Treatment of ST Elevation MI Treatment of ST Elevation MI in the ED: Fibrinolytics, in the ED: Fibrinolytics,

Antiplatelets and Antiplatelets and AntithrombinsAntithrombins

James Hoekstra, MDProfessor and Chair

Department of Emergency MedicineWake Forest University

Treatment of ST Elevation MI Treatment of ST Elevation MI in the ED: Fibrinolytics, in the ED: Fibrinolytics,

Antiplatelets and Antiplatelets and AntithrombinsAntithrombins

James Hoekstra, MDProfessor and Chair

Department of Emergency MedicineWake Forest University

Atherothrombosis: Thrombus Superimposed on Atherosclerotic Plaque

Adapted with permission from Falk E, et al. Circulation. 1995 ;92:657-671.Adapted with permission from Falk E, et al. Circulation. 1995 ;92:657-671.

Slide reproduced with permission from Cannon CP: Atherothrombosis slide compendium; www.theheart.orgSlide reproduced with permission from Cannon CP: Atherothrombosis slide compendium; www.theheart.org

Annual Admissions for Acute Coronary Syndrome (ACS)

Annual Admissions for Acute Coronary Syndrome (ACS)

1.4 MillionNon-ST-segment

elevation ACS

600,000ST-segment elevation

MI

~ 2.0 MM patients admittedto CCU or telemetry annually

Class I ED Treatment of STEMI:AHA/ACC Guidelines

(ST Elevation, BBB, Pain<12 Hours)

Class I ED Treatment of STEMI:AHA/ACC Guidelines

(ST Elevation, BBB, Pain<12 Hours)

Targeted ED Protocol and Collaboration

O2, IV, monitor

ASA immediately (162-325 mg)

Nitrates, beta blockers (IV)

Heparin weight based dosing (60 IVP and 12/k/h, max 4000/1000)

Fibrinolytics in less than 30 minutes (esp if CP<3 hours)

PCI less than 90 minutes if available

Treatment of Complications

Targeted ED Protocol and Collaboration

O2, IV, monitor

ASA immediately (162-325 mg)

Nitrates, beta blockers (IV)

Heparin weight based dosing (60 IVP and 12/k/h, max 4000/1000)

Fibrinolytics in less than 30 minutes (esp if CP<3 hours)

PCI less than 90 minutes if available

Treatment of Complications

Rapid time to treatment with fibrinolytics improves outcomes in ST MI

Absolute %difference

in mortalityat 35 days

0-1 2-3 4-6 7-12 12-24

The Fibrinolytics Therapy Trialists’ collaborative group. Lancet. 1994; 343: 311-322

Time from onset of symptoms to treatment (hours)

3.5%

2.5%

1.8% 1.6%

0.5%

STEMI Treatment in the ED: The Options

STEMI Treatment in the ED: The Options

STEMI: ST segment elevation MI, new LBBB, pain less than 12 hours, eligible for fibrinolytics Treatment with Fibrinolytic Therapy and UFH Treatment with Fibrinolytic Therapy with

LMWH Addition of Clopidogrel to Fibrinolytics Treatment with Primary PCI Treatment with Facilitated PCI with IIb/IIIa or

half dose fibrinolytic

STEMI: ST segment elevation MI, new LBBB, pain less than 12 hours, eligible for fibrinolytics Treatment with Fibrinolytic Therapy and UFH Treatment with Fibrinolytic Therapy with

LMWH Addition of Clopidogrel to Fibrinolytics Treatment with Primary PCI Treatment with Facilitated PCI with IIb/IIIa or

half dose fibrinolytic

STEMI Treatment with Fibrinolytic Therapy

STEMI Treatment with Fibrinolytic Therapy

Reperfusion GuidelinesReperfusion Guidelines

STEMI patients presenting to a facility without PCI capability should undergo fibrinolysis unless contraindicated (class I)

STEMI patients presenting to a facility without PCI capability should undergo fibrinolysis unless contraindicated (class I)

