new england journal

n engl j med 360;19 nejm.org may 7, 2009 1933

The new england journal of medicineestablished 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 tr ac t

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 Car-diology, 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, Upp-sala (S.K.J., J.L., L.W., B.L.) — all in Swe-den. Address reprint requests to Dr. James at the Uppsala Clinical Research Center, Uppsala University Hospital, 751 85 Uppsala, Sweden, or at [email protected].

*Members of the Swedish Coronary An-giography and Angioplasty Registry (SCAAR) study group are listed in the Appendix.

N Engl J Med 2009;360:1933-45.Copyright © 2009 Massachusetts Medical Society.

Background

The long-term safety and efficacy of drug-eluting coronary stents have been ques-tioned.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 drug-eluting 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 strati-fied according to the indication for stent implantation. Patients who received drug-eluting 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.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 impor-tant decrease in the rate of restenosis among high-risk patients.

Copyright © 2009 Massachusetts Medical Society. All rights reserved. Downloaded from www.nejm.org on July 22, 2010 . For personal use only. No other uses without permission.

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

n engl j med 360;19 nejm.org may 7, 20091934

Prospective, 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 pro-spectively designed and powered for the evalua-tion 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 in-dications 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 drug-eluting 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 fol-low-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 re-corded in the Swedish Coronary Angiography and Angioplasty Registry (SCAAR). Our results indicated that there was an increase in late mor-tality 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 follow-up 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 le-sions and stents in addition to characteristics of patients.

Me thods

Study Population

In the present study, we included all patients in Sweden who had received a coronary stent during

the period from January 1, 2003, through Decem-ber 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 implant-ed at the first recorded procedure. In the primary analysis, patients who received only one drug-eluting stent at the initial percutaneous coronary intervention (PCI) were compared with patients who received only one bare-metal stent. In a sec-ondary 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, regard-less 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 per-sonal identification number that all Swedish citi-zens 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 record-ed); 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 infor-mation about restenosis in every implanted stent be recorded at the time of any subsequent coro-nary angiography for a clinical indication.

The study and the statistical analysis were designed and interpreted by the authors, all of whom contributed to the final report and partici-pated in the decision to submit the findings for publication. No stent manufacturer had any role in the study.


Long-Term Outcome with Drug-Eluting Stents


Tabl

e 1.

Bas

elin

e C

hara

cter

istic

s an

d Tr

eatm

ents

in th

e C

ohor

t of P

atie

nts

Who

Rec

eive

d O

nly

One

Ste

nt a

nd in

the

Coh

ort o

f All

Patie

nts

Who

Rec

eive

d O

ne o

r M

ore

Sten

ts.*

Var

iabl

eO

ne-S

tent

Coh

ort

Tota

l Coh

ort

Bar

e-M

etal

Ste

nt(N

= 1

8,65

9)D

rug-

Elut

ing

Sten

t(N

= 1

0,29

4)

Dru

g-El

utin

g St

ent

with

Adj

ustm

ent

for

Prop

ensi

ty S

core

†

Bar

e-M

etal

Ste

nt(N

= 2

8,28

6)D

rug-

Elut

ing

Sten

t(N

= 1

9,68

1)

Dru

g-El

utin

g St

ent

with

Adj

ustm

ent

for

Prop

ensi

ty S

core

†

Year

of t

reat

men

t — %

(no

.)

2003

26.2

(48

82)

11.0

(11

32)

25.6

26.4

(74

79)

11.2

(22

08)

27.0

2004

25.5

(47

65)

22.7

(23

34)

21.4

26.0

(73

62)

22.6

(44

53)

23.4

2005

21.6

(40

23)

35.6

(36

68)

25.3

21.2

(60

06)

34.9

(68

66)

21.3

2006

26.7

(49

89)

30.7

(31

60)

27.6

26.3

(74

39)

31.3

(61

54)

28.3

Mea

n ag

e —

yr

65.8

±11.

064

.8±1

0.8

65.8

66.2

±11.

065

.5±1

0.7

66.1

Mal

e se

x —

% (

no.)

72.2

(13

,476

)70

.4 (

7244

)71

.072

.6 (

20,5

41)

71.6

(14

,082

)73

.2

Reg

ion

of S

wed

en —

% (

no.)

Nor

th14

.4 (

2684

)2.

7 (2

81)

14.1

13.5

(38

06)

2.7

(525

)15

.9

Stoc

khol

m19

.3 (

3596

)14

.0 (

1442

)19

.318

.5 (

5226

)14

.7 (

2889

)18

.3

Sout

heas

t11

.4 (

2123

)14

.1 (

1455

)10

.99.

7 (2

734)

12.4

(24

31)

9.8

Sout

h15

.8 (

2957

)26

.1 (

2689

)16

.616

.6 (

4685

)26

.3 (

5178

)18

.6

Mid

dle

23.0

(42

88)

39.1

(40

29)

24.1

22.2

(62

76)

39.6

(77

85)

21.6

Wes

t16

.1 (

3011

)3.

9 (3

98)

14.9

19.7

(55

59)

4.4

(873

)15

.8

Indi

catio

n —

% (

no.)

