mortality in randomized controlled trials comparing drug ... · mi (%) reference diameter (mm)...

Clinical researchInterventional cardiology

Mortality in randomized controlled trials comparingdrug-eluting vs. bare metal stents in coronary arterydisease: a meta-analysis

Alain Joel Nordmann*, Matthias Briel, and Heiner Claudins Bucher

Basel Institute for Clinical Epidemiology, University Hospital Basel, Hebelstrasse 10, 4031 Basel, Switzerland

Received 28 April 2006; revised 20 July 2006; accepted 11 September 2006; online publish-ahead-of-print 4 October 2006

See page 2737 for the editorial comment on this article (doi:10.1093/eurheartj/ehl378)

Aims To evaluate the effect of drug-eluting vs. bare metal stents for the treatment of coronary arterydisease on overall, cardiac, and non-cardiac mortalities.Methods and results We conducted a systematic literature search to identify all randomized controlledtrials comparing sirolimus or paclitaxel-eluting stents with bare metal stents and reporting mortalitydata after at least 1 year of follow-up. Trial data were reviewed and extracted independently by twoinvestigators in an unblinded standardized manner. Seventeen trials including a total of 8221 patientswere analysed. Peto’s odds ratios (ORs) for total mortality after 1 (n ¼ 8221), 2 (n ¼ 4631), 3(n ¼ 4105), and 4 (n ¼ 1293) years of follow-up were 0.94 [95% confidence interval (CI) 0.66–1.34],1.11 (95% CI 0.76–1.61), 1.25 (95% CI 0.91–1.73), and 1.46 (95% CI 0.92–2.31), respectively. Correspond-ing ORs for non-cardiac mortality were 1.07 (95% CI 0.64–1.80), 1.72 (95% CI 1.01–2.94), 1.45 (95% CI0.93–2.25), and 1.65 (95% CI 0.89–3.10). There was no difference in OR for cardiac mortality amongall trials. In sensitivity analyses, sirolimus- but not paclitaxel-eluting stents were associated with anincrease in non-cardiac mortality at 2 and 3 years of follow-up.Conclusion Drug-eluting stents for the treatment of coronary artery disease do not reduce total mor-tality when compared with bare metal stents. Preliminary evidence suggests that sirolimus- but notpaclitaxel-eluting stents may lead to increased non-cardiac mortality. Long-term follow-up and assess-ment of cause-specific deaths in patients receiving drug-eluting stents is mandatory to determine thelong-term safety of these devices.

KEYWORDSDrug-eluting stents;

Meta-analysis;

Coronary artery disease

Introduction

In the past decade, stent implantation has become thetreatment of choice among patients with coronary arterydisease.1,2 Stents when compared with simple balloon angio-plasty may reduce overall mortality in non-acute coronaryartery disease3 and re-infarction rates in acute coronaryartery disease.4 However, in-stent restenosis due to neointi-mal hyperplasia continues to limit the long-term success ofcoronary artery stenting.5,6 In order to resolve theproblem of restenosis, drug-eluting stents were developed.In recently published meta-analyses of randomized con-trolled trials, drug-eluting stents were found to reduce rest-enoses and the need for revascularization procedures, butnot to reduce overall mortality or the incidence of myocar-dial infarction.7–9 These meta-analyses were limited to afollow-up of 1 year after placement of the stents.Despite some technical problems associated with

drug-eluting stents10 and the publication of case reports oflate thrombosis in drug-eluting stents after discontinuationof antiplatelet therapy,11 drug-eluting stents continue to

be widely used. Recent estimates suggest that in the USA�90% of currently deployed coronary stents are drug-elutingstents.12 The vast majority of implanted drug-eluting stentsis either sirolimus- or paclitaxel-eluting stents. A recentmeta-analysis of head-to-head comparisons of thesedrug-eluting stents demonstrated a reduced need for revas-cularization procedures associated with sirolimus- whencompared with paclitaxel-eluting stents.13

In this meta-analysis of randomized controlled trials, weevaluate the effects of drug-eluting stents compared withbare metal stents on overall, cardiac, and non-cardiac mor-talities as well as the occurrence of stent thromboses duringan extended follow-up for up to 4 years.

