A Meta-Analysis Of

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Archives of Cardiovascular Disease (2012) 105, 544—556

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CLINICAL RESEARCH

Zotarolimus-eluting stent versus sirolimus-eluting

and paclitaxel-eluting stents for percutaneous

coronary intervention: A meta-analysis of

randomized trials

Stent actif au zotarolimus versus sirolimus et paclitaxel dans les procédures

coronaires percutanées : méta-analyse des essais randomisés

a,∗ a a

Ankur Sethi , Amol Bahekar , Rohit Bhuriya ,

b a

Anurag Bajaj , Param Puneet Singh ,

a a

Rohit Arora , Sandeep Khosla

Department of Medicine, Rosalind Franklin University of Medicine and Sciences, 3333, Green

Bay Road, North Chicago, IL 60064, USA

Department of Medicine, Wright Center of Graduate Medical Education, Scranton, PA, USA

Received 10 December 2011; received in revised form 27 December 2011; accepted 6 January

2012

Available online 9 November 2012

KEYWORDS Summary

Zotarolimus; Background. — The zotarolimus-eluting stent (ZES) is a new drug-eluting stent that delivers

Drug-eluting stents; zotarolimus, a synthetic analogue of sirolimus, through a biocompatible phosphorylcholine

Percutaneous polymer coating. ZES has shown promising results compared with bare-metal stents, but its

coronary intervention safety and efﬁcacy against sirolimus-eluting (SES) and paclitaxel-eluting (PES) stents is yet to

be established.

Aims. — We aimed to summarize current evidence from randomized trials comparing ZES with

SES and PES.

Methods. — We searched the Medline, Embase and CENTRAL databases for randomized studies

comparing ZES with SES and PES for percutaneous coronary intervention. Relevant clinical and

Abbreviations: CI, conﬁdence interval; DES, drug-eluting stent(s); MACE, major adverse cardiovascular events; OR, odds ratio; PCI, per-

cutaneous coronary intervention; PES, paclitaxel -eluting stent(s); RCT, randomized controlled trial; SES, sirolimus-eluting stent(s); STEMI,

ST-segment elevation myocardial infarction; TLR, target lesion revascularization; TVR, target vessel revascularization; ZES, zotarolimus-

eluting stent.

∗

Corresponding author. Fax: +1 773 257 6726.

E-mail address: [email protected] (A. Sethi).

ZES compared with SES and PES in PCI 545

angiographic outcomes were extracted and combined using random and ﬁxed-effect models for

heterogeneous and homogenous outcomes, respectively.

Results. — Seven randomized trials met the inclusion criteria: ZES group, n = 3787; SES group,

n = 2606; PES group, n = 1966. Compared with SES, ZES was associated with signiﬁcantly higher

odds of clinically driven target vessel revascularization (odds ratio [OR] 2.36, 95% conﬁdence

interval [CI] 1.78—3.14) and target lesion revascularization (OR 2.46, 95% CI 1.36—4.46). Com-

pared with SES, ZES had higher in-stent restenosis (OR 6.13, 95% CI 3.96—9.50), late lumen loss

‘in-stent’ (mean difference [MD] 0.39 mm, 95% CI 0.34—0.44) and late lumen loss ‘in-segment’

(MD 0.18 mm, 95% CI 0.15—0.21). ZES was associated with higher in-stent late lumen loss than

PES (MD 0.18 mm, 95% CI 0.07—0.28). There were no differences in mortality, reinfarction or

stent thrombosis with ZES compared with SES and PES.

Conclusion. — ZES is not superior to PES and is inferior to SES in terms of angiographic outcomes

and clinically driven revascularization.

