Interventional Cardiology
Randomized Comparison of Everolimus-Eluting Stent
Versus Sirolimus-Eluting Stent Implantation for De Novo
Coronary Artery Disease in Patients With Diabetes
Mellitus (ESSENCE-DIABETES)
Results From the ESSENCE-DIABETES Trial
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Won-Jang Kim, MD, PhD*; Seung-Whan Lee, MD, PhD*; Seong-Wook Park, MD, PhD;
Young-Hak Kim, MD, PhD; Sung-Cheol Yun, PhD; Jong-Young Lee, MD; Duk-Woo Park, MD, PhD;
Soo-Jin Kang, MD, PhD; Cheol Whan Lee, MD, PhD; Jae-Hwan Lee, MD, PhD;
Si Wan Choi, MD, PhD; In-Whan Seong, MD, PhD; Bong-Ki Lee, MD, PhD; Nae-Hee Lee, MD, PhD;
Yoon Haeng Cho, MD, PhD; Won-Yong Shin, MD, PhD; Seung-Jin Lee, MD, PhD;
Se-Whan Lee, MD, PhD; Min-Su Hyon, MD, PhD; Duk-Won Bang, MD, PhD;
Woo-Jung Park, MD, PhD; Hyun-Sook Kim, MD, PhD; Jei Keon Chae, MD, PhD;
Keun Lee, MD, PhD; Hoon-Ki Park, MD, PhD; Chang-Bum Park, MD; Sang-Gon Lee, MD, PhD;
Min-Kyu Kim, MD, PhD; Kyoung-Ha Park, MD, PhD; Young-Jin Choi, MD, PhD;
Sang-Sig Cheong, MD, PhD; Tae-Hyun Yang, MD, PhD; Jae-Sik Jang, MD, PhD; Sung Ho Her, MD,
PhD; Seung-Jung Park, MD, PhD; on behalf of the ESSENCE–DIABETES Study Investigators
Background—Drug-eluting stents significantly improved angiographic and clinical outcomes compared with bare metal
stents in diabetic patients. However, a comparison of everolimus-eluting stents and sirolimus-eluting stents in diabetic
patients has not been evaluated. Therefore we compared effectiveness of everolimus-eluting stents and sirolimus-eluting
stents in patients with diabetes mellitus.
Methods and Results—This prospective, multicenter, randomized study compared everolimus-eluting stent (n⫽149) and
sirolimus-eluting stent (n⫽151) implantation in diabetic patients. The primary end point was noninferiority of angiographic
in-segment late loss at 8 months. Clinical events were also monitored for at least 12 months. Everolimus-eluting stents were
noninferior to sirolimus-eluting stents for 8-month in-segment late loss (0.23⫾0.27 versus 0.37⫾0.52 mm; difference,
⫺0.13 mm; 95% confidence interval, ⫺0.25 to ⫺0.02; upper 1-sided 95% confidence interval, ⫺0.04; P⬍0.001 for
noninferiority), with reductions in in-stent restenosis (0% versus 4.7%; P⫽0.029) and in-segment restenosis (0.9% versus
6.5%; P⫽0.035). However, in-stent late loss (0.11⫾0.26 versus 0.20⫾0.49 mm; P⫽0.114) was not statistically different
between the 2 groups. At 12 months, ischemia-driven target lesion revascularization (0.7% versus 2.6%; P⫽0.317), death
(1.3% versus 3.3%; P⫽0.448), and myocardial infarction (0% versus 1.3%; P⫽0.498) were not statistically different between
the 2 groups. Major adverse cardiac events, including death, myocardial infarction, and ischemia-driven target lesion
revascularization (2.0% versus 5.3%; P⫽0.218), were also not statistically different between the 2 groups.
Conclusions—Everolimus-eluting stents were noninferior to sirolimus-eluting stents in reducing in-segment late loss and
reduced angiographic restenosis at 8 months in patients with diabetes mellitus and coronary artery disease.
Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00997763.
(Circulation. 2011;124:886-892.)
Key Words: coronary artery disease 䡲 drug-eluting stent 䡲 diabetes mellitus
Received December 27, 2010; accepted June 3, 2011.
From the Asan Medical Center, University of Ulsan College of Medicine, Seoul (W.-J.K., S.-W.L., S.-W.P., Y.-H.K., S.-C.Y., J.-Y.L., D.-W.P., S.-J.K.,
C.W.L., S.-J.P.); Chungnam National University Hospital, Daejeon (J.-H.L., S.W.C., I.-W.S.); Kangwon National University Hospital, Chuncheon (B.-K.L.);
Soon Chun Hyang University Bucheon Hospital, Bucheon (N.-H.L., Y.H.C.); Soon Chun Hyang University Cheonan Hospital, Cheonan (W.-Y.S., S.-J.L.,
S.-W.L.); Soon Chun Hyang University Hospital, Seoul (M.-S.H., D.-W.B.); Hallym University Sacred Heart Hospital, Pyeongchon (W.-J.P., H.-S.K.); ChonBuk
National University Hospital, Jeonju (J.K.C.); Seoul Veterans Hospital, Seoul (K.L., H.-K.P., C.-B.P.); Ulsan University Hospital, Ulsan (S.-G.L.); Hangang
Sacred Heart Hospital, Seoul (M.-K.K., K.-H.P., Y.-J.C.); Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung (S.-S.C.); Inje
University Pusan Paik Hospital, Pusan (T.-H.Y., J.-S.J.); and The Catholic University of Korea, Daejeon St. Mary’s Hospital, Daejeon (S.H.H.), Korea.
*Drs W.-J. Kim and S.-W. Lee contributed equally to this article.
The online-only Data Supplement is available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA.
110.015453/-/DC1.
Correspondence to Seung-Jung Park, MD, PhD, Department of Cardiology, University of Ulsan College of Medicine, Cardiac Center, Asan Medical
Center, 388 –1 Poongnap-dong, Songpa-gu, Seoul, 138-736, Korea. E-mail [email protected]
© 2011 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org
DOI: 10.1161/CIRCULATIONAHA.110.015453
886
Kim et al
D
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iabetic patients often present unfavorable coronary anatomy with small and/or diffusely diseased vessels1 and
exhibit exaggerated neointimal hyperplasia after bare metal
stent implantation compared with nondiabetics.2 Although
drug-eluting stent (DES) implantation significantly reduced
the neointimal hyperplasia and angiographic restenosis compared with bare metal stents in diabetic patients,3 the presence
of diabetes mellitus (DM) continues to be associated with an
increased risk of restenosis and unfavorable clinical outcomes
in the era of DES.4,5 Recently, the relative efficacies of
sirolimus-eluting stent (SES) and paclitaxel-eluting stent
(PES) in patients with DM have been evaluated in randomized, registry, and meta-analysis studies,6 –10 which found
SES to have promising efficacy compared with PES in
diabetic patients. Recently, everolimus-eluting stents (EES)
also showed superior efficacy over PES in large randomized
trials.11–14 In A Clinical Evaluation of the XIENCE V
Everolimus-Eluting Coronary Stent System in the Treatment
of Patients With De Novo Coronary Artery Lesions (SPIRIT)
III and IV subgroup analysis, no significant differences were
observed between EES and PES among diabetic patients, and
a significant interaction was noted between stent type and
event-free survival.13–15 However, it is unclear whether there
are differences in efficacy and safety between EES and SES
in diabetic patients. This prospective randomized study compared angiographic and clinical outcomes of EES and SES in
diabetic patients.
Editorial see p 869
Clinical Perspective on p 892
Methods
Patient Selection
This prospective randomized study included 300 patients between 18
years and 75 years of age with coronary artery disease. The study
involved 15 cardiac centers in Korea between June 2008 and August
2009. Patients were considered eligible if they had DM with either
stable angina or an acute coronary syndrome and had at least 1
coronary lesion (defined as stenosis of ⬎50% and visual reference
diameter ⱖ2.5 mm) suitable for stent implantation. Patients were
excluded if they had contraindication to aspirin or clopidogrel;
unprotected left main disease (diameter stenosis ⱖ50% by visual
estimate); graft vessel disease; left ventricular ejection fraction
⬍30%; recent history of hematologic disease or leukocyte count
⬍3000 per 1 mm3 and/or platelet count ⬍100 000 per 1 mm3;
hepatic dysfunction with aspartate aminotransferase or alanine aminotransferase ⱖ3 times the upper normal reference limit; history of
renal dysfunction or serum creatinine level ⱖ2.0 mg/dL; serious
noncardiac comorbid disease with a life expectancy ⬍1 year;
primary angioplasty for acute myocardial infarction (MI) within 24
hours; or inability to follow the protocol. In patients with multiple
lesions who fulfilled the inclusion and exclusion criteria, the first
stented lesion was considered the target lesion. The institutional
review board at each participating center approved the protocol. All
patients provided written informed consent.
Randomization and Procedures
Once the guidewire had crossed the target lesion, patients were
randomly assigned in a 1:1 ratio to EES (Xience V, Abbott Vascular)
or SES (Cypher Select and Cypher Select Plus, Cordis, Johnson &
Johnson) implantation through the use of an interactive Web response system. The allocation sequence was computer generated,
stratified according to participating center, and blocked with block
Drug-Eluting Stents for Diabetic Patients
887
sizes of 4 and 6 that varied randomly. Random assignments were
stratified according to participation sites. Before or during the
procedure, all patients received at least 100 mg aspirin and a 300- to
600-mg loading dose of clopidogrel. Heparin was administered
throughout the procedure to maintain an activated clotting time of
ⱖ250 seconds. Administration of glycoprotein IIb/IIIa inhibitors was
at the discretion of the operator. After the procedure, all patients
received 100 mg/d aspirin indefinitely and 75 mg/d clopidogrel for at
least 12 months. A 12-lead ECG was obtained after the procedure
and before discharge. Serum levels of creatine kinase and its MB
isoenzyme were assessed 8, 12, and 24 hours after the procedure and
thereafter if considered necessary.
Study End Point and Definitions
The primary end point of this trial was in-segment late loss at the
8-month angiographic follow-up. The secondary end points included
8-month angiographic outcomes of in-stent late loss and in-stent and
in-segment restenosis at 8 months (defined as in-stent or in-segment
stenosis of at least 50%). At 12 months, stent thrombosis, ischemiadriven target lesion revascularization, ischemia-driven target vessel
revascularization, and major adverse cardiac events, including death
resulting from any cause, MI, or ischemia-driven target lesion
revascularization, were also assessed.
The diagnosis of DM was considered confirmed in all patients
receiving active treatment with an oral hypoglycemic agent or
insulin. For patients with a diagnosis of DM who were on a dietary
therapy alone, enrollment in the trial required documentation of an
abnormal blood glucose level after an overnight fast.
Angiographic success was defined as in-segment diameter stenosis
⬍30% by quantitative coronary angiographic analysis. We defined
MI as creatine kinase-MB elevation ⬎3 times or creatine kinase
elevation ⬎2 times the upper normal limit with at least one of the
following: ischemic symptoms, development of pathological Q
waves, and ischemic ECG changes. Revascularization was defined as
ischemia driven if there was stenosis of at least 50% of the diameter,
as documented by a positive functional study, ischemic changes on
an ECG, or ischemic symptoms, or, in the absence of documented
ischemia, if there was stenosis of at least 70% as assessed by
quantitative coronary analysis. Stent thrombosis was assessed according to the Academic Research Consortium definitions16 and was
classified by the timing of the event (acute, 0 to 24 hours; subacute,
0 to 30 days; late, ⬎31 days).
Follow-Up
Repeat coronary angiography was mandatory at 8 months after
stenting or earlier if indicated by clinical symptoms or evidence of
myocardial ischemia. Clinical follow-up visits were scheduled at 30,
120, and 240 days and 1 year. At every visit, physical examination,
ECG, cardiac events, and angina recurrence were monitored. At each
participating center, patient data were recorded prospectively on
standard case report forms and gathered in the central data management center (Asan Medical Center, Seoul, Korea). All adverse
clinical events were adjudicated by an independent events committee
blinded to the treatment groups.
Quantitative Coronary Angiographic Analysis
Coronary angiograms were obtained after intracoronary nitroglycerin
administration. Procedure (baseline), postprocedure, and follow-up
angiograms were submitted to the angiographic core analysis center
(Asan Medical Center, Seoul, Korea). Digital angiograms were
analyzed with an automated edge detection system (CASS II; Pie
Medical, Maastricht, the Netherlands). Angiographic variables included absolute lesion length, stent length, reference vessel diameter,
minimum lumen diameter, percent diameter stenosis, binary restenosis
rate, acute gain, late loss, and the patterns of recurrent restenosis.
Quantitative coronary angiographic measurements of target lesions were
obtained for both the stented segment only (in stent) and the region
including the stented segment and the margins 5 mm proximal and distal
888
Table 1.
