off-label use of drug-eluting versus bare metal stents: a lesion-specific systematic review of...

C©2010, Wiley Periodicals, Inc.DOI: 10.1111/j.1540-8183.2010.00588.x

Off-Label Use of Drug-Eluting versus Bare Metal Stents: A Lesion-Specific

Systematic Review of Long-Term Outcomes

NIRAT BEOHAR, M.D.,1 SHERIDAN N. MEYERS, M.D.,1 ATA ERDOGAN, M.D.,1

MATTHEW E. HARINSTEIN, M.D.,1 KAREN PIEPER, M.S.,2 STEPHANIE GAGNON, M.S.,2

and CHARLES J. DAVIDSON, M.D.1

From the 1Division of Cardiology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois; 2DukeClinical Research Institute, Duke University, Durham, North Carolina, and 3Private Consultant, Montreal, Canada

Objective: The purpose of this systematic review was to evaluate differences in lesion-specific outcomes with the“off-label” use of drug-eluting stents (DES) versus bare metal stents (BMS).Methods: MEDLINE, PubMed, the Cochrane databases, and other Web were searched for studies evaluatingoff-label use of DES and BMS with the same characteristics. Of 1,258 abstracts or manuscripts reviewed, 112studies were included (total N = 23,438). Studies were excluded if patients received both types of stent or nostent; lesion type was unknown; lesion-specific outcomes for ≥6 months were unavailable; or <25 patients wereenrolled.Results: Overall mortality at 6–12 months was approximately 3% for BMS and DES for off-label use. Increase inmortality was greater from 6–12 months to 2 years with BMS than with DES (3.3%–9.1%; 2.8%–4.1%); however,rates were similar at 3 years (BMS: 18.8%; DES:15.3%). Myocardial Infarction rates were similar for both types at6–12 months (BMS: 6.5%; DES: 6.0%). Overall rates of stent thrombosis were 1.8% and 1.7% for BMS and DES,respectively. Similar or slightly lower rates of stent thrombosis were seen for most lesion types, except higher ratesfor small vessels for BMS (5.2%) and true bifurcation for DES (3.3%). Rates of target lesion revascularization(TLR) were 7.5% for BMS and 19.6% for DES at 6–12 months. At 2-years TLR remained lower than DES. Whenthe combined group was compared to registry data alone, similar values were seen.Conclusions: Rates of mortality, myocardial infarction (MI), and stent thrombosis were similar in patients receivingBMS or DES, while TLR rates were lower in DES patients. (J Interven Cardiol 2010;23:528–545)

Conflicts of Interest/Financial Disclosures. Nirat Beohar reports re-ceiving compensation from Speakers Bureaus for Boston Scientific,Abbott Vascular, and The Medicines Company. Charles Davidsonreports receiving grant support from Cordis Corporation, BostonScientific, and Abbott Vascular. Sheridan Meyers is a consultant forAbbott Vascular. None of the other authors has any conflict of interestto disclose.

Source of Funding. Catheterization Lab research funds.

Address for reprints: Nirat Beohar, M.D., Division of Cardi-ology, Feinberg School of Medicine, Northwestern University,Feinberg 8-526, Cardiac Catheterization Laboratories, 251 EastHuron Street, Chicago, IL 60611. Fax: 312-695-0052; e-mail:[email protected].

Introduction

The safety and superior efficacy of drug-elutingstents (DES) as demonstrated in initial random-ized controlled trials (RCTs) led to their approvalby the U.S. Food and Drug Administration (FDA).Subsequent FDA labeling indications were consis-tent with these RCTs: sirolimus-eluting stents (SES)(CypherTM) were indicated for de novo lesions≤30 mm length in coronary arteries with referencediameter 2.5–3.5 mm; paclitaxel-eluting stents (PES)(Taxus R©) were indicated for de novo lesions <28 mmin coronary arteries with reference diameters of2.5–3.75 mm.1–3 Because of the perceived advantages

528 Journal of Interventional Cardiology Vol. 23, No. 6, 2010

OFF-LABEL USE OF DES VERSUS BMS

associated with these devices, global use of DES in-creased rapidly and their clinical utilization quicklyexpanded to include applications outside of the origi-nally approved indications (i.e., “off-label” use).4–6

These more complex off-label applications includeduse in coronary lesion types such as the left main coro-nary artery, ostial lesions, bifurcation lesions, chronictotal occlusions, saphenous vein grafts (SVGs), in-stentrestenosis, small-vessel disease, long lesions, and cal-cified lesions. But although prior studies suggest thatthe relative safety and long-term effectiveness of off-label DES use are lower compared with on-label use,few studies have compared lesion-specific clinical out-comes of DES and BMS in off-label lesions.6 In thisstudy, we examined clinical outcomes based on specificlesion subtypes.

We conducted a systematic review that evaluated allavailable evidence on the safety and efficacy of DESand BMS according to their application in specific le-sion types. By doing so, we sought to elucidate ex-pected rates of clinical outcomes for DES and BMS inoff-label, lesion-specific settings.

Methods

Search Strategy and Study Selection Criteria.We conducted a search of the MEDLINE, PubMed,and Cochrane databases (May 2000–April 2008) andpertinent Web sites (www.acc.org, www.theheart.org,www.tctmd.com, www.clinicaltrialresults.org) weresearched by a research librarian (Galter Health Sci-ences Library, Feinberg School of Medicine, North-western University) to identify relevant studies. Allstudies that evaluated off-label use of DES and BMSwith the same characteristics were extracted fromthe medical literature using the following terms:“drug-eluting,” “bare metal,” “sirolimus-eluting,”“paclitaxel-eluting,” “humans,” “English,” “editorial,”“letter,” “case report,” “clinical trial,” “meta-analysis,”“RCT,” “review,” “comparative study,” and “controlledclinical trial.” The contents of 1,258 abstracts and arti-cles identified by this search were then independentlyreviewed by two investigators (N.B., S.N.M.) to deter-mine whether the studies met eligibility criteria for in-clusion. Studies were eliminated if (1) they containedfewer than 25 patients; (2) <6 months of follow-updata were available; (3) lesion-specific outcomes werenot reported (at least one was required); and/or (4) afull-text English-language version of the article was

not available. A total of 112 studies were found tobe eligible and were included in the analysis (Fig. 1;Table 1). These studies primarily consisted of registrydatabases, but RCTs reporting outcomes of specificlesion subtypes were also included.

