- Email: [email protected]
Comparison of the Efficacy of Direct Coronary Stenting With Sirolimus-Eluting Stents Versus Stenting With Predilation by Intravascular Ultrasound Imaging (from the DIRECT Trial)
Comparison of the Efficacy of Direct Coronary Stenting With Sirolimus-Eluting Stents Versus Stenting With Predilation by Intravascular Ultrasound Imaging (from the DIRECT Trial) Atsushi Hirohata, MDa, Yoshihiro Morino, MDa, Junya Ako, MDa, Ryota Sakurai, MDa, Maurice Buchbinder, MDb, Ronald P. Caputo, MDc, Steven P. Karas, MDd, Gregory J. Mishkel, MDe, Michael R. Mooney, MDf, Charles D. O’Shaughnessy, MDg, Albert E. Raizner, MDh, Robert L. Wilensky, MDi, David O. Williams, MDj, Shing-Chiu Wong, MDk, Paul G. Yock, MDa, Yasuhiro Honda, MDa, Jeffrey W. Moses, MDl, and Peter J. Fitzgerald, MD, PhDa,*, for the DIRECT Investigators A direct coronary stenting technique using drug-eluting stents may decrease drug-eluting stent efficacy due to possible damage to the surface coating of the stent. The DIRECT is a multicenter, prospective, nonrandomized trial designed to evaluate the direct stenting strategy for the sirolimus-eluting Bx-Velocity stent compared with the historical control (SIRIUS trial, stenting with predilation). Volumetric and cross-sectional intravascular ultrasound analyses at 8-month follow-up were performed in 115 patients (DIRECT nⴝ 64, control n ⴝ 51). Patient and lesion characteristics were comparable between groups. The DIRECT group achieved an equivalent uniform expansion index, defined as minimum stent area/maximum stent area ⴛ 100, compared with the control group (65.9 ⴞ 11.7 vs 63.1 ⴞ 12.7, p ⴝ NS). At 8-month follow-up, vessel, stent, lumen, and neointimal volume index (volume in cubic millimeters/length in millimeters) and percent neointimal volume were similar between the DIRECT and control groups (vessel volume index 13.9 ⴞ 4.40 vs 15.0 ⴞ 3.83; stent volume index 6.83 ⴞ 2.02 vs 6.94 ⴞ 2.04; lumen volume index 6.71 ⴞ 2.04 vs 6.81 ⴞ 2.07; neointimal volume index 0.14 ⴞ 0.24 vs 0.16 ⴞ 0.23; percent neointimal volume 3.73 ⴞ 6.97 vs 3.14 ⴞ 5.32, p ⴝ NS for all). In addition, in-stent neointimal hyperplasia distribution was significantly smaller near the distal stent edge (0.22 vs 0.098 mm3/mm, p ⴝ 0.01 for an average neointimal volume index within 3 mm from the distal stent edge). In conclusion, direct coronary stenting with the sirolimus-eluting Bx-Velocity stent is equally effective in terms of uniform stent expansion and long-term quantitative intravascular ultrasound results compared with conventional stenting using predilation. This strategy appears to be associated with less neointimal hyperplasia near the distal stent edge. © 2006 Elsevier Inc. All rights reserved. (Am J Cardiol 2006;98:1464 –1467) Recently, stent-based local drug delivery with sirolimus has demonstrated very promising results in the suppression of in-stent neointimal hyperplasia in coronary artery lesions.1–3 However, previous clinical trials using bare metal stents have reported some potential benefit using a direct coronary stenting strategy, presumably due to decreased vessel injury
a Center for Research in Cardiovascular Intervention, Stanford University, Stanford, California; bScripps Memorial Hospital, La Jolla, California; c St. Joseph’s Hospital, Syracuse, New York; dHealth First Institution, Melbourne, Florida; eSt. John’s Hospital and Memorial Medical Center, Springfield, Illinois; fMinneapolis Heart Institute Foundation, Minneapolis, Minnesota; gNorth Ohio Heart Institute, Elyria, Ohio; hMethodist DeBakey Heart Center, Houston, Texas; iHospital of the University of Pennsylvania, Philadelphia, Pennsylvania; jRhode Island Hospital, Providence, Rhode Island; kNew York Presbyterian Hospital, New York, New York; lNew York-Presbyterian Hospital/Columbia University Medical Center, New York, New York. Manuscript received February 28, 2006; revised manuscript received and accepted June 20, 2006. *Corresponding author: Tel: 650-498-6034; fax: 650-498-6027. E-mail address: [email protected] (P.J. Fitzgerald).
