Peter Clemmensen MD, PhD, FESC

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

Copenhagen, Denmark

Strategies to reduce AMI size during reperfusion therapy

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.

Disclosure of Conflict of Interest

TARGETS

Epicardial Flow Myocardial PerfusionMyocardial OxygenationMyocyte surfaceIntracellular mechanisms“Inflammation”

Organisational

Strategies to reduce AMI size during reperfusion therapy

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

Drug administration

Patients at riskMI / Death

IV cariporide for 2 to 7 days

• 10 days• 36 days (primary endpoint)• 180 days

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

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

Primary Endpoint:• Death or MI(ECG and CK-MBevaluation by Core Lab)

Randomization

Follow - up

10.8 1.2

Relative Risk (95% C.I.)

Primary Endpoint ResultsRelative Risk

Entry/Trt Group Death/MI UAP/NQMI Placebo 12.4% 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%

Epicardial vs. Myocardial Reperfusion

No Reflow in Reperfused AMI

CAG

CAG

MCE

MCE

Ito Circ. 1996;93:1993

Reperfusion Therapy

Targets against No-Reflow

GP IIb/IIIa receptor antagonists

CD 9/11 receptor antagonists

Complement System inhibition

LIMIT AMI Trial (n=493)

Methods

rhuMAB (White Cell CD 18 blockade)+thrombolysis

Endpoint: TIMI Frame Count

Results: No difference

ACC 2001

PexelizumabPexelizumab2mg/kg bolus + 0.05 mg/kg/hr 2mg/kg bolus + 0.05 mg/kg/hr

for 24 hoursfor 24 hoursn=2860n=2860

PexelizumabPexelizumab2mg/kg bolus + 0.05 mg/kg/hr 2mg/kg bolus + 0.05 mg/kg/hr

for 24 hoursfor 24 hoursn=2860n=2860

APEX AMI Trial: Study Design

Primary Endpoint: All-cause mortality through 30 days.Primary Endpoint: All-cause mortality through 30 days. Secondary Endpoint: Death at day 90 and the composite of death, cardiogenic Secondary Endpoint: Death at day 90 and the composite of death, cardiogenic

shock, or congestive heart failure through days 30 or 90.shock, or congestive heart failure through days 30 or 90.

Primary Endpoint: All-cause mortality through 30 days.Primary Endpoint: All-cause mortality through 30 days. Secondary Endpoint: Death at day 90 and the composite of death, cardiogenic Secondary Endpoint: Death at day 90 and the composite of death, cardiogenic

shock, or congestive heart failure through days 30 or 90.shock, or congestive heart failure through days 30 or 90.

PlaceboPlacebo2 mg/kg bolus + 0.05 mg/kg/hr 2 mg/kg bolus + 0.05 mg/kg/hr

for 24 hoursfor 24 hoursn=2885n=2885

PlaceboPlacebo2 mg/kg bolus + 0.05 mg/kg/hr 2 mg/kg bolus + 0.05 mg/kg/hr

for 24 hoursfor 24 hoursn=2885n=2885

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

excluding those with prior fibrinolytic therapy for treatment of the index MI; complement deficiency;excluding those with prior fibrinolytic therapy for treatment of the index MI; complement deficiency;pregnant; breast-feeding; isolated, low-risk, inferior wall MIpregnant; breast-feeding; isolated, low-risk, inferior wall MI

Prospective. Double-Blind. Placebo-Controlled. Randomized. Mean follow-up 90 days.Prospective. Double-Blind. Placebo-Controlled. Randomized. Mean follow-up 90 days.23% female, mean age 61 years, mean follow-up 90 days.23% female, mean age 61 years, mean follow-up 90 days.

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

excluding those with prior fibrinolytic therapy for treatment of the index MI; complement deficiency;excluding those with prior fibrinolytic therapy for treatment of the index MI; complement deficiency;pregnant; breast-feeding; isolated, low-risk, inferior wall MIpregnant; breast-feeding; isolated, low-risk, inferior wall MI

Prospective. Double-Blind. Placebo-Controlled. Randomized. Mean follow-up 90 days.Prospective. Double-Blind. Placebo-Controlled. Randomized. Mean follow-up 90 days.23% female, mean age 61 years, mean follow-up 90 days.23% female, mean age 61 years, mean follow-up 90 days.

