transform-oct*: a prospective, randomized trial using … · giulio guagliumi 1, kunihiro...
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TRANSFORM-OCT*: A Prospective, Randomized Trial Using OCT Imaging to Evaluate Strut Coverage at 3 Months and Neoatherosclerosis at 18 Months in Bioresorbable Polymer-Based and Durable Polymer-Based Drug-Eluting Stents
ClinicalTrial.gov NCT01972022
*TRiple Assessment of Neointima Stent FOrmation to Reabsorbable polyMer with OCT
Giulio Guagliumi1, Kunihiro Shimamura2, Vasile Sirbu1, Roberto Garbo3, Luigi Fiocca1, Angelina Vassileva1,
Francesco Colombo3, Daisuke Nakamura4, Gabriel Tensor Rodriguez Pereira4, Guilherme F Attizzani4,
Giuseppe Musumeci1, Orazio Valsecchi1, Irene Pescetelli1, Leonardo De Luca6, Francesco Saia7, Davide Capodanno8
1 ASST Papa Giovanni XXIII, Bergamo, Italy 2 Wakayama Medical University, Wakayama, Japan 3 Ospedale San Giovanni Bosco, Torino, Italy 4 Cardiovascular Imaging Core Laboratory, Cleveland, OH, US
6 Ospedale S. Giovanni Evangelista, Tivoli, Italy 7 Cardiothoracic Vascular Department, University Hospital, Bologna, Italy 8 Ferrarotto Hospital, University of Catania, Catania, Italy
Why is this study important?
Background
One of the mechanism implicated in late stent failure is the development of
atherosclerosis within the neointimal tissue, called neoatherosclerosis (NA).
Otsuka F. et al. Eur H J 2015;36:2147-59
Pathological and imaging reports have demonstrated that neoatherosclerosis is more common and occurs earlier in DES compared with BMS
Nakazawa G. et al, JACC 2011; 57, 1314-22 Higo T. et al. JACC Cardiovasc. Img 2009;5: 616-24
Durable polymers have been suggested to delay healing and increased NA Otsuka F. et al. Circulation 2014;129: 211-23
• To mitigate the risk related to durable polymer (DP), bioabsorbable polymers (BP) that coats only the abluminal side of the stent, avoiding contact with circulating blood, and render stent surface similar to those of BMS after complete absorption, have been developed.
• Whether bioabsorbable-polymer abluminal coating may counteract in-vivo delayed healing and NA development in current thin-strut DES is unknown.
Why is this study important?
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• Prospective, randomized (1:1), single-blind, dual center, investigator-driven study
• 90 pts with multivessel CAD and unselected lesions long up to 50 mm, undergoing ≥2 vessels staged PCI. By study protocol ≥60% pts had to present with ACS, including STEMI
• BP-EES (SYNERGY™) vs DP-ZES (RESOLUTE Integrity™)
• Serial OCT imaging: index (pre and post stent), 3- and 18-month FU
• Optimal Medical Therapy with intensive lipid-lowering treatment
Endpoints
Maximum length of uncovered stent at 3 month, powered for non inferiority of BP-EES
Percentage of patients presenting with frames of NA at 18 month, powered for superiority of BP-EES
Methods
ClinicalTrial.gov NCT01972022
Optical Coherence Tomography (OCT)
With near-histological resolution OCT has high accuracy for detecting:
• Stent strut coverage (specificity > 95%)
• Components of neoatherosclerosis, including lipid laden neointima, macrophage
infiltration, in-stent calcification, neaotherosclerotic plaques
Lipid laden neointima Macrophages in-stent TCFA