“On-label” and “off-label” indications were definedby the device instructions for use when evaluating allstudies. For SES, off-label use included stenting of aleft main lesion, ostial lesion, bifurcation lesion, totallyoccluded lesion, restenotic lesion, lesion in a bypassgraft, lesion length >30 mm, or reference vessel di-ameter (RVD) <2.5 mm or >3.5 mm. For PES, lesioncriteria were identical except for lesion length >28 mmand coronary artery RVD <2.5 mm or >3.75 mm. Forthe BMS group, the majority of which used the CordisBx-Velocity platform, lesion criteria for off-label usewere identical to those for SES. We prespecified the fol-lowing primary safety outcomes: (1) overall mortality;(2) myocardial infarction (MI) as defined by protocol inincluded studies (including fatal and nonfatal non-ST-segment elevation MI and ST-segment elevation MI);(3) death or MI (however, an insufficient number ofstudies reported this event; therefore, it has been ex-cluded from the results); and (4) stent thrombosis (asdefined by protocol). The primary effectiveness out-come was target lesion revascularization (TLR) (targetvessel revascularization [TVR] was used as a surrogatewhen TLR was not reported).

Data Collection. Each article was reviewed by atrained data extractor and the relevant information re-garding the number and percentage of patients with thecharacteristic of interest was entered into a spreadsheet.Data were entered separately for studies according tostent type received. All data presented were retrievedfrom the original publications; no patient-level datawere available for any analyses.

Statistical Analysis. Patient characteristics arepresented as weighted means with standard deviationsfor continuous measures or as weighted rates with 95%confidence intervals (CIs) for categorical factors. Allevents were calculated by type of stent and are pre-sented as weighted proportions with associated 95%CI. Events are categorized into the time period mostclosely matching the median follow-up when a specifictime period is not provided. Inverse variance weightingwas used to calculate the proportion and variance of theproportion for each outcome within each stent type. Allanalyses were performed using SAS version 9.1 (SASCorporation, Cary, NC, USA). Random-effects modelswere generated using PROC NLMIXED to compare to

Vol. 23, No. 6, 2010 Journal of Interventional Cardiology 529

BEOHAR, ET AL.

vein grafts (8)

Figure 1. Study selection flowchart.

fixed-effects models. The random-effects models wereunstable for several subgroups and not able to con-verge. Therefore, this fixed-effects type of compari-son was employed using PROC GENMOD with studyas a repeated measure and adjusting for type of trial(randomized vs. registry). Some of the rates are basedon fairly small numbers of patients. Therefore, CIsshould also be considered when evaluating each rate.The rates are unadjusted to give a better indication ofthe average rate across different types of studies. Pa-

tient subsets vary from one time period to the next,making interpretation of changes in rates across timeproblematic.

Results

A total of 112 studies, comprising 8,739 BMSpatients and 13,699 DES patients, were includedin the study analysis (combined overall baseline



Table 1. Study Characteristics

Outcomes CollectedPatients,

Study Location N Stent Types 6 Months 2 Years 3 Years

BifurcationsPan et al.10 Europe 91 DES Death, thrombus, TLR – MIGe et al.11 Europe, Asia 174 DES Death, MACE,

thrombus, TLR– MI

Ge et al.12 Europe 182 DES Death, MACE,thrombus, TLR

– MI

Ge et al.13 Europe, Asia 181 DES Death, MACE,thrombus, TLR

– MI

Moussa et al.14 USA 120 DES Death, MACE, MI,thrombus, TLR

– MI

Hoye et al.15 Europe 231 DES Death, MACE, TLR – MIKaplan et al.16 Europe 80 DES Death, MACE,

thrombus, TLR– MI

Chen et al.17 Asia 112 DES Death, MACE, MI,thrombus, TLR

– MI

Galassi et al.18 Europe 45 DES Death, MACE,thrombus, TLR

– MI

Pan et al.19 Europe 205 DES Thrombus Death, MI, TLR ThrombusKang et al.20 Asia 582 Both Death, MACE,

thrombus– –

Assali et al.21 Europe 53 DES Death, MACE, MI,thrombus

– –

Vigna et al.22 Middle East 53 DES Death, MACE,thrombus, TLR

Death, MACE, TLR MI

TULIPE23 Europe 186 BMS Death, MACE, MI,thrombus, TLR

– MI

Calcified lesionsMoussa et al.24 USA 1,310 DES, BMS Death, MACE, MI,

thrombus, TLR– MI

Clavijo et al.25 USA 150 DES Death, MACE,thrombus, TLR

– MI

Seo et al.26 Asia 79 DES, BMS Death, MACE, MI,thrombus, TLR

– MI

Khattab et al.27 Europe 61 DES, BMS Death, MACE, MI,TLR

Death, MACE, MI,TLR

MI, thrombus

Mosseri et al.28 USA, MiddleEast

2,484 BMS Death, TLR – MI

Total occlusionsSheiban et al.29 Europe 89 BMS Death, TLR – MIHoye et al.30 Europe 84 DES, BMS Death, MACE,

thrombus, TLR– MI

Werner et al.31 Europe, USA 96 DES, BMS Death, MACE – –Nakamura et al.32 Asia 180 DES, BMS Death, MACE, TLR – MIGe et al.33 Europe, Asia 381 DES, BMS Death, MACE,

thrombus, TLR– MI

PRISON II34 Europe 200 DES, BMS Death, MACE, MI,thrombus, TLR

– MI

Werner et al.35 Europe 122 DES, BMS Death, MACE – MIMigliorini et al.36 Europe 118 DES, BMS Death, MACE, MI – –Jang et al.37 Asia 136 DES Death, MACE, TLR – MISICTO38 Europe,

Middle East25 DES Death, MACE, MI,

thrombus, TLR– MI

Prasad et al.39 USA 1,093 DES, BMS MACE, TLR – MI

Continued.