Circulation
August 23, 2011
Baseline Clinical Characteristics
Table 2.
Angiographic Characteristics and Procedural Results
Variable
EES
(n⫽149)
SES
(n⫽151)
P
Age, y
63.2⫾8.3
63.5⫾8.1
0.831
78 (52.3)
99 (65.6)
0.020
Left anterior descending artery
91 (61.1)
89 (58.9)
0.706
102 (68.5)
110 (72.8)
0.404
Left circumflex artery
21 (14.1)
25 (16.6)
0.554
Right coronary artery
37 (24.8)
37 (24.5)
0.947
105 (70.5)
115 (76.2)
0.265
Procedure-related non–Q-wave MI, n (%)
11 (7.4)
10 (6.6)
0.825
Insulin
27 (18.1)
19 (12.6)
0.183
Maximal inflation pressure, atm
12.9⫾3.8
13.6⫾3.8
0.077
Dietary therapy alone
17 (11.4)
17 (11.3)
0.967
Use of intravascular ultrasound, n (%)
117 (78.5)
119 (78.8)
0.952
0.173
Men, n (%)
Hypertension, n (%)
Treatment of diabetes mellitus, n (%)
Oral hypoglycemic agent
Variable
EES
(n⫽149)
SES
(n⫽151)
P
Target vessel, n (%)
Glycosylated hemoglobin, %
7.9⫾1.6
7.7⫾1.4
0.274
Use of glycoprotein IIb/IIIa inhibitor, n (%)
2 (1.3)
7 (4.6)
Total cholesterol ⱖ200 mg/dL, n (%)
62 (41.6)
53 (35.1)
0.246
Predilation before stenting, n (%)
134 (89.9)
135 (89.4)
0.880
Current smoker, n (%)
31 (20.8)
41 (27.2)
0.199
102 (68.5)
113 (75.3)
0.186
Previous PCI, n (%)
11 (7.4)
6 (4.0)
0.222
Poststenting adjunctive balloon
dilatation, n (%)
Previous CABG, n (%)
1 (0.7)
1 (0.7)
0.999
3.52⫾0.48
3.54⫾0.45
0.744
Previous MI, n (%)
2 (1.3)
3 (2.0)
0.999
Largest balloon size for adjunctive
dilatation, mm
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Clinical diagnosis, n (%)
Stable angina
85 (57.0)
90 (59.6)
0.653
Unstable angina
60 (40.3)
49 (32.5)
0.159
Acute MI
Left ventricular ejection fraction, %
Multivessel disease, n (%)
4 (2.7)
12 (7.9)
0.043
59.9⫾7.6
61.4⫾5.9
0.084
84 (56.4)
81 (53.6)
0.634
EES indicates everolimus-eluting stent; SES, sirolimus-eluting stent; PCI,
percutaneous coronary intervention; CABG, coronary artery bypass surgery; and
MI, myocardial infarction.
to the stent (in segment). In-segment late loss was calculated within the
analysis segment itself but separately considering stented segment and
the proximal and distal edges, taking the maximum change in minimum
lumen diameter within those 3 segments, and applying it to this segment
as a whole (maximal regional late loss method).17 Patterns of angiographic restenosis were quantitatively assessed with the Mehran et al18
classification.
Statistical Analysis
On the basis of results from previous trial,10 we assumed an
in-segment angiographic late loss of 0.43⫾0.45 mm in both arms.
Calculation of the sample size was based on a margin of noninferiority for in-segment late loss of 0.15 mm, which is equal to 35% of
an assumed mean late loss after the implantation of SES. Using a
1-sided 5% significance level, we estimated that 112 patients per
group were needed to demonstrate noninferiority of EES with a
statistical power of 80%. Expecting that ⬇20% of the patients would
not return for follow-up angiography, the total sample size was
estimated to be 280 patients (140 patients per group). Analyses of the
2 groups were performed according to the intention-to-treat principle. Continuous variables are presented as mean⫾SD or median
(interquartile range) and compared by use of the Student unpaired t
or Mann–Whitney U test. Categorical variables are presented as
numbers or percentages and were compared by use of the ␹2 or
Fisher exact test. The noninferiority hypothesis was assessed statistically with the use of a z test, by which 1-sided P values for
noninferiority were calculated to compare differences between
groups with margins of noninferiority, according the method of Chow
and Liu.19 All P values are 2 sided except those from noninferiority
testing of the primary end point. A value of P⬍0.05 was considered to
indicate a significant difference. All statistical analyses were performed
with SAS version 9.1 (SAS Institute, Cary, NC).
Results
Baseline Characteristics of the Patients
Table 1 shows the baseline clinical characteristics of study
Multivessel stenting, n (%)
41 (27.5)
Used stents at the target lesion, n
1.3⫾0.6
Patients with angiographic
follow-up, n (%)
108 (72.5)
46 (30.5%) 0.574
1.3⫾0.5
0.865
107 (70.9)
0.755
EES indicates everolimus-eluting stent; SES, sirolimus-eluting stent; and MI,
myocardial infarction.
groups. Most of the clinical characteristics were similar
between the 2 groups, although the SES group included
significantly more men and acute MI.
Procedural Results and In-Hospital Outcomes
Table 2 shows the angiographic characteristics and procedural results. The 2 groups have similar anatomic and
procedural characteristics. All stents were successfully implanted, and the angiographic success rate was 100% in all
groups. The 2 groups were treated with similar stented
lengths and the number of implanted stents per target lesion.
Procedure-related non–Q-wave MI occurred similarly in both
arms. In-hospital events, including Q-wave MI, emergency
bypass surgery, or death, did not occur in either group.
Angiographic Outcomes
Baseline and postprocedural quantitative coronary angiographic outcomes for the study groups are shown in Table 3.
The 2 groups had similar baseline and postprocedural quantitative coronary angiographic characteristics.
Follow-up angiography was performed in 215 patients
(71.7%): 108 EES patients (72.5%) and 107 SES patients
(70.9%). The median duration of angiographic follow-up was
similar in the 2 groups (247 days [interquartile range, 228 to
261 days] and 249 days [interquartile range, 238 to 264 days]
for the EES and SES groups; P⫽0.725). Patients undergoing
angiographic follow-up were more likely to have stable
angina (P⫽0.026) than those who did not return for angiographic follow-up (Tables I and II in the online-only Data
Supplement). The results of quantitative coronary angiographic measurements at follow-up are shown in Table 3.
In-segment late loss of EES with maximal regional late loss
method, the prespecified primary end point, was noninferior
Kim et al
Table 3.
Quantitative Angiographic Measurements
Drug-Eluting Stents for Diabetic Patients
Table 4.
Angiographic Patterns of Restenosis*
EES
(n⫽149)
SES
(n⫽151)
P
Reference diameter, mm
2.77⫾0.53
2.77⫾0.45
0.965
Lesion length, mm
22.4⫾12.90
23.9⫾14.0
0.337
IA (articulation or gap)
Stented length, mm
27.7⫾12.7
29.7⫾14.8
0.217
IB (margin)
Variable
Variable
EES (n⫽1),
n (%)
SES (n⫽7),
n (%)
P
1 (100)
5 (71.4)
0.092
0
0
1
2
Focal
Minimum lumen diameter, mm
In-segment
IC (focal body)
0
3
ID (multifocal)
0
0
Before procedure
0.90⫾0.41
0.87⫾0.46
0.497
0
2 (28.6)
After procedure
2.36⫾0.51
2.38⫾0.44
0.606
Diffuse
II (intrastent)
0
2
At follow-up
2.34⫾0.44
2.20⫾0.56
0.056
III (proliferative)
0
0
IV (total occlusion)
0
0
In-stent
After procedure
2.65⫾0.46
2.64⫾0.41
0.819
At follow-up
2.57⫾0.45
2.48⫾0.56
0.203
889
0.092
EES indicates everolimus-eluting stent; SES, sirolimus-eluting stent.
*Classified with the Mehran et al18 criteria.
Diameter stenosis, %
In-segment
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Before procedure
69.1⫾13.6
70.7⫾14.4
0.318
After procedure
14.8⫾8.9
13.8⫾10.3
0.405
At follow-up
17.2⫾10.5
21.4⫾17.3
0.032
6.8⫾5.1
7.4⫾5.2
0.255
individual and composite clinical outcomes did not differ
significantly between the 2 groups. During 12 months, 1 stent
thrombosis occurred in each group, which was subacute and
probable stent thrombosis.
In-stent
After procedure
At follow-up
12.0⫾10.4
14.4⫾15.5
0.190
In-segment
1.45⫾0.58
1.51⫾0.55
0.339
In-stent
1.75⫾0.53
1.77⫾0.55
0.717
In-segment
0.23⫾0.27
0.37⫾0.52
0.020
In-stent
0.11⫾0.26
0.20⫾0.49
0.114
In-segment
1/108 (0.9)
7/107 (6.5)
0.035
In-stent
0/108 (0)
5/107 (4.7)
0.029
Acute gain, mm
Late loss, mm
Binary angiographic restenosis, n/N (%)
Discussion
The major finding of this study is that both EES and SES
implantation showed favorable performance in diabetic patients. At 8 months, EES was noninferior to SES in reducing
in-segment late loss and reduced angiographic restenosis in
patients with DM and coronary artery disease.
Drug-eluting stents significantly reduced angiographic restenosis and cardiac events compared with bare metal stent in
patients with DM. Compared with PES, SES showed promising efficacy in DM patients.6 –10 Recently, newer DES has
Table 5.
Clinical Outcomes at 12 Months
EES indicates everolimus-eluting stent; SES, sirolimus-eluting stent.
EES (n⫽149),
n (%)
SES (n⫽151),
n (%)
P
2 (1.3)
5 (3.3)
0.448
Cardiac
1 (0.7)
2 (1.3)
Noncardiac
1 (0.7)
3 (2.0)
0
2 (1.3)
0
0
Variable
to that of the SES group (0.23⫾0.27 versus 0.37⫾0.52 mm;
difference, ⫺0.13 mm; 95% confidence interval, ⫺0.25 to
⫺0.02; upper 1-sided 95% confidence interval, ⫺0.04;
P⬍0.001 for noninferiority). In-segment late loss using the
analysis segment late loss method was lower in EES versus
SES patients (0.04⫾0.29 versus 0.18⫾0.51 mm; difference,
⫺0.14 mm; 95% confidence interval, ⫺0.25 to ⫺0.03;
P⫽0.015). However, in-stent late loss (0.11⫾0.26 versus
0.19⫾0.49 mm; difference, ⫺0.09 mm; 95% confidence
interval, ⫺0.19 to ⫺0.02; P⫽0.11) was not statistically
different between the 2 groups. The rate of in-segment
restenosis was 0.9% in the EES group and 6.5% in the SES
group (P⫽0.035). The in-stent restenosis rate was also lower
in the EES than the SES group (0% versus 4.7%; P⫽0.029).
In patients with restenosis, the pattern of restenosis was not
different between the 2 groups (Table 4).
Death
MI
Q-wave
0
2 (1.3)
Ischemia-driven TLR
Non–Q-wave
1 (0.7)
4 (2.6)
Drug-eluting stent
1 (0.7)
1 (0.7)
0
4 (2.6)
1 (0.7)
1 (0.7)
0
0
1 (0.7)
1 (0.7)
0
0
Cutting balloon
Stent thrombosis
Acute
Subacute
Late
0.498
0.371
0.999
Ischemia-driven TVR
1 (0.7)
6 (4.0)
Death/MI/ischemia-driven TVR
3 (2.0)
10 (6.6)
0.121
0.085
3 (2.0)
8 (5.3)
0.218
Clinical Outcomes
MACEs (death/MI/ischemia-driven
TLR)
Major adverse cardiac events during follow-up are shown in
Table 5. A minimum 12-month clinical follow-up was performed in all patients. At 12 months, the incidence of
EES indicates everolimus-eluting stent; SES, sirolimus-eluting stent; MI,
myocardial infarction; TLR, target lesion revascularization; TVR, target vessel
revascularization; and MACE, major adverse cardiac events.
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August 23, 2011
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been a default strategy in routine practice in the treatment of
coronary artery disease. In several randomized trials, EES
showed superior efficacy over PES.11–14 Furthermore, intravascular analysis study showed that EES showed greater
neointimal suppression without significant vessel expansion
than PES in diabetic patients.20 However, the relative efficacy
of EES versus SES in diabetic patients has not been tested in
a randomized study.
