L A P A Z Daniel Berrocal, MD, PhD, FACC
Jefe de Cardiologia Intervencionista
Stents Coronarios
Pasado, Presente y Futuro
L A P A Z Daniel Berrocal, MD, PhD, FACC
Jefe de Cardiologia Intervencionista
Conferencista
Biosensors, Boston Scientific, Terumo
Fondos para investigación
Abbot, Eurocor
Programas de entrenamiento y educación
Biosensors, Terumo
Roads opened by “insane”
will be later traveled by the “wise man”
C. Dossi
Balloon angioplasty
Andreas Gruentzig
September 1977
Modified from
ACC/AHA TASK FORCE,1988/1993
HFMA February 1998
32.000
133.000
300.000
665.000
1.000.000
1977 1983 1986 1990 1997 1999
Evolución de la angioplastia en sus comienzos
NHLBI Coronary Angioplsty Registry
%
año
0
10
20
30
40
50
60
70
80
90
100
81 82 83 84 85 86 87 88 89 90 91 92
Clinical succes
Uneventful failure
MACE
New Balloons
New devices
1977: Balloon Angioplsty 1981 (NHBLI Registry)
Response to vascular injury
Thrombosis
Proliferation
Remodeling
Inflamation Neointimal
hyperplasia Elastic recoil
RESTENOSIS
30% 70%
Palmaz balloon expandable stent
Balloon angioplasty
Balloon expanded stent
Balloon result
Stent implanted
Stent result
First Palmaz-SchatzTM (1986)
13-years post stent
48% *
37% *
27% *
BENESTENT II study trial E
ve
nt %
STENT
BALOON
1986: Stent angioplasty 1994 (BENESTENT)
6
0
65
70
75
80
85
90
95
100
0 30 60 90 120 150 180 210
So
bre
vid
a lib
re d
e e
ve
nto
s %
Días
Sobrevida libre de eventos: Muerte, Infarto, CRM o Re-ATC
Benestent I Balloon
72.0%
1980
Benestent II Stent
83.2%
Benestent I Stent
80.3%
1990
IMPACTO CLÍNICO DE LOS STENTS
First CypherTM (1999)
2-years post DES stenting
6
0
65
70
75
80
85
90
95
100
0 30 60 90 120 150 180 210
So
bre
vid
a lib
re d
e e
ve
nto
s %
Días
Sobrevida libre de eventos: Muerte, Infarto, CRM o Re-ATC
Benestent I Balloon
72.0%
DES
96.7% 2000↑
1980
Benestent II Stent
83.2%
Benestent I Stent
80.3%
1990
IMPACTO CLÍNICO DE LOS STENTS
Plataforma Droga Polímero
Stent con liberación de drogas
Inflamación Trombosis Migración Proliferación
WCC Congress 2006
The Wall Street Journal
Thursday ,June 22, 2006
PercentagePercentage
100
80
60
40
20
02003 2004 2005 2006
USAInternationalJapan
100
80
60
40
20
02003 2004 2005 2006
USAInternationalJapan
Use of DES world wide
72%
Dec 2006
Spaulding C, et al. N Engl J of Med. March 2007
?
Complete FU
3 Years Follow-up
Comparision with BMS
Full 18 month F/U
of total cohort 826 p
Kaiser C. World Congress of Cardiology
September 2006; Barcelona, Spain
P=.05 P=.83 P=.66 P=.26
Basket–Late
Interim 7 – 18 months
Internal Medicine World Report January 2007
“Off – label” uses = Not always bad
ISIS 2 published in 1988
Aspirin reduced Mortality in AMI
FDA approved Aspirin for this indication in 1998
There was a 10 years delay !!!!!!!!!!
Courtesy Conrad Simpfendorfer
Thanks a lot Dr. Camenzind!