Stab

le c

oron

ary

arte

ry d

isea

se19

.0 (

3547

)26

.5 (

2726

)20

.419

.8 (

5612

)28

.5 (

5618

)20

.7

Uns

tabl

e co

rona

ry a

rter

y di

seas

e48

.8 (

9099

)52

.0 (

5349

)49

.748

.7 (

13,7

89)

52.8

(10

,386

)48

.1

STEM

I31

.2 (

5820

)20

.0 (

2060

)28

.730

.4 (

8612

)17

.3 (

3399

)30

.3

Oth

er1.

0 (1

93)

1.5

(159

)1.

21.

0 (2

73)

1.4

(278

)0.

9

Smok

ing

stat

us —

% (

no.)

Nev

er s

mok

ed37

.4 (

6980

)41

.3 (

4251

)37

.936

.8 (

10,4

17)

41.2

(81

17)

36.2

Form

er s

mok

er30

.2 (

5629

)32

.3 (

3325

)30

.230

.9 (

8727

)33

.0 (

6488

)31

.4

Cur

rent

sm

oker

22.0

(41

04)

19.4

(19

98)

22.4

21.7

(61

36)

18.9

(37

26)

22.1

Unk

now

n10

.4 (

1946

)7.

0 (7

20)

9.5

10.6

(30

06)

6.9

(135

0)10

.3

Dia

bete

s —

% (

no.)

17.4

(32

47)

23.8

(24

47)

20.0

17.7

(50

07)

24.3

(47

84)

17.3

Hyp

erlip

idem

ia —

% (

no.)

Pres

ent

46.0

(85

91)

51.4

(52

86)

46.0

47.1

(13

,321

)53

.7 (

10,5

64)

48.0

Abs

ent

49.2

(91

72)

44.6

(45

96)

48.6

47.9

(13

,561

)42

.6 (

8375

)47

.0

Unk

now

n4.

8 (8

96)

4.0

(412

)5.

45.

0 (1

404)

3.8

(742

)5.

1




Hyp

erte

nsio

n —

% (

no.)

Pres

ent

44.1

(82

27)

46.5

(47

84)

46.6

45.0

(12

,734

)48

.7 (

9578

)45

.7

Abs

ent

53.0

(98

90)

50.6

(52

09)

49.9

52.0

(14

,697

)48

.8 (

9598

)51

.5

Unk

now

n2.

9 (5

42)

2.9

(301

)3.

53.

0 (8

55)

2.6

(505

)2.

8

Hea

rt fa

ilure

— %

(no

.)6.

3 (1

178)

6.9

(711

)6.

86.

7 (1

907)

7.3

(143

0)7.

1

Ren

al fa

ilure

— %

(no

.)1.

2 (2

28)

1.5

(159

)1.

41.

3 (3

79)

1.5

(288

)1.

5

Dia

lysi

s —

% (

no.)

0.3

(55)

0.6

(62)

0.5

0.3

(98)

0.5

(106

)0.

3

CO

PD —

% (

no.)

6.3

(117

6)5.

7 (5

83)

8.0

6.5

(183

3)5.

6 (1

096)

6.7

Dem

entia

— %

(no

.)0.

1 (1

9)<0

.1 (

4)0.

00.

1 (2

7)<0

.1 (

9)0.

0

Peri

pher

al v

ascu

lar

dise

ase

— %

(no

.)3.

2 (5

88)

3.6

(369

)3.

23.

4 (9

58)

3.9

(773

)3.

5

Can

cer

diag

nosi

s w

ithin

pre

viou

s 3

yr —

% (

no.)

2.6

(476

)2.

4 (2

51)

3.6

2.7

(754

)2.

5 (4

92)

2.8

Prev

ious

myo

card

ial i

nfar

ctio

n —

% (

no.)

26.9

(50

17)

28.7

(29

56)

27.7

28.6

(80

84)

30.4

(59

75)

29.0

Prev

ious

PC

I — %

(no

.)9.

7 (1

801)

14.4

(14

83)

10.8

9.7

(273

6)14

.1 (

2772

)11

.8

Prev

ious

CA

BG

— %

(no

.)8.

7 (1

630)

11.2

(11

53)

10.0

9.2

(259

0)11

.3 (

2217

)9.

8

Prev

ious

str

oke

— %

(no

.)5.

9 (1

104)

6.2

(641

)5.

46.

3 (1

772)

6.4

(126

7)5.

9

Med

ical

trea

tmen

t — %

(no

.)‡

Asp

irin

bef

ore

PCI

88.0

(16

,412

)91

.1 (

9381

)90

.488

.6 (

25,0

67)

92.1

(18

,119

)89

.3

Clo

pido

grel

bef

ore

PCI

62.4

(11

,642

)68

.0 (

6997

)64

.762

.3 (

17,6

28)

69.8

(13

,735

)64

.8

Gly

copr

otei

n II

b/II

Ia in

hibi

tor

37.9

(70

71)

26.3

(27

12)

34.3

39.3

(11

,116

)27

.4 (

5394

)37

.2

Ang

iogr

aphi

c fin

ding

s —

% (

no.)