Methods

Literature search

We used the Cochrane Collaboration search strategy and searchedMEDLINE, EMBASE, Web of Science, and the Cochrane Library fromJanuary 1980 up to April 2006 to identify all randomized controlledtrials that compare sirolimus or paclitaxel-eluting stents with baremetal stents for the treatment of coronary artery disease. Weadditionally reviewed UptoDate version 2005 and Clinical Evidence

& The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: [email protected]

* Corresponding author. Tel: þ 41 61 265 31 00; fax: þ 41 61 265 31 09.E-mail address: [email protected]

European Heart Journal (2006) 27, 2784–2814doi:10.1093/eurheartj/ehl282

Concise 2004 (issue 12), three websites dedicated to dissemination ofresults from cardiovascular trials (www.tctmd.com, www.theheart.org, www.clinicaltrialresults.org), contacted experts of the field, andsearched reference lists of identified publications for citations ofadditional relevant articles. We contacted original trial investigatorsand stent manufacturers for additional information where needed.

Data processing and data extraction

Two investigators (A.J.N./M.B.) independently assessed trial eligi-bility and quality. Disagreement was resolved by consensus. Dataof eligible trials were extracted in duplicate. We assessed thequality of included trials with respect to concealed treatment allo-cation, blinding of patients and caregivers, blinded outcome assess-ment, loss to follow-up, and full description of losses to follow-upand withdrawals.14

Eligible trials were required to have a randomized controlleddesign comparing drug-eluting sirolimus or paclitaxel stents withbare metal stents in patients with coronary artery disease, toreport mortality data, and to have a follow-up of at least 1 year.Trials were excluded if they compared drug-eluting with baremetal stents in non-native coronary arteries, if they used othereluting drugs than sirolimus or paclitaxel (e.g. everolimus), and ifthey compared drug-eluting stents with each other.

Data aggregation

We calculated Peto’s odds ratios (ORs) for total, cardiac, and non-cardiac mortalities and stent thromboses based on intention-to-treat

data. Simulation suggests that with rare events, meta-analysis under-estimates the true effect of treatment over control, but Peto’s ORs arethe least biased and most powerful method of pooling trial resultsamong the methods in common use.15,16 When events are rare, ORsare a close approximation to the relative risk.17

We tested for heterogeneity with the Cochran Q-test andmeasured inconsistency (I2; the percentage of total varianceacross studies that is due to heterogeneity rather than chance) oftreatment effects across trials.18 In addition, we performed sensi-tivity analyses for all outcomes comparing trials using sirolimus vs.trials using paclitaxel-eluting stents.We investigated the presence of publication bias by means of

funnel plots.19 All statistical analyses were performed using Stata8.2 (StataCorp, College Station, TX, USA).

Results

We identified 17 trials including a total of 8221 patients whichreported mortality data after 1 year. Seven trials (n ¼ 2487)used sirolimus, nine (n ¼ 4908) used paclitaxel, and one20

(n ¼ 826) used both sirolimus- and paclitaxel-eluting stents.Figure 1 illustrates the flow of the selection process for poten-tially eligible trials and reasons for exclusion. Funnel plots ontotal, cardiac, and non-cardiac mortalities from year 1 to 3indicated little evidence for the presence of publication bias(Egger’s test consistently P � 0.1). Twelve trials including4631 patients reported mortality data after 2 years. Nine

Figure 1 Flow chart on selection of included trials. DES, drug-eluting stent.

