Stents Coronarios Pasado, Presente y Futuro

(1)

LAPAZ

Daniel Berrocal, MD, PhD, FACC Jefe de Cardiologia Intervencionista [email protected]

Stents Coronarios

Pasado, Presente y Futuro

(2)

LAPAZ

 Conferencista

Biosensors, Boston Scientific, Terumo

 Fondos para investigación Abbot, Eurocor

 Programas de entrenamiento y educación Biosensors, Terumo

(3)

Roads opened by “insane”

will be later traveled by the “wise man”

C. Dossi

Balloon angioplasty

Andreas Gruentzig

September 1977

(4)

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

(5)

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)

(6)

Response to vascular injury

Thrombosis

Proliferation

Remodeling

Inflamation

Neointimal hyperplasia Elastic recoil

RESTENOSIS

70% 30%

(7)

Palmaz balloon expandable stent

Balloon angioplasty

Balloon expanded stent

Balloon result

Stent implanted

Stent result

(8)

First Palmaz-Schatz

^TM

(1986)

13-years post stent

(9)

48% *

37% *

27% *

BENESTENT II study trial

Event %

STENT

BALOON

1986: Stent angioplasty 1994

(BENESTENT)

(10)

6 0 65 70 75 80 85 90 95 100

0 30 60 90 120 150 180 210

Sobrevida libre de eventos %

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

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First Cypher ^TM (1999)

2-years post DES stenting

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6 0 65 70 75 80 85 90 95 100

0 30 60 90 120 150 180 210

Sobrevida libre de eventos %

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

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Plataforma Droga Polímero Stent con liberación de drogas

Inflamación Trombosis Migración Proliferación

(14)

WCC Congress 2006

(15)

The Wall Street Journal Thursday ,June 22, 2006

(16)

Percentage Percentage 100

80 60 40 20

0 2003 2004 2005 2006

USA

International Japan

100 80 60 40 20

0 2003 2004 2005 2006

USA

International Japan

Use of DES world wide

72%

Dec 2006

(17)

Spaulding C, et al. N Engl J of Med. March 2007

?

(18)

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

(19)

Internal Medicine World Report January 2007

(20)

“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

(21)

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.

(22)

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%

(23)

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

(24)

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

LOG (OR) FOR DEATH OR MI LOG (OR) FOR DEATH OR MI

P= .005

NO STENTING STENTING NO AGRESSIVE

ANTITHROMBOTIC THERAPY

AGRESSIVE

ANTITHROMBOTIC THERAPY

Very early PCI in ACS Invasive vs. Conservative

in NSTEMI

(25)

Naik H et al. JACC Intervention 2009; 2: 730-747

Meta-Análisis (3773 pacientes)

Death, MI and Stroke

No differences up to 3 years

(26)

Naik H et al. JACC Intervention 2009; 2: 730-747

TVR

Increased up to 3 years Meta-Análisis

(3773 pacientes)

(27)

Daemen J et al. Circulation 2008;118;1146-1154



Metánalisis DES vs. CABG

Adjusted Risk of Death, MI and stroke (I.C. 95%)

Diabetes

(28)

Fuster V. AHA Nov. 3–7, 2012

(29)

(30)



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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

(32)

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 0.72^a

RCT: “on-label” 4818 10 1.05 0.69^a RCT: “off-label” 4049 12 0.84 0.24^a Registros 161 232 28 0.80 <0.001^b

(33)

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!!!

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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.

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Radiopacidad

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Conformabilidad

(37)

Access to

side branches

(38)

Fuerza Radial

(39)

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.

RECOIL (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

(40)

270 360 450 540

180

90

SIMMETRIC ASIMMETRIC

EQUAL VARIANCES -2.36 30 0.0250 (-148.59, -10.718) TESTS FOR EQUALITY --- --- --- ---

OF VARIANCES 3.19 13 17 0.0135

NEOINTIMAL THICKENING (μ)

Symmetry and restenosis

(41)

210 300 390 480

120

30

METAL

-

^METAL+

EQUAL VARIANCES -2.38 40 0.0224 (-137.98, -11.141) TESTS FOR EQUALITY --- --- --- ---

OF VARIANCES 1.31 24 16 0.2935

NEOINTIMAL THICKENING (μ)

Metal amount and restenosis

(42)

Asymmetry and heterogeneous drug distribution

Hwang et al, Circulation 2001

2.5x

Berrocal et al,

Catheter Cardiovasc Interv. 2006

(43)

10x 10x

D. Berrocal y cols

Reparación Inflamación

A, Farb A, Farb

Hemorragia Necrosis

(44)

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

(45)

(46)

(47)

Drugs deposited in multi-layered

degradable polymer inlays

(48)

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) AMOUNT RELEASED (x 10-6 mmol)

Jensen et al. European Journal of Pharmacological Sciences. 15( 2002) 139-148

       





Aprotinin 1 Aprotinin spontaneous release

Lysozime spontaneous release

Chondrityn 4-sulphate hydrogel

(49)

Absorbable metallic Mg+ stent

(50)

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

Tests performed by and data on file at Abbott Vascular.

(51)

BVS

B

ioabsorbable e

V

erolimus-eluting

S tent ;

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

(52)

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

(53)

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

(54)

1978

1986

2000

2012

FUTURO

0 1 2 3 4 5 6 400

300 200 100

0

7

Mass released (ng)

Time (days)

PCI CON BALON

STENTS

DES

SCAFFOLDS

(55)

Exclusion de los >75 años de los RCTs

Review of 593 UA/MI Trials

Lee, JAMA 2001

Trials Not Including Elderly (%)

(56)

“Market share” of GRANTS

Modified from Holmes D et al.

Am Heart J. 2004; 147: 228-237

40%

60% 60%

40%

Participation in research founding %

(57)

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 Drug Approvals (NMEs) Pharma R&D ($billions)

Pharma R&D Spending New Drug Approvals

1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003

Innovation Gap

(58)

LAPAZ

 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?

Stents Coronarios Pasado, Presente y Futuro