MOTS CLÉS Résumé

Zotarolimus ; Justiﬁcation. — Le stent actif au zotarolimus est un nouveau stent libérant du zotarolimus,

Stent actif ; analogue synthétique du sirolimus, au travers d’un polymère biocompatible (phosphoryl-

Angioplastie choline). Les résultats initiaux sont prometteurs en comparaison des stents métalliques

coronaire percutanée mais l’efﬁcacité et la sécurité, comparativement aux stents au sirolimus ou au paclitaxel,

n’ont pas été établies. L’objectif était donc de faire la synthèse des données actuelles des

études randomisées comparant ces trois types de stents (zotarolimus, sirolimus et pacli-

taxel).

Méthode. — Nous avons interrogé les bases Medline, Embase et CENTRAL, en nous intéressant

aux études randomisées comparant ces différents types de stents pour les interventions coron-

aires percutanées. Les données cliniques et angiographiques, ainsi que les données évolutives

ont été extraites et associées en utilisant des modèles préétablis (randomisés et ﬁxes) pour

évaluer les données évolutives en incluant leur caractère homogène ou hétérogène.

Résultats. — Sept études randomisées répondaient aux critères d’inclusion incluant

3787 patients dans le groupe zotarolimus, 2606 patients dans le groupe sirolimus et 1966 patients

dans le groupe paclitaxel. Le groupe zotarolimus est associé à un taux accru d’efﬁcacité

sur la revascularisation du vaisseau site (OR 2,36, IC 95 % 1,78—3,14) et de traitement de

la lésion cible (OR 2,46, IC 95 % 1,36—4,46), comparativement aux stents au sirolimus. Le

stent au sirolimus était associé à un taux de resténose intra-stent plus élevé (OR 6,13, IC

95 % 3,87—9,50), une réduction de calibre intra-stent (différence moyenne 0,39 mm, IC 95 %

0,34—0,44) ainsi qu’à la réduction de calibre du segment considéré (différence moyenne

0,18 mm, IC 95 % 0,15—0,21) comparativement aux stents au sirolimus. Enﬁn, le stent au

zotarolimus est associé avec une réduction de calibre intra-stent plus élevé (différence

0,18 mm, IC 95 % 0,07—0,28) comparativement au paclitaxel. Il n’y avait pas de différence du

taux de réinfarctus ou de thrombose de stent avec le stent au zotarolimus, comparativement

aux stents au sirolimus ou au paclitaxel.

Conclusion. — Le stent au zotarolimus n’est pas supérieur au stent au paclitaxel et est inférieur

en termes d’efﬁcacité sur les critères angiographiques et l’indication à une revascularisation

sur les critères cliniques, comparativement au stent au sirolimus.

Introduction be responsible for late stent thrombosis events after DES

implantation [4,5].

The ﬁrst commercially available drug-eluting stents (DES) Zotarolimus is a novel agent with structural homology

— the sirolimus-eluting stent (SES) and the paclitaxel-eluting to sirolimus, developed exclusively for its use in DES. The

stent (PES) — signiﬁcantly reduced rates of restenosis and zotarolimus-eluting stent (ZES) has a low proﬁle, a thin

repeat revascularization after percutaneous coronary inter- strut design and a biocompatible phosphorylcholine polymer

vention (PCI) compared with bare-metal stents, in a wide coating (which mimics the red blood cell outer membrane),

variety of patients [1]. However, the long-term safety and it elutes more than 90% of the drug in the ﬁrst few

of these stents has been questioned by the reports of weeks after implantation [6]. These advances in stent

increased incidence of stent thrombosis, especially with design, polymer and drug elution kinetics are thought to

PES [2,3]. Arterial wall inﬂammation, delayed healing and reduce platelet adhesion and improve arterial healing, and

poor endothelialization are some of the factors thought to may therefore decrease the incidence of stent thrombosis

546 A. Sethi et al.

compared with SES and PES. ZES has been found to have

better neointimal strut coverage compared with SES, as

measured by optical coherence tomography at 9 months

[7]. Also, a randomized controlled trial (RCT) comparing

ZES with a bare-metal stent showed a reduction in the rates

of angiographic and clinical restenosis, with no difference

in stent thrombosis [8]. Despite early success, the role of

ZES compared with SES and PES is unclear. RCTs comparing

ZES with SES and PES have shown mixed results. Therefore,

we decided to perform a meta-analysis of RCTs comparing

ZES with SES and PES for PCI.