Mortality in randomized controlled trials 2785

Table 1 Characteristics of included trials

Author Trials Type ofdrug

Number ofpatients inDES/BMS

Follow-up(months)

Mean (SD)age(years)

Men(%)

Diabetes(%)

PriorMI (%)

Referencediameter(mm)

LesionLength(mm)

Post-interventionalprophylaxis

Concealedtreatmentallocation

Blinding ofpatients/caregivers/assessors

Moriceet al.21,38,39

RAVEL Sirolimus 120/118 48 62 70 16 36 2.6 9.6 Aspirin indefinitely.Clopidogrel orticlopidine for 2months

Yes Yes/yes/yes

Moseset al. 22,40,41,

SIRIUS Sirolimus 533/525 48 62 73 25 31 2.8 14.4 Aspirin indefinitely.Clopidogrel for 3months

Yes Yes/yes/yes

Schoferet al.23,42

E-SIRIUS Sirolimus 175/177 36 62 70 19 42 2.6 15.0 Aspirin indefinitely.Clopidogrel orticlopidine for 2months

Yes Yes/yes/yes

Grube et al.25,43 TAXUS I Paclitaxel 31/30 36 66 89 18 28 3 11.3 Aspirin for at least 1year. Clopidogrelfor 6 months

Unclear Yes/yes/yes

Colomboet al. MR26

TAXUS II MR Paclitaxel 135/134 36 59 56 12 30 2.8 10.5 Aspirin indefinitely.Clopidogrel orticlopidine for atleast 6 months

Unclear Yes/yes/yes

Colomboet al. SR26

TAXUS II SR Paclitaxel 131/136 36 61 56 10 29 2.8 10.5 Aspirin indefinitely.Clopidogrel orticlopidine for atleast 6 months

Unclear Yes/yes/yes

Park et al.35 ASPECT Paclitaxel 117/59 24 58 80 18 24 3.2 11 Aspirin indefinitely.Clopidogrel,ticlopidine orcilostazol for 1 to6 months.

Yes Yes/yes/yes

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Schampaertet al.24,44

C-SIRIUS Sirolimus 50/50 36 60 70 24 45 2.7 13.6 Aspirin indefinitely.Clopidogrel for 2months

Yes Yes/yes/yes

Lansky et al.30 DELIVER Paclitaxel 517/512 12 62 71 31 26 2.9 11.3 Aspirin for 1 year.Clopidogrel for 3months

Unclear Not stated inpublication

Gershlick et al.32 ELUTES Paclitaxel 152/38 24 56 81 11 35 3 10.8 Aspirin and clopidogrel for 3 months

Yes Yes/yes/yes

Ardissino et al.34 SES-SMART Sirolimus 129/128 12 63 72 25 28 2.2 11.8 Aspirin and clopidogrel for at least 2months

Yes Yes/yes/yes

Stone et al.27,45 TAXUS IV Paclitaxel 662/652 36 63 72 23 31 2.8 13.4 Aspirin indefinitely.Clopidogrel for 6months

Yes Yes/yes/yes

Dawkinset al.28,46

TAXUS VI Paclitaxel 219/227 36 63 76 20 42 2.8 20.6 Aspirin indefinitely.Clopidogrel for 6months

Yes Yes/yes/yes

Stone et al.47 TAXUS V Paclitaxel 577/579 12 63 70 31 28 2.7 17.3 Aspirin indefinitely.Clopidogrel for atleast 6 months

Yes Yes/yes/yes

Sabate et al.33 DIABE-TES Sirolimus 80/80 24 67 63 100 37 2.4 15.0 Aspirin indefinitely.Clopidogrel for 1year.

Yes No/No/yes

Kelbaek31 SCAND-STENT Sirolimus 163/159 12 63 76 18 52 2.9 18.0 Aspirin indefinitely.Clopidogrel for 1year.

Yes No/no/yes

Kaiser20 et al. BASKET Sirolimus 264 12 64 79 19 27 NA NA Aspirin indefinitely.Clopidogrel for 6months

Unclear No/no/yes

Paclitaxel 281281 (BMS)

Mortality

inrand

omized

controlledtrials

2787

Table 2 Data sources and event rates for overall, cardiac, and non-cardiacmortalities in randomized controlled trials comparing sirolimus-and paclitaxel-eluting stents to bare metal stents

Trial Data source Follow-up (years) Event rates in patients treated with DES and BMS (%)