Because of your “metanalysis”….. …...we have learnt that evidences are not always obvious
…... industry and physicians will look for deeper pathophysiological
understanding of new developments
…... we are moving faster towards “true” new generations of DES
…... the debate about “off label” indications and Regulatory Agencies
is now wide open
…... we understood that we were right extending the use of DES to
more complex patients, improving quality of life and MACE.
…... we “ALL” have learnt that medical evidences should be
addressed in scientific forums and peer-review Journals but NOT in
newspaper Headlines.
Pasceri V. Am Heart J 2007;153:749-754.
MACE at 8-12 months DES (n=1177)
BMS (n=1180) RR=0.53
p<0.0001
p=NS p=NS p=NS
RR=0.40
p<0.0001
DES for AMI
Metanalysis (n= 2357 p)
43%
TRITON/TIMI 38 Key Efficacy, Safety EP: Stratified by Stent Type
CVD/MI/CVA Major Bleeding
HR 0.80
(0.69-0.93)
p=0.003
HR 0.81
(0.72-0.90)
p=0.0001
HR 0.82
(0.69-0.97)
p=0.02
HR 1.37
(0.95-1.99)
p=0.09
HR 1.27
(0.99-1.63)
p=0.06
HR 1.19
(0.83-1.72)
p=0.34
N=12844 N=6461 N=5743
CLOPIDOGREL
PRASUGREL
DES vs. BMS
in NSTEMI
Meta-regression. Am Heart J 2005
.4
.2
0.0
-.2
-.4
-.6
-.8
.4
.2
0.0
-.2
-.4
-.6
-.8
P= .011
Early invasive worse
Early invasive better
Early invasive worse
Early invasive better
LO
G (
OR
) F
OR
DE
AT
H O
R M
I
LO
G (
OR
) F
OR
DE
AT
H O
R M
I
P= .005
NO STENTING STENTING NO AGRESSIVE
ANTITHROMBOTIC
THERAPY
AGRESSIVE
ANTITHROMBOTIC
THERAPY
Very early PCI in ACS
Invasive vs. Conservative
in NSTEMI
Naik H et al. JACC Intervention 2009; 2: 730-747
Meta-Análisis
(3773 pacientes)
Death, MI and Stroke
No differences up to 3 years
Naik H et al. JACC Intervention 2009; 2: 730-747
TVR
Increased up to 3 years
Meta-Análisis
(3773 pacientes)
Daemen J et al. Circulation 2008;118;1146-1154
Metánalisis DES vs. CABG
Adjusted Risk of Death, MI and stroke (I.C. 95%)
Diabetes
Fuster V. AHA Nov. 3–7, 2012
Fuster V. AHA Nov. 3–7, 2012
Fuster V. AHA Nov. 3–7, 2012
Tipo de estudio N de
Pacientes
N de
Estudios
Riesgo
Relativo
Valor de P
RCT: Todos 7291 16 0.45 <0.001
RCT: “on-label” 4618 9 0.53 <0.001
RCT: “off-label” 2673 8 0.38 <0.001
Registros 73 819 17 0.53 <0.001
*Modelo de efecto randomizado
47 to 62% RCT= Estudios Randomizados
Kirtane AJ, Stone GW. Comprehensive meta-analysis of DES
vs BMS randomized trials and registries; ACC 2008; Chicago, IL.
Revascularización del vaso culpable (Megametanálisis)
IMPACTO CLÍNICO DE LOS STENTS
a. Modelo de efecto fijo
b. Modelo de efecto randomizado 20% RCT= Estudios Randomizados
Mortalidad de cualquier causa (Megametanálisis)
IMPACTO CLÍNICO DE LOS STENTS
Kirtane AJ, Stone GW. Comprehensive meta-analysis of DES
vs BMS randomized trials and registries; ACC 2008; Chicago, IL.