One

-ves

sel d

isea

se55

.8 (

10,4

10)

57.7

(59

35)

55.8

47.4

(13

,395

)43

.3 (

8521

)47

.6

Two-

vess

el d

isea

se24

.6 (

4583

)22

.7 (

2332

)23

.729

.5 (

8357

)31

.3 (

6169

)29

.5

Thre

e-ve

ssel

dis

ease

14.7

(27

43)

14.1

(14

47)

14.4

17.8

(50

44)

18.9

(37

25)

17.0

Left

mai

n co

rona

ry a

rter

y di

seas

e3.

4 (6

38)

4.2

(428

)4.

73.

8 (1

078)

4.9

(972

)4.

3

Unk

now

n1.

5 (2

85)

1.5

(152

)1.

11.

5 (4

12)

1.5

(294

)1.

2

Com

plet

e re

vasc

ular

izat

ion

— %

(no

.)

Yes

59.9

(11

,179

)63

.7 (

6555

)59

.058

.4 (

16,5

28)

62.5

(12

,310

)57

.7

No

36.2

(67

61)

31.8

(32

69)

36.9

37.7

(10

,664

)32

.9 (

6466

)38

.9

Unk

now

n3.

9 (7

19)

4.6

(470

)4.

23.

9 (1

094)

4.6

(905

)3.

3

No.

of s

tent

s —

% (

no.)

167

.4 (

19,0

53)

53.0

(10

,432

)69

.4

223

.1 (

6534

)29

.4 (

5790

)21

.8

≥39.

5 (2

699)

17.6

(34

59)

8.8




Statistical Analysis

The study methods have been described in detail previously.10 The primary objective was to evaluate late-occurring events after the implantation of a drug-eluting stent. The primary end point was the composite of death or myocardial infarction. Secondary end points were death, myocardial in-farction, and restenosis. To compensate for the nonrandomized design of this study, propensity-score methods12 were used. The propensity score was defined as the conditional probability of re-ceiving a drug-eluting stent on the basis of avail-able variables and was estimated with a multiple logistic-regression model. All prespecified vari-ables were included in the respective models (Table 1). To determine whether the propensity score would balance the baseline variables, a stan-dardized mean of each variable was calculated for the drug-eluting–stent group. Standardization was performed according to the propensity-score distribution (categorized in deciles) in the bare-metal–stent group.

To provide separate descriptions of the early and late relative risks of events, we performed “landmark analyses”13 with a prespecified land-mark set at 6 months. Adjusted relative risks were estimated with the use of Cox regression models in which the propensity score and the stent group were entered as covariates.

The risk of restenosis was evaluated in the complete sample of patients who received only one stent and in subgroups previously found to be at an increased risk for restenosis.5,14 We re-port the rate of restenosis at 1 year as well as the rate per 100 person-years, which was calculated as the ratio of the number of patients with an event within 1 year to the sum of the time at risk. The number of patients who would need to be treat-ed with a drug-eluting stent to prevent one case of restenosis was calculated according to the method of Altman and Andersen.15 All analyses were performed with the use of the R statistical program, version 2.7.2.16

R esult s

Characteristics of Patients and Stents

During the 2003–2006 period, 48,892 patients were treated with 86,552 stents during a total of 55,465 PCIs in Sweden. The 925 patients (1.9%) with incomplete baseline data were excluded from the analyses. Table 1 shows the characteristics of St

ent s

ize

— m

m

Dia

met

er

3.2±

0.5

2.9±

0.4

3.2

Leng

th

16.5

±5.1

18.6

±6.1

16.2

Trea

ted

vess

el o

r pr

oced

ure

— %

(no

.)

Rig

ht c

oron

ary

arte

ry34

.1 (

6357

)18

.2 (

1876

)34

.1

Left

mai

n co

rona

ry a

rter

y0.

9 (1

59)

2.3

(236

)1.

3

Left

ant

erio

r de

scen

ding

art

ery

38.9

(72

56)

55.4

(57

04)

39.4

Left

cir

cum

flex

arte

ry22

.9 (

4264

)20

.5 (

2115

)21

.4

Cor

onar

y-ar

tery

byp

ass

graf

t3.

3 (6

23)

3.5

(363

)3.

9

Sten

osis

type

— %

(no

.)

New

ste

nosi

s99

.1 (

18,5

00)

95.9

(98

75)

98.4

Res

teno

sis

0.6

(106

)1.

4 (1

43)

1.2

In-s

tent

res

teno

sis

0.3

(53)

2.7

(276

)0.

4

Occ

lusi

on —

% (

no.)

Non

e71

.6 (

13,3

67)

77.2

(79

49)

73.6

With

in 3

mo

27.3

(50

93)

19.9

(20

46)

25.4

At o

r af

ter

3 m

o1.

1 (1

99)

2.9

(299

)1.

