Longterm Clinical Outcomes of DrugEluting ... - Wiley Online Library

Clinical Investigations Long-term Clinical Outcomes of Drug-Eluting Stents Vs Bare-Metal Stents in Chinese Patients

Address for correspondence: Wing-Hing Chow Cardiac Medical Unit Grantham Hospital 125 Wong Chuk Hang Road Hong Kong [email protected]

Hee-Hwa Ho, MRCP; Vincent Pong, MBBS; Chung-Wah Siu, MRCP; Man-Hong Jim, MD; Raymond Miu, MRCP; Kai-Hang Yiu, MRCP; Ryan Ko, MRCP; Hung-Fat Tse, MD, PhD; On-Hing Kwok, FRCP; Wing-Hing Chow, FRCP Cardiology Division, Department of Medicine, Queen Mary Hospital, University of Hong Kong (Ho, Pong, Siu, Miu, Yiu, Ko, Tse), Hong Kong; Cardiac Medical Unit, Grantham Hospital (Ho, Pong, Siu, Jim, Kwok, Chow), Hong Kong; Research Center of Heart, Brain, Hormone and Healthy Aging, University of Hong Kong (Siu, Miu, Yiu, Ko, Tse), Hong Kong SAR, China.

Background: There is limited data on the magnitude of the problem of drug-eluting stent (DES) thrombosis in the Asian population. Hypothesis: We evaluated the long-term clinical outcomes of DES vs bare metal stents (BMS) in Chinese patients. Methods: From January 2002 to October 2005, 1236 consecutive patients underwent percutaneous coronary intervention with DES or BMS coronary stent implantation at our institution. We analyzed major clinical end points like all-cause mortality, cardiovascular death, myocardial infarction, target lesion revascularization (TLR), and stent thrombosis. Results: The 3-year cumulative rates of all-cause mortality, cardiovascular death, and myocardial infarction were significantly lower in the DES group (3.4%, 0.9%, 3.6%) when compared with the BMS group (7.5%, 4.4%, 6.2%; P < .05). No significant differences were found in the 3-year cumulative rates for TLR or stent thrombosis when comparing the DES group (8.3%, 1.63%) vs the BMS group (9.6%, 1.6%; P > .05). However, after 1 year, there were 8 episodes of stent thrombosis in the DES group vs 1 episode of stent thrombosis in the BMS group (P = .04). Conclusion: Drug-eluting stents are associated with a significant reduction in the 3-year cumulative rates of all-cause mortality, cardiovascular death, and myocardial infarction when compared to BMS. However, there were no significant differences in the cumulative rates of TLR or stent thrombosis at 3 years. Stent thrombosis after 1 year was more common in the DES group, but this did not translate to increased mortality. The suggestion that DES might confer a mortality benefit should be interpreted with caution as there could be several confounding factors that were not identified in our study.

Introduction Drug-eluting stents (DES) were quickly embraced as a breakthroughtechnology by cardiologists worldwidefor the treatment of obstructive coronary artery disease following the results of randomized,controlledstudies1 – 4 that showed reduced rates of target vessel failure, revascularization, or both at 9 months when compared with bare metal stents (BMS). Its clinical application was quickly expanded to relatively more complex lesion subsets.5 – 10 Safety concerns have surfaced for the past 3 years with many studies11 – 14 highlighting the genuine risk of late stent thrombosis after implantationof DES with possible increase in cardiovascular

Hee-Hwa Ho, Vincent Pong, and Chung-Wah Siu contributed equally to the manuscript.

E22

Clin. Cardiol. 33, 6, E22 – E29 (2010) Published online in Wiley InterScience. (www.interscience.wiley.com) DOI:10.1002/clc.20655 © 2010 Wiley Periodicals, Inc.

mortality related to stent thrombosis. Most of the data on the efficacy and safety of DES vs BMS comes from the Western population.11– 19 There is limited data in the Asian population on the magnitude of the problem with DES stent thrombosis. We therefore sought to evaluate the long-term clinical outcomes (safety and efficacy) of DES vs BMS in our Chinese population.