BEOHAR, ET AL.

Table 1. Continued



In-stent restenosisDegertekin et al.40 Europe, USA,

SouthAmerica

86 DES Death, MACE, MI,TLR

Death, MACE, TLR MI, thrombus

RESEARCH41 Europe 44 DES Death, MACE,thrombus, TLR

– MI

Schiele et al.42 Europe, USA 50 DES Death, MACE, MI,TLR

– MI

ISAR-DESIRE43 Europe 200 DES Death, MACE, MI – –Liu et al.44 Asia 27 DES Death, MACE, MI – –Iofina et al.45 Europe 62 DES Death, MACE, MI,

TLR– MI

Medina et al.46 Europe 140 DES – Death, MACE, MI,thrombus, TLR

Thrombus

Pohl et al.47 Europe 28 DES Death, MACE, MI,TLR

– MI

LeFeuvre et al.48 Europe 100 DES Death, MACE, MI,TLR

Death, MACE, MI,TLR

MI, thrombus

Schiele et al.49 Europe, USA 25 DES Death, MACE, MI – –Migliorini et al.50 Europe 136 DES Death, MACE, MI – –Feres et al.51 USA, South

America25 DES MACE Death, MACE, MI,

thrombus, TLRThrombus

Anderson et al.52 Europe 121 DES – Death, MACE, TLR ThrombusSISR53 USA 259 DES Death, MACE,

thrombus, TLR– MI

RIBS-II54 Europe 76 DES Death, MACE, MI –Li et al.55 Asia 36 DES Death, MACE,

thrombus– MI

TRUE56 Europe 244 DES Death, MACE, MI,thrombus, TLR

– MI

Lim et al57 Europe 94 DES Death, MACE, MI,thrombus, TLR

– MI

Sakamoto et al.58 Asia 134 DES, BMS Death, MACE, MI,thrombus, TLR

– MI

Lee et al.59 Asia 224 DES MACE Death, MACE, MI,TLR

Thrombus

Lee et al.60 Asia 120 DES – – Death, MACE,MI,thrombus,TLR

Brambilla et al.61 Europe 100 DES Death, MACE,thrombus, TLR

– MI

Long lesionsDegertekin et al.62 Europe 96 DES Death, MACE, MI,

TLR– MI

TAXUS VI63 Europe, USA 446 DES, BMS Death, MACE,thrombus, TLR

– MI

Kim et al.64 Asia 527 DES, BMS Death, MACE,thrombus, TLR

– MI

Long-DES-II65 Asia 500 DES Death, MACE,thrombus, TLR

– MI

Continued.



Table 1. Continued



OstialVijayakumar et al.66 Europe 50 DES Death, MI, TLR – MIKini et al.67 USA 100 DES Death, MACE, MI,

thrombus–

Tsagalou et al.68 Europe 86 DES Death, MACE,thrombus, TLR

– MI

Park et al.69 Asia 356 DES, BMS Death, MACE,thrombus, TLR

– MI

Saphenous vein graftsGe et al.70 Europe, Asia 150 DES, BMS Death, MACE,

thrombus, TLR– MI

Price et al.71 USA 35 DES Death, MACE, MI,thrombus

– –

Tsuchida et al.72 Europe 33 DES Death, MACE – MILee et al.73 USA 223 DES, BMS Death, MACE, MI – –Chu et al.74 USA 105 DES, BMS Death, MACE,

thrombus, TLR– MI

Chu et al.75 USA 89 DES Death, MACE,thrombus, TLR

– MI

RRISC76 Europe 150 DES, BMS Death, MACE, TLR – Death, MACE,MI, TLR

Ruchin et al.77 Australia 55 DES Death, MACE, MI,TLR

– MI

Left mainKelley et al.78 Europe, USA 142 BMS Death, MACE, MI,

TLR– MI

de Lezo et al.79 Europe 52 DES Death, MACE, TLR – MIPark et al.80 USA, Asia 223 DES, BMS Death, MACE, TLR – MIChieffo et al.81 Europe 149 DES, BMS Death, MACE, MI,

TLR– MI

Agostoni et al.82 Europe 34 DES Death, MACE – –Valgimigli et al.83 Europe 181 DES, BMS – Death, MACE, MI,

TLRThrombus

Carrie et al.84 (truebifurcation)

Europe 57 BMS Death, MACE – –

Lee et al.85 Asia 35 DES MACE – –Gao et al.86 Asia 224 BMS – Death, MACE, MI,

TLRThrombus

Valgimigli et al.87 Europe 110 DES – Death, Death/MI,MACE, MI,thrombus, TLR

Thrombus

Lee et al.88 USA 50 DES Death, MACE – –Han et al.89 Asia 34 BMS Death, MACE, MI,

TLR– Mi

Valgimigli et al.90 Europe 130 DES – Death/MI, MACE,TLR

Thrombus

Chieffo et al.91 Europe 107 DES Death, MACE, MI,TLR

– MI

Kim et al.92 (truebifurcation)

Asia 116 DES – Death, MACE, MI,thrombus, TLR

Thrombus

Palmerini et al.93 Europe 94 DES – Death, MI –Migliorini et al.94 Europe 101 DES Death, MACE – –

Continued.


