- Email: [email protected]
Benestent Disease Trial (SCANDSTENT)
Interventional Cardiology
Comparison of sirolimus-eluting and bare metal stents in coronary bifurcation lesions: Subgroup analysis of the Stenting Coronary Arteries in Non-Stress/Benestent Disease Trial (SCANDSTENT) Leif Thuesen, MD,a Henning Kelb& &k, MD,b Lene Kløvgaard, RN,b Steffen Helqvist, MD,b Erik Jørgensen, MD,b b Samir Aljabbari, MD, Lars R. Krusell, MD,a Gunnar V.H. Jensen, MD,c Hans E. Bøtker, MD,a Kari Saunama¨ki, MD,b Jens F. Lassen, MD,a and Anton van Weert, PhD,d for the SCANDSTENT Investigators Skejby, Copenhagen and Roskilde, Denmark; and Leiden, The Netherlands
Background Sirolimus-eluting stent implantation improves the outcome in simple coronary artery lesions compared with bare metal stents, but there is limited evidence of their safety and efficacy when implanted in complex lesions like coronary bifurcations. Methods SCANDSTENT was a randomized controlled study comparing implantation of sirolimus-eluting stents with bare-metal stents in patients with complex coronary artery disease. This substudy evaluates the angiographic and clinical outcome of 126 patients with lesions located in a coronary bifurcation. Results The baseline characteristics of the patients were comparable: 15% had diabetes, and 1.7 stents were implanted per lesion. At follow-up, the minimum lumen diameter of the main branch was 2.35 mm in patients who received sirolimus-eluting stents compared with 1.68 mm in those who received bare-metal stents, and that of the side branch was 1.70 versus 1.19 mm (both P b .001). The late lumen loss in the main branch was 0.12 mm in the sirolimus-eluting stent group versus 0.99 mm in the bare-metal stent group and 0.03 versus 0.56 mm in the side branch (both P b .001). Thus, sirolimus-eluting stents reduced the restenosis rate from 28.3% to 4.9% in the main branch and from 43.4% to 14.8% in the side branches (both P b .001). Major adverse cardiac events occurred in 9% with sirolimus-eluting stents versus 28% with bare-metal stents ( P = .01), and stent thrombosis was observed in 0% versus 9% ( P = .02). Conclusion
Sirolimus-eluting stent implantation improves both the angiographic and clinical outcomes considerably compared with that of bare-metal stents in patients with stenoses located in coronary bifurcations. (Am Heart J 2006;152:114025.)
Percutaneous coronary intervention of atherosclerotic disease located in coronary bifurcations has always been challenging, as a high restenosis rate persists even after stent implantation. The introduction of polymer-based anti-inflammatory and antiproliferative drugs released in From the aSkejby Sygehus, Skejby, Denmark, bRigshospitalet, Copenhagen, Denmark, c Roskilde Amtssygehus, Roskilde, Denmark, and dHeart Core, Leiden, The Netherlands. Submitted February 14, 2006; accepted June 26, 2006. Conflict of interest and financial disclosures: The authors have received unrestricted research grants from Johnson and Johnson. Supported by grants from Boston Scientific, Johnson and Johnson, and Guidant and Medtronic. Reprint request: Henning Kelbæk, MD, Cardiac Cath. Lab. 2013, Rigshospitalet, DK2100 Copenhagen, Denmark. E-mail: [email protected] 0002-8703/$ - see front matter n 2006, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2006.06.035
a controlled manner from coronary stents has changed the treatment results of percutaneous coronary interventions considerably in patients with coronary artery disease.1-5 However, patients with certain complex lesions have routinely been excluded from most trials probably because of the combined fear of problems with obtaining a high procedural success rate and of the difficulties in interpreting the angiographic and clinical results. In a recent study, Colombo et al6 randomized patients to receive sirolimus-eluting stents in either the main branch only or in both the main and side branch of coronary artery bifurcations. The results of that study indicated that the restenosis rate was rather high in both groups, but a high rate of cross-over from the stent-inmain-branch-only group to the stent-in-both-branches group impaired the interpretation of the data. Accordingly, experts are reluctant to recommend the use of
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drug-eluting stents in certain coronary lesions and advise to await further investigations, before recommendations are made to implant drug-eluting stents in complex coronary lesions such as bifurcations.7 Therefore, we performed a randomized trial to evaluate the clinical and angiographic outcome after implantation of 1 or more sirolimus-eluting stents or bare-metal stents in patients with complex coronary artery lesions.8 The present study is a subgroup analysis of patients with a bifurcation lesion encompassed in that trial.
Methods Patients and study design Patients N18 years of age with stable or unstable angina or a recent non–ST-segment elevation myocardial infarction (MI) and who had 1 or more de novo lesion in native coronary bifurcation with a main branch of V4.0 mm and a side branch of N1.75 mm in diameter were included in the study. Major clinical exclusion criteria were a life expectancy of b1 year, allergy to any of the used pharmaceuticals, and MI of b3 days before the procedure. Angiographic exclusion criteria were lesions located in unprotected left main stem coronary arteries and lesions containing visible thrombus. The protocol was approved by the local ethics committee, and all patients provided written informed consent. The treatment schedule of SCANDSTENT has been explained in detail previously. Briefly, patients were pretreated with aspirin and clopidogrel. Heparin was administered to maintain the activated clotting time of N250 seconds during the procedure. Glycoprotein receptor antagonists were used at the discretion of the operator. Aspirin and clopidogrel were continued indefinitely and for 1 year after stent implantation, respectively. A repeat coronary angiography was scheduled after 6 months, and clinical follow-up was performed for 7 months. A nonscheduled angiogram performed 3 to 6 months after stent implantation replaced the 6-month angiogram.