Methods Study Population

This study was a single-center registry on the 3-year clinical outcomes of Chinese patients with obstructive coronary artery disease undergoing elective or early percutaneous coronary intervention (PCI) using DES or BMS at our institution in Hong Kong. From January 2002 to October 2005, a total of 1236 consecutive Chinese patients Received: March 11, 2009 Accepted: June 28, 2009

underwent PCI with coronary stent implantation. Patients were assigned to either the DES or BMS group according to the stent type used during the index procedure. A total of 562 patients who received BMS and 674 patients treated with DES (317 patients with sirolimus-eluting stents [SES; Cypher, Cordis Corp., Johnson & Johnson, Warren, NJ], and 357 patients with paclitaxel-eluting stents [PES; TAXUS Express,Boston Scientific,Natick, MA]) were recruitedinto our study.

in the presence of an elevation in cardiac troponins or in creatine kinase > 2 times the upper limit of normal range. Target lesion revascularization was defined as any repeat revascularization (percutaneous or surgical) secondary to a stenosis > 50% within the stent or within 5 mm proximal or distal to the stented segment. Stent thrombosis was defined according to the Academic Research Consortium criteria.20 Statistical Analysis

Interventional Procedure

All PCIs were performed using standard techniques and according to current practice guidelines. All patients were treated with aspirin (80 mg-300 mg daily) prior to the procedure and indefinitely thereafter. Patients also received clopidogrel (an oral loading dose of 300 mg followed by 75 mg daily) before the procedure, followed by a minimum of 1 month in patients who received BMS, 3 months in patients who received SES, and 6 months in patients who received PES. Additional duration of clopidogrel treatment was at the discretion of the attending physician. Study Design

Upon hospital discharge, demographic characteristics and procedural data were entered into the Grantham Hospital Cardiovascular Interventional Services Database. All patients were followed up in the cardiac clinic at 4 weeks, 12 weeks, and then every 3 months. For the present study, clinical data concerning major adverse cardiovascular events during any subsequent hospitalization within the 3-year follow-up period after the index procedure were retrieved from the medical records and discharge summaries from our hospital as well as other institutions. Patients who were lost to follow-up within the 3 year follow-up period were contacted by phone. End Points and Definitions

The major clinical end points that we analyzed in our study include death from any cause, cardiovascular death, myocardial infarction, target lesion revascularization (TLR), and stent thrombosis. Information on the circumstances of all deaths was obtained as much as possible from the available sources. Death from cardiovascular causes was defined as death due to acute myocardial infarction, cardiac perforation or tamponade, arrhythmia, a complication of the PCI procedure, or as any death in which a cardiovascular cause could not be ruled out. Death from noncardiovascular causes was defined as any death not due to a cardiovascular cause. Myocardial infarction (MI) was defined as the presence of new Q waves with elevation in cardiac troponins or in creatine kinase above the upper limit of the normal range, or in the absence of pathologic Q waves, MI was diagnosed

Continuous variables were expressed as mean ± standard error of mean. Dichotomous variables were expressed as counts and percentages. Statistical comparisons were performed using the Student t test or Fisher’s exact test, as appropriate. We used Kaplan-Meier time-to-event analysis with log-rank test to assess the cumulative incidence of events over time and to evaluate differences between the 2 groups. Cox regression analysis was used to evaluate independent predictors of cardiovascular death at 3 years. Calculations were performed using SPSS software (version 12.0; SPSS, Inc., Chicago, IL). All P values were 2-sided and P values < .05 were considered statistically significant. All investigations were carried out in accordance with the Declaration of Helsinki.

