n most cases, the clinical presentation of in-stent restenosiss asymptomatic or presents as angina pectoris. Sometimes,t presents as acute myocardial infarction (AMI; usually ason–Q-wave AMI). In addition, although usually unevent-ul, treatment of in-stent restenosis may be associated withMI in 1% to 20% of cases.1–5 Therefore, we hypothesized
hat, because drug-eluting stents (DESs) decrease the risk ofngiographic restenosis in comparison with bare metaltents (BMSs), DESs might decrease the risk of AMI duringollow-up. To test this hypothesis, we performed a meta-nalysis from 25 randomized trials comparing DESs withMSs that included 9,791 patients overall.
ethods and Results
o identify trials to include in the study, we conducted aomputerized bibliographic search of the MEDLINE data-ase (National Library of Medicine, Bethesda, Maryland)nd in the abstract supplements of major scientific meetingsf the European Society of Cardiology, American Collegef Cardiology, American Heart Association, and Transcath-ter Cardiovascular Therapeutics until January 2006. Weelected all randomized trials that compared DESs withMSs. We included only trials in which coronary stentsommercially available in Europe by February 2006 werevaluated. We included 25 randomized trials that evaluatedhe following DESs (Tables 1 and 2). (1) The sirolimus-luting Cypher stent (Cordis Corp., Miami Lakes, Florida)as investigated in the RAVEL, SIRIUS, E-SIRIUS, C-
aUnit of Interventional Cardiology, University Hospital La Paz, andHospital Clinico San Carlos, Madrid, Spain. Manuscript received July 13,006; revised manuscript received and accepted September 25, 2006.
IRIUS, DIABETES, SCANDSTENT, SES-SMART,TRATEGY, PRISON-II, BASKET-Cypher trials, and thetudy by Pache et al .6 (2) The paclitaxel-eluting Taxus stentBoston Scientific, Natick, Massachusetts) was investigated inhe TAXUS-I, TAXUS-II (slow release), TAXUS-II (mod-rate release), TAXUS-IV, TAXUS-V, TAXUS-VI, andASKET-Taxus trials. Because the TAXUS-II evaluated 2ifferent release kinetics of paclitaxel (slow and moderate),ach with a control group of patients, we analyzed these 2ubstudies separately. (3) The tacrolimus-eluting Janus stentSorin biomedica, Saluggia, Italy) was assessed in theUPITER-I and JUPITER-II studies. (4) The zotarolimus-elut-ng Endeavor stent (Medtronic Inc., Santa Rosa, California)as evaluated in the ENDEAVOR-II trial. (5) The everolimus-
luting stent (currently the Xience V stent; Guidant Corp.)as studied in the FUTURE-I, FUTURE-II, and SPIRIT-I
rials. (6) The biolimus-eluting Axxon stent (Biosensorsnternational, Singapore) was investigated in the STEALTHrial. Overall, 9,791 patients were included in these trials4,903 allocated to DESs and 4,888 to BMSs).
The review was conducted according to the Quality ofeports of Meta-Analyses of Randomized Clinical Trials
QUOROM) recommendations (Table 2). Reviewer Man-ger 4.1.1 (2000 Cochrane Collaboration, Oxford, Unitedingdom) and SPSS 10.0 (SPSS, Inc., Chicago, Illinois)ere used. Odds ratios (ORs) for AMI and 95% confidence
ntervals (CIs) were calculated by comparing DES withMS rates using raw data for each study and for the pooledopulation (intention-to-treat basis). Although rates of Q-ave and non–Q-wave AMI were not provided separately
n all studies, the OR for the 2 types of AMI were alsoalculated. AMI was defined in most trials as a new increasen serum creatine kinase of �2 times the upper limit of theormal reference range, with a concomitant increase in the
B fraction of the enzyme (Q-wave or non–Q-wave infarc-
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ion according to the development or not of new Q waves onhe electrocardiogram). In most studies, periprocedural in-arction was included in the cumulative incidence of AMIuring follow-up. The Der Simonian and Laird randomffects, Peto, or fixed effect models were used according tohe results of the tests of heterogeneity. The combined effector heterogeneity was calculated by taking the inverse vari-nce estimated. The effect of each study was weighted forts number of patients.
