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Comparison of Outcomes of Drug-Eluting Stents Versus Bare-Metal Stents in Nonostial Proximal Left Anterior Descending Coronary Arteries
Comparison of Outcomes of Drug-Eluting Stents Versus Bare-Metal Stents in Nonostial Proximal Left Anterior Descending Coronary Arteries Laurent Bonello, MD, Axel De Labriolle, MD, Gilles Lemesle, MD, Probal Roy, MD, Daniel H. Steinberg, MD, Tina L. Pinto Slottow, MD, Zhenyi Xue, MS, Rebecca Torguson, MPH, Kimberly Kaneshige, BS, William O. Suddath, MD, Lowell F. Satler, MD, Kenneth M. Kent, MD, Joseph Lindsay, MD, Augusto D. Pichard, MD, and Ron Waksman, MD* Drug-eluting stents (DES) have reduced the rate of in-stent restenosis compared with bare-metal stents, but are associated with an increased risk of late stent thrombosis. The proximal left anterior descending artery (LAD) is a large vessel and is considered to be at increased risk of both restenosis and stent thrombosis. The risk-benefit ratio of each type of stent therefore is of great clinical interest in this location. The aim was to compare 1-year outcomes of DESs and bare-metal stents in nonostial proximal LADs. Historic cohorts of patients who underwent percutaneous coronary intervention of nonostial proximal LAD lesions were compared. A total of 137 patients in the bare-metal stent group and 350 patients in the DES group were compared. The primary and secondary end points were target-lesion revascularization (TLR) rate and major adverse cardiac event rate, including death, myocardial infarction and TLR at 1-year follow-up. Patients in both groups had similar baseline characteristics. Intravascular ultrasound guidance was used in most percutaneous coronary intervention (bare-metal stents vs DESs 72.4% vs 74.5%; p ⴝ 0.6). Stent diameter was large in both groups (3.2 ⴞ 0.5 vs 3.2 ⴞ 0.3 mm; p ⴝ 0.6). Patients in the DES group had longer stents implanted (15 ⴞ 7 vs 17 ⴞ 7 mm; p <0.01). Major adverse cardiac event and TLR rates were not different (bare-metal stents vs DESs 16.4% vs 14.7%; p ⴝ 0.7 and 4.5% vs 5.2%; p ⴝ 0.8). In multivariate analysis, the TLR rate was independent of type of stent used. In conclusion, DESs carry no clinical benefit over bare-metal stents for nonostial proximal LAD lesions. Bare-metal stents therefore could be a cost-effective alternative in this location. © 2009 Elsevier Inc. All rights reserved. (Am J Cardiol 2009; 103:496 –500) To date, no study has compared the use of drug-eluting stents (DESs) and bare-metal stents in patients undergoing nonostial proximal left anterior descending (LAD) percutaneous coronary interventions. We hypothesized that because a nonostial proximal LAD is a large vessel, there may be no advantage associated with DES implantation. We aimed to compare 1-year outcomes of patients with baremetal stents with those with DESs who underwent nonostial proximal LAD percutaneous coronary intervention. Methods Under a protocol approved by the institutional review board, the existing percutaneous coronary intervention database in our institution was used to identify all patients who underwent percutaneous coronary intervention of a nonostial proximal LAD. Nonostial proximal LAD was defined as any lesion beginning ⱖ3 mm distally to the LAD ostium, to exclude ostial disease, to either the first septal or first diagDepartment of Internal Medicine, Division of Cardiology, Washington Hospital Center, Washington, DC. Manuscript received August 8, 2008; revised manuscript received and accepted October 7, 2008. *Corresponding author: Tel: 202-877-2812; fax: 202-877-2715. E-mail address: [email protected] (R. Waksman). 0002-9149/09/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2008.10.028
onal according to the Coronary Artery Surgery Study classification. The bare-metal stent group was a historic cohort of 137 nonselected patients who underwent nonostial proximal LAD lesion percutaneous coronary intervention from January 2002 to January 2003 (before DES approval). In this group, bare-metal stents were used in all treated lesions. The DES group included 350 consecutive unselected patients undergoing nonostial proximal LAD percutaneous coronary intervention from January 2003 to January 2005 using a paclitaxel- or sirolimus-eluting stent. In this group, DESs were used in all treated lesions. Exclusion criteria were ST-elevation myocardial infarction, cardiogenic shock, previous coronary bypass graft surgery, or restenotic lesion. Patients in the DES group who had a bare-metal stent placed for another lesion were also excluded. Contemporary percutaneous coronary intervention was performed according to guidelines current at the time of implantation. In all cases, the interventional strategy, including the use of direct stenting, pre-/postdilatation, intravascular ultrasound (IVUS), choice of periprocedural adjunctive antiplatelet therapy, and use of ablative devices was at the discretion of the physician. Angiographic success was defined as stenosis ⱕ30% with Thrombolysis In Myocardial Infarction flow grade 3. All patients received aspirin www.AJConline.org
Coronary Artery Disease/DES vs BMS in Proximal LAD Table 1 Baseline characteristics Variable Age (yrs) Men Body mass index (kg/m2) Current smoker Diabetes mellitus Insulin use Hyperlipidemia Systemic hypertension Peripheral vascular disease Previous myocardial infarction Unstable angina pectoris Left ventricular ejection fraction Dialysis
497
Table 2 Angiographic and interventional data (lesion based) Bare-Metal Stent (n ⫽ 137)
DES (n ⫽ 350)
p Value
Variable
64 ⫾ 11 91 (66.4%) 29.5 ⫾ 5.8 24 (17.5%) 38 (27.7%) 10 (7.3%) 113 (85%) 101 (73.7%) 16 (12.1%) 38 (29.2%) 85 (62%) 0.49 ⫾ 0.16 4 (3%)
64 ⫾ 12 243 (69.4%) 29.2 ⫾ 6 63 (18%) 118 (34%) 43 (12.4%) 293 (84.4%) 252 (72%) 50 (14.5%) 77 (23.1%) 182 (52%) 0.5 ⫾ 0.15 6 (1.7%)
0.9 0.5 0.7 0.9 0.2 0.1 0.9 0.7 0.5 0.2 0.045 0.6 0.5
No. of treated vessels Type A Type B1B2 Type C LAD intervention procedures Stenosis pre-PCI (%) Stenosis post-PCI (%) Rotational atherectomy IVUS used Stent diameter (mm) Stent length (mm) Angiographic success
Values expressed as mean ⫾ SD or number (percent).