Fibrinolytic Therapy InclusionsFibrinolytic Therapy Inclusions

Symptoms >30 minutes<12 hours

ECG ST elevation >2mm in 2 contiguous precordial leads or >1mm in 2 contiguous limb leads, or ST depression >2mm in precordial leads with reciprocal ST elevation in II, AVF, V6

New BBB

Patient Consent

Symptoms >30 minutes<12 hours

ECG ST elevation >2mm in 2 contiguous precordial leads or >1mm in 2 contiguous limb leads, or ST depression >2mm in precordial leads with reciprocal ST elevation in II, AVF, V6

New BBB

Patient Consent

Thrombolytic Therapy ExclusionsThrombolytic Therapy Exclusions

Prior ICH

Active Bleeding

Altered Mental Status

Major CNS Surgery <6 weeks PTA

CVA <3 mo PTA

Bleeding Diathesis

CHI < 3 mo PTA

Prior ICH

Active Bleeding

Altered Mental Status

Major CNS Surgery <6 weeks PTA

CVA <3 mo PTA

Bleeding Diathesis

CHI < 3 mo PTA

CNS AVM, Aneurysm, Tumor

AAA/Dissection

CNS AVM, Aneurysm, Tumor

AAA/Dissection

Thrombolytic Therapy Relative Contraindications

Thrombolytic Therapy Relative Contraindications

SBP >180, DBP >110

Recent CPR

Recent Surgery or Trauma <3 wks

Ischemic CVA >3 mo

Recent Int Bleeding

Coumadin Use

Chronic Severe HTN

Noncompressible Vascular Punctures

SBP >180, DBP >110

Recent CPR

Recent Surgery or Trauma <3 wks

Ischemic CVA >3 mo

Recent Int Bleeding

Coumadin Use

Chronic Severe HTN

Noncompressible Vascular Punctures

Cardiogenic Shock

Peptic Ulcer Disease

Pregnancy

Cardiogenic Shock

Peptic Ulcer Disease

Pregnancy

Reperfusion guidelinesReperfusion guidelines

Mortality reduction is greatest when thrombolysis is performed within the first 60 minutes of symptoms

If symptoms have persisted beyond 12 hours, PCI is suggested

Guideline recommendations are not made regarding the selection of fibrinolytic agents

Mortality reduction is greatest when thrombolysis is performed within the first 60 minutes of symptoms

If symptoms have persisted beyond 12 hours, PCI is suggested

Guideline recommendations are not made regarding the selection of fibrinolytic agents

Deficiencies of Current Thrombolytic Regimens for STEMI

Deficiencies of Current Thrombolytic Regimens for STEMI

Suboptimal macroperfusion ± 60% TIMI grade 3 flow at 90 min

Inadequate microperfusion Impaired tissue flow in > 50% of pts with

TIMI grade 3 flow High rates of reocclusion

Inhospital reinfarction ± 4% High rates of ICH

0.5 – 1.0% Angiographically proven reocclusion ± 25%

at 3 months

Suboptimal macroperfusion ± 60% TIMI grade 3 flow at 90 min

Inadequate microperfusion Impaired tissue flow in > 50% of pts with

TIMI grade 3 flow High rates of reocclusion

Inhospital reinfarction ± 4% High rates of ICH

0.5 – 1.0% Angiographically proven reocclusion ± 25%

at 3 months

STEMI Treatment with LMWH and Fibrinolytic Therapy

STEMI Treatment with LMWH and Fibrinolytic Therapy

Trials of Enoxaparin plus Fibrinolytics in STEMI

Trials of Enoxaparin plus Fibrinolytics in STEMI

Hart 2: LMWH plus TPA

AMI-SK: LMWH plus SK (NOT)

ENTIRE: LMWH, Reopro, TNK-TPA

ASSENT III: LMWH, Reopro, TNK-TPA

EXTRACT TIMI 25

Hart 2: LMWH plus TPA

AMI-SK: LMWH plus SK (NOT)