Randomization and stent implantation Randomization was performed by computerized assignment with stratification with regard to sex and the presence of diabetes. The lesions were treated by standard percutaneous interventional methods without debulking. The treatment strategy was performed independently of whether bare-metal or drug-eluting stents were implanted. The bare-metal BX Velocity stent mounted on the balloon expandable sonic delivery system, or on the corresponding sirolimus-eluting Cypher stent (both from Cordis/Johnson and Johnson, Spring House, PA), was implanted in the lesions with N12 atm pressure. Stents were implanted in all main branches of the bifurcations, whereas side-branch treatment including stent implantation could be avoided whenever the residual diameter stenosis was b50% by visual evaluation. Side-branch treatment after stent implantation in the main branch should be finalized with a bkissing balloonQ maneuver. Both operator and patient were aware of the assigned treatment.
Quantitative coronary angiography Coronary angiograms were acquired in identical projections after intracoronary injection of nitroglycerin before,
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Table I. Baseline characteristics of the patients and the lesions Sirolimus-eluting Bare-metal stent (n = 68) stent (n = 58) Age (y) Male sex (%) Diabetes (%) Hypertension (%) Hyperlipidemia (%) Currently smoking (%) Family predisposition (%) Prior MI (%) Unstable angina (%) Left ventricular ejection fraction (%) Previous percutaneous or surgical intervention (%) Multivessel disease (%) Target lesion coronary artery (%) Left anterior descending artery/diagonal branch Left circumflex artery/marginal branch Posterolateral branch/posterior descending artery No. of stents Stented length
P
61 (8) 78 16 43 82 34 43 51 25 55 (13)
63 (10) 79 14 31 83 25 57 53 38 55 (11)
.28 .85 .71 .16 .95 .40 .12 .65 .12 .86
19
12
.28
40
45
.73 .50
77
65
.50
21
22
.50
2
13
1.8 (0.8) 29.8 (11.7)
1.6 (0.6) 24.6 (8.3)
.75 .006
Values are shown as mean (SD).
immediately after, and 6 months after stent implantation. All angiograms were analyzed by an independent core laboratory blinded to the treatment sequence and the clinical outcomes of the patients using the Medis computerized edge-detection system (Medis Medical Imaging System, Nuenen, Netherlands) with a special version for bifurcation analyses.9 The reference diameter of the main branches was determined by interpolation throughout the length of the lesion from a point proximal to the lesion to a point distal in the main branch distally to the side branch ostium. The reference diameter of the side branches was determined immediately distally to the lesion. Binary restenosis was present whenever the diameter stenosis was z50% at follow-up. Late lumen loss was calculated as the reduction in minimal lumen diameter from the index treatment to followup Angiographic lesion measures were made within 5 mm of the stent borders also in the side branches (at least 10 mm from the ostium in case a stent was not implanted).
Study end points The primary end point of the study was the difference in minimal lumen diameter in the target lesion at follow-up as determined by quantitative coronary angiography and analyzed by the independent core laboratory. Secondary end points were the rate of major adverse cardiac events: death, MI or target lesion revascularization in addition to late lumen loss, and the rate of binary restenosis at the 6-month angiogram.
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Table II. Quantitative coronary angiography Main vessel
Reference vessel diameter (mm) Minimal lumen diameter (mm) Before procedure After procedure At 6 m follow-up Diameter stenosis, % Before procedure After procedure At 6 m follow-up Late lumen loss (mm) Binary (N50%) restenosis (%)
Side branch
BMS (n = 57)
SES (n = 67)
P
BMS (n = 57)
SES (n = 67)
P
2.93 (0.43)
2.78 (0.49)
.08
2.22 (0.38)
2.21 (0.44)
.90
0.94 (0.43) 2.69 (0.55) 1.68 (0.85)
1.01 (0.61) 2.47 (0.46) 2.35 (0.55)
.49 .02 b.001
1.27 (0.54) 1.73 (0.62) 1.19 (0.61)
1.23 (0.66) 1.77 (0.57) 1.70 (0.65)
.67 .70 b.001
67.7 (14.9) 13.9 (9.5) 42.5 (26.9) 0.99 (0.81) 28.3
64.4 (20.6) 14.4 (9.6) 20.7 (15.2) 0.12 (0.55) 4.9
.33 .78 b.001 b.001 .001
41.5 (24.5) 26.1 (19.5) 45.1 (26.7) 0.56 (0.72) 43.4
43.4 (28.4) 24.5 (19.2) 28.0 (24.0) 0.03 (0.61) 14.8
.70 .66 b.001 b.001 .001
Values are shown as mean (SD).
Non–Q-wave and Q-wave MIs were defined as previously described.8 Target lesion revascularization was defined as repeat revascularization of the index lesion or the vessel that contained it in the presence of symptoms or signs of myocardial ischemia as judged by the clinical events committee. Stent thrombosis was defined as definite in case of angiographically visible signs of a contrast filling defect in the target lesion in connection with an acute coronary syndrome. A possible stent thrombosis was present in case of a sudden and unexpected death during the observation period that could not be ascribed to another cause.
Statistical analysis Comparison of categorical variables was analyzed by the m2 test or by the Fisher exact test. Continuous variables were analyzed using the Student t test for unpaired samples. The occurrence of adverse events was analyzed by the KaplanMeier method. Event-free survival curves were compared by the log-rank test. All P values were 2-sided.
Results The baseline characteristics and primary findings of SCANDSTENT have been described previously.8 There were 109 patients with a lesion type primarily categorized as a bifurcation. In addition, 17 complex lesions (primarily categorized as total occlusions or ostial lesions) were located in bifurcations and were therefore included in the present analysis. The angiographic data of 2 patients were precluded from the analyses because of technical issues. Thus, clinical data of 126 patients and angiographic data of 124 patients were available for the present study.