Methods

Objective

Our goal was to compare ZES with two established stents

used for PCI — SES and PES — in terms of angiographic and

clinical endpoints.

Search strategy

Figure 1. Study selection process.

We performed a systematic search of the Medline,

Cochrane Central Register of Controlled Trials (CENTRAL)

lesion revascularization (TLR); and stent thromboses. The

and Embase databases for RCTs comparing ZES with SES

following angiographic outcomes were evaluated: in-stent

and/or PES, published before 30 September 2010. The

and in-segment restenosis; and in-stent and in-segment late

keywords ‘zotarolimus’ and ‘zotarolimus eluting stent’

lumen loss.

were used. All retrieved abstracts and/or articles were

reviewed for possible inclusion. The references of review

Statistical analysis

articles and included studies were hand-searched for any

relevant studies. In addition; the manufacturer’s website A study-level analysis was done. Data were analysed using

(http://www.medtronic.com/for-healthcare-professionals/ Review Manager 5 (The Nordic Cochrane Centre, The

products-therapies/cardiovascular/coronary-stents/index. Cochrane Collaboration, 2008). Odds ratios (ORs) and 95%

htm) was screened for any potentially relevant studies on conﬁdence intervals (CIs) were used as summary statistics

30 September 2010. No language restriction was imposed. for all outcomes except the continuous variables in-stent

RCTs comparing ZES with SES and/or PES and reporting and in-segment late lumen loss, for which mean differences

angiographic and clinical endpoints were eligible for inclu- were calculated. Studies were evaluated for heterogene-

sion. Non-randomized studies or registries; comparisons ity by visual inspection of the CIs and by means of I

2 2

with stents other than SES or PES and studies reporting no [I = (Q—df)/Q], where Q is the ␹ statistic and df is degree

clinical or angiographic endpoints were excluded. of freedom. A value of I > 30% was considered as an

indicator of signiﬁcant heterogeneity. A Mantel—Haenszel

Data extraction and validity assessment ﬁxed-effect model was used to calculate the pooled ORs

for non-heterogeneous endpoints. Random effect (DerSimo-

Tw o investigators (A.S. and A.B.) independently searched nian) analysis was performed in the presence of signiﬁcant

the databases for eligible studies. The original manuscripts heterogeneity across the studies. A P value < 0.05 was con-

of potentially relevant studies were reviewed. The study sidered signiﬁcant.

characteristics and endpoints were entered on a prespe-

ciﬁed data form. The following study characteristics were

extracted: sample size; method of randomization; inclusion Results

and exclusion criteria; mean age; use of angiographic follow-

up; primary endpoint; duration of dual antiplatelet therapy; Seven RCTs were included in the meta-analysis (Fig. 1)

follow-up duration; method of evaluation of angiographic [9—15], resulting in a total of 8359 patients: 3787 patients

outcomes; and criteria for target vessel or lesion revascu- in the ZES group; 2606 in the SES group; and 1966 in

larization. Any inconsistencies were reviewed with the help the PES group. The characteristics of included studies are

of a third author. shown in Table 1. Three studies compared ZES with SES,

two compared ZES with PES and two compared all three

Endpoints stents. Three studies included patients with elective PCI

only, one study included stable angina or acute coronary

The following clinical endpoints were evaluated: major syndrome but excluded ST-segment elevation myocardial

adverse cardiac events (MACE); mortality; myocardial infarction (STEMI), one study included patients with STEMI

infarction; target vessel revascularization (TVR); target only and two included all-comers (Table 1). In addition,