ENTIRE: LMWH, Reopro, TNK-TPA

ASSENT III: LMWH, Reopro, TNK-TPA

EXTRACT TIMI 25

ASSENT 3 Randomization ASSENT 3 Randomization

EnoxaparinI.V. bolus

EnoxaparinI.V. bolus

ENOXAPARIN

UFH I.V. bolusUFH I.V. bolus

ABCIXIMAB

TNK-tPA full doseI.V. bolus

TNK-tPA full doseI.V. bolus

AbciximabI.V. bolus

AbciximabI.V. bolus

TNK-tPA half doseI.V. bolus

TNK-tPA half doseI.V. bolus

EnoxaparinS.C.injections every

12 hours up to discharge or

revascularization (max of 7 days)

EnoxaparinS.C.injections every

12 hours up to discharge or

revascularization (max of 7 days)

AbciximabI.V. infusion for 12

hrs

AbciximabI.V. infusion for 12

hrs

UFH I.V. Infusion for up to 48 hrs

UFH I.V. Infusion for up to 48 hrs

RANDOMIZATION 1:1:1

RANDOMIZATION 1:1:1

UFH I.V. bolusUFH I.V. bolus

UFH

TNK-tPA full doseI.V. bolus

TNK-tPA full doseI.V. bolus

UFH I.V. infusionfor up to 48 hrs

UFH I.V. infusionfor up to 48 hrs

n=6000n=6000

ASSENT-3 Primary Efficacy Endpoint: Significant Improvement in TNK + Enox and TNK + Abx vs TNK +

UFH

ASSENT-3 Primary Efficacy Endpoint: Significant Improvement in TNK + Enox and TNK + Abx vs TNK +

UFH

11.4 11.1

15.4

0

5

10

15

20

TNK + EnoxTNK + Enox 1/2 TNK + Abx1/2 TNK + Abx

Per

cent

(%

)P

erce

nt (

%)

3 way 3 way P=0.0001=0.00013 way 3 way P=0.0001=0.0001

P=0.0002*P=0.0002*P=0.0009*P=0.0009*

*P values are the Bonferroni P-values after correcting for multiple comparisons. *P values are the Bonferroni P-values after correcting for multiple comparisons.

TNK + UFHTNK + UFHTNK + UFHTNK + UFH

Primary Efficacy Endpoint: Composite of 30-day mortality, recurrent MI, refractory ischemia.

ASSENT 3: Individual EndpointsASSENT 3: Individual Endpoints

Endpoint Enoxaparin Abciximab Unfractionated heparin

p value

30-day death 5.4% 6.6% 6.0% 0.25

In-hospital re-infarction

2.7% 2.2% 4.2% 0.0009

In-hospital refractory ischemia

4.5% 3.2% 6.5% <0.0001

In-hospital ICH 0.9% 0.9% 0.9% 0.98

Other major bleeding

3.0% 4.3% 2.2% 0.0005

ASSENT 3

The ASSENT 3 Investigators. Lancet 2001; 358: 605-13

LMWH versus UFHLMWH versus UFH ASSENT-3 PLUS

Prehospital study of tenecteplase + (LMWH versus UFH)LMWH group demonstrated

increased rates of major bleeding (4% vs 2.8%, p = 0.18)

LMWH group demonstrated increased intracranial bleeding (2.2% vs 1.0%, P = 0.05)

Thus, because of concerns of increased bleeding and not clear mortality benefit, LMWH receives a IIb recommendation.

ASSENT-3 PLUS Prehospital study of tenecteplase +

(LMWH versus UFH)LMWH group demonstrated

increased rates of major bleeding (4% vs 2.8%, p = 0.18)

LMWH group demonstrated increased intracranial bleeding (2.2% vs 1.0%, P = 0.05)

Thus, because of concerns of increased bleeding and not clear mortality benefit, LMWH receives a IIb recommendation.

