Stephen G. Ellis, MDStephen G. Ellis, MDDirector, Sones Cardiac Catheterization LabsDirector, Sones Cardiac Catheterization Labs

Associate, Joseph J. Jacobs Center for Thrombosis and Arterial BAssociate, Joseph J. Jacobs Center for Thrombosis and Arterial BiologyiologyProfessor of Medicine, Ohio State UniversityProfessor of Medicine, Ohio State University

TTHEHE CCLEVELANDLEVELAND CCLINICLINIC FFOUNDATIONOUNDATION

Treatment ofTreatment ofAcute Myocardial Infarction Acute Myocardial Infarction

The FINESSE TrialThe FINESSE Trial

Miami, FloridaMiami, FloridaMay 6, 2003May 6, 2003

PathophysiologyPathophysiology: The Basics: The Basics

AMI RxAMI Rx

•• Five Five ““driversdrivers”” of mortality risk (age, of mortality risk (age, sBPsBP, Killip , Killip class, HR, MI location establish baseline risk)class, HR, MI location establish baseline risk)

•• ““Time is muscleTime is muscle””

•• TIMI 3 flow is goodTIMI 3 flow is good

•• TIMI 3 flow with microvascular perfusion is betterTIMI 3 flow with microvascular perfusion is better

SGE; 0802-3, 1

AMI RxAMI Rx

00--11 9.5%9.5% 13.0%13.0% 353522--33 8.2%8.2% 10.7%10.7% 252544--66 9.7%9.7% 11.5%11.5% 191977--1212 11.1%11.1% 12.7%12.7% 16161313--2424 10.0%10.0% 10.5%10.5% 55

Time is MuscleTime is Muscle

HoursHours FF CCfromfrom BenefitBenefit

OnsetOnset per 1000per 1000

Mortality 0Mortality 0--35d35d

FTT CollaborativeFTT CollaborativeGroup Lancet 1994Group Lancet 1994

SGE; 0802-3, 2

Acute MIAcute MIImportance of Importance of ““Door to NeedleDoor to Needle”” TimeTime

Cannon for NRMICannon for NRMI--2 Study, JACC 35:376A, 20002 Study, JACC 35:376A, 2000

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

Door-to-Needle Time (min)28,624 33,867 11,616 10, 316N =

0 - 30 31 - 60 61 - 90 > 90

1.4

1.2

1.0

0.8

Door-to-Needle Time (min)

Adjusted Odds of DeathAdjusted Odds of Death

0 - 30 31 - 60 61 - 90 > 90

1.4

1.2

1.0

0.8

p = NS

p = 0.01

p = 0.0001

SGE; 0802-3, 3

Primary PCIPrimary PCIImportance of Door to Balloon TimeImportance of Door to Balloon Time

SGE; 1002-3, 1

25

15

5

0

20

10

25

15

5

0

30 Day Mortality (%)

>91N = 140

PTCA notperformed

N = 93

76 - 90N = 76

< 60N = 104

61 - 75N = 109

Time to PTCA (minutes)

30 Day Mortality (%)

>91N = 140

PTCA notperformed

N = 93

76 - 90N = 76

< 60N = 104

61 - 75N = 109

Time to PTCA (minutes)

20

10

p = 0.001

Berger for the GUSTO IIb Investigators, Circ 100:14, 1999Berger for the GUSTO IIb Investigators, Circ 100:14, 1999

Acute MIAcute MIPTCA vs LysisPTCA vs Lysis

SGE; 0802-3, 5

< 2 h< 2 h 2-4 h2-4 h > 4 h> 4 h

3.93.95.05.0 4.14.1

6.36.34.74.7

12.112.1

PP TT PP TT PP TT

30 Day Mortality30 Day Mortality

Timing of PresentationTiming of Presentation

Mortality/Time Mortality/Time InteractionInteraction

PCI: p=.90PCI: p=.90

Lytics: p=.0005Lytics: p=.0005

n=838(<2h), 1035 (2n=838(<2h), 1035 (2--4h), 612(<4h)4h), 612(<4h)↑↑ time time ∝∝ ↑↑ age, female gender, DM, age, female gender, DM, ↑↑HRHR

PCAT Collaborative GroupPCAT Collaborative Group

Facilitated PCI for AMIFacilitated PCI for AMIMight Time to Reperfusion be Less Important Might Time to Reperfusion be Less Important for PCI than for Fibrinolysis?for PCI than for Fibrinolysis?

