 16 (64%) 7 (28%) 2 (8%)
1.0 1.0 1.0
22 10 (45.5%) 3 (13.6%) 9 (40.9%)
16 8 (50%) 2 (12.5%) 6 (37.5%)
1.0 1.0 1.0
14 7 (50%) 0 (0%) 7 (50%)
17 7 (41.2%) 3 (17.6%) 6 (35.3%)
0.26 0.29 0.71 1.0 0.92 1.0 1.0
6 (27.3%) 2 (12.5%) 6 (27.3%) 8 (50%) 6 (27.3%) 4 (25%) 4 (18.2%) 2 (12.5%) 9.71 ⫾ 3.26 11.78 ⫾ 3.51 4 (18.2%) 3 (18.8%) 20 (90.9%) 15 (93.8%)
5 (38.5%) 5 (20%) 3 (23.1%) 11 (44%) 4 (30.8%) 6 (24%) 1 (7.7%) 3 (12%) 10.53 ⫾ 3.32 10.27 ⫾ 3.86 1 (7.7%) 3 (12%) 12 (92.3%) 24 (96%)
0.43 0.19 1.0 1.0 0.07 1.0 1.0
1 (7.1%) 3 (17.6%) 8 (57.1%) 9 (52.9%) 5 (35.7%) 4 (23.5%) 0 (0%) 1 (5.9%) 10.05 ⫾ 2.66 10.53 ⫾ 3.26 3 (21.4%) 3 (17.6%) 13 (92.9%) 16 (94.1%)
0.58 0.66
0.72 0.23 0.48 0.61 1.0 0.69 1.0 0.66 1.0 1.0
* Diabetics enrolled in FUTURE 11 only. † Defined as total cholesterol level ⬎220 mg/dl and/or triglyceride level ⬎200 mg/dl. ‡ Available in 21 patients. § According to the Canadian Cardiovascular Society angina status classification. 储 According to the American College of Cardiology and American Heart Association classification. TIMI ⫽ Thrombolysis In Myocardial Infarction.
antagonist was administered (based on operator’s discretion), the activated clotting time was to be maintained at 225 to 300 seconds. Predilation of the target lesion was mandatory before stent placement, and multiple stent implantation was permitted. All cineangiograms and intravascular ultrasound images were analyzed at independent core laboratories that were blinded to the treatment protocol. After intracoronary nitrate administration, coronary angiograms were obtained in multiple views. Quantitative coronary angiography was performed using the CMS-GFT algorithm (MEDIS, Leiden, The Netherlands). Quantitative measurements of the target lesions were performed “in stent” (only the stented segment), “in segment” (stented segment plus 5-mm proximal and distal peristent zones), and in the 5-mm proximal and distal “peristent” areas immediately adjacent to the stent. Binary restenosis was defined as ⬎50% diameter stenosis, late lumen loss was the change in minimum lumen diameter from after the procedure to follow-up. Intravascular ultrasound images were acquired using automated pullback at 0.5 mm/s after