Death Cardiac death Non-cardiac death

RAVEL (2002) P 1 Sirolimus 1.7 0 1.7BMS 1.7 0.85 0.85

CP/PI 2 Sirolimus 5 0 5BMS 2.5 1.7 0.8

CP/PI 3 Sirolimus 7.5 0.8 6.7BMS 4.2 2.5 1.7

CP 4 Sirolimus 10.8 2.5 8.3BMS 5.9 4.2 1.7

SIRIUS (2003) CP/PI 1 Sirolimus 1.3 0.6 0.7BMS 0.8 0.4 0.4

P 2 Sirolimus 2.1 0.8 1.1BMS 1.3 0.6 0.4

M 3 Sirolimus 3.9 2.1 1.9BMS 2.9 1.7 1.1

M 4 Sirolimus 6 3.2 2.8BMS 4.6 2.1 2.4

E-SIRIUS (2003) P 1 Sirolimus 1.1 0.6 0.6P BMS 0.6 0 0.6

PI 2 Sirolimus 2.3 1.1 1.1BMS 2.8 2.3 0.6

M 3 Sirolimus 5.1 4 1.1BMS 3.9 2.8 1.1

TAXUS I (2003) P 1 Paclitaxel 0 0 0BMS 0 0 0

M 2 Paclitaxel 3.2 0 3.2BMS 0 0 0

M 3 Paclitaxel 3.2 0 3.2BMS 0 0 0

TAXUS II MR (2003) P 1 Paclitaxel 0.7 0 0.7BMS 0.7 0 0.7

CP/M 2 Paclitaxel 3 0.7 2.3BMS 1.5 0 1.5

CP/M 3 Paclitaxel 3.7 1.5 2.2BMS 2.2 0 2.2

TAXUS II SR (2003) P 1 Paclitaxel 0 0 0BMS 1.5 1.5 0

M 2 Paclitaxel 1.6 0.8 0.8BMS 2.2 2.2 0

M 3 Paclitaxel 4.6 1.5 3.1BMS 2.9 2.2 0.7

ASPECT (2003) P/PI 1 Paclitaxel 0.9 0.9 0BMS 0 0 0

PI 2 Paclitaxel 0.9 0.9 0BMS 0 0 0

C-SIRIUS (2004) CP/PI 1 Sirolimus 0 0 0BMS 0 0 0

CP/PI 2 Sirolimus 2 0 2BMS 0 0 0

M 3 Sirolimus 4 2 2BMS 0 0 0

DELIVER (2004) M 1 Paclitaxel 1 0.2 0.8BMS 1.4 0.8 0.6

ELUTES (2004) P 1 Paclitaxel 0.7 0.7 0BMS 0 0 0

PI 2 Paclitaxel 0.7 0.7 0BMS 0 0 0

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trials including 4105 patients reported mortality data after 3years, and two trials including 1293 patients reported mor-tality data after 4 years of follow-up.Most trialsweredesigned toassess theefficacyofdrug-eluting

stents at 9–12 months after the index percutaneous coronaryintervention indenovo (not restenotic) lesions. Thus, full-paperpublications mostly reported 9-month or 1-year follow-upresults. Later, follow-up information was retrieved from eitherweb-posted conference proceedings, personal communicationwith the principle investigators, or stent manufacturers. TheRAVEL,21 SIRIUS,22–24 and TAXUS24–28 trials pre-specified report-ing of long-term follow-up for up to 5 years, whereas in all othertrials protocol-defined follow-up ended after 6 months,29

9 months,3012 months,31 18 months,20 and 2 years.32–34

Requested collaboration was obtained in all cases.Mean age of patients enrolled in individual trials ranged

between 56 and 67 years and patients were mostly male(Table 1). Only one trial included patients with acute ST-elevation myocardial infarctions (21% of patients includedin the BASKET-trial20). One trial included only patients withdiabetes.33 Antiplatelet therapy with clopidogrel, ticlopidine,or cilostazol was recommended in all trials for at least 2–6months after percutaneous coronary intervention. Onepublication included results of two trials; one comparingthe TAXUS MR stent wirh a control group and the othercomparing the TAXUS SR stent to a different control group.26

Two trials compared the effects of bare metal stents withvarious doses of paclitaxel-eluting stents.25,35 For the

purpose of this analysis, we compared patients assigned tobare metal stents with all patients assigned to any dose ofpaclitaxel-eluting stents.Event rates for total, cardiac, and non-cardiac mortalities

in individual trials comparing sirolimus and paclitaxel-eluting stents are summarized in Table 2.