Results The baseline clinical characteristics of the study patients are summarized in Table 1. The mean age at presentation (64 yrs) was similar with male preponderance(> 70%) noted for both groups. No significant differences were observed for both groups with respect to cardiovascular risk factors like diabetes mellitus, hyperlipidemia, and hypertension. For the DES group, they were more likely to have undergone PCI in the past and had a slightly higher left ventricular function at presentation when compared with the BMS group. For the latter group, they were more often current smokers and were more likely to have received vascular brachytherapy in the past. Stable angina pectoris was the most common indication for PCI (> 70%) in both groups. However, the DES group had a higher proportion of patients presenting as stable angina whereas the BMS group had a higher proportion of patients presenting as unstable angina. The duration of clopidogrel treatment was also significantly longer in the DES group when compared with the BMS group. Table 2 summarized the angiographic findings and procedural data for the study patients. The proportion of 3-vessel disease found on coronary angiography was significantly higher in the DES group and there was a trend towards a higher proportion of 2-vessel disease in the BMS group. No significant differences were found for both groups with respect to the target vessel for PCI. There was a higher administration of glycoprotein IIb/IIIa inhibitors during PCI for the BMS group. The mean number of stents

Clin. Cardiol. 33, 6, E22 – E29 (2010) H.-H. Ho et al: Safety and Efficacy of Drug-Eluting Stents in Chinese Patients Published online in Wiley InterScience. (www.interscience.wiley.com) DOI:10.1002/clc.20655 © 2010 Wiley Periodicals, Inc.

E23

Clinical Investigations

continued

Table 1. Baseline Clinical Characteristics for Patients Undergoing PCI With DES Vs BMS DES (n = 674)

BMS (n = 562)

P

64.4 ± 10.7

64.3 ± 10.4

.79

490:184 (72.7:27.3)

427:135 (76:24)

.19

Current smokers, n (%)

89 (13.2)

102 (18.1)

.02

Former smokers, n (%)

209 (31)

186 (33.1)

.46

Diabetes, n (%)

261 (38.7)

231 (41.1)

.41

Hyperlipidemia, n (%)

323 (47.9)

248 (44.1)

.19

Hypertension, n (%)

419 (62.2)

341 (60.7)

.59

Renal failure, n (%)

13 (1.9)

19 (3.4)

.15

Previous myocardial infarction, n (%)

81 (12)

83 (14.8)

.18

Previous PCI, n (%)

303 (45)

166 (29.5)

< .0.0001

Previous CABG, n (%)

82 (12.2)

55 (9.8)

.2

1 (0.15)

16 (2.85)

< .0001

64.9 ± 14.3

62.4 ± 14.7

.002

227.85 ± 274.83

96.43 ± 261.29

< .0001

566 (84.0)

437 (77.7)

.006

Unstable angina, n (%)

84 (12.4)

103 (18.3)

.005

Others

24 (3.6)

22 (4.0)

.76

Mean age (yrs) Male:Female, n (%)

Previous VBT, n (%) LVEF (%) Duration of clopidogrel, number of days Presentation: Stable angina, n (%)

Abbreviations: BMS, bare metal stent; CABG, coronary artery bypass graft; DES, drug-eluting stent; LVEF, left ventricular ejection fraction; PCI, percutaneous coronary intervention; VBT, vascular brachytherapy.

implanted per patient was slightly higher in the DES group when compared to the BMS group although this was not statistically significant. The mean stent size was often larger in the BMS group whereas total stent length was often longer in the DES group. Table 3 showed the cumulative 3-year rates of major clinical end points (all-cause death, cardiovascular death, MI, TLR, and stent thrombosis) for the study patients. Stent Thrombosis

From stent implantation through 3-year follow-up, the cumulative 3-year rate for stent thrombosis among patients in the DES group did not differ significantly from those patients in the BMS group (1.63% vs 1.6%, P = 1.0; Table 3 and Figure 1A). At 1 year, the rate of stent thrombosis was not significantlyhigher in the BMS group when compared to the DES group (1.42% vs 0.44%, P = .12). However, between 1 and 3 years, the rate of stent thrombosis was significantly higher in the DES group than in the BMS group (1.2% vs 0.2%, P = .04). Of the 11 cases of stent thrombosis in the

E24

DES group, 5 patients received SES and 6 received PES. All 5 cases of SES-related stent thrombosis were very late; whereas for PES, there was 1 case of subacute, 2 cases of late, and 3 cases of very late stent thrombosis. Of the 8 patients with very late stent thrombosis, only 1 patient was taking both aspirin and clopidogrel and the rest of the patients were taking only aspirin. Revascularization

The cumulative 3-year rate for TLR was similar in the DES and the BMS group (8.3% vs 9.6%, P = .42; Table 3 and Figure 1B). At 1 year however, there was a difference in the rate of TLR favoring DES over BMS (3.3% vs 7.1%, P = .002) but this advantage was not sustained after 1 year. Death and Myocardial Infarction

There was a lower cumulative 3-year rate of all-cause death for the DES group when compared to the BMS group (3.4% vs 7.5%, P = .002; Table 3 and Figure 1C).