intracoronary nitrate administration. Two-dimensional and volumetric intravascular ultrasound analyses were performed using planimetry software (TapeMeasure/EchoPlaque, Indec Systems, Mountain View, California). Vessel, stent, lumen, and neointimal volumes were analyzed in stent and in segment. To adjust for different stent lengths, volume index was calculated as volume data divided by stent length (vessel volume index, stent volume index, lumen volume index, and neointimal volume index). Percent neointimal volume was defined as neointimal volume index divided by stent volume index. Data are presented as mean ⫾ SD or frequency. Statistical analyses were performed with SAS software (SAS Institute, Cary, North Carolina). For comparisons of continuous variables, a 2-tailed, unpaired Student’s t test was used. Categorical data were compared by Fisher’s exact test. A p value ⬍0.05 was considered statistically significant. In total, 106 patients (107 lesions) were categorized into 3 groups according to baseline reference diameter (small ⬍2.75 mm, 12 patients with 13 lesions in the EES group, 25
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Table 2 Quantitative coronary angiographic and intravascular ultrasound results Variable
Medium (2.75–3.25 mm)
Large (⬎3.25 mm)
EES
BMS
p Value
EES
BMS
p Value
EES
BMS
p Value
13
25
—
22
16
—
14
17
—
2.49 ⫾ 0.20 0.75 ⫾ 0.34 70.1 ⫾ 12.8
2.51 ⫾ 0.17 0.85 ⫾ 0.35 66.0 ⫾ 15.4
0.76 0.41 0.41
3.01 ⫾ 0.13 1.12 ⫾ 0.36 62.7 ⫾ 12.0
3.01 ⫾ 0.14 1.08 ⫾ 0.44 63.8 ⫾ 14.8
0.94 0.76 0.79
3.50 ⫾ 0.25 1.34 ⫾ 0.37 61.5 ⫾ 10.9
3.61 ⫾ 0.31 1.31 ⫾ 0.48 63.5 ⫾ 13.6
0.30 0.83 0.66
2.70 ⫾ 0.25 ⫺5.1 ⫾ 14.6
2.68 ⫾ 0.30 ⫺4.5 ⫾ 11.2
0.84 0.88
2.90 ⫾ 0.27 3.2 ⫾ 9.9
2.91 ⫾ 0.36 4.5 ⫾ 14.3
0.91 0.75
3.38 ⫾ 0.33 4.0 ⫾ 8.5
3.16 ⫾ 0.33 11.6 ⫾ 9.5
0.07 0.03
2.11 ⫾ 0.23 18.4 ⫾ 8.8 12
1.98 ⫾ 0.34 23.0 ⫾ 12.2 19
0.24 0.23 —
2.50 ⫾ 0.22 16.5 ⫾ 7.2 21
2.33 ⫾ 0.44 23.9 ⫾ 14.3 15
0.15 0.07 —
2.87 ⫾ 0.44 18.6 ⫾ 10.2 13
2.68 ⫾ 0.45 25.2 ⫾ 12.1 13
0.23 0.11 —
2.50 ⫾ 0.20 1.9 ⫾ 9.3 0.19 ⫾ 0.22 0 (0%)
1.86 ⫾ 0.79 26.7 ⫾ 30.3 0.86 ⫾ 0.68 5 (26.3%)
0.003 0.003 0.0006 0.13
2.84 ⫾ 0.26 1.0 ⫾ 10.5 0.05 ⫾ 0.23 0 (0%)
2.01 ⫾ 0.64 31.1 ⫾ 22.1 0.90 ⫾ 0.44 2 (13.3%)
0.0002 0.0001 ⬍0.0001 0.17
3.25 ⫾ 0.40 6.7 ⫾ 12.0 0.14 ⫾ 0.29 0 (0%)
2.24 ⫾ 0.49 32.7 ⫾ 13.9 0.77 ⫾ 0.39 1 (7.7%)
⬍0.0001 ⬍0.0001 ⬍0.0001 1.0
1.97 ⫾ 0.43 22.7 ⫾ 16.6 0.12 ⫾ 0.36 1 (8.3%)
1.51 ⫾ 0.63 40.6 ⫾ 24.4 0.51 ⫾ 0.46 7 (36.8%)
0.03 0.03 0.002 0.11
2.35 ⫾ 0.28 18.2 ⫾ 9.7 0.15 ⫾ 0.24 0 (0%)
1.76 ⫾ 0.60 35.7 ⫾ 21.4 0.56 ⫾ 0.51 4 (26.7%)
0.002 0.002 0.009 0.02
2.62 ⫾ 0.67 29.6 ⫾ 15.2 0.22 ⫾ 0.50 1 (7.7%)
2.17 ⫾ 0.44 37.7 ⫾ 12.7 0.42 ⫾ 0.59 2 (15.4%)
0.051 0.04 0.37 1.0