325 mg/day ⱖ24 hours before the procedure and continued this regimen indefinitely. Additional antiplatelet therapy with clopidogrel 75 mg/day (after a loading dose of 300 or 600 mg) was instituted in all patients. For all patients with an acute coronary syndrome, clopidogrel was recommended for ⱖ12 months. For stable patients, clopidogrel maintenance therapy was recommended for 3 months in the baremetal stent era and 6 months in the DES era. Intraprocedural anticoagulation was ensured using unfractionated heparin or bivalirudin. Glycoprotein IIb/IIIa inhibitors were used at the operator’s discretion and according to guidelines. The primary end point was defined as the rate of targetlesion revascularization (TLR) at 1 year. Other recorded events were major adverse cardiac events, including death, myocardial infarction, and target-vessel revascularization. Death was defined as all causes of mortality. Myocardial infarction was defined as a total creatinine kinase increase ⱖ2 times normal and/or creatinine kinase-MB ⱖ20 ng/ml with or without new pathologic Q waves in ⱖ2 contiguous leads. TLR and target-vessel revascularization were characterized as repeated percutaneous or surgical intervention of the treated lesion or vessel and were clinically driven, respectively. Acute (ⱕ24 hours) and subacute (⬎1 to 30 days) stent thromboses were defined as evidence of angiographic thrombus of the target lesion.1 Because late stent thrombosis was not recorded in the bare-metal stent era, to evaluate this rate, a composite end point of death and myocardial infarction was used to compare the rate of cumulative stent thrombosis between bare-metal stents and DESs at 1-year follow-up. A dedicated data coordinating center (Data Center, MedStar Research Institute, Washington, DC) performed all data management and analyses. Prespecified clinical and laboratory data during hospitalization periods were obtained from hospital charts reviewed by independent research personnel who were unaware of the study objectives. The occurrence of major late clinical events was recorded, including death (all-cause), myocardial infarction, TLR, target-vessel revascularization, and stent thrombosis. All clinical events were adjudicated by source documentation by independent physicians who were not involved in the procedures.
Bare-Metal Stent (n ⫽ 273)
DES (n ⫽ 595)
p Value
1.9 ⫾ 0.9 30 (12%) 147 (58.8%) 73 (29.2%) (n ⫽ 137) 0.89 ⫾ 0.11 0.05 ⫾ 0.2 16 (5.9%) 186 (72.4%) 3.2 ⫾ 0.5 15 ⫾ 7 133 (97%)
1.7 ⫾ 0.8 49 (8.2%) 430 (72.2%) 97 (19.6%) (n ⫽ 350) 0.88 ⫾ 0.11 0.04 ⫾ 0.1 18 (5.1%) 260 (74.5%) 3.2 ⫾ 0.3 17 ⫾ 7 345 (98.6%)
0.2 0.2
0.4 0.5 0.6 0.6 0.6 ⬍0.01 0.5
PCI ⫽ percutaneous coronary intervention. Values expressed as mean ⫾ SD or number (percent).
Table 3 In-hospital and 1-month outcomes Outcome In-hospital Death Myocardial infarction Urgent target-vessel revascularization Subacute thrombosis 1-Month follow-up Death Myocardial infarction Target-vessel revascularization TLR Major adverse cardiac events
Bare-Metal Stent DES p Value (n ⫽ 137) (n ⫽ 350) 4 (2.9%) 0 (0%) 3 (2.2%)
5 (1.4%) 1 (0.3%) 6 (1.7%)
0.5 1 0.7
1 (0.7%)
3 (0.9%)
0.7
4 (2.9%) 1 (0.7%) 0 (0%) 0 (0%) 5 (3.6%)
5 (1.4%) 2 (0.6%) 4 (1.1%) 2 (0.6%) 5 (1.4%)
0.5 1 0.6 1 0.2
Statistical analysis was performed using the Statistical Analysis System, version 8.2 (SAS Institute, Inc., Cary, North Carolina). Data were expressed as mean ⫾ SD for continuous variables and percentages for categorical variables. Student’s t test was used to compare continuous variables, and chi-square test or Fischer’s exact test was used to compare categorical variables. Event-free survival curves were constructed using the Kaplan-Meier method. Cox proportional hazard analysis was used to identify predictors of TLR. Cox proportional regression models were used to control for differences between the bare-metal stent and DES groups, with final results expressed as adjusted hazard ratios. Results Baseline characteristics are listed in Table 1. Patients in both groups had similar baseline characteristics. Patients in the bare-metal stent group more frequently presented with unstable angina pectoris (62% vs 52%; p ⫽ 0.045). Angiographic and procedural data are listed in Table 2. The number of diseased vessels was high in both groups (baremetal stents vs DESs 1.9 ⫾ 0.9 vs 1.7 ⫾ 0.8; p ⫽ 0.2). In the DES group, 65.5% of implanted stents were sirolimus-
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Figure 1. One-year outcomes. BMS ⫽ bare-metal stent; MACE ⫽ major adverse cardiac event; MI ⫽ myocardial infarction; TVR ⫽ target-vessel revascularization.