The present study shows that EES was noninferior to SES
in reducing in-segment late loss and reduced angiographic
restenosis. Although in-stent late loss may be served as a
useful measure of the pure biological potency of DES and a
more reliable predictor of restenosis,21 we chose in-segment
late loss as the primary end point because it is the most
sensitive measure of the antiproliferative effectiveness of
DES and accounts for the magnitude of lumen renarrowing
that occurs at the margins of the stent. Because isolated
stenoses at stent edges represent an increasingly greater
proportion of target lesion revascularization events with a
DES than a bare metal stent, in-segment measures might be a
wise choice as a clinical event surrogate.22
In this trial, EES was noninferior to SES for in-segment
late loss with the maximal regional late loss method, the
prespecified primary end point, and reduced in-segment late
loss with the analysis segment late loss method. However,
in-stent late loss was not statistically different between the 2
groups. In the previous studies, the late loss of the SES group
in diabetic patients (in-stent late loss, 0.09 to 0.26 mm;
in-segment late loss, 0.31 to 0.43 mm) was comparable to that
observed in our study.3,9,10,23,24 Late loss of the EES group of
a nonselective population study using the analysis segment
late loss method (in-stent late loss, 0.11 to 0.19 mm; insegment late loss, 0.06 to 0.10) was also comparable to that
observed in our study.12,13,25–27 Furthermore, a previous
randomized trial comparing EES and SES also showed that
in-stent late loss is lower in EES compared with SES
(0.23⫾0.52 versus 0.28⫾0.57 mm; P⫽0.08).28 In addition, a
randomized trial comparing EES and SES showed that the
relative efficacy of EES was noninferior to SES in inhibiting
in-segment late loss as a primary end point (0.10⫾0.36 versus
0.05⫾0.34 mm; upper 1-sided 95% confidence interval, 0.09;
P⫽0.023 for noninferiority).29 Therefore, our findings demonstrated that the effectiveness of EES for neointimal suppression is extrapolated to the diabetic population.
We also observed that EES reduced in-stent and insegment restenosis compared with SES. In a previous study,
restenosis rates of the SES group in a diabetic population
(in-stent restenosis, 3.4% to 4.9%; in-segment restenosis,
4.0% to 8.8%) were comparable to those observed in our
study.3,9,10,23,24 However, in our EES group, the restenosis
rates were numerically lower than those of the previous
nonselective population study (in-stent restenosis rate, 2.3%
to 3.8%; in-segment restenosis rate, 4.7% to 6.5%).12,13,25–27
A recently published EES study comparing Japanese and
American populations showed that intravascular ultrasound–
guided aggressive post– balloon dilation and stent optimization reduced percent neointimal obstruction.30 Although the
exact mechanism underlying our findings remains unclear,
79% patients of the EES group were treated by intravascular
ultrasound guidance, which partially explained the low restenosis rate in the EES group in our diabetic population. The
reduced strut thickness (81 versus 140 ␮m) and thinner
polymer coating (7.6 versus 12.6 ␮m), in conjunction with
improved biocompatibility of the EES polymer, may favorably affect neointimal hyperplasia.
Although a noninferior rate of late loss and reduction in
angiographic restenosis was shown in the EES versus the SES
group, all clinical end points, including stent thrombosis,
death, MI, ischemia-driven target lesion revascularization,
ischemia-driven target vessel revascularization, and major
adverse cardiac events, ie, composite outcomes of death, MI,
or ischemia-driven target vessel revascularization, were not
statistically different, which is supported by previous studies
showing similar efficacy and safety for EES and SES.31–33
Recently, a large-scale randomized clinical study (A Prospective, Randomized Trial of Everolimus-Eluting and SirolimusEluting Stents in Patients with Coronary Artery Disease
[SORT-OUT IV]) which included ⬎2600 patients across a
wide range of lesion and patient complexity, also demonstrated a similar rate of the composite end point of major
adverse cardiac events between the EES and SES groups
(4.9% versus 5.2%).33
Study Limitations
The present study has limitations that should be addressed.
First, in our study, in-segment late loss was calculated with
the maximal regional late loss method.17 However, a previous
study showed that the clinical relevance of the maximal
regional late loss was similar to that of the analysis segment
late loss.17 Second, the angiographic follow-up rate was lower
than the protocol-based estimated rate. However, the number
of patients undergoing angiographic follow-up provided a
statistical power of 78% to demonstrate noninferiority of
EES, which almost reached our protocol-based statistical
power of 80%. Third, the SES group included significantly
more men, a higher prevalence of acute MI, and marginally
higher values of left ventricular ejection fraction. Therefore,
we investigated whether these variables were effect modifiers
and/or confounding effectors for in-segment and in-stent late
loss. On linear regression adjusting for these variables, there
were no significant interaction effects between groups and
variables on both outcomes (P⬎0.10 for both). However,
because of the low event number, we could not analyze the
binary restenosis and clinical outcomes with adjustment of
these variables. Finally, our study is a small angiographic
outcomes study that was not powered for clinical outcomes.
Therefore, our findings should be confirmed or rebutted by
larger, longer-term follow-up study in diabetic patients.
Conclusion
The present study showed that EES implantation resulted in
noninferior 8-month angiographic in-segment late loss and
reduced 8-month angiographic restenosis rate without significant differences in MI, death, or stent thrombosis compared
with SES implantation in patients with DM and coronary
artery disease.
Kim et al
Drug-Eluting Stents for Diabetic Patients
Sources of Funding
This study was supported by a grant from the Cardiovascular
Research Foundation (Korea) and a grant from the Ministry for
Health, Welfare and Family Affairs, Republic of Korea as part of the
Korea Health 21 R&D Project (0412-CR02-0704-0001).
Disclosures
None.
15.
16.
References
Downloaded from http://circ.ahajournals.org/ by guest on June 14, 2017
1. Kip KE, Faxon DP, Detre KM, Yeh W, Kelsey SF, Currier JW.
Coronary angioplasty in diabetic patients: the National Heart, Lung,
and Blood Institute Percutaneous Transluminal Coronary Angioplasty
Registry. Circulation. 1996;94:1818 –1825.
2. Kornowski R, Mintz GS, Kent KM, Pichard AD, Satler LF, Bucher TA,
Hong MK, Popma JJ, Leon MB. Increased restenosis in diabetes mellitus
after coronary interventions is due to exaggerated intimal hyperplasia: a
serial intravascular ultrasound study. Circulation. 1997;95:1366 –1369.
3. Sabate M, Jimenez-Quevedo P, Angiolillo DJ, Gomez-Hospital JA,
Alfonso F, Hernandez-Antolin R, Goicolea J, Banuelos C, Escaned J,
Moreno R, Fernandez C, Fernandez-Aviles F, Macaya C; for the
DIABETES Investigators. Randomized comparison of sirolimus-eluting
stent versus standard stent for percutaneous coronary revascularization in
diabetic patients: the Diabetes and Sirolimus-Eluting Stent (DIABETES)
trial. Circulation. 2005;112:2175–2183.
4. Kumar R, Lee TT, Jeremias A, Ruisi CP, Sylvia B, Magallon J, Kirtane
AJ, Bigelow B, Abrahamson M, Pinto DS, Ho KKL, Cohen DJ, Carrozza
JP Jr, Cutlip DE. Comparison of outcomes using sirolimus-eluting
stenting in diabetic versus nondiabetic patients with comparison of insulin
versus non-insulin therapy in the diabetic patients. Am J Cardiol. 2007;
100:1187–1191.
5. Hong SJ, Kim MH, Ahn TH, Ahn YK, Bae JH, Shim WJ, Ro YM, Lim
DS. Multiple predictors of coronary restenosis after drug-eluting stent
implantation in patients with diabetes. Heart. 2006;92:1119 –1124.
6. Zhang F, Dong L, Ge J. Meta-analysis of five randomized clinical trials
comparing sirolimus- versus paclitaxel-eluting stents in patients with
diabetes mellitus. Am J Cardiol. 2010;105:64 – 68.
7. Yang TH, Park SW, Hong MK, Park DW, Park KM, Kim YH, Han KH,
Lee CW, Cheong SS, Kim JJ, Park SJ. Impact of diabetes mellitus on
angiographic and clinical outcomes in the drug-eluting stents era. Am J
Cardiol. 2005;96:1389 –1392.
8. Lee SW, Park SW, Kim YH, Yun SC, Park DW, Lee CW, Hong MK,
Rhee KS, Chae JK, Ko JK, Park JH, Lee JH, Choi SW, Jeong JO, Seong
IW, Cho YH, Lee NH, Kim JH, Chun KJ, Kim HS, Park SJ. A randomized comparison of sirolimus- versus paclitaxel-eluting stent implantation in patients with diabetes mellitus: 2-year clinical outcomes of the
DES-DIABETES trial. J Am Coll Cardiol. 2009;53:812– 813.
9. Lee SW, Park SW, Kim YH, Yun SC, Park DW, Lee CW, Hong MK, Rhee
KS, Chae JK, Ko JK, Park JH, Lee JH, Choi SW, Jeong JO, Seong IW, Cho
YH, Lee NH, Kim JH, Chun KJ, Kim HS, Park SJ. A randomized comparison of sirolimus- versus paclitaxel-eluting stent implantation in patients
with diabetes mellitus. J Am Coll Cardiol. 2008;52:727–733.
10. Dibra A, Kastrati A, Mehilli J, Pache J, Schühlen H, von Beckerath N,
Ulm K, Wessely R, Dirschinger J, Schömig A. Paclitaxel-eluting or
sirolimus-eluting stents to prevent restenosis in diabetic patients. N Engl
J Med. 2005;353:663– 670.
11. Kedhi E, Joesoef KS, McFadden E, Wassing J, van Mieghem C, Goedhart
D, Smits PC. Second-generation everolimus-eluting and paclitaxeleluting stents in real-life practice (COMPARE): a randomised trial.
Lancet. 2010;375:201–209.
12. Serruys PW, Ruygrok P, Neuzner J, Piek JJ, Seth A, Schofer JJ, Richardt
G, Wiemer M, Carrié D, Thuesen L, Boone E, Miquel-Herbert K,
Daemen J. A randomised comparison of an everolimus-eluting coronary
stent with a paclitaxel-eluting coronary stent: the SPIRIT II trial. EuroIntervention. 2006;2:286 –294.
13. Stone GW, Midei M, Newman W, Sanz M, Hermiller JB, Williams J,
Farhat N, Mahaffey KW, Cutlip DE, Fitzgerald PJ, Sood P, Su X, Lansky
AJ. Comparison of an everolimus-eluting stent and a paclitaxel-eluting
stent in patients with coronary artery disease. JAMA. 2008;299:
1903–1913.
14. Stone GW, Rizvi A, Newman W, Mastali K, Wang JC, Caputo R,
Doostzadeh J, Cao S, Simonton CA, Sudhir K, Lansky AJ, Cutlip DE,
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
891
Kereiakes DJ. Everolimus-eluting versus paclitaxel-eluting stents in
coronary artery disease. N Engl J Med. 2010;362:1663–1674.
Kereiakes DJ, Cutlip DE, Applegate RJ, Wang J, Yaqub M, Sood P, Su
X, Su G, Farhat N, Rizvi A, Simonton CA, Sudhir K, Stone GW.
Outcomes in diabetic and nondiabetic patients treated with everolimus- or
paclitaxel-eluting stents: results from the SPIRIT IV clinical trial
(Clinical Evaluation of the XIENCE V Everolimus Eluting Coronary
Stent System). J Am Coll Cardiol. 2010;56:2084 –2089.
Laskey WK, Yancy CW, Maisel WH. Thrombosis in coronary drugeluting stents: report from the meeting of the Circulatory System Medical
Devices Advisory Panel of the Food and Drug Administration Center for
Devices and Radiologic Health, December 7– 8, 2006. Circulation. 2007;
115:2352–2357.
Ellis SG, Popma JJ, Lasala JM, Koglin JJ, Cox DA, Hermiller J,
O’Shaughnessy C, Mann JT, Turco M, Caputo R, Bergin P, Greenberg J,
Stone GW. Relationship between angiographic late loss and target lesion
revascularization after coronary stent implantation: analysis from the
TAXUS-IV trial. J Am Coll Cardiol. 2005;45:1193–1200.
Mehran R, Dangas G, Abizaid AS, Mintz GS, Lansky AJ, Satler LF,
Pichard AD, Kent KM, Stone GW, Leon MB. Angiographic patterns of
in-stent restenosis: classification and implications for long-term outcome.
Circulation. 1999;100:1872–1878.
Chow S-C, Liu J-P. Design and Analysis of Clinical Trials. 2nd ed. New
York, NY: John Wiley and Sons; 2004.
Otake H, Ako J, Yamasaki M, Tsujino I, Shimohama T, Hasegawa T,
Sakurai R, Waseda K, Honda Y, Sood P, Sudhir K, Stone GW,
Fitzgerald PJ. Comparison of everolimus- versus paclitaxel-eluting
stents implanted in patients with diabetes mellitus as evaluated by
three-dimensional intravascular ultrasound analysis. Am J Cardiol.
2010;106:492– 497.