2.41 ⫾ 0.40 0.00 ⫾ 0.24 0 (0%)
2.33 ⫾ 0.59 0.23 ⫾ 0.59 1 (5.3%)
0.68 0.14 1.0
2.75 ⫾ 0.32 0.18 ⫾ 0.36 0 (0%)
2.48 ⫾ 0.66 0.24 ⫾ 0.33 1 (6.7%)
0.16 0.62 0.42
3.07 ⫾ 0.90 0.35 ⫾ 0.78 1 (7.7%)
3.11 ⫾ 0.56 0.08 ⫾ 0.36 0 (0%)
0.89 0.37 1.0
2.03 ⫾ 0.44 0.11 ⫾ 0.38 1 (8.3%) 11 4.93 ⫾ 0.96 12.64 ⫾ 3.36 5.99 ⫾ 1.03 6.16 ⫾ 1.17 0.17 ⫾ 0.18 2.4 ⫾ 2.1
2.03 ⫾ 0.37 0.17 ⫾ 0.40 1 (5.3%) 16 3.66 ⫾ 1.14 14.06 ⫾ 3.51 5.24 ⫾ 1.42 6.75 ⫾ 1.52 1.51 ⫾ 1.12 21.6 ⫾ 15.0
0.97 0.70 1.0
2.56 ⫾ 0.42 0.14 ⫾ 0.34 0 (0%) 19 6.16 ⫾ 1.71 15.99 ⫾ 3.98 7.74 ⫾ 1.83 7.95 ⫾ 1.87 0.21 ⫾ 0.19 2.6 ⫾ 2.3
2.39 ⫾ 0.39 0.11 ⫾ 0.51 0 (0%) 13 4.35 ⫾ 1.45 17.18 ⫾ 2.11 5.66 ⫾ 1.80 7.68 ⫾ 1.54 2.02 ⫾ 1.13 27.0 ⫾ 15.0
0.22 0.84 —
2.84 ⫾ 0.49 0.07 ⫾ 0.40 0 (0%) 13 8.04 ⫾ 2.31 20.48 ⫾ 4.30 9.69 ⫾ 2.50 9.75 ⫾ 2.60 0.12 ⫾ 0.14 1.1 ⫾ 1.4
2.69 ⫾ 0.56 0.07 ⫾ 0.43 1 (7.7%) 11 6.01 ⫾ 1.39 21.02 ⫾ 4.11 7.92 ⫾ 2.17 9.64 ⫾ 1.91 1.72 ⫾ 1.15 18.4 ⫾ 11.7
0.46 0.99 1.0
0.006 0.31 0.15 0.29 0.0002 0.0001
0.004 0.32 0.005 0.68 ⬍0.0001 ⬍0.0001
0.02 0.76 0.09 0.91 0.002 0.056
The American Journal of Cardiology (www.AJConline.org)
No. of lesions Quantitative angiography Preprocedure Reference diameter (mm) Minimum lumen diameter (mm) Diameter stenosis (%) Final In stent Minimum lumen diameter (mm) Diameter stenosis (%) In segment Minimum lumen diameter (mm) Diameter stenosis (%) No. of lesions at follow-up In stent Minimum lumen diameter (mm) Diameter stenosis (%) Late loss (mm) Binary restenosis In segment Minimum lumen diameter (mm) Diameter stenosis (%) Late loss (mm) Binary restenosis Proximal edge Minimum lumen diameter (mm) Late loss (mm) Binary restenosis Distal edge Minimum lumen diameter (mm) Late loss (mm) Binary restenosis No. of quantitative intravascular ultrasounds Minimum lumen area (mm2) Vessel volume index (mm3/mm) Lumen volume index (mm3/mm) Stent volume index (mm3/mm) Neointimal volume index (mm3/mm) Neointimal volume (%)
Small (⬍2.75 mm)
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467
Figure 1. Cumulative frequency distribution curves for (A) small vessels (⬍2.75 mm), (B) medium vessels (2.75 to 3.25 mm), and (C) large vessels (⬎3.25 mm) for EESs (solid line) versus BMSs (dashed line) at baseline (crosses), after procedure (open circles), and at follow-up (solid circles). Mean minimum lumen diameter in the EES group was significantly larger than that in the BMS group at 6-month follow-up in all vessel sizes (p ⬍0.005).