In-hospital and 30-day outcomes are listed in Table 3. The bare-metal stent and DES groups had similar in-hospital outcomes. At 1 month and 1 year, no difference in outcome was observed between the 2 groups. In particular, the rate of major adverse cardiac events was similar (baremetal stents vs DESs 3.6% vs 1.4%; p ⫽ 0.2 and 16.4% vs 14.7%; p ⫽ 0.7, respectively; Figure 1). Rates of death and myocardial infarction at 1 year were similar in both groups (7.4% vs 6.1%; p ⫽ 0.6). Rates of target-vessel revascularization and TLR at 1 year were also identical in both groups (9% vs 8.6%; p ⫽ 0.9 and 4.5% vs 5.2%, p ⫽ 0.8, respectively). The Kaplan-Meier curve showed similar survival free of both TLR and major adverse cardiac events between the 2 types of stents (Figure 2). Univariate and multivariate analyses of predictors of TLR at 1-year follow-up in univariate analysis included age, systemic hypertension, diabetes mellitus, number of diseased vessels, IVUS use, and length and diameter of the stent and were associated with TLR at 1-year follow-up with p ⬍0.2. In multivariate analysis, diabetes mellitus and stent diameter were the only variables significantly associated with TLR, with hazard ratios of 1.4 (95% confidence interval 1.2 to 1.9, p ⫽ 0.02) and 0.4 (95% confidence interval 0.2 to 1, p ⫽ 0.04), respectively. Discussion
Figure 2. Kaplan-Meier 1-year survival free of major adverse cardiac events and TLR. Abbreviations as in Figure 1.
eluting stents and 34.5% were paclitaxel-eluting stents. Mean stent length was longer in the DES group (15 ⫾ 6 vs 17 ⫾ 7 mm; p ⬍0.01). Discharge medications were similar in the 2 groups. In particular, rates of patients discharged on aspirin and thienopyridine therapies were identical (baremetal stents vs DESs 97.7% vs 97.9%; p ⫽ 0.8 and 96.4% vs 97%; p ⫽ 0.9, respectively).
The present study suggested that bare-metal stents and DESs had similar 1-year outcomes in patients with nonostial proximal LAD lesions. Both efficacy measured using TLR and safety measured using death and myocardial infarction were similar at 1-year follow-up in the 2 groups. Proximal LAD stenting is of major prognostic value because this artery supplies a large part of the myocardium. The balance of safety and efficacy for each stent type had to be established because studies have shown that this artery had increased risk of restenosis and stent thrombosis.2,3 Results of the present study were therefore of major clinical interest to optimize the risk-benefit ratio and reduce the cost-effectiveness of percutaneous coronary intervention in patients with nonostial proximal LAD lesions. Previous studies have shown that ostial lesions had a higher restenosis rate and benefited from DES use.4 In addition, ostial percutaneous coronary intervention results were highly dependent on the technique applied.5,6 We therefore excluded ostial LAD lesions from the present study. A subgroup analysis of the TAXUS IV trial was the only available data comparing DESs and bare-metal stents in patients undergoing proximal LAD percutaneous coronary intervention to date. This analysis suggested a decreased rate of major adverse cardiac events with the use of DESs compared with bare-metal stents.7 However, the rate of major adverse cardiac events in the bare-metal stent group was 22.1%, which was higher than in the present report (14.6%) or other published reports.8 –10 Such differences may be related to several design and procedural differences between the TAXUS IV trial subgroup analysis and the present study. First, ostial lesions were included in the TAXUS IV trial, which may explain the higher TLR rate observed in the bare-metal stent group. Second, it must be noted that half the patients in the TAXUS IV trial had
Coronary Artery Disease/DES vs BMS in Proximal LAD
angiographic follow-up, which may be associated with an increased rate of target lesion revascularization and may therefore have overestimated the major adverse cardiac event rate in the bare-metal stent group. Third, the mean diameter of the stent implanted in the subgroup analysis of patients undergoing proximal LAD percutaneous coronary intervention was 2.8 mm in TAXUS IV trial, which is less than the 3.2 mm used in the present study. The difference in stent diameter may be related to the extensive use of IVUS in the present study. IVUS studies have shown that the proximal LAD had a mean minimum lumen area of 7 mm2, which corresponded to a mean minimal vessel diameter of 3 mm.11 In addition, IVUS use allowed more accurate determination of a vessel’s diameter compared with angiography, thus preventing stent undersizing. Accordingly, a previous study has shown that IVUS-guided percutaneous coronary intervention was associated with an increase in mean stent diameter compared with angiographically guided percutaneous coronary intervention.12 Several studies performed in the bare-metal stent era have shown that IVUS-guided percutaneous coronary intervention decreased the rate of restenosis, which may explain the particularly low rate of restenosis in our group of patients treated with bare-metal stents together with the high rate of IVUS guidance.13–15 Therefore, the high rate of events in the TAXUS IV trial may have been related to use of a stent with a relatively small diameter in such a large vessel. Finally, use of a large stent in the present study may be responsible for the low rates of TLR and major adverse cardiac events observed in the bare-metal stent group and the lack of difference between the DES and bare-metal stent group. Previous studies observed that in large vessels (ⱖ3.5 mm), bare-metal stents and DESs had similar major adverse cardiac event and TLR rates.16,17 Similarly, the Basel Stent Cost Effectiveness Trial (BASKET) showed that DESs were not associated with clinical benefit in vessels with a diameter ⬎3 mm.18 Delayed endothelialization resulting from the antiproliferative action of the eluting drugs has been associated with the occurrence of late stent thrombosis.19 Recent studies have suggested a slight, but constant, increase in the rate of stent thrombosis over time with DESs compared with bare-metal stents, with an incidence of 0.6% vs 0.25% per year, respectively.20 In the present study, there was no difference in rates of stent thrombosis at 30 days or death and myocardial infarction at 1 year between DESs and bare-metalstents.ThecurrentAmericanCollegeofCardiology/ American Heart Association guidelines advocate that DESs be considered an alternative to bare-metal stents in patients for whom clinical trials indicated a favorable effectiveness/ safety profile.21 In the present study, we observed no difference in rates of major adverse cardiac events for patients with nonostial proximal LAD between DESs and bare-metal stents. These findings suggest that in patients with proximal LAD lesions, when the ostium is not involved, use of bare-metal stents could be cost-effective. The present study had several limitations, including its retrospective design and the small number of patients included. A prospective randomized trial is warranted to determine which type of stent is cost-effective in this location.