NN 666666 11351135 ——SxSx→→ER (hr)ER (hr) 1.31.3 1.51.5 .55.55ER ER →→reperfusion (hr)reperfusion (hr) 3.03.0 2.12.1 <.001<.001Ant MI %Ant MI % 4040 3636 NSNSPeak CKPeak CK--MBMB 187187 164164 .003.00330 day mortality (%)30 day mortality (%) 7.67.6 8.18.1 NSNS∆∆ acute acute →→ 6 mo6 mo +2.7+2.7 +3.8+3.8 NSNS

LVEF*LVEF*

4 referral hosp4 referral hosp44--34 miles distance34 miles distance TransferredTransferred

NotNotTransferredTransferred PP

SGE; 0802-3, 6

**available in 45% of patientsavailable in 45% of patients Brodie, AJC '02Brodie, AJC '02

Importance of Time to TreatmentImportance of Time to Treatment

Facilitated PCIFacilitated PCI

SGE; 0903-5, 1

264 AMI patients in RCT264 AMI patients in RCTSalvation index by Sestamibi scanSalvation index by Sestamibi scanPrePre--Rx and at 7Rx and at 7--14 days14 days

SchSchöömigmig, Circulation 108:1084;2003, Circulation 108:1084;2003

0.60.6

0.40.4

0.20.2

0.00.0<< 116655 mmiinn

Salvage IndexSalvage Index

116655 -- 228800 mmiinn >> 228800 mmiinn

StentingThrombolysis

AMIAMIEffect of Time to PCI on 6 Month MortalityEffect of Time to PCI on 6 Month Mortality

AntoniucciAntoniucci, AJC 89:1248 , AJC 89:1248 ‘‘0202+ age < 70 yrs, non+ age < 70 yrs, non--ant MI, HR <100ant MI, HR <100

Low RiskLow Risk High RiskHigh Risk

< 2< 2 2-42-4 4-64-6 > 6> 600

55

1010

1515

2020PercentPercent

HoursHours

1.6 1.3 1.30.0

P=NS

< 2< 2 2-42-4 4-64-6 > 6> 600

55

1010

1515

2020PercentPercent

HoursHours

4.87.9

12.911.5

P=0.04

N=394N=394 N=942N=942

SGE; 0703-1, 01

PTCA vs. Lytics for AMIPTCA vs. Lytics for AMI

GrinesGrines, NEJM 1996, NEJM 1996

Impact of TIMI 3 Flow on MortalityImpact of TIMI 3 Flow on Mortality

GUSTO Study of Thrombolysis1. Occluded arteries (all patients)2. Patients given subcutaneous SK and heparin3. Patients given intravenous SK and heparin4. Patients given SK plus t-PA5. Patients given accel t-PA

GUSTO Study of Thrombolysis1. Occluded arteries (all patients)2. Patients given subcutaneous SK and heparin3. Patients given intravenous SK and heparin4. Patients given SK plus t-PA5. Patients given accel t-PA

Studies of Primary PTCA6. GUSTO IIb7. PAMI - 18. PAR9. PAMI - 2

Studies of Primary PTCA6. GUSTO IIb7. PAMI - 18. PAR9. PAMI - 2

Patients with TIMI Grade 3 Flow (%)

12

3

45

6

7

8

9

0 20 40 60 80 1000

2

4

6

8

10Death (%)