The results showed no heterogeneity across trials (Q testor heterogeneity, p � 0.6786). Of 9,791 patients includedn all trials, 6- to 12-month follow-up was completed in,703 (4,860 and 4,843 of those allocated to DESs andMSs, respectively). Of these, 364 (3.8%) developed anMI during follow-up. The risk of AMI was significantly
ower in patients allocated to DESs (3.3% vs 4.2% in thosellocated to BMSs, OR 0.79, 95% CI 0.64 to 0.97, p � 0.03;igure 1). That means a relative risk decrease of 21% in theisk of AMI (95% CI 3 to 36).
The ORs for AMI were 0.69 (95% CI 0.49 to 0.97), 0.88
able 1ain clinical and angiographic baseline characteristics of trials included i
BASKET � Basel Stent Kosten Effektivitäts Trial; C-SIRIUS � Canaelocity balloon-expandable stent in the treatment of patients with de novoM � diabetes mellitus; ENDEAVOR � A randomized trial to Evaluate
tEnt in de novo nAtiVe corOnary aRtery lesions; E-SIRIUS � European malloon-expandable stent in the treatment of patients with de novo coronarverolimus; JUPITER � Janus Tacrolimus-Eluting Stent Compared to a C
umen diameter; PRISON-II � Primary Stenting of Occluded Native Coroalloon-expandable stent in the treatment of patients with de novo nativetenting Coronary Arteries in Non-stress/benestent Disease Trial; SES-SMArteries; SIRIUS � SIRolImUS-Eluting balloon-expandable stent in the
andomized comparison of a durable polymer everolimus-eluting stent witumans; STRATEGY � Single High Dose Bolus Tirofiban and Sirolimu
95% CI 0.66 to 1.18), and 0.78 (95% CI 0.44 to 1.40) in c
rials evaluating DESs containing sirolimus, paclitaxel, andther drugs, respectively.
In those trials in which rates of Q-wave and non–Q-waveMIs were provided, the rate of Q-wave infarction did notiffer in patients allocated to DESs from those allocated toMSs (0.7% vs 0.6%, respectively, OR 1.20, 95% CI 0.65
o 2.20, p � 0.56; Figure 2). However, there was a trendoward a lower risk of non–Q-wave infarction in patientsllocated to DESs (2.7% vs 3.4%, OR 0.79, 95% CI 0.60 to.06, p � 0.11; Figure 3).
iscussion
ESs are associated with a striking decrease in restenosisates compared with BMSs. Apparently, the only clinicalenefit derived from this angiographic benefit is a de-rease in the need for subsequent revascularization pro-edures, whereas harder end points, such as death orMI, are not affected by the type of stent implanted.7,8
onversely, we have demonstrated that DESs signifi-
ulticenter, randomised, double-blind study of the SIRolImUS-coated Bxary artery lesions; DIABETES � DIABETes and sirolimus-Eluting Stent;ty and efficacy of the medtroNic AVE ABT-578 eluting Driver coronaryter, randomised, double-blind study of the SIRolImUS-coated Bx Velocitylesions; FUTURE � First Use To Underscore Restenosis reduction withoated Stent in Patients With Coronary Artery Disease; MLD � minimum
rteries; RAVEL � Randomized study with the sirolimus-eluting Velocityry artery Lesions; RVD � reference vessel diameter; SCANDSTENT �Sirolimus-Eluting Stent in the Prevention of Restenosis in Small Coronarynt of patients with de novo native coronary-artery lesions; SPIRIT � Ametal coronary stent; STEALTH � STent Eluting A9 BioLimus Trial ing Stent vs Abciximab and Bare Metal Stent in Myocardial Infarction.
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623Coronary Artery Disease/AMI After Drug-Eluting Stents
able 2ncidence of major adverse events, target lesion revascularization, death, angiographic restenosis, and stent thrombosis in each trial for patients allocatedo drug-eluting stents or bare metal stents
MACEs � major adverse cardiac events; TLR � target lesion revascularization; other abbreviations as in Table 1.
Figure 1. Incidence of AMI in patients allocated to DESs or BMSs in each trial and in overall patient population. Abbreviations as in Table 1.