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1. Cutlip DE, Windecker S, Mehran R, Boam A, Cohen DJ, van Es GA, Steg PG, Morel MA, Mauri L, Vranckx P, et al; Academic Research Consortium. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation 2007;115:2344 –2351. 2. Roy P, Torguson R, Okabe T, Pinto Slottow TL, Steinberg DH, Smith K, Xue Z, Satler LF, Pichard AD, Waksman R. Angiographic and procedural correlates of stent thrombosis after intracoronary implantation of drug-eluting stents. J Interv Cardiol 2007;20:307–313. 3. Roy P, Okabe T, Pinto Slottow TL, Steinberg DH, Smith K, Torguson R, Xue Z, Gevorkian N, Satler LF, Kent KM, et al. Correlates of clinical restenosis following intracoronary implantation of drug-eluting stents. Am J Cardiol 2007;100:965–969. 4. Mavromatis K, Ghazzal Z, Veledar E, Diamandopoulos L, Weintraub WS, Douglas JS, Kalynych AM. Comparison of outcomes of percutaneous coronary intervention of ostial versus nonostial narrowing of the major epicardial coronary arteries. Am J Cardiol 2004;94:583–587. 5. Cubeddu RJ, Wood FO, Saylors EK, Mann T. Isolated disease of the ostium left anterior descending or circumflex artery: management using a left main stenting technique. Clinical outcome at 2 years. J Invasive Cardiol 2007;19:457– 461. 6. Seung KB, Kim YH, Park DW, Lee BK, Lee CW, Hong MK, Kim PJ, Chung WS, Tahk SJ, Park SW, Park SJ. Effectiveness of sirolimuseluting stent implantation for the treatment of ostial left anterior descending artery stenosis with intravascular ultrasound guidance. J Am Coll Cardiol 2005;46:787–792. 7. Stone GW, Ellis SG, Cox DA, Hermiller J, O’Shaughnessy C, Mann JT, Turco M, Caputo R, Bergin P, Greenberg J, Popma JJ, Russell ME; TAXUS-IV Investigators. A polymer-based, paclitaxel-eluting stent in patients with coronary artery disease. N Engl J Med 2004;350:221– 231. 8. Iakovou I, Dangas G, Mehran R, Lansky AJ, Stamou SC, Pfister AJ, Dullum MK, Leon MB, Corso PJ. Minimally invasive direct coronary artery bypass (MIDCAB) versus coronary artery stenting for elective revascularization of the left anterior descending artery. Am J Cardiol 2002;90:885– 887. 9. Drenth DJ, Veeger NJ, Winter JB, Grandjean JG, Mariani MA, Boven van AJ, Boonstra PW. A prospective randomized trial comparing stenting with off-pump coronary surgery for high-grade stenosis in the proximal left anterior descending coronary artery: three-year followup. J Am Coll Cardiol 2002;40:1955–1960. 10. Shirai K, Lansky AJ, Mehran R, Dangas GD, Costantini CO, Fahy M, Slack S, Mintz GS, Stone GW, Leon MB. Minimally invasive coronary artery bypass grafting versus stenting for patients with proximal left anterior descending coronary artery disease. Am J Cardiol 2004; 93:959 –962. 11. Ge J, Erbel R, Gerber T, Görge G, Koch L, Haude M, Meyer J. Intravascular ultrasound imaging of angiographically normal coronary arteries: a prospective study in vivo. Br Heart J 1994;71:572–578. 12. St. Goar FG, Pinto FJ, Alderman EL, Fitzgerald PJ, Stadius ML, Popp RL. Intravascular ultrasound imaging of angiographically normal coronary arteries: an in vivo comparison with quantitative angiography. J Am Coll Cardiol 1991;18:952–958. 13. Fitzgerald PJ, Oshima A, Hayase M, Metz JA, Bailey SR, Baim DS, Cleman MW, Deutsch E, Diver DJ, Leon MB, et al. Final results of the Can Routine Ultrasound Influence Stent Expansion (CRUISE) Study. Circulation 2000;102:523–530. 14. Schiele F, Meneveau N, Vuillemenot A, Zhang DD, Gupta S, Mercier M, Danchin N, Bertrand B, Bassand JP. Impact of intravascular ultrasound guidance in stent deployment on 6-month restenosis rate: a multicenter, randomized study comparing two strategies—with and without intravascular ultrasound guidance. RESIST Study Group. REStenosis after Ivus guided STenting. J Am Coll Cardiol 1998; 32:320 –328. 15. Oemrawsingh PV, Mintz GS, Schalij MJ, Zwinderman AH, Jukema JW, van der Wall EE; TULIP Study. Thrombocyte activity evaluation and effects of Ultrasound guidance in Long Intracoronary stent Placement. Intravascular ultrasound guidance improves angiographic and clinical outcome of stent implantation for long coronary artery stenoses: final results of a randomized comparison with angiographic guidance (TULIP Study). Circulation 2003;107:62– 67. 16. Steinberg DH, Mishra S, Javaid A, Slottow TL, Buch AN, Roy P, Okabe T, Smith KA, Torguson R, Xue Z, et al. Comparison of