0002-9149/06/$ – see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2006.06.046
and subsequent neointimal hyperplasia,4 – 6 because there is no predilation. Therefore, a direct stent strategy using sirolimus-eluting stents (SESs) may be associated with decreased in-stent neointimal hyperplasia, by preventing “geographic miss” between injured and stented vessel segments. However, some concerns have arisen regarding direct stenting of drug-eluting stents. Among these are the possible damage to the surface coating of the stent and nonuniform stent expansion, thereby disrupting the efficacy of the pharmacologic agent. Thus, the purpose of this intravascular ultrasound (IVUS) study was to evaluate the efficacy of the direct stent strategy using SESs, in terms of mechanical stent expansion and biologic vessel response, compared with conventional SESs using predilation. Methods and Results Patients enrolled in the Sirolimus-eluting Bx-Velocity balloon expandable stent with DIRECT stenting in the treatment of patients with de novo native coronary artery lesions (DIRECT) trial comprised the study sample. The DIRECT www.AJConline.org
Coronary Artery Disease/Direct Coronary Stenting With SESs
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Table 1 Baseline clinical characteristics Variable Age (yrs) Men Unstable angina pectoris Diabetes mellitus Hypertension† Dyslipidemia‡ Smoking
SES DIRECT (n ⫽ 64)
SES Predilation (n ⫽ 51)
63 ⫾ 12 73% 20% 27% 70% 82% 61%*
57 ⫾ 9 69% 15% 24% 71% 78% 20%*
Values are means ⫾ SDs or percentages. * p ⫽ 0.01. † Hypertension is defined as systolic/diastolic blood pressure level ⬎140/90 mm Hg. ‡ Dyslipidemia is defined as a low-density lipoprotein cholesterol level ⬎130 mg/dl. Table 2 Lesion and procedural characteristics Variable Target coronary vessel Left anterior descending Left circumflex Right Preprocedure minimum lumen diameter (mm) Reference vessel diameter (mm) Lesion length (mm) Final postdilation balloon size (mm) Maximum postdilation pressure (atm) Final balloon/artery ratio Postprocedure minimum lumen diameter (mm)
SES DIRECT (n ⫽ 64)
SES Predilation (n ⫽ 51)
44% 27% 30% 1.0 ⫾ 0.4
53% 24% 24% 0.9 ⫾ 0.4
2.8 ⫾ 0.4 13.3 ⫾ 5.9 3.2 ⫾ 0.4 16.7 ⫾ 2.8 1.2 ⫾ 0.2 2.6 ⫾ 0.4
2.8 ⫾ 0.4 11.2 ⫾ 3.4 3.1 ⫾ 0.5 17.1 ⫾ 3.1 1.2 ⫾ 0.2 2.7 ⫾ 0.3
Values are means ⫾ SDs or percentages.
is a multicenter, prospective, nonrandomized trial examining the efficacy of direct coronary stenting without predilation using the sirolimus-eluting Bx-Velocity stent compared with a historical control (SIRolImUS-coated Bx Velocity balloon-expandable stent in the teatment of patients with de novo coronary artery lesions [SIRIUS] trial, in which a strategy of mandatory balloon predilation stenting with SESs was used).3,7 Enrolled patients had a single de novo lesion 15 to 30 mm in length, with a reference lumen diameter between 2.5 and 3.5 mm based on angiographic visual estimate. Patients with a history of myocardial infarction within the previous 24 hours were excluded unless the creatine kinase and creatine kinase-MB normalized. Other major exclusion criteria were patients with an ejection fraction ⬍25% or target lesion located in an ostial location, bifurcation, or significant unprotected left main disease, or in a vessel with excessive tortuosity, evidence of thrombus, or severe calcification that cannot be successfully treated with a direct stenting strategy. All SESs used in this study had a nominal diameter of 3.0 or 3.5 mm and length of 8 or 18 mm. All procedures for stent implantation, except direct stenting, were performed according to standard protocol as previously described.3 In case of failure with direct stent
Figure 1. Comparison of uniform expansion index (minimum stent area/ maximum stent area ⫻ 100) is presented. Values are means ⫾ SDs or percentages.