BEOHAR, ET AL.

Table 1. Continued



Dudek et al.95 Europe 64 DES, BMS Death, MACE, MI,thrombus

– –

Valgimigli et al.96 Europe 94 DES Death, Death/MI,MACE, MI,thrombus

– –

Sanmartin et al.97 Europe 100 DES Death, MACE, MI – –Ge et al.98 (truebifurcation)

Europe, Asia 70 DES Death, MACE,thrombus, TLR

– MI

Chieffo et al.99 Europe, Asia 147 DES – – Death, MACE,MI, TLR

Sheiban et al.100 Europe 85 DES Death, MACE, MI,thrombus, TLR

Death, MACE, MI,thrombus, TLR

MI, thrombus

Erglis et al.101 Australia 103 DES, BMS Death, MACE, TLR – MISanmartin et al.102 Europe 96 DES Death, MACE –Vecchio et al.103 Europe 114 DES Death, MACE, MI,

thrombus, TLR– MI

Khattab et al.104 Europe 200 DES Death, MACE, MI – Death, Death/MI,MACE, MI,TLR

Kim et al.105 USA 63 BMS Death, MACE, TLR MISueng et al.8 Asia 603 DES, BMS Death Death Death

Small vesselsE-SIRIUS106 Europe,

Canada352 DES, BMS Death, MACE,

thrombus, TLR– TLR

Lemos et al.107 Europe 91 DES Death, Death & MI,TLR, MACE

– –

C-SIRIUS.108 Europe, USA,Canada

100 DES, BMS Death, MACE, TLR – MI

Rodriguez-Granilloet al.109

Europe 197 DES Death, Death/MI,MACE, MI,thrombus, TLR

– MI

LASMAL110 USA, SouthAmerica

124 BMS Death, MACE, MI –

Mehilli et al.111 Europe 360 DES Death, Death/MI, MI,TLR

– MI

Park et al.112 Asia 197 DES Death, MACE, TLR – MIQiao et al.113 Asia 242 DES, BMS Death, MACE,

thrombus, TLR– MI

Meier et al.114 Europe, SouthAmerica,Middle East

774 DES, BMS Death, MACE, MI,TLR

– MI

Tsuchiya et al.115 Europe, USA 25 BMS MACE, thrombus – MIDe Luca et al.116 Europe 387 BMS Death, MACE, MI,

thrombus–

SIRIUS 2.25117 USA 400 DES, BMS Death, MACE, MI,thrombus, TLR

– MI

Tanimoto et al.118 Europe 197 DES – Death, Death/MI,MACE, MI,thrombus, TLR

Thrombus

Lee et al.119 Asia 1,092 DES Death/MI, MACE Death, MACE, TLR ThrombusLi et al.120 Asia 87 DES Death, MACE,

thrombus, TLR– MI

Authors in boldface type are registry studies. Authors italicized are randomized controlled trials.BMS = bare metal stent; DES = drug-eluting stent; MACE = major adverse cardiovascular event; MI = myocardial infarction; TLR = totallesion revascularization.



Table 2. Overall Baseline Characteristics by Stent Type

Characteristic BMS% n = 8,739 DES% n = 13,699

Medical history Mean (95% CI)Age 63 (62–65) n = 8,243 63 (62–64) n = 12,519Ejection fraction 55% (50%–59%) n = 2,487 54% (52%–57%) n = 6,846

BMS% (95% CI) DES% (95% CI)Male 74 (73–75) n = 8,332 77 (76–78) n = 12,882Diabetes mellitus 21 (20–22) n = 5,985 27 (26–27) n = 12,454Insulin-dependent DM 7.3 (5.7–8.8) n = 1,063 9.5 (8.1–10.9) n = 1,522Hypertension 58 (56–59) n = 5,751 64 (63–65) n = 12,660Hypercholesterolemia 57 (56–58) n = 5,751 58 (57–59) n = 12,569Ever smoke 46 (32–60) n = 50 53 (48–57) n = 508History of MI 27 (26–28) n = 4,580 28 (27–28) n = 9,536History of PCI 20 (19–22) n = 2,886 20 (19–21) n = 6,176History of CABG 8.0 (7.1–8.8) n = 3,608 4.7 (4.3–5.1) n = 9,236COPD 3.1 (0.1–6.2) n = 122 4.9 (2.7–7.1) n = 363History of CVD 5.4 (4.2–6.6) n = 1,418 3.2 (2.3–4.2) n = 1,222Renal insufficiency 3.3 (2.3–4.2) n = 1,418 6.2 (5.1–7.4) n = 1,222Peripheral artery disease 8.9 (7.2–10.5) n = 1,151 12 (9–14) n = 768Multivessel disease 52 (49–54) n = 1,196 64 (63–66) n = 5,477

MedicationsHeparin 96 (92–100) n = 84 96 (93–99) n = 139GP IIb/IIIa inhibitors 17 (16–19) n = 3,227 8.3 (7.8–8.9) n = 6,364Lipid lowering/statin 50 (44–56) n = 225 74 (71–76) n = 878Beta blockers 70 (63–77) n = 177 75 (72–77) n = 830ACE inhibitors 37 (31–42) n = 225 43 (40–46) n = 678

n refers to the number of patients within the studies who contributed to the estimate of interest. Values for age and ejection fraction are means.All others are estimates of the percentage of patients (95% confidence interval). BMS = bare metal stent; CABG = coronary artery bypass graft;COPD = chronic obstructive pulmonary disease; DES = drug-eluting stent; DM = diabetes mellitus; GP = glycoprotein; MI = myocardialinfarction; PCI = percutaneous coronary intervention.