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effectiveness of bare metal stents versus drug-eluting stents in large (⬎ or ⫽ 3.5 mm) coronary arteries. Am J Cardiol 2007;99:599 – 602. 17. Quizhpe AR, Feres F, de Ribamar Costa J Jr., Abizaid A, Maldonado G, Costa R, Abizaid A, Cano M, Moreira AC, Staico R, et al. Drugeluting stents vs bare metal stents for the treatment of large coronary vessels. Am Heart J 2007;154:373–378. 18. Brunner-La Rocca HP, Kaiser C, Pfisterer M; BASKET Investigators. Targeted stent use in clinical practice based on evidence from the Basel Stent Cost Effectiveness Trial (BASKET). Eur Heart J 2007; 28:719 –725. 19. Finn AV, Joner M, Nakazawa G, Kolodgie F, Newell J, John MC, Gold HK, Virmani R. Pathological correlates of late drug-eluting stent
thrombosis: strut coverage as a marker of endothelialization. Circulation 2007;115:2435–2441. 20. Daemen J, Wenaweser P, Tsuchida K, Abrecht L, Vaina S, Morger C, Kukreja N, Jüni P, Sianos G, Hellige G, et al. Early and late coronary stent thrombosis of sirolimus-eluting and paclitaxel-eluting stents in routine clinical practice: data from a large two-institutional cohort study. Lancet 2007;369:667– 678. 21. King SB III, Smith SC Jr., Hirshfeld JW Jr., Jacobs AK, Morrison DA, Williams DO, Feldman TE, Kern MJ, O’Neill WW, Schaff HV, et al. 2007 Focused update of the ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2008;51:172–209.
onal according to the Coronary Artery Surgery Study classification. The bare-metal stent group was a historic cohort of 137 nonselected patients who underwent nonostial proximal LAD lesion percutaneous coronary intervention from January 2002 to January 2003 (before DES approval). In this group, bare-metal stents were used in all treated lesions. The DES group included 350 consecutive unselected patients undergoing nonostial proximal LAD percutaneous coronary intervention from January 2003 to January 2005 using a paclitaxel- or sirolimus-eluting stent. In this group, DESs were used in all treated lesions. Exclusion criteria were ST-elevation myocardial infarction, cardiogenic shock, previous coronary bypass graft surgery, or restenotic lesion. Patients in the DES group who had a bare-metal stent placed for another lesion were also excluded. Contemporary percutaneous coronary intervention was performed according to guidelines current at the time of implantation. In all cases, the interventional strategy, including the use of direct stenting, pre-/postdilatation, intravascular ultrasound (IVUS), choice of periprocedural adjunctive antiplatelet therapy, and use of ablative devices was at the discretion of the physician. Angiographic success was defined as stenosis ⱕ30% with Thrombolysis In Myocardial Infarction flow grade 3. All patients received aspirin www.AJConline.org
Coronary Artery Disease/DES vs BMS in Proximal LAD Table 1 Baseline characteristics Variable Age (yrs) Men Body mass index (kg/m2) Current smoker Diabetes mellitus Insulin use Hyperlipidemia Systemic hypertension Peripheral vascular disease Previous myocardial infarction Unstable angina pectoris Left ventricular ejection fraction Dialysis
497
Table 2 Angiographic and interventional data (lesion based) Bare-Metal Stent (n ⫽ 137)
DES (n ⫽ 350)
p Value
Variable
64 ⫾ 11 91 (66.4%) 29.5 ⫾ 5.8 24 (17.5%) 38 (27.7%) 10 (7.3%) 113 (85%) 101 (73.7%) 16 (12.1%) 38 (29.2%) 85 (62%) 0.49 ⫾ 0.16 4 (3%)
64 ⫾ 12 243 (69.4%) 29.2 ⫾ 6 63 (18%) 118 (34%) 43 (12.4%) 293 (84.4%) 252 (72%) 50 (14.5%) 77 (23.1%) 182 (52%) 0.5 ⫾ 0.15 6 (1.7%)
0.9 0.5 0.7 0.9 0.2 0.1 0.9 0.7 0.5 0.2 0.045 0.6 0.5
No. of treated vessels Type A Type B1B2 Type C LAD intervention procedures Stenosis pre-PCI (%) Stenosis post-PCI (%) Rotational atherectomy IVUS used Stent diameter (mm) Stent length (mm) Angiographic success
Values expressed as mean ⫾ SD or number (percent).
