European Heart Journal (2014) 35, 2812–2820
doi:10.1093/eurheartj/ehu318
CLINICAL RESEARCH
Interventional cardiology
Endeavour zotarolimus-eluting stent reduces stent
thrombosis and improves clinical outcomes
compared with cypher sirolimus-eluting stent:
4-year results of the PROTECT randomized trial
William Wijns 1†, Ph. Gabriel Steg 2,3,4,5, Laura Mauri 6, Volkhard Kurowski 7,
Keyur Parikh 8, Runlin Gao 9, Christoph Bode 10, John P. Greenwood 11, Erik Lipsic 12,
Farqad Alamgir 13, Tessa Rademaker-Havinga 14, Eric Boersma 15, Peter Radke16,
Frank van Leeuwen17, and Edoardo Camenzind 18,19,†*, for the PROTECT Steering
Committee and Investigators‡
Received 17 June 2014; revised 14 July 2014; accepted 22 July 2014; online publish-ahead-of-print 8 August 2014
Aims
To compare the long-term clinical safety between two drug-eluting stents with different healing characteristics in the Patient
Related Outcomes with Endeavour (E-ZES) vs. Cypher (C-SES) Stenting Trial (PROTECT). At 3 years, there was no difference in the primary outcome of definite or probable stent thrombosis or in the other main secondary clinical outcomes
consisting of the composite of death or myocardial infarction (MI). Prespecified 4-year clinical follow-up was analysed.
.....................................................................................................................................................................................
Methods
Patient Related OuTcomes with Endeavour vs. Cypher Stenting Trial was a prospective, open-label randomizedand results
controlled superiority trial powered to look at differences in long-term clinical safety, including stent thrombosis.
Dual antiplatelet therapy (DAPT) was prescribed for ≥3 months and up to 12 months based on current guidelines.
Patient Related OuTcomes with Endeavour vs. Cypher Stenting Trial enrolled 8791 patients undergoing elective or emergency PCI to E-ZES or C-SES. There was no difference in DAPT usage between the two groups up to 4 years. At 4-year
follow-up, the primary outcome occurred in 1.6% of E-ZES vs. 2.6% of C-SES patients [HR 0.63 (95% CI 0.46 –0.85),
P ¼ 0.003]. The composite of all-cause death or large MI occurred in 6.7% of E-ZES vs. 8.0% of C-SES-treated patients
[HR 0.84 (95% CI 0.71–0.98), P ¼ 0.024].
.....................................................................................................................................................................................
Conclusions
Drug-eluting coronary stents with different healing characteristics demonstrated different late safety profiles: after
4 years, compared with C-SES, E-ZES reduced the risk of stent thrombosis and the risk of the composite endpoints
of death or MI. Appropriately powered large-scale trials with long-term follow-up are critical to determine clinical
safety and efficacy of permanently implanted coronary stents.
This trial is registered with ClinicalTrials.gov, number NCT00476957.
----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords
Drug-eluting stent † Late stent thrombosis † Myocardial infarction † Endothelialization † Sirolimus †
Zotarolimus
* Corresponding author. Tel: +33 3 8315 4264, Fax: +33 3 8315 4213, Email: [email protected]
†
These authors contributed equally to the manuscript.
‡
The full list of investigators is detailed in the see Supplementary material online, Table S1.
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2014. For permissions please email: [email protected].
Downloaded from by guest on October 21, 2014
1
Cardiovascular Center, OLV Hospital, Aalst, Belgium; 2De´partement Hospitalo-Universitaire FIRE, INSERM U-1148, F75018 Paris, France; 3Universite´ Paris-Diderot, Sorbonne-Paris
Cite´, Paris, France; 4AP-HP, Hoˆpital Bichat, F75018 Paris, France; 5NHLI Imperial College, ICMS, Royal Brompton Hospital, London, UK; 6Harvard Medical School and Brigham and
Women’s Hospital, Boston, MA, USA; 7Universita¨tsklinikum Lu¨beck, Lu¨beck, Germany; 8The Heart Care Clinic, Ahmedabad, India; 9Cardiovascular Institute and Fuwai Hospital, Beijing,
China; 10University Hospital Freiburg, Freiburg im Breisgau, Germany; 11Leeds General Infirmary, Leeds, UK; 12University Medical Center Groningen, Groningen, The Netherlands;
13
Castle Hill Hospital, Cottingham, UK; 14Cardialysis BV, Rotterdam, The Netherlands; 15Erasmus Medical Center, Rotterdam, The Netherlands; 16Scho¨n Klinik Neustadt, Neustadt,
Germany; 17Medtronic Bakken Research Center, Maastricht, The Netherlands; 18University of Geneva, 1 rue Micheli-Servet, Geneva, Switzerland; and 19CHU Nancy, Institut Lorrain du
Coeur et des Vaisseaux, F54511 Vandoeuvre-le`s-Nancy, France
2813
4 year results of the PROTECT randomized trial
Introduction
The Patient Related OuTcomes with Endeavour vs. Cypher Stenting
Trial (PROTECT) was designed and powered to compare long-term
clinical safety between the EndeavorTM zotarolimus-eluting stent
(E-ZES) and the CypherTM sirolimus-eluting stent (C-SES).1 These
stent systems were designed with differing bare metal structures,
polymers, and drugs conveying different potency profiles2 and
healing characteristics.3 While a higher rate of target vessel revascularization was observed at 3 years with E-ZES, presumably reflecting
less potent neointimal suppression, clinical outcomes such as the
composite of death and myocardial infarction (MI) as well as the
primary outcome of definite or probable stent thrombosis did not
differ at 3 years.4 Importantly, stent thrombosis rates at 3 years
were slightly lower than anticipated, thereby decreasing the power
of the analysis. Prospective follow-up of patients in this randomized
trial was mandated by the study protocol on a yearly basis for
5 years. This manuscript reports outcomes at 4-year follow-up.
