Abstract. Background The long-term safety and efficacy of drug-eluting coronary stents have been questioned

new england journal of medicine The established in 1812 may 7, 2009 vol. 360  no. 19 Long-Term Safety and Efficacy of Drug-Eluting versus Bare-M...
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new england journal of medicine The

established in 1812

may 7, 2009

vol. 360  no. 19

Long-Term Safety and Efficacy of Drug-Eluting versus Bare-Metal Stents in Sweden Stefan K. James, M.D., Ph.D., Ulf Stenestrand, M.D., Ph.D., Johan Lindbäck, M.Sc., Jörg Carlsson, M.D., Ph.D., Fredrik Scherstén, M.D., Ph.D., Tage Nilsson, M.D., Ph.D., Lars Wallentin, M.D., Ph.D., and Bo Lagerqvist, M.D., Ph.D., for the SCAAR Study Group*

A bs t r ac t Background

The long-term safety and efficacy of drug-eluting coronary stents have been questioned. Methods

We evaluated 47,967 patients in Sweden who received a coronary stent and were entered into the Swedish Coronary Angiography and Angioplasty Registry between 2003 and 2006 and for whom complete follow-up data were available for 1 to 5 years (mean, 2.7). In the primary analysis, we compared patients who received one drugeluting coronary stent (10,294 patients) with those who received one bare-metal stent (18,659), after adjustment for differences in clinical characteristics of the patients and characteristics of the vessels and lesions. Results

Analyses of outcome were based on 2380 deaths and 3198 myocardial infarctions. There was no overall difference between the group that received drug-eluting stents and the group that received bare-metal stents in the combined end point of death or myocardial infarction (relative risk with drug-eluting stents, 0.96; 95% confidence interval [CI], 0.89 to 1.03) or the individual end points of death (relative risk, 0.94; 95% CI, 0.85 to 1.05) and myocardial infarction (relative risk, 0.97; 95% CI, 0.88 to 1.06), and there was no significant difference in outcome among subgroups stratified according to the indication for stent implantation. Patients who received drugeluting stents in 2003 had a significantly higher rate of late events than patients who received bare-metal stents in the same year, but we did not observe any difference in outcome among patients treated in later years. The average rate of restenosis during the first year was 3.0 events per 100 patient-years with drug-eluting stents versus 4.7 with bare-metal stents (adjusted relative risk, 0.43; 95% CI, 0.36 to 0.52); 39 patients would need to be treated with drug-eluting stents to prevent one case of restenosis. Among high-risk patients, the adjusted risk of restenosis was 74% lower with drug-eluting stents than with bare-metal stents, and only 10 lesions would need to be treated to prevent one case of restenosis.

From the Department of Cardiology, Uppsala University Hospital, Uppsala (S.K.J., L.W., B.L.); the Department of Cardiology, University Hospital Linköping, Linköping (U.S.); the Department of Cardiology, Länssjukhuset Kalmar, Kalmar (J.C.); the Department of Cardiology, Helsingborg Lasarett, Helsingborg (F.S.); Svensk PCI, Karlstad Lasarett, Karlstad (T.N.); and Uppsala Clinical Research Center, Uppsala University Hospital, Uppsala (S.K.J., J.L., L.W., B.L.) — all in Sweden. Address reprint requests to Dr. James at the Uppsala Clinical Research Center, Uppsala University Hospital, 751 85 Uppsala, Sweden, or at stefan.james@ akademiska.se. *Members of the Swedish Coronary Angiography and Angioplasty Registry (SCAAR) study group are listed in the Appendix. N Engl J Med 2009;360:1933-45. Copyright © 2009 Massachusetts Medical Society.

Conclusions

As compared with bare-metal stents, drug-eluting stents are associated with a similar long-term incidence of death or myocardial infarction and provide a clinically important decrease in the rate of restenosis among high-risk patients. n engl j med 360;19  nejm.org  may 7, 2009

The New England Journal of Medicine Downloaded from nejm.org on January 17, 2017. For personal use only. No other uses without permission. Copyright © 2009 Massachusetts Medical Society. All rights reserved.

