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?

+

+ + +

+

+

+

+

+

+ + +

+

+

• 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