Quality of trials

In general, the quality of included trials was very good. Alltrials reported intention-to-treat analyses. All but threetrials20,26,30 reported concealed treatment allocation. Allbut four trials20,30,31,33 reported blinding of patients andcaregivers. In all trials, clinical endpoints were adjudicatedby an independent clinical events committee (blindedoutcome assessment). Four trials did not fully describe thereasons for withdrawals and losses to follow-up.21,26,27,31

All trials had a loss of follow-up of ,10% at the time of pub-lication of the main pre-specified outcome report(6–12-month follow-up examinations). No trial reportedrates of patients lost to follow up after 1 year.

Overall mortality

ORs for overall mortality in patients treated withdrug-eluting when compared WITH patients treated withbare metal stents were after 1 year (n ¼ 17 trials) 0.94[95% confidence interval (CI) 0.66–1.34; test for heterogen-eity P ¼ 0.6], after 2 years (n ¼ 12 trials) 1.11 (95% CI

SES-SMART (2004) PI 1 Sirolimus 0.8 0 0.8BMS 3.9 0.8 3.1

TAXUS IV (2004) P 1 Paclitaxel 2.1 1.4 0.8BMS 1.7 1.2 0.5

M 2 Paclitaxel 3.6 1.8 1.8BMS 2.6 2.1 1.5

M 3 Paclitaxel 3.9 1.4 2.6BMS 4.1 1.5 2.6

TAXUS V (2005) P/CP/M 1 Paclitaxel 2.1 1 1BMS 1.7 1 0.7

TAXUS VI (2005) P/M 1 Paclitaxel 0 0 0BMS 1.8 0.9 0.9

CP 2 Paclitaxel 1.4 1.4 0BMS 1.4 0.5 0.9

M 3 Paclitaxel 2.3 1.4 0.9BMS 3.2 2.3 0.9

DIABETES (2004) P/PI 1 Sirolimus 3.8 1.3 2.5BMS 5 2.5 2.5

PI 2 Sirolimus 6.3 2.5 3.8BMS 6.3 3.8 2.5

SCANDSTENT (2005) CP/PI 1 Sirolimus 0.6 0.6 0BMS 0.6 0.6 0

BASKET (2005) PI 1 Sirolimus 2.7 1.5 1.1Paclitaxel 3.6 2.8 0.7BMS 3.6 2.1 1.4

BMS, bare metal stents; DES, drug-eluting stents; NA, not available; P, publication; CP, conference proceeding; PI, principal investigator; M, manufacturer.


Figure 2 Forest plots on overall, cardiac and non-cardiac mortalities in randomized controlled trials comparing drug-eluting stents with bare metal stents incoronary artery disease. BMS, bare metal stent; DES, drug-eluting stent; UI, uncertainty interval. (Asterisk) The BASKET trial had three arms (a bare metal stent,a sirolimus- and a paclitaxel-eluting stent arm). Thus, there are 17 trials in total, eight comparisons between sirolimus-eluting and bare metal stents, and 10comparisons between paclitaxel-eluting and bare metal stents.


0.76–1.61; test for heterogeneity P ¼ 0.7), after 3 years(n ¼ 9 trials) 1.25 (95% CI 0.91–1.73; test for heterogeneityP ¼ 0.9), and after 4 years (n ¼ 2 trials) 1.46 (95% CI0.92–2.31; test for heterogeneity P ¼ 0.5) (Figure 2).

Cardiac mortality

ORs for cardiac mortality in patients treated withdrug-eluting when compared with patients treated withbare metal stents were after 1 year (n ¼ 17 trials) 0.84(95% CI 0.52–1.36; test for heterogeneity P ¼ 0.7), after 2years (n ¼ 12 trials) 0.73 (95% CI 0.44–1.23; test for hetero-geneity P ¼ 0.8), after 3 years (n ¼ 9 trials) 1.00 (95% CI0.62–1.60; test for heterogeneity P ¼ 0.6), and after 4years (n ¼ 2 trials) 1.24 (95% CI, 0.64–2.40; test for hetero-geneity P ¼ 0.2).