0

2

4

6

8

10

0 20 40 60 80 100Patients with TIMI Grade 3 Flow (%)

Death (%)

SGE; 0802-3, 8

Facilitated PCI for AMIFacilitated PCI for AMIImportance of TIMI 3 Flow Pre PCIImportance of TIMI 3 Flow Pre PCI

NN 19521952 375375 ——Age (yr)Age (yr) 60 60 ±± 1212 60 60 ±± 1313 NSNSSxSx→→Angio (min)Angio (min) 261 261 ±± 275275 264 264 ±± 200200 NSNSKillip 2Killip 2--3 (%)3 (%) 11.611.6 7.07.0 .009.009LAD infarct (%)LAD infarct (%) 3939 3939 NSNSBaseline EFBaseline EF 53 53 ±±1111 57 57 ±±1010 .003.003Final TIMI 3 (%)Final TIMI 3 (%) 91.491.4 98.198.1 <.001<.0016 mo mortality (%)6 mo mortality (%) 4.24.2 0.50.5 <.001<.001

PAMI TrialsPAMI Trials TIMI 0TIMI 0--22PrePre

TIMI 3TIMI 3PrePre PP

SGE; 0802-3, 9

Stone, Circ 104:636 '01Stone, Circ 104:636 '01

AMIAMIOn Site Lysis vs Transfer On Site Lysis vs Transfer →→ PCIPCI

Keeley, Lancet 361:13 Keeley, Lancet 361:13 ‘‘0303AIR PAMI, CAPTIM, DANAMIAIR PAMI, CAPTIM, DANAMI--2, PRAGUE2, PRAGUE--22

Frequency (%)Frequency (%)2020

1515

1010

55

00DeathDeath NonNon--fatalfatal

MIMITotalTotal

StrokeStrokeHaemorrhagicHaemorrhagic

StrokeStrokeDeath, NonDeath, Non--fatalfatal

ReinfarctionReinfarctionor Strokeor Stroke

PTCA (n=1466)Thrombolytic therapy (n=1443)

P=0.057 P<0.0001 P<0.049 P=0.25

P<0.0001

SGE; 0703-1, 02

Acute MIAcute MI

•• Speed reperfusion therapySpeed reperfusion therapy

•• Improve microvascular flowImprove microvascular flow

•• Explore novel methods to lessen Explore novel methods to lessen ““reperfusion injuryreperfusion injury”” and / or repopulate and / or repopulate lost myocardiumlost myocardium

Remaining Needs in 2004Remaining Needs in 2004

SGE; 0802-3, 19

Acute MIAcute MI

•• ~20% US patients live > 60 min from cath lab~20% US patients live > 60 min from cath lab

•• 20%20%--90% African, Asian, Canadian, European, 90% African, Asian, Canadian, European, Pacific region and South American patients live Pacific region and South American patients live >60 min from cath lab>60 min from cath lab

•• Not all cath labs offer 24/7 PCINot all cath labs offer 24/7 PCI

Therefore, need for early pharmacologic reperfusionTherefore, need for early pharmacologic reperfusion