LMWH Management: ACC/AHA GuidelinesLMWH Management: ACC/AHA Guidelines Anticoagulation Low molecular weight heparin

(LMWH)may be used as an

alternative to heparin (Class IIb) if:

–Age < 75–No renal dysfunction

“Enoxaparin (30 mg IV bolus followed by 1.0 mg/kg sq) used in combination with full-dose tenecteplase is the most comprehensively studied regimen in patients less than 75 years of age.”

Anticoagulation Low molecular weight heparin

(LMWH)may be used as an

alternative to heparin (Class IIb) if:

–Age < 75–No renal dysfunction

“Enoxaparin (30 mg IV bolus followed by 1.0 mg/kg sq) used in combination with full-dose tenecteplase is the most comprehensively studied regimen in patients less than 75 years of age.”

STEMI < 6 hSTEMI < 6 hLytic eligibleLytic eligible

Lytic choice by MDLytic choice by MD(TNK, tPA, rPA, SK)(TNK, tPA, rPA, SK)

ENOXENOX

< 75 y: 30 mg IV bolus < 75 y: 30 mg IV bolus SC 1.0 mg / kg q 12 h (Hosp DC)SC 1.0 mg / kg q 12 h (Hosp DC)

≥≥ 75 y: No bolus75 y: No bolus

SC 0.75 mg / kg q 12 h (Hosp DCSC 0.75 mg / kg q 12 h (Hosp DC))

CrCl CrCl << 30: 1.0 mg / kg q 24 30: 1.0 mg / kg q 24 hh

Double-blind, double-dummyDouble-blind, double-dummy

ASAASA

Day 30Day 3011°° Efficacy Endpoint: Death or Nonfatal MI Efficacy Endpoint: Death or Nonfatal MI1° Safety Endpoint: TIMI Major Hemorrhage1° Safety Endpoint: TIMI Major Hemorrhage

EXTRACT Protocol DesignEXTRACT Protocol Design

UFHUFH60 U / kg bolus (4000 U) 60 U / kg bolus (4000 U)

Inf 12 U / kg / h (1000 U / h)Inf 12 U / kg / h (1000 U / h)Duration: at least 48 hDuration: at least 48 hCont’d at MD discretionCont’d at MD discretion

N=20,478N=20,478

EXTRACT Primary End Point Death or Nonfatal MI

EXTRACT Primary End Point Death or Nonfatal MI

0

3

6

9

12

15

0 5 10 15 20 25 30

Pri

ma

ry E

nd

Po

int

(%)

Pri

ma

ry E

nd

Po

int

(%)

ENOX

UFH

Relative RiskRelative Risk0.83 (0.77 to 0.90)0.83 (0.77 to 0.90)

P<0.0001P<0.0001

Days Days

9.9%

12.0%

Lost to follow up = 3 Lost to follow up = 3

17% RRR

EXTRACT Outcomes at 30 DaysEXTRACT Outcomes at 30 Days

7.5

4.5

2.8

6.9

3

2.1

0

1

2

3

4

5

6

7

8

Death Nonfatal MI Urg Revasc

8%8%

33%33%26%26%

P= 0.11 <0.0001 0.0008P= 0.11 <0.0001 0.0008

%%

EXTRACT Outcomes by PCI versus MedicalPrimary Outcome: Death/MI

EXTRACT Outcomes by PCI versus MedicalPrimary Outcome: Death/MI

0

5

10

15

PCI Medical Rx

ENOX

UFH

0

5

10

15

PCI Medical Rx

ENOX

UFH

%% 10.710.7

13.813.8

9.79.7

11.411.4

P= 0.001 0.0004P= 0.001 0.0004

Death or Nonfatal MI - Day 30 Major Subgroups

Death or Nonfatal MI - Day 30 Major Subgroups

B

B

B

> Median

< Median

Fibrin-specific

Streptokinase

Prior MI

No Prior MI

DM

No DM

Other

Anterior

0.5 1 2

PRIOR MI

OVERALLOVERALL

DIABETES

FIBRINOLYTIC

INFARCT

LOCATION

ENOX Better UFH BetterRelative Risk

TIME TO Rx

20,479

1123

1721

1720

1318

2312

17

Reduction In Risk (%)