Procedural and patient characteristics The demographic baseline characteristics of the 2 patient groups were comparable and only the stented segment was slightly longer in the sirolimus-eluting stent group (Table I). We implanted 1.8 versus 1.6 stents per lesion in the sirolimus-eluting stent group versus the
bare-metal stent group ( P = .75), and stents were implanted in 37 (55%) and 30 patients (53%) of the side branches, respectively ( P = .90). The mean length of the main branch lesions was 16.6 mm in the sirolimuseluting stent group versus 14.4 mm in the bare-metal stent group ( P = .14) and 4.7 versus 5.4 mm in the side branches ( P = .41). The corresponding length of segments stented with sirolimus-eluting stents and bare-metal stents in the main branches was 21.7 and 19.1 mm ( P = .25) and in the side branches 14.6 and 10.4 mm, respectively ( P = .15).
Angiographic findings Follow-up coronary angiography was available in 91.9% of the patients. The patient groups were well matched with regard to angiographic findings (Table II). The minimal lumen diameter of both the main and side branch was approximately 40% larger at follow-up in patients treated with sirolimus-eluting stents. Thus, in the main branches, late lumen loss was considerably lower in patients treated with sirolimus-eluting stents than in those who received bare-metal stents. In the side branches, late lumen loss was also reduced remarkably with sirolimus-eluting stents compared with bare-metal stents, although stents were only implanted in approximately one half of the cases. Fourteen side branches were left with a residual stenosis of N50% (1 with a stent) because the operator judged that further attempts to improve the side branch lesion would imply a risk of jeopardizing the main branch result. At follow-up, 5 (63%) of these residual stenoses in the sirolimus-eluting stent group and 2 (33%) in the bare-metal stent group were resolved to b50% diameter stenosis. Compared with baremetal stents, sirolimus-eluting stents reduced the restenosis rate from 28.8% to 4.8% in the main branch and from 43.4% to 14.8% in the side branches (both P b .001). Of 32 patients who had restenosis in the side branch at follow-up, 5 (16%) had a drug-eluting stent and 16 (50%)
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Figure 1
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Figure 2
Clinical outcome in patients with bifurcation lesions during 7 months of follow-up. Hierarchical ranking. Kaplan-Meier estimates of event-free survival among patients who received sirolimus-eluting and bare-metal stents.
a bare-metal stent implanted ( P b .01). Side branch instent restenosis occurred in 14% of the drug-eluting stents versus 53% of bare-metal stents ( P b .001). Four patients who had sirolimus-eluting stents implanted developed restenosis, all 4 in the side branch and 3 of these in the main vessel as well. One of these was initially treated with bV stening,Q 1 with bT stenting,Q and 2 had stents implanted in the main vessel only. In patients who had bare-metal stents implanted, 81% developed restenosis after V stenting, 75% after using the side-branch bcrushQ stent technique, and 43% after implantation of a stent in the main vessel only ( P b .01). Of those who had a stent implanted in the side branch, 77% in the bare-metal stent group and 18% in the drugeluting stent group developed restenosis ( P b .001). Late loss was 0.96 mm in side branches in which a baremetal stent had been implanted versus 0.24 mm in those with a sirolimus-eluting stent ( P = .001). In side branches that were not stented, the corresponding figures were 0.07 and 0.25 mm, respectively ( P b .01).
Clinical outcomes The clinical outcomes of the patients are shown in Figure 1. The rate of death and MI was insignificantly different in the 2 groups, whereas target lesion revascularization was performed in 4 cases (5.9%) in the sirolimus-eluting stent group, 3 in both the main vessel and side branch, and 1 in only the side branch compared with 16 cases (28.1%) in the bare-metal stent group, 9 in both, 4 in only the main vessel, and 3 in only the side branch ( P b .001). The diameter stenosis in patients who were revascularized was 73% in the bare-metal stent group and 63% in the sirolimus-eluting stent groups. There were no acute stent thromboses within 24 hours after stent implantation. There were 5 cases of stent thrombosis in the bare-metal stent group, of which 3 occurred subacutely and 2 lately. All patients received
dual antiplatelet therapy when the stent thromboses occurred. The stent techniques used in these 5 patients were as follows: stent in the main branch only in 2, side branch crush stenting in 2, and Y stenting in 1. All patients had taken clopidogrel or ticlopidine for at least 3 months. Kaplan-Meier estimates of freedom from major adverse cardiac events are shown in Figure 2.