Table 2. Baseline Angiographic and Procedural Characteristics for Patients Undergoing PCI With DES Vs BMS DES (n = 674)

BMS (n = 562)

P

1, n (%)

188 (27.9)

170 (30.2)

.37

2, n (%)

200 (29.7)

197 (35.1)

.05

3, n (%)

231 (34.3)

154 (27.4)

.01

55 (8.2)

41 (7.3)

.59

22 (3.3)

19 (3.4)

1.0

LAD, n (%)

313 (46.4)

243 (43.2)

.28

CIRC, n (%)

171 (25.4)

123 (21.9)

.15

RCA, n (%)

208 (30.9)

150 (26.7)

.11

Vein graft, n (%)

30 (4.5)

21 (3.7)

.56

Glycoprotein IIb/IIIa inhibitors, n (%)

41 (6.1)

57 (10.1)

.01

Mean number of stents per patient

1.58 ± 0.79

1.5 ± 0.75

.07

Mean stent size, mm

2.88 ± 0.38

3.08 ± 0.45

< .0001

Total stent length, mm

33.55 ± 23.2

29.23 ± 19.5

.0005

No. of obstructive coronary arteries

Left main, n (%) Target vessel LMCA, n (%)

Abbreviations: BMS, bare metal stent; CIRC, circumflex; DES, drug-eluting stent; LAD, left anterior descending; LMCA, left main coronary artery, RCA, right coronary artery. Table 3. Clinical Outcomes (All-Cause Death, Cardiovascular Death, Myocardial Infarction, TLR, and Stent Thrombosis) for Patients Undergoing PCI With DES Vs BMS DES (n = 674)

BMS (n = 562)

P

All-cause death, n (%)

23 (3.4)

42 (7.5)

.002

Cardiovascular death, n (%)

6 (0.9)

25 (4.4)

< .0001

Noncardiovascular death, n (%)

17 (2.5)

17 (3.0)

.6

Myocardial infarction, n (%)

24 (3.6)

35 (6.2)

.03

TLR, n (%)

56 (8.3)

54 (9.6)

.42

Stent thrombosis as defined by the ARC, n (%)

11 (1.63)

9 (1.6)

1.0

Definite, n

4

1

Probable, n

3

6

Possible, n

4

2

Acute, n

0

1

Subacute, n

1

1

Late, n

2

6

Very late, n

8

1

Abbreviations: ARC, Academic Research Consortium; BMS, bare metal stent; DES, drug-eluting stent; TLR, target lesion revascularization.


E25


continued

12.00

Stent thrombosis (%)

Bare metal stent 1.50

1.00 Drug-eluting stent 0.50 p = 0.86

Target lesion revascularisation (%)

2.00

8.00 6.00 4.00

Drug-eluting stent

2.00 p = 0.44 0.00

0.00 0.0

200.0

400.0

(A)

600.0 Days

800.0

1000.0

0

10.00

5.00

8.00

4.00

Bare metal stent 6.00

4.00 Drug-eluting stent

2.00

p = 0.004

0.00 0

200

400

(C)

600 Days

200

400

(B)

Cardiovascular death (%)

All cause death (%)

Bare metal stent

10.00

800

600 Days

800

1000

Bare metal stent

3.00

2.00 p = 0.0001 1.00 Drug-eluting stent

0.00

1000

0 (D)

200

400

600 Days

800

1000

My0cardial infarction (%)

8.00

6.00

Bare metal stent

4.00

Drug-eluting stent

2.00

p = 0.05

0.00 0 (E)

200

400

600 Days

800

1000

Figure 1. Kaplan-Meier curves representing 3-year cumulative incidence rates of stent thrombosis, TLR, all-cause death, cardiovascular death, and MI.