Methods
Study design and patients
Randomization
Details of study randomization in PROTECT have been described previously.1,4 Briefly, patients were randomized to stent type following enrolment using a central telephone- or Internet-based service. Stratification
was by centre in groups of four, six, or eight patients.
Follow-up
Clinical visits following the index procedure were planned at 30 days,
6 months, 12, 18, 24, 30, 36, and 48 months and the final study visit will
be at 60 months. In addition to site-reported events, repeat ECGs
were obtained at 3 years and centrally reviewed in order to capture all
non-fatal Q-wave MIs.
Statistical analysis
Statistical analysis was performed by intention to treat in the entire study
population. Dichotomous and categorical variables are listed as counts
and percentages. Time to predefined clinical outcomes was calculated
by the Kaplan– Meier method and tested for significance between
groups by log rank. A two-sided P-value ,0.05 was considered significant. Statistical analyses were done using SAS software versions 9.1 or
higher (SAS Institute, Cary, NC, USA).
The sample size was calculated assuming an incidence of the primary
endpoint (definite or probable stent thrombosis at 3 years) of 1.5% in
the E-ZES group and 2.5% in the C-SES group (relative risk 0.60).
A sample size of 8800 patients would provide power of 90% with a twosided a level of 0.05 assuming ≤5% loss to follow-up.
Role of funding
Project management for PROTECT was the responsibility of Medtronic
Bakken Research Center (Maastricht, the Netherlands), and the study
was sponsored by Medtronic Cardiovascular (Santa Rosa, CA, USA).
The Steering Committee designed the study, in collaboration with the
sponsor. An independent academic research organization (Cardialysis,
Rotterdam, the Netherlands), blinded to the patients’ study stent assignment, was responsible for the organization of meetings involving the clinical events committee and data safety monitoring board, and for the data
analysis. Access to the unblinded database was provided to a limited
number of Medtronic staff not involved in the study for vigilance and regulatory reporting requirements. Members of the Steering Committee
wrote the manuscript and vouch for the completeness and accuracy of
the data gathering and analysis. The authors were not restricted from disclosing the study results. All data collection (except for sites in Canada
and the USA where the sponsor’s staff performed the monitoring
visits), data analysis, data interpretation, and writing of the report were
done by independent groups, and the sponsor had only oversight of
these activities. The corresponding author had full access to all data in
the study and final responsibility to submit for publication.
Results
Subjects were randomized between May 2007 and December 2008,
and 4-year follow-up was available for 8432/8709 (97%) of randomized subjects (96.8% in the E-ZES group and 96.9% in the C-SES
group; Figure 1). There were no major clinically relevant differences
in baseline characteristics between arms (see Supplementary
Downloaded from by guest on October 21, 2014
Study design, patient characteristics, randomization, and procedures
have been described in detail.1,4 This pragmatic trial enrolled 8791
patients, of whom 8709 were randomized 1 : 1 to receive either E-ZES
(4357 patients) or C-SES (4352 patients) but otherwise treated according to clinical practice. Standard implantation techniques were followed,
and postoperative dual antiplatelet therapy (DAPT) was aspirin indefinitely and a thienopyridine for 3 – 12 months. Key safety and efficacy
metrics were collected up to 4 years.
The primary endpoint was definite or probable stent thrombosis at
3 years. Stent thrombosis was defined according to the Academic Research Consortium (ARC).5 The main secondary outcomes included
combinations of death and MI: total death and large non-fatal MI; total
death and non-fatal MI; cardiac death and large non-fatal MI; and
cardiac death and non-fatal MI. Cardiac death was defined according to
the ARC definition as any death without an unequivocal non-cardiac
cause.6 Myocardial infarctions were reported according the historical
World Health Organization7 and the ARC/2007 Universal definitions.6,8
Using the historical definition, a MI was total creatinine kinase .2 times
the upper limits of normal.7 Using the ARC/2007 Universal definition, a
periprocedural MI was troponin or creatine kinase MB .3 times the
upper limits of normal, and a spontaneous MI was when either of these
biomarkers was greater than the upper limits of normal.6,8 The ARC/
2007 Universal definition of MI was used in the probable stent thrombosis
component of the primary endpoint definite or probable stent thrombosis, while the historical definition was used in secondary endpoints
for comparability to previously published studies. A large MI was
defined as acute ST-elevation MI, new pathological Q-waves not
present on the baseline electrocardiogram, or creatine kinase .5
times the upper limits of normal. Death, MI, stent thrombosis and bleeding events were adjudicated by an independent Clinical Events Committee. Revascularizations and strokes not related to bleeding were site
reported.
