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Strategies to reduce AMI size during reperfusion therapy. Peter Clemmensen MD, PhD, FESC Department of Cardiology B, The Heart Center, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. Disclosure of Conflict of Interest.

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slide1

Strategies to reduce AMI size

during reperfusion therapy

Peter Clemmensen MD, PhD, FESC

Department of Cardiology B, The Heart Center, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark

slide2

Disclosure of Conflict of Interest

The presenter has previously or currently been involved in research contracts, consulting or received research and educational grants from:

AstraZeneca, Aventis, Bayer, Bristol Myers Squibb, Eli-Lilly, Merck, Myogen, Medtronic, Mitsubishi Pharma, Nycomed, Organon, Pfizer, Pharmacia, Sanofi-Synthelabo, Searle.

slide3

Strategies to reduce AMI size

during reperfusion therapy

TARGETS

Epicardial Flow

Myocardial Perfusion

Myocardial Oxygenation

Myocyte surface

Intracellular mechanisms

“Inflammation”

Organisational

slide6

The GUARDIAN Trial(Guard During Ischemia Against Necrosis)

  • A multicenter, double-blind, randomized, placebo-controlled, phase IIb/III trial
  • The first large-scale trial to test the hypothesis that potent and selective Na+/H+ (NHE) inhibition with cariporide provides direct cardiocellular protection in high-risk coronary situations
guardian study design
GUARDIAN Study Design

Randomization

Patients at riskMI / Death

  • Entry groups:
  • UA / non-Q-wave MI
  • High-risk PCI
  • High-risk CABG

Drug administration

IV cariporide for 2 to 7 days

  • Treatment arms:
  • Placebo
  • 20 mg tid
  • 80 mg tid
  • 120 mg tid

Follow - up

  • 10 days
  • 36 days (primary endpoint)
  • 180 days
  • Primary Endpoint:
  • Death or MI
  • (ECG and CK-MB
  • evaluation by Core Lab)
slide8

Primary Endpoint ResultsRelative Risk

Entry/Trt Group Death/MI

UAP/NQMI

Placebo12.4%

20mg 13.6%

80mg 12.9%

120mg 12.6%

PTCA

Placebo 12.1%

20mg 9.4%

80 mg 12.5%

120 mg 11.1%

CABG

Placebo 16.7%

20mg 18.1%

80mg 18.2%

120mg 12.8%

Relative Risk (95% C.I.)

0.8

1

1.2

slide10

No Reflow in Reperfused AMI

CAG

MCE

Ito Circ.

1996;93:1993

CAG

MCE

slide11

Reperfusion Therapy

Targets against No-Reflow

GP IIb/IIIa receptor antagonists

CD 9/11 receptor antagonists

Complement System inhibition

slide12

LIMIT AMI Trial (n=493)

Methods

rhuMAB (White Cell CD 18 blockade)

+thrombolysis

Endpoint: TIMI Frame Count

Results: No difference

ACC 2001

apex ami trial study design
APEX AMI Trial: Study Design

5745 patients > 18 yrs with acute MI within 6 hours of symptom onset; high-risk anterior lateral or inferior MI; planned primary PCI; or new left-bundle branch block

excluding those with prior fibrinolytic therapy for treatment of the index MI; complement deficiency;

pregnant; breast-feeding; isolated, low-risk, inferior wall MI

Prospective. Double-Blind. Placebo-Controlled. Randomized. Mean follow-up 90 days.

23% female, mean age 61 years, mean follow-up 90 days.

R

Placebo

2 mg/kg bolus + 0.05 mg/kg/hr

for 24 hours

n=2885

Pexelizumab

2mg/kg bolus + 0.05 mg/kg/hr

for 24 hours

n=2860

90 days follow-up

  • Primary Endpoint: All-cause mortality through 30 days.
  • Secondary Endpoint: Death at day 90 and the composite of death, cardiogenic shock, or congestive heart failure through days 30 or 90.