Mauri L, Orav EJ, O’Malley AJ, Moses JW, Leon MB, Holmes DR Jr,
Teirstein PS, Schofer J, Breithardt G, Cutlip DE, Kereiakes DJ, Shi C,
Firth BG, Donohoe DJ, Kuntz RE. Relationship of late loss in lumen
diameter to coronary restenosis in sirolimus-eluting stents. Circulation.
2005;111:321–327.
Pocock SJ, Lansky AJ, Mehran R, Popma JJ, Fahy MP, Na Y, Dangas G,
Moses JW, Pucelikova T, Kandzari DE, Ellis SG, Leon MB, Stone GW.
Angiographic surrogate end points in drug-eluting stent trials: a systematic evaluation based on individual patient data from 11 randomized,
controlled trials. J Am Coll Cardiol. 2008;51:23–32.
Baumgart D, Klauss V, Baer F, Hartmann F, Drexler H, Motz W, Klues
H, Hofmann S, Völker W, Pfannebecker T, Stoll H-P, Nickenig G.
One-year results of the SCORPIUS study: a German multicenter investigation on the effectiveness of sirolimus-eluting stents in diabetic
patients. J Am Coll Cardiol. 2007;50:1627–1634.
Tomai F, Reimers B, De Luca L, Galassi AR, Gaspardone A, Ghini AS,
Ferrero V, Favero L, Gioffrè G, Prati F, Tamburino C, Ribichini F.
Head-to-head comparison of sirolimus- and paclitaxel-eluting stent in the
same diabetic patient with multiple coronary artery lesions. Diabetes
Care. 2008;31:15–19.
Bartorelli AL, Serruys PW, Miquel-Hébert K, Yu S, Pierson W, Stone
GW. An everolimus-eluting stent versus a paclitaxel-eluting stent in small
vessel coronary artery disease: a pooled analysis from the SPIRIT II and
SPIRIT III trials. Catheter Cardiovasc Interv. 2010;76:60 – 66.
Khattab AA, Richardt G, Verin V, Kelbaek H, Macaya C, Berland J, MiquelHebert K, Dorange C, Serruys PW. Differentiated analysis of an everolimuseluting stent and a paclitaxel-eluting stent among higher risk subgroups for
restenosis: results from the SPIRIT II trial. EuroIntervention. 2008;3:
566–573.
Serruys PW, Silber S, Garg S, van Geuns RJ, Richardt G, Buszman PE,
Kelbæk 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 zotarolimus-eluting and
everolimus-eluting coronary stents. N Engl J Med. 2010;363:136 –146.
Kastrati A. Clinical and angiographic results from a randomized trial
sirolimus-eluting and everolimus-eluting stent: ISAR-TEST 4. Paper presented at: Transcatheter Cardiovascular Therapeutics 2009-Session V.
Current generation DES; September 24, 2009; San Francisco, CA.
Kim HS. Efficacy of XIENCE/PROMUS versus Cypher to reduce late
loss in stent: the EXCELLENT trial. Paper presented at: Transcatheter
Cardiovascular Therapeutics 2010-First Report Investigations Sessions;
September 25, 2010; Washington, DC.
Shimohama T, Ako J, Yamasaki M, Otake H, Tsujino I, Hasegawa T,
Nakatani D, Sakurai R, Chang H, Kusano H, Waseda K, Honda Y, Stone
892
Circulation
August 23, 2011
GW, Saito S, Fitzgerald PJ, Sudhir K. SPIRIT III JAPAN versus SPIRIT
III USA: a comparative intravascular ultrasound analysis of the
everolimus-eluting stent. Am J Cardiol. 2010;106:13–17.
31. Byrne RA, Kastrati A, Kufner S, Massberg S, Birkmeier KA, Laugwitz
K-L, Schulz S, Pache J, Fusaro M, Seyfarth M, Schömig A, Mehilli J.
Randomized, non-inferiority trial of three limus agent-eluting stents with
different polymer coatings: the Intracoronary Stenting and Angiographic
Results: Test Efficacy of 3 Limus-Eluting Stents (ISAR-TEST-4) trial.
Eur Heart J. 2009;30:2441–2449.
32. Onuma Y, Kukreja N, Piazza N, Eindhoven J, Girasis C, Schenkeveld L, van
Domburg R, Serruys PW. The everolimus-eluting stent in real-world
patients: 6-month follow-up of the X-SEARCH (Xience V Stent Evaluated at
Rotterdam Cardiac Hospital) registry. J Am Coll Cardiol. 2009;54:269–276.
33. Jensen LO. A prospective randomized trial of everolimus-eluting stents
and sirolimus-eluting stents in patients with coronary artery disease: the
SORT-OUT IV trial. Paper presented at: Transcatheter Cardiovascular
Therapeutics 2010-Late Breaking Trial Sessions; September 24, 2010;
Washington, DC.
CLINICAL PERSPECTIVE
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Diabetic patients have worse clinical outcomes after coronary intervention compared with nondiabetics. With the
introduction of drug-eluting stents, the rate of restenosis was reduced compared with bare metal stents in diabetic patients,
although the presence of diabetes mellitus remains a significant predictor of adverse outcomes in the drug-eluting stent era.
The Randomized Comparison of Everolimus-Eluting Stent Versus Sirolimus-Eluting Stent Implantation for De Novo
Coronary Artery Disease in Patients with Diabetes Mellitus (ESSENCE-DIABETES) trial was a prospective randomized
trial that compared everolimus-eluting stents (n⫽149) and sirolimus-eluting stents (n⫽151) in diabetic patients.
Everolimus-eluting stents were noninferior to sirolimus-eluting stents for 8-month in-segment late loss (0.23⫾0.27 versus
0.37⫾0.52 mm; difference, ⫺0.13 mm; 95% confidence interval, ⫺0.25 to ⫺0.02; upper 1-sided 95% confidence interval,
⫺0.04; P⬍0.001 for noninferiority), with reductions in in-stent restenosis (0% versus 4.7%; P⫽0.029) and in-segment
restenosis (0.9% versus 6.5%; P⫽0.035). However, in-stent late loss (0.11⫾0.26 versus 0.19⫾0.49 mm; difference,
⫺0.09 mm; 95% confidence interval, ⫺0.19 to ⫺0.02; P⫽0.11) was not statistically different between the 2 groups. At
12 months, ischemia-driven target lesion revascularization (0.7% versus 2.6%; P⫽0.317), death (1.3% versus 3.3%;
P⫽0.448), and myocardial infarction (0% versus 1.3%; P⫽0.498) were not statistically different between the 2 groups. In
conclusion, everolimus-eluting stents were noninferior to sirolimus-eluting stents in reducing in-segment late loss and
reduced angiographic restenosis at 8 months in patients with diabetes mellitus and coronary artery disease. Therefore, our
findings suggested that everolimus-eluting stent implantation is a good option for the diabetic population.
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Randomized Comparison of Everolimus-Eluting Stent Versus Sirolimus-Eluting Stent
Implantation for De Novo Coronary Artery Disease in Patients With Diabetes Mellitus
(ESSENCE-DIABETES): Results From the ESSENCE-DIABETES Trial
Won-Jang Kim, Seung-Whan Lee, Seong-Wook Park, Young-Hak Kim, Sung-Cheol Yun,
Jong-Young Lee, Duk-Woo Park, Soo-Jin Kang, Cheol Whan Lee, Jae-Hwan Lee, Si Wan Choi,
In-Whan Seong, Bong-Ki Lee, Nae-Hee Lee, Yoon Haeng Cho, Won-Yong Shin, Seung-Jin
Lee, Se-Whan Lee, Min-Su Hyon, Duk-Won Bang, Woo-Jung Park, Hyun-Sook Kim, Jei Keon
Chae, Keun Lee, Hoon-Ki Park, Chang-Bum Park, Sang-Gon Lee, Min-Kyu Kim, Kyoung-Ha
Park, Young-Jin Choi, Sang-Sig Cheong, Tae-Hyun Yang, Jae-Sik Jang, Sung Ho Her and
Seung-Jung Park
on behalf of the ESSENCEDIABETES Study Investigators
Circulation. 2011;124:886-892; originally published online August 1, 2011;
doi: 10.1161/CIRCULATIONAHA.110.015453
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2011 American Heart Association, Inc. All rights reserved.
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SUPPLEMENTAL MATERIAL
Table 1. Baseline Clinical Characteristics
Variable
Follow-Up
Follow-Up
Angiography
Angiography
(+)
(-)
(N=215)
(N=85)
62.9±8.3
64.6±7.9
0.113
Men
129 (60.0%)
48 (56.5%)
0.575
Hypertension
66 (30.7%)
22 (25.9%)
0.409
Age, years
Treatment of diabetes mellitus
P
0.490
Oral hypoglycemic agent
157 (73.0%)
63 (74.1%)
Insulin
31 (14.4%)
15 (17.6%)
Dietary therapy alone
27 (12.6%)
7 (8.2%)
7.7±1.4%
7.8±1.8%
0.627
Total cholesterol ≥200 mg/dL
85 (39.5%)
30 (35.3%)
0.496
Current smoker
47 (21.9%)
25 (29.4%)
0.168
Previous PCI
13 (6.0%)
4 (4.7%)
0.786
Previous CABG
1 (0.5%)
1 (1.2%)
0.487
Previous MI
4 (1.9%)
1 (1.2%)
1.000
Glycosylated hemoglobin
Clinical diagnosis
0.031
Stable angina
134 (62.3%)
41 (48.2%)
0.026
Unstable angina
73 (34.0%)
36 (42.4%)
0.173
8 (3.7%)
8 (9.4%)
0.082
61.1±6.6
59.5±7.4
0.089
Acute MI
Left ventricular ejection fraction, %
Multivessel disease
111 (51.6%)
54 (55.0%)
0.062
Abbreviations: PCI, percutaneous coronary intervention; CABG, coronary artery bypass
surgery; MI, myocardial infarction.
Table 2. Angiographic Characteristics and Procedural Results
Variable
Follow-Up
Follow-Up
Angiography
Angiography
(+)
(-)
(N=215)
(N=85)
Target vessel
P
0.582
Left anterior descending artery
130 (60.5%)
50 (58.8)
Left circumflex artery
35 (16.3%)
11 (12.9%)
Right coronary artery
50 (23.3%)
24 (28.2%)
Procedure-related non-Q MI
14 (6.5%)
7 (8.2%)
0.598
Maximal inflation pressure, atm
13.3±3.8
13.3±4.0
0.940
Use of intravascular ultrasound
173 (80.5%)
63 (74.1%)
0.277
6 (2.8%)
3 (3.5%)
0.735
Predilation before stenting
193 (89.8%)
76 (89.4%)
0.927
Post-stenting adjunctive balloon dilatation
148 (69.2%)
67 (78.8%)
0.094
3.53±0.44
3.53±0.50
0.930
68 (31.6%)
19 (22.4%)
0.111
1.3±0.5
1.3±0.6
0.584
Use of glycoprotein IIb/IIIa inhibitor
Largest balloon size for adjunctive dilatation,
mm
Multivessel stenting
Number of used stents at the target lesion
Abbreviations: MI, myocardial infarction.
60
당뇨병 환자들에서 Everolimus 방출 스텐트는
Sirolimus 방출 스텐트에 비해 열등하지 않다
강 현 재 교수 서울대학교병원 순환기내과
Summary
배경
당뇨병 환자에서 everolimus 방출 스텐트와 sirolimus
P =0.029)과 구간내 재협착도(in-segment restenosis,
방출 스텐트를 비교한 연구가 없어서 본 연구를 통해
0.9% vs. 6.5%; P =0.035)를 감소시켰다. 그러나 in-stent
당뇨병 환자에서 이들의 효과를 비교해보고자 한다
late loss는 유의한 차이가 없었다(0.11±0.26 vs. 0.20±
(ESSENCE-DIABETES 연구).