Non-cardiac mortality

The OR for non-cardiac mortality in patients treated withdrug-eluting compared with patients treated with baremetal stents was not different after 1 year of follow-up(n ¼ 17 trials) (OR 1.07; 95% CI 0.64–1.80; test for hetero-geneity P ¼ 0.8). However, from 2 to 4 years of follow-up,OR for non-cardiac mortality tended to be higher in patientstreated with drug-eluting than in patients treated with baremetal stents: After 2 years (n ¼ 12 trials), the OR was 1.72(95% CI 1.01–2.94; test for heterogeneity P ¼ 0.6), after 3years (n¼9 trials) 1.45 (95% CI 0.93–2.25; test for hetero-geneity P ¼ 0.7), and after 4 years (n¼2 trials) 1.65 (95%CI 0.88–3.10; test for heterogeneity P ¼ 0.08).

Sensitivity analyses

Sensitivity analyses did not reveal any difference in overallor cardiac mortality between trials using sirolimus- andtrials using paclitaxel-eluting stents. However, at 2 and 3years of follow-up, non-cardiac mortality was significantlyincreased when compared with bare metal stents in trialsusing sirolimus-, but not paclitaxel-eluting stents (OR 2.74,95% CI 1.22–6.13; test for heterogeneity P ¼ 0.5 in trialsusing sirolimus-eluting stents compared with OR 1.21, 95%CI 0.59–2.45; test for heterogeneity P ¼ 0.4 in trials usingpaclitaxel-eluting stents at 2 years, and OR 2.04, 95% CI1.00–4.15; test for heterogeneity P ¼ 0.6 in trials usingsirolimus-eluting stents compared with OR 1.17, 95% CI0.67–2.05; test for heterogeneity P ¼ 0.6 in trials usingpaclitaxel-eluting stents at 3 years) (Figure 2). Cause-specific reasons for non-cardiac deaths in patients treatedwith sirolimus-eluting stents are summarized in Table 3.

Stent thromboses

In general, stent thromboses occurring 30 days or more afterstent implantation were rare (Table 4). There was no differ-ence in the incidence of early or late stent thromboses inpatients treated with drug-eluting stents compared withpatients treated with bare metal stents (OR 1.15, 95% CI0.63–2.11; test for heterogeneity P ¼ 0.7 for stent throm-boses occurring �30 days after stent implantation, and OR1.33, 95%CI 0.68–2.58; test for heterogeneity P ¼ 0.13 forstent thromboses occurring from 30 days to the latest avail-able follow-up after stent implantation).

Discussion

In this meta-analysis of randomized controlled trials, we founda trend towards an increased risk for overall mortality inpatients treated with drug-eluting stents compared with baremetal stents among trials providing data from the second tothe fourth year of follow-up. However, CIs for this findingwere wide and included 1. Although there was no differencein cardiac mortality, non-cardiac mortality seemed to behigher among patients treated with drug-eluting than amongpatients treated with bare metal stents. In sensitivity analysescomparing trials using sirolimus- and trials using paclitaxel-eluting stents, this increase in non-cardiac mortality seemedto be limited to trials using sirolimus-eluting stents.We have conducted an extensive literature search to retrieve

all relevant eligible trials. Although formal testing did not indi-cate any publication bias, such a bias cannot definitely be ruledout due to the small number of trials included and the lowpower of any test to detect a publication bias. Although

Table 3 Non-cardiac deaths in patients randomized tosirolimus-eluting stents

Trial Follow-up(years)

n Cause of death

RAVEL 4 10 4 � cancer (lung,prostate,pancreas,gastro-intestinal)

3 � stroke (2 �

haemorrhage,1 � ischaemia)2 � pneumonia1 � pulmonary

embolismSIRIUS 4 15 4 � cancer (2 �

renal, 1 � colon,1 � unspecified)