E26


The higher rate of all-cause death in the BMS group was mainly driven by a higher rate of cardiovascular death observed in the BMS group than in the DES group (4.4% vs 0.9%, P < .0001; Table 3 and Figure 1D) as the rate of noncardiovascular deaths were similar for both groups (3% vs 2.52%, P = .6). Approximately 50% (12 patients) of cardiovascular deaths for the BMS group occurred within the first year after the index procedure. There was also a lower cumulative 3-year rate of MI for the DES group when compared to the BMS group (3.6% vs 6.2%, P = .03; Table 3 and Figure 1E). This would also account partly for the reduction in all-cause death observed for the DES group. A total of 17 patients in the BMS group developed MI within the first year after the index procedure and 8 cases were fatal. Predictors of Cardiovascular Death

Cox regression analysis showed that independent predictors of cardiovascular death at 3 years follow-up were use of DES (odds ratio [OR]: 0.4, 95% confidence interval [CI]: 0.2–0.8, P = .002), renal failure (OR: 7.8, 95% CI: 2.6–24, P = .0001), and prior history of acute MI (OR: 2.6, 95% CI: 1.1–6.24, P = .03).

Discussion Stent Thrombosis

The cumulative 3-year rate of stent thrombosis was similar for both groups, but a temporal pattern was observed. Stent thrombosis for patients in the BMS group mostly occurred within the first year after the index procedure whereas for patients in the DES group, stent thrombosis mostly occurred beyond 1 year, a phenomenon that had been consistently observed in many clinical studies.11,13 – 15 Despite this temporal pattern, the overall risk of stent thrombosis with DES did not translate into higher mortality in our study. The causes of stent thrombosis are multifactorial.21– 24 For DES, it appears that delayed healing with poor endothelialization21,22 is one of the most important substrates of late stent thrombosis. Prolonged dual antiplatelet therapy25 may have some protective effect in reducing the risk of late DES stent thrombosis although we had 1 patient who developed the event despite taking both aspirin and clopidogrel. Target Lesion Revascularization

No significant difference was observed for the cumulative 3-year rate of TLR between the 2 groups which were both < 10%. However, the rate of TLR at 1 year was significantly lower in the DES group than in the BMS group, but this advantage was not maintained after 1 year. Our findings are in contrast with randomized controlled trials15,16,18 which had shown marked and persistent reduction in TLR with DES when compared to BMS. This discrepancy could be explained by the fact that DES were implanted in many of

our patients in an ‘‘off-label’’ manner and this could give rise to the ‘‘catch-up’’ phenomenon of late restenosis. On the contrary, we could have underestimated the true rate of restenosis and TLR in the BMS group as angiographic follow-up in our study was purely ischemic driven. Our ‘‘realworld’’ registry had many patients with complex features including a high percentage of diabetes mellitus (40%), hence, a higher rate of TLR (> 10%) would be expected for the BMS group. Death and Myocardial Infarction

Our study also demonstrated a marked and persistent reduction in the cumulative 3-year rate of all-cause death, cardiovascular death, and MI with DES when compared to BMS. This benefit in all-cause mortality observed with DES came as a surprise and it was mainly driven by a reduction in cardiovascular death and MI. By Cox regression analysis, the use of DES was found to be associated with a lower rate of cardiovascular mortality. Our findings differed from most investigators14– 18,26,27 who had suggested that overall rates of death and MI were either similar or higher with DES than with BMS. Some studies15,28 had suggested that the reductions in the rates of death or MI that otherwise might result from prevention of restenosis by DES might be neutralized by adverse events resulting from late stent thrombosis. Following this line of argument, we would expect the rates of death and MI to be higher among patients in the DES group, but this was not the case. This discrepancy could be explained by the possibility that patients in the BMS group had developed a higher than the observed rate of restenosis and TLR which resulted in higher rates of both MI (fatal in some cases) and cardiovascular death. Lending support to this hypothesis was the fact that approximately half of the total cases of cardiovascular deaths and MI in the BMS group occurred within the first year of the index procedure and we knew from clinical studies,29,30 in-stent restenosis for BMS mainly occurred within the first 6 to 9 months after stent implantation. In-stent restenosis is not always a benign process31,32 and could present as acute MI in 3% to 19% of patients with fatality in some cases. There were several limitations to our study. Our sample size was relatively small when compared to other studies and we made no adjustments for the multiple end points analyzed. We believe that our patients were comparable in most of the baseline clinical characteristics and representative of the real-world patients we encounter in daily clinical practice. Furthermore, as a result of the nonrandomized nature of our observational study, multiple selection bias remained and would impact on the results.For the BMS group, there were higher proportions of patients presenting with unstable angina pectoris, prior vascular brachytherapy,and history of smoking which may represent a higher risk group prone to developing more cardiovascular