0.49mm; P =0.114). 12개월 시점에서 비교하였을 때, 허
혈에 의한 목표 병변 재개통술 시행률(0.7% vs. 2.6%;
방법 및 결과
P =0.317), 사망률(1.3% vs. 3.3%; P =0.448), 그리고 심근
본 전향적, 다기관, 무작위 배정연구에서는 everolimus
경색증(0% vs. 1.3%; P =0.498)은 양군 간에 유의한 차
방출 스텐트(n=149)와 sirolimus 방출 스텐트(n=151)
이가 없었다. 이들을 모두 함께 분석한 주요 심장 이상
를 당뇨병 환자에서 비교하였다. 연구의 1차 평가점은
반응의 발생률(major adverse cardiac event)도 양군 간
8개월에서의 조영술상의 in-segment late loss에 관한
에 유의한 차이가 없다(2.0% vs. 5.3%; P =0.218).
everolimus 방출 스텐트의 비열등성이었다. 임상경과
는 최소 12개월간 관찰하였다. Everolimus 방출 스텐트
결론
는 sirolimus 방출 스텐트에 비해 8개월에서의 조영술상
Everolimus 방출 스텐트가 sirolimus 방출 스텐트에 비
의 in-segment late loss를 비교하였을 때 비열등하였다
해 당뇨병이 있는 관동맥질환자에서 8개월 추적관찰상
(0.23±0.27 vs. 0.37±0.52mm; 차이, -0.13mm; 95% CI,
에서 in-segment late loss와 조영술상의 재협착을 줄이
-0.25~0.02; upper 1-sided 95% CI, -0.04; P<0.001 for
는 데 있어 열등하지 않았다.
noninferiority). 그리고 스텐트내 재협착(0% vs. 4.7%;
Coronary Artery Disease
Commentary
Sirolimus 방출 스텐트의 도입 이후, 우리는 수많은 약물
자인은 중요한 시사점을 보여주고 있다. 즉, 단기 재협착
방출 스텐트 간의 비교연구 결과들을 보아왔다. 전반적으
의 억제 효과 측면에서 기존의 sirolimus 방출 스텐트보
로 개선된 약물 방출 스텐트의 효능으로 인해 스텐트 간
다 뚜렷하게 우월한 스텐트의 등장은 현실적으로 쉽지 않
의 임상경과를 비교하기는 현실적으로 거의 불가능하게
을 것임을 보여주는 것이다. 결국, sirolimus 방출 스텐트
되었고(지나치게 많은 대상 환자가 필요하므로), 따라서
와 유사한 효능을 보이는 스텐트가 ‘state of the art’의 스
대부분의 연구는 조영술상의 재협착의 정도와 같은 대
텐트가 된다면, 결국 스텐트의 선택에 있어 중요한 것은
리 표지자를 통한 비교연구로 이루어져 왔다. 이와 같은
드물지만 치명적인 스텐트 혈전증과 같은 합병증의 발생,
연구를 통해 과연 우리가 스텐트의 임상적 효능을 적절
즉 안전성이나 임상 현장에서 현실적으로 중요한 시술의
히 평가할 수 있는지에 대한 의문은 항상 제기되어 왔다.
편의성 등이 될 것이다. 그러나 불행히도 현재의 임상연
실제로 스텐트 재협착이 임상경과에 직접적인 큰 영향을
구는 이와 같은 현실적이고, 중요한 문제에 관해서는 과
줄 수 있다는 결과가 충분치 않은 상황이라는 점을 고려
학적이고 결론적인 정보를 주지 못하고 있다. 상대적으로
하면 더욱 그러하다. 그럼에도 우리는 일상적인 환자 진료
소규모 임상연구에서는 더욱 그러하다는 점이 아쉬움으
상에서 경험하는 직관적인 차이를 잘 반영하는 재협착이
로 남는다. 또한, 본 연구에서는 8개월에서 관동맥 조영술
라는 지표에 큰 가중치를 두고 스텐트의 효능을 비교하
을 시행한 환자의 수가 통계적 검증력 확보를 위해 계산
여 왔다. 더구나 최근에는 임상연구의 실현성을 고려하여
된 각 군당 112명에 미치지 못해 계획된 검증력을 확보하
우월성이 아닌 비열등성을 평가하는 연구가 주를 이루고
지 못했다는 점은 더욱 아쉬움이 남는다(everolimus 방
있다. 본 연구 또한 최근의 예를 따르고 있다. 그렇다면 과
출 스텐트, n=108; sirolimus 방출 스텐트, n=107).
연 이 같은 비교 기준상에서 두 가지의 스텐트를 비교하
본 연구 결과에서 흥미로운 점은 평가 변수 간의 결과
였을 때 우리가 얻게 되는 임상적인 의의는 무엇인가를
차이이다. 본 연구에서 선택한 in-segment late loss는 in-
생각해 볼 필요가 있다.
stent late loss에 비해 목표 혈관의 재개통술 시행 여부
본 연구에서는 당뇨병 환자에서 두 가지 약물 방출 스텐
에 더 큰 영향을 미치는, 임상적인 의의가 더욱 큰 평가
트를 비교하였을 때, everolimus 방출 스텐트가 sirolimus
변수라고 할 수 있다. 그러나 스텐트의 효과를 비교함에
방출 스텐트에 비해 재협착 정도에 있어 열등하지 않음을
있어 생물학적인 측면에서는 in-segment late loss보다는
보고하였다. 이와 같은 결과는 국내에서 시행된 좀 더 대
in-stent late loss가 스텐트 자체의 효능을 비교함에 있어
규모 연구인 EXCELLENT 연구에서도 동일하게 보고되고
서는 좀 더 적합하다고 판단된다. 물론 특정 스텐트를 전
있다. 즉, everolimus 방출 스텐트가 우리나라 환자들에
달하기 위한 풍선카테터 등의 전달 시스템의 차이, 혹은
서는 sirolimus 방출 스텐트에 비해 재협착 측면에서 최소
스텐트의 확장 특성 등에 의해 스텐트 시술 부위 인접부,
한 열등하지는 않거나, 우월할 가능성이 반복적으로 확인
특히 원위 스텐트 인접부에 영향을 주고 이것이 치료의
되고 있다고 할 수 있겠다. Sirolimus 방출 스텐트가 더 이
효과에 영향을 미치는 등의 상황을 함께 고려할 수 있다
상 사용이 불가능해질 상황에서 이에 대한 좋은 대안으
는 측면에서는 in-segment late loss를 이용하는 타당성
로 everolimus 방출 스텐트가 고려될 수 있음을 보여주고
도 인정된다.
있다. 그러나 본 연구를 포함한 유사 연구들의 결과나 디
그러나 흥미로운 점은 왜 in-stent late loss의 차이는 없
61
62
는데 in-segment late loss가 차이가 나는지 이다. Instent late loss의 비교를 통해 약물 방출 스텐트 자체의
효능에는 차이가 없다고 판단되는데, 왜 in-segment late
loss는 유의한 차이가 관찰되는지에 대한 설명이 분명치
않다. 물론, 우월성을 평가할 수 있는 통계적인 검증력을
확보할 만큼의 수가 평가되지 못하여 우연히 나타난 현상
일 가능성을 우선적으로 고려하여야 할 것이나, 이에 대
한 기전적 고찰은 추후에 스텐트의 효능 평가 비교에 있
어 주목할 만한 가치가 있다고 판단된다.
Reference
111 Park KW, Chae IH, Lim DS, Han KR, Yang HM, Lee HY, Kang HJ, Koo BK, Ahn T,
Yoon JH, Jeong MH, Hong TJ, Chung WY, Jo SH, Choi YJ, Hur SH, Kwon HM, Jeon
DW, Kim BO, Park SH, Lee NH, Jeon HK, Gwon HC, Jang YS, Kim HS. EverolimusEluting Versus Sirolimus-Eluting Stents in Patients Undergoing Percutaneous
Coronary Intervention The EXCELLENT (Efficacy of Xience/Promus Versus
Cypher to Reduce Late Loss After Stenting) Randomized Trial. J Am Coll Cardiol.
2011;58:1844-1854.
Interventional Cardiology
Randomized Comparison of Everolimus-Eluting Stent
Versus Sirolimus-Eluting Stent Implantation for De Novo
Coronary Artery Disease in Patients With Diabetes
Mellitus (ESSENCE-DIABETES)
Results From the ESSENCE-DIABETES Trial
Won-Jang Kim, MD, PhD*; Seung-Whan Lee, MD, PhD*; Seong-Wook Park, MD, PhD;
Young-Hak Kim, MD, PhD; Sung-Cheol Yun, PhD; Jong-Young Lee, MD; Duk-Woo Park, MD, PhD;
Soo-Jin Kang, MD, PhD; Cheol Whan Lee, MD, PhD; Jae-Hwan Lee, MD, PhD;
Si Wan Choi, MD, PhD; In-Whan Seong, MD, PhD; Bong-Ki Lee, MD, PhD; Nae-Hee Lee, MD, PhD;
Yoon Haeng Cho, MD, PhD; Won-Yong Shin, MD, PhD; Seung-Jin Lee, MD, PhD;
Se-Whan Lee, MD, PhD; Min-Su Hyon, MD, PhD; Duk-Won Bang, MD, PhD;
Woo-Jung Park, MD, PhD; Hyun-Sook Kim, MD, PhD; Jei Keon Chae, MD, PhD;
Keun Lee, MD, PhD; Hoon-Ki Park, MD, PhD; Chang-Bum Park, MD; Sang-Gon Lee, MD, PhD;
Min-Kyu Kim, MD, PhD; Kyoung-Ha Park, MD, PhD; Young-Jin Choi, MD, PhD;
Sang-Sig Cheong, MD, PhD; Tae-Hyun Yang, MD, PhD; Jae-Sik Jang, MD, PhD; Sung Ho Her, MD,
PhD; Seung-Jung Park, MD, PhD; on behalf of the ESSENCE–DIABETES Study Investigators
Background—Drug-eluting stents significantly improved angiographic and clinical outcomes compared with bare metal
stents in diabetic patients. However, a comparison of everolimus-eluting stents and sirolimus-eluting stents in diabetic
patients has not been evaluated. Therefore we compared effectiveness of everolimus-eluting stents and sirolimus-eluting
stents in patients with diabetes mellitus.
Methods and Results—This prospective, multicenter, randomized study compared everolimus-eluting stent (n�149) and
sirolimus-eluting stent (n�151) implantation in diabetic patients. The primary end point was noninferiority of angiographic
in-segment late loss at 8 months. Clinical events were also monitored for at least 12 months. Everolimus-eluting stents were
noninferior to sirolimus-eluting stents for 8-month in-segment late loss (0.23�0.27 versus 0.37�0.52 mm; difference,
�0.13 mm; 95% confidence interval, �0.25 to �0.02; upper 1-sided 95% confidence interval, �0.04; P�0.001 for
noninferiority), with reductions in in-stent restenosis (0% versus 4.7%; P�0.029) and in-segment restenosis (0.9% versus
6.5%; P�0.035). However, in-stent late loss (0.11�0.26 versus 0.20�0.49 mm; P�0.114) was not statistically different
between the 2 groups. At 12 months, ischemia-driven target lesion revascularization (0.7% versus 2.6%; P�0.317), death
(1.3% versus 3.3%; P�0.448), and myocardial infarction (0% versus 1.3%; P�0.498) were not statistically different between
the 2 groups. Major adverse cardiac events, including death, myocardial infarction, and ischemia-driven target lesion
revascularization (2.0% versus 5.3%; P�0.218), were also not statistically different between the 2 groups.
Conclusions—Everolimus-eluting stents were noninferior to sirolimus-eluting stents in reducing in-segment late loss and
reduced angiographic restenosis at 8 months in patients with diabetes mellitus and coronary artery disease.
Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00997763.
(Circulation. 2011;124:886-892.)
Key Words: coronary artery disease � drug-eluting stent � diabetes mellitus
Received December 27, 2010; accepted June 3, 2011.
From the Asan Medical Center, University of Ulsan College of Medicine, Seoul (W.-J.K., S.-W.L., S.-W.P., Y.-H.K., S.-C.Y., J.-Y.L., D.-W.P., S.-J.K.,
C.W.L., S.-J.P.); Chungnam National University Hospital, Daejeon (J.-H.L., S.W.C., I.-W.S.); Kangwon National University Hospital, Chuncheon (B.-K.L.);
Soon Chun Hyang University Bucheon Hospital, Bucheon (N.-H.L., Y.H.C.); Soon Chun Hyang University Cheonan Hospital, Cheonan (W.-Y.S., S.-J.L.,
S.-W.L.); Soon Chun Hyang University Hospital, Seoul (M.-S.H., D.-W.B.); Hallym University Sacred Heart Hospital, Pyeongchon (W.-J.P., H.-S.K.); ChonBuk
National University Hospital, Jeonju (J.K.C.); Seoul Veterans Hospital, Seoul (K.L., H.-K.P., C.-B.P.); Ulsan University Hospital, Ulsan (S.-G.L.); Hangang
Sacred Heart Hospital, Seoul (M.-K.K., K.-H.P., Y.-J.C.); Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung (S.-S.C.); Inje
University Pusan Paik Hospital, Pusan (T.-H.Y., J.-S.J.); and The Catholic University of Korea, Daejeon St. Mary’s Hospital, Daejeon (S.H.H.), Korea.
*Drs W.-J. Kim and S.-W. Lee contributed equally to this article.
The online-only Data Supplement is available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA.
110.015453/-/DC1.