ZES compared with SES and PES in PCI 547 NA 63

64.3 NA (years)

age

ZES SES PES 61.4 61.7 NA 63 Mean 67.2 66.6 NA 64.3 63.5 NA 63.6 61.7 61.9 62 61.9 57.8 59.3 main

left

main; 30%; TIMI left

a target

within

left <

shock disease;

left

in-stent 30%; shock;

than

LVEF

30%; <

lesion criteria

< main

lesion

25%; occlusion;

PCI;

shock LVEF

2 other <

left LVEF

< ostial

or disease;

cardiogenic MI;

ostial total or

MI AMI; MI;

unprotected

LVEF

30%; exclusion

lesion

or disease

grade < main

40% mm

Recent stenosis; > Recent ﬂow chronic None STEMI; previous 2 Left disease Recent main lesion; main

mm de

mm or ≥

native

lesion with ACS

length

evidence 27

in & ischaemia

or < 10—30 single

with

angina vessel

ACS with

symptomatic positive

angina length length

stenosis ischaemia

or & & for

diameter

native diameter

study symptoms

evidence

2.5—3.5 unstable criteria Major

to novo

PCI

mm mm stable CAD

angina or mm

de lesion

lesion

due

myocardial

50%

2.5—3.5 2.5—3.5 > objective Chronic diameter of CAD functional with lesion vessels novo 14—27

NA studies.

patients Inclusion

1170 of

included

773 NA 775 Clinical 339 335 NA Ischaemic 323 113 NA Elective 883 878 884 Stable 108 110 110 STEMI LVEF 199 NA 197 Stable ZES SES PES 1162

[13] [11] [15]

[9]

III IV III

Characteristics

[12] [10]

1 OUT

[14]

Table StudyENDEAVOR Number ENDEAVOR SORT ISAR-TEST-2 ZEST-AMI ZoMaxx ZEST

548 A. Sethi et al. MI:

dual

(months) myocardial events;

Duration 3 6 6 antiplatelet therapy elevation 12 12 12 12

2 cardiovascular

ST-segment

adverse NA (Boston scientific) PES NA Taxus Express (Boston Scientific) NA Taxus Liberte (Boston Scientific) Taxus Liberte (Boston Scientific) Taxus Express

STEMI: stent.

major

stent;

MACE:

(Cordis)

(Cordis) (Cordis) Select/Plus Select (Cordis) fraction;

zotarolimus-eluting

sirolimus-eluting

ZES: (Cordis) SES Cypher NA Cypher Cypher Cypher Cypher NA

ejection

SES:

stent;

ventricular

left

revascularization;

(Medtronic) (Medtronic) (Medtronic) (Medtronic) (Medtronic) (Medtronic)

(Abbott) LVEF:

type vessel

paclitaxel-eluting

Stent ZES Endeavor Endeavor Endeavor Endeavor Endeavor Endeavor ZoMaxx disease; target

PES:

TVR:

artery

(months)

failure;

available

coronary intervention; -up

vessel

CAD:

follow Longest 9 24 24 18 12 12 36 coronary

target

TVF: infarction;

months

late late months at at

months

12 months

9 12 endpoint

9 percutaneous

at restenosis loss loss here.

at at

c at infarction;

myocardial PCI: b

months months

Primary 8 9 In-segment TVF MACE MACE MACE In-segment Binary lumen lumen acute

presented

myocardial AMI:

are applicable;

TVR. in

-up

years not

months 2 done

) criteria NA: TVR. months months months months months

and Routine angiographic follow 8 8 6—8 Not 8 9 9 syndrome; or

thrombolysis

[13] [11]

[15]

[9] exclusion

ischaemia-driven III IV Continued

III infarction;

coronary ( TIMI:

[12]

[10] death,

MI, I

major 1

OUT

[14]

acute

Cardiac Only Death, infarction; myocardial Table Study ENDEAVOR ACS: a b c ENDEAVOR SORT ZEST ISAR-TEST-2 ZEST-AMI ZoMaxx