E27


continued

deaths and MI. However, there was no significant difference in the baseline low-density lipoprotein for both groups and they were both equally likely to be prescribed statin in addition to β-blockers and angiotensin-converting enzyme inhibitors. The suggestion that DES might confer a mortality benefit as shown by our findings should be interpreted with caution as there could be several confounding factors that were not identified. An interesting possibility is that genetic or ethnic factors may play a role in drug responsiveness (DES in this case) and will warrant further studies. One of the strengths of our study was the effort to retrieve the duration of clopidogrel treatment for every patient and that information was available for > 95% of patients.

Conclusion We found that the use of DES in the Chinese population in a real-world setting was associated with a significant reduction in the cumulative 3-year rates of all-cause mortality, cardiovascular death, and MI when compared to BMS. On the other hand, we found no significant difference between both groups in terms of cumulative 3-year rates of TLR and stent thrombosis. Beyond 1 year, the rate of stent thrombosis was significantly higher in the DES group than the BMS group, but this did not translate to increased mortality. Further studies are needed to identify predictors of DES stent thrombosis and elucidate the appropriate preventive and treatment strategies. References 1.

2.

3.

4.

5.

6.

7.

8.

E28

Morice MC, Serruys PW, Sousa JE, et al. A randomised comparison of a sirolimus-eluting stent with a standard stent for coronary revascularisation. N Engl J Med. 2002;346:1773–1780. 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– 1323. Grube E, Silber S, Hauptmann KE, et al. TAXUS I: six and twelvemonth results from a randomised, double blind trial on a slow release paclitaxel-eluting stent for de novo coronary lesions. Circulation. 2003;107:38–42. Stone GW, Ellis SG, Cox DA, et al. A polymer based paclitaxeleluting stent in patients with coronary artery disease. N Engl J Med. 2004;350:221–231. Schofer J, Schl¨ uter M, Gershlick AH, et al; E-SIRIUS Investigators. Sirolimus-eluting stents for treatment of patients with long atherosclerotic lesions in small coronary arteries: a doubleblind randomised controlled trial (E-SIRIUS). Lancet. 2003;362: 1093–1099. Ge L, Iakovou I, Cosgrave J, et al. Immediate and mid-term outcomes of sirolimus-eluting stents implantation for chronic total occlusions. Eur Heart J. 2005;26:1056–1062. Kastrati A, Mehilli J, von Beckerath N, et al; ISAR-DESIRE Study Investigators. Sirolimus-eluting stent of paclitaxel-eluting stent versus balloon angioplasty for prevention of recurrences in patients with coronary in-stent restenosis: a randomised controlled trial. JAMA. 2005;293:165–171. Ellis SG, Kandzari D, Kereiakes DJ, et al. Utility of sirolimuseluting Cypher stents to reduce 12-month target vessel revascularisation in saphenous vein graft stenoses: results of a multicenter 350-patient case-control study. J Invasive Cardiol. 2007;19(10):404 –409.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.