RR

90 days follow-up 90 days follow-up

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

3,9% 4,1%

0%

2%

4%

6%

Placebo Pexelizumab

3,9% 4,1%

0%

2%

4%

6%

Placebo Pexelizumab

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

% p

atie

nts

% p

atie

nts

APEX AMI Trial: Primary EndpointAPEX AMI Trial: Primary Endpoint

p = 0.78p = 0.78

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

Primary endpoint of 30 day mortalityPrimary endpoint of 30 day mortality

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

Follow-up 4 months

400 mg FX06 i.v.

(n = 114)

Placebo(n = 120)

Trea

tmen

t

Visit 3

STEMI at - 6 to 0 hrs

= randomisation

R

Study flowchart

R

0 m

in F

X06

10 m

in F

X06

1.5h

CKM

B

24h T

roponin

Pri

ma

ry

PC

I

48h T

roponin

5-7d

CM

R

2m M

ACE

4m M

ACE/CM

R

Visit 12 day in house follow up

Visit 2

MVO zone

necrotic core zone

total LGE zone

normal myocardium

LV lumen

Acute Myocardial Infarction Imaged with LGE CMR

Median with 25- and 75-percentile

5 days post PCI: No difference in total late enhancement zoneNecrotic core significantly reduced (ITT Population)

* statistically significant# Wilcoxon rank sum test

1.77 (0; 9.09)

4.2 (0.30;9.93)

21.68(8.33;47.09)

27.34(11.74;44.89)

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

Median with 25- and 75-percentile

4 mths post PCI: No difference in • Total late enhancement zone• Scar mass (ITT population)

# Wilcoxon rank sum test

15.37(5.70;36.43)

2.84(0.35; 7.26)

1.79(0;8.78)

19.32(7.51;31.37)

LV ejection fraction FX06 Placebo

LVEF at 5 days: 46.7 % 46.6 %

LVEF at 4 months: 49.1% 48.9 %

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

Clinical Results and Left Ventricular Function 8 Months after Primary PCI Performed with and

without Distal Protection

New Observations from the DEDICATION Trial

Copenhagen University HospitalRigshospitalet

Aarhus University HospitalSkejby

Denmark

STEMI - PPCI n = 626

Randomization

+ Distal Protectionn = 312

- Distal Protectionn = 314

Number of Patients

Primary:LVEF at 8 months

Secondary:LVEF at dischargeΔ LVEF from discharge to 8 monthsMACCE at 8 months

Endpoints

0

20

40

60

80

100

TIMI 0-1

TIMI flow pre and post procedure

ns

pre procedure

Distal ProtectionConventional Treatment

TIMI 3post procedure*

p < 0.001

* By core lab analysis

% o

f pa

tient

s

7.1

1.0

2.2

2.92.9

3.8

5.7

1.6

0.61.3

2.9

3.8

0

2

4

6

8

10

Death Cardiacdeath

Myocardialinfarction

Re-infarction

Stroke MACCE

Events

, %

Distal protectionConventional treatment

8 months Clinical Events

p=1.00

p=1.00 p=0.17p=0.11

p=0.73

p=0.52

Change in LVEF after PPCI within groups

Conventional Treatment

30

35

40

45

50

55

60

65

8-month Follow-Up

BeforeDischarge

L V

EF

, %

5.1% 5.6%

5.1% vs 5.6% = ns

p < 0.01

n=234 n=245

Distal Protection

30

35

40

45

50

55

60

65

p < 0.01

8-month Follow-Up

BeforeDischarge

n=247 n=257

Cardioprotective Effects of Mechanical Cardioprotective Effects of Mechanical Postconditioning in Patients Treated Postconditioning in Patients Treated

with Primary PCI Evaluated with with Primary PCI Evaluated with Magnetic ResonanceMagnetic Resonance

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

S Jensen, Henning KelbækS Jensen, Henning Kelbæk

Copenhagen University HospitalCopenhagen University HospitalRigshospitaletRigshospitalet