implantation, balloon predilation was allowed, with a balloon of short length and low inflation pressure, so that areas treated with the balloon were adequately covered by SESs. In the present study, the IVUS procedure was performed during the 8-month follow-up angiography. After intracoronary administration of nitroglycerin, IVUS images were acquired with automated pullback at 0.5 mm/s using 1 of 2 commercially available imaging systems (Boston Scientific Corporation, Natick, Massachusetts; Volcano Therapeutics, Rancho Cordova, California) and recorded on 0.5-in s-VHS videotape or CD for off-line quantitative analysis. The protocol was approved by the medical ethics committee of each institution, and written informed consent was obtained from all patients. All cineangiograms and IVUS measurements were obtained by analysts blinded to clinical and angiographic information. Using standard protocols, angiographic analysis was performed, including assessment of the minimal lumen diameter and reference vessel diameter. Lesion length was measured as the distance (millimeters) from the proximal to the distal shoulder in the angiographic projection with the least amount of foreshortening. Cross-sectional and volumetric IVUS analyses were performed using commercially available planimetry software (EchoPlaque, Indec Systems, Mountain View, California), according to previously validated and published protocols. In cross-sectional analyses, minimum lumen area and minimum stent area were measured in the stented segment. To evaluate axial variability in stent expansion, the uniform expansion index, defined as minimum stent area/maximum stent area ⫻ 100, was also calculated. In volumetric analyses, vessel, stent, lumen, and neointimal volumes were computed for the stented segment and 5-mm adjacent segments. To adjust for different stent lengths, volume index was calculated as volume divided by stent length. Percent neointimal volume was defined as neointimal volume index divided by stent volume index ⫻ 100. Average percent plaque burden was calculated as plaque volume divided by vessel volume ⫻ 100. To examine the neointimal distribution pattern, we calculated an average neointimal volume index of every 1-mm section within the entire stented segment in all cases using a single 18-mm SES for which 8-month follow-up volumetric IVUS analysis was available.
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Table 3 Intravascular ultrasound analyses at eight-month follow-up Variable
SES DIRECT (n ⫽ 64)
SES Predilation (n ⫽ 51)
5.4 ⫾ 1.9 5.1 ⫾ 2.0
5.5 ⫾ 1.8 4.9 ⫾ 1.9
13.9 ⫾ 4.4 6.5 ⫾ 1.9 6.4 ⫾ 2.0 0.20 ⫾ 0.34 3.7 ⫾ 7.0
15.0 ⫾ 3.8 6.8 ⫾ 2.0 6.7 ⫾ 2.0 0.17 ⫾ 0.30 3.1 ⫾ 5.3
2
Cross-sectional analysis (mm ) Minimum stent area Minimum lumen area Volumetric analysis (mm3/mm) Vessel volume index Stent volume index Lumen volume index Neointimal volume index Percent neointimal volume (%) Values are means ⫾ SDs.
Data are presented as mean ⫾ SD or frequencies. Statistical analysis was performed with StatView 5.0 (SAS Institute, Cary, North Carolina). Comparisons between groups were performed using unpaired Student’s t test for continuous variables or chi-square test for categorical variables. A p value ⬍0.05 was considered statistically significant. Overall, the DIRECT trial included 225 patients, and the SIRIUS trial (control group) included 1,101 patients. Among those assigned to the IVUS cohort, 85 became eligible for analyses from DIRECT and 96 from the control group. Crosssectional and volumetric measurements were comparable between the DIRECT and control groups. In these 2 participating trials, volumetric IVUS analysis at 8-month follow-up was completed for 64 patients from the DIRECT group and 51 patients from the control group. Patients’ clinical characteristics and procedural data are listed in Tables 1 and 2, respectively. All clinical and procedural characteristics, except percentage of smokers, were similar between groups. Although 10 patients (16%) required balloon predilation in the DIRECT group, postdilation strategies, including maximum balloon inflation pressure and final balloon/artery ratio, were also identical for the 2 groups. The DIRECT group achieved an equivalent uniform expansion index compared with the control group (Figure 1). At 8-month follow-up, there was no difference between the 2 groups with respect to all cross-sectional and volumetric IVUS parameters (Table 3). At 8-month follow-up, stent incomplete apposition was observed in 11 of 64 patients (17%) from the DIRECT group and 7 of 51 (14%) from the control group (p ⫽ NS). There was no difference in any volumetric IVUS parameter for the 5-mm adjacent segment to the proximal stent edge; however, percent plaque burden for the 5-mm distal adjacent segment was significantly smaller in the DIRECT than in the control group (Table 4). Thirty-four patients from the DIRECT group and 39 from the control group were eligible for analysis of neointimal distribution pattern within SESs. At 8-month followup, lumen, vessel, stent, and neointimal volume indexes were similar between the DIRECT and control groups (vessel volume index 14.0 ⫾ 4.2 vs 15.2 ⫾ 4.0; stent volume index 6.8 ⫾ 2.0 vs 6.9 ⫾ 2.0; lumen volume index 6.7 ⫾ 2.0 vs 6.8 ⫾ 2.1; neointimal volume index 0.14 ⫾ 0.24 vs 0.16 ⫾ 0.23 mm3/mm, p ⫽ NS for all). On average, there was no significant difference in the overall distribution pattern of neointimal hyperplasia between groups. There
Table 4 Adjacent segment intravascular ultrasound analyses at eight-month follow-up 8-Month Follow-up Proximal adjacent (5 mm) Lumen volume index (mm3/mm) Plaque volume index (mm3/mm) Vessel volume index (mm3/mm) Average percent plaque burden (%) Distal adjacent (5 mm) Lumen volume index (mm3/mm) Plaque volume index (mm3/mm) Vessel volume index (mm3/mm) Average percent plaque burden (%)
SES DIRECT
SES Predilation
7.6 ⫾ 2.6 6.8 ⫾ 2.8 14.6 ⫾ 4.0 47 ⫾ 13
7.3 ⫾ 2.6 6.8 ⫾ 2.4 14.3 ⫾ 3.9 48 ⫾ 12
6.7 ⫾ 2.7 4.1 ⫾ 2.5* 10.8 ⫾ 4.8 36 ⫾ 15†
6.3 ⫾ 2.4 5.2 ⫾ 2.6* 11.3 ⫾ 3.8 45 ⫾ 15†
Values are means ⫾ SDs. * p ⫽ 0.08; † p ⫽ 0.01.