Cheiffo A, Stankovic G, Bonizzoni E, et al. Early and mid-term results of drug-eluting stent implantation in unprotected left main. Circulation. 2005;111:791–795. Lemos PA, Saia F, Hofma SH, et al. Short and long-term clinical benefit of sirolimus-eluting stents compared to conventional bare stents for patients in acute myocardial infarction. J Am Coll Cardiol. 2004;43:704–708. Daemen J, Wenaweser P, Tsuchida K, 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. Camenzind E, Steg PG, Wijns W. Stent thrombosis late after implantation of first generation drug-eluting stents. A cause of concern. Circulation. 2007;1155:1440–1455. Pfisterer M, Brunner-La Rocca HP, Buser PT, et al; for the BASKET-LATE Investigators. Late clinical events after clopidogrel discontinuation may limit the benefit of drug-eluting stents: an observational study of drug-eluting versus bare metal stents. J Am Coll Cardiol. 2006;48:2584 –2591. Lagerqvist B, James SK, Stenestrand U, et al. Long term outcomes with drug-eluting stents versus bare metal stents in Sweden. N Engl J Med. 2007;356:1009–1019. Stone GW, Moses JW, Ellis SG, et al. Safety and efficacy of sirolimus and paclitaxel eluting coronary stents. N Engl J Med. 2007;356:998– 1008. Kastrati A, Mehilli J, Pache J, et al. Analysis of 14 trials comparing sirolimus-eluting stents with bare metal stents. N Engl J Med. 2007;356:1030 –1039. Spaulding C, Daemen J, Boersma E, et al. A pooled analysis of data comparing sirolimus-eluting stents with bare metal stents. N Engl J Med. 2007;356:989–997. Stettler C, Wandel S, Allemann S, et al. Outcomes associated with drug-eluting and bare metal stents: a collaborative network metaanalysis. Lancet. 2007;370:937–948. Mauri L, Hsieh WH, Massaro JM, et al. Stent thrombosis in randomised clinical trials of drug-eluting stents. N Engl J Med. 2007;356(10):1020 –1029. Cutlip DE, Windecker S, Mehran R, et al; Academic Research Consortium. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation. 2007;115(17):2344– 2351. Luscher TF, Steffel J, Eberli FR, et al. Drug-eluting stent and coronary thrombosis:biological mechanisms and clinical implications. Circulation. 2007;115:1051–1058. Joner M, Finn AV, Farb A, et al. Pathology of drug-eluting stents in humans: delayed healing and late thrombotic risk. J Am Coll Cardiol. 2006;48:193–202. Iakovou I, Schmidt T, Bonizzoni E, et al. Incidence, predictors and outcome of thrombosis after successful implantation of drugeluting stents. JAMA. 2005;293:2126–2130. Virmani R, Guagliumi G, Farb A, et al. Localised hypersensitivity and late coronary thrombosis secondary to a sirolimus-eluting stent: should we be cautious? Circulation. 2004;109:701–705. Eisenstein EL, Anstrom KJ, Kong DF, et al. Clopidogrel use and long term clinical outcomes after drug-eluting stent implantation. JAMA. 2007;297:159–168. Jensen LO, Maeng M, Kaltoft A, et al. Stent thrombosis, myocardial infarction and death after drug-eluting and bare metal stent coronary interventions. J Am Coll Cardiol. 2007;50:463–470. Nordmann AJ, Briell M, Bucher HC. Mortality in randomized controlled trials comparing drug-eluting verses bare metal stents in coronary artery disease. Eur Heart J. 2006;277:2784–2814. Stone GW, Ellis SG, Colombo A, et al. Offsetting impact of thrombosis and restenosis on the occurrence of death and myocardial infarction after paclitaxel-eluting and bare metal stent implantation. Circulation. 2007;115:2842 –2847. Serruys PW, de Jaegere P, Kiemeneij F, et al. A comparison of balloon-expandable-stent implantation with balloon angioplasty

30.

in patients with coronary artery disease. N Engl J Med. 1994;331:489–495. Fischman DL, Leon MB, Baim DS, et al. A randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease. N Engl J Med. 1994;331:496–501.

31.

32.

Walters DL, Harding SA, Walsh CR, et al. Acute coronary syndrome is a common clinical presentation of in-stent restenosis. Am J Cardiol. 2002;89:491–494. Chen MS, John JM, Chew DP, et al. Bare metal stent restenosis is not a benign clinical entity. Am Heart J. 2006;151:1260–1264.


E29