ZES compared with SES and PES in PCI 549 or

CK CK MI

two TVR: >

two two

or or ULN of in [28] leads leads

times times

in in

changes 2 2

al. CKMB > >

ULN samples

CKMB CKMB times

et and/or or

wave wave ECG CK CK

elevated elevated

q q

> or

deﬁnition times

contiguous blood contiguous MI: MI:

with with 3

waves waves

wave: wave:

ULN revascularization;

elevated CKMB elevated Q Q Q Q

deﬁned Thygesen

more more more wave wave

lesion Q MI Universal New times with Symptoms or New per CKMB Non Non normal normal CKMB CKMB with with or or

target

TLR:

50% if

> or or study

with

70% or

only deﬁned Not deﬁned Q TVR/TLR > stenosis

changes and infarction;

or not not

study) ischaemia

70%

ECG

> follow-up stenosis study

symptoms symptoms

signs functional clinically or

but but

or symptoms

50% myocardial

stenosis stenosis

routine MI: functional

70% 50%

angiography, revascularization ischaemia-driven or Clinically Reported Clinical Documented Reported > ischaemia indicated abnormal functional (symptoms, with stenosis > stenosis objective events;

cardiovascular

reported only Ischaemic probable) Ischaemic

Research probable probable probable probable

and

adverse [27]

protocol

major thrombosis

possible) possible) possible) possible) per Academic (definite, (definite, (definite)(definite, No (definite, (definite

MACE: Yes No, Yes per Yes Yes Yes Consortium and and and and

studies.

electrocardiogram;

TVR normal. and and

TVR TVR TVR

included

TVR

months; MI MI

ECG: in clinically clinically TLR Yes and

MI at limit

and and and and and driven

death, death,

MI MI MI MI MI TLR TLR

upper

kinase-MB; death, endpoints

years

ULN: Death, Cardiac clinically ischaemia-driven ischaemia-driven ischaemia-driven Death, Death, Death, Death, Cardiac driven driven 3 and

creatine clinical

CKMB:

[13] [11] [15]

[9] revascularization;

kinase;

III IV

III

Deﬁnitions

[12]

[10]

2 vessel OUT

[14]

creatine

target Table StudyENDEAVOR MACE Stent CK: ISAR-TEST-2 ZoMaxx ZEST-AMI SORT ENDEAVOR ZEST

550 A. Sethi et al.

three studies [10,11,13] had speciﬁc angiographic crite- Clinically driven target vessel and lesion

ria for inclusion, as shown in Table 1. The mean age of revascularization

the study population varied from 57 to 67 years. Patients

All seven studies reported an incidence of clinically or

groups were well balanced with regard to the most rel-

ischaemia-driven TVR and/or TLR, as deﬁned in Table 2. ZES

evant characteristics within individual studies. All studies

was associated with signiﬁcantly higher odds of clinically

except SORT OUT III [15] had routine angiographic follow-

driven TVR compared with SES up to 1 year (OR 2.31, 95%

up. All studies used the Endeavor stent (Medtronic, Santa

CI 1.65—3.22) and at longest available follow-up (OR 2.36,

Rosa, CA, USA) in the ZES group, except for one study

95% CI 1.78—3.14), as shown in Fig. 2A. Similarly, ZES use

[10], which used the ZoMaxx stent (Abbott Laboratories,

was associated with signiﬁcantly higher odds of clinically

Chicago, IL, USA). The deﬁnitions of the relevant clinical

driven TLR compared with SES up to 1 year (OR 2.87, 95% CI

endpoints used in the included studies are shown in Table 2.