DenmarkDenmark

Conventionaltreatment

coronary arteryReperfusionOccluded

Postconditioning

Reperfusioninjury

Reperfusioninjury

Post-conditioning

30 30 30 sec 30 30 30 30 30

Balloon inflations - deflations

Endpoints

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

14

534951

37

63

17

53

0

20

40

60

80

100

LVEF Infarct size / LV mass

Infarct size / Area At Risk

Salvage ratio

%

Postconditioning

Conventional treatment

p=0.987

p=0.037

p=0.007

p=0.007

Δ Δ 32%32%

Outcomes CMR

TARGETS

Epicardial Flow Myocardial PerfusionMyocardial OxygenationMyocyte surfaceIntracellular mechanisms“Inflammation”

Organisational

Strategies to reduce AMI size during reperfusion therapy

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

1,03

1,11

1,23

0,8

1

1,2

1,4

0-30 31-60 61-90 >90Door-to-drug time (min)

MV

ad

just

ed o

dd

s o

f m

ort

alit

y

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

P=NS

P=0.01

P=0.0001

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

Eligible patients, 31% (n=84,663)

24%

76%

No RT (n=20,319)

RT (n=64,344)

Use of Thrombolytic Therapies in Eligible Patients

RT=reperfusion therapy

Barron HV, et al. Circulation 1998

Mortality in Men and Women, by Age

0

5

10

15

20

25

30

50 50-60 60-70 70-80 >80Age, years

Mo

rtal

ity,

%

Women, No TT Men, No TT Women, TT Men, TT

Adapted from Chandra NC et al. Arch Intern Med 1998

0

20

40

1970 1980 1990 2000 2010

STEMI In-hospital mortality

40%

20%

<10%

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

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.

Conclusions

Circulation 2002;105:1285-1290

SAFER

Enrolledn=801

Distal protection Guardwire(median graft age 10.4 y)

n=406

Standard guide wire(median graft age 10.9 y)

n=395

Stentimplantation

Circulation 2002;105:1285-1290

14,713,7

2,31

7,48,6

9,6

16,5

02468

101214161820

MACE MI CKMB>3xULN Death

Guardwire

Guide wire

SAFEREvent rate at 30 days (%)

p=0.08p=0.004

Circulation 2002;105:1285-1290

1,7

4,2

9

3

0,71,5

0123456789

10

TIMI 0-1 TIMI 2 No reflow

Guardwire

Guide wire

SAFERAngiographic events (%)

p=0.001

p=0.001

Circulation 2002;105:1285-1290

FIRE

Enrolledn=651

Filter Wiren=332

Guard Wiren=319

Stentimplantation

Circulation 2003;108:548-553

10

1,9

11,69,9

1,2

9

0,9 0,9

02468

101214161820

Death MI TVR MACE

FilterWire EX (n=332)

GuardWire (n=319)

FIREEvent rate at 30 days (%)

Circulation 2003;108:548-553

X-tract

Enrolledn=797

+ X-Sizer(75% SVG)

n=400

- X-Sizer(72% SVG)

n=397

Stentimplantation

JACC 2003;42:2007-2013

9,3

16,6

8,3

0,31

4,5

15,8

9

16,8 17,1

0

5

10

15

20

MACE MACE in nat.Coronaries

MI CKMB>8xUNL

Death

+X-Sizer

-X-Sizer

X-tractEvent rate at 30 days (%)

p=0.04

JACC 2003;42:2007-2013

4,9

1,2

5,2

0,2

12,1

3,9

1,3

4,3

0,5

4,6

0

2

4

6

8

10

12

14

TIMI 0-2 No reflow Thrombus oremboli

Dissection GP for bail-out

+X-Sizer

-X-Sizer

X-tractAngiographic events (%)

p=0.04

JACC 2003;42:2007-2013

FINDINGS / COMPOSITIONFINDINGS / COMPOSITION– Fibrin – Thrombi– Fatty streaks– Calcificed plaque – Blood clots– Endothelium– Leucocytes– Macrophage foam cells