1933

The

P

n e w e ng l a n d j o u r na l

rospective, randomized clinical trials and meta-analyses have shown that rates of target-lesion revascularization are unequivocally lower with drug-eluting coronary stents than with bare-metal stents and that rates of death and myocardial infarction are similar.1-4 However, no randomized trials have been prospectively designed and powered for the evaluation of rare outcome events during very-long-term follow-up. Drug-eluting stents are also widely used in broader populations than those specified by the Food and Drug Administration (FDA) and for indications that are not approved by the FDA on the basis of prospective, randomized trials. Registry studies have also suggested that rates of death and myocardial infarction with drug-eluting stents are similar to or lower than those with bare-metal stents,5-7 but these studies have shown trends toward increased rates of late events with drugeluting stents after discontinuation of clopidogrel therapy.8 Although the risk of stent thrombosis is highest early after stent implantation, incomplete neointimal coverage and hypersensitivity reactions from the polymers may increase the risk of late stent thrombosis.9 Therefore, very-long-term follow-up after cessation of dual antiplatelet therapy in large patient cohorts is important. We have previously reported the outcomes among all patients who received coronary stents in Sweden during the 2003–2004 period, as recorded in the Swedish Coronary Angiography and Angioplasty Registry (SCAAR). Our results indicated that there was an increase in late mortality among patients who received a drug-eluting stent.10 To obtain a more reliable estimate of the long-term outcome and efficacy, we have now extended the study to include all patients in Sweden who received a stent during the 2003– 2006 period for whom at least 1 year of followup until the end of 2007 was available. We have also focused primarily on patients who received only one drug-eluting stent as compared with those who received one bare-metal stent, thereby allowing the adjustment for characteristics of lesions and stents in addition to characteristics of patients.

of

m e dic i n e

the period from January 1, 2003, through December 31, 2006, and for whom follow-up data were available for at least 1 year and up to 5 years. The analyses were based on the type of stent implanted at the first recorded procedure. In the primary analysis, patients who received only one drugeluting stent at the initial percutaneous coronary intervention (PCI) were compared with patients who received only one bare-metal stent. In a secondary analysis, all patients who received any stent were included. For these analyses, patients who received at least one drug-eluting stent were assigned to the drug-eluting–stent group, regardless of whether they received a stent of another type at any time; all other patients were assigned to the bare-metal–stent group. The SCAAR Data

The SCAAR records information on consecutive patients from all 29 centers that perform coronary angiography and PCI in Sweden. The list of the most important variables is shown in Table 1.11 Patients were informed about the registration, but written informed consent is not required by Swedish law. Long-term follow-up data were obtained by merging the SCAAR database with other national registries on the basis of the unique 10-digit personal identification number that all Swedish citizens have. Vital status and date of death were obtained from the National Population Registry, and information on the incidence of myocardial infarction (International Classification of Diseases, 10th revision, codes I21 and I22) was obtained from the National Public Registry (in which information on diagnoses at hospital discharge are recorded); all this information was obtained through December 31, 2007. Merging of the registries was performed by the Epidemiologic Centre of the Swedish National Board of Health and Welfare and was approved by the ethics committee at Uppsala University. Since March 1, 2004, the electronic case-report form of the SCAAR requires that information about restenosis in every implanted stent be recorded at the time of any subsequent coronary angiography for a clinical indication. The study and the statistical analysis were designed and interpreted by the authors, all of Me thods whom contributed to the final report and particiStudy Population pated in the decision to submit the findings for In the present study, we included all patients in publication. No stent manufacturer had any role Sweden who had received a coronary stent during in the study. 1934

n engl j med 360;19  nejm.org  may 7, 2009

The New England Journal of Medicine Downloaded from nejm.org on January 17, 2017. For personal use only. No other uses without permission. Copyright © 2009 Massachusetts Medical Society. All rights reserved.

21.6 (4023)

2005

19.3 (3596) 11.4 (2123) 15.8 (2957) 23.0 (4288) 16.1 (3011)

Stockholm

Southeast

South

Middle

West

31.2 (5820) 1.0 (193)

Unstable coronary artery disease

STEMI

Other

n engl j med 360;19  nejm.org  may 7, 2009

The New England Journal of Medicine Downloaded from nejm.org on January 17, 2017. For personal use only. No other uses without permission. Copyright © 2009 Massachusetts Medical Society. All rights reserved. 22.0 (4104) 10.4 (1946)

Current smoker

Unknown

4.8 (896)

49.2 (9172)

Absent

Unknown

46.0 (8591)

Present

Hyperlipidemia — % (no.)

17.4 (3247)

30.2 (5629)

Former smoker

Diabetes — % (no.)

37.4 (6980)

Never smoked

Smoking status — % (no.)

19.0 (3547) 48.8 (9099)

Stable coronary artery disease

Indication — % (no.)

14.4 (2684)

72.2 (13,476)

65.8±11.0

North

Region of Sweden — % (no.)

Male sex — % (no.)

Mean age — yr

26.7 (4989)

25.5 (4765)

2006

26.2 (4882)

2004

Bare-Metal Stent (N = 18,659)

2003

Year of treatment — % (no.)