Figure 2. Longitudinal average neointimal volume index within SESs (every 1 mm on an 18-mm stented segment) is presented.
was no difference in neointimal volume index within 3 mm from the proximal stent edge; however, at the distal 3 mm of the stent edge, neointimal volume index was significantly higher in the control than in the DIRECT group (Figure 2). Discussion The major findings of the present study are (1) a direct coronary stent strategy with SESs is equally effective in terms of uniform stent expansion and long-term quantitative IVUS results compared with stenting with predilation, and (2) this strategy appears to be associated with less neointimal hyperplasia near the distal stent edge. There have been concerns that direct coronary stenting with SESs may result in poor outcomes, perhaps due to damage to the stent surface coating or nonuniform stent expansion, thus limiting the effectiveness of the antiproliferative agent. However, the present IVUS study indicates that a direct stent strategy with SESs showed no apparent adverse results compared with the stent strategy with predilation. Direct stenting enables decreased utilization of contrast agent, equipment, and procedure time, translating to lower overall procedural cost.8 –12 In addition, the potential benefit of this strategy is
Coronary Artery Disease/Direct Coronary Stenting With SESs
that direct stenting may improve clinical outcomes, mainly by decreasing procedural vessel trauma and subsequent neointimal hyperplasia with respect to bare metal stents and SESs.4,6,12–17 Animal studies have indicated that balloon inflation causes nearly complete denudation of the endothelium, and this loss plays an important role in the pathogenesis of intimal thickening and, correspondingly, restenosis. Thus, direct stenting without predilation may avoid complete endothelial ablation, thus decreasing subsequent neointimal hyperplasia. In the present study, the direct stent strategy appears to be associated with less neointimal hyperplasia near the distal stent edge compared with a conventional stent strategy using predilation. This difference of neointimal distribution pattern may be 1 potential benefit of direct stent strategy with SESs. Assuming that neointimal hyperplasia response is in part proportional to vessel injury, a direct stent strategy may be able to decrease segments not receiving the antiproliferative agent by avoiding the geographic miss between the predilation and stenting segment. Therefore, it may result in less neointimal hyperplasia near the distal stent edge. However, a similar neointimal distribution pattern was still observed near the proximal stent edge in the 2 strategies. Mechanical factors may be associated with this phenomenon. Interventional devices, such as stent delivery systems, may potentially damage the endothelium in tracking to the lesion, thus resulting in a similar distribution of neointimal hyperplasia near the proximal edge in the 2 groups. In consequence, direct stent strategy may be associated with less neointimal hyperplasia near the distal stent edge, possibly by matching the injured and biologically treated segment. It may confirm previous findings primarily based on comparison with bare metal stents.16 The results of the present study are encouraging, suggesting that direct stenting with SESs may be a successful therapeutic approach in view of limited financial resources, increasing health consciousness, and overall efficacy of this strategy. Major limitations of this study are its nonrandomized design and the small number of patients in each group. The criteria for selecting lesions suitable for direct stenting were at the operator’s discretion; thus, patients with heavily calcified lesions or more tortuous stenoses were excluded. The results of this analysis apply only to select patients with 8-month volumetric IVUS available; therefore, some selection bias may exist. In addition, study results were compared with historical controls. 1. 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. 2. Serruys PW, Degertekin M, Tanabe K, Abizaid A, Sousa JE, Colombo A, Guagliumi G, Wijns W, Lindeboom WK, Ligthart J, et al. Intravascular ultrasound findings in the multicenter, randomized, doubleblind RAVEL (RAndomized study with the sirolimus-eluting VElocity