The placement of a stent in a subject with at least one of the following
clinical or lesion characteristics was considered as a complex patient:
renal insufficiency [creatinine level ≥140 mmol/L (1.6 mg/dL)], ejection
fraction ,30%, acute myocardial infarction ≤72 h, more than one
lesion per vessel, more than two vessels with stents, lesion length
.27 mm, bifurcation lesion, lesion in bypass graft, in-stent restenosis, unprotected left main artery, lesion with thrombus, or total occlusion.4,9
2814
W. Wijns et al.
material online, Table S2). The indication for angioplasty was MI (ST or
non-ST-segment elevation) in 26% of subjects, and unstable angina
was present in 19%. As previously described,2 some site-reported
lesion and procedure characteristics, such as calcification, and
number of stents implanted per lesion, differed between treatment
arms.
The use of DAPT was similar between groups at all follow-up intervals (see Supplementary material online, Figure S1). Mean DAPT use
was 95.1% at 6 months, 87.7% at 1 year, 36.5% at 2 years, 29.9% at 3,
and 27.5% at 4 years.
Mean DAPT use averaged over time from discharge to 1 year was
93% and decreased from 1 to 4 to 45.4%, from 2 to 4 years to 31.3%,
and from 3 to 4 to 28.8%.
Incidence of clinical outcomes at 4 years according to Kaplan–
Meier estimates are summarized in Table 1. The primary outcome
of definite or probable stent thrombosis at 4 years occurred in
1.6% of E-ZES vs. 2.6% of C-SES patients [HR 0.63 (95% CI 0.46–
0.85), P ¼ 0.003] (Figure 2). This difference was driven by the
higher rates of very late (.1 year) definite or probable stent thrombosis in the C-SES group (1.9%) compared with the E-ZES group
(0.5%, P , 0.001). Specifically, there was a greater increase in the incidence of definite or probable stent thrombosis from year 3 to year 4
for the C-SES group (1.8% at 3 years, 2.6% at 4 years; delta +0.8%)
than the E-ZES group (1.4% at 3 years, 1.6% at 4 years; delta +
0.2%) (Figure 2). At 4 years, the incidence of death or large non-fatal
MI were lower with E-ZES [6.7 vs. 8.0%, HR 0.84 (95% CI 0.71–0.98),
P ¼ 0.024] (Figure 3A), as were rates of death and any MI [9.2 vs.
10.8%, HR 0.85 (95% CI 0.74 –0.97), P ¼ 0.017] (Figure 3B). The composites of cardiac death and large MI or cardiac death and any MI were
also reduced by E-ZES compared with C-SES (Figure 3C and D). These
differences in primary and main secondary endpoints were driven by
differences in events beyond 1 year (Figures 3 and 4). Clinically driven
target lesion revascularization was significantly reduced with C-SES
(4.5 vs. 5.9%, P ¼ 0.002) while clinically driven target vessel revascularization was not (8.6% with C-SES vs. 9.0% with E-ZES, P ¼ 0.37).
Indices of combined safety and efficacy such as target lesion failure,
target vessel failure, or major adverse cardiac events did not differ
between groups.
Over time, the risk of stent thrombosis became progressively
lower with E-ZES than with C-SES (Figures 2 and 4A). This progression over time was paralleled by the main secondary endpoints
(Figures 3 and 4B). The reduction in definite or probable stent thrombosis with E-ZES over C-SES was consistent across 12 prespecified
subgroups defined according to demographics, clinical, and procedural characteristics, with the following significant interactions: age,
multivessel, and long lesion (Figure 5).
Downloaded from by guest on October 21, 2014
Figure 1 Patient disposition at 4 years follow-up. E-ZES, endeavor zotarolimus-eluting stent; C-SES, cypher sirolimus-eluting stent.
