L A P A Z Daniel Berrocal, MD, PhD, FACC

Jefe de Cardiologia Intervencionista

daniel.berrocal@hospitalitaliano.org.ar

Stents Coronarios

Pasado, Presente y Futuro

L A P A Z Daniel Berrocal, MD, PhD, FACC

Jefe de Cardiologia Intervencionista

daniel.berrocal@hospitalitaliano.org.ar

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

daniel.berrocal@hospitalitaliano.org.ar

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?