325 mg/day ⱖ24 hours before the procedure and continued this regimen indefinitely. Additional antiplatelet therapy with clopidogrel 75 mg/day (after a loading dose of 300 or 600 mg) was instituted in all patients. For all patients with an acute coronary syndrome, clopidogrel was recommended for ⱖ12 months. For stable patients, clopidogrel maintenance therapy was recommended for 3 months in the baremetal stent era and 6 months in the DES era. Intraprocedural anticoagulation was ensured using unfractionated heparin or bivalirudin. Glycoprotein IIb/IIIa inhibitors were used at the operator’s discretion and according to guidelines. The primary end point was defined as the rate of targetlesion revascularization (TLR) at 1 year. Other recorded events were major adverse cardiac events, including death, myocardial infarction, and target-vessel revascularization. Death was defined as all causes of mortality. Myocardial infarction was defined as a total creatinine kinase increase ⱖ2 times normal and/or creatinine kinase-MB ⱖ20 ng/ml with or without new pathologic Q waves in ⱖ2 contiguous leads. TLR and target-vessel revascularization were characterized as repeated percutaneous or surgical intervention of the treated lesion or vessel and were clinically driven, respectively. Acute (ⱕ24 hours) and subacute (⬎1 to 30 days) stent thromboses were defined as evidence of angiographic thrombus of the target lesion.1 Because late stent thrombosis was not recorded in the bare-metal stent era, to evaluate this rate, a composite end point of death and myocardial infarction was used to compare the rate of cumulative stent thrombosis between bare-metal stents and DESs at 1-year follow-up. A dedicated data coordinating center (Data Center, MedStar Research Institute, Washington, DC) performed all data management and analyses. Prespecified clinical and laboratory data during hospitalization periods were obtained from hospital charts reviewed by independent research personnel who were unaware of the study objectives. The occurrence of major late clinical events was recorded, including death (all-cause), myocardial infarction, TLR, target-vessel revascularization, and stent thrombosis. All clinical events were adjudicated by source documentation by independent physicians who were not involved in the procedures.
Bare-Metal Stent (n ⫽ 273)
DES (n ⫽ 595)
p Value
1.9 ⫾ 0.9 30 (12%) 147 (58.8%) 73 (29.2%) (n ⫽ 137) 0.89 ⫾ 0.11 0.05 ⫾ 0.2 16 (5.9%) 186 (72.4%) 3.2 ⫾ 0.5 15 ⫾ 7 133 (97%)
1.7 ⫾ 0.8 49 (8.2%) 430 (72.2%) 97 (19.6%) (n ⫽ 350) 0.88 ⫾ 0.11 0.04 ⫾ 0.1 18 (5.1%) 260 (74.5%) 3.2 ⫾ 0.3 17 ⫾ 7 345 (98.6%)
0.2 0.2
0.4 0.5 0.6 0.6 0.6 ⬍0.01 0.5
PCI ⫽ percutaneous coronary intervention. Values expressed as mean ⫾ SD or number (percent).
Table 3 In-hospital and 1-month outcomes Outcome In-hospital Death Myocardial infarction Urgent target-vessel revascularization Subacute thrombosis 1-Month follow-up Death Myocardial infarction Target-vessel revascularization TLR Major adverse cardiac events
Bare-Metal Stent DES p Value (n ⫽ 137) (n ⫽ 350) 4 (2.9%) 0 (0%) 3 (2.2%)
5 (1.4%) 1 (0.3%) 6 (1.7%)
0.5 1 0.7
1 (0.7%)
3 (0.9%)
0.7
4 (2.9%) 1 (0.7%) 0 (0%) 0 (0%) 5 (3.6%)
5 (1.4%) 2 (0.6%) 4 (1.1%) 2 (0.6%) 5 (1.4%)
0.5 1 0.6 1 0.2
Statistical analysis was performed using the Statistical Analysis System, version 8.2 (SAS Institute, Inc., Cary, North Carolina). Data were expressed as mean ⫾ SD for continuous variables and percentages for categorical variables. Student’s t test was used to compare continuous variables, and chi-square test or Fischer’s exact test was used to compare categorical variables. Event-free survival curves were constructed using the Kaplan-Meier method. Cox proportional hazard analysis was used to identify predictors of TLR. Cox proportional regression models were used to control for differences between the bare-metal stent and DES groups, with final results expressed as adjusted hazard ratios. Results Baseline characteristics are listed in Table 1. Patients in both groups had similar baseline characteristics. Patients in the bare-metal stent group more frequently presented with unstable angina pectoris (62% vs 52%; p ⫽ 0.045). Angiographic and procedural data are listed in Table 2. The number of diseased vessels was high in both groups (baremetal stents vs DESs 1.9 ⫾ 0.9 vs 1.7 ⫾ 0.8; p ⫽ 0.2). In the DES group, 65.5% of implanted stents were sirolimus-
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Figure 1. One-year outcomes. BMS ⫽ bare-metal stent; MACE ⫽ major adverse cardiac event; MI ⫽ myocardial infarction; TVR ⫽ target-vessel revascularization.
In-hospital and 30-day outcomes are listed in Table 3. The bare-metal stent and DES groups had similar in-hospital outcomes. At 1 month and 1 year, no difference in outcome was observed between the 2 groups. In particular, the rate of major adverse cardiac events was similar (baremetal stents vs DESs 3.6% vs 1.4%; p ⫽ 0.2 and 16.4% vs 14.7%; p ⫽ 0.7, respectively; Figure 1). Rates of death and myocardial infarction at 1 year were similar in both groups (7.4% vs 6.1%; p ⫽ 0.6). Rates of target-vessel revascularization and TLR at 1 year were also identical in both groups (9% vs 8.6%; p ⫽ 0.9 and 4.5% vs 5.2%, p ⫽ 0.8, respectively). The Kaplan-Meier curve showed similar survival free of both TLR and major adverse cardiac events between the 2 types of stents (Figure 2). Univariate and multivariate analyses of predictors of TLR at 1-year follow-up in univariate analysis included age, systemic hypertension, diabetes mellitus, number of diseased vessels, IVUS use, and length and diameter of the stent and were associated with TLR at 1-year follow-up with p ⬍0.2. In multivariate analysis, diabetes mellitus and stent diameter were the only variables significantly associated with TLR, with hazard ratios of 1.4 (95% confidence interval 1.2 to 1.9, p ⫽ 0.02) and 0.4 (95% confidence interval 0.2 to 1, p ⫽ 0.04), respectively. Discussion
Figure 2. Kaplan-Meier 1-year survival free of major adverse cardiac events and TLR. Abbreviations as in Figure 1.
eluting stents and 34.5% were paclitaxel-eluting stents. Mean stent length was longer in the DES group (15 ⫾ 6 vs 17 ⫾ 7 mm; p ⬍0.01). Discharge medications were similar in the 2 groups. In particular, rates of patients discharged on aspirin and thienopyridine therapies were identical (baremetal stents vs DESs 97.7% vs 97.9%; p ⫽ 0.8 and 96.4% vs 97%; p ⫽ 0.9, respectively).