Discussion Coronary bifurcation lesions represent an unresolved problem for catheter-based treatment of ischemic heart disease, and despite the introduction of newly developed bifurcation-designed devices and drug-eluting stents, the angiographic restenosis rates and frequency of adverse cardiac events remain high.10-12 SCANDSTENT was a randomized, controlled study that showed the beneficial effect of drug-eluting stents compared with bare-metal stents in a large series of entirely complex coronary artery lesions.8 The superiority of the sirolimus-eluting stent was evident in all subgroups of patients, and among patients who had received the drug-eluting stent, target lesion revascularization was only necessary in those with bifurcation lesions. The main result of the present study is that drugeluting stents can be implanted safely in lesions located in bifurcation lesion, that neointimal hyperplasia is suppressed to a relevant extent by these stents during the succeeding 6 months, and that they can be used without the occurrence of stent thrombosis. Percutaneous treatment of bifurcation lesions results in a higher rate of restenosis and major adverse cardiac events compared with nonbifurcation lesions, whether or not stents are implanted.13 Despite the fact that 3 of
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1144 Thuesen et al
the side-branch stenoses in the sirolimus-eluting stent group (4 in the bare-metal stent group) observed at the follow-up angiograms in the present study were actually residual stenoses from the initial treatment rather than restenoses, sirolimus-eluting stents reduced the restenosis rate in both the main and side branches. Five of the residual stenoses in the sirolimus-eluting stent group (2 in the bare-metal stent group) were actually resolved. Stents were implanted in approximately half of the side branches in both groups to obtain an optimal immediate result. Still, side-branch restenosis occurred in only 15% of the patients in the sirolimus-eluting stent group compared with 43% in the bare-metal stent group. Our results demonstrated an 83% relative restenosis reduction in the main branch and a 66% reduction in side branches in patients who had sirolimus-eluting stents implanted in comparison with those who had received bare-metal stents. Our results in the drug-eluting stent group are at least as favorable as those reported by Colombo et al,6 who found a restenosis rate of 17% in the group who did not have a stent in the side branch and 28% in those who received sirolimus-eluting stents in both branches. A high frequency of cross-over from the group who was expected to have stent in the main branch only probably biased the outcome in the doublestent group in that trial. The high frequency of in-stent restenosis in side branches after implantation of baremetal stents in the present study indicates that their use in such lesions should be restricted. Despite treatment with clopidogrel for 12 months in all patients, stent thrombosis occurred in 5 patients (8.8%), all of whom had received bare-metal stents in their lesions. This is a considerably higher level of stent thrombosis than that previously reported in larger series and indicates that bifurcation stenting is associated with a higher risk of this potentially dangerous event.14-17 We observed no cases of stent thrombosis in patients who received sirolimus-eluting stents, which is in accordance with the findings of Jeremias et al18 who reported a stent thrombosis rate of b1% in a consecutive series of sirolimus-eluting stent implantations that involved 20% of bifurcations. Still, another large register reported recently that stent implantation in bifurcation lesions is an independent risk factor for stent thrombosis.19 Diabetes was present in 37% of their patients, whereas the frequency of diabetes in our study is lower. On the other hand, Sabate´ et al20 found a similar reduction in the restenosis rate induced by sirolimus-eluting stents in diabetic patients, both insulin-dependent and those treated with oral medication without any case of stent thrombosis. In the randomized study by Colombo et al,6 stent thrombosis occurred in 6.3% of those who received 2 stents. The challenge to treat coronary bifurcation stenoses lies in the side branch, and a wide range of techniques and equipment have been developed to overcome the
problem of stenting both branches without a temporary loss of guidewire access to one of the branches.21 The technique that crushes the side-branch stent might seem advantageous in some cases. However, the long-term results even with the use of drug-eluting stents seem markedly worse than those reported in the present study.12,22 It seems preferable to use a technique that allows access to the vascular bed located distal to the lesion (main and side branch) in case of restenosis or development of de novo lesions distally to the treated bifurcation.23 However, no single technique may apply to all problems encompassed in bifurcation lesion treatment.
Study limitations The trial was randomized but not blinded. So both patients and interventionalists were aware of which stent type was used. On the other hand, all angiograms were analyzed by an independent core laboratory, and all clinical events were adjudicated by a clinical events committee that did not have access to the randomization code. The decision to implant a stent in the side branches was performed at the discretion of the operator who aimed at a final angiographic result with b50% residual stenosis in both branches. The study was initiated by the investigators, and sponsorships were offered from stent manufacturers without dedication to this specific trial. Conclusions Together with the results of other trials, the present findings indicate that drug-eluting stents can be used safely and efficiently in both simple and complex coronary artery lesions. A high frequency of restenosis after implantation of bare-metal stents especially in side branches suggests a limitation of their use in bifurcation lesions. Risk factors for development of restenosis have to be revisited in the drug-eluting stent era.
References 1. Morice M-C, Serruys PW, Sousa JE, et al. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med 2002;346:1773 - 80. 2. Moses JW, Leon MB, Popma JJ, et al. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med 2003;349:1315 - 23. 3. Colombo A, Drzewiecki J, Banning A, et al. Randomized study to assess the effectiveness of slow- and moderate-release polymerbased paclitaxel-eluting stent for coronary artery lesions. Circulation 2003;108:788 - 94. 4. Stone GW, Ellis SG, Cannon L, et al. Comparison of a polymerbased paclitaxel-eluting stent with a bare metal stent in patients with complex coronary artery disease. JAMA 2005;294: 1215 - 1223. 5. Stone GW, Ellis SG, Cox DA, et al. A polymer-based, paclitaxeleluting stent in patients with coronary artery disease. N Engl J Med 2004;350:221 - 31.
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6. Colombo A, Moses J, Morice MC, et al. Randomized study to evaluate sirolimus-eluting stents implanted at coronary bifurcation lesions. Circulation 2004;109:1244 - 9. 7. Silber S, Albertsson P, Avile´s FF, et al. Guidelines for percutaneous coronary interventions. The Task Force for Percutaneous Coronary Intervention of the European Society of Cardiology. Eur Heart J 2005;26:804 - 47. 8. Kelb&k H, Thuesen L, Helqvist S, et al. Randomized multicenter comparison of sirolimus versus bare metal stent implantation in patients with complex coronary lesions. J Am Coll Cardiol 2006;47:449 - 55. 9. van Weert A, Lesperance J, Reiber JHC. Standardization of central off-line quantitative image analysis: implications from experiences with quantitative coronary angiography. Heart Drug 2001;1:44 - 51. 10. Williams DO, Abbott JD. Bifurcation intervention. Is it crush time yet? J Am Coll Cardiol 2005;46:621 - 4. 11. Lefe`vre T, Ormiston J, Guagliumi G, et al. The FRONTIER stent registry. Safety and feasibility of a novel dedicated stent for the treatment of bifurcation coronary artery lesions. J Am Coll Cardiol 2005;46:592 - 8. 12. Ge L, Airoldi F, Iakovou I, et al. Clinical and angiographic outcome after implantation of drug-eluting stents in bifurcation lesions with the crush stent technique. J Am Coll Cardiol 2005;46: 613 - 20. 13. Garot P, Lefe`vre T, Savage M, et al. Nine-month outcome of patients treated by percutaneous coronary interventions for bifurcation lesions in the recent era. J Am Coll Cardiol 2005;46:606 - 12. 14. Bavry AA, Kumbhani DJ, Helton TJ, et al. What is the risk of stent thrombosis associated with the use of paclitaxel-eluting stents for percutaneous coronary intervention? J Am Coll Cardiol 2005;45:941 - 6.
