Online Appendix for the following JACC article
TITLE: Biodegradable Polymer Versus Permanent Polymer Drug-Eluting Stents and
Everolimus- Versus Sirolimus-Eluting Stents in Patients With Coronary Artery Disease: 3Year Outcomes From a Randomized Clinical Trial
AUTHORS: Robert A. Byrne, MB BCh, Adnan Kastrati, MD, Steffen Massberg, MD, Anna
Wieczorek, Karl-Ludwig Laugwitz, MD, Martin Hadamitzky, MD, Stefanie Schulz, MD, Jürgen
Pache, MD, Massimiliano Fusaro, MD, Jörg Hausleiter, MD, Albert Schömig, MD, Julinda
Mehilli, MD, for the ISAR-TEST 4 (Intracoronary Stenting and Angiographic Results: Test
Efficacy of 3 Limus-Eluting Stents) Investigators
APPENDIX
METHODS
Angiographic surveillance
Baseline, post procedural, and follow-up coronary angiograms were digitally recorded and
assessed off-line in the quantitative coronary angiographic (QCA) core laboratory
(ISARESEARCH Center, Munich. Germany) with an automated edge-detection system (CMS
version 7.1, Medis Medical Imaging Systems). Quantitative analysis was performed on both
the “in-stent” and “in-segment” area (including the stented segment, as well as both 5-mm
margins proximal and distal to the stent). Qualitative morphological lesion characteristics and
restenosis morphology were characterized by standard criteria.(1,2)
In analyzing 2-year angiographic outcomes, in order to account for missing data at the second
angiographic follow-up consequent on TLR at the time of the first angiographic follow-up, we
used a composite analysis as previously described (3) based on the inclusion of angiographic
follow-up data at the latest available time point for an individual patient (whether at 6-8
months or 2 years).
Statistical Analysis
Continuous data are presented as mean (±SD) or median [25th-75th percentiles]. Categorical
data are presented as counts and proportions (%). Unless otherwise stated, differences
between groups were checked for significance using Student’s t-test (continuous data) and
chi-squared or Fisher’s exact test (categorical variables). Survival was analyzed according to
Kaplan-Meier methods and hazard ratios were calculated using Cox proportional hazards
methods. The proportional hazards assumption was checked by the method of Grambsch and
Therneau (4) and was fulfilled in all cases in which we used Cox proportional hazards
models. Analysis of the primary outcome was also performed for pre-specified subsets of
interest: old and young patients (above and at or below the median age), women and men,
diabetic and nondiabetic patients, small and large vessels (below and at or above the median
value) and interaction between treatment effect and these covariates was assessed with Cox
proportional hazards models. All analyses were by intention to treat using all patients
randomized in the study, regardless of the treatment actually received. Statistical software SPLUS, version 4.5 (S-PLUS, Insightful Corp, Seattle, Wa, USA) was used for analysis.
RESULTS
Patient-oriented outcomes: Three-year clinical follow-up
At 3-years there were no significant differences between biodegradable polymer versus
permanent polymer DES concerning all cause death (9.3% vs. 9.8%; HR 0.95 [0.74-1.23];
P=0.71), any myocardial infarction (5.3% vs. 5.0%; HR 1.07 [0.76-1.50]; P=0.72), target
vessel revascularization (21.3% vs. 21.4%; HR 0.99 [0.84-1.18]; P=0.93) and non-target
vessel revascularization. (19.0% vs. 19.2%; HR 0.99 [0.83-1.19]; 0.96).
Similarly there were no significant differences between everolimus-eluting versus sirolimuseluting stents concerning all cause death (9.3% vs. 10.3%; HR 0.90 [0.63-1.29]; P=0.57), any
myocardial infarction (4.7% vs. 5.2%; HR 0.91 [0.56-1.50]; P=0.72), target vessel
revascularization (20.3% vs. 22.5%; HR 0.87 [0.68-1.11]; P=0.27) and non-target vessel
revascularization. (17.9% vs. 20.5%; HR 0.85 [0.65-1.10]; 0.21).
Landmark analysis
Landmark analyses at 1 year are shown in Supplementary Table 1.
Angiographic surveillance
Follow-up angiographic data at 6-8 months was available for 78% of patients with no
differences across the groups. In patients undergoing 6-8 month angiographic surveillance and
not requiring repeat intervention, an additional angiographic follow-up was scheduled at 2
years. At this time point follow-up angiography was available for 71% of eligible patients
with no differences across the groups.