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balloon-expandable stent in the treatment of patients with de novo native coronary artery Lesions) trial. Circulation 2002;106:798 – 803. Moses JW, Leon MB, Popma JJ, Fitzgerald PJ, Holmes DR, O’Shaughnessy C, Caputo RP, Kereiakes DJ, Williams DO, Teirstein PS, et al. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med 2003;349: 1315–1323. Bonan R, Paiement P, Scortichini D, Cloutier MJ, Leung TK. Coronary restenosis: evaluation of a restenosis injury index in a swine model. Am Heart J 1993;126:1334 –1340. Hoffmann R, Mintz GS, Dussaillant GR, Popma JJ, Pichard AD, Satler LF, Kent KM, Griffin J, Leon MB. Patterns and mechanisms of in-stent restenosis. A serial intravascular ultrasound study. Circulation 1996;94:1247–1254. Rogers C, Parikh S, Seifert P, Edelman ER. Endogenous cell seeding. Remnant endothelium after stenting enhances vascular repair. Circulation 1996;94:2909 –2914. Ako J, Morino Y, Sonoda S, Terashima M, Hassan AH, Jaeger JL, C Perin EC, Wilensky RL, Yock PG, Moses JW, Fitzgerald PJ. Effect of sirolimus-eluting stents on neointimal hyperplasia: a serial in-stent IVUS interim analysis from the SIRIUS trial (abstr). Circulation 2002;106(suppl):II-520. Figulla HR, Mudra H, Reifart N, Werner GS. Direct coronary stenting without predilatation: a new therapeutic approach with a special balloon catheter design. Catheter Cardiovasc Diagn 1998;43:245–253. Danzi GB, Capuano C, Fiocca L, Dallavalle F, Pirelli S, Mauri L, Quaini E. Stent implantation without predilation in patients with a single, noncalcified coronary artery lesion. Am J Cardiol 1999;84: 1250 –1253. Briguori C, Sheiban I, De Gregorio J, Anzuini A, Montorfano M, Pagnotta P, Marsico F, Leonardo F, Di Mario C, Colombo A. Direct coronary stenting without predilation. J Am Coll Cardiol 1999;34: 1910 –1915. Brito FS Jr, Caixeta AM, Perin MA, Rati M, Arruda JA, Cantarelli M, Castello H Jr, Machado BM, Silva LA, Ribeiro EE, da Luz PL. Comparison of direct stenting versus stenting with predilation for the treatment of selected coronary narrowings. Am J Cardiol 2002;89: 115–120. Wilson SH, Berger PB, Mathew V, Bell MR, Garratt KN, Rihal CS, Bresnahan JF, Grill DE, Melby S, Holmes DR Jr. Immediate and late outcomes after direct stent implantation without balloon predilation. J Am Coll Cardiol 2000;35:937–943. Timurkaynak T, Ozdemir M, Cengel A, Ciftci H, Cemri M, Erdem G, Yalcin R, Boyaci B, Dortlemez O, Dortlemez H. Myocardial injury after apparently successful coronary stenting with or without balloon dilation: direct versus conventional stenting. J Invasive Cardiol 2002; 14:167–170. Carrie D, Khalife K, Citron B, Izaaz K, Hamon M, Juiliard JM, Leclercq F, Fourcade J, Lipiecki J, Sabatier R, et al. Comparison of direct coronary stenting with and without balloon predilatation in patients with stable angina pectoris. BET (Benefit Evaluation of Direct Coronary Stenting) Study Group. Am J Cardiol 2001;87:693– 698. Brueck M, Scheinert D, Wortmann A, Bremer J, von Korn H, Klinghammer L, Kramer W, Flachskampf FA, Daniel WG, Ludwig J. Direct coronary stenting versus predilatation followed by stent placement. Am J Cardiol 2002;90:1187–1192. Hoffmann R, Guagliumi G, Musumeci G, Reimers B, Petronio AS, Disco C, Amoroso G, Moses JW, Fitzgerald PJ, Schofer J, et al. Vascular response to sirolimus-eluting stents delivered with a nonaggressive implantation technique: comparison of intravascular ultrasound results from the multicenter, randomized E-SIRIUS, and SIRIUS trials. Catheter Cardiovasc Interv 2005;66:499 –506. Schluter M, Schofer J, Gershlick AH, Schampaert E, Wijns W, Breithardt G. Direct stenting of native de novo coronary artery lesions with the sirolimus-eluting stent: a post hoc subanalysis of the pooled E- and C-SIRIUS trials. J Am Coll Cardiol 2005;45:10 –13.
a Center for Research in Cardiovascular Intervention, Stanford University, Stanford, California; bScripps Memorial Hospital, La Jolla, California; c St. Joseph’s Hospital, Syracuse, New York; dHealth First Institution, Melbourne, Florida; eSt. John’s Hospital and Memorial Medical Center, Springfield, Illinois; fMinneapolis Heart Institute Foundation, Minneapolis, Minnesota; gNorth Ohio Heart Institute, Elyria, Ohio; hMethodist DeBakey Heart Center, Houston, Texas; iHospital of the University of Pennsylvania, Philadelphia, Pennsylvania; jRhode Island Hospital, Providence, Rhode Island; kNew York Presbyterian Hospital, New York, New York; lNew York-Presbyterian Hospital/Columbia University Medical Center, New York, New York. Manuscript received February 28, 2006; revised manuscript received and accepted June 20, 2006. *Corresponding author: Tel: 650-498-6034; fax: 650-498-6027. E-mail address: [email protected] (P.J. Fitzgerald).