Tipo de estudio N de
Pacientes
N de
Estudios
Riesgo
Relativo
Valor de
P
RCT: Todos 8867 21 0.97 0.72a
RCT: “on-label” 4818 10 1.05 0.69a
RCT: “off-label” 4049 12 0.84 0.24a
Registros 161 232 28 0.80 <0.001b
Biolimus-A9™ Eluting Stent
• Biolimus is a semi-synthetic sirolimus analogue
with 10x higher lipophilicity and similar potency
as sirolimus.
• Biolimus 15.6 g/mm applied solely to the abluminal stent surface.
• Biolimus is co-released with polylactic acid and
completely desolves into carbon dioxide and
water after a 6-9 months period.
• Stainless steel stent platform has a strut thickness
of 120 m with a quadrature link design.
Turns into a BMS!!!
PtCr Promus Element™
Stent 0.0032” (0.0813mm)
CoCr Xience V™ Stent
0.0032” (0.0813mm)
CoNi Endeavor™ Stent
0.0036” (0.0914mm)
CoCr Xience Prime™ Stent 0.0032” (0.0813mm)
CoNi Resolute Integrity™ Stent
0.0035” (0.0889mm)
Visibility Bench Test Comparison
Data on file. Based on 2.50 mm stents. Copper phantom to simulate body mass. Photographs taken by Boston Scientific. Bench test results may not necessarily be indicative of clinical performance.
Radiopacidad
Conformabilidad
Access to side branches
Fuerza Radial
0.4
0.6
0.8
0.2
0
Box and Whisker Plot
3.0
20 atm.
ASSUMPTION T DF P 95% CI FOR DIFFERENCE
----------------- ------ ------ ------ ---------------------
EQUAL VARIANCES 9.14 244 0.0000 (0.1432, 0.2218)
UNEQUAL VARIANCES 9.59 234.5 0.0000 (0.1450, 0.2200)
F NUM DF DEN DF P
TESTS FOR EQUALITY ------- ------ ------ ------
OF VARIANCES 2.41 136 108 0.0000
3.5
8 atm.
RE
CO
IL (
mm
)
STENT
Impactation Presure
246 cases
Berrocal D et al. Cardiovasc Pathol. 2008 Sep-Oct;17(5):289-96. Epub 2008 Feb 19.
Overexpansion and acute loss
270
360
450
540
180
90
Box and Whisker Plot
SIMMETRIC ASIMMETRIC
EQUAL VARIANCES -2.36 30 0.0250 (-148.59, -10.718)
TESTS FOR EQUALITY ------- ------ ------ ------
OF VARIANCES 3.19 13 17 0.0135
NE
OIN
TIM
AL T
HIC
KE
NIN
G (μ
)
Symmetry and restenosis
Berrocal D et al. Cardiovasc Pathol. 2008 Sep-Oct;17(5):289-96. Epub 2008 Feb 19.
210
300
390
480
120
30
Box and Whisker Plot
METAL - METAL +
EQUAL VARIANCES -2.38 40 0.0224 (-137.98, -11.141)
TESTS FOR EQUALITY ------- ------ ------ ------
OF VARIANCES 1.31 24 16 0.2935
NE
OIN
TIM
AL T
HIC
KE
NIN
G (μ
)
Metal amount and restenosis
Berrocal D et al. Cardiovasc Pathol. 2008 Sep-Oct;17(5):289-96. Epub 2008 Feb 19.
Asymmetry and heterogeneous drug distribution
Hwang et al,
Circulation 2001
2.5x
2.5x
Berrocal et al,
Catheter Cardiovasc Interv. 2006
10x 10x
D. Berrocal y cols D. Berrocal y cols
Reparación Inflamación
A, Farb A, Farb
Hemorragia Necrosis
10x 10x
Berrocal D, et al. Berrocal D, et al. Berrocal D, et al.