Correspondence to Seung-Jung Park, MD, PhD, Department of Cardiology, University of Ulsan College of Medicine, Cardiac Center, Asan Medical
Center, 388 –1 Poongnap-dong, Songpa-gu, Seoul, 138-736, Korea. E-mail [email protected]
© 2011 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org
DOI: 10.1161/CIRCULATIONAHA.110.015453
Downloaded from http://circ.ahajournals.org/
886 by IMED Korea on November 13, 2011
63
Kim et al
64
D
iabetic patients often present unfavorable coronary anatomy with small and/or diffusely diseased vessels1 and
exhibit exaggerated neointimal hyperplasia after bare metal
stent implantation compared with nondiabetics.2 Although
drug-eluting stent (DES) implantation significantly reduced
the neointimal hyperplasia and angiographic restenosis compared with bare metal stents in diabetic patients,3 the presence
of diabetes mellitus (DM) continues to be associated with an
increased risk of restenosis and unfavorable clinical outcomes
in the era of DES.4,5 Recently, the relative efficacies of
sirolimus-eluting stent (SES) and paclitaxel-eluting stent
(PES) in patients with DM have been evaluated in randomized, registry, and meta-analysis studies,6 –10 which found
SES to have promising efficacy compared with PES in
diabetic patients. Recently, everolimus-eluting stents (EES)
also showed superior efficacy over PES in large randomized
trials.11–14 In A Clinical Evaluation of the XIENCE V
Everolimus-Eluting Coronary Stent System in the Treatment
of Patients With De Novo Coronary Artery Lesions (SPIRIT)
III and IV subgroup analysis, no significant differences were
observed between EES and PES among diabetic patients, and
a significant interaction was noted between stent type and
event-free survival.13–15 However, it is unclear whether there
are differences in efficacy and safety between EES and SES
in diabetic patients. This prospective randomized study compared angiographic and clinical outcomes of EES and SES in
diabetic patients.
Clinical Perspective on p 69
Methods
Patient Selection
This prospective randomized study included 300 patients between 18
years and 75 years of age with coronary artery disease. The study
involved 15 cardiac centers in Korea between June 2008 and August
2009. Patients were considered eligible if they had DM with either
stable angina or an acute coronary syndrome and had at least 1
coronary lesion (defined as stenosis of �50% and visual reference
diameter �2.5 mm) suitable for stent implantation. Patients were
excluded if they had contraindication to aspirin or clopidogrel;
unprotected left main disease (diameter stenosis �50% by visual
estimate); graft vessel disease; left ventricular ejection fraction
�30%; recent history of hematologic disease or leukocyte count
�3000 per 1 mm3 and/or platelet count �100 000 per 1 mm3;
hepatic dysfunction with aspartate aminotransferase or alanine aminotransferase �3 times the upper normal reference limit; history of
renal dysfunction or serum creatinine level �2.0 mg/dL; serious
noncardiac comorbid disease with a life expectancy �1 year;
primary angioplasty for acute myocardial infarction (MI) within 24
hours; or inability to follow the protocol. In patients with multiple
lesions who fulfilled the inclusion and exclusion criteria, the first
stented lesion was considered the target lesion. The institutional
review board at each participating center approved the protocol. All
patients provided written informed consent.
Randomization and Procedures
Once the guidewire had crossed the target lesion, patients were
randomly assigned in a 1:1 ratio to EES (Xience V, Abbott Vascular)
or SES (Cypher Select and Cypher Select Plus, Cordis, Johnson &
Johnson) implantation through the use of an interactive Web response system. The allocation sequence was computer generated,
stratified according to participating center, and blocked with block
Drug-Eluting Stents for Diabetic Patients
887
sizes of 4 and 6 that varied randomly. Random assignments were
stratified according to participation sites. Before or during the
procedure, all patients received at least 100 mg aspirin and a 300- to
600-mg loading dose of clopidogrel. Heparin was administered
throughout the procedure to maintain an activated clotting time of
�250 seconds. Administration of glycoprotein IIb/IIIa inhibitors was
at the discretion of the operator. After the procedure, all patients
received 100 mg/d aspirin indefinitely and 75 mg/d clopidogrel for at
least 12 months. A 12-lead ECG was obtained after the procedure
and before discharge. Serum levels of creatine kinase and its MB
isoenzyme were assessed 8, 12, and 24 hours after the procedure and
thereafter if considered necessary.
Study End Point and Definitions
The primary end point of this trial was in-segment late loss at the
8-month angiographic follow-up. The secondary end points included
8-month angiographic outcomes of in-stent late loss and in-stent and
in-segment restenosis at 8 months (defined as in-stent or in-segment
stenosis of at least 50%). At 12 months, stent thrombosis, ischemiadriven target lesion revascularization, ischemia-driven target vessel
revascularization, and major adverse cardiac events, including death
resulting from any cause, MI, or ischemia-driven target lesion
revascularization, were also assessed.
The diagnosis of DM was considered confirmed in all patients
receiving active treatment with an oral hypoglycemic agent or
insulin. For patients with a diagnosis of DM who were on a dietary
therapy alone, enrollment in the trial required documentation of an
abnormal blood glucose level after an overnight fast.
Angiographic success was defined as in-segment diameter stenosis
�30% by quantitative coronary angiographic analysis. We defined
MI as creatine kinase-MB elevation �3 times or creatine kinase
elevation �2 times the upper normal limit with at least one of the
following: ischemic symptoms, development of pathological Q
waves, and ischemic ECG changes. Revascularization was defined as
ischemia driven if there was stenosis of at least 50% of the diameter,
as documented by a positive functional study, ischemic changes on
an ECG, or ischemic symptoms, or, in the absence of documented
ischemia, if there was stenosis of at least 70% as assessed by
quantitative coronary analysis. Stent thrombosis was assessed according to the Academic Research Consortium definitions16 and was
classified by the timing of the event (acute, 0 to 24 hours; subacute,
0 to 30 days; late, �31 days).
Follow-Up
Repeat coronary angiography was mandatory at 8 months after
stenting or earlier if indicated by clinical symptoms or evidence of
myocardial ischemia. Clinical follow-up visits were scheduled at 30,
120, and 240 days and 1 year. At every visit, physical examination,
ECG, cardiac events, and angina recurrence were monitored. At each
participating center, patient data were recorded prospectively on
standard case report forms and gathered in the central data management center (Asan Medical Center, Seoul, Korea). All adverse
clinical events were adjudicated by an independent events committee
blinded to the treatment groups.
Quantitative Coronary Angiographic Analysis
Coronary angiograms were obtained after intracoronary nitroglycerin
administration. Procedure (baseline), postprocedure, and follow-up
angiograms were submitted to the angiographic core analysis center
(Asan Medical Center, Seoul, Korea). Digital angiograms were
analyzed with an automated edge detection system (CASS II; Pie
Medical, Maastricht, the Netherlands). Angiographic variables included absolute lesion length, stent length, reference vessel diameter,
minimum lumen diameter, percent diameter stenosis, binary restenosis
rate, acute gain, late loss, and the patterns of recurrent restenosis.
Quantitative coronary angiographic measurements of target lesions were
obtained for both the stented segment only (in stent) and the region
including the stented segment and the margins 5 mm proximal and distal
Downloaded from http://circ.ahajournals.org/ by IMED Korea on November 13, 2011
888
Table 1.
Circulation
August 23, 2011
65
Baseline Clinical Characteristics
Table 2.
Angiographic Characteristics and Procedural Results
Variable
EES
(n�149)
SES
(n�151)
P
Age, y
63.2�8.3
63.5�8.1
0.831
78 (52.3)
99 (65.6)
0.020
Left anterior descending artery
91 (61.1)
89 (58.9)
0.706
102 (68.5)
110 (72.8)
0.404
Left circumflex artery
21 (14.1)
25 (16.6)
0.554
Right coronary artery
37 (24.8)
37 (24.5)
0.947
105 (70.5)
115 (76.2)
0.265
Procedure-related non–Q-wave MI, n (%)
11 (7.4)
10 (6.6)
0.825
Insulin
27 (18.1)
19 (12.6)
0.183
Maximal inflation pressure, atm
12.9�3.8
13.6�3.8
0.077
Dietary therapy alone
17 (11.4)
17 (11.3)
0.967
Use of intravascular ultrasound, n (%)
117 (78.5)
119 (78.8)
0.952
Men, n (%)
Hypertension, n (%)
Treatment of diabetes mellitus, n (%)
Oral hypoglycemic agent
Variable
EES
(n�149)
SES
(n�151)
P
Target vessel, n (%)
Glycosylated hemoglobin, %
7.9�1.6
7.7�1.4
0.274
Use of glycoprotein IIb/IIIa inhibitor, n (%)
2 (1.3)
7 (4.6)
0.173
Total cholesterol �200 mg/dL, n (%)
62 (41.6)
53 (35.1)
0.246
Predilation before stenting, n (%)
134 (89.9)
135 (89.4)
0.880
Current smoker, n (%)
31 (20.8)
41 (27.2)
0.199
113 (75.3)
0.186
11 (7.4)
6 (4.0)
0.222
Poststenting adjunctive balloon
dilatation, n (%)
102 (68.5)
Previous PCI, n (%)
Previous CABG, n (%)
1 (0.7)
1 (0.7)
0.999
3.52�0.48
3.54�0.45
0.744
Previous MI, n (%)
2 (1.3)
3 (2.0)
0.999
Largest balloon size for adjunctive
dilatation, mm
Clinical diagnosis, n (%)
Stable angina
85 (57.0)
90 (59.6)
0.653
Unstable angina
60 (40.3)
49 (32.5)
0.159
4 (2.7)
12 (7.9)
0.043
59.9�7.6
61.4�5.9
0.084
84 (56.4)
81 (53.6)
0.634
Acute MI
Left ventricular ejection fraction, %
Multivessel disease, n (%)
EES indicates everolimus-eluting stent; SES, sirolimus-eluting stent; PCI,
percutaneous coronary intervention; CABG, coronary artery bypass surgery; and
MI, myocardial infarction.
to the stent (in segment). In-segment late loss was calculated within the
analysis segment itself but separately considering stented segment and
the proximal and distal edges, taking the maximum change in minimum
lumen diameter within those 3 segments, and applying it to this segment
as a whole (maximal regional late loss method).17 Patterns of angiographic restenosis were quantitatively assessed with the Mehran et al18
classification.
Statistical Analysis
On the basis of results from previous trial,10 we assumed an
in-segment angiographic late loss of 0.43�0.45 mm in both arms.
Calculation of the sample size was based on a margin of noninferiority for in-segment late loss of 0.15 mm, which is equal to 35% of
an assumed mean late loss after the implantation of SES. Using a
1-sided 5% significance level, we estimated that 112 patients per
group were needed to demonstrate noninferiority of EES with a
statistical power of 80%. Expecting that �20% of the patients would
not return for follow-up angiography, the total sample size was
estimated to be 280 patients (140 patients per group). Analyses of the
2 groups were performed according to the intention-to-treat principle. Continuous variables are presented as mean�SD or median
(interquartile range) and compared by use of the Student unpaired t
or Mann–Whitney U test. Categorical variables are presented as
numbers or percentages and were compared by use of the �2 or
Fisher exact test. The noninferiority hypothesis was assessed statistically with the use of a z test, by which 1-sided P values for
noninferiority were calculated to compare differences between
groups with margins of noninferiority, according the method of Chow
and Liu.19 All P values are 2 sided except those from noninferiority
testing of the primary end point. A value of P�0.05 was considered to
indicate a significant difference. All statistical analyses were performed
with SAS version 9.1 (SAS Institute, Cary, NC).
Results
Baseline Characteristics of the Patients
Table 1 shows the baseline clinical characteristics of study
Multivessel stenting, n (%)
41 (27.5)
Used stents at the target lesion, n
1.3�0.6
Patients with angiographic
follow-up, n (%)
108 (72.5)
46 (30.5%) 0.574
1.3�0.5
0.865
107 (70.9)
0.755
EES indicates everolimus-eluting stent; SES, sirolimus-eluting stent; and MI,
myocardial infarction.
groups. Most of the clinical characteristics were similar
between the 2 groups, although the SES group included
significantly more men and acute MI.
Procedural Results and In-Hospital Outcomes
Table 2 shows the angiographic characteristics and procedural results. The 2 groups have similar anatomic and
procedural characteristics. All stents were successfully implanted, and the angiographic success rate was 100% in all
groups. The 2 groups were treated with similar stented
lengths and the number of implanted stents per target lesion.
Procedure-related non–Q-wave MI occurred similarly in both
arms. In-hospital events, including Q-wave MI, emergency
bypass surgery, or death, did not occur in either group.
Angiographic Outcomes
Baseline and postprocedural quantitative coronary angiographic outcomes for the study groups are shown in Table 3.
The 2 groups had similar baseline and postprocedural quantitative coronary angiographic characteristics.
Follow-up angiography was performed in 215 patients
(71.7%): 108 EES patients (72.5%) and 107 SES patients
(70.9%). The median duration of angiographic follow-up was
similar in the 2 groups (247 days [interquartile range, 228 to
261 days] and 249 days [interquartile range, 238 to 264 days]
for the EES and SES groups; P�0.725). Patients undergoing
angiographic follow-up were more likely to have stable
angina (P�0.026) than those who did not return for angiographic follow-up (Tables I and II in the online-only Data
Supplement). The results of quantitative coronary angiographic measurements at follow-up are shown in Table 3.