0

* Pl

us–m

inus

val

ues

are

mea

ns ±

SD. C

OPD

den

otes

chr

onic

obs

truc

tive

pulm

onar

y di

seas

e, P

CI

perc

utan

eous

cor

onar

y in

terv

entio

n, a

nd S

TEM

I ST

-seg

men

t el

evat

ion

myo

card

ial i

nfar

c-tio

n. P

erce

ntag

es in

som

e ca

tego

ries

may

not

sum

to

100

beca

use

of r

ound

ing.

† T

he p

erce

ntag

es r

epre

sent

pro

port

ions

of p

atie

nts

in t

he d

rug-

elut

ing-

sten

t gr

oup

whe

n st

anda

rdiz

ed a

ccor

ding

to

the

prop

ensi

ty-s

core

dis

trib

utio

n in

the

bar

e-m

etal

-ste

nt g

roup

.‡

Som

e pa

tient

s re

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the cohort of 10,294 patients who received one drug-eluting stent and 18,659 patients who re-ceived one bare-metal stent at the index procedure (one-stent cohort), as well as of the total cohort of 19,681 patients who received at least one drug-eluting stent and 28,286 patients who received one or more bare-metal stents but no drug-eluting stent. In the total cohort, the drug-eluting–stent group, as compared with the bare-metal–stent group, included a higher proportion of women and a larger number of patients who had features associated with a high risk of restenosis. In addi-tion, more stents were implanted in the drug-eluting–stent group than in the bare-metal–stent group. Pretreatment with clopidogrel was more common and treatment with glycoprotein IIb/IIIa inhibitors was less common in the drug-eluting–stent group than in the bare-metal–stent group. The mean stent length was longer and the diam-eter smaller with drug-eluting stents than with bare-metal stents. On the other hand, as com-pared with patients in the drug-eluting–stent group, patients in the bare-metal–stent group were older and more likely to have cancer, three-vessel disease, and incomplete revascularization. Patients in the bare-metal–stent group were also treated with primary PCI for ST-segment elevation myocardial infarction considerably more often than patients in the drug-eluting–stent group (Ta-ble 1). After adjustment for the propensity score, however, the groups were similar with respect to all baseline characteristics.

Baseline characteristics for the one-stent co-hort, stratified by year of inclusion in the study, are shown in Table 1 of the Supplementary Ap-pendix (available with the full text of this article at NEJM.org). The regional differences in the use of drug-eluting stents were large and persisted over time. The frequencies of pretreatment with clopidogrel and the use of primary PCI for ST-segment elevation myocardial infarction increased in both the drug-eluting–stent group and the bare-metal–stent group over the course of the study. The average rate of use of drug-eluting stents dur-ing the entire period was 35.6% (18.8% in 2003, 32.9% in 2004, 47.7% in 2005, and 38.8% in 2006). Paclitaxel-eluting stents (TAXUS Express and TAXUS Liberté, Boston Scientific) were used in 6247 patients (21.6% of all patients in the one-stent cohort), sirolimus-eluting stents (CYPHER and CYPHER SELECT, Cordis, Johnson & John-

son) in 3351 (11.6%), and zotarolimus-eluting stents (Endeavor, Medtronic) in 686 (2.4%).

Death and Myocardial Infarction

During the 1 to 5 years of follow-up (mean, 2.7), a total of 5578 events occurred in 5046 patients in the one-stent cohort: 3198 myocardial infarc-tions (2044 in the bare-metal–stent group and 1154 in the drug-eluting–stent group) and 2380 deaths (1616 and 764 in the two groups, respec-tively). After adjustment for the propensity score, there was no overall difference in the composite incidence of death or myocardial infarction be-tween the two groups (Fig. 1A). During the initial 6 months, the event rate was lower in the drug-eluting–stent group than in the bare-metal–stent group (relative risk, 0.79; 95% confidence inter-val [CI], 0.71 to 0.87), but this difference was off-set by a higher event rate in the drug-eluting–stent group thereafter (relative risk, 1.11; 95% CI, 1.01 to 1.23). There were no significant differences in event rates among patients who received pacli-taxel-eluting stents, those who received sirolimus-eluting stents, and those who received zotaroli-mus-eluting stents (data not shown).

In the total cohort, 9812 events occurred in 8824 patients; 5565 had at least one myocardial infarction (3292 in the bare-metal–stent group and 2273 in the drug-eluting–stent group), and 4247 died (2706 and 1541 in the two groups, respectively), with no overall difference between the groups (Fig. 1B).

Adjusted mortality alone in the one-stent co-hort was lower with drug-eluting stents than with bare-metal stents during the initial 6 months (relative risk, 0.76; 95% CI, 0.64 to 0.91) and was similar thereafter (relative risk, 1.08; 95% CI, 0.94 to 1.24), with the result that there was no overall long-term difference between the groups (Fig. 1C). The adjusted rate of myocardial infarction was also lower with drug-eluting stents than with bare-metal stents during the initial 6 months (relative risk, 0.79; 95% CI, 0.70 to 0.90) but was higher thereafter (relative risk, 1.16; 95% CI, 1.03 to 1.32), with the result that there was no overall difference between the groups (Fig. 1D). In ad-dition, in the total cohort, mortality and rates of myocardial infarction were similar between the groups (relative risk of death with drug-eluting stents, 0.96; 95% CI, 0.89 to 1.03; relative risk of myocardial infarction with drug-eluting stents,




1.01; 95% CI, 0.95 to 1.08) (see Fig. IA and IB in the Supplementary Appendix).