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15. Bavry AA, Kumbhani DJ, Helton TJ, et al. Risk of thrombosis with the use of sirolimus-eluting stents for percutaneous coronary intervention (from registry and clinical trial data). Am J Cardiol 2005; 95:1469 - 72. 16. Moreno R, Fernandez C, Hernandez R, et al. Drug-eluting stent thrombosis. Results from a pooled analysis including 10 randomized studies. J Am Coll Cardiol 2005;45:954 - 9. 17. Ong ATL, Hoye A, Aoki J, et al. Thirty-day incidence and six-month clinical outcome of thrombotic stent occlusion after bare-metal, sirolimus, or paclitaxel stent implantation. J Am Coll Cardiol 2005;45:947 - 53. 18. Jeremias A, Sylvia B, Bridges J, et al. Stent thrombosis after successful sirolimus-eluting stent implantation. Circulation 2004; 109:1930 - 2. 19. Kuchulakanti PK, Chu WW, Torguson R, et al. Correlates and longterm outcomes of angiographically proven stent thrombosis with sirolimus- and paclitaxel-eluting stents. Circulation 2006; 113:1108 - 13. 20. Sabate´ M, Jime´nez-Quevedo P, Angiolillo DJ, et al. Randomized comparison of sirolimus-eluting stent versus standard stent for percutaneous coronary revascularization in diabetic patients. Circulation 2005;112:2175 - 83. 21. Louvard Y, Lefe`vre T, Morice M-C. Percutaneous coronary intervention for bifurcation coronary disease. Heart 2004; 90:713 - 22. 22. Costa RA, Mintz GS, Carlier SG, et al. Bifurcation coronary lesions treated with the bcrushQ technique. J Am Coll Cardiol 2005;46:599 - 605. 23. Helqvist S, Jbrgensen E, Kelb&k H, et al. Percutaneous treatment of coronary bifurcation lesions: a novel Qextended-YQ technique with complete lesion stent coverage using drug eluting stents. Heart 2006;92:981 - 2.
Comparison of sirolimus-eluting and bare metal stents in coronary bifurcation lesions: Subgroup analysis of the Stenting Coronary Arteries in Non-Stress/Benestent Disease Trial (SCANDSTENT) Leif Thuesen, MD,a Henning Kelb& &k, MD,b Lene Kløvgaard, RN,b Steffen Helqvist, MD,b Erik Jørgensen, MD,b b Samir Aljabbari, MD, Lars R. Krusell, MD,a Gunnar V.H. Jensen, MD,c Hans E. Bøtker, MD,a Kari Saunama¨ki, MD,b Jens F. Lassen, MD,a and Anton van Weert, PhD,d for the SCANDSTENT Investigators Skejby, Copenhagen and Roskilde, Denmark; and Leiden, The Netherlands
Background Sirolimus-eluting stent implantation improves the outcome in simple coronary artery lesions compared with bare metal stents, but there is limited evidence of their safety and efficacy when implanted in complex lesions like coronary bifurcations. Methods SCANDSTENT was a randomized controlled study comparing implantation of sirolimus-eluting stents with bare-metal stents in patients with complex coronary artery disease. This substudy evaluates the angiographic and clinical outcome of 126 patients with lesions located in a coronary bifurcation. Results The baseline characteristics of the patients were comparable: 15% had diabetes, and 1.7 stents were implanted per lesion. At follow-up, the minimum lumen diameter of the main branch was 2.35 mm in patients who received sirolimus-eluting stents compared with 1.68 mm in those who received bare-metal stents, and that of the side branch was 1.70 versus 1.19 mm (both P b .001). The late lumen loss in the main branch was 0.12 mm in the sirolimus-eluting stent group versus 0.99 mm in the bare-metal stent group and 0.03 versus 0.56 mm in the side branch (both P b .001). Thus, sirolimus-eluting stents reduced the restenosis rate from 28.3% to 4.9% in the main branch and from 43.4% to 14.8% in the side branches (both P b .001). Major adverse cardiac events occurred in 9% with sirolimus-eluting stents versus 28% with bare-metal stents ( P = .01), and stent thrombosis was observed in 0% versus 9% ( P = .02). Conclusion
Sirolimus-eluting stent implantation improves both the angiographic and clinical outcomes considerably compared with that of bare-metal stents in patients with stenoses located in coronary bifurcations. (Am Heart J 2006;152:114025.)