characteristics are displayed in Table 2). When com-pared with patients receiving BMS, DES patients weremore likely to be male and to have diabetes mel-litus (DM) (distributions of insulin-dependent DM,however, were similar for both groups), hypertension,and/or renal insufficiency. Patients in the BMS grouphad a greater prevalence of prior coronary artery by-pass grafting (CABG). BMS and DES groups showedsimilar use of heparin, beta blockers, and angiotensin-converting enzyme inhibitors (ACEIs). However, DESpatients were more likely to receive hydroxy methylglutaryl Coenzyme A reductase inhibitors, while BMSpatients were more likely to receive glycoproteinIIb/IIIa inhibitors. Due to inconsistent reporting ofuse of antiplatelet therapies, data on these medi-cations are not presented. Outcome rates were notavailable for some lesion types beyond six months.Although there is variation in rates between lesiontypes, the CIs often overlap and the data are fromdifferent populations. Thus, differences in outcome

across lesion types or across time are difficult to in-terpret.

Lesion-Specific Outcomes: Left Main CoronaryArtery. Mortality rates at 6–12 months postproce-dure were 7.2% and 5.7%, and 18.8% and 17.0%,at 3 years for BMS and DES groups, respectively(Table 3). Mortality rates within the left main BMSsubgroups doubled from 6–12 months to 2–3 years. Inpatients treated with DES, there was a tripling of eventrates from 6–12 months to 3 years. Rates of MI at6–12 months postprocedure appeared similar in bothgroups (Table 4). Rates of TLR were lower at 6–12months in patients with DES compared with patientswith BMS (9% vs 19%). These rates are similar at twoyears (9.6% vs 14.9%) (Table 6).

In-Stent Restenosis. Comparative data for mor-tality, MI, stent thrombosis, or TLR in the setting ofin-stent restenosis were not available for the BMSgroup. For the DES group, rates of mortality, MI,stent thrombosis, and TLR in the setting of in-stent


BEOHAR, ET AL.

Table 3. Estimated Mortality Rates by Stent Type—Overall and by Lesion Type

Patient Stent Combined Combined Combined Registry Only Registry Only Registry OnlyPopulation Type 6–12 Months 2 Years 3 Years 6–12 Months 2 Years 3 Years

Overall BMS 3.32 (2.57–4.27)n = 6,077

9.07(5.83–13.86)n = 551

18.84(13.49–24.14)n = 207

3.85 (3.03–4.88)n = 4,863

8.70(5.41–13.70)n = 517

18.84(13.49–24.14)n = 207

DES 2.82 (2.22–3.57)n = 7,052

4.05 (1.69–9.41)n = 2,836

15.27(8.46–26.01)n = 860

3.03 (2.35–3.91)n = 5,215

4.14(1.63–10.13)n = 2,609

14.64(7.57–26.42)n = 822

Left main BMS 7.23 (4.20–12.17)n = 567

8.70(5.41–13.70)n = 517

18.84(13.51–24.17)n = 207

7.23 (4.20–12.17)n = 567

8.70(5.41–13.70)n = 517

–

DES 5.70 (4.53–7.15)n = 1,579

10.80(8.59–13.49)n = 759

17.00(10.24–26.88)n = 702

5.83 (4.62–7.32)n = 1,529

10.80(8.59–13.49)n = 759

17.00(10.24–26.88)n = 702

In-stent restenosis BMS – – – – – –DES 1.95 (1.49–2.56)

n = 1,1261.68 (0.90–3.11)

n = 6550.83 (0.00–2.46)

n = 1202.00 (1.56–2.55)

n = 7501.68 (0.90–3.11)

n = 6550.83 (0.00–2.46)

n = 120SVG BMS 5.50 (2.36–12.31)

n = 218– – 5.50 (2.36–12.31)

n = 218– –

DES 3.94 (2.13–7.19)n = 355

– – 4.10 (2.10–7.84)n = 317

– –

Ostial BMS 1.74 (0.00–3.7)n = 172

– – – – –

DES 1.88 (1.62–2.18)n = 372

– – 1.88 (1.62–2.18)n = 372

– –

Bifurcation BMS 1.76 (0.11–3.41)n = 243

– – – – –

DES 1.80 (1.29–2.51)n = 722

1.00 (0.00–2.38)n = 369

– 1.77 (1.24–2.52)n = 678

– –

Total occlusion BMS 1.74 (1.03–2.94)n = 459

– – 1.95 (1.02–3.70)n = 359

– –

DES 1.72 (1.03–2.86)n = 290

– – 1.72 (1.03–2.86)n = 290

– –

Small vessel BMS 3.75 (1.38–9.76)n = 877

– – 4.49 (1.77–10.89)n = 710

– –

DES 1.83 (1.38–2.41)n = 1,369

1.26 (0.39–3.93)n = 1,195

– 1.91 (1.27–2.87)n = 838

1.26 (0.39–3.93)n = 1,195

–

Long lesions BMS 0.77 (0.59–1.01)n = 389

– – – – –

DES 0.78 (0.36–1.72)n = 511

– – 0.78 (0.36–1.72)n = 511

– –

Calcified lesions BMS 3.06 (2.46–3.81)n = 3,209

– – – – –

DES 2.75 (1.02–7.23)n = 798

– – – – –

n refers to the number of patients within the studies who contributed to the estimate of interest. Weighted proportions represent the estimatedpercentage of patients who died and associated 95% confidence intervals. BMS = bare metal stent; DES = drug-eluting stent; SVG = saphenousvein graft.

restenosis remained similar at 6–12 months, 2 years,and 3 years.

Saphenous Vein Graft Lesions. Rates of mortal-ity and myocardial infarction among patients receiv-ing stenting for SVG lesions appeared similar between

both groups, while rates of TLR appeared lower amongthe DES group at 6–12 months (3.8% vs 18.6%). Out-comes results were not available at 2 years and 3 years.