Angiographic outcomes at 6-8 months
Results of angiographic follow-up at 6-8 months are shown in Supplementary Tables 2 and 3.
At 6-8 months patients treated with biodegradable polymer compared with permanent
polymer DES showed similar rates of angiographic restenosis (11.6% versus 11.8%; P=0.85)
and late loss (0.24±0.57 mm versus 0.26±0.55 mm P=0.49). In patients allocated to treatment
with permanent polymer DES, there was a trend towards lower rates of angiographic
restenosis with everolimus-eluting compared to sirolimus-eluting stents (10.1% versus 13.4%;
P=0.07) and late loss (0.23±0.52 mm versus 0.28±0.57 mm; P=0.08).
Angiographic outcomes at 2 years
Results of angiographic follow-up based on composite analysis at 2 years are also shown in
Supplementary Tables 2 and 3. At 2 years composite binary angiographic restenosis occurred
in 15.3% of patients treated with biodegradable polymer DES versus 14.8% treated with
permanent polymer DES (P=0.76). Incident binary restenosis between 6-8 months and 2 years
was comparable in both groups: Δ3.9% with biodegradable polymer DES versus Δ3.0% with
permanent polymer DES (P=0.19). Mean composite in-stent late loss at 2 years was
0.35±0.64 mm with biodegradable polymer DES versus 0.34±0.62 mm with permanent
polymer DES (P=0.73).
Results of angiographic follow-up based on composite analysis at 2 years are shown in
Supplementary Table 2. At 2 years composite binary angiographic restenosis occurred
significantly less frequently in patients treated with everolimus-eluting stent, 12.7% versus
16.9% of patients treated with sirolimus-eluting stent (P=0.03). Incident binary restenosis
between 6-8 months and 2 years was comparable in both groups: Δ2.6% with everolimuseluting stent versus Δ3.5% with sirolimus-eluting stent (P=0.37). Mean composite in-stent
late loss at 2 years was 0.32±0.59 mm with everolimus-eluting stent versus 0.37±0.64 mm
with sirolimus-eluting stent (P=0.23).
STUDY ORGANIZATION
ISAR-TEST-4 trial organization
Steering committee: A. Schömig (Chairman), A. Kastrati (Principal Investigator), J. Mehilli.
Participating centres: Deutsches Herzzentrum, Technische Universität, Munich, Germany
and 1. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität, Munich,
Germany.
Data Safety Monitoring Board: J. Mann (Chairman); F. Hoffmann; K. Ulm (biostatistician)
Clinical Event Adjudication Committee: †D. Hall (Chairman); G. Ndrepepa; D. Poci
Data Coordination: ISARESEARCH Centre: S. Schulz; M. Dirlewanger; H. Holle; S. Kufner;
K. Hösl; I. Pastor; H. Pauli; N. Rifatov; F. Maimer-Rodrigues; N. Sargon
Angiographic Core Laboratory: ISARESEARCH Centre: R.A. Byrne (Director); S. Pinieck; D.
Blersch; S. Hurt; S. Ranftl
† Deceased
SUPPLEMENTARY REFERENCES
1.
Ellis SG, Vandormael MG, Cowley MJ, et al. Coronary morphologic and clinical
determinants of procedural outcome with angioplasty for multivessel coronary disease.
Implications for patient selection. Multivessel Angioplasty Prognosis Study Group.
Circulation 1990;82:1193-202.
2.
Mehran R, Dangas G, Abizaid AS, et al. Angiographic patterns of in-stent restenosis:
classification and implications for long-term outcome. Circulation 1999;100:1872-8.
3.
Byrne RA, Iijima R, Mehilli J, et al. Durability of antirestenotic efficacy in drugeluting stents with and without permanent polymer. JACC Cardiovasc Interv
2009;2:291-9.
4.
Grambsch PM, Therneau TM. Proportional hazards tests and diagnostics based on
weighted residuals. Biometrika 1994;81:515-526.