Access to Reperfusion TherapyAccess to Reperfusion Therapy

SGE; 0802-3, 20

t-PAt-PA PIPI

3.03.0 2.62.6

t-PAt-PA PIPI

3.63.6 3.33.3

PACTPACTAMI RxAMI Rx

N=606N=606

Eligible acute infarct patientsEligible acute infarct patients

ASA, IV heparinASA, IV heparin

RandomizedRandomized

Immediate angiographyImmediate angiography

FollowFollow--up angiogram at 5up angiogram at 5--7 days7 days

rTrT--PAPA50mg bolus50mg bolus

TIMI 3TIMI 3

Second bolusSecond bolusof Study Drug of Study Drug

PlaceboPlacebobolusbolus

TIMI 0,1,2TIMI 0,1,2

Immediate Immediate AngioplastyAngioplasty

MortalityMortality ReRe--MIMI30 Day30 Day

p=.81 p=.80

Ross, JACC 34: 1954 Ross, JACC 34: 1954 ‘‘9999

Follow up LVEFTIMI 3 Flow 62±11%*

Pre/Post PCITIMI 3 Flow 58±13%

Post PCI onlyNo TIMI 3 Flow 54±14%

Follow up LVEFFollow up LVEFTIMI 3 FlowTIMI 3 Flow 6262±±11%*11%*

Pre/Post PCIPre/Post PCITIMI 3 FlowTIMI 3 Flow 5858±±13%13%

Post PCI onlyPost PCI onlyNo TIMI 3 FlowNo TIMI 3 Flow 5454±±14%14%

**p=0.004 vs p=0.004 vs TIMI 3 post onlyTIMI 3 post only SGE; 0802-3, 21

Acute MIAcute MIPlatelet Activation by FibrinolyticsPlatelet Activation by Fibrinolytics

Rudd and Rudd and LoscalzoLoscalzo, , CircResCircRes ‘‘9090Rabbit model, .05mM ADP as agonistRabbit model, .05mM ADP as agonist

Normalized Maximal Aggregation RateNormalized Maximal Aggregation Rate

Time (min)Time (min)00 5050 100100 150150 200200 250250

1.51.5

1.01.0

0.50.5

t-PASK

SGE; 0802-3, 22

30 min30 min 60 min60 min 90 min 90 min 120 min120 min 240 min240 min

PercentPercent

34 3748

5764

73 73 8087 89

LyticsCombo

Fascilitated Fascilitated PCIPCITiming of ST Resolution >50%Timing of ST Resolution >50%

KrucoffKrucoff, ACC , ACC ‘‘0303

TimeTime

P=.34

P=.03

P=.02P=.06

P=.30

SGE; 0403SGE; 0403--6, 16, 1IMPACTIMPACT--AMI, PARADIGM, GUSTO V, INTEGRITI (n=654)AMI, PARADIGM, GUSTO V, INTEGRITI (n=654)

Facilitated PCI for AMIFacilitated PCI for AMIADMIRAL / Effect of Time of Administration ADMIRAL / Effect of Time of Administration of Abciximab on 24 hr LVEFof Abciximab on 24 hr LVEF

Mobile ICU or ERMobile ICU or ER CCU or Cath LabCCU or Cath Lab OverallOverall00

2525

5050

7575

100100PercentPercent

5347

55 53 54 51

AbciximabPlacebo

P=.05 P=.23 P=.05

SGE; 0802-3, 23

Acute MIAcute MIGUSTO VGUSTO V

* * including ICH in > 75yrs 2.1 v 1.1% p=0.07including ICH in > 75yrs 2.1 v 1.1% p=0.07 Lancet 357: 1905 Lancet 357: 1905 ‘‘0101

•• 16,588 pts ST16,588 pts ST↑↑MIMI

•• RPA vs halfRPA vs half--dosedoseRPA + abciximabRPA + abciximab

•• Heparin to aPTT Heparin to aPTT 5050--70sec70sec

RPA: RPA: 5000+1000u/hr5000+1000u/hrRPA+Abc: RPA+Abc: 60u/kg+7u/kg/hr60u/kg+7u/kg/hr

•• 30 day outcomes30 day outcomes DeathDeath ReMIReMI Major BleedingMajor Bleeding00

22

44

66

88

1010PercentPercent

5.9 5.6

3.52.3

0.51.1

RPARPA+Abc

P=0.45

P<0.001

P<0.001*

SGE; 0802-3, 14

AMI Treatment LessonsAMI Treatment LessonsFINESSEFINESSE

Early RxEarly Rx TIMI 3TIMI 3 MicrovascMicrovascIC StreptokinaseIC Streptokinase –– +/ +/ –– ––IV StreptokinaseIV Streptokinase ++ +/ +/ –– ––IV tIV t--PA PA →→ 3rd gen. lytics3rd gen. lytics ++ ++ ––Primary PTCAPrimary PTCA –– ++++ ––Primary StentPrimary Stent –– ++++ ––Lytics, Lytics, llbllb//llla llla + 1+ 1°°stents stents ++++ ++++ +/+/--Lytics, Lytics, llbllb//lllallla + 1+ 1°° stents + EPD/RI blockersstents + EPD/RI blockers ++++ ++++ ?+?+