Ostial Lesions. Rates of mortality and stentthrombosis and TLR at 6–12 months in patients who



Table 4. Estimated Myocardial Infarction Rates by Stent Type—Overall and by Lesion Type


Overall BMS 6.46 (5.18–8.03)n = 3,878

5.03(1.85–12.98)n = 344

– 7.26 (5.48–9.55)n = 2,429

4.94(1.61–14.17)n = 310

–

DES 5.97 (5.02–7.09)n = 7,961

3.69 (2.66–5.10)n = 996

5.10(2.33–10.82)n = 400

6.75 (5.65–8.04)n = 5,572

4.12 (2.92–5.78)n = 796

3.70 (1.71–7.83)n = 362

Left main BMS 6.34(3.92–10.08)n = 347

4.94(1.61–14.17)n = 310

– 5.05 (3.45–7.33)n = 297

4.94(1.61–14.17)n = 310

–

DES 6.18 (4.27–8.87)n = 745

4.95 (4.11–5.96)n = 359

5.13 (2.89–8.95)n = 242

5.93 (3.97–8.78)n = 692

4.95 (4.11–5.96)n = 359

5.13 (2.89–8.95)n = 242


n = 1,1912.08 (1.25–3.45)

n = 2400.83 (0–2.46)

n = 1202.34 (1.79–3.06)

n = 5562.08 (1.25–3.45)

n = 2400.83 (0–2.46)

n = 120SVG BMS 17.98

(11.04–27.90)n = 267

– – 18.70(10.82–30.36)n = 230

– –

DES 11.09(6.29–18.81)n = 460

– – 9.24(5.42–115.33)n = 422

– –

Ostial BMS – – – – – –DES 7.86

(5.06–12.01)n = 420

– – 7.86(5.06–12.01)n = 420

– –


– – 4.17 (3.51–4.94)n = 243

– –

DES 7.49 (5.63–9.90)n = 1,295

2.00 (0.06–3.94)n = 316

– 7.70(5.71–10.30)n = 1,195

– –


– – 6.35 (4.45–8.97)n = 457

– –

DES 6.00 (3.94–9.01)n = 467

– – 7.08 (5.44–9.18)n = 367

– –

Small vessel BMS 5.09 (3.21–7.97)n = 1,261

– – 5.62 (3.35–9.27)n = 910

– –

DES 4.72 (3.28–6.75)n = 1,628

5.08 (2.56–9.81)n = 197

– 5.25 (3.11–8.72)n = 1,044

5.08 (2.56–9.81)n = 197

–


– – – – –

DES 8.58(7.14–10.29)n = 1,165

– – 8.67 (6.94,10.77)n = 946

– –

Calcified lesions BMS 4.57 (3.80–5.47)n = 684

– – – – –

DES 3.45 (3.13–3.79)n = 660

– – – – –

n refers to the number of patients within the studies who contributed to the estimate of interest. Weighted proportions represent the estimatedpercentage of patients who experience myocardial infarctions and associated 95% confidence intervals. BMS = bare metal stent; DES =drug-eluting stent; SVG = saphenous vein graft.


BEOHAR, ET AL.

Table 5. Estimated Stent Thrombosis Rates by Stent Type Overall and by Lesion Type


Overall BMS 1.80 (0.83–3.83)n = 2,081

– – 2.42 (0.90–6.33)n = 1,039

– –

DES 1.71 (1.22–2.38)n = 4,052

2.17 (2.12–2.23)n = 230

0.83 (0–2.46)n = 120

2.02 (1.47–2.76)n = 2,332

2.17 (2.12–2.23)n = 230

0.83 (0–2.46)n = 120

Left main BMS – – – – – –DES 2.21 (0.82–5.82)

n = 181– – 2.21 (0.82–5.82)

n = 181– –


n = 6212.14 (0.00–4.54)

n = 1400.83 (0.00–2.46)

n = 1201.08 (0.70–1.66)

n = 371– 0.83 (0.00–2.46)

n = 120SVG BMS – – – – – –

DES – – – – – –Ostial BMS 1.20 (0.00–2.85)

n = 167– – – – –

DES 0.88 (0.37–2.07)n = 227

– – 0.88 (0.37–2.07)n = 227

– –


– – – – –

DES 3.28 (2.65–4.05)n = 1,189

– – 3.28 (2.44–4.39)n = 854

– –


– – –

DES 1.92 (1.79–2.06)n = 156

– – –


– – –

DES 1.66 (1.29–2.12)n = 604

2.22 (0.00–5.26)n = 90

1.86 (1.48–2.35)n = 429

– –

Long lesions BMS 1.32 (0–2.81)n = 227

– – –

DES 0.67 (0.49–0.91)n = 450

– – –

Calcified lesions BMS 1.00 (0.15–1.85)n = 524

– – –

DES 0.64 (0.27–1.48)n = 660

– – –

n refers to the number of patients within the studies who contributed to the estimate of interest. Weighted proportions represent the estimatedpercentage of patients who experience a stent thrombosis and associated 95% confidence intervals. BMS = bare metal stent; DES = drug-elutingstent; SVG = saphenous vein graft.

received stenting for ostial lesions were similar be-tween BMS and DES groups. MI rates were not re-ported for BMS patients in this subgroup; 2- and 3-yearoutcomes also were not reported.

Bifurcation. Rates of mortality and TLR at 6–12months were similar between BMS and DES groups.The rates of MI and stent thrombosis at 6–12 monthsappeared higher in the DES group than the BMS group.Rates of MI and TLR did not appear to increase amongDES patients from 6–12 months to 2 years; data for 3-year outcomes in this group are not available.

Total Occlusion. In patients who received stentingfor total occlusion, rates of mortality and MI at 6–12months were similar between BMS and DES groups,while rates of TLR at 6–12 months were lower in theDES group compared with the BMS group and rates ofstent thrombosis were higher with DES use. Outcomesat 2 and 3 years were not available for these patients.