Percutaneous coronary intervention of atherosclerotic disease located in coronary bifurcations has always been challenging, as a high restenosis rate persists even after stent implantation. The introduction of polymer-based anti-inflammatory and antiproliferative drugs released in From the aSkejby Sygehus, Skejby, Denmark, bRigshospitalet, Copenhagen, Denmark, c Roskilde Amtssygehus, Roskilde, Denmark, and dHeart Core, Leiden, The Netherlands. Submitted February 14, 2006; accepted June 26, 2006. Conflict of interest and financial disclosures: The authors have received unrestricted research grants from Johnson and Johnson. Supported by grants from Boston Scientific, Johnson and Johnson, and Guidant and Medtronic. Reprint request: Henning Kelbæk, MD, Cardiac Cath. Lab. 2013, Rigshospitalet, DK2100 Copenhagen, Denmark. E-mail: [email protected] 0002-8703/$ - see front matter n 2006, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2006.06.035
a controlled manner from coronary stents has changed the treatment results of percutaneous coronary interventions considerably in patients with coronary artery disease.1-5 However, patients with certain complex lesions have routinely been excluded from most trials probably because of the combined fear of problems with obtaining a high procedural success rate and of the difficulties in interpreting the angiographic and clinical results. In a recent study, Colombo et al6 randomized patients to receive sirolimus-eluting stents in either the main branch only or in both the main and side branch of coronary artery bifurcations. The results of that study indicated that the restenosis rate was rather high in both groups, but a high rate of cross-over from the stent-inmain-branch-only group to the stent-in-both-branches group impaired the interpretation of the data. Accordingly, experts are reluctant to recommend the use of
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drug-eluting stents in certain coronary lesions and advise to await further investigations, before recommendations are made to implant drug-eluting stents in complex coronary lesions such as bifurcations.7 Therefore, we performed a randomized trial to evaluate the clinical and angiographic outcome after implantation of 1 or more sirolimus-eluting stents or bare-metal stents in patients with complex coronary artery lesions.8 The present study is a subgroup analysis of patients with a bifurcation lesion encompassed in that trial.
Methods Patients and study design Patients N18 years of age with stable or unstable angina or a recent non–ST-segment elevation myocardial infarction (MI) and who had 1 or more de novo lesion in native coronary bifurcation with a main branch of V4.0 mm and a side branch of N1.75 mm in diameter were included in the study. Major clinical exclusion criteria were a life expectancy of b1 year, allergy to any of the used pharmaceuticals, and MI of b3 days before the procedure. Angiographic exclusion criteria were lesions located in unprotected left main stem coronary arteries and lesions containing visible thrombus. The protocol was approved by the local ethics committee, and all patients provided written informed consent. The treatment schedule of SCANDSTENT has been explained in detail previously. Briefly, patients were pretreated with aspirin and clopidogrel. Heparin was administered to maintain the activated clotting time of N250 seconds during the procedure. Glycoprotein receptor antagonists were used at the discretion of the operator. Aspirin and clopidogrel were continued indefinitely and for 1 year after stent implantation, respectively. A repeat coronary angiography was scheduled after 6 months, and clinical follow-up was performed for 7 months. A nonscheduled angiogram performed 3 to 6 months after stent implantation replaced the 6-month angiogram.
Randomization and stent implantation Randomization was performed by computerized assignment with stratification with regard to sex and the presence of diabetes. The lesions were treated by standard percutaneous interventional methods without debulking. The treatment strategy was performed independently of whether bare-metal or drug-eluting stents were implanted. The bare-metal BX Velocity stent mounted on the balloon expandable sonic delivery system, or on the corresponding sirolimus-eluting Cypher stent (both from Cordis/Johnson and Johnson, Spring House, PA), was implanted in the lesions with N12 atm pressure. Stents were implanted in all main branches of the bifurcations, whereas side-branch treatment including stent implantation could be avoided whenever the residual diameter stenosis was b50% by visual evaluation. Side-branch treatment after stent implantation in the main branch should be finalized with a bkissing balloonQ maneuver. Both operator and patient were aware of the assigned treatment.
Quantitative coronary angiography Coronary angiograms were acquired in identical projections after intracoronary injection of nitroglycerin before,
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Table I. Baseline characteristics of the patients and the lesions Sirolimus-eluting Bare-metal stent (n = 68) stent (n = 58) Age (y) Male sex (%) Diabetes (%) Hypertension (%) Hyperlipidemia (%) Currently smoking (%) Family predisposition (%) Prior MI (%) Unstable angina (%) Left ventricular ejection fraction (%) Previous percutaneous or surgical intervention (%) Multivessel disease (%) Target lesion coronary artery (%) Left anterior descending artery/diagonal branch Left circumflex artery/marginal branch Posterolateral branch/posterior descending artery No. of stents Stented length
P
61 (8) 78 16 43 82 34 43 51 25 55 (13)
63 (10) 79 14 31 83 25 57 53 38 55 (11)
.28 .85 .71 .16 .95 .40 .12 .65 .12 .86
19
12
.28
40
45
.73 .50
77
65
.50
21
22
.50
2
13
1.8 (0.8) 29.8 (11.7)
1.6 (0.6) 24.6 (8.3)
.75 .006
Values are shown as mean (SD).
immediately after, and 6 months after stent implantation. All angiograms were analyzed by an independent core laboratory blinded to the treatment sequence and the clinical outcomes of the patients using the Medis computerized edge-detection system (Medis Medical Imaging System, Nuenen, Netherlands) with a special version for bifurcation analyses.9 The reference diameter of the main branches was determined by interpolation throughout the length of the lesion from a point proximal to the lesion to a point distal in the main branch distally to the side branch ostium. The reference diameter of the side branches was determined immediately distally to the lesion. Binary restenosis was present whenever the diameter stenosis was z50% at follow-up. Late lumen loss was calculated as the reduction in minimal lumen diameter from the index treatment to followup Angiographic lesion measures were made within 5 mm of the stent borders also in the side branches (at least 10 mm from the ostium in case a stent was not implanted).
Study end points The primary end point of the study was the difference in minimal lumen diameter in the target lesion at follow-up as determined by quantitative coronary angiography and analyzed by the independent core laboratory. Secondary end points were the rate of major adverse cardiac events: death, MI or target lesion revascularization in addition to late lumen loss, and the rate of binary restenosis at the 6-month angiogram.