The present study suggested that bare-metal stents and DESs had similar 1-year outcomes in patients with nonostial proximal LAD lesions. Both efficacy measured using TLR and safety measured using death and myocardial infarction were similar at 1-year follow-up in the 2 groups. Proximal LAD stenting is of major prognostic value because this artery supplies a large part of the myocardium. The balance of safety and efficacy for each stent type had to be established because studies have shown that this artery had increased risk of restenosis and stent thrombosis.2,3 Results of the present study were therefore of major clinical interest to optimize the risk-benefit ratio and reduce the cost-effectiveness of percutaneous coronary intervention in patients with nonostial proximal LAD lesions. Previous studies have shown that ostial lesions had a higher restenosis rate and benefited from DES use.4 In addition, ostial percutaneous coronary intervention results were highly dependent on the technique applied.5,6 We therefore excluded ostial LAD lesions from the present study. A subgroup analysis of the TAXUS IV trial was the only available data comparing DESs and bare-metal stents in patients undergoing proximal LAD percutaneous coronary intervention to date. This analysis suggested a decreased rate of major adverse cardiac events with the use of DESs compared with bare-metal stents.7 However, the rate of major adverse cardiac events in the bare-metal stent group was 22.1%, which was higher than in the present report (14.6%) or other published reports.8 –10 Such differences may be related to several design and procedural differences between the TAXUS IV trial subgroup analysis and the present study. First, ostial lesions were included in the TAXUS IV trial, which may explain the higher TLR rate observed in the bare-metal stent group. Second, it must be noted that half the patients in the TAXUS IV trial had
Coronary Artery Disease/DES vs BMS in Proximal LAD
angiographic follow-up, which may be associated with an increased rate of target lesion revascularization and may therefore have overestimated the major adverse cardiac event rate in the bare-metal stent group. Third, the mean diameter of the stent implanted in the subgroup analysis of patients undergoing proximal LAD percutaneous coronary intervention was 2.8 mm in TAXUS IV trial, which is less than the 3.2 mm used in the present study. The difference in stent diameter may be related to the extensive use of IVUS in the present study. IVUS studies have shown that the proximal LAD had a mean minimum lumen area of 7 mm2, which corresponded to a mean minimal vessel diameter of 3 mm.11 In addition, IVUS use allowed more accurate determination of a vessel’s diameter compared with angiography, thus preventing stent undersizing. Accordingly, a previous study has shown that IVUS-guided percutaneous coronary intervention was associated with an increase in mean stent diameter compared with angiographically guided percutaneous coronary intervention.12 Several studies performed in the bare-metal stent era have shown that IVUS-guided percutaneous coronary intervention decreased the rate of restenosis, which may explain the particularly low rate of restenosis in our group of patients treated with bare-metal stents together with the high rate of IVUS guidance.13–15 Therefore, the high rate of events in the TAXUS IV trial may have been related to use of a stent with a relatively small diameter in such a large vessel. Finally, use of a large stent in the present study may be responsible for the low rates of TLR and major adverse cardiac events observed in the bare-metal stent group and the lack of difference between the DES and bare-metal stent group. Previous studies observed that in large vessels (ⱖ3.5 mm), bare-metal stents and DESs had similar major adverse cardiac event and TLR rates.16,17 Similarly, the Basel Stent Cost Effectiveness Trial (BASKET) showed that DESs were not associated with clinical benefit in vessels with a diameter ⬎3 mm.18 Delayed endothelialization resulting from the antiproliferative action of the eluting drugs has been associated with the occurrence of late stent thrombosis.19 Recent studies have suggested a slight, but constant, increase in the rate of stent thrombosis over time with DESs compared with bare-metal stents, with an incidence of 0.6% vs 0.25% per year, respectively.20 In the present study, there was no difference in rates of stent thrombosis at 30 days or death and myocardial infarction at 1 year between DESs and bare-metalstents.ThecurrentAmericanCollegeofCardiology/ American Heart Association guidelines advocate that DESs be considered an alternative to bare-metal stents in patients for whom clinical trials indicated a favorable effectiveness/ safety profile.21 In the present study, we observed no difference in rates of major adverse cardiac events for patients with nonostial proximal LAD between DESs and bare-metal stents. These findings suggest that in patients with proximal LAD lesions, when the ostium is not involved, use of bare-metal stents could be cost-effective. The present study had several limitations, including its retrospective design and the small number of patients included. A prospective randomized trial is warranted to determine which type of stent is cost-effective in this location.