Outcome Stratified by Indication

In subgroups defined according to the indication for implantation of a stent, there were no signifi-cant differences in the outcomes between the drug-eluting–stent group and the bare-metal–stent group. In the one-stent cohort, the adjusted event rate for the combined end point was lower

with drug-eluting stents than with bare-metal stents during the initial 6 months but was simi-lar during the subsequent period, with a similar pattern for all clinical indications (Fig. 2).

Outcome Stratified by Year of First Stent Implantation

In the one-stent cohort of patients treated in 2003, the rate of the composite end point was similar in the two groups during the initial 6 months

36p6

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Bare-metalstent

Drug-eluting stent

Years

A Death or Myocardial Infarction in the One-Stent Cohort

Relative risk, 0.96 (95% CI, 0.89–1.03)

No. at RiskBare-metal stentDrug-eluting

stent

18,65910,294

16,5679,223

11,6976,105

7,9882,842

3,929879

50

0.30

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0.10

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Bare-metalstent

Drug-elutingstent

Years

B Death or Myocardial Infarction in the Total Cohort

Relative risk, 1.00 (95% CI, 0.95–1.05)


stent

12,28619,681

24,83217,593

17,63611,526

12,1495,367

5,9561,687

50

0.15

Cum

ulat

ive

Ris

k of

Dea

th

0.10

0.05

0.000 1 2 3 4 5

Bare-metalstent

Drug-elutingstent

Years

C Death in the One-Stent Cohort

Relative risk, 0.94 (95% CI, 0.85–1.05)


stent

18,65910,294

17,8309,902

12,8256,717

8,8903,180

4,3911,016

60

0.20

Cum

ulat

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Ris

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Infa

rctio

n

0.15

0.10

0.05

0.000 1 2 3 4 5

Bare-metalstent

Drug-elutingstent

Years

D Myocardial Infarction in the One-Stent Cohort

Relative risk, 0.97 (95% CI, 0.88–1.06)


stent

18,65910,294

16,5679,223

11,6976,105

7,9882,842

3,929879

50

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Figure 1. Cumulative Rates of the Primary Composite End Point and Two of the Secondary End Points.

Cumulative event rates, estimated at the mean propensity score, are shown for patients who received one drug-eluting stent and those who received one bare-metal stent (Panels A, C, and D) and for those who received one or more drug-eluting stents (regardless of whether they received a stent of another type at any time) and those who received only bare-metal stents (one or more) (Panel B). The relative risks (with 95% confidence intervals [CIs]) are for the occurrence of an event among patients who received drug-eluting stents, as compared with those who received bare-metal stents.




(Fig. 3A). During the subsequent 4.5 years of follow-up, the event curves diverged, with a sig-nificantly higher rate in the drug-eluting–stent group than in the bare-metal–stent group. In the 2004 cohort, the event rates were similar during the initial 6 months (Fig. 3B), as well as during the subsequent 3.5 years of follow-up. In contrast, in the 2005 and 2006 cohorts, there were signifi-cantly lower event rates in the drug-eluting–stent group during the initial 6 months (Fig. 3C and 3D), with similar event rates thereafter.

In the 2003–2004 cohort, for whom data for up to 3 years were reported previously, extended follow-up for up to 5 years showed no significant difference in the primary event rates, because a trend toward a lower combined event rate with drug-eluting stents during the initial 6 months (relative risk, 0.89; 95% CI, 0.80 to 1.00) was off-set by a higher event rate thereafter (relative risk, 1.19; 95% CI, 1.09 to 1.29) (Fig. II in the Supple-mentary Appendix).

Restenosis and New Revascularization

On the basis of SCAAR data for the period from March 2004 through May 2008, restenosis oc-curred in 683 of 12,358 patients who received bare-metal stents (5.5%), as compared with 387 of 8648 patients who received drug-eluting stents (4.5%). In a Cox regression analysis that adjusted for differences in baseline clinical characteristics of the patients as well as characteristics of the lesions and stents at baseline, the rate of resteno-sis was lower among patients who received drug-eluting stents than among those who received bare-metal stents (relative risk, 0.43; 95% CI, 0.36 to 0.52) (Table 2). Accordingly, to prevent one case of restenosis per year, 39 lesions would need to be treated with drug-eluting stents. Stent diam-

22p3

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0.20

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Bare-metalstent

Drug-elutingstent

Years

A Stable CAD

Relative risk, 1.10 (95% CI, 0.89–1.36)

Relative risk, 0.66(95% CI, 0.46–0.94)

Relative risk, 0.86(95% CI, 0.74–1.00)

Relative risk, 0.73(95% CI, 0.62–0.85)


stent

35472726

33732608

25391808

1852914

973313

00

0.30

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0.000 1 2 3 4 5

Bare-metalstent

Drug-elutingstent

Years

Relative risk, 1.13 (95% CI, 0.99–1.29)


stent

90995349

82174767

59123100

41771435

2168441

50

B Unstable CAD

0.30

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0.20

0.10

0.000 1 2 3 4 5

Bare-metalstent

Drug-elutingstent

Years

Relative risk, 1.09 (95% CI, 0.90–1.34)


stent

58202060

48121712

31551119

1907461

755113

00

C STEMI

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Figure 2. Landmark Analyses of the Primary Composite End Point in the One-Stent Cohort, Stratified According to the Indication for Stent Implantation.