Armstrong et al., JAMA. 2007 Jan; 297(1):43 - 51.

apex ami trial primary endpoint
APEX AMI Trial: Primary Endpoint

Primary endpoint of 30 day mortality

  • There was no difference in the primary endpoint (mortality at 30 days) between placebo and pexelizumab (3.9% vs 4.1% respectively), ie, each experiencing a low mortality.

p = 0.78

% patients

Armstrong et al., JAMA. 2007 Jan; 297(1):43 - 51.

f i r e a phase ii trial of fx06 in stemi
F.I.R.E. – a Phase II trial of FX06 in STEMI

FX06: A Novel Compound

Small peptide derived from the human fibrin sequence

Human fibrinopeptide Bß15-42, MW 3039 D

Prepared by solid phase peptide synthesis

Mode of action

FX06: peptide that potently inhibits the binding of fibrin E1 fragment to vascular endothelial (VE) cadherin

Preserves endothelial barrier function, prevents capillary leak

Inhibits transmigration of inflammatory cells through endothelium

Exhibits anti-inflammatory effect

F.I.R.E. - Rationale

To investigate the cardioprotective efficacy of FX06 as an adjunct to reperfusion therapy in patients with acute ST elevation myocardial infarction (STEMI)

To assess safety and tolerability

slide16

Study flowchart

4m MACE/CMR

0 min FX06

1.5h CKMB

10 min FX06

24h Troponin

48h Troponin

2m MACE

5-7d CMR

400 mg FX06 i.v.

(n = 114)

STEMI at - 6 to 0 hrs

Primary PCI

R

Follow-up 4 months

Placebo(n = 120)

Visit 2

Visit 3

Visit 1

2 day in house follow up

Treatment

R

= randomisation

acute myocardial infarction imaged with lge cmr
Acute Myocardial Infarction Imaged with LGE CMR

LV lumen

normal myocardium

MVO zone

necrotic core zone

total LGE zone

slide18

5 days post PCI: No difference in total late

enhancement zone

Necrotic core significantly reduced (ITT Population)

Median with 25- and 75-percentile

4.2 (0.30;9.93)

27.34(11.74;44.89)

21.68(8.33;47.09)

1.77

(0; 9.09)

* statistically significant

# Wilcoxon rank sum test

  • Incidence of microvascular obstruction (MVO): 27.6% versus 37.5%
  • (not statistically significant)
slide19

4 mths post PCI: No difference in

  • Total late enhancement zone
  • Scar mass (ITT population)

Median with 25- and 75-percentile

2.84(0.35; 7.26)

19.32(7.51;31.37)

1.79(0;8.78)

15.37(5.70;36.43)

# Wilcoxon rank sum test

slide20

Clinical Results and Left Ventricular Function 8 Months after Primary PCI Performed with and without Distal ProtectionNew Observations from the DEDICATION Trial

Henning Kelbæk, Klaus Kofoed, Leif Thuesen, Jens F. Lassen, Christian Juhl Terkelsen, Peter Clemmensen, Steffen Helqvist, Lene Kløvgaard, Anne Kaltoft, Lars Krusell, Kari Saunamäki, Erik Jørgensen, Hans E. Bøtker, Jan Ravkilde, Hans Henrik T. Hansen, Evald H. Christiansen, Thomas Engstrøm, Lars Køber

Copenhagen University Hospital

Rigshospitalet

Aarhus University Hospital

Skejby

Denmark

slide21

Number of Patients

STEMI - PPCI

n = 626

Randomization

- Distal Protection

n = 314

+ Distal Protection

n = 312

slide22

Endpoints

Primary:

LVEF at 8 months

Secondary:

LVEF at discharge

Δ LVEF from discharge to 8 months

MACCE at 8 months

slide23

TIMI flow pre and post procedure

p < 0.001

post procedure*

* By core lab analysis

Distal Protection

Conventional Treatment

% of patients

ns

pre procedure

slide24

8 months Clinical Events

p=0.52

p=1.00

p=1.00

p=0.17

p=0.11

p=0.73

slide25

Change in LVEF after PPCI within groups

Distal Protection

65

65

60

60

 5.1%

 5.6%

55

55

50

50

45

45

40

40

p < 0.01

35

35

30

30

Before

Discharge

8-month

Follow-Up

n=247

n=257

Conventional Treatment

L VEF, %

p < 0.01

Before

Discharge

8-month

Follow-Up

n=234

n=245

 5.1% vs  5.6% = ns

slide26

Cardioprotective Effects of Mechanical Postconditioning in Patients Treated with Primary PCI Evaluated with Magnetic Resonance

Thomas Engstrøm, Jacob T Lønborg, Niels Vejlstrup, Erik Jørgensen, Steffen Helqvist, Kari Saunamäki, Peter Clemmensen, Lene Holmvang, Marek Treiman, Jan S Jensen, Henning Kelbæk

Copenhagen University Hospital

Rigshospitalet

Denmark

slide27

Occluded

Reperfusion

coronary artery

Conventional

treatment

Post-

conditioning

30

30

30

30

30

30

30

30 sec

Balloon inflations - deflations

Postconditioning

Reperfusion

injury

Reperfusion

injury

slide28

Endpoints

  • Primary:
  • Infarct size measured with CMR 3 months after the initial
  • procedure (analysis blinded)
slide29

Outcomes CMR

p=0.007

Δ 32%

p=0.987

p=0.007

p=0.037

slide30

Strategies to reduce AMI size

during reperfusion therapy

TARGETS

Epicardial Flow

Myocardial Perfusion

Myocardial Oxygenation

Myocyte surface

Intracellular mechanisms

“Inflammation”

Organisational

early treatment in ami reappraisal of the golden hour
Early treatment in AMI: reappraisal of the golden hour

Boersma et al. Lancet 1996;348: 771-75

odds for mortality associated with longer door to drug time
Odds for Mortality Associated with Longer Door-to-drug Time

P=0.0001

P=0.01

P=NS

n=28,624 n=33,867 n=11,616 n=10,316

Cannon et al. JACC 2000 (Abstract, Suppl A)

use of thrombolytic therapies in eligible patients
Use of Thrombolytic Therapies in Eligible Patients

RT=reperfusion therapy

Barron HV, et al. Circulation 1998

mortality in men and women by age
Mortality in Men and Women, by Age

Adapted from Chandra NC et al. Arch Intern Med 1998

slide36

Conclusions

Lack of myocardial reperfusion is not uncommen despite angiographic patency of the infarct related coronary (epicardial) artery

Hybrid reperfusion strategies have not overcome this limitation after either fibrinolysis or primary PCI

slide37

Conclusions

With the current <10% case fatality rate in STEMI, it becomes increasingly difficult for new treatment principles to demonstrate superiority on hard endpoints.

Conditioning currently holds the greater potential.

In the quest to salvage more mycardium and save more lives, there remains a large potential in optimizing the STEMI networks and improving pre-hospital and hospital organisations.

slide39

SAFER

Distal protection Guardwire

(median graft age 10.4 y)

n=406

Enrolled

n=801

Stent

implantation

Standard guide wire

(median graft age 10.9 y)

n=395

Circulation 2002;105:1285-1290

slide40

SAFER

Event rate at 30 days (%)

p=0.004

p=0.08

Circulation 2002;105:1285-1290

slide41

SAFER

Angiographic events (%)

p=0.001

p=0.001

Circulation 2002;105:1285-1290

slide42

FIRE

Filter Wire

n=332

Enrolled

n=651

Stent

implantation

Guard Wire

n=319

Circulation 2003;108:548-553

slide43

FIRE

Event rate at 30 days (%)