0002-9149/06/$ – see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2006.06.046
and subsequent neointimal hyperplasia,4 – 6 because there is no predilation. Therefore, a direct stent strategy using sirolimus-eluting stents (SESs) may be associated with decreased in-stent neointimal hyperplasia, by preventing “geographic miss” between injured and stented vessel segments. However, some concerns have arisen regarding direct stenting of drug-eluting stents. Among these are the possible damage to the surface coating of the stent and nonuniform stent expansion, thereby disrupting the efficacy of the pharmacologic agent. Thus, the purpose of this intravascular ultrasound (IVUS) study was to evaluate the efficacy of the direct stent strategy using SESs, in terms of mechanical stent expansion and biologic vessel response, compared with conventional SESs using predilation. Methods and Results Patients enrolled in the Sirolimus-eluting Bx-Velocity balloon expandable stent with DIRECT stenting in the treatment of patients with de novo native coronary artery lesions (DIRECT) trial comprised the study sample. The DIRECT www.AJConline.org
Coronary Artery Disease/Direct Coronary Stenting With SESs
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Table 1 Baseline clinical characteristics Variable Age (yrs) Men Unstable angina pectoris Diabetes mellitus Hypertension† Dyslipidemia‡ Smoking
SES DIRECT (n ⫽ 64)
SES Predilation (n ⫽ 51)
63 ⫾ 12 73% 20% 27% 70% 82% 61%*
57 ⫾ 9 69% 15% 24% 71% 78% 20%*
Values are means ⫾ SDs or percentages. * p ⫽ 0.01. † Hypertension is defined as systolic/diastolic blood pressure level ⬎140/90 mm Hg. ‡ Dyslipidemia is defined as a low-density lipoprotein cholesterol level ⬎130 mg/dl. Table 2 Lesion and procedural characteristics Variable Target coronary vessel Left anterior descending Left circumflex Right Preprocedure minimum lumen diameter (mm) Reference vessel diameter (mm) Lesion length (mm) Final postdilation balloon size (mm) Maximum postdilation pressure (atm) Final balloon/artery ratio Postprocedure minimum lumen diameter (mm)
SES DIRECT (n ⫽ 64)
SES Predilation (n ⫽ 51)
44% 27% 30% 1.0 ⫾ 0.4
53% 24% 24% 0.9 ⫾ 0.4
2.8 ⫾ 0.4 13.3 ⫾ 5.9 3.2 ⫾ 0.4 16.7 ⫾ 2.8 1.2 ⫾ 0.2 2.6 ⫾ 0.4
2.8 ⫾ 0.4 11.2 ⫾ 3.4 3.1 ⫾ 0.5 17.1 ⫾ 3.1 1.2 ⫾ 0.2 2.7 ⫾ 0.3
Values are means ⫾ SDs or percentages.
is a multicenter, prospective, nonrandomized trial examining the efficacy of direct coronary stenting without predilation using the sirolimus-eluting Bx-Velocity stent compared with a historical control (SIRolImUS-coated Bx Velocity balloon-expandable stent in the teatment of patients with de novo coronary artery lesions [SIRIUS] trial, in which a strategy of mandatory balloon predilation stenting with SESs was used).3,7 Enrolled patients had a single de novo lesion 15 to 30 mm in length, with a reference lumen diameter between 2.5 and 3.5 mm based on angiographic visual estimate. Patients with a history of myocardial infarction within the previous 24 hours were excluded unless the creatine kinase and creatine kinase-MB normalized. Other major exclusion criteria were patients with an ejection fraction ⬍25% or target lesion located in an ostial location, bifurcation, or significant unprotected left main disease, or in a vessel with excessive tortuosity, evidence of thrombus, or severe calcification that cannot be successfully treated with a direct stenting strategy. All SESs used in this study had a nominal diameter of 3.0 or 3.5 mm and length of 8 or 18 mm. All procedures for stent implantation, except direct stenting, were performed according to standard protocol as previously described.3 In case of failure with direct stent
Figure 1. Comparison of uniform expansion index (minimum stent area/ maximum stent area ⫻ 100) is presented. Values are means ⫾ SDs or percentages.