2815
4 year results of the PROTECT randomized trial
Table 1
Incidence of clinical outcomes at 4 years according to Kaplan –Meier estimates
E-ZES
N 5 4357 patients
N 5 6151 lesions
C-SES
N 5 4352 patients
N 5 6139 lesions
Hazard ratio (95% CI)a
1.6% (67)
2.6% (106)
0.63 [0.46, 0.85]
0.003
Total death and large non-fatal MIc
6.7% (288)
8.0% (342)
0.84 [0.71, 0.98]
0.024
Total death and non-fatal MIc
9.2% (396)
10.8% (463)
0.85 [0.74, 0.97]
0.017
Cardiac death and large non-fatal MIc
Cardiac death and non-fatal MIc
4.2% (181)
6.9% (294)
5.4% (229)
8.4% (354)
0.78 [0.65, 0.95]
0.83 [0.71, 0.96]
0.015
0.015
All deaths
5.5% (235)
6.0% (256)
0.91 [0.76, 1.09]
0.311
Cardiac death
MIc
2.9% (124)
4.6% (196)
3.4% (143)
5.8% (246)
0.86 [0.68, 1.10]
0.79 [0.66, 0.96]
0.227
0.015
Large MIc
1.7% (74)
2.7% (111)
0.66 [0.49, 0.89]
0.006
MId
Definite stent thrombosisb
14.9% (646)
0.8% (35)
16.0% (685)
1.8% (74)
0.95 [0.85, 1.05]
0.47 [0.31, 0.70]
0.295
,0.001
Probable stent thrombosisb
0.8% (32)
0.8% (34)
0.94 [0.58, 1.52]
0.793
Possible stent thrombosisb
Definite or possible or probable stent thrombosisb
1.9% (79)
3.4% (144)
2.2% (90)
4.6% (192)
0.87 [0.65, 1.18]
0.75 [0.60, 0.92]
0.376
0.007
Clinically driven target lesion revascularization
5.9% (252)
4.5% (189)
1.35 [1.12, 1.63]
0.002
Clinically driven target vessel revascularization
Non-target vessel revascularization
9.0% (382)
9.3% (392)
8.6% (361)
9.6% (404)
1.07 [0.93, 1.23]
0.97 [0.84, 1.11]
0.368
0.623
Haemorrhagic stroke
2.3% (95)
2.3% (95)
1.00 [0.77, 1.32]
0.977
MACE
MACCE
14.0% (602)
15.3% (659)
13.8% (588)
15.1% (645)
1.03 [0.92, 1.16]
1.03 [0.93, 1.15]
0.563
0.564
Bleeding events (TIMI)e
5.5% (232)
5.2% (220)
1.05 [0.88, 1.27]
0.577
2.2% (92)
3.1% (129)
2.0% (85)
3.0% (127)
1.08 [0.80, 1.45]
1.01 [0.79, 1.29]
0.617
0.919
Log-rank
P-value
...............................................................................................................................................................................
Primary endpoint
Definite or probable stent thrombosisb
...............................................................................................................................................................................
Main secondary endpoints
...............................................................................................................................................................................
Other secondary endpoints
Data are percentage failure based on Kaplan–Meier estimates, in brackets are the number of events.
E-ZES, Endeavor zotarolimus-eluting stent; C-SES, cypher sirolimus-eluting stent; MI, myocardial infarction; MACE, major adverse cardiac events; MACCE, major adverse cardiac and
cerebrovascular events; TIMI, thrombolysis in myocardial infarction.
a
Cox model, assuming proportional hazards.
b
Based on the Academic Research Consortium definition.
c
Based on the extended historical definition.
d
Based on the Academic Research Consortium definition.
e
TIMI bleed consists of major + minor + minimal.
Discussion
The results of PROTECT demonstrate that different drug-eluting
stents, when compared in a study powered to examine stent thrombosis and clinical events in a broad patient population, can manifest
clear differences in clinical outcomes with extended follow-up.
While the primary analysis at 3 years did not show a significant difference in the primary endpoint, a substantial increase in the hazard of
definite or probable stent thrombosis associated with the C-SES
compared with E-ZES emerged at 4 years, while under a similar
DAPT coverage between treatment arms. These trial results highlight
the crucial importance of properly powered studies with sufficient
long-term follow-up to determine the safety and efficacy of permanently implanted devices such as coronary stents, using appropriate
patient-oriented outcomes.
These results illustrate that differences in drug-eluting stent types
are determined by long-term vascular biocompatibility, which may
substantially impact late clinical outcomes. Drug-eluting stents vary
according to the bare metal scaffold, the chemical nature and thickness of polymeric coating(s), and the drug type with respective
release kinetics. Since the introduction of the first commercially
available drug-eluting stent, C-SES, these stents have been developed to have thinner struts and to explore various polymeric coatings and polymer-drug combinations proven to be effective in
randomized trials.9 – 12 Nonetheless, to date, trials have not been
powered to compare stent thrombosis rates or differences in
hard clinical events.9 – 12 Furthermore, outcomes were generally
assessed at 1 year follow-up, while most patients were still on
DAPT, therefore minimizing potential safety differences between
devices.13
Downloaded from by guest on October 21, 2014
Major
Major + minor
2816
W. Wijns et al.
Figure 2 Incidence of definite or probable stent thrombosis according to Kaplan – Meier estimates over 4 years of follow-up. E-ZES, endeavour
zotarolimus-eluting stent; C-SES, cypher sirolimus-eluting stent.
Downloaded from by guest on October 21, 2014
Figure 3 Incidence of major secondary endpoints according to Kaplan– Meier estimates over 4 years of follow-up. (A) Total death and large nonfatal MI. (B) Total death or non-fatal MI. (C) Cardiac death and large non-fatal MI. (D) Cardiac death and non-fatal MI. E-ZES, endeavour
zotarolimus-eluting stent; C-SES, cypher sirolimus-eluting stent.
Stent thrombosis can have serious and often lethal consequences.14 – 18 The difference in both definite or probable as well
as definite stent thrombosis of 1% at 4 years in PROTECT translated
into an almost 1% difference in large MI. It is notable that these
infarctions were not confined to minor release of biochemical
markers induced by coronary interventions but included in almost
half of the cases large, spontaneous or Q-wave MIs. While the
total number of deaths attributable to the initial stent choice is
4 year results of the PROTECT randomized trial
2817
Figure 4 Forest plot depicting the relative risk of (A) definite or probable stent thrombosis and (B) death and large myocardial infarction as a
function of follow-up time. E-ZES, endeavour zotarolimus-eluting stent; C-SES, cypher sirolimus-eluting stent.
device-specific properties13 and suggests that prolonged DAPT may
be of value to mitigate the thrombotic risk after potent drug-eluting
stents like C-SES13 but not in those with more predictable healing characteristics.22 Generic recommendations for either shorter or longer
term treatment durations that do not account for differing device features are unlikely to offer the best trade-off between the risks of stent
thrombosis and the risk of bleeding.