Nakano M, et al. J Am Coll Cardiol. 2012; 5: 71-82
Templin C et al. Eur Heart J 2010; 31: 1792-801
Kang SJ. et al. Circulation 2011;123:2954-63
in-stent calcification
Study Flow
Clinical QCA & OCT 1st target lesion PCI
3-Month 18-Month 5 Years Index
QCA & OCT FU 1st target lesion* + 2nd target Lesion PCI (same stent)
QCA & OCT 1st and 2nd target lesions
Clinical
2
0
2 mm
18 Months
2
0
2
mm
3 Months
2
0
2 mm
Pre-PCI
2
0
2
mm
Rate of High Intensity Statin Therapy (Atorvastatin 40/80 mg/day, Rosuvastatin 20/40 mg/day)
Admission(n=90)
Discharge(n=90)
3 months(n=89)
18 months(n=85)
0%
20%
40%
60%
80%
100%
77 (86 %)
68 (80 %)
2 (2 %)
74 (83 %)
Lower Intensity
High Intensity
0%
20%
40%
60%
80%
100%
Admission(n=90)
Discharge(n=90)
3 months(n=90)
18 months(n=88)
32 (36 %)
90 (100 %)
89 (99 %)
85 (97 %)
No Yes
Statin use rate
Therapy during Follow-up
Discharge (N=90) Aspirin, % (n) P2Y12 inhibitor, % (n) 3 months (N=90) Aspirin, % (n) P2Y12 inhibitor, % (n) 12 months (N=90) Aspirin, % (n) P2Y12 inhibitor, % (n) 18 months (N=88) Aspirin, % (n) P2Y12 inhibitor, % (n)
99 (89)
100 (90)
99 (89) 100 (90)
98 (88) 100 (90)
98 (86) 24 (21)
Antiplatelets use rate
Quantitative OCT Analysis- 3 Months 90 patients -100% OCT FU - 43.607 struts
50
40
30
20
10
0
-10
(%) p = 0.87
P = 0.25
P = 0.99
27
23
1,2
26 23
0,7
Uncovered struts Uncovered struts fulyapposed
Acquired malapposedstruts
EES ZES
(mm)
10
2,7
0,1
11
3,1
0,1
-5
0
5
10
15
20
Max uncovered stentlength
Max malapposed stentlength
Mean neointimalthickness
BP-EES DP-ZES
p = 0.45
p = 0.52
p = 0.61
Co- primary end point
BP-EES DP-ZES
Primary end point: intra-class correlation for 2 readers
CCC Standard Error Lower CL Upper CL
0.9971 0.0021 0.9878 0.9993
Uncovered struts fully apposed
Values are given as mean ± SD
Max uncovered stent length Mean difference
-1.3 (95% CI -4.6-2.0) Co-primary endpoint hypothesis met
Serial Changes of Strut Coverage
* % of completely embedded struts
*
3 months median percentage of covered struts
18 months median percentage of covered struts 99.4 (IQR 96.6-100)
98.0 (IQR 94.4- 99.8)
79.1 (IQR 60.4, 89.8)
78.4 (IQR 62.1, 87.8) p = 0.93
p = 0.14
BP-EES
DP-ZES
Primary Endpoint: In-stent NA by OCT at 18 months
87/88 patients (98.9% of all the eligible), 42.262 struts
EES
0.0% 0.1% 0.0% 0.0% 0.0% 0.5% 0.3% 0.1%
EES EES EES ZES ZES ZES ZES
P=0.32 P=0.32 P=0.53
Lipid laden neointima Macrophages Neovessels Calcification TCFA
0
10
20
30
0.8% 2.4%
EES ZES
P=0.25
%
% Patients with frames of neoatherosclerosis
0
10
20
30
40
50
11.6% 15.9%
EES ZES
P=0.59
%
N= 5/43 7/44
546 ± 52 days
BP-EES DP-ZES
% of frames with neoatherosclerosis
2.5 ± 9.1 1.1 ± 3.1 vs
p= 0.33
• In this head-to-head in-vivo comparison of early and late healing response, an
everolimus-eluting stent with ultra-thin struts and bioresorbable abluminal polymer
was non-inferior at 3-month and similar at 18-month follow-up to a zotarolimus
eluting stent with thin struts and durable polymer.
• In patients with complex coronary artery disease on intensive statin regimen,
excellent long term vascular responses were seen for both stent types, with almost
complete strut coverage, high percentage of mature tissue, limited neointimal
volume, and low rate of neoatherosclerosis.