4 � respiratoryfailure

2 � stroke (1 �

haemorrhage,1 � ischaemia)

2 � sepsis1 � lymphoma1 � car accident1 � seizure disorder

(Alzheimer’sdisease)

C-SIRIUS 3 1 1 � cancer (lung)E-SIRIUS 3 2 1 � cancer (lung)

1 � sepsisSES-SMART 1 1 1 � pancreatic

cancerDIABETES 1 3 1 � septic shock

1 � stroke1 � pulmonary

embolismBASKET 1 3 3 � cancer (2 �

colon cancer, 1 �

rectum cancer)*

*2 cancers already known at time of trial inclusion.No non-cardiac deaths in patients randomized to drug-eluting stents so

far in the SCANDSTENT trial.


Table 4 Stent thrombosis in trials of sirolimus or paclitaxel-eluting stents vs. bare metal stents in coronary artery disease

Trial (reference) Eluting drug Randomizedindividuals (n)

Follow-up(months)

Subacute(� 30 days), n (%)

31–365 days,n (%)

1–2 years,n (%)

2–3 years,n (%)

3–4 years,n (%)

DES BMS DES BMS DES DES BMS BMS DES BMS DES BMS

RAVEL (2002) Sirolimus 120 118 48 0 0 0 0 0 0 0 0 0 0SIRIUS (2003) Sirolimus 533 525 48 1 (0.2) 1 (0.2) 1 (0.2) 3 (0.6) 1 (0.2) 0 1 (0.2) 0 1 (0.2) 0E-SIRIUS (2003) Sirolimus 175 177 36 2 (1.1) 0 0 0 1 (0.6) 0 1 (0.6) 0C-SIRIUS (2004) Sirolimus 50 50 36 1 (2.0) 0 0 1 (2.0) 0 0 0 0TAXUS I (2003) Paclitaxel 31 30 36a 0 0 0 0 0 0 0 0 0 0TAXUS II (MRþ SR)

(2003)Paclitaxel 266 270 36 1 (0.4) 0 2 (0.8) 0 3 (1.1) 0 0 1 (0.4)

ASPECT (2003) Paclitaxel 117 59 24 4 (3.4) 0 0 0 0 0DELIVER (2004) Paclitaxel 517 512 12 1 (0.2) 1 (0.2) 1 (0.2) 1 (0.2)ELUTES (2004) Paclitaxel 152 38 24 1 (0.7) 1 (2.6) 0 0 0 0SES-SMART (2004) Sirolimus 129 128 12b 1 (0.8) 1 (0.8) 0 3 (2.3)TAXUS IV (2004) Paclitaxel 662 652 36 2 (0.3) 4 (0.6) 2 (0.3) 1 (0.2) 3 (0.5) 0 0 0TAXUS VI (2005) Paclitaxel 219 227 36 1 (0.5) 2 (0.9) 0 0 1 (0.5) 0 0 0TAXUS V (2005) Paclitaxel 577 579 12 4 (0.7) 3 (0.5) 0 1 (0.2)DIABETES (2005) Sirolimus 80 80 24 0 0 0 1 (1.3) 2 (2.5) 1 (1.3)SCANDSTENT

(2005)Sirolimus 163 159 12c 1 (0.6) 3 (1.9) 0 2 (1.3)

BASKET (2005) Sirolimus 264 281 12 3 (1.1) 2 (0.7)BASKET (2005) Paclitaxel 281 3 (1.1)

BMS, bare metal stents; DES, drug-eluting stents.aMortality data available up to 36 months of follow-up, data on stent thromboses available for up to 48 months of follow-up.bData on stent thromboses available for 8 months follow-up only.cData on stent thromboses available for 9 months follow-up only.