Limitations of this study pertain to the completeness and quality of
follow-up, in order to constrain under-reporting to the minimum.
This limitation is particularly relevant to studies in which primary
endpoint events are rare. The absolute number of thrombosis
events was larger than in any prior study and completeness of followup was similar between randomization arms. Long-term follow-up
to 4 and 5 years was protocol mandated. Given the statistical significance of these findings, one has to emphasize that (i) a signal of a potential difference among DES types was already present at 3 years
with definite stent thrombosis being significantly more frequent
after C-SES; (ii) the interfering effect of DAPT according to DES
type on thrombotic complications could be demonstrated on 3
year outcomes;13 and (iii) the currently observed P-values were well
below the 0.025 ( ¼ 0.05/2) threshold that one might suggest to
apply in order to adjust for the fact that the endpoint was tested
for the second time (3- and 4-year follow-up). Although C-SES has
been succeeded by more recent drug-eluting stents and the
PROTECT trial might be regarded as ‘historical’, millions of patients
worldwide are currently living with these permanent coronary
implants. Furthermore, the conceptually newer stent designs have
thus far not proven clinically safer in sufficiently powered and longterm clinical trials despite their widespread use.9 – 12 The selected
stent types (E-ZES and C-SES) in PROTECT are typologically representative of different efficacy levels and healing properties and thus
convey a generalizable message important for patients, physicians,
and regulatory bodies.
Downloaded from by guest on October 21, 2014
small, when translated to broad clinical practice, the numerical difference detected in this randomized trial suggest an important
benefit to a stent with lower long-term (late: .1 year) prothrombotic properties.
During the first year of follow-up in PROTECT, a higher incidence
of TLR and TVR and a non-significant but numerically higher incidence of definite or probable stent thrombosis was observed in
the E-ZES arm.4 This difference, however, either disappeared or
even reversed over time and were overshadowed by the development of a substantial difference favouring E-ZES with respect to
the composite clinical outcomes of death and MI. Had the evaluation
of outcomes been done after 1 year, the conclusions would have
been that C-SES was more efficacious and safer to E-ZES. Likewise,
differences in definite or probable stent thrombosis and the main secondary endpoints were not apparent at 3 years, when the primary
trial outcomes was assessed,4 but emerged between year 3 and
year 4 for all the various stent thrombosis definitions and consistently
for the various composites of death and MI. When PROTECT was
designed, the incidence of late (30 days to 1 year) and very late
(.1 year) stent thrombosis was estimated at 0.2 –0.6% per year to
which – according to the modality of calculation – an incidence of
0.5 –1.0% early stent thrombosis had to be added (PROTECT estimation for definite or probable stent thrombosis at 3 years: E-ZES 1.5%
and C-SES 2.5%).1,5,19 – 21 These figures were the rates actually
observed at 4 rather than 3 years, with both later onset and lower
rates of stent thrombosis after C-SES than anticipated (see Supplementary material online, Figure S2). Extended duration of DAPT
may have modulated the time course of thrombotic events differentially: DAPT being more thrombo-protective in C-SES patients with a
longer enduring in-stent prothrombotic milieu (e.g. delayed healing
response and/or neo-atherosclerosis with plaque rupture).13 Thus,
PROTECT shows that the need and duration of device-mandated antiplatelet therapy cannot be determined without consideration for
2818
W. Wijns et al.
Table 2
Translational perspective: literature search results
Stent type
n
All death, n (%)
Non-fatal MI, n (%)
BMS (BxVelocity)
BMS (driver)
870
599
46 (5.4)
31 (5.2)
53 (6.2)
26 (4.4)
BMS
1469
77 (5.2)
79 (5.4)
...............................................................................................................................................................................
Pooled analysis24
Endeavor II23
Mean
...............................................................................................................................................................................
Endeavor II23
E-ZES
598
30 (5.0)
19 (3.2)
E-ZES/BMS
2067
107 (5.2)
98 (4.7)
PROTECT
E-ZES
4357
235 (5.4)
196 (4.5)
Pooled analysis24
Pooled analysis25
C-SES
C-SES
878
1704
57 (6.7)
163 (10.0)
55 (6.4)
109 (6 8)
Mean
C-SES
2582
220 (8.5)
164 (6.4)
PROTECT
C-SES
4352
256 (5.9)
246 (5.7)
Mean
...............................................................................................................................................................................
...............................................................................................................................................................................
In conclusion, PROTECT illustrates the importance of appropriately powered, long-term large studies to assess safety and efficacy
of two typologically different drug-eluting stents, particularly as
hard outcomes (death, MI, or stent thrombosis) are relatively rare.