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Table II. Quantitative coronary angiography Main vessel
Reference vessel diameter (mm) Minimal lumen diameter (mm) Before procedure After procedure At 6 m follow-up Diameter stenosis, % Before procedure After procedure At 6 m follow-up Late lumen loss (mm) Binary (N50%) restenosis (%)
Side branch
BMS (n = 57)
SES (n = 67)
P
BMS (n = 57)
SES (n = 67)
P
2.93 (0.43)
2.78 (0.49)
.08
2.22 (0.38)
2.21 (0.44)
.90
0.94 (0.43) 2.69 (0.55) 1.68 (0.85)
1.01 (0.61) 2.47 (0.46) 2.35 (0.55)
.49 .02 b.001
1.27 (0.54) 1.73 (0.62) 1.19 (0.61)
1.23 (0.66) 1.77 (0.57) 1.70 (0.65)
.67 .70 b.001
67.7 (14.9) 13.9 (9.5) 42.5 (26.9) 0.99 (0.81) 28.3
64.4 (20.6) 14.4 (9.6) 20.7 (15.2) 0.12 (0.55) 4.9
.33 .78 b.001 b.001 .001
41.5 (24.5) 26.1 (19.5) 45.1 (26.7) 0.56 (0.72) 43.4
43.4 (28.4) 24.5 (19.2) 28.0 (24.0) 0.03 (0.61) 14.8
.70 .66 b.001 b.001 .001
Values are shown as mean (SD).
Non–Q-wave and Q-wave MIs were defined as previously described.8 Target lesion revascularization was defined as repeat revascularization of the index lesion or the vessel that contained it in the presence of symptoms or signs of myocardial ischemia as judged by the clinical events committee. Stent thrombosis was defined as definite in case of angiographically visible signs of a contrast filling defect in the target lesion in connection with an acute coronary syndrome. A possible stent thrombosis was present in case of a sudden and unexpected death during the observation period that could not be ascribed to another cause.
Statistical analysis Comparison of categorical variables was analyzed by the m2 test or by the Fisher exact test. Continuous variables were analyzed using the Student t test for unpaired samples. The occurrence of adverse events was analyzed by the KaplanMeier method. Event-free survival curves were compared by the log-rank test. All P values were 2-sided.
Results The baseline characteristics and primary findings of SCANDSTENT have been described previously.8 There were 109 patients with a lesion type primarily categorized as a bifurcation. In addition, 17 complex lesions (primarily categorized as total occlusions or ostial lesions) were located in bifurcations and were therefore included in the present analysis. The angiographic data of 2 patients were precluded from the analyses because of technical issues. Thus, clinical data of 126 patients and angiographic data of 124 patients were available for the present study.
Procedural and patient characteristics The demographic baseline characteristics of the 2 patient groups were comparable and only the stented segment was slightly longer in the sirolimus-eluting stent group (Table I). We implanted 1.8 versus 1.6 stents per lesion in the sirolimus-eluting stent group versus the
bare-metal stent group ( P = .75), and stents were implanted in 37 (55%) and 30 patients (53%) of the side branches, respectively ( P = .90). The mean length of the main branch lesions was 16.6 mm in the sirolimuseluting stent group versus 14.4 mm in the bare-metal stent group ( P = .14) and 4.7 versus 5.4 mm in the side branches ( P = .41). The corresponding length of segments stented with sirolimus-eluting stents and bare-metal stents in the main branches was 21.7 and 19.1 mm ( P = .25) and in the side branches 14.6 and 10.4 mm, respectively ( P = .15).
Angiographic findings Follow-up coronary angiography was available in 91.9% of the patients. The patient groups were well matched with regard to angiographic findings (Table II). The minimal lumen diameter of both the main and side branch was approximately 40% larger at follow-up in patients treated with sirolimus-eluting stents. Thus, in the main branches, late lumen loss was considerably lower in patients treated with sirolimus-eluting stents than in those who received bare-metal stents. In the side branches, late lumen loss was also reduced remarkably with sirolimus-eluting stents compared with bare-metal stents, although stents were only implanted in approximately one half of the cases. Fourteen side branches were left with a residual stenosis of N50% (1 with a stent) because the operator judged that further attempts to improve the side branch lesion would imply a risk of jeopardizing the main branch result. At follow-up, 5 (63%) of these residual stenoses in the sirolimus-eluting stent group and 2 (33%) in the bare-metal stent group were resolved to b50% diameter stenosis. Compared with baremetal stents, sirolimus-eluting stents reduced the restenosis rate from 28.8% to 4.8% in the main branch and from 43.4% to 14.8% in the side branches (both P b .001). Of 32 patients who had restenosis in the side branch at follow-up, 5 (16%) had a drug-eluting stent and 16 (50%)
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Figure 1
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Figure 2
Clinical outcome in patients with bifurcation lesions during 7 months of follow-up. Hierarchical ranking. Kaplan-Meier estimates of event-free survival among patients who received sirolimus-eluting and bare-metal stents.
a bare-metal stent implanted ( P b .01). Side branch instent restenosis occurred in 14% of the drug-eluting stents versus 53% of bare-metal stents ( P b .001). Four patients who had sirolimus-eluting stents implanted developed restenosis, all 4 in the side branch and 3 of these in the main vessel as well. One of these was initially treated with bV stening,Q 1 with bT stenting,Q and 2 had stents implanted in the main vessel only. In patients who had bare-metal stents implanted, 81% developed restenosis after V stenting, 75% after using the side-branch bcrushQ stent technique, and 43% after implantation of a stent in the main vessel only ( P b .01). Of those who had a stent implanted in the side branch, 77% in the bare-metal stent group and 18% in the drugeluting stent group developed restenosis ( P b .001). Late loss was 0.96 mm in side branches in which a baremetal stent had been implanted versus 0.24 mm in those with a sirolimus-eluting stent ( P = .001). In side branches that were not stented, the corresponding figures were 0.07 and 0.25 mm, respectively ( P b .01).