implantation, balloon predilation was allowed, with a balloon of short length and low inflation pressure, so that areas treated with the balloon were adequately covered by SESs. In the present study, the IVUS procedure was performed during the 8-month follow-up angiography. After intracoronary administration of nitroglycerin, IVUS images were acquired with automated pullback at 0.5 mm/s using 1 of 2 commercially available imaging systems (Boston Scientific Corporation, Natick, Massachusetts; Volcano Therapeutics, Rancho Cordova, California) and recorded on 0.5-in s-VHS videotape or CD for off-line quantitative analysis. The protocol was approved by the medical ethics committee of each institution, and written informed consent was obtained from all patients. All cineangiograms and IVUS measurements were obtained by analysts blinded to clinical and angiographic information. Using standard protocols, angiographic analysis was performed, including assessment of the minimal lumen diameter and reference vessel diameter. Lesion length was measured as the distance (millimeters) from the proximal to the distal shoulder in the angiographic projection with the least amount of foreshortening. Cross-sectional and volumetric IVUS analyses were performed using commercially available planimetry software (EchoPlaque, Indec Systems, Mountain View, California), according to previously validated and published protocols. In cross-sectional analyses, minimum lumen area and minimum stent area were measured in the stented segment. To evaluate axial variability in stent expansion, the uniform expansion index, defined as minimum stent area/maximum stent area ⫻ 100, was also calculated. In volumetric analyses, vessel, stent, lumen, and neointimal volumes were computed for the stented segment and 5-mm adjacent segments. To adjust for different stent lengths, volume index was calculated as volume divided by stent length. Percent neointimal volume was defined as neointimal volume index divided by stent volume index ⫻ 100. Average percent plaque burden was calculated as plaque volume divided by vessel volume ⫻ 100. To examine the neointimal distribution pattern, we calculated an average neointimal volume index of every 1-mm section within the entire stented segment in all cases using a single 18-mm SES for which 8-month follow-up volumetric IVUS analysis was available.
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Table 3 Intravascular ultrasound analyses at eight-month follow-up Variable
SES DIRECT (n ⫽ 64)
SES Predilation (n ⫽ 51)
5.4 ⫾ 1.9 5.1 ⫾ 2.0
5.5 ⫾ 1.8 4.9 ⫾ 1.9
13.9 ⫾ 4.4 6.5 ⫾ 1.9 6.4 ⫾ 2.0 0.20 ⫾ 0.34 3.7 ⫾ 7.0
15.0 ⫾ 3.8 6.8 ⫾ 2.0 6.7 ⫾ 2.0 0.17 ⫾ 0.30 3.1 ⫾ 5.3
2
Cross-sectional analysis (mm ) Minimum stent area Minimum lumen area Volumetric analysis (mm3/mm) Vessel volume index Stent volume index Lumen volume index Neointimal volume index Percent neointimal volume (%) Values are means ⫾ SDs.
Data are presented as mean ⫾ SD or frequencies. Statistical analysis was performed with StatView 5.0 (SAS Institute, Cary, North Carolina). Comparisons between groups were performed using unpaired Student’s t test for continuous variables or chi-square test for categorical variables. A p value ⬍0.05 was considered statistically significant. Overall, the DIRECT trial included 225 patients, and the SIRIUS trial (control group) included 1,101 patients. Among those assigned to the IVUS cohort, 85 became eligible for analyses from DIRECT and 96 from the control group. Crosssectional and volumetric measurements were comparable between the DIRECT and control groups. In these 2 participating trials, volumetric IVUS analysis at 8-month follow-up was completed for 64 patients from the DIRECT group and 51 patients from the control group. Patients’ clinical characteristics and procedural data are listed in Tables 1 and 2, respectively. All clinical and procedural characteristics, except percentage of smokers, were similar between groups. Although 10 patients (16%) required balloon predilation in the DIRECT group, postdilation strategies, including maximum balloon inflation pressure and final balloon/artery ratio, were also identical for the 2 groups. The DIRECT group achieved an equivalent uniform expansion index compared with the control group (Figure 1). At 8-month follow-up, there was no difference between the 2 groups with respect to all cross-sectional and volumetric IVUS parameters (Table 3). At 8-month follow-up, stent incomplete apposition was observed in 11 of 64 patients (17%) from the DIRECT group and 7 of 51 (14%) from the control group (p ⫽ NS). There was no difference in any volumetric IVUS parameter for the 5-mm adjacent segment to the proximal stent edge; however, percent plaque burden for the 5-mm distal adjacent segment was significantly smaller in the DIRECT than in the control group (Table 4). Thirty-four patients from the DIRECT group and 39 from the control group were eligible for analysis of neointimal distribution pattern within SESs. At 8-month followup, lumen, vessel, stent, and neointimal volume indexes were similar between the DIRECT and control groups (vessel volume index 14.0 ⫾ 4.2 vs 15.2 ⫾ 4.0; stent volume index 6.8 ⫾ 2.0 vs 6.9 ⫾ 2.0; lumen volume index 6.7 ⫾ 2.0 vs 6.8 ⫾ 2.1; neointimal volume index 0.14 ⫾ 0.24 vs 0.16 ⫾ 0.23 mm3/mm, p ⫽ NS for all). On average, there was no significant difference in the overall distribution pattern of neointimal hyperplasia between groups. There
Table 4 Adjacent segment intravascular ultrasound analyses at eight-month follow-up 8-Month Follow-up Proximal adjacent (5 mm) Lumen volume index (mm3/mm) Plaque volume index (mm3/mm) Vessel volume index (mm3/mm) Average percent plaque burden (%) Distal adjacent (5 mm) Lumen volume index (mm3/mm) Plaque volume index (mm3/mm) Vessel volume index (mm3/mm) Average percent plaque burden (%)
SES DIRECT
SES Predilation
7.6 ⫾ 2.6 6.8 ⫾ 2.8 14.6 ⫾ 4.0 47 ⫾ 13
7.3 ⫾ 2.6 6.8 ⫾ 2.4 14.3 ⫾ 3.9 48 ⫾ 12
6.7 ⫾ 2.7 4.1 ⫾ 2.5* 10.8 ⫾ 4.8 36 ⫾ 15†
6.3 ⫾ 2.4 5.2 ⫾ 2.6* 11.3 ⫾ 3.8 45 ⫾ 15†
Values are means ⫾ SDs. * p ⫽ 0.08; † p ⫽ 0.01.