Such long-term follow-up of clinical safety is critical for patient
safety given that these devices are permanently implanted. The
Downloaded from by guest on October 21, 2014
Figure 5 Forest plot depicting the relative risk of definite or probable stent thrombosis in prespecified subgroups. ACS, acute coronary syndrome;
AMI, acute myocardial infarction; E-ZES, endeavour zotarolimus-eluting stent; C-SES, cypher sirolimus-eluting stent; RVD, reference vessel
diameter; STEMI, ST-segment elevation myocardial infarction.
2819
4 year results of the PROTECT randomized trial
extended follow-up of PROTECT demonstrates that differences in
the pharmaco-polymeric properties of two drug-eluting stents translate into differences in clinical adverse events that prior smaller randomized trials did not discern. These findings highlight the need for
long-term follow-up of a broad range of patients in appropriately
powered trials to fully understand the safety and efficacy of implantable devices.
Translational perspective
Authors’ contributions
W.W., P.G.S., L.M., and E.C. were the principal investigators, participated in the study design and data analysis, and co-wrote the manuscript. V.K., K.P., R.G., C.B., J.P.G., E.L., and F.A. participated in data
collection and critical revision of the manuscript. E.B. and T.R.H. participated in the statistical analysis, data analysis, and critical revision of
the manuscript. P.R. and F.v.L. participated in study organization and
critical revision of the manuscript.
Supplementary material
Supplementary material is available at European Heart Journal online.
Acknowledgements
Nicole Brilakis, Tim Peoples, and Colleen Gilbert (all of Medtronic,
Inc.) assisted with preparation of the figures and references, and
editing of the manuscript.
This work was supported by Medtronic, Inc.
Conflict of interest: W.W. reports grants from Medtronic and Cordis
J&J during the conduct of the study; grants from Boston Scientific, Biosensors, Terumo, MI-CELL, Pfizer, and Boehringer-Ingelheim outside the
submitted work; grants and non-financial support from Abbott Vascular,
Astra Zeneca, Biotronik, Cardio3 BioSciences, and St Jude outside the
submitted work; non-financial support from Volcano outside the submitted work; serving as a co-founder, stockholder, and board member for
Cardio3BioSciences (biotech start-up) and Argonauts; being a stockholder and board member Genae, Inc.; and serving as (co)-Chairman of
EuroPCR, PCR, and Africa PCR. P.G.S.reports personal fees from Medtronic during the conduct of the study; personal fees from Amarin,
Bayer, Boehringer-Ingelheim, Bristol-Myers-Squibb, Daiichi-Sankyo,
GlaxoSmithKline, Lilly, Merck-Sharpe-Dohme, Novartis, Otsuka, Pfizer,
Roche, The Medicines Company, and Vivus outside the submitted
work; and grants and personal fees from Sanofi and Servier outside the
submitted work. L.M. reports grants from Medtronic during the
conduct of the study and grants from Abbott, Cordis, Boston Scientific,
Medtronic, Eli Lilly/Daiichi-Sankyo, Bristol-Myers-Squibb/sanofi-aventis,
and Biotronik outside the submitted work. R.G. reports grants from
Abbott Vascular, B Braun, Boston Scientific, and MicroPort (Shanghai,
China) outside the submitted work. E.B. reports grants and personal
fees from Medtronic, Inc., Servier, and Sanofi for study-related activities.
P.R. reports personal fees from Medtronic during the conduct of the
study. F.v.L. reports employment by Medtronic during the conduct of
the study.
References
1. Camenzind E, Wijns W, Mauri L, Boersma E, Parikh K, Kurowski V, Gao R, Bode C,
Greenwood JP, Gershlick A, O’Neill W, Serruys PW, Jorissen B, Steg PG, Committee
PS, Investigators. Rationale and design of the Patient Related OuTcomes with Endeavor versus Cypher stenting Trial (PROTECT): randomized controlled trial comparing the incidence of stent thrombosis and clinical events after sirolimus or
zotarolimus drug-eluting stent implantation. Am Heart J 2009;158:902 –909.
2. Kandzari DE, Leon MB, Popma JJ, Fitzgerald PJ, O’Shaughnessy C, Ball MW, Turco M,
Applegate RJ, Gurbel PA, Midei MG, Badre SS, Mauri L, Thompson KP, LeNarz LA,
Kuntz RE. Comparison of zotarolimus-eluting and sirolimus-eluting stents in patients
with native coronary artery disease: a randomized controlled trial. J Am Coll Cardiol
2006;48:2440 – 2447.
3. Joner M, Nakazawa G, Finn AV, Quee SC, Coleman L, Acampado E, Wilson PS,
Skorija K, Cheng Q, Xu X, Gold HK, Kolodgie FD, Virmani R. Endothelial cell recovery between comparator polymer-based drug-eluting stents. J Am Coll Cardiol 2008;
52:333–342.
4. Camenzind E, Wijns W, Mauri L, Kurowski V, Parikh K, Gao R, Bode C,
Greenwood JP, Boersma E, Vranckx P, McFadden E, Serruys PW, O’Neil WW,
Jorissen B, Van Leeuwen F, Steg PG, Committee PS, Investigators. Stent thrombosis
and major clinical events at 3 years after zotarolimus-eluting or sirolimus-eluting coronary stent implantation: a randomised, multicentre, open-label, controlled trial.
Lancet 2012;380:1396 –1405.