>= 75

< 75AGE (y)

206

Female

MaleSEX 1816

All Interaction TestsAll Interaction TestsP = NSP = NS

P < 0.0001

10,256 Assigned ENOX10,256 Assigned ENOX

20,479 Patients Randomized into 20,479 Patients Randomized into ExTRACT-TIMI 25ExTRACT-TIMI 25

2,272 Underwent2,272 Underwent

PCI by 30 daysPCI by 30 days

22.8%22.8%

10,223 Assigned UFH10,223 Assigned UFH

2,404 Underwent2,404 Underwent

PCI by 30 daysPCI by 30 days

24.2%24.2%

EXTRACT PCI Study Profile

PCI Cohort: Primary EndpointDeath or Nonfatal MI by 30 days

PCI Cohort: Primary EndpointDeath or Nonfatal MI by 30 days

ENOX

DaysDays

13.8%

0055

1010

1515

00 55 1010 1515 2020 2525 3030

De

ath

or

MI (

%)

De

ath

or

MI (

%)

UFH

10.7%

RR 0.77RR 0.77p=0.001p=0.001

EXTRACT PCI Cohort: SafetyEXTRACT PCI Cohort: Safety

Event ENOX UFH RR P-Value n=2,238 n=2,377

TIMI Major Bleed 1.4% 1.6% 0.87 (0.55-1.39) 0.56

TIMI Minor Bleed 3.3% 2.4% 1.34 (0.95-1.88) 0.09

TIMI Major or 4.6% 4.0% 1.15 (0.88-1.51) 0.31 Minor Bleed

ICH 0.2% 0.4% 0.42 (0.13-1.35) 0.18

Stroke 0.3% 0.9% 0.30 (0.12-0.75) 0.006

Outcomes by 30 Days in Patients Undergoing PCI on Blinded Study Drug

Outcomes by 30 Days in Patients Undergoing PCI on Blinded Study Drug

16.7

2.4

13.0

1.8

0

5

10

15

20 UFH UFH (n=1,075)(n=1,075)

ENOX ENOX (n=1,103)(n=1,103)

%

% E

ven

tsE

ven

ts

Death or Nonfatal reMIDeath or Nonfatal reMI Major BleedMajor Bleed

RR 0.77RR 0.77P=0.002P=0.002

RR 0.75RR 0.75P=0.33P=0.33

Use of LMWH with Thrombolytics in STEMI: Non Cath Lab Centers

Use of LMWH with Thrombolytics in STEMI: Non Cath Lab Centers

ASA, NTG, Beta Blockers

Enoxaparin 30 mg IVP, 1 mg/kg sub q q12 hours (reduced in elderly)

TNK Weight Based Dosing (50 mg max) or Retavase 10 + 10

Treat Complications

Transfer to cath lab center if no resolution of ST changes or pain in 90 minutes (RESCUE PCI)

Avoid in patients >75 years old, CRF

ASA, NTG, Beta Blockers

Enoxaparin 30 mg IVP, 1 mg/kg sub q q12 hours (reduced in elderly)

TNK Weight Based Dosing (50 mg max) or Retavase 10 + 10

Treat Complications

Transfer to cath lab center if no resolution of ST changes or pain in 90 minutes (RESCUE PCI)

Avoid in patients >75 years old, CRF

ConclusionsConclusions Fibrinolytic Therapy remains a Class

IA recommendation in non-cath lab centers

Enoxaparin demonstrates advantages over UFH in conjunction with fibrinolysis, based on ASSENT 3

Enoxaparin should probably be avoided in CRF, elderly

EXTRACT TIMI 25 should answer many questions regarding enoxaparin in STEMI

Fibrinolytic Therapy remains a Class IA recommendation in non-cath lab centers

Enoxaparin demonstrates advantages over UFH in conjunction with fibrinolysis, based on ASSENT 3