Filter debris analysisDIPLOMAT

Max Diameter (µm) n = 28n = 28

Mean + SD 344 + 306*

Min 8.9

Max 1979

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

Filter debris analysisDIPLOMAT

1

5,9

4,2

0

2

4

6

8

Mo

rtalit

y (

%)

p<.0001

ST-RES ST-RES >> 70% 70%

ST-RESST-RES30-70%30-70%

ST-RESST-RES<< 30% 30%

ST Resolution and MortalityST Resolution and Mortality

AJC

77 73 78

TIMI 14 SPEED INTRO AMI

tPA 15/35Abx

tPA 5/5Abx

tPA 15/35Eptifibatide

TIMI 3, 90 min

HYBRID REPERFUSION

44

70 68

5663

0

20

40

60

80

n 80 54 97 36 8n 80 54 97 36 8 tPA alonetPA alone Abx+50mgAbx+50mg

tPAtPAAbx+otherAbx+othertPA dosestPA doses

Abx+SKAbx+SK Abx Abx alonealone

p=0.01p=0.01

p=0.001p=0.001

Impact of Treament AssignmentImpact of Treament Assignment TIMI 3 Flow OnlyTIMI 3 Flow Only

%

wit

h C

om

ple

te S

T R

ES

%

wit

h C

om

ple

te S

T R

ES

Thrombolytic therapy ± GPIIb/IIIa

TIMI 2/3 61% 44% NS

after primary PTCA no difference in angiographic results

TT+GP TT

SBH TIMMIS JACC: A2001

4540

5863

5749

62

74

0

20

40

60

80

100

100 mg bolus bolus + 30 mininfusion

bolus + 60 mininfusion

% o

f P

atie

nts

60 Min 90 Min

TIMI 14 Primary Results Speed and Extent of Thrombolysis: TIMI 3 Flow

Antman et al. Circulation 1999;99:2720

tPAtPA tPA + AbciximabtPA + Abciximab 2 Trend, p < 0.0022 Trend, p < 0.002

Normal Normal Flow Flow

cTFC < 28cTFC < 28

tPA 100 mg 36tPA 100 mg 36

tPA 50 (15b/35inf) + Abx tPA 50 (15b/35inf) + Abx 2828

Abx 100Abx 100

SK + Abx 45SK + Abx 45

cTFCcTFC Median Median

P=0.005P=0.005

%

Pat

ien

ts%

Pat

ien

ts

0101020203030404050506060707080809090

100100

0Corrected TIMI Frame Count

20 40 60 80 100

TIMI 14 Efficacy Results TIMI Frame Count at 90 Min

Antman et al. Circulation 1999;99:2720

Integrins Platelets Receptor

GP Ib

GP Ib/IIa

GP IIb/IIIa

Binds

vWF

Collagen

FibrinogenFibronectin……….……….

Platelet Adhesion

0,5

4,8

0

2

4

6

Mo

rta

lity

(%)

p=0.01

ST-RES ST-RES >> 70% 70%

ST-RES < 70%ST-RES < 70%

ST Resolution vs Mortality Among ST Resolution vs Mortality Among Patients with a Patent (TFG 2/3) IRAPatients with a Patent (TFG 2/3) IRA

AJC

Cumulative Distribution of Corrected TIMI Frame Counts and In Hospital Survival

0 10 20 30 40 50 60 70 80 90 10090 minute CTFC

0

20

40

60

80

% o

f P

ts. w

ith

CT

FC

< X

ax

is

Alive: 49.4 + 32.3 frames (n=1,191)

Dead: 69.6 + 35.4 frames (n=53)

p=0.0003

Gibson, Circulation 1999; 99: 1945-1950

3744 44

5359

6975 73

0

20

40

60

80 tPA Comb

Effect of Abciximab on ST ResolutionEffect of Abciximab on ST Resolution

p<0.001p<0.001

p<0.001p<0.001 p<0.001p<0.001 p<0.05p<0.05

n 125 221 80 151 50 88 47 90n 125 221 80 151 50 88 47 90

All Pts TFG 3 CTFC<28 Patent 60’All Pts TFG 3 CTFC<28 Patent 60’

%

Pts

wit

h C

om

ple

te S

T R

ES

18 14

33

2030

19

28

3759

4363

44

69

272130 2917

0

20

40

60

80

100

> 70%30-70%< 30%

ST Resolution

tPA Comb tPA Comb tPA Combn 125 221 102 191 80 151

All Patients Patent IRA TIMI 3 Flow

P<0.001 P<0.001P<0.001

Effect of Abciximab on ST Resolution%

of

Pat

ien

ts

32

42

79

ReoPro 1/3 SK+ ReoPro 1/2 tPA +ReoPro

%90 minTIMI 3

TIMI 14 trial

ReoPro + Fibrinolysis

Antman JACC;1998:191A

LIMIT AMI Trial (n=493)

