Cải tiến về công nghệ stent ảnh hưởng thế nào đến quyết định can thiệp mạch vành

Ở BỆNH NHÂN NGUY CƠ CAO
CÁC CẢI TIẾN VỀ CÔNG NGHỆ VÀ THUỐC CÓ GIÚP
CÁC STENT PHỦ THUỐC KHÁC BIỆT NHAU?
In high risk patients does stent technology evolution make
DES different from each other?

VÕ THÀNH NHÂN MD, PhD, FSCAI


Disclosure
Speaker name: Võ Thành Nhân
I have the following potential conflicts of interest to report:


Consulting



Employment in industry



Stockholder of a healthcare company



Owner of a healthcare company



Speaker’s Honoraria: from Abbott, BSc, Medtronic, Terumo,

St Jude, Biotronik, Elixir, AGA, B Braun, United Healthcare



I do not have any potential conflict of interest


Coronary stenting - timeline
Restenosis rate
1970

1980

1969 Charles Theodore
Dotter invents first
coronary stent,
experimenting on dogs.

~4-5%

~20-30%

~30-40%
1990

1986 Jacques Puel
implants first stent.

minimal LL with DES & 74% reduction in TLR

2000

2008 2nd gen DES:
Xience (EES),
Endeavor, Resolute
(ZES)

2010

2014 DES
recommended
over BMS in
ESC guidelines.
2011 Newer Gen
DES Orsiro (SES)

2009 DES regain
terrain.
1970

1980

1990

2000

2010

2006 ESC firestorm,

concern about DES
safety
1977 Andreas
Gruentzig performs
first PTCA on human.

1999 Adjunctive antiplatelet medication
becomes standard.
Stenting composes
84% of all PCI.

2003 Launch of Taxus.
2002 Launch of Cypher.


Important stent characteristics
Characteristic

Definition

Determinants

Biocompatibility

Resistance to corrosion, thrombosis

Materials, coatings,
metal surface area

Conformability

Degree to which an expanded stent can bend around its
longitudinal axis

Material, stent design

Deliverability

Ability to deliver stent to target lesion

Longitudinal flexibility, crossing profile, trackability,
nesting

Outer contour

Separation of the stent strut from the delivery balloon during
insertion around bends

Stent design
(bigger problems with open or coil designs)

Flexibility

Degree to which an unexpanded stent can bend around its
longitudinal axis

Material, stent design

Metal surface area

Percent of surface area covered by metal after stent deployment

Stent design, strut thickness

Nesting

Security of stent attachment to delivery system

Stent design, profile

Radial strength

Resistance to vessel recoil

Stent design, strut thickness

Radiopacity

Ability to identify stent during fluoroscopy

Strut thickness, material

Scaffolding

Ability of stent to completely cover and support the vessel

Material, stent design, strut thickness, metal surface
area, radial strength

Trackability

Ease of movement over guide wire

Profile, shaft coating, stiffness, distal tapering

“Fish scaling„

Source:

Watson and Gorski. Invasive Cardiology: A manual for cath lab personnel. 2000/


Background

• The optimal management of patients at high risk of adverse clinical events
remains a challenging clinical problem.
• Newer-generation DES with durable polymer (DP-DES):
– significantly improved safety and efficacy outcomes (death, MI, TVR,
stent thrombosis), compared with both BMS and early-generation
durable polymer DES;
– represent the current standard-of-care for PCI in all patient and lesion
subsets.

• Newer-generation DP-DES in high-risk patients remain associated with
higher rates of DES failure, including ISR, TVR and late/very late stent
thrombosis.


Background (Con’t)
• Permanent polymer coatings on newer-generation DP-DES:

– recently associated with chronic inflammation, hypersensitivity reactions, and
neoatherosclerosis, resulting in persisting late thrombotic events;
– concerns about long-term durable polymer biocompatibility.

• Biodegradable polymer DES (BP-DES):
- recently introduced to overcome current limitations of newer-generation DP-DES.
- enhance biocompatibility, promote vascular healing, reduce inflammation and
hypersensitivity reactions, and reduce long-term adverse outcomes.
- safe and effective alternative to newer-generation DP-DES in large all-comers
Populations.