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1. Cutlip DE, Windecker S, Mehran R, Boam A, Cohen DJ, van Es GA, Steg PG, Morel MA, Mauri L, Vranckx P, et al; Academic Research Consortium. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation 2007;115:2344 –2351. 2. Roy P, Torguson R, Okabe T, Pinto Slottow TL, Steinberg DH, Smith K, Xue Z, Satler LF, Pichard AD, Waksman R. Angiographic and procedural correlates of stent thrombosis after intracoronary implantation of drug-eluting stents. J Interv Cardiol 2007;20:307–313. 3. Roy P, Okabe T, Pinto Slottow TL, Steinberg DH, Smith K, Torguson R, Xue Z, Gevorkian N, Satler LF, Kent KM, et al. Correlates of clinical restenosis following intracoronary implantation of drug-eluting stents. Am J Cardiol 2007;100:965–969. 4. Mavromatis K, Ghazzal Z, Veledar E, Diamandopoulos L, Weintraub WS, Douglas JS, Kalynych AM. Comparison of outcomes of percutaneous coronary intervention of ostial versus nonostial narrowing of the major epicardial coronary arteries. Am J Cardiol 2004;94:583–587. 5. Cubeddu RJ, Wood FO, Saylors EK, Mann T. Isolated disease of the ostium left anterior descending or circumflex artery: management using a left main stenting technique. Clinical outcome at 2 years. J Invasive Cardiol 2007;19:457– 461. 6. Seung KB, Kim YH, Park DW, Lee BK, Lee CW, Hong MK, Kim PJ, Chung WS, Tahk SJ, Park SW, Park SJ. Effectiveness of sirolimuseluting stent implantation for the treatment of ostial left anterior descending artery stenosis with intravascular ultrasound guidance. J Am Coll Cardiol 2005;46:787–792. 7. Stone GW, Ellis SG, Cox DA, Hermiller J, O’Shaughnessy C, Mann JT, Turco M, Caputo R, Bergin P, Greenberg J, Popma JJ, Russell ME; TAXUS-IV Investigators. A polymer-based, paclitaxel-eluting stent in patients with coronary artery disease. N Engl J Med 2004;350:221– 231. 8. Iakovou I, Dangas G, Mehran R, Lansky AJ, Stamou SC, Pfister AJ, Dullum MK, Leon MB, Corso PJ. Minimally invasive direct coronary artery bypass (MIDCAB) versus coronary artery stenting for elective revascularization of the left anterior descending artery. Am J Cardiol 2002;90:885– 887. 9. Drenth DJ, Veeger NJ, Winter JB, Grandjean JG, Mariani MA, Boven van AJ, Boonstra PW. A prospective randomized trial comparing stenting with off-pump coronary surgery for high-grade stenosis in the proximal left anterior descending coronary artery: three-year followup. J Am Coll Cardiol 2002;40:1955–1960. 10. Shirai K, Lansky AJ, Mehran R, Dangas GD, Costantini CO, Fahy M, Slack S, Mintz GS, Stone GW, Leon MB. Minimally invasive coronary artery bypass grafting versus stenting for patients with proximal left anterior descending coronary artery disease. Am J Cardiol 2004; 93:959 –962. 11. Ge J, Erbel R, Gerber T, Görge G, Koch L, Haude M, Meyer J. Intravascular ultrasound imaging of angiographically normal coronary arteries: a prospective study in vivo. Br Heart J 1994;71:572–578. 12. St. Goar FG, Pinto FJ, Alderman EL, Fitzgerald PJ, Stadius ML, Popp RL. Intravascular ultrasound imaging of angiographically normal coronary arteries: an in vivo comparison with quantitative angiography. J Am Coll Cardiol 1991;18:952–958. 13. Fitzgerald PJ, Oshima A, Hayase M, Metz JA, Bailey SR, Baim DS, Cleman MW, Deutsch E, Diver DJ, Leon MB, et al. Final results of the Can Routine Ultrasound Influence Stent Expansion (CRUISE) Study. Circulation 2000;102:523–530. 14. Schiele F, Meneveau N, Vuillemenot A, Zhang DD, Gupta S, Mercier M, Danchin N, Bertrand B, Bassand JP. Impact of intravascular ultrasound guidance in stent deployment on 6-month restenosis rate: a multicenter, randomized study comparing two strategies—with and without intravascular ultrasound guidance. RESIST Study Group. REStenosis after Ivus guided STenting. J Am Coll Cardiol 1998; 32:320 –328. 15. Oemrawsingh PV, Mintz GS, Schalij MJ, Zwinderman AH, Jukema JW, van der Wall EE; TULIP Study. Thrombocyte activity evaluation and effects of Ultrasound guidance in Long Intracoronary stent Placement. Intravascular ultrasound guidance improves angiographic and clinical outcome of stent implantation for long coronary artery stenoses: final results of a randomized comparison with angiographic guidance (TULIP Study). Circulation 2003;107:62– 67. 16. Steinberg DH, Mishra S, Javaid A, Slottow TL, Buch AN, Roy P, Okabe T, Smith KA, Torguson R, Xue Z, et al. Comparison of
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effectiveness of bare metal stents versus drug-eluting stents in large (⬎ or ⫽ 3.5 mm) coronary arteries. Am J Cardiol 2007;99:599 – 602. 17. Quizhpe AR, Feres F, de Ribamar Costa J Jr., Abizaid A, Maldonado G, Costa R, Abizaid A, Cano M, Moreira AC, Staico R, et al. Drugeluting stents vs bare metal stents for the treatment of large coronary vessels. Am Heart J 2007;154:373–378. 18. Brunner-La Rocca HP, Kaiser C, Pfisterer M; BASKET Investigators. Targeted stent use in clinical practice based on evidence from the Basel Stent Cost Effectiveness Trial (BASKET). Eur Heart J 2007; 28:719 –725. 19. Finn AV, Joner M, Nakazawa G, Kolodgie F, Newell J, John MC, Gold HK, Virmani R. Pathological correlates of late drug-eluting stent
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