• TRANSFORM-OCT adds a novel mechanistic dimension to the serial assessment of
new-generation DESs, consolidating the understanding that well designed and
biocompatible polymers, regardless of whether they are durable or biodegradable,
may favorably impact the long term vascular response of DES.
What is the impact on patients and delivery of care?
• First prospective study of the natural history of stented lesion in which current
generation stent are serially studied at different time periods after implantation.
• Performed in unselected patients (not based on symptom or stent failure) with
almost complete early and late intracoronary imaging follow-up (3 and 18 months).
• Excellent long term imaging and clinical follow-up in complex patient and lesions
predisposed to stent failure (MVD, long lesions, ACS).
• The rate of NA observed with thin strut DES currently in use was lower than was
anticipated by post-mortem studies, that reflect a certain selection bias of pathology.
• As clinical practice moves toward adoption of stent with more biocompatible polymer
these data should be relevant in the development of safe drug delivery systems.
How many people does the study impact?
Lipid Profile During Follow-up
Synergy
BP-EES
DP-ZES
0
20
40
60
80
100
120
140
160
180
200
(mg/dl)
Total Cholesterol LDL-Cholesterol HDL-Cholesterol
Ave
rage
val
ues
178
170
144
133
153 148
110 103
81
71
82 76
45 44 44 41 46 46
No significant differences between the two types of stents at Baseline, 3Mo and 18Mo
p<0.01
p<0.01
p<0.01
p<0.01
p<0.01
p<0.01
p<0.01
p<0.01
P = 0.70
(%)
Values are given as mean ± SD
DP-ZES BP-EES
3,5
20,1
1,1
11,6
3,3
20.9
2,3
11,6
-10
-5
0
5
10
15
20
25
30
35
40
4,9
16,3
2,5
15,6
4,7
16.7
1,3
9,5
-10
-5
0
5
10
15
20
25
30
35
40
(%)
P = 0.94
P = 0.82
P = 0.32
% Frames with uncovered struts
% neointimal obstruction
% Patients with frames with NA
% Frames with NA
% Frames with uncovered struts
% neointimal obstruction
% Patients with frames with NA
% Frames with NA
P = 0.66
P = 0.39
P = 1.00 P = 0.38
Assessment of strut coverage, neointimal, and neoatherosclerosis
18 Months (1st lesion) vs. 15 Months (2nd lesion)
18 Months (N=43)
15 Months (N=43)
18 Months (N=44)
15 Months (N=42)
Second-Generation DES Stratified by Duration of Implant in Lesion with Neoatherosclerosis and Late Stent Failure
Otsuka F et al Eur Heart J 2015, 36:2147-59
66 SES Median: 200 days (121-360)
Nakazawa G. et al JACC 2011; 57:1314-22 209 SES and PES. Median: 420 days (361-683)
Otsuka F. et al Eur Heart J 2015; 36:2147-59 348 First and Second generation DES
Median: 220 days
Otsuka F. et al Circulation 2014; 129:211-23 204 SES,PES,EES. Median: 200 days (116-510)
• The two investigated devices elute different antiproliferative drugs and differ in platform design (material and geometry)
• The rate of NA was lower than anticipated based on post-mortem and previous OCT studies of selected patients and lesions
• Uncovered struts by OCT (percentage and max length) used as surrogate markers of delayed healing
• OCT has limitation in penetrating lipid rich tissue. However, the small amount of neointima thickness observed at 18 months and the superficial location of in-stent atheroma previously observed by pathology are reassuring on imaging study adequacy
• It remains unclear whether longer-term follow-up may reveal differential healing characteristics of contemporary DES
Limitations
3 Months 18 Months
Maps of the stented regions at 3 and 18 months
10 20 30 40 50 60
Length (mm)
10 20 30 40 50 60
Length (mm)
10 20 30 40 50 60
Length (mm)
10 20 30 40 50 60
Length (mm)
10 20 30 40 50 60
Length (mm)
10 20 30 40 50 60
Length (mm)
10 20 30 40 50 60
Length (mm)
Overlap region Neoatherosclerosis region . . . .