Small-Vessel Lesions. In patients with small-vessel lesions, rates of mortality and MI at 6–12 monthswere similar between BMS and DES groups. Rates ofthrombosis and TLR appeared lower in the DES group



Table 6. Estimated Target Lesion Restenosis Rates by Stent Type—Overall and by Lesion Type. Target vessel restenosis was used if targetlesion restenosis was not available

Stent Combined Combined Combined Registry Only Registry Only Registry OnlyType 6–12 Months 2 Years 3 Years 6–12 Months 2 Years 3 Years

Overall BMS 19.62 (17.80–21.57)n = 7,087

16.89(10.26–26.56)n = 342

– 20.07(17.94–23.39)n = 5,696

14.86(9.60–23.31)n = 308

–

DES 7.50 (6.46–8.69)n = 8,234

6.58 (4.53–9.47)n = 2,643

11.11(4.93–23.14)n = 447

7.88 (6.67–9.28)n = 6,035

6.42 (4.35–9.37)n = 2,416

8.34(2.59–23.76)n = 345

Left main BMS 18.98 (16.82–21.34)n = 469

14.86(9.60–22.31)n = 308

– 19.33(16.97–21.93)n = 419

14.86(9.60–22.31)n = 308

–

DES 8.93 (5.73–13.66)n = 661

9.60(7.44–12.30)n = 448

9.67(1.98–36.21)n = 225

9.49(6.14–14.40)n = 611

9.60(7.44–12.30)n = 448

9.67(1.98–36.21)n = 225


n = 1,1297.83 (6.41–9.52)

n = 6265.83

(1.64–10.03)n = 120

6.90 (5.24–9.02)n = 870

7.83 (6.41–9.52)n = 626

5.83(1.64–10.03)n = 120

SVG BMS 18.58 (15.41–22.23)n = 183

– – 17.81(14.08–22.26)n = 146

– –

DES 3.81 (2.48–5.81)n = 315

– – 3.61 (2.18–5.92)n = 277

– –

Ostial BMS 11.63 (6.84–16.42)n = 172

– – – – –

DES 8.13 (3.68–17.02)n = 320

– – 8.13(3.68–17.02)n = 320

– –


– – – – –

DES 12.13 (9.35–15.58)n = 1,284

8.61(5.10–14.16)n = 302

– 12.76(9.85–16.36)n = 1,197

8.82(5.21–14.57)n = 102

–

Total occlusion BMS 25.93 (20.10–32.76)n = 1,558

– – 26.27(20.00–33.68)n = 1,458

– –

DES 7.38 (4.74–11.33)n = 711

– – 7.77(4.86–12.20)n = 611

– –


– – 15.28(12.38–18.71)n = 613

– –

DES 7.54 (5.38–10.47)n = 1,859

4.65 (3.20–6.71)n = 1,289

– 6.92 (4.98–9.52)n = 1,274

4.65 (3.20–6.71)n = 1,289

–


– – – – –

DES 5.15 (3.73–7.08)n = 1,164

– – 4.76 (3.22–7.00)n = 945

– –

Calcified lesions BMS 18.11 (17.07–19.20)n = 3,209

– – – – –

DES 4.92 (4.14–5.84)n = 861

– – – – –

n refers to the number of patients within the studies who contributed to the estimate of interest. Weighted proportions represent the estimatedpercent of patients who experience a target lesion restenosis and associated 95% confidence intervals. BMS = bare metal stent; DES =drug-eluting stent; SVG = saphenous vein graft.


BEOHAR, ET AL.

at this time point. Rates of mortality, MI, stent throm-bosis, and TLR remained similar among DES patientsat 6–12 months and at 2 years.

Long Lesions. Rates of mortality and MI amongpatients with long lesions were similar for BMS andDES groups at 6–12 months postprocedure. Rates ofTLR and stent thrombosis at 6–12 months appearedlower with DES than with BMS.

Calcified Lesions. In patients with calcified le-sions, rates of mortality, MI, and stent thrombosis at6–12 months were similar in the BMS and DES groups.The rate of TLR at 6–12 months was lower in the DESgroup than in the BMS group.

Combined Overall Outcomes Compared withRegistry-Only Off-Label Outcomes. Outcomes forthe DES versus BMS groups were compared for thecombination of all studies (including clinical trials,RCTs, and registries) versus outcomes from registrystudies only. In all cases, the rates of occurrence ofoutcomes were similar. There was no obvious trend forthose in the registry to be higher or lower than the ratesin the two types of studies combined.

Discussion

In this lesion-specific, systematic analysis of off-label use of DES and BMS in the setting of current per-cutaneous coronary intervention (PCI) practice, ratesof TLR are lower in patients who received DES than inpatients who received BMS in all lesion subtypes ex-cept ostial and bifurcation lesions. Rates of mortality,MI, and stent thrombosis are similar at 6–12 monthsfor both stent types. The rate of stent thrombosis washigher in DES patients with true bifurcation, and inBMS patients with small lesions. These findings arerepresentative of real-world practice, as they encom-pass different operators with varying levels of skill, var-ious practice environments (including different coun-tries), and comorbid conditions that differ from thoseseen in pivotal trials of DES and BMS. In additionto complex lesion morphology and histopathology asthe commonly perceived causes of stent thrombosisand restenosis, additional factors include drug, poly-mer, and metal composition as potential hypersensi-tivity etiologies leading to restenosis, thrombosis, andvessel remodeling with aneurysm formation. Nebekeret al. identified 17 cases of hypersensitivity syndromesthought to be caused by DES. Of these patients, 4 diedwith stent thrombosis and eosinophilic infiltration into

the stent was seen on histology. Polymer was thoughtto be the major factor.121 In addition, Koster and col-leagues reported that skin tests positive for allergy tonickel and molybdenum were more frequent in patientswith recurrent in-stent restenosis.122 The possible con-tribution of clopidogrel or aspirin resistance is also aconsideration. Given a relative paucity of publishedmeta-analyses examining outcomes of DES and BMSuse in off-label lesion subtypes, we wish to briefly high-light two recent publications that examined outcomesin labeled use of stents.