Circulation 2003;108:548-553

slide44

X-tract

+ X-Sizer

(75% SVG)

n=400

Enrolled

n=797

Stent

implantation

- X-Sizer

(72% SVG)

n=397

JACC 2003;42:2007-2013

slide45

X-tract

Event rate at 30 days (%)

p=0.04

JACC 2003;42:2007-2013

slide46

X-tract

Angiographic events (%)

p=0.04

JACC 2003;42:2007-2013

slide47
FINDINGS / COMPOSITION

Fibrin

Thrombi

Fatty streaks

Calcificed plaque

Blood clots

Endothelium

Leucocytes

Macrophage foam cells

DIPLOMAT

Filter debris analysis

slide48

DIPLOMAT

Filter debris analysis

* Discover: Native (n=35) Mean 247 + 21 SVG (n=49) Mean 313 + 19

slide49

ST Resolution and Mortality

ST-RES

> 70%

ST-RES

30-70%

ST-RES

< 30%

AJC

slide50

HYBRID REPERFUSION

TIMI 3, 90 min

tPA 15/35

Abx

tPA 5/5

Abx

tPA 15/35

Eptifibatide

slide51

Impact of Treament Assignment

TIMI 3 Flow Only

p=0.001

p=0.01

% with Complete ST RES

n 80 54 97 36 8

Abx+50mg

tPA

tPA alone

Abx+other

tPA doses

Abx alone

Abx+SK

slide52

Thrombolytic therapy ± GPIIb/IIIa

TT+GP

TT

TIMI 2/3 61% 44% NS

after primary PTCA no difference in angiographic results

SBH TIMMIS JACC: A2001

slide53

Primary Results

TIMI 14

Speed and Extent of Thrombolysis: TIMI 3 Flow

 tPA + Abciximab

tPA

2 Trend, p < 0.002

Antman et al. Circulation 1999;99:2720

slide54

100

90

80

70

60

50

% Patients

40

30

20

10

0

0

20

40

60

80

100

Efficacy Results

TIMI 14

TIMI Frame Count at 90 Min

cTFC Median

tPA 50 (15b/35inf) + Abx 28

P=0.005

tPA 100 mg 36

Normal Flow cTFC < 28

SK + Abx 45

Abx 100

Corrected TIMI Frame Count

Antman et al. Circulation 1999;99:2720

slide55

Platelet Adhesion

Integrins

Platelets Receptor

GP Ib

GP Ib/IIa

GP IIb/IIIa

Binds

vWF

Collagen

Fibrinogen

Fibronectin

……….

……….

slide57

Cumulative Distribution of Corrected TIMI Frame Counts and In Hospital Survival

Alive: 49.4

+

32.3 frames

(n=1,191)

80

p=0.0003

60

% of Pts. with CTFC < X axis

$

$

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$

$

$

$

40

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$

$

$

$

$

$

$

$

$

$

Dead: 69.6

+

35.4 frames

$

$

$

$

(n=53)

$

$

$

$

$

$

$

20

$

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$

0

0

10

20

30

40

50

60

70

80

90

100

90 minute CTFC

Gibson, Circulation 1999; 99: 1945-1950

slide58

Effect of Abciximab on ST Resolution

p<0.001

p<0.001

p<0.05

p<0.001

% Pts with Complete ST RES

n 125 221 80 151 50 88 47 90

All Pts TFG 3 CTFC<28 Patent 60’

slide59

Effect of Abciximab on ST Resolution

P<0.001

  • P<0.001
  • P<0.001

ST Resolution

% of Patients

tPAComb tPA Comb tPA Comb

n 125 221 102 191 80 151

All Patients Patent IRA TIMI 3 Flow

slide60

ReoPro + Fibrinolysis

TIMI 14 trial

79

%

90 min

TIMI 3

42

32

ReoPro

1/3 SK+ ReoPro

1/2 tPA +

ReoPro

Antman JACC;1998:191A

slide61

LIMIT AMI Trial (n=493)