Cumulative rates of death or myocardial infarction, esti-mated at the mean propensity score, are shown for the first 6 months and for the subsequent period among patients who received one drug-eluting stent and those who received one bare-metal stent. The relative risks (with 95% confidence intervals) are for the occurrence of an event among patients who received a drug-eluting stent, as compared with those who received a bare-metal stent. CAD denotes coronary artery disease, and STEMI ST-segment elevation myocardial infarction.




eter was the most important factor contributing to the reduction in the rate of restenosis with drug-eluting stents. For stents that were less than 3 mm in diameter, the absolute rate of restenosis at 1 year was 3.6 percentage points lower with drug-eluting stents than with bare-metal stents; the corresponding adjusted risk reduction was 65%, and the number needed to treat was 22. The number needed to treat was more than twice

as high in the case of larger stents. The incidence of clinical restenosis was highest among patients with diabetes who received bare-metal stents that were 20 mm long or longer and less than 3 mm wide; the absolute rate of restenosis for this sub-group was 8.3 percentage points higher per year than the rate for patients with diabetes who re-ceived equivalent-size drug-eluting stents, and the number needed to treat was 10.

36p6

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Bare-metalstent

Drug-elutingstent

Years

A 2003

Relative risk, 1.27 (95% CI, 1.06–1.52)

Relative risk, 0.88(95% CI, 0.66–1.17) Relative risk, 0.81

(95% CI, 0.65–1.01)

Relative risk, 0.70(95% CI, 0.58–0.84)

Relative risk, 0.83(95% CI, 0.69–0.99)


stent

48821132

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B 2004

Relative risk, 1.13 (95% CI, 0.95–1.35)


stent

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00

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Years

C 2005

Relative risk, 0.96 (95% CI, 0.80–1.17)


stent

40233668

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Relative risk, 1.09 (95% CI, 0.84–1.40)


stent

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Figure 3. Landmark Analyses of the Primary Composite End Point in the One-Stent Cohort, Stratified According to the Year of Stent Implantation.

Cumulative rates of death or myocardial infarction, estimated at the mean propensity score, are shown for the first 6 months and for the subsequent period among patients who received one drug-eluting stent and those who received one bare-metal stent. The relative risks (with 95% confidence intervals) are for the occurrence of an event among patients who received a drug-eluting stent, as compared with those who received a bare-metal stent.




Tabl

e 2.

Res

teno

sis

in S

ubgr

oups

of P

atie

nts

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nly

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1 Y

ear

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t R

ate

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e R

isk

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D

rug-

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ts

(95%

CI)

N

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Tre

at†

Bar

e-M

etal

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nts

Dru

g-El

utin

g St

ents

Bar

e-M

etal

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nts

Dru

g-El

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g St

ents

no./

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l no.

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vent

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0 pe

rson

-yr

Tota

l54

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(4.

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2.9)

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3.0

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(0.

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39

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t siz

e

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m in

dia

met

er20

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43.

30.

35 (

0.27

–0.4

6)22

≥3 m

m in

dia

met

er33

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33 (

3.6)

122/

4629

(2.

6)3.

82.

80.

52 (

0.41

–0.6

6)56

<20

mm

in le

ngth

377/

9068

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00 (

2.6)

4.

42.

70.

44 (

0.35

–0.5

5)42

≥20

mm

in le

ngth

168/

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3.3)

5.5

3.5

0.42

(0.

31–0

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33

Cor

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y ar

tery

dis

ease

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le

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4.9

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37

Uns

tabl

e 26

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93.

20.

43 (

0.34

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6)38

STEM

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36 (

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44 (

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No

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etes

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0.35

–0.5

3)40

Sten

t dia

met

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19

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50.

53 (

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Sten

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83/2

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0.50

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53

Sten

t dia

met

er <

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m a

nd le

ngth

<20

mm

118/

1994

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0.33

(0.

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25

Sten

t dia

met

er <

3 m

m a

nd le

ngth

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mm

45/4

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0.31

(0.

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14

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90.

46 (

0.32

–0.6

5)36

Sten

t dia

met

er ≥

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ngth

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38/1

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72.

20.

43 (

0.21

–0.8

8)49

Sten

t dia

met

er ≥

3 m

m a

nd le

ngth

≥20

mm

26/4

81 (

5.4)

18/4

07 (

4.4)

5.9

4.7

0.60

(0.

30–1

.23)

45

Sten

t dia

met

er <

3 m

m a

nd le

ngth

<20

mm

29/4

75 (

6.1)

26/6

09 (

4.3)

6.7

4.5

0.47

(0.