5. Mauri L, Hsieh WH, Massaro JM, Ho KK, D’Agostino R, Cutlip DE. Stent thrombosis
in randomized clinical trials of drug-eluting stents. N Engl J Med 2007;356:
1020 –1029.
6. Cutlip DE, Windecker S, Mehran R, Boam A, Cohen DJ, van Es GA, Steg PG,
Morel MA, Mauri L, Vranckx P, McFadden E, Lansky A, Hamon M, Krucoff MW,
Serruys PW, for the Academic Research Consortium. Clinical end points in coronary
stent trials: a case for standardized definitions. Circulation 2007;115:2344 –2351.
7. Vranckx P, Cutlip DE, Mehran R, Kint PP, Silber S, Windecker S, Serruys PW. Myocardial infarction adjudication in contemporary all-comer stent trials: balancing sensitivity and specificity. Addendum to the historical MI definitions used in stent
studies. EuroIntervention 2010;5:871 –874.
8. Thygesen K, Alpert JS, White HD. Universal definition of myocardial infarction. Eur
Heart J 2007;28:2525 –2538.
9. Serruys PW, Silber S, Garg S, van Geuns RJ, Richardt G, Buszman PE, Kelbaek H, van
Boven AJ, Hofma SH, Linke A, Klauss V, Wijns W, Macaya C, Garot P, DiMario C,
Manoharan G, Kornowski R, Ischinger T, Bartorelli A, Ronden J, Bressers M,
Gobbens P, Negoita M, van Leeuwen F, Windecker S. Comparison of
Downloaded from by guest on October 21, 2014
Patient Related OuTcomes with Endeavor vs. Cypher Stenting Trial is
the sole trial thus far powered for stent thrombosis and comparing
two drug-eluting stents with different healing characteristics (E-ZES
and C-SES), in an all-comers population with 4 years follow-up. Furthermore, PROTECT revealed a difference between these two
stents in the composite clinical outcome of death and MI. Therefore,
to compare relevant patient outcomes (death and MI) from current
literature to those observed in PROTECT, we searched PubMed for
randomized trials or pooled analyses with 4-year follow-up with at
least one study arm including E-ZES23 or C-SES.24,25 Given the
paucity of 4-year data with E-ZES, we also used data from the BMS
control arm in E-ZES randomized trials23 and from the C-SES
pooled analysis24 based on the knowledge of similar long-term
healing characteristics of E-ZES and BMS (Table 2).
The 4-year rates of death and MI in PROTECT were very similar to
those from the pooled E-ZES/BMS data (E-ZES PROTECT vs. E-ZES/
BMS: death 5.5 vs. 5.2%; MI 4.6 vs. 4.7%). The sole randomized midsized trial performed in a selected patient population with long-term
result using E-ZES (Endeavor II trial23) revealed a remarkably low incidence of MI and death. In contrast, C-SES controls showed a slightly
higher incidence of MI than the C-SES arm from PROTECT (C-SES
PROTECT vs. C-SES control: 5.8 vs. 6.4%) and a noticeably higher incidence of death (C-SES PROTECT vs. C-SES control: 6.0 vs. 8.5%).
Though 4-year follow-up data from E-ZES and C-SES are scarce,
our review of the published literature confirms the main findings of
PROTECT. EndeavorTM zotarolimus-eluting stent is associated
with lower rates of MI and death compared with C-SES. Drugeluting stents with established long-term safety profiles should be
recommended.
Funding
2820
10.
11.
12.
13.
14.
15.
17.
18. Kereiakes DJ, Choo JK, Young JJ, Broderick TM. Thrombosis and drug-eluting stents:
a critical appraisal. Rev Cardiovasc Med 2004;5:9 –15.
19. Daemen J, Wenaweser P, Tsuchida K, Abrecht L, Vaina S, Morger C, Kukreja N, Juni P,
Sianos G, Hellige G, van Domburg RT, Hess OM, Boersma E, Meier B, Windecker S,
Serruys PW. Early and late coronary stent thrombosis of sirolimus-eluting and
paclitaxel-eluting stents in routine clinical practice: data from a large
two-institutional cohort study. Lancet 2007;369:667 – 678.
20. Lagerqvist B, Carlsson J, Frobert O, Lindback J, Schersten F, Stenestrand U, James SK,
Swedish Coronary A, Angioplasty Registry Study G. Stent thrombosis in Sweden: a
report from the Swedish Coronary Angiography and Angioplasty Registry. Circ
Cardiovasc Interv 2009;2:401 – 408.
21. Stettler C, Wandel S, Allemann S, Kastrati A, Morice MC, Schomig A, Pfisterer ME,
Stone GW, Leon MB, de Lezo JS, Goy JJ, Park SJ, Sabate M, Suttorp MJ, Kelbaek H,
Spaulding C, Menichelli M, Vermeersch P, Dirksen MT, Cervinka P, Petronio AS,
Nordmann AJ, Diem P, Meier B, Zwahlen M, Reichenbach S, Trelle S,
Windecker S, Juni P. Outcomes associated with drug-eluting and bare-metal
stents: a collaborative network meta-analysis. Lancet 2007;370:937–948.