Stettler and colleagues conducted a meta-analysis of38 randomized trials comparing DES to BMS, or DESto each other (SES head-to-head with PES);7 however,there was no analysis of PCI performed for labeledor off-label indications (trials incorporating both typesof stent use were included in the meta-analysis). Theyfound that mortality and stent thrombosis rates weresimilar between DES and BMS groups at 4 years. How-ever, they also found that DES use (specifically SES)was associated with a lower incidence of MI when com-pared with BMS use Hazard Ratio (HR) 0.81, 95% CI0.66–0.97; P = 0.03), a finding that differs from ourresults. Finally, compared with BMS, the incidence ofTLR was found to be significantly reduced with bothtypes of DES, the reduction being more pronouncedwith SES than with PES (HR 0.70, 95% CI 0.56–0.84;P = 0.0021).7

Marroquin and colleagues analyzed data from 6,551patients in the National Heart, Lung and Blood In-stitute (NHLBI) Dynamic Registry to compare BMSand DES use for off-label indications.6 Patients werefollowed for 1 year for occurrence of cardiovascularevents and death. Marroquin et al. found that withinthe off-label group, patients with DES (as comparedwith BMS) had lower rates of MI (4.4% vs. 5.9%,P = 0.06), death (3.7% vs. 6.4%, P < 0.001), and deathor MI (7.5% vs. 11.6%, P < 0.001). These results dif-fer from those observed in the Stettler meta-analysisin that mortality in the dynamic study was noted to belower in the DES group at 1 year. In findings similarto those of our own analysis, the authors observed thatrates of repeat revascularization (combined TLR andTVR) were lower with DES use than with BMS usefor off-label indications (12.7% vs. 17.5%, P < 0.001).To specifically address our results for use of DES orBMS in saphenous bypass grafts, we provide compar-ison with results published by Vermeersch et al. whoevaluated the use of DES (SES) and BMS in 75 pa-tients with diseased SVGs.9 At a median follow-up of



32 months, 11 deaths occurred after SES (29% [95% CI17%–45%]) vs. 0 after BMS (0% [95% CI 0%–9%]);P < 0.001). Rates of MI and TVR did not substantiallydiffer: 18% and 34% after SES, respectively, versus5% and 38% after BMS, respectively. Vermeersch andcolleagues found that use of DES in this cohort wasassociated with significantly higher mortality, with nobenefit in TVR. These results differ from those seenin our analysis, which revealed a similar incidence ofmortality and stent thrombosis and a lower rate of TLRat 6–12 months with use of DES compared with BMS.

Limitations

An extensive literature search was performed to re-trieve all studies applicable to our analysis; however,some studies may have been inadvertently excluded.Comparisons between BMS and DES are not possiblebecause these groups comprise subjects drawn fromdifferent studies and represent different patient charac-teristics, and likely introduced confounding that cannotbe accounted for in this review. Similarly, outcomesacross time do not necessarily reflect the same studies,as many studies reported results at only one time pe-riod. Also, the numbers of patients with certain lesiontypes are small and can result in unstable estimates ofoutcomes, although all results that were based on anal-ysis of fewer than 100 patients have been excluded.In addition, rates of stent thrombosis in patients withleft main disease who received BMS, as well as 2-and 3-year outcomes for patients with total occlusion,were not available, which may affect the overall inter-pretation of results. Another important factor that maybear upon the interpretation of our findings is the lackof available data characterizing the use of antiplatelettherapy, which may appreciably affect rates of stentthrombosis for both BMS and DES.

The studies were primarily unadjusted and observa-tional, with noted differences in patient characteristicsbetween studies and between patients from DES andBMS studies. Therefore, formal comparisons of dif-ferences in stent type are fraught with biases and notappropriate. All comparisons made in this article aredescriptive only and cannot be used to identify causalrelations. Care should also be taken when comparingacross time intervals, since few trials had results at allthree time points. Therefore, the populations at onetime point are likely different than those at another,

causing outcomes to be representative of different setsof patients.

Conclusions

In this lesion-specific systematic analysis evaluatingoff-label use of DES and BMS in PCI, mortality (over-all and lesion-specific) was similar at 6–12 months forboth stent types, as were rates of MI except higherrates for bifurcation lesions with DES use. The overallstent thrombosis rate was low and was similar betweenDES and BMS groups at 6–12 months except for anobserved high rate of stent thrombosis with BMS insmall vessels and with DES in bifurcation lesions.

In terms of overall efficacy, the rate of TLR wasmarkedly lower in patients receiving DES than thosewith BMS across all lesion subtypes (except for os-tial and bifurcation lesions) at 6–12 months. The trendremained in the overall stent groups at 2 years. Exam-ining these efficacy and safety rates of lesion-specificoutcomes using BMS or DES for PCI may prove help-ful for cardiologists seeking the best option when con-fronted with a decision regarding stent use in “off-label” lesion anatomy, and our analysis may also serveas a useful benchmark for comparing clinical out-comes as lesion-specific stent technologies continueto evolve.

Acknowledgments: The authors thank Jonathan McCall foreditorial assistance with this manuscript.

Author Contributions. NB, SNM, and CJD conceived and de-signed the study. KP and SG performed the analysis. AE and MEHwere responsible for acquisition of the data. NB and SNM wrote thefirst draft of the manuscript. All authors critically revised the articlefor important intellectual content and approved the final version ofthe manuscript.

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