Methods

rhuMAB (White Cell CD 18 blockade)+thrombolysis

Endpoint: TIMI Frame Count

Results: No difference

ACC 2001

• TIMI 3 FLOWTIMI 3 FLOW• MACE in HOSP MACE in HOSP • MACE 12 MonthsMACE 12 Months

• DeathDeath

• TVRTVR

CADILLACCADILLAC PCI in AMI PCI in AMI n=2082n=2082

PTCAPTCA(n=519)(n=519)

PTCA+AbcxPTCA+Abcx(n=529)(n=529)

STENTSTENT(n=513)(n=513)

9696%%

4.6%4.6%

19.8%19.8%

2.92.9%%

15.9%15.9%

94%94%

8.5%8.5%

21.2%21.2%

5.3%5.3%

16.816.8%%

STENT+Abcx STENT+Abcx ((n=522)n=522)

96%96%

4.6%4.6%

1414%%

5.0%5.0%

6.2%6.2%

93%93%

5.7%5.7%

14%14%

3.23.2%%

9.3%9.3%

Patient Patient treatmenttreatment

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

CE-MRI Evaluation.

MASSIMO MANCONE, MD; RAFFAELE SCARDALA, MD; CHIARA BUCCIARELLI DUCCI,MD;ANGELO DI ROMA,MD; IACOPO CARBONE,MD*;GIULIA BENEDETTIGIULIA CONTI,MD ; FRANCESCO FEDELE, MD.

GENNARO SARDELLA, MD, FACC ,FESC;

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

Policlinico Umberto I - University “La Sapienza ROME

gg

0

2

4

6

8

10

12

14

16

18

20

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

Standard PCI

Thrombectomy

gr

MRI Results-2

p=0.004

P<0.001

p=0.004

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

4.04 0.122.7

17.39

11.01

44 50

32 28

79

2422

15

6

0

20

40

60

80

100

TIMI 0/1 Flow

TIMI 2 Flow

TIMI 3 Flow

ST-RES < 30% n=118

ST-RES 30-70% n=118

ST-RES > 70% n=208

p <0.001 for trend of TIMI 3 flowST Resolution and TIMI Flow GradeP

erce

nt

of

Pat

ien

ts

AJC

no <30%

partial30-70%

ST-resolution

Complete >70%

13

29

6

14

0

4

0

5

10

15

20

25

30

In hospital

3 yrs follow-up

ST resolution in TIMI 3 flow pts

n = 398 after pPCI

%

Van‘t Hof: Lancet 98;350:615

MORTALITY

TIMI Frame Count & Risk Stratification Within TIMI Flow Grades

0

10

7.9%

15.5%18.8% 21.7% 22.2%

42.9%

50

40

30

20

10

50

40

30

20

10

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

0 < 20 20 < 40 40 < 60 60 < 80 80 < 100 > 100

% R

isk

of

Ad

vers

e O

utc

om

e%

Ris

k o

f A

dve

rse

Ou

tco

me

Grade 3 FlowGrade 2 Flow

13.0%

27.0%

TIMI Flow Gradesp = 0.024

TIMI Frame Countsp = 0.015

Risk of In Hospital Mortality by TIMI Frame Count

0

1

2

3

4

5

6

7

CTFC < 14 CTFC > 40

0.0%(n=41) (n = 18/640) (n =35/563)

2.8%

p= 0.003

“TIMI 4” Flow TIMI 3 Flow

14 < CTFC < 40

6.2%

% R

isk

of

In H

osp

ital

Mo

rtal

ity

Gibson, Circulation 1999; 99: 1945-1950

Hyperemic FlowReproducibility:

r = 0.97 between readersAccuracy:

r=0.88 vs Doppler velocity

21

0

10

15

5

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

Manginas et alAm J Card 1999

P =0.001R=0.88

Coronary Flow Reserve Using the Frame Count

Co

ron

ary

Flo

w R

eser

ve

Usi

ng

th

e D

op

ple

r V

elo

city

Wir

e

No Reflow in Reperfused AMI

Iwakura Circ. 1996;94:1269