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publication of the TAXUS trials25–28 generally did not presentdata on overall, but only on cardiac mortality, we were ableto obtain data on overall mortality for all trials by directly con-tacting the stent manufacturer. The quality of the includedtrials was generally very good, and there was no evidence ofheterogeneity among treatment effects on mortality.Our study has several limitations and should be inter-

preted with caution. Most non-cardiac deaths in patientstreated with sirolimus-eluting stents were either due tocancer, stroke, or infectious diseases. Owing to the smallnumber of non-cardiac deaths in the included trials, we werenot able to explore whether one of these individual cause-specific deaths occurred more commonly in patients treatedwith sirolimus-eluting stents than in patients treated withbare metal stents. Therefore, we cannot rule out that theobserved association of an increase in non-cardiac mortalitywith the use of sirolimus-eluting stents might be due tochance alone. However, especially the association of cancer-related deaths associated with the use of sirolimus-elutingstents requires further attention. There is little evidence inthe medical literature about serious side effects associatedwith the use of sirolimus. However, a large multicentre trial toevaluate pre-emptive sirolimus therapy in recipients of orthoto-pic liver transplantation reported an increased incidence ofdeath in the group treated with sirolimus and tacrolimus whencompared with the group treated with tacrolimus alone.36 Afurther limitation of our analysis is the lack of information ondifferential loss of follow-up after regular termination oftrials. Follow-up data were in majority retrieved from web-posted conference proceedings or personal correspondencewith either theprinciple investigators of trials or stentmanufac-turers. All trials including sirolimus-eluting stents pre-specifiedthe reporting of total mortality. In contrast, publications of theTAXUS trials did not routinely report overall mortality, but wererestricted to the report of cardiac mortality as an individualcomponent of a combined primary outcome ofmajor cardiovas-cular events. The database of all TAXUS trials is entirely undercontrol of the stent manufacturer (Boston ScientificCorporation, USA). We were therefore unable to verify thereported mortality rates in the TAXUS trials and had to rely oninformation provided by the manufacturer. Non-cardiac mor-tality was not pre-specified in any trial. Any potential bias orig-inating from a biased data source such as the stentmanufacturer, however, would introduce a bias towards a lackof association between the use of drug-eluting stents andincreased mortality. Therefore, the findings of our analysis

should all the more so raise concern about the safety ofdrug-eluting stents. This concern is supported by the results ofthe late BASKET trial that observed an increase in a combinedoutcome of cardiac death and non-fatal myocardial infarctionafter 18 months in patients treated with drug-eluting stentswhen compared with patients treated with bare metalstents.37 The preliminary findings from this meta-analysisdemand full disclosure of cause-specific mortality data in alltrials with drug-eluting stents with extended observationperiods. The databases of randomized controlled trials compar-ing drug-eluted stents with bare metal stents should be con-trolled by an independent organization and not by the stentmanufacturers. Our results further stress the importance ofmonitoring long-term safety of drug-eluted devices in cohortstudies.In summary,our results fail todemonstrateamortalitybenefit

for drug-eluting stents when compared with bare metal stentsfor the treatment of coronary artery disease during an extendedfollow-up of up to 4 years. In the absence of any difference incardiac mortality, the use of sirolimus-eluting stents seems tobe associated with an increase in non-cardiac mortality. Long-term surveillance of patients treated with drug-eluted stentsand full disclosure of causes of deaths of these patients arecrucial for theassessmentof the long-termsafetyofdrug-elutedstents.

Acknowledgements

We thank Santesuisse and the Gottfried Bangerter-Rhyner-Foundation for supporting our work. We thank all principle investi-gators of included trials for providing us with original data fromtheir trials. We also thank Joerg Koglin from Boston ScientificCorporation, Boston, USA, for providing us with data from theTAXUS trials. We thank Gordon Guyatt, Department of Biostatisticsand Clinical Epidemiology, McMaster University, Hamilton, Canada,for critically reviewing the manuscript. All the authors are sup-ported by Santesuisse and the Gottfried and Julia Bangerter-Rhyner-Foundation. The funding source had no role in the studydesign, in the collection, analysis, and interpretation of data, inthe writing of the report, and in the decision to submit the paperfor publication. All the listed authors have substantially contributedto the conception and design of the study, were involved in theanalysis and interpretation of data, drafted the article or revisedit critically for important intellectual content, and approved thefinal version of the manuscript.

Conflict of interest: none declared.


Appendix

Funnel plots

Forest plots


References

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