25–0

.86)

30

Sten

t dia

met

er <

3 m

m a

nd le

ngth

≥20

mm

14/1

11 (

12.6

)17

/398

(4.

3)14

.94.

60.

26 (

0.11

–0.5

9)10

* ST

EMI

deno

tes

ST-s

egm

ent

elev

atio

n m

yoca

rdia

l inf

arct

ion.

† T

he n

umbe

r ne

eded

to

trea

t re

fers

to

the

num

ber

of le

sion

s.




In the group that received drug-eluting stents, 1571 patients (15.3%) underwent a repeat PCI and 222 (2.2%) underwent coronary-artery bypass grafting during the 1 to 5 years of follow-up. In the bare-metal–stent group, the corresponding numbers were 2780 (14.9%) and 501 (2.7%), re-spectively. Among the 1423 patients who received a second stent, the median intervals to repeat PCI were similar (696 days in the drug-eluting–stent group and 693 in the bare-metal–stent group). In a Cox regression analysis, the drug-eluting–stent group, as compared with the bare-metal–stent group, had lower adjusted rates of any repeat revascularization (relative risk, 0.89; 95% CI, 0.83 to 0.96) and of a repeat PCI (rela-tive risk, 0.90; 95% CI, 0.84 to 0.97). In addition, the rate of coronary-artery bypass grafting tend-ed to be lower in the drug-eluting–stent group than in the bare-metal–stent group (relative risk, 0.87; 95% CI, 0.72 to 1.06).

Discussion

In this study, we evaluated the long-term outcome with drug-eluting stents as compared with bare-metal stents in a very large cohort of unselected, consecutive patients, from all interventional cen-ters in Sweden, in whom a coronary stent was implanted. The conclusion of our previous study10 was based on the total patient population for the 2003–2004 period, which included patients who received multiple stents. With the extended study period, we were able to collect data on a suffi-cient number of patients (28,953) and primary-outcome events to evaluate patients who received only one stent (either a drug-eluting stent or a bare-metal stent) during the index procedure. This one-stent cohort was more than 30% larger than the total patient cohort in the earlier SCAAR study, which included patients who received any number of stents (19,771),10 and the total number of patients in a network meta-analysis that in-cluded 23 randomized trials (18,023).4 The one-stent cohort allowed for adjustments for lesion, vessel, and stent characteristics in the multivari-able analyses, which provided a better balance between the drug-eluting–stent group and the bare-metal–stent group. The availability of this information reduced the difference in the outcome between the two cohorts, explaining in part the difference between the findings for the previous total cohort and the current one-stent cohort.

One factor that may explain the difference in the outcome between the current and previous analyses is a change in the outcome over time, with an early outcome that became gradually worse in the bare-metal–stent group and gradu-ally better in the drug-eluting–stent group. The most important change in clinical practice dur-ing the extended study period was an increase in the use of primary PCI for patients with ST-seg-ment elevation myocardial infarction. The pro-portion of such patients who received stents in-creased more in the bare-metal–stent group than in the drug-eluting–stent group. An increasing proportion of patients pretreated with clopidogrel, progressively higher balloon pressures, and a gradual increase in the duration of clopidogrel treatment after the implantation of drug-eluting stents might have contributed to the relatively lower rate of late events in the drug-eluting–stent group in the current study as compared with the rates in our previous study.

The average use of drug-eluting stents in-creased during the study period, but the varia-tions among centers and among indications for stent implantation remained large. Although the geographic differences accounted for most of the difference in the use of drug-eluting stents, stent selection was also based on risk criteria for reste-nosis, as suggested by the higher percentage of patients with high-risk clinical and angiographic features in the drug-eluting–stent group.17 Stent selection was also based on the clinical risk of an adverse outcome, since ST-segment elevation myocardial infarction was more common in the bare-metal–stent group. However, the multivari-able propensity-score analysis was very effective in adjusting for differences in the characteristics for which we had data (Table 1).

There was no significant difference in the pri-mary composite end point between the drug-eluting–stent group and the bare-metal–stent group during long-term follow-up. In the initial 6 months, mortality tended to be lower in the group that received drug-eluting stents than in the group that received bare-metal stents, a find-ing that is consistent with the results of other registry studies.5,8,18 In contrast to the results of our previous study of SCAAR data, the current study shows no late-occurring increase in mortal-ity after implantation of drug-eluting stents. This finding is consistent with the results of random-ized trials, meta-analyses, and large-scale regis-




try studies.4,19,20 Although late and very-late stent thromboses appear to occur infrequently,8,9 they might still affect mortality.21 The lower clinical need for reinterventions with drug-eluting stents (with an adjusted rate that was 10% lower than that with bare-metal stents) may, however, have led to a subsequent reduction in fatal events, off-setting a possible increase in the risk of late stent thrombosis.22

There seemed to be a trend toward a very-late increase in the rate of myocardial infarction among patients who received drug-eluting stents, a find-ing that is consistent with the slightly higher rate of myocardial infarction after the cessation of clopidogrel therapy in other registry studies and in extended follow-up analyses of data from randomized trials.5,8,23,24 However, the upward shift in the rate of myocardial infarction that oc-curred very late in the drug-eluting–stent group appears to represent an increased event rate only among patients who were treated in 2003, rather than an actual increase of events in the total co-hort. Unmeasured selection bias during the peri-od when drug-eluting stents were first available may have contributed to this result. In the sub-groups of patients who had stent procedures in 2004, 2005, and 2006, the event rates were simi-lar between the drug-eluting–stent group and the bare-metal–stent group, without any signal of an increase in late events.