In-segment late loss of EES with maximal regional late loss
method, the prespecified primary end point, was noninferior
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Kim et al
66
Table 3.
Quantitative Angiographic Measurements
Table 4.
EES
(n�149)
SES
(n�151)
P
Reference diameter, mm
2.77�0.53
2.77�0.45
0.965
Lesion length, mm
22.4�12.90
23.9�14.0
0.337
Stented length, mm
27.7�12.7
29.7�14.8
0.217
Variable
Drug-Eluting Stents for Diabetic Patients
Angiographic Patterns of Restenosis*
EES (n�1),
n (%)
SES (n�7),
n (%)
P
1 (100)
5 (71.4)
0.092
IA (articulation or gap)
0
0
IB (margin)
1
2
IC (focal body)
0
3
ID (multifocal)
0
0
0
2 (28.6)
Variable
Focal
Minimum lumen diameter, mm
In-segment
Before procedure
0.90�0.41
0.87�0.46
0.497
Diffuse
After procedure
2.36�0.51
2.38�0.44
0.606
II (intrastent)
0
2
At follow-up
2.34�0.44
2.20�0.56
0.056
III (proliferative)
0
0
IV (total occlusion)
0
0
After procedure
2.65�0.46
2.64�0.41
0.819
At follow-up
2.57�0.45
2.48�0.56
0.203
Before procedure
69.1�13.6
70.7�14.4
0.318
After procedure
14.8�8.9
13.8�10.3
0.405
At follow-up
17.2�10.5
21.4�17.3
0.032
6.8�5.1
7.4�5.2
0.255
12.0�10.4
14.4�15.5
0.190
In-segment
1.45�0.58
1.51�0.55
0.339
In-stent
1.75�0.53
1.77�0.55
0.717
In-segment
0.23�0.27
0.37�0.52
0.020
In-stent
0.11�0.26
0.20�0.49
0.114
In-segment
1/108 (0.9)
7/107 (6.5)
0.035
In-stent
0/108 (0)
5/107 (4.7)
0.029
In-stent
889
0.092
EES indicates everolimus-eluting stent; SES, sirolimus-eluting stent.
*Classified with the Mehran et al18 criteria.
Diameter stenosis, %
In-segment
individual and composite clinical outcomes did not differ
significantly between the 2 groups. During 12 months, 1 stent
thrombosis occurred in each group, which was subacute and
probable stent thrombosis.
In-stent
After procedure
At follow-up
Acute gain, mm
Late loss, mm
Binary angiographic restenosis, n/N (%)
Discussion
The major finding of this study is that both EES and SES
implantation showed favorable performance in diabetic patients. At 8 months, EES was noninferior to SES in reducing
in-segment late loss and reduced angiographic restenosis in
patients with DM and coronary artery disease.
Drug-eluting stents significantly reduced angiographic restenosis and cardiac events compared with bare metal stent in
patients with DM. Compared with PES, SES showed promising efficacy in DM patients.6 –10 Recently, newer DES has
Table 5.
Clinical Outcomes at 12 Months
EES indicates everolimus-eluting stent; SES, sirolimus-eluting stent.
Variable
to that of the SES group (0.23�0.27 versus 0.37�0.52 mm;
difference, �0.13 mm; 95% confidence interval, �0.25 to
�0.02; upper 1-sided 95% confidence interval, �0.04;
P�0.001 for noninferiority). In-segment late loss using the
analysis segment late loss method was lower in EES versus
SES patients (0.04�0.29 versus 0.18�0.51 mm; difference,
�0.14 mm; 95% confidence interval, �0.25 to �0.03;
P�0.015). However, in-stent late loss (0.11�0.26 versus
0.19�0.49 mm; difference, �0.09 mm; 95% confidence
interval, �0.19 to �0.02; P�0.11) was not statistically
different between the 2 groups. The rate of in-segment
restenosis was 0.9% in the EES group and 6.5% in the SES
group (P�0.035). The in-stent restenosis rate was also lower
in the EES than the SES group (0% versus 4.7%; P�0.029).
In patients with restenosis, the pattern of restenosis was not
different between the 2 groups (Table 4).
Death
EES (n�149),
n (%)
SES (n�151),
n (%)
P
0.448
2 (1.3)
5 (3.3)
Cardiac
1 (0.7)
2 (1.3)
Noncardiac
1 (0.7)
3 (2.0)
0
2 (1.3)
0
0
MI
Q-wave
0
2 (1.3)
Ischemia-driven TLR
Non–Q-wave
1 (0.7)
4 (2.6)
Drug-eluting stent
1 (0.7)
1 (0.7)
0
4 (2.6)
1 (0.7)
1 (0.7)
0
0
1 (0.7)
1 (0.7)
Cutting balloon
Stent thrombosis
Acute
Subacute
Late
0.498
0.371
0.999
0
0
Ischemia-driven TVR
1 (0.7)
6 (4.0)
0.121
Death/MI/ischemia-driven TVR
3 (2.0)
10 (6.6)
0.085
Clinical Outcomes
MACEs (death/MI/ischemia-driven
TLR)
3 (2.0)
8 (5.3)
0.218
Major adverse cardiac events during follow-up are shown in
Table 5. A minimum 12-month clinical follow-up was performed in all patients. At 12 months, the incidence of
EES indicates everolimus-eluting stent; SES, sirolimus-eluting stent; MI,
myocardial infarction; TLR, target lesion revascularization; TVR, target vessel
revascularization; and MACE, major adverse cardiac events.
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890
Circulation
August 23, 2011
been a default strategy in routine practice in the treatment of
coronary artery disease. In several randomized trials, EES
showed superior efficacy over PES.11–14 Furthermore, intravascular analysis study showed that EES showed greater
neointimal suppression without significant vessel expansion
than PES in diabetic patients.20 However, the relative efficacy
of EES versus SES in diabetic patients has not been tested in
a randomized study.
The present study shows that EES was noninferior to SES
in reducing in-segment late loss and reduced angiographic
restenosis. Although in-stent late loss may be served as a
useful measure of the pure biological potency of DES and a
more reliable predictor of restenosis,21 we chose in-segment
late loss as the primary end point because it is the most
sensitive measure of the antiproliferative effectiveness of
DES and accounts for the magnitude of lumen renarrowing
that occurs at the margins of the stent. Because isolated
stenoses at stent edges represent an increasingly greater
proportion of target lesion revascularization events with a
DES than a bare metal stent, in-segment measures might be a
wise choice as a clinical event surrogate.22
In this trial, EES was noninferior to SES for in-segment
late loss with the maximal regional late loss method, the
prespecified primary end point, and reduced in-segment late
loss with the analysis segment late loss method. However,
in-stent late loss was not statistically different between the 2
groups. In the previous studies, the late loss of the SES group
in diabetic patients (in-stent late loss, 0.09 to 0.26 mm;
in-segment late loss, 0.31 to 0.43 mm) was comparable to that
observed in our study.3,9,10,23,24 Late loss of the EES group of
a nonselective population study using the analysis segment
late loss method (in-stent late loss, 0.11 to 0.19 mm; insegment late loss, 0.06 to 0.10) was also comparable to that
observed in our study.12,13,25–27 Furthermore, a previous
randomized trial comparing EES and SES also showed that
in-stent late loss is lower in EES compared with SES
(0.23�0.52 versus 0.28�0.57 mm; P�0.08).28 In addition, a
randomized trial comparing EES and SES showed that the
relative efficacy of EES was noninferior to SES in inhibiting
in-segment late loss as a primary end point (0.10�0.36 versus
0.05�0.34 mm; upper 1-sided 95% confidence interval, 0.09;
P�0.023 for noninferiority).29 Therefore, our findings demonstrated that the effectiveness of EES for neointimal suppression is extrapolated to the diabetic population.
We also observed that EES reduced in-stent and insegment restenosis compared with SES. In a previous study,
restenosis rates of the SES group in a diabetic population
(in-stent restenosis, 3.4% to 4.9%; in-segment restenosis,
4.0% to 8.8%) were comparable to those observed in our
study.3,9,10,23,24 However, in our EES group, the restenosis
rates were numerically lower than those of the previous
nonselective population study (in-stent restenosis rate, 2.3%
to 3.8%; in-segment restenosis rate, 4.7% to 6.5%).12,13,25–27
A recently published EES study comparing Japanese and
American populations showed that intravascular ultrasound–
guided aggressive post– balloon dilation and stent optimization reduced percent neointimal obstruction.30 Although the
exact mechanism underlying our findings remains unclear,
79% patients of the EES group were treated by intravascular
67
ultrasound guidance, which partially explained the low restenosis rate in the EES group in our diabetic population. The
reduced strut thickness (81 versus 140 �m) and thinner
polymer coating (7.6 versus 12.6 �m), in conjunction with
improved biocompatibility of the EES polymer, may favorably affect neointimal hyperplasia.
Although a noninferior rate of late loss and reduction in
angiographic restenosis was shown in the EES versus the SES
group, all clinical end points, including stent thrombosis,
death, MI, ischemia-driven target lesion revascularization,
ischemia-driven target vessel revascularization, and major
adverse cardiac events, ie, composite outcomes of death, MI,
or ischemia-driven target vessel revascularization, were not
statistically different, which is supported by previous studies
showing similar efficacy and safety for EES and SES.31–33
Recently, a large-scale randomized clinical study (A Prospective, Randomized Trial of Everolimus-Eluting and SirolimusEluting Stents in Patients with Coronary Artery Disease
[SORT-OUT IV]) which included �2600 patients across a
wide range of lesion and patient complexity, also demonstrated a similar rate of the composite end point of major
adverse cardiac events between the EES and SES groups
(4.9% versus 5.2%).33
Study Limitations
The present study has limitations that should be addressed.
First, in our study, in-segment late loss was calculated with
the maximal regional late loss method.17 However, a previous
study showed that the clinical relevance of the maximal
regional late loss was similar to that of the analysis segment
late loss.17 Second, the angiographic follow-up rate was lower
than the protocol-based estimated rate. However, the number
of patients undergoing angiographic follow-up provided a
statistical power of 78% to demonstrate noninferiority of
EES, which almost reached our protocol-based statistical
power of 80%. Third, the SES group included significantly
more men, a higher prevalence of acute MI, and marginally
higher values of left ventricular ejection fraction. Therefore,
we investigated whether these variables were effect modifiers
and/or confounding effectors for in-segment and in-stent late
loss. On linear regression adjusting for these variables, there
were no significant interaction effects between groups and
variables on both outcomes (P�0.10 for both). However,
because of the low event number, we could not analyze the
binary restenosis and clinical outcomes with adjustment of
these variables. Finally, our study is a small angiographic
outcomes study that was not powered for clinical outcomes.
Therefore, our findings should be confirmed or rebutted by
larger, longer-term follow-up study in diabetic patients.
Conclusion
The present study showed that EES implantation resulted in
noninferior 8-month angiographic in-segment late loss and
reduced 8-month angiographic restenosis rate without significant differences in MI, death, or stent thrombosis compared
with SES implantation in patients with DM and coronary
artery disease.
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Kim et al
68
Drug-Eluting Stents for Diabetic Patients
Sources of Funding
This study was supported by a grant from the Cardiovascular
Research Foundation (Korea) and a grant from the Ministry for
Health, Welfare and Family Affairs, Republic of Korea as part of the
Korea Health 21 R&D Project (0412-CR02-0704-0001).
Disclosures
None.
15.
16.
References
1. Kip KE, Faxon DP, Detre KM, Yeh W, Kelsey SF, Currier JW.
Coronary angioplasty in diabetic patients: the National Heart, Lung,
and Blood Institute Percutaneous Transluminal Coronary Angioplasty
Registry. Circulation. 1996;94:1818 –1825.
2. Kornowski R, Mintz GS, Kent KM, Pichard AD, Satler LF, Bucher TA,
Hong MK, Popma JJ, Leon MB. Increased restenosis in diabetes mellitus
after coronary interventions is due to exaggerated intimal hyperplasia: a
serial intravascular ultrasound study. Circulation. 1997;95:1366 –1369.
3. Sabate M, Jimenez-Quevedo P, Angiolillo DJ, Gomez-Hospital JA,
Alfonso F, Hernandez-Antolin R, Goicolea J, Banuelos C, Escaned J,
Moreno R, Fernandez C, Fernandez-Aviles F, Macaya C; for the
DIABETES Investigators. Randomized comparison of sirolimus-eluting
stent versus standard stent for percutaneous coronary revascularization in
diabetic patients: the Diabetes and Sirolimus-Eluting Stent (DIABETES)
trial. Circulation. 2005;112:2175–2183.