Berrocal D, et al. Berrocal D, et al. Courtesy Dr. A Abizaid
Drugs deposited in multi-layered
degradable polymer inlays
80
70
60
50
40
30
20
10
0 0 20 40 60 80 100 120 140 160 180
90
Aprotinin 2
Lysozime1
Lysozime2
TIME (min)
AM
OU
NT
RE
LE
AS
ED
(x 1
0-6
mm
ol)
Jensen et al. European Journal of Pharmacological Sciences. 15( 2002) 139-148
Aprotinin 1 Aprotinin spontaneous release
Lysozime spontaneous release
Chondrityn 4-sulphate hydrogel
Absorbable metallic Mg+ stent
Porcine Coronary Artery:
Representative Photomicrographs (2x)
BVS Cohort A
CYPHER
Photos taken by and on file at Abbott Vascular.
2 years 1 month 6 months 1 year 3 years
1 month 6 months 1 year 2 years 3 years
4 years
4 years
Tests performed by and data on file at Abbott Vascular.
BVS
Bioabsorbable eVerolimus-eluting Stent; Abbott Vascular
JA Ormiston, PW Serruys et al
Lancet, 373, 9667: 887,.March 2009
6 Months
(n = 26)
2 Years
(n = 19)
P Value
In-Stent RVD, mm 2.64 2.43 0.0058
In-Stent MLD, mm 1.89 1.76 0.23
In-Stent DS 27.0% 27.0% 0.81
In-Stent Late Loss, mm 0.43 0.48 0.233
Proximal Late Loss, mm 0.23 0.34 0.0553
Distal Late Loss, mm 0.23 0.36 0.0091
In-Stent Binary Restenosis 7.7% 0% 1.00
In-Segment Binary Restenosis 7.7% 0% 1.00
34.5% struts reduction over 2 years
A, Stenosis in the obtuse marginal branch of the left circumflex coronary artery before ABSORB bioresorbable vascular scaffold (BVS) implantation; B, artery after deployment of a
3.0×18 mm ABSORB BVS scaffold and after dilatation with a 3.25-mm noncompliant...
Ormiston J A et al. Circ Cardiovasc Interv 2011;4:535-538
Copyright © American Heart Association
A, Apparently good angiographic result after postdilatation with a compliant 3.5-mm balloon at 16 atm.
Ormiston J A et al. Circ Cardiovasc Interv 2011;4:535-538
Copyright © American Heart Association
1978
1986
2000
2012 FUTURO
0 1 2 3 4 5 6
400
300
200
100
0 7
Ma
ss r
ele
ase
d (
ng
)
Time (days)
PCI CON BALON
STENTS
DES
SCAFFOLDS
Exclusion de los >75 años de los RCTs
Review of 593 UA/MI Trials
Lee, JAMA 2001
Trials
Not
Inclu
din
g E
lderly (
%)
“Market share” of GRANTS
Modified from Holmes D et al.
Am Heart J. 2004; 147: 228-237
40%
60% 60%
40%
Par
tici
pat
ion
in r
esea
rch
fo
un
din
g %
Carol B. VanBuren. Removing Roadblocks Along the Medical Pipeline The FDA’s Critical Path Initiative: Update on Progress & Outlook for 2007
http://www.dawnbreaker.com/about/phase3_sum07/medical.php
60
50
40
30
20
10
0
35
30
25
20
15
10
5
0
New
Dru
g A
pp
rova
ls (
NM
Es) P
harm
a R&
D ($
billio
ns)
Pharma R&D Spending
New Drug Approvals
1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003
Innovation Gap
L A P A Z Daniel Berrocal, MD, PhD, FACC
Jefe de Cardiologia Intervencionista
Los stents han representado el máximo avance
desde que nació la angioplastia
La capacidad de liberar substancias localmente,
los convirtió en un nuevo concepto terapéutico
El futuro nos traerá nuevos desarrollos en drogas y polímeros,
stents dedicados (DAPT mas corta)
Deberán seguir mejorando desde el punto de vista mecánico
Lo “scaffolds” bioabsorvibles NO son simplemente otro stent
Stents inteligentes?
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