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624 The American Journal of Cardiology (www.AJConline.org)
ollow-up. This seems to be due to a decrease in thencidence of non–Q-wave AMI, whereas the risk of Q-ave infarction was not affected by the type of coronary
tent used. We believe that there are 2 potential expla-ations for the lower incidence of AMI associated withhe use of DESs. First, although most angiographic re-tenoses present clinically as asymptomatic or effort an-ina, the clinical presentation of restenosis may be as anMI (especially as non–Q-wave AMI) in 1% to 20% of
ases, a proportion that seems to be higher compared with
Figure 2. Incidence of Q-wave AMI in patients allocated to DESs or BM
Figure 3. Incidence of non–Q-wave AMI in patients allocated to DESs or
hat of restenosais after percutaneous coronary interven- p
ions without coronary stent implantation.2,3 Stenting isssociated with an aggressive proliferative response withevere intimal hyperplasia, and the tissue inside the stentas been demonstrated to be rich in the highly thrombo-enic tissue factor, which may provide the substrate forhe development of an acute coronary syndrome.9 Sec-nd, although treatment of in-stent restenosis is usuallyneventful, in 1% to 20% of cases, it may be complicatedith a periprocedural AMI (especially non–Q-wave in-
arction)3–5; this risk is higher in elderly and diabetic
ach trial and in overall patient population. Abbreviations as in Table 1.
n each trial and in overall patient population. Abbreviations as in Table 1.
BMSs i
atients.5 The main limitation of this work is that due to
tem
1
2
3
4
5
6
7
8
9
625Coronary Artery Disease/AMI After Drug-Eluting Stents
he follow-up of the trials included (�12 months), theffect of very late stent thrombosis over the risk ofyocardial infarction has not been evaluated.
. Bossi I, Klersy C, Black A, Cortina R, Choussat R, Cassagneau B,Jordan C, Laborde JC, Laurent JP, Bernies M, Fajadet J, Marco J.In-stent restenosis: long term outcome and predictors of subsequenttarget lesion revascularization after repeat balloon angiplasty. J Am CollCardiol 2000;35:1569–1576.
. Walters DL, Harding SA, Walsh CR, Wong P, Pomerantsev E, Jang IK.Acute coronary syndrome is a common clinical presentation of in-stentrestenosis. Am J Cardiol 2002;89:491–494.
. Alfonso F, Auge JM, Zueco J, Bethencourt A, Lopez-Minguez JR,Hernandez JM, Bullones JA, Calvo I, Esplugas E, Perez-VizcaynoMJ, et al, for the RIBS investigators. Long-term results (three to fiveyears) of the Restenosis Intra-stent: Balloon angioplasty versuselective Stenting (RIBS) randomized study. J Am Coll Cardiol2005;46:756 –760.
Teirstein PS, Massullo V, Bass T, Henderson R, Silber S, et al, for the
Stents And Radiation Therepy (START) Investigators. Randomizedtrial of 90Sr/90Y beta-radiation versus placebo control for treatment ofin-stent restenosis. Circulation 2002;106:1090–1096.
. Ajani AE, Waksman R, Sharma AK, Heuser RR, Speiser B, TeirsteinPS, Massullo V, Bass T, Henderson R, Silber S, et al, for the Stents AndRadiation Therepy (START) Investigators. Usefulness of periproce-dural creatinine phosphokinase-MB release to predict adverse outcomesafter intracoronary radiation therapy for in-stent restenosis. Am J Car-diol 2004;93:313–317.
. Pache J, Dibra A, Mehilli J, Dirschinger J, Schömig A, Kastrati A.Drug-eluting stents compared with thin-strut bare stents for the reduc-tion of restenosis: a prospective, randomized trial. Eur Heart J 2005;26:1262–1268.
. Moreno R. Drug-eluting stents and other anti-restenosis devices. RevEsp Cardiol 2005;58:842–862.
. Babapulle MN, Joseph L, Belisle P, Brophy JM, Eisenberg MJ. Ahierarchical Bayesian meta-analysis of randomised clinical trials ofdrug-eluting stents. Lancet 2004;364:583–591.
. Moreno PR, Palacios IF, Leon MB, Rhodes H, Fuster V, Fallon JT.Histopathologic comparison of human coronary in-stent and post-bal-
loon angioplasty restenotic tissue. Am J Cardiol 1999;84:462–466.