4. Kumar R, Lee TT, Jeremias A, Ruisi CP, Sylvia B, Magallon J, Kirtane
AJ, Bigelow B, Abrahamson M, Pinto DS, Ho KKL, Cohen DJ, Carrozza
JP Jr, Cutlip DE. Comparison of outcomes using sirolimus-eluting
stenting in diabetic versus nondiabetic patients with comparison of insulin
versus non-insulin therapy in the diabetic patients. Am J Cardiol. 2007;
100:1187–1191.
5. Hong SJ, Kim MH, Ahn TH, Ahn YK, Bae JH, Shim WJ, Ro YM, Lim
DS. Multiple predictors of coronary restenosis after drug-eluting stent
implantation in patients with diabetes. Heart. 2006;92:1119 –1124.
6. Zhang F, Dong L, Ge J. Meta-analysis of five randomized clinical trials
comparing sirolimus- versus paclitaxel-eluting stents in patients with
diabetes mellitus. Am J Cardiol. 2010;105:64 – 68.
7. Yang TH, Park SW, Hong MK, Park DW, Park KM, Kim YH, Han KH,
Lee CW, Cheong SS, Kim JJ, Park SJ. Impact of diabetes mellitus on
angiographic and clinical outcomes in the drug-eluting stents era. Am J
Cardiol. 2005;96:1389 –1392.
8. Lee SW, Park SW, Kim YH, Yun SC, Park DW, Lee CW, Hong MK,
Rhee KS, Chae JK, Ko JK, Park JH, Lee JH, Choi SW, Jeong JO, Seong
IW, Cho YH, Lee NH, Kim JH, Chun KJ, Kim HS, Park SJ. A randomized comparison of sirolimus- versus paclitaxel-eluting stent implantation in patients with diabetes mellitus: 2-year clinical outcomes of the
DES-DIABETES trial. J Am Coll Cardiol. 2009;53:812– 813.
9. Lee SW, Park SW, Kim YH, Yun SC, Park DW, Lee CW, Hong MK, Rhee
KS, Chae JK, Ko JK, Park JH, Lee JH, Choi SW, Jeong JO, Seong IW, Cho
YH, Lee NH, Kim JH, Chun KJ, Kim HS, Park SJ. A randomized comparison of sirolimus- versus paclitaxel-eluting stent implantation in patients
with diabetes mellitus. J Am Coll Cardiol. 2008;52:727–733.
10. Dibra A, Kastrati A, Mehilli J, Pache J, Schühlen H, von Beckerath N,
Ulm K, Wessely R, Dirschinger J, Schömig A. Paclitaxel-eluting or
sirolimus-eluting stents to prevent restenosis in diabetic patients. N Engl
J Med. 2005;353:663– 670.
11. Kedhi E, Joesoef KS, McFadden E, Wassing J, van Mieghem C, Goedhart
D, Smits PC. Second-generation everolimus-eluting and paclitaxeleluting stents in real-life practice (COMPARE): a randomised trial.
Lancet. 2010;375:201–209.
12. Serruys PW, Ruygrok P, Neuzner J, Piek JJ, Seth A, Schofer JJ, Richardt
G, Wiemer M, Carrié D, Thuesen L, Boone E, Miquel-Herbert K,
Daemen J. A randomised comparison of an everolimus-eluting coronary
stent with a paclitaxel-eluting coronary stent: the SPIRIT II trial. EuroIntervention. 2006;2:286 –294.
13. Stone GW, Midei M, Newman W, Sanz M, Hermiller JB, Williams J,
Farhat N, Mahaffey KW, Cutlip DE, Fitzgerald PJ, Sood P, Su X, Lansky
AJ. Comparison of an everolimus-eluting stent and a paclitaxel-eluting
stent in patients with coronary artery disease. JAMA. 2008;299:
1903–1913.
14. Stone GW, Rizvi A, Newman W, Mastali K, Wang JC, Caputo R,
Doostzadeh J, Cao S, Simonton CA, Sudhir K, Lansky AJ, Cutlip DE,
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
891
Kereiakes DJ. Everolimus-eluting versus paclitaxel-eluting stents in
coronary artery disease. N Engl J Med. 2010;362:1663–1674.
Kereiakes DJ, Cutlip DE, Applegate RJ, Wang J, Yaqub M, Sood P, Su
X, Su G, Farhat N, Rizvi A, Simonton CA, Sudhir K, Stone GW.
Outcomes in diabetic and nondiabetic patients treated with everolimus- or
paclitaxel-eluting stents: results from the SPIRIT IV clinical trial
(Clinical Evaluation of the XIENCE V Everolimus Eluting Coronary
Stent System). J Am Coll Cardiol. 2010;56:2084 –2089.
Laskey WK, Yancy CW, Maisel WH. Thrombosis in coronary drugeluting stents: report from the meeting of the Circulatory System Medical
Devices Advisory Panel of the Food and Drug Administration Center for
Devices and Radiologic Health, December 7– 8, 2006. Circulation. 2007;
115:2352–2357.
Ellis SG, Popma JJ, Lasala JM, Koglin JJ, Cox DA, Hermiller J,
O’Shaughnessy C, Mann JT, Turco M, Caputo R, Bergin P, Greenberg J,
Stone GW. Relationship between angiographic late loss and target lesion
revascularization after coronary stent implantation: analysis from the
TAXUS-IV trial. J Am Coll Cardiol. 2005;45:1193–1200.
Mehran R, Dangas G, Abizaid AS, Mintz GS, Lansky AJ, Satler LF,
Pichard AD, Kent KM, Stone GW, Leon MB. Angiographic patterns of
in-stent restenosis: classification and implications for long-term outcome.
Circulation. 1999;100:1872–1878.
Chow S-C, Liu J-P. Design and Analysis of Clinical Trials. 2nd ed. New
York, NY: John Wiley and Sons; 2004.
Otake H, Ako J, Yamasaki M, Tsujino I, Shimohama T, Hasegawa T,
Sakurai R, Waseda K, Honda Y, Sood P, Sudhir K, Stone GW,
Fitzgerald PJ. Comparison of everolimus- versus paclitaxel-eluting
stents implanted in patients with diabetes mellitus as evaluated by
three-dimensional intravascular ultrasound analysis. Am J Cardiol.
2010;106:492– 497.
Mauri L, Orav EJ, O’Malley AJ, Moses JW, Leon MB, Holmes DR Jr,
Teirstein PS, Schofer J, Breithardt G, Cutlip DE, Kereiakes DJ, Shi C,
Firth BG, Donohoe DJ, Kuntz RE. Relationship of late loss in lumen
diameter to coronary restenosis in sirolimus-eluting stents. Circulation.
2005;111:321–327.
Pocock SJ, Lansky AJ, Mehran R, Popma JJ, Fahy MP, Na Y, Dangas G,
Moses JW, Pucelikova T, Kandzari DE, Ellis SG, Leon MB, Stone GW.
Angiographic surrogate end points in drug-eluting stent trials: a systematic evaluation based on individual patient data from 11 randomized,
controlled trials. J Am Coll Cardiol. 2008;51:23–32.
Baumgart D, Klauss V, Baer F, Hartmann F, Drexler H, Motz W, Klues
H, Hofmann S, Völker W, Pfannebecker T, Stoll H-P, Nickenig G.
One-year results of the SCORPIUS study: a German multicenter investigation on the effectiveness of sirolimus-eluting stents in diabetic
patients. J Am Coll Cardiol. 2007;50:1627–1634.
Tomai F, Reimers B, De Luca L, Galassi AR, Gaspardone A, Ghini AS,
Ferrero V, Favero L, Gioffrè G, Prati F, Tamburino C, Ribichini F.
Head-to-head comparison of sirolimus- and paclitaxel-eluting stent in the
same diabetic patient with multiple coronary artery lesions. Diabetes
Care. 2008;31:15–19.
Bartorelli AL, Serruys PW, Miquel-Hébert K, Yu S, Pierson W, Stone
GW. An everolimus-eluting stent versus a paclitaxel-eluting stent in small
vessel coronary artery disease: a pooled analysis from the SPIRIT II and
SPIRIT III trials. Catheter Cardiovasc Interv. 2010;76:60 – 66.
Khattab AA, Richardt G, Verin V, Kelbaek H, Macaya C, Berland J, MiquelHebert K, Dorange C, Serruys PW. Differentiated analysis of an everolimuseluting stent and a paclitaxel-eluting stent among higher risk subgroups for
restenosis: results from the SPIRIT II trial. EuroIntervention. 2008;3:
566–573.
Serruys PW, Silber S, Garg S, van Geuns RJ, Richardt G, Buszman PE,
Kelbæk 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 zotarolimus-eluting and
everolimus-eluting coronary stents. N Engl J Med. 2010;363:136 –146.
Kastrati A. Clinical and angiographic results from a randomized trial
sirolimus-eluting and everolimus-eluting stent: ISAR-TEST 4. Paper presented at: Transcatheter Cardiovascular Therapeutics 2009-Session V.
Current generation DES; September 24, 2009; San Francisco, CA.
Kim HS. Efficacy of XIENCE/PROMUS versus Cypher to reduce late
loss in stent: the EXCELLENT trial. Paper presented at: Transcatheter
Cardiovascular Therapeutics 2010-First Report Investigations Sessions;
September 25, 2010; Washington, DC.
Shimohama T, Ako J, Yamasaki M, Otake H, Tsujino I, Hasegawa T,
Nakatani D, Sakurai R, Chang H, Kusano H, Waseda K, Honda Y, Stone
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892
Circulation
69
August 23, 2011
GW, Saito S, Fitzgerald PJ, Sudhir K. SPIRIT III JAPAN versus SPIRIT
III USA: a comparative intravascular ultrasound analysis of the
everolimus-eluting stent. Am J Cardiol. 2010;106:13–17.
31. Byrne RA, Kastrati A, Kufner S, Massberg S, Birkmeier KA, Laugwitz
K-L, Schulz S, Pache J, Fusaro M, Seyfarth M, Schömig A, Mehilli J.
Randomized, non-inferiority trial of three limus agent-eluting stents with
different polymer coatings: the Intracoronary Stenting and Angiographic
Results: Test Efficacy of 3 Limus-Eluting Stents (ISAR-TEST-4) trial.
Eur Heart J. 2009;30:2441–2449.
32. Onuma Y, Kukreja N, Piazza N, Eindhoven J, Girasis C, Schenkeveld L, van
Domburg R, Serruys PW. The everolimus-eluting stent in real-world
patients: 6-month follow-up of the X-SEARCH (Xience V Stent Evaluated at
Rotterdam Cardiac Hospital) registry. J Am Coll Cardiol. 2009;54:269–276.
33. Jensen LO. A prospective randomized trial of everolimus-eluting stents
and sirolimus-eluting stents in patients with coronary artery disease: the
SORT-OUT IV trial. Paper presented at: Transcatheter Cardiovascular
Therapeutics 2010-Late Breaking Trial Sessions; September 24, 2010;
Washington, DC.
CLINICAL PERSPECTIVE
Diabetic patients have worse clinical outcomes after coronary intervention compared with nondiabetics. With the
introduction of drug-eluting stents, the rate of restenosis was reduced compared with bare metal stents in diabetic patients,
although the presence of diabetes mellitus remains a significant predictor of adverse outcomes in the drug-eluting stent era.
The Randomized Comparison of Everolimus-Eluting Stent Versus Sirolimus-Eluting Stent Implantation for De Novo
Coronary Artery Disease in Patients with Diabetes Mellitus (ESSENCE-DIABETES) trial was a prospective randomized
trial that compared everolimus-eluting stents (n�149) and sirolimus-eluting stents (n�151) in diabetic patients.
Everolimus-eluting stents were noninferior to sirolimus-eluting stents for 8-month in-segment late loss (0.23�0.27 versus
0.37�0.52 mm; difference, �0.13 mm; 95% confidence interval, �0.25 to �0.02; upper 1-sided 95% confidence interval,
�0.04; P�0.001 for noninferiority), with reductions in in-stent restenosis (0% versus 4.7%; P�0.029) and in-segment
restenosis (0.9% versus 6.5%; P�0.035). However, in-stent late loss (0.11�0.26 versus 0.19�0.49 mm; difference,
�0.09 mm; 95% confidence interval, �0.19 to �0.02; P�0.11) was not statistically different between the 2 groups. At
12 months, ischemia-driven target lesion revascularization (0.7% versus 2.6%; P�0.317), death (1.3% versus 3.3%;
P�0.448), and myocardial infarction (0% versus 1.3%; P�0.498) were not statistically different between the 2 groups. In
conclusion, everolimus-eluting stents were noninferior to sirolimus-eluting stents in reducing in-segment late loss and
reduced angiographic restenosis at 8 months in patients with diabetes mellitus and coronary artery disease. Therefore, our
findings suggested that everolimus-eluting stent implantation is a good option for the diabetic population.
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