• Long-term potential benefit of BP-DES for the management of high-risk
subgroups remains unclear.


In-Stent Restenosis in High-Risk Subgroup
INCIDENCE OF ANGIOGRAPHICALLY DOCUMENTED IN-STENT RESTENOSIS (1998-2009, N=12’904)
PREDICTORS OF ISR

Cassese S, Heart 2014

LONG-TERM MORTALITY

Cassese S, Eur Heart J 2015


Stent Thrombosis in High-Risk Subgroup
PREDICTORS AND INCIDENCE OF LATE/VERY LATE STENT THROMBOSIS
PREDICTORS OF STENT THROMBOSIS @ 3 YEARS (N=18’334)

DEFINITE/PROBABLE STENT THROMBOSIS @ 1 YEAR (N=12’198)

HR 3.07

Tada T, J Am Coll Cardiol Intv 2013

Loh JP, Am J Cardiol. 2014


Recent Developments in DES Technology
Overview of Current Stents Designs

NEW METALLIC PLATFORM MATERIALS
THINNER STRUTS
THINNER, MORE BIOCOMPATIBLE/BIODEGRADABLE POLYMERS
NEW LIMUS-ANALOGUES ANTIPROLIFERATIVE DRUGS
REDUCED DRUG LOAD
IMPROVED CONTROLLED DRUG RELEASE

IMPROVE BIOCOMPATIBILITY, REDUCE CHRONIC INFLAMMATION
AND HYPERSENSITIVITY REACTIONS.
Iglesias JF, Minerva Cardioangiologica 2015 (adapted from Stefanini GG, Heart 2014)


Newer-Generation Biodegradable Polymer DES
ORSIRO® DRUG-ELUTING STENT (BIOTRONIK AG, SWITZERLAND)
UNIQUE HYBRID TECHNOLOGY

ULTRATHIN STRUTS

REDUCE THROMBOGENICITY
(PLATELET ADHESION)

BIOCOMPATIBLE POLYMER
BIOABSORBABLE POLYMER
THIN POLYMER COATING

REDUCED LIMUS DRUG LOAD

REDUCE INFLAMMATORY RESPONSE, IMPROVE ENDOTHELIALIZATION, PROMOTE VASCULAR HEALING


The clinical program for Orsiro is
comprehensive and well underway
Study

Primary
endpoint

Status

ClinicalTrials.gov
Identifier:

30

9 mo LLL

Completed

NCT01214148

RCT vs. Xience Prime

440

9 mo LLL

Primary endpoint
reached

NCT01356888

International registry

1,356

12 mo TLF

Primary endpoint
reached

NCT01553526

>3,000

12 mo TLF

Enrolling

555

12 mo TVF

Enrollment completed

NCT01939249

RCT vs. Xience

1,334

12 mo TLF

Enrolling

NCT02389946

RCT vs. Xience

440

9 mo LLL

Enrolling

Indian single-armed trial

120

9 mo LLL

Completed

NCT01426139

RCT vs. Pantera Lux in ISR

210

6 mo LLL

Enrollment completed

NCT01651390

Study design

BIOTRONIK initiated

FIM

Satellite registries (14)
RCT vs. Xience
Prime/Xpedition

Total
patients

Sources: www.clinicaltrials.gov/ct2/results?term=orsiro; Investigator updates

Investigator initiated

The clinical program for Orsiro is
comprehensive and well underway
Total
patients

Primary
endpoint

Status

ClinicalTrials.g
ov Identifier:

RCT vs. Xience Prime

2,100

12 mo TLF

Primary endpoint
reached

NCT01443104

SORT OUT VII

RCT vs. Nobori

2,525

12 mo TLF

Primary endpoint
reached

NCT01879358

BIO-RESORT

RCT vs.
Synergy & Resolute integrity

3,530

12 mo TVF

Enrolling

NCT01674803

ORIENT

RCT vs. Resolute Integrity

375

9 mo LLL

Enrollment completed

NCT01826552

PRISON-IV

RCT vs. Xience Prime

330

9 mo LLL

Enrolling

NCT01516723

HAT-TRICK-OCT

RCT vs. Endeavor Resolute

40

3 mo
Strut coverage

Primary endpoint
reached

NCT01391871

ISAR OCT

RCT vs. Xience Prime

87

6 & 24 mo
Strut coverage

Enrollment completed

NCT01594736

Enrolling

NCT02079194

Study

Study design

BIOSCIENCE

SMART-Choice

RCT vs. Promus and Xience

5,100

3-15 mo
Composite of
Death, MI and
cerebrovascular
events

Revolute Registry

Orsiro, Elixir DESyne,
Biomatrix Flex, Cilotax

1,000

12 mo MACE

Enrolling

BIODEGRADE

RCT vs. Biomatrix Flex

3,850

18 mo TLF

Enrolling

NCT02299011

BIONYX

RCT vs. Onyx

2,470

12 mo TVF

Enrolling

NCT02508714

Total >26,000

Sources: www.clinicaltrials.gov/ct2/results?term=orsiro; Investigator updates


Safety and Clinical Performance of the Orsiro DES in
the treatment of subjects with single de novo
coronary artery lesions
DESIGN
An international, prospective, multi-center,
randomized, controlled trial comparing the
Orsiro hybrid DES to Xience Prime
OBJECTIVE
To compare the Orsiro stent with a
bioabsorbable polymer to the XIENCE
Prime® stent with a durable polymer for the
treatment of de novo coronary lesions with
respect to non-inferiority for in-stent Late

Lumen Loss (LLL) at 9-months
COORDINATING CLINICAL
INVESTIGATORS
Prof. Stephan Windecker, Bern, Switzerland
Dr. Thierry Lefèvre, Massy, France
PRIMARY ENDPOINT
In-Stent Late Lumen Loss at 9-month

Source: T. Slagboom, Poster, EuroPCR 2015

440 Patients with stable CAD
2:1 randomization

Orsiro

Xience Prime

Clinical follow-up at 1 and 6- months
Clinical, angiographic, IVUS* and OCT*
follow-up at 9 months
* Pre-specified subgroups with
60 patients in each

Clinical follow-up at 12 months
Clinical follow-up to 5 years


Primary Angiographic Endpoint
ULTRATHIN-STRUT BP-SES vs. THIN-STRUT DP-EES (RCT, 2:1, N=452)
IN-STENT LATE LUMEN LOSS @ 9 MONTHS

Windecker S, Circ Cardiovasc Interv. 2015


Secondary Clinical Composite Endpoint
ULTRATHIN-STRUT BP-SES vs. THIN-STRUT DP-EES (RCT, 2:1, N=452)
TARGET LESION FAILURE @ 36 MONTHS

TLF univ. def. (%)

20
P=0.5800

Orsiro BP-SES
Xience DP-EES

10.6%
9.0%

10

0.0

0

180

365

730

1095

days after PCI

Composite endpoints (%)

Orsiro
N=298

Xience
N=154

P value

Cardiac Death

0.7

1.3

0.5069

Target vessel MI

3.4

2.6

0.6590

TLR (clinically driven)

5.6

6.7

0.6361

CABG (emergent)

0.0

0.0

>0.9999

Slagboom et al. Poster EuroPCR 2015, Paris, France


High-Risk Subgroups Diabetics
TARGET LESION FAILURE @ 36 MONTHS

TLF univ. def. (%)

20%

P=0.6021
Orsiro
Xience

Prime

10%

0.0%
0

12.3%
9.1%

180

365

730

1095 days after PCI

Composite endpoints (%)

Orsiro
N=84

Xience
N=44

P value

Cardiac Death

0.0

2.3

0.3437

Target vessel MI

1.2

0.0

>0.9999

TLR (clinically driven)

11.1

6.9

0.4688

CABG (emergent)