lesions in the BMS group; medium 2.75 to 3.25 mm, 22 lesions in the EES group, 16 lesions in the BMS group; large ⬎3.25 mm, 14 lesions in the EES group, 17 lesions in the BMS group). Baseline clinical and lesion characteristics were similar across groups regardless of vessel size (Table 1). Diabetics represented 10.4% of the EES group versus 20.7% of the BMS group and did not differ across subgroups regardless of vessel size. All patients had successful stent implantations without increased creatine kinase or creatine kinase-MB levels and were discharged without complications. Thirteen asymptomatic patients refused angiographic follow-up (2 in the EES group and 11 in the BMS group); 1 patient in the EES group had a noncardiac death on the 138th day of follow-up. Therefore, 92 patients (86.8% of initial cohort) had followup angiograms at 6 months. Angiographic data are presented in Table 2. At 6-month follow-up, EES patients had larger in-stent and in-segment minimum lumen diameters with significantly lower in-stent late loss regardless of vessel size. Cumulative frequency distribution curves for instent minimum lumen diameter according to vessel size demonstrated the consistent benefit of EESs across all vessel sizes (Figure 1). The EES group had no in-stent restenosis and 4.3% (2 of 46) had in-segment restenosis (1 at the distal edge in the small-vessel group and 1 at the proximal edge in the large-vessel group). In contrast, the BMS group
Figure 2. (A) In-stent and (B) in-segment binary restenosis rates at 6-month follow-up for EESs (white bars) versus BMSs (black bars).
had 17% (8 of 47) in-stent and 27.7% (13 of 47) in-segment restenoses, with higher binary restenosis observed in smaller vessels (Figure 2). EESs significantly decreased
468
The American Journal of Cardiology (www.AJConline.org)
Figure 3. Mean ⫾ SD (lines above bars) in-stent and in-segment late lumen losses for EESs (white bars) versus BMSs (black bars).
in-stent late loss (lower rate range of 78% to 94%) compared with BMSs and decreased in-segment late loss across all vessel sizes (Figure 3). Quantitative intravascular ultrasound analysis at 6 months showed that EESs produced a significantly larger minimum lumen area compared with BMSs in all vessel sizes. For volumetric analysis, EESs showed a decreased volume in neointimal formation as assessed by neointimal volume index (lower rate range of 89% to 93%) and percent neointimal volume compared with BMSs (Table 2). Overall, there was a trend for decreased 6-month major adverse cardiac events in the EES group compared with the BMS group (6.4% vs 15.1%, respectively, p ⫽ 0.17). In the EES group, small- and large-vessel groups had 1 target lesion revascularization each, with 1 target vessel revascularization by bypass surgery in the large-vessel group. The BMS group had 4 target lesion revascularizations in the smallvessel group, 3 target lesion revascularizations in the mediumvessel group, and a non–Q-wave myocardial infarction in the large-vessel group. There was a single noncardiac death in the EES group on day 138 of follow-up. There was no stent thrombosis or aneurysm formation at 6-month follow-up in either group. Incomplete stent apposition was observed in 9.8% of the EES group and 4.9% in the BMS group after the procedure (p ⫽ 0.68), and no late (or acquired) incomplete stent apposition was observed at follow-up. •••
Vessel diameter is an established predictor of angiographic restenosis after catheter-based intervention, with a higher rate of restenosis in smaller vessels.4 Several studies have attempted to demonstrate the efficacy of stenting versus balloon angioplasty in small vessels (SISA, BESMART, and ISAR-SMART trials) and have demonstrated conflicting results.5–7 In the present study, in-stent restenosis rates of the control BMS group approximately tripled from the largestdiameter vessels to the smallest-diameter vessels (26.3% to 7.7%; Figure 2), whereas late loss increased only slightly (from 0.77 to 0.86 mm). This is attributed to the disproportionately larger amount of neointimal tissue compared with vessel caliber in smaller vessels.4 Dramatic decreases in neointimal proliferation with EESs were consistent across all vessel sizes (78% to 94% decrease in late loss as assessed by quantitative coronary angiography and 89% to 93% volume decrease in neointimal volume index as assessed by intravascular ultrasound compared with BMSs). In consequence, no in-stent restenosis was observed even in the small vessels. The inverse tendency between vessel size and angiographic restenosis rate was not found in the EES group. The mechanism of action of EESs has been described in detail.2 Everolimus and sirolimus are similar in pharmacology, potency, and structure but differ in solubility, with everolimus being more lipophilic than sirolimus.8 The effi-
Coronary Artery Disease/Effect of Everolimus Stent in Different Vessel Sizes
cacy of sirolimus-eluting stents in small vessels has been reported.9 However, the effect of different solubilities on treatment effect in different vessel sizes is unknown. In this present study, we found no significant decrease in late loss at the distal and proximal edges of the stent regardless of vessel size. There was no significant treatment effect in the peristent areas, implying that the benefit of everolimus is localized to the stent. The study included only 106 patients, thus limiting its power to demonstrate significant restenosis and clinical differences in the subgroups. In addition, the relatively lower angiographic follow-up rate in the BMS group may have introduced a possible bias; however, the present study supports the feasibility, safety, and likely efficacy of EESs in all vessel sizes.