Variable

4.0 (412)

44.6 (4596)

51.4 (5286)

23.8 (2447)

7.0 (720)

19.4 (1998)

32.3 (3325)

41.3 (4251)

1.5 (159)

20.0 (2060)

52.0 (5349)

26.5 (2726)

3.9 (398)

39.1 (4029)

26.1 (2689)

14.1 (1455)

14.0 (1442)

2.7 (281)

70.4 (7244)

64.8±10.8

30.7 (3160)

35.6 (3668)

22.7 (2334)

11.0 (1132)

5.4

48.6

46.0

20.0

9.5

22.4

30.2

37.9

1.2

28.7

49.7

20.4

14.9

24.1

16.6

10.9

19.3

14.1

71.0

65.8

27.6

25.3

21.4

25.6

Drug-Eluting Stent Drug-Eluting Stent with Adjustment (N = 10,294) for Propensity Score†

One-Stent Cohort

5.0 (1404)

47.9 (13,561)

47.1 (13,321)

17.7 (5007)

10.6 (3006)

21.7 (6136)

30.9 (8727)

36.8 (10,417)

1.0 (273)

30.4 (8612)

48.7 (13,789)

19.8 (5612)

19.7 (5559)

22.2 (6276)

16.6 (4685)

9.7 (2734)

18.5 (5226)

13.5 (3806)

72.6 (20,541)

66.2±11.0

26.3 (7439)

21.2 (6006)

26.0 (7362)

26.4 (7479)

Bare-Metal Stent (N = 28,286)

3.8 (742)

42.6 (8375)

53.7 (10,564)

24.3 (4784)

6.9 (1350)

18.9 (3726)

33.0 (6488)

41.2 (8117)

1.4 (278)

17.3 (3399)

52.8 (10,386)

28.5 (5618)

4.4 (873)

39.6 (7785)

26.3 (5178)

12.4 (2431)

14.7 (2889)

2.7 (525)

71.6 (14,082)

65.5±10.7

31.3 (6154)

34.9 (6866)

22.6 (4453)

11.2 (2208)

5.1

47.0

48.0

17.3

10.3

22.1

31.4

36.2

0.9

30.3

48.1

20.7

15.8

21.6

18.6

9.8

18.3

15.9

73.2

66.1

28.3

21.3

23.4

27.0

Drug-Eluting Stent Drug-Eluting Stent with Adjustment (N = 19,681) for Propensity Score†

Total Cohort

Table 1. Baseline Characteristics and Treatments in the Cohort of Patients Who Received Only One Stent and in the Cohort of All Patients Who Received One or More Stents.*

Long-Term Outcome with Drug-Eluting Stents

1935

1936 2.6 (476) 26.9 (5017)

Cancer diagnosis within previous 3 yr — % (no.)

Previous myocardial infarction — % (no.)

62.4 (11,642) 37.9 (7071)

Clopidogrel before PCI

Glycoprotein IIb/IIIa inhibitor

24.6 (4583) 14.7 (2743) 3.4 (638) 1.5 (285)

Two-vessel disease

Three-vessel disease

Left main coronary artery disease

Unknown

4.6 (470)

36.2 (6761) 3.9 (719)

No

n engl j med 360;19  nejm.org  may 7, 2009

The New England Journal of Medicine Downloaded from nejm.org on January 17, 2017. For personal use only. No other uses without permission. Copyright © 2009 Massachusetts Medical Society. All rights reserved. 23.1 (6534) 9.5 (2699)

2

≥3

3.9 (1094)

37.7 (10,664)

58.4 (16,528)

1.5 (412)

3.8 (1078)

67.4 (19,053)

4.2

36.9

59.0

1.1

4.7

17.8 (5044)

29.5 (8357)

47.4 (13,395)

39.3 (11,116)

62.3 (17,628)

88.6 (25,067)

6.3 (1772)

9.2 (2590)

9.7 (2736)

28.6 (8084)

2.7 (754)

3.4 (958)

0.1 (27)

6.5 (1833)

0.3 (98)

1.3 (379)

6.7 (1907)

3.0 (855)

52.0 (14,697)

45.0 (12,734)

1

No. of stents — % (no.)

Unknown

31.8 (3269)

59.9 (11,179)

Yes

63.7 (6555)

1.5 (152)

4.2 (428)

14.4

23.7

55.8

34.3

64.7

90.4

5.4

10.0

10.8

27.7

3.6

3.2

0.0

8.0

0.5

1.4

6.8

3.5

49.9

46.6

17.6 (3459)

29.4 (5790)

53.0 (10,432)

4.6 (905)

32.9 (6466)

62.5 (12,310)

1.5 (294)

4.9 (972)

18.9 (3725)

31.3 (6169)

43.3 (8521)

27.4 (5394)

69.8 (13,735)

92.1 (18,119)

6.4 (1267)

11.3 (2217)

14.1 (2772)

30.4 (5975)

2.5 (492)

3.9 (773)

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