Clinical outcomes The clinical outcomes of the patients are shown in Figure 1. The rate of death and MI was insignificantly different in the 2 groups, whereas target lesion revascularization was performed in 4 cases (5.9%) in the sirolimus-eluting stent group, 3 in both the main vessel and side branch, and 1 in only the side branch compared with 16 cases (28.1%) in the bare-metal stent group, 9 in both, 4 in only the main vessel, and 3 in only the side branch ( P b .001). The diameter stenosis in patients who were revascularized was 73% in the bare-metal stent group and 63% in the sirolimus-eluting stent groups. There were no acute stent thromboses within 24 hours after stent implantation. There were 5 cases of stent thrombosis in the bare-metal stent group, of which 3 occurred subacutely and 2 lately. All patients received
dual antiplatelet therapy when the stent thromboses occurred. The stent techniques used in these 5 patients were as follows: stent in the main branch only in 2, side branch crush stenting in 2, and Y stenting in 1. All patients had taken clopidogrel or ticlopidine for at least 3 months. Kaplan-Meier estimates of freedom from major adverse cardiac events are shown in Figure 2.
Discussion Coronary bifurcation lesions represent an unresolved problem for catheter-based treatment of ischemic heart disease, and despite the introduction of newly developed bifurcation-designed devices and drug-eluting stents, the angiographic restenosis rates and frequency of adverse cardiac events remain high.10-12 SCANDSTENT was a randomized, controlled study that showed the beneficial effect of drug-eluting stents compared with bare-metal stents in a large series of entirely complex coronary artery lesions.8 The superiority of the sirolimus-eluting stent was evident in all subgroups of patients, and among patients who had received the drug-eluting stent, target lesion revascularization was only necessary in those with bifurcation lesions. The main result of the present study is that drugeluting stents can be implanted safely in lesions located in bifurcation lesion, that neointimal hyperplasia is suppressed to a relevant extent by these stents during the succeeding 6 months, and that they can be used without the occurrence of stent thrombosis. Percutaneous treatment of bifurcation lesions results in a higher rate of restenosis and major adverse cardiac events compared with nonbifurcation lesions, whether or not stents are implanted.13 Despite the fact that 3 of
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the side-branch stenoses in the sirolimus-eluting stent group (4 in the bare-metal stent group) observed at the follow-up angiograms in the present study were actually residual stenoses from the initial treatment rather than restenoses, sirolimus-eluting stents reduced the restenosis rate in both the main and side branches. Five of the residual stenoses in the sirolimus-eluting stent group (2 in the bare-metal stent group) were actually resolved. Stents were implanted in approximately half of the side branches in both groups to obtain an optimal immediate result. Still, side-branch restenosis occurred in only 15% of the patients in the sirolimus-eluting stent group compared with 43% in the bare-metal stent group. Our results demonstrated an 83% relative restenosis reduction in the main branch and a 66% reduction in side branches in patients who had sirolimus-eluting stents implanted in comparison with those who had received bare-metal stents. Our results in the drug-eluting stent group are at least as favorable as those reported by Colombo et al,6 who found a restenosis rate of 17% in the group who did not have a stent in the side branch and 28% in those who received sirolimus-eluting stents in both branches. A high frequency of cross-over from the group who was expected to have stent in the main branch only probably biased the outcome in the doublestent group in that trial. The high frequency of in-stent restenosis in side branches after implantation of baremetal stents in the present study indicates that their use in such lesions should be restricted. Despite treatment with clopidogrel for 12 months in all patients, stent thrombosis occurred in 5 patients (8.8%), all of whom had received bare-metal stents in their lesions. This is a considerably higher level of stent thrombosis than that previously reported in larger series and indicates that bifurcation stenting is associated with a higher risk of this potentially dangerous event.14-17 We observed no cases of stent thrombosis in patients who received sirolimus-eluting stents, which is in accordance with the findings of Jeremias et al18 who reported a stent thrombosis rate of b1% in a consecutive series of sirolimus-eluting stent implantations that involved 20% of bifurcations. Still, another large register reported recently that stent implantation in bifurcation lesions is an independent risk factor for stent thrombosis.19 Diabetes was present in 37% of their patients, whereas the frequency of diabetes in our study is lower. On the other hand, Sabate´ et al20 found a similar reduction in the restenosis rate induced by sirolimus-eluting stents in diabetic patients, both insulin-dependent and those treated with oral medication without any case of stent thrombosis. In the randomized study by Colombo et al,6 stent thrombosis occurred in 6.3% of those who received 2 stents. The challenge to treat coronary bifurcation stenoses lies in the side branch, and a wide range of techniques and equipment have been developed to overcome the
problem of stenting both branches without a temporary loss of guidewire access to one of the branches.21 The technique that crushes the side-branch stent might seem advantageous in some cases. However, the long-term results even with the use of drug-eluting stents seem markedly worse than those reported in the present study.12,22 It seems preferable to use a technique that allows access to the vascular bed located distal to the lesion (main and side branch) in case of restenosis or development of de novo lesions distally to the treated bifurcation.23 However, no single technique may apply to all problems encompassed in bifurcation lesion treatment.
Study limitations The trial was randomized but not blinded. So both patients and interventionalists were aware of which stent type was used. On the other hand, all angiograms were analyzed by an independent core laboratory, and all clinical events were adjudicated by a clinical events committee that did not have access to the randomization code. The decision to implant a stent in the side branches was performed at the discretion of the operator who aimed at a final angiographic result with b50% residual stenosis in both branches. The study was initiated by the investigators, and sponsorships were offered from stent manufacturers without dedication to this specific trial. Conclusions Together with the results of other trials, the present findings indicate that drug-eluting stents can be used safely and efficiently in both simple and complex coronary artery lesions. A high frequency of restenosis after implantation of bare-metal stents especially in side branches suggests a limitation of their use in bifurcation lesions. Risk factors for development of restenosis have to be revisited in the drug-eluting stent era.
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