Historical ProgressionHistorical Progression

SGE; 0802-3, 24

Early RxEarly Rx

MicrovascularMicrovascularFlowFlow

TIMI 3 FlowTIMI 3 Flow

PlateletsPlateletsWBC/Reperfusion InjuryWBC/Reperfusion InjuryDebrisDebris

EPD=Emboli Protection Device EPD=Emboli Protection Device RI=Reperfusion InjuryRI=Reperfusion Injury

Cath lab availableCath lab available< 60 minutes< 60 minutes

abciximab + PCI abciximab + PCI

Cath lab delayCath lab delay> 4 hours or not available> 4 hours or not available

ReteplaseReteplase

AMIpresentation

Cath lab availabilityCath lab availabilityuncertain or delay ofuncertain or delay of> 60 min, < 4 hours> 60 min, < 4 hours

Options for Treating AMI PatientsOptions for Treating AMI Patients

Triage

SGE; 0802-3, 29

Facilitated PCI for AMIFacilitated PCI for AMI

MI < 6 hrs and cath likely in 1MI < 6 hrs and cath likely in 1--4 hrs4 hrsExclude low risk (age <60 yrs and localized IMI)Exclude low risk (age <60 yrs and localized IMI)

FINESSE Protocol DesignFINESSE Protocol Design

Heparin 40Heparin 40µµ/kg (70/kg (70µµ/kg in placebo group)/kg in placebo group)or Enoxaparin 30 mg IV + 0.3 mg/kg SCor Enoxaparin 30 mg IV + 0.3 mg/kg SC

90 day Death, Stroke90 day Death, StrokeRehospitalization Rehospitalization for CHF, Late VFfor CHF, Late VF

Cath Cath ±± PCIPCICath Cath ±± PCIPCI Cath Cath ±± PCIPCI(with Abciximab)(with Abciximab)

AbciximabAbciximabASAPASAP

PlaceboPlaceboASAPASAP

RPA (5 + 5U)*RPA (5 + 5U)*AbciximabAbciximabASAPASAP

N = 3000N = 3000*5U only for age >75 yrs*5U only for age >75 yrs

SGE; 0802-3, 25

Fascilitated Fascilitated PCIPCIBRAVE TrialBRAVE Trial Outcomes Combination Abciximb P

only

TIMI 3 flow pre PCI (%) 40 18 <.001

Final infarct size (%) 13 11.5 0.81

Death at 30 days (%) 1.6 1.6 NS

Death/MI at 30 days 2.4 1.6 NS

30 day death, MI, 3.2 1.6 0.66

stroke (%)

Major bleeding (%) 5.6 1.6 0.16

N=253 pts. withSTEMI < 12 hrs.

Randomized to• Abciximab X 12 hrs. or• RPA 5U X 2+ abciximab

1o endpoint: infarct size

Kastrati, AHA ‘03

Facilitated PCI for AMIFacilitated PCI for AMI

•• Inadequate dataInadequate data

•• Consider for large MI and transfer delayConsider for large MI and transfer delay

•• Use 1/2 dose lytics (possibly 1/4 dose lytics for Use 1/2 dose lytics (possibly 1/4 dose lytics for elderly or higher risk for hemorrhagic CVA); elderly or higher risk for hemorrhagic CVA); use low dose UFH/LMWHuse low dose UFH/LMWH

Current Status (5/04)Current Status (5/04)

SGE; 0802-3, 27