Uncovered struts
Stent Length (mm)
10 20 30 40 50 60
Length (mm)
10 20 30 40 50 60
Length (mm)
10 20 30 40 50 60
Length (mm)
BP-EES SYNERGYTM (N=45)
DP-ZES RESOLUTETM (N=45)
P value
Clinical presentation STEMI, % (n) NSTEMI, % (n) Unstable angina, % (n) Stable angina, % (n)
Values are given as % (n)
31 (14)
9 (4) 31 (14) 29 (13)
20 (9) 13 (6)
33 (15) 33 (15)
0.65
Clinical Presentation
69
31
0
20
40
60
80
100
ACS Stable Angina
%
%
BP-EES SYNERGYTM (N=45)
DP-ZES RESOLUTETM (N=45)
P value
Angiographic Findings
Number of vessel disease
2VD, % (n)
3VD, % (n)
Target vessel location
LAD, % (n)
LCx, % (n)
RCA, % (n)
Pre-procedure
Lesion length, mm±SD
RVD, mm±SD
MLD, mm±SD
Diameter stenosis, %±SD
78 (35)
22 (10)
51 (23)
27 (12)
22 (10)
22 ± 12
2.7 ± 0.5
0.8 ± 0.5
72 ± 18
73 (33)
27 (12)
47 (21)
22 (10)
31 (14)
21 ± 13
2.8 ± 0.6
0.7 ± 0.4
73 ± 15
0.62
0.48
0.54
0.79
0.59
0.75
0.85
BP-EES SYNERGYTM (N=45)
DP-ZES RESOLUTETM (N=45)
P value
Procedure Characteristics
Stents per target lesion, n±SD Total stent length, mm±SD Stent diameter, mm±SD Pre-dilation, % (n) Post-dilation, % (n) Max pressure at deployment, atm±SD Max pressure at post-dilation, atm±SD Post-procedure QCA MLD, mm±SD Diameter stenosis, %±SD
1.5 ± 0.7
35 ± 14 3.1 ± 0.4
78 (35) 84 (38)
16 ± 3
20 ± 4 (38)
2.5 ± 0.4 3 ± 10
1.4 ± 0.6
33 ± 15 3.1 ± 0.4
73 (33) 84 (38)
16 ± 4
22 ± 3 (38)
2.5 ± 0.5 2 ± 13
0.40
0.57 0.58
0.62 1.00
0.88 0.06
0.80 0.43
MACCE: 3 and 18 months follow-up
BP-EES SYNERGYTM (N=45)
DP-ZES RESOLUTETM (N=45)
P value
3-months follow-up, n (%) Death Myocardial infarction Stent thrombosis TLR Stroke
18-months follow-up, n (%) Death Cardiac Non cardiac Myocardial infarction Stent thrombosis TLR TVR Stroke
0 0 0 0 0
0
1 (2.2) 0 0 0
-
1.0 - - -
1 (2.2)
0 1 (2.2) 2 (4.4)
0 2 (4.4) 1 (2.2) 1 (2.2)
1 (2.2)
0 1 (2.2) 2 (4.4)
0 2 (4.4) 1 (2.2) 1 (2.2)
1.0
- 1.0 1.0
- 1.0 1.0 1.0
OCT Tissue Characterization - 3 and 18 Months
89 98
81
100
0
20
40
60
80
100
120P = 0.21 P = 0.14
(%)
3 Months 18 Months
Intensity (Pixel Intensity) of the tissue covering the stent struts normalized for the intensity of the stent struts.
Normalized Intensity = PItissue / PIstrut blooming
10 20 30
Mature neointima Immature neointima
Values are given as mean ± SD
BP-EES DP-ZES
Mature neointima frames Mean optical density
P < 0.0001
P < 0.0001
1
0.8
0.6
0.4
0.2
0
(U)
0,7 0,8
0,7 0,8
P = 0.61 P = 0.28
3 Months 18 Months
P < 0.0001
P < 0.0001