0.0

0.0

>0.9999

Slagboom et al. Poster EuroPCR 2015, Paris, France


High-Risk Subgroups Small Vessels
TARGET LESION FAILURE @ 36 MONTHS

P=0.3494

TLF univ. def. (%)

20%

14.4%

Orsiro
Xience Prime

10.6%

10%

0.0%
0

180

365

730

1095

days after PCI

Composite endpoints (%)

Orsiro
N=168

Xience
N=91

P value

Cardiac Death

0.0

1.1

0.3514

Target vessel MI

3.7

4.4

0.7475

TLR (clinically driven)

8.1

8.9

0.8249

CABG (emergent)

0.0

0.0

>0.9999

Slagboom et al. Poster EuroPCR 2015, Paris, France


Long term Safety Endpoint
STENT THROMBOSIS @ 36 MONTHS
OVERALL POPULATION

HIGH-RISK SUBGROUPS

ST (%)

Orsiro
Xience
Prime

10

DIABETICS

10

P=0.3437
0.0
0

ST (%)

P=0.3407
10

0.0%

365

SMALL VESSELS

ST (%)

0.7%
0.0

180

P>0.9999

0.0

0

180

365

730
1095
Days after PCI

2.3%
0.0%
730
1095
Days after PCI

0

0.0%
180

365

730
1095
Days after PCI

COMPARABLE LONG-TERM EFFICACYAND SAFETY AS BEST-IN-CLASS NEWER GENERATION DP-DES

IN AN OVERALL LOW-RISK PATIENT POPULATION AND IN HIGH-RISK SUBGROUPS
Slagboom et al. Poster EuroPCR 2015, Paris, France


OCT results at 9 months
Neointimal Area

Apposition and Coverage
Orsiro

Xience
Prime

P

98.6%

98.8%

0.62

Incomplete Strut
Apposition

1.0%

0.6%

0.32

Non-apposed side
branch

0.4%

0.6%

0.37

100%

100%

98.3%

97.5%

100
Mean value
0.74± 0.38
mm2

90

Percent of lesions (%)

80

Well-apposed
struts

70

P=0.024

60
50
Mean value
1.00± 0.44 mm2

40
30

Sum

20

Orsiro
Xience Prime

10

Covered Struts

0
0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

2

2.2

Median of neo-intimal area (mm2)

Source: S. Windecker, Late breaking trial presentation, EuroPCR 2013

0.042


Orsiro has also shown superior strut
coverage compared to Resolute Integrity
HATTRICK-OCT study
•

Orsiro v.s. Resolute Integrity (n=44, 1:1 randomization)

•

To access “early healing pattern of 2nd and 3rd
generation DES”

•

Primary endpoint: Stent strut coverage at 3 months

•

Presented at EuroPCR 2013 by T. Kiviniemi, PI: P
Karjalainen

•

No significant baseline differences between study arms

•

Most interesting result – Uncovered struts at 3 months
Orsiro 3.9% vs. Resolute Integrity 8.9%, p<0.001

•

Conclusion
“Sirolimus-eluting stents with bioabsorbable polymer
were more completely covered compared to
zotarolimus-eluting stents with durable polymer at 3

months after PCI for ACS”

Published in Official Journal of the Japanese
Circulation Society December 2014

/>

Registry for an all-comers patient population
with the limus eluting Orsiro stent system in
daily clinical practice
DESIGN
An international, prospective, multi-center
open-label, registry of the Orsiro hybrid DES
in daily clinical practice
OBJECTIVE
Evaluate safety and clinical performance of the
Orsiro drug eluting stent with a bioabsorbable
polymer in a large patient population in standard
clinical care
COORDINATING INVESTIGATOR
Prof. Dr. Johannes Waltenberger,
Universitätsklinikum Münster, Germany
PRIMARY ENDPOINT
Target Lesion Failure (TLF) at 12 months

NCT01553526

1’356 all-comers patients
Predefined subgroups
 Diabetic patients

 Acute MI (STEMI and NSTEMI)
 Small vessels (≤2.75 mm)
 Chronic Total Occlusion

Clinical follow-up at 6 months

Clinical follow-up at 12 months*
Clinical follow-up at 36 months

Clinical follow-up at 60 months
* 97.4 % FUP compliance

Source: Waltenberger et al. EuroIntervention 2015; 10-online publish-ahead-of-print March 2015.
.