22. Feres F, Costa RA, Abizaid A, Leon MB, Marin-Neto JA, Botelho RV, King SB III,
Negoita M, Liu M, de Paula JE, Mangione JA, Meireles GX, Castello HJ Jr,
Nicolela EL Jr, Perin MA, Devito FS, Labrunie A, Salvadori D Jr, Gusmao M,
Staico R, Costa JR Jr, de Castro JP, Abizaid AS, Bhatt DL, Investigators OT. Three
vs. twelve months of dual antiplatelet therapy after zotarolimus-eluting stents: the
OPTIMIZE randomized trial. JAMA 2013;310:2510 – 2522.
23. Eisenstein EL, Wijns W, Fajadet J, Mauri L, Edwards R, Cowper PA, Kong DF,
Anstrom KJ. Long-term clinical and economic analysis of the Endeavor drug-eluting
stent versus the Driver bare-metal stent: 4-year results from the ENDEAVOR II trial
(Randomized Controlled Trial to Evaluate the Safety and Efficacy of the Medtronic
AVE ABT-578 Eluting Driver Coronary Stent in De Novo Native Coronary Artery
Lesions). JACC Cardiovasc Interv 2009;2:1178 –1187.
24. Spaulding C, Daemen J, Boersma E, Cutlip DE, Serruys PW. A pooled analysis of data
comparing sirolimus-eluting stents with bare-metal stents. N Engl J Med 2007;356:
989 –997.
25. Stefanini GG, Byrne RA, Serruys PW, de Waha A, Meier B, Massberg S, Juni P,
Schomig A, Windecker S, Kastrati A. Biodegradable polymer drug-eluting stents
reduce the risk of stent thrombosis at 4 years in patients undergoing percutaneous
coronary intervention: a pooled analysis of individual patient data from the
ISAR-TEST 3, ISAR-TEST 4, and LEADERS randomized trials. Eur Heart J 2012;33:
1214 –1222.
Downloaded from by guest on October 21, 2014
16.
zotarolimus-eluting and everolimus-eluting coronary stents. N Engl J Med 2010;363:
136 –146.
von Birgelen C, Sen H, Lam MK, Danse PW, Jessurun GA, Hautvast RW, van
Houwelingen GK, Schramm AR, Gin RM, Louwerenburg JW, de Man FH,
Stoel MG, Lowik MM, Linssen GC, Said SA, Nienhuis MB, Verhorst PM,
Basalus MW, Doggen CJ, Tandjung K. Third-generation zotarolimus-eluting and
everolimus-eluting stents in all-comer patients requiring a percutaneous coronary
intervention (DUTCH PEERS): a randomised, single-blind, multicentre, noninferiority trial. Lancet 2014;383:413 –423.
Stone GW, Rizvi A, Newman W, Mastali K, Wang JC, Caputo R, Doostzadeh J, Cao S,
Simonton CA, Sudhir K, Lansky AJ, Cutlip DE, Kereiakes DJ, Investigators SI.
Everolimus-eluting versus paclitaxel-eluting stents in coronary artery disease.
N Engl J Med 2010;362:1663 –1674.
Windecker S, Serruys PW, Wandel S, Buszman P, Trznadel S, Linke A, Lenk K,
Ischinger T, Klauss V, Eberli F, Corti R, Wijns W, Morice MC, di Mario C, Davies S,
van Geuns RJ, Eerdmans P, van Es GA, Meier B, Juni P. Biolimus-eluting stent with biodegradable polymer versus sirolimus-eluting stent with durable polymer for coronary revascularisation (LEADERS): a randomised non-inferiority trial. Lancet 2008;
372:1163 –1173.
Camenzind E, Boersma E, Wijns W, Mauri L, Rademaker-Havinga T, Suttorp MJ, Al
Kurdi M, Steg PG. Modifying effect of dual antiplatelet therapy on incidence of stent
thrombosis according to implanted drug-eluting stent type. Eur Heart J 2014;35:
1932 –1948.
Schomig A, Neumann FJ, Kastrati A, Schuhlen H, Blasini R, Hadamitzky M, Walter H,
Zitzmann-Roth EM, Richardt G, Alt E, Schmitt C, Ulm K. A randomized comparison
of antiplatelet and anticoagulant therapy after the placement of coronary-artery
stents. N Engl J Med 1996;334:1084 –1089.
Moussa I, Di Mario C, Reimers B, Akiyama T, Tobis J, Colombo A. Subacute stent
thrombosis in the era of intravascular ultrasound-guided coronary stenting
without anticoagulation: frequency, predictors and clinical outcome. J Am Coll
Cardiol 1997;29:6 –12.
Colombo A, Hall P, Nakamura S, Almagor Y, Maiello L, Martini G, Gaglione A,
Goldberg SL, Tobis JM. Intracoronary stenting without anticoagulation accomplished with intravascular ultrasound guidance. Circulation 1995;91:1676 –1688.
Iakovou I, Schmidt T, Bonizzoni E, Ge L, Sangiorgi GM, Stankovic G, Airoldi F,
Chieffo A, Montorfano M, Carlino M, Michev I, Corvaja N, Briguori C,
Gerckens U, Grube E, Colombo A. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA 2005;293:
2126 –2130.
W. Wijns et al.