1.89—4.35) and at longest available follow-up (OR 2.46, 95%

Clinical endpoints were adjudicated by an independent com-

CI 1.36—4.46), as shown in Fig. 2B. There was no difference

mittee blinded to stent assignment in all seven studies.

in clinically driven TVR and TLR between ZES and PES up to

Angiographic analysis was done at independent core labo-

1 year (TVR: OR 0.85, 95% CI 0.61—1.18; TLR: OR 0.94, 95%

ratories blinded to stent assignment in all studies. A 3-year

CI 0.71—1.26) and at longest available follow-up (TVR: OR

follow-up for the ENDEAVOR III study [16] and 2-year follow-

0.88, 95% CI 0.63—1.23; TLR: OR 1.11, 95% CI 0.58—2.13),

up for the ENDEAVOR IV [17] and ISART-TEST-2 [9] studies

as shown in Fig. 3A and B.

were reported subsequently, in addition to the respective

9-month, 12-month and 12-month follow-ups published ini-

Stent thromboses

tially. Also, the SORT OUT III trial reported clinical endpoints

at 9 months and 18 months. The other three studies had a There was no signiﬁcant difference in stent thromboses

follow-up duration of 1 year or less (Table 1). To accommo- between ZES and SES up to 1 year (OR 1.53, 95% CI

date the variable follow-up periods, we decided to combine 0.39—5.96) and at longest available follow-up (OR 1.12, 95%

the clinical endpoints at follow-up of up to 1 year and at CI 0.41—3.08), as shown in Fig. 2C. Similarly, there was no

longest available follow-up. No signiﬁcant disagreement was difference in stent thromboses between ZES and PES up to

found between the data retrieved by two investigators. 1 year (OR 1.05, 95% CI 0.56—2) and at longest available

follow-up (OR 0.88, 95% CI 0.51—1.55), as shown in Fig. 3C.

Angiographic outcomes

Clinical endpoints

MACE Compared with SES, ZES was associated with a signiﬁ-

cantly higher rate of in-stent restenosis (OR 6.13, 95% CI

The deﬁnition of MACE used in each study is shown in Table 2.

3.96—9.50) and in-segment restenosis (OR 3.46, 95% CI

MACE were experienced by 12%, 8.6% and 11.8% of patients

1.59—7.50), as shown in Fig. 4A and B, respectively. There

randomized to the ZES, SES and PES groups, respectively.

was no difference between ZES and PES in in-stent resteno-

There was moderate heterogeneity among the studies for

2 sis (OR 1.56, 95% CI 0.84—2.90) and in-segment restenosis

the endpoint of MACE, as evidenced by the I in excess of

(OR 1.44, 95% CI 0.88—2.35) (Fig. 5A and B). Also, compared

40% for all four comparisons. Therefore, a random-effect

with SES, ZES was associated with higher in-stent late lumen

meta-analysis was performed. Compared with SES, ZES was

loss (mean difference 0.39 mm, 95% CI 0.34—0.44; Fig. 4C)

associated with signiﬁcantly higher MACE up to 1 year (OR

and in-segment late lumen loss (mean difference 0.18 mm,

1.50, 95% CI 1.06—2.13) and at longest available follow-up

95% CI 0.15—0.21). However, in-segment late lumen loss was

(OR 1.39, 95% CI 1.01—1.91). There was no difference in

similar (mean difference 0.06 mm, 95% CI —0.04—0.16) but

MACE between PES and ZES up to 1 year (OR 0.94, 95% CI

in-stent lumen loss was higher (mean difference 0.18 mm,

0.67—1.32) and at longest available follow-up (OR 0.94, 95%

95% CI 0.07—0.28) in the ZES group compared with the PES

CI 0.68—1.30).

group (Fig. 5C).

Myocardial infarction Discussion

There was no difference in myocardial infarction between

The present meta-analysis found that ZES use was associated

ZES versus SES (OR 1.0, 95% CI 0.41—2.45) and ZES versus PES

with signiﬁcantly higher revascularization rates compared

(OR 0.55, 95% CI 0.55—1.04) up to 1 year and at longest avail-

with SES use. Also, ZES was inferior to SES in terms of the

able follow-up (ZES versus SES: OR 0.83, 95% CI 0.40—1.72;

angiographic endpoints of restenosis and late lumen loss.