Methods

rhuMAB (White Cell CD 18 blockade)

+thrombolysis

Endpoint: TIMI Frame Count

Results: No difference

ACC 2001

slide62

CADILLAC PCI in AMI n=2082

PTCA(n=519)

STENT(n=513)

STENT+Abcx (n=522)

Patient treatment

PTCA+Abcx(n=529)

93%

5.7%14%

3.2%

9.3%

  • TIMI 3 FLOW
  • MACE in HOSP
  • MACE 12 Months
  • Death
  • TVR

94%

8.5%

21.2%

5.3%

16.8%

96%

4.6%

19.8%

2.9%

15.9%

96%

4.6% 14%

5.0%6.2%

slide63

Impact of Thromboaspiration during Primary PCI on Microvascular Damage and Infarct Size: Acute and Long term

CE-MRI Evaluation.

GENNARO SARDELLA, MD, FACC ,FESC;

MASSIMO MANCONE, MD; RAFFAELE SCARDALA, MD; CHIARA BUCCIARELLI DUCCI,MD;ANGELO DI ROMA,MD; IACOPO CARBONE,MD*;GIULIA BENEDETTI

GIULIA CONTI,MD ; FRANCESCO FEDELE, MD.

O.U. of Invasive Cardiology, Dept. of Cardiovascular Sciences

*Dept.of Radiology

Policlinico Umberto I - University “La Sapienza

ROME

slide64

MRI Results-2

g

p=0.004

P<0.001

17.39

p=0.004

gr

11.01

4.04

2.7

0.12

Hypo 3 Days Hypo 3 Months Hyper 3 Days Hyper 3 Months

slide65

ST Resolution and TIMI Flow Grade

  • p <0.001 for trend of TIMI 3 flow

Percent of Patients

ST-RES < 30%

n=118

ST-RES 30-70%

n=118

ST-RES > 70%

n=208

AJC

slide66

ST resolution in TIMI 3 flow pts

n = 398 after pPCI

MORTALITY

29

30

In hospital

25

3 yrs follow-up

%

20

14

13

15

10

6

4

5

0

0

no

<30%

partial

30-70%

ST-resolution

Complete

>70%

Van‘t Hof: Lancet 98;350:615

timi frame count risk stratification within timi flow grades
TIMI Frame Count & Risk Stratification Within TIMI Flow Grades

50

TIMI Flow Grades

p = 0.024

40

27.0%

30

Grade 2 Flow

13.0%

20

Grade 3 Flow

10

% Risk of Adverse Outcome

42.9%

50

TIMI Frame Counts

p = 0.015

40

22.2%

30

21.7%

18.8%

15.5%

20

7.9%

10

0 < 20

20 < 40

40 < 60

60 < 80

80 < 100

> 100

Gibson et al, Circulation 1999; 99: 1945-1950

risk of in hospital mortality by timi frame count
Risk of In Hospital Mortality by TIMI Frame Count

0

5

6.2%

p= 0.003

10

% Risk of In Hospital Mortality

2.8%

15

0.0%

(n = 18/640)

(n =35/563)

21

(n=41)

14 < CTFC < 40

CTFC < 14

CTFC > 40

“TIMI 4” Flow

TIMI 3 Flow

Reproducibility:

r = 0.97 between readers

Accuracy:

r=0.88 vs Doppler velocity

Hyperemic Flow

Gibson, Circulation 1999; 99: 1945-1950

slide69

Validation of the CTFC in Assessing Coronary Flow Reserve

Coronary Flow Reserve =

Maximum Flow

Baseline Flow

If the CTFC is cut in half (i.e. the time to go down the artery is halved), then the velocity doubled

Coronary Flow Reserve Using the Doppler Velocity Wire

P =0.001

R=0.88

Manginas et al

Am J Card 1999

Coronary Flow Reserve Using the Frame Count

slide70

No Reflow in Reperfused AMI

Iwakura Circ. 1996;94:1269

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