SUPPLEMENTARY TABLES
Table 1. Landmark Analysis: Clinical Outcomes Between Years 1 and 3 Year*
Biodegradable Polymer versus Permanent Polymer
Biodegradable Polymer
Permanent Polymer
Hazard Ratio (95%
Drug-Eluting Stents
Stents
Stents
CI)
Definite/probable stent thrombosis
2 (0.2)
2 (0.2)
1.00 (0.14-7.13)
>0.99
Cardiac death or target vessel myocardial infarction
26 (2.4)
32 (2.8)
0.82 (0.49-1.37)
0.44
Target lesion revascularization
60 (5.7)
56 (5.3)
1.07 (0.74-1.54)
0.72
Primary endpoint†
77 (7.5)
80 (7.8)
0.96 (0.70-1.31)
0.79
Everolimus-Eluting
Sirolimus-Eluting
Hazard Ratio (95%
P-Value
Stents
Stents
CI)
0
2 (0.3)
0.00 (0.00-3.47)
0.85
Cardiac death or target vessel myocardial infarction
14 (2.5)
18 (3.2)
0.79 (0.39-1.59)
0.52
Target lesion revascularization
27 (5.2)
29 (5.5)
0.91 (0.54-1.55)
0.74
Primary endpoint†
36 (7.0)
44 (8.6)
0.80 (0.52-1.25)
0.33
Everolimus-Eluting Versus Sirolimus-Eluting
Stents
Definite/probable stent thrombosis
*Data shown as number (percentage as Kaplan-Meier estimate); † Primary endpoint = composite of cardiac death, target vessel myocardial
infarction or target lesion revascularization
P-Value
Supplementary Table 2. Biodegradable Polymer versus Permanent Polymer Drug-Eluting Stents: Angiographic
Characteristics of the Lesions at Follow-up*
Biodegradable Polymer
Permanent Polymer
P
Stents
Stents
Value
1323
1314
Minimum lumen diameter (in-segment) – mm
2.04±0.67
2.04±0.62
0.84
Percent stenosis (in-segment) – %
30.9±17.8
30.7±17.0
0.32
Late lumen loss (in-stent) – mm
0.24±0.57
0.26±0.55
0.49
Binary restenosis (in-segment) – no (%)
153 (11.6)
155 (11.8)
0.85
Minimum lumen diameter (in-segment) – mm
2.01±0.72
2.00±0.66
0.70
Percent stenosis (in-segment) – %
31.4±19.9
31.7±19.2
0.76
Late lumen loss (in-stent) – mm
0.35±0.64
0.34±0.62
0.73
Binary restenosis (in-segment) – no (%)
202 (15.3)
195 (14.8)
0.76
Variable
Number of investigated lesions
6-8-month
2-year composite
Restenosis morphology
>0.99
Focal – no.
138
134
Diffuse intra-stent – no.
35
33
Diffuse proliferative – no.
15
16
Occlusive – no.*
14
12
* no difference between groups in number of patients undergoing revascularization (p=0.74)
Supplementary Table 3. Everolimus-Eluting Versus Sirolimus-Eluting Stents: Angiographic Characteristics of the Lesions at
Follow-up*
Everolimus-Eluting
Sirolimus-Eluting
P
Stent
Stents
Value
651
n=663
Minimum lumen diameter (in-segment) – mm
2.07±0.58
2.00±0.65
0.06
Percent stenosis (in-segment) – %
29.2±16.1
32.1±17.7
0.002
Late lumen loss (in-stent) – mm
0.23±0.52
0.28±0.57
0.08
Binary restenosis (in-segment) – no (%)
66 (10.1)
89 (13.4)
0.07
Minimum lumen diameter (in-segment) – mm
2.04±0.63
1.97±0.70
0.05
Percent stenosis (in-segment) – %
30.1±18.3
33.2±19.9
0.004
Late lumen loss (in-stent) – mm
0.32±0.59
0.37±0.64
0.23
Binary restenosis (in-segment) – no (%)
83 (12.7)
112 (16.9)
0.03
Variable
Number of investigated lesions
6-8-month
2-year composite
Restenosis morphology
0.64
Focal – no.
57
77
Diffuse intra-stent – no.
16
17
Diffuse proliferative – no.
6
10
Occlusive – no.*
4
8
* no difference between groups in number of patients undergoing revascularization (p>0.99)
SUPPLEMENTARY FIGURES
Supplementary Figure 1
Comparison of Incidence of Primary Endpoint in Patients Treated with
Biodegradable Polymer versus Permanent Polymer Drug-Eluting Stents
According to Pre-specified Subgroups
DES = drug-eluting stent
Supplementary Figure 2
Comparison of Incidence of Primary Endpoint in Patients Treated with
Everolimus-Eluting versus Sirolimus-Eluting Stents According to Pre-specified
Subgroups