ZES versus PES: OR 0.71, 95% CI 0.48—1.07).

ZES was similar to PES for all clinical and most angiographic

endpoints, except in-stent late lumen loss. In addition, no

difference in stent thromboses was apparent during follow-

Mortality

up when ZES was compared with SES and PES. To the best of

There was no difference in mortality between ZES versus SES

our knowledge, this is the ﬁrst meta-analysis comparing ZES

(OR 1.23, 95% CI 0.80—1.89) and ZES versus PES (OR 1.11, 95%

directly with SES and PES separately. The included studies

CI 0.59—2.06) up to 1 year and at longest available follow-up

varied in terms of patient population, ranging from stable

(ZES versus SES: OR 1.01, 95% CI 0.62—1.65; ZES versus PES:

coronary artery disease to acute coronary syndrome, STEMI

OR 1.20, 95% CI 0.74—1.96).

and all-comers, a pattern that represents the state of DES

ZES compared with SES and PES in PCI 551

Figure 2. Forest plots comparing the zotarolimus-eluting stent (ZES) with the sirolimus-eluting stent (SES) for the following endpoints:

(A) target vessel revascularization; (B) target lesion revascularization; (C) stent thrombosis. CI: conﬁdence interval; M-H: Mantel—Haenszel.

use in contemporary practice (Table 1). We combined these Rosa, CA, USA) and ZoMaxx (Abbott Laboratories, Chicago,

studies to achieve a higher power to evaluate ZES (a rela- IL, USA) — have rapid drug elution kinetics, a clear dis-

tively new DES), against established DESs (SES and PES), in tinction from currently available SES, which have a slower

terms of both clinical and angiographic endpoints. drug release [18]. These pharmacological differences may

Zotarolimus is an analogue of sirolimus, which binds to explain the relatively weak antiproliferative effect of ZES

the immunophillin protein FKBP 12 to inhibit a growth- and consequently higher restenosis compared with SES. On

regulating enzyme known as mammalian target of rapamycin the other hand, ZES was similar to PES with regard to most

(mTOR) [18]. Zotarolimus has a shorter half-life and less angiographic endpoints, which is consistent with previous

afﬁnity for FKBP 12 than sirolimus. In addition, the two studies [19,20] that showed a higher incidence of clinical

ZES evaluated in our analysis — Endeavor (Medtronic, Santa and angiographic stenosis with PES compared with SES. The

552 A. Sethi et al.

Figure 3. Forest plots comparing the zotarolimus-eluting stent (ZES) with the paclitaxel-eluting stent (PES) for the following endpoints:

(A) target vessel revascularization; (B) target lesion revascularization; (C) stent thrombosis. CI: conﬁdence interval; M-H: Mantel—Haenszel.

difference in late lumen loss between SES and ZES was All studies except the SORT OUT III study had a rou-

higher than reported previously between SES and PES [20]. tine angiographic follow-up (Table 1), which raises concern

As some authors have suggested a curvilinear relationship about increased revascularization rates secondary to ocu-

between late lumen loss and probability of TLR [21], this lostenotic reﬂex. All included studies reported clinically or

accentuated late lumen loss may place patients treated with ischaemia-driven revascularization rates. In addition, stud-

ZES closer to the steeper slope of the curve. Although the ies comparing ZES with SES reported explicit indications

ZoMaxx and Endeavor stents have a similar thin strut design, used for clinically or ischaemia-driven revascularization

biocompatible phosphorylcholine polymer and zotarolimus (Table 2). Although more than 70% stenosis on follow-up

␮

concentration (10 g/mm), there are some differences in angiogram was considered as one of the indication for TLR,

the stent platforms and drug elution kinetics [18]. Exclusion but TLR in the ZES group in the SORT OUT III study (6.1%),

of the ZoMaxx I study from the meta-analysis did not change which had no angiographic follow-up, and in the ENDEAVOR

the results for any endpoint signiﬁcantly. III (6.3%) and ZEST (4.8%) studies, which had planned