Acknowledgment: The investigators thank Yingbo Na, BSc, for statistical assistance. 1. Eisen HJ, Tuzcu EM, Dorent R, Kobashigawa J, Mancini D, Valantinevon Kaeppler HA, Starling RC, Sorensen K, Hummel M, Lind JM, et al. Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients. N Engl J Med 2003;349:847– 858. 2. Grube E, Sonoda S, Ikeno F, Honda Y, Kar S, Chan C, Gerckens U, Lansky AJ, Fitzgerald PJ. Six- and twelve-month results from first human experience using everolimus-eluting stents with bioabsorbable polymer. Circulation 2004;109:2168 –2171.
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3. Costa RA, Lansky AJ, Mintz GS, Mehran R, Tsuchiya Y, Negoita M, Gilutz Y, Nikolsky E, Fahy M, Pop R, et al. Angiographic results of the first human experience with everolimus-eluting stents for the treatment of coronary lesions (the FUTURE I trial). Am J Cardiol 2005;95:113– 116. 4. Kuntz RE, Gibson CM, Nobuyoshi M, Baim DS. Generalized model of restenosis after conventional balloon angioplasty, stenting and directional atherectomy. J Am Coll Cardiol 1993;21:15–25. 5. Koning R, Eltchaninoff H, Commeau P, Khalife K, Gilard M, Lipiecki J, Coste P, Bedossa M, Lefevre T, Brunel P, et al. Stent placement compared with balloon angioplasty for small coronary arteries: inhospital and 6-month clinical and angiographic results. Circulation 2001;104:1604 –1608. 6. Doucet S, Schalij MJ, Vrolix MC, Hilton D, Chenu P, de Bruyne B, Udayachalerm W, Seth A, Bilodeau L, Reiber JH, et al. Stent placement to prevent restenosis after angioplasty in small coronary arteries. Circulation 2001;104:2029 –2033. 7. Kastrati A, Schomig A, Dirschinger J, Mehilli J, Dotzer F, von Welser N, Neumann FJ. A randomized trial comparing stenting with balloon angioplasty in small vessels in patients with symptomatic coronary artery disease. ISAR-SMART Study Investigators Intracoronary Stenting or Angioplasty for Restenosis Reduction in Small Arteries. Circulation 2000;102:2593–2598. 8. Schuler W, Sedrani R, Cottens S, Haberlin B, Schulz M, Schuurman HJ, Zenke G, Zerwes HG, Schreier MH. SDZ RAD, a new rapamycin derivative: pharmacological properties in vitro and in vivo. Transplantation 1997;64:36 – 42. 9. Regar E, Serruys PW, Bode C, Holubarsch C, Guermonprez JL, Wijns W, Bartorelli A, Constantini C, Degertekin M, Tanabe K, et al. Angiographic findings of the multicenter Randomized Study With the Sirolimus-Eluting Bx Velocity Balloon-Expandable Stent (RAVEL): sirolimus-eluting stents inhibit restenosis irrespective of the vessel size. Circulation 2002;106:1949 –1956.