Figure 2. Longitudinal average neointimal volume index within SESs (every 1 mm on an 18-mm stented segment) is presented.
was no difference in neointimal volume index within 3 mm from the proximal stent edge; however, at the distal 3 mm of the stent edge, neointimal volume index was significantly higher in the control than in the DIRECT group (Figure 2). Discussion The major findings of the present study are (1) a direct coronary stent strategy with SESs is equally effective in terms of uniform stent expansion and long-term quantitative IVUS results compared with stenting with predilation, and (2) this strategy appears to be associated with less neointimal hyperplasia near the distal stent edge. There have been concerns that direct coronary stenting with SESs may result in poor outcomes, perhaps due to damage to the stent surface coating or nonuniform stent expansion, thus limiting the effectiveness of the antiproliferative agent. However, the present IVUS study indicates that a direct stent strategy with SESs showed no apparent adverse results compared with the stent strategy with predilation. Direct stenting enables decreased utilization of contrast agent, equipment, and procedure time, translating to lower overall procedural cost.8 –12 In addition, the potential benefit of this strategy is
Coronary Artery Disease/Direct Coronary Stenting With SESs
that direct stenting may improve clinical outcomes, mainly by decreasing procedural vessel trauma and subsequent neointimal hyperplasia with respect to bare metal stents and SESs.4,6,12–17 Animal studies have indicated that balloon inflation causes nearly complete denudation of the endothelium, and this loss plays an important role in the pathogenesis of intimal thickening and, correspondingly, restenosis. Thus, direct stenting without predilation may avoid complete endothelial ablation, thus decreasing subsequent neointimal hyperplasia. In the present study, the direct stent strategy appears to be associated with less neointimal hyperplasia near the distal stent edge compared with a conventional stent strategy using predilation. This difference of neointimal distribution pattern may be 1 potential benefit of direct stent strategy with SESs. Assuming that neointimal hyperplasia response is in part proportional to vessel injury, a direct stent strategy may be able to decrease segments not receiving the antiproliferative agent by avoiding the geographic miss between the predilation and stenting segment. Therefore, it may result in less neointimal hyperplasia near the distal stent edge. However, a similar neointimal distribution pattern was still observed near the proximal stent edge in the 2 strategies. Mechanical factors may be associated with this phenomenon. Interventional devices, such as stent delivery systems, may potentially damage the endothelium in tracking to the lesion, thus resulting in a similar distribution of neointimal hyperplasia near the proximal edge in the 2 groups. In consequence, direct stent strategy may be associated with less neointimal hyperplasia near the distal stent edge, possibly by matching the injured and biologically treated segment. It may confirm previous findings primarily based on comparison with bare metal stents.16 The results of the present study are encouraging, suggesting that direct stenting with SESs may be a successful therapeutic approach in view of limited financial resources, increasing health consciousness, and overall efficacy of this strategy. Major limitations of this study are its nonrandomized design and the small number of patients in each group. The criteria for selecting lesions suitable for direct stenting were at the operator’s discretion; thus, patients with heavily calcified lesions or more tortuous stenoses were excluded. The results of this analysis apply only to select patients with 8-month volumetric IVUS available; therefore, some selection bias may exist. In addition, study results were compared with historical controls. 1. 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. 2. Serruys PW, Degertekin M, Tanabe K, Abizaid A, Sousa JE, Colombo A, Guagliumi G, Wijns W, Lindeboom WK, Ligthart J, et al. Intravascular ultrasound findings in the multicenter, randomized, doubleblind RAVEL (RAndomized study with the sirolimus-eluting VElocity
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