The average crude absolute rate of restenosis at 1 year was low with both stent types and was 1.5 percentage points lower with drug-eluting stents than with bare-metal stents, correspond-ing to an average 50% relative reduction in the adjusted rate of clinical restenosis. The overall absolute rate of restenosis in this study was lower than the rates in randomized clinical trials but similar to the rates in other registry studies.25-27 The low rates of restenosis and of reintervention after implantation of bare-metal stents and the small absolute difference between these rates and the rates for drug-eluting stents do not support the use of drug-eluting stents in patients who are at low or intermediate risk for restenosis. On the basis of the data from the one-stent cohort, this trial clearly shows that when lesions require stents that are less than 3 mm in diameter and 20 mm or more in length, the event rate for reste-nosis with bare-metal stents is approximately 11

per 100 person-years in patients without diabe-tes and 15 per 100 person-years in patients with diabetes, a risk that is reduced with drug-eluting stents to approximately 4 in patients without dia-betes and 5 in patients with diabetes. For pa-tients with such lesions, drug-eluting stents provide a clear clinical benefit, with one case of restenosis averted for every 10 to 14 lesions treated — a number needed to treat that is re-duced by a factor of four as compared with that for patients at average risk and by a factor of six as compared with that for patients at low risk for restenosis.

The inherent limitations of a nonrandomized, registry study should be acknowledged. Despite appropriate statistical adjustments, unknown con-founders may have affected the results. Moreover, it is not possible to attribute individual events to the individual stents or the stented vessel. Another major limitation of our study is the lack of infor-mation about the duration of clopid ogrel treat-ment, making it impossible to determine whether the timing of events was related to discontinuation of the drug.8 Prolongation of clopid ogrel treat-ment in later years may have contributed to the differences in the outcome over time.

In conclusion, in the present study, which in-cluded a very large, consecutive cohort of all patients who received a coronary stent in Sweden during a 4-year period and who were followed for 1 to 5 years, there was no difference in long-term survival or in the risk of myocardial infarction between the patients who received drug-eluting stents and those who received bare-metal stents. Among patients who required stents that were less than 3 mm in diameter and 20 mm or more in length, there was a relative reduction of ap-proximately 70% and an absolute reduction of more than 10 percentage points in the rate of clinical restenosis. Thus, the use of drug-eluting stents is safe and, in patients with lesions at high risk for restenosis, is also very effective in reduc-ing the risk of clinical restenosis.

Supported by grants from the Swedish Association of Local Authorities and Regions and the Swedish Heart–Lung Foundation (to SCAAR and the Uppsala Clinical Research Center) and the Swedish Board of Health and Welfare and the Swedish Medical Products Agency.

Dr. James reports receiving lecture fees from Boston Scientific, Cordis, and Eli Lilly; and Dr. Scherstén, consulting fees from Medtronic. No other potential conflict of interest relevant to this article was reported.




AppendixThe members of the SCAAR study group are as follows: SCAAR Steering Committee — S. James, Uppsala (chair); B. Lagerqvist, Upp-sala (vice chair); T. Nilsson, Karlstad; E. Omerovic, Göteborg; J. Carlsson, Kalmar; J. Nilsson, Umeå; N. Saleh, Stockholm; O. Fröbert, Örebro; A. Flinck, Göteborg; F. Scherstén, Helsingborg; G. Olivecrona, Lund. Uppsala Clinical Research Center — L. Wallentin (direc-tor); R. Svensson (system developer); O. Felton (system developer); K. Spångberg (data manager); E. Svensson (monitor). Epidemio-logic Center, Swedish Board of Health and Welfare — M. Köster (statistician). SCAAR hospitals and participating physicians — Borås: L. Robertson; Danderyd: T. Särev; Eskilstuna: F. Hjortevang; Falun: I. Sjögren; Gävle: L. Hellsten; Halmstad: P. Hårdhammar; Helsingborg: L. Sandhall; Karolinska University in Huddinge: B. Lindvall; Kalmar: J. Carlsson; Karolinska University in Solna: N. Saleh; Karlskrona: C.-M. Pripp; Kristianstad: R. Uher; Linköping University: U. Stenestrand; Lund University: B. Thorvinger; Ryhov in Jönköping: W. Puskar; Malmö University: C.-G. Gustavsson; Sahlgrenska University in Göteborg: P. Albertsson; Skövde: A. Kallryd; St. Göran in Stockholm: H. Enhörning; Sunderby in Luleå: A. Johansson; Södersjukhuset in Stockholm: M. Aasa; Trollhättan: D. Ioanes; Umeå University: J. Nilsson; Uppsala University: B. Lagerqvist; Västerås: O. Herterich; Örebro University: O. Fröbert.

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