Primary Efficacy and Safety Endpoints
TARGET LESION FAILURE @ 12 MONTHS

DEFINITE STENT THROMBOSIS @ 12 MONTHS

LOW TLF AND ST RATES IN AN UNSELECTED, ALL-COMERS POPULATION
WITH COMPLEX CORONARY ARTERY DISEASE
Waltenberger J, Eurointervention 2015


Primary Efficacy Composite Endpoint
ULTRATHIN-STRUT BP-SES vs. THIN-STRUT DP-EES @ 2 YEARS (N=2’119)
12

10.5% - BP SES

RR (95%CI)=1.00 (0.77-1.31)
P= 0.98

11
10

PRIMARY ENDPOINT TLF @ 1 YEAR

9

10.4% - DP EES

TLF (%)

8
7

PNON INFERIORITY

= 0.0004

6.7% - DP EES
6.7% - BP SES

6
5
4
3

2
1
0
0

60

120

180

240

300

360

420

480

Days since index procedure
Zbinden R, J APimlgrHimea

540

600

660

730


Composites of Primary Efficacy Endpoint
ULTRATHIN-STRUT BP-SES vs. THIN-STRUT DP-EES @ 2 YEARS (N=2’119)
10.5% - BP SES
10.4% - DP EES

6
5

3.2% - DP EES

4
3
2

3.2% - BP SES

0
0

60

120 180 240 300 360 420 480 540

600 660

730

935 929 924 917
928 918 911 908

907
889

8

RR (95%CI)=0.91 (0.60-1.39), P=0.67

6

4.5% - DP EES

5
4
3

4.1% - BP SES

2

0

1
0

Number at risk
DP-EES 1056 1036 1033 1030 1030 1022 1014 992 989 988 986 985
BP-SES 1063 1036 1031 1026 1022 1014 1007 988 984 976 974 971

8
7
6
5
4
3
2
1
0

60

120 180 240 300 360 420

480 540 600 660

730

Days since index procedure

Number at risk
DP-EES 1056 1013 1009 1004 1000 990 981 959 955 953 948 944
BP-SES 1063 1017 1011 1002 995 987 979 957 949 941 936 933

Zbinden R, J Am Heart Assoc. 2016

937
922

730
979
960

RR (95%CI)=1.17 (0.81-1.71), P=0.40

6.0% - BP SES

5.1% - DP EES

0
0

60 120 180 240 300 360 420 480 540 600 660

Days since index procedure

TLR clinically driven (%)

Days since index procedure

Target vessel MI (%)

RR (95%CI)=1.01 (0.62-1.63), P=0.98

7

1

Number at risk

DP-EES 1056 1007 1001 996 988 975 965 940
BP-SES 1063 1012 1002 989 975 967 958 935

7

8

Cardiac death (%)

RR (95%CI)=1.00 (0.77-1.31), P=0.98

TLF
(%)

11
10
9
8
7
6
5
4
3
2
1
0

60

120 180 240 300 360 420 480 540 600 660

730

Days since index procedure
Number at risk
DP-EES 1056 1028 1023 1019 1013 1000 990 965 961 955 948 941
BP-SES 1063 1027 1017 1005 992 983 974 950 944 934 929 925

931
908


Subgroup Analysis
Primary Efficacy Composite Endpoint
ULTRATHIN-STRUT BP-SES vs. THIN-STRUT DP-EES @ 2 YEARS (N=2’119)
TARGET LESION FAILURE ACROSS PRESPECIFIED SUBGROUPS

STRONG SIGNAL TOWARDS A SIGNIFICANT REDUCTION IN TLF
IN THE PRESPECIFIED SUBGROUP OF PATIENTS WITH STEMI

Zbinden R, J Am Heart Assoc. 2016