ZES compared with SES and PES in PCI 553

Figure 4. Forest plots comparing the zotarolimus-eluting stent (ZES) with the sirolimus-eluting stent (SES) for: (A) in-stent restenosis; (B)

in-segment restenosis; (C) in-segment late lumen loss. CI: conﬁdence interval; M-H: Mantel—Haenszel.

angiographic follow-up, were not signiﬁcantly different. On ZES versus SES were robust, and remain signiﬁcant on

the other hand, TLR in the ISAR-TEST-2 study was higher exclusion of one study at a time from the meta-analysis.

in both the ZES (14%) and SES (10.7%) groups. All statisti- Also, the odds of in-stent restenosis were lower in the

cal heterogeneity in the analysis for TLR was explained by ENDEAVOR III study (4.67), which systematically excluded

the ISAR-TEST-2 study; its exclusion reduced I from 74% to patients with complex lesions or acute coronary syndrome,

0% without loss of statistical signiﬁcance (OR 3.43, 95% CI than in the SORT OUT III (6.38), ZEST (5.86) and ZEST-AMI

2.36—4.98). Therefore, the impact of routine angiographic (13.66) studies, which included patients with acute coro-

follow-up of revascularization rates cannot be clearly deter- nary syndrome and had no angiographic exclusion criteria

mined from our analysis. However, the results of TLR for (Fig. 4). Moreover, both the ZEST and SORT OUT III trials

554 A. Sethi et al.

Figure 5. Forest plots comparing the zotarolimus-eluting stent (ZES) with the paclitaxel-eluting stent (PES) for: (A) in-stent restenosis;

(B) in-segment restenosis; (C) in-segment late lumen loss. CI: conﬁdence interval; M-H: Mantel—Haenszel.

independently found a signiﬁcant increase in TVR and TLR meta-analysis, considering the difference in duration of

with ZES use. Therefore, it is possible that clinical and angio- follow-up [21]. This could be due to the inclusion of acute

graphic differences between ZES and SES will become appar- myocardial infarction and complex lesions in the studies

ent in high-risk patients in the real-world clinical setting. [9,14,15], which contributed the majority of patients to

ZES was designed with the intention of reducing stent our analysis, compared with elective PCI for a single angio-

thrombosis compared with SES and PES. The cumulative graphically deﬁned lesion in the ENDEAVOR I—IV studies. The

incidence of stent thrombosis in the ENDEAVOR I—IV and incidence of stent thromboses in the SES (0.8%) and PES

PK studies at 5 years was about 0.8% (95% CI 0.06—1.54), (1.3%) cohorts in our analysis were similar to those in pre-

which is lower than the cumulative incidence of 1% in our vious studies [22,23]. It is important to note that only the

ZES compared with SES and PES in PCI 555

ENDEAVOR III [16], ENDEAVOR IV [17] and ISAR-TEST-2 [9]

Disclosure of interest

trials reported the incidence of stent thromboses later than

6 months after completion of the recommended duration of The authors declare that they have no conﬂicts of interest

dual antiplatelet therapy, at follow-up periods of 3 years, concerning this article.

2 years and 2 years, respectively (Table 1). Although there

was no difference in very late stent thromboses between ZES

and SES in the ENDEAVOR III and ISAR-TEST-2 studies, a trend

Appendix A. Supplementary data

(P = 0.069) towards higher very late stent thromboses with

PES compared with ZES was seen in the ENDEAVOR IV trial.

Supplementary data associated with this article can be

The results of the PROTECT trial — a large randomized-

found, in the online version, at http://dx.doi.org/10.1016/

design trial comparing ZES with SES for the primary endpoint j.acvd.2012.01.014.

of stent thromboses at 3 years — recently became available

[24]. Considering the magnitude and relevance of this study,

we performed an updated analysis. The addition of the PRO-

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