Enoxaparin should probably be avoided in CRF, elderly

EXTRACT TIMI 25 should answer many questions regarding enoxaparin in STEMI

Utilization of Clopidogrel in STEMI

Utilization of Clopidogrel in STEMI

CURE: MI/Stroke/CV Death/Severe

Ischemia Within 24 h of Randomization

CURE: MI/Stroke/CV Death/Severe

Ischemia Within 24 h of Randomization

CURE, Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events; MI, myocardial infarction; CURE, Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events; MI, myocardial infarction; CV, cardiovascular; RRR, relative risk reduction; RR, relative risk.CV, cardiovascular; RRR, relative risk reduction; RR, relative risk.Adapted from Adapted from Yusuf S, et al. Yusuf S, et al. Circulation.Circulation. 2003;107:966-972. 2003;107:966-972.

Hours After RandomizationHours After Randomization

Cu

mu

lati

ve H

azar

d R

ates

Cu

mu

lati

ve H

azar

d R

ates

0.00.0

0.0050.005

0.0100.010

0.0150.015

0.0200.020

0.0250.025

00 22 44 66 88 1010 1212 1414 1616 1818 2020 2222 2424

RR = 0.67RR = 0.67P P = 0.003= 0.003

PlaceboPlacebo+ ASA+ ASA

ClopidogrelClopidogrel+ ASA+ ASA

33%33%RRRRRR

CLARITY TIMI 28 Study DesignCLARITY TIMI 28 Study Design

Fibrinolytic, ASA, HeparinFibrinolytic, ASA, Heparin

Clopidogrel300 mg + 75 mg qd

Coronary Angiogram(2-8 days)

Primary endpoint:Occludedartery (TIMI Flow Grade 0/1)or D/MI by timeof angio

Primary endpoint:Occludedartery (TIMI Flow Grade 0/1)or D/MI by timeof angio

randomize

Placebo

Double-blind, randomized, placebo-controlled trial in3491 patients, age 18-75 yrs with STEMI < 12 hours

Double-blind, randomized, placebo-controlled trial in3491 patients, age 18-75 yrs with STEMI < 12 hours

StudyDrug

StudyDrug

30-day clinical follow-up30-day clinical follow-up

Open-labelclopidogrelper MD in

both groups

Open-labelclopidogrelper MD in

both groups

Primary Endpoint:Occluded Artery (or D/MI thru Angio/HD)

Primary Endpoint:Occluded Artery (or D/MI thru Angio/HD)

15.0

21.7

0

5

10

15

20

25

Occ

lud

ed A

rter

y o

r D

eath

/MI

(%

)

PlaceboPlaceboClopidogrelClopidogrel

P=0.00000036P=0.00000036P=0.00000036P=0.00000036

Odds Ratio 0.64Odds Ratio 0.64(95% CI 0.53-0.76)(95% CI 0.53-0.76)

Odds Ratio 0.64Odds Ratio 0.64(95% CI 0.53-0.76)(95% CI 0.53-0.76)

1.00.4 0.6 0.8 1.2 1.6

ClopidogrelClopidogrelbetterbetter

PlaceboPlacebobetterbetter

n=1752 n=1739

36%Odds Reduction

36%Odds Reduction

CV Death, MI, RI Urg RevascCV Death, MI, RI Urg Revasc

days

Per

cen

tag

e w

ith

en

dp

oin

t (%

)P

erce

nta

ge

wit

h e

nd

po

int

(%)

05

1015

0 5 10 15 20 25 30

PlaceboPlacebo

ClopidogrelClopidogrel

Odds Ratio 0.80Odds Ratio 0.80(95% CI 0.65-0.97)(95% CI 0.65-0.97)

P=0.026P=0.026

20%20%20%20%

BleedingBleeding

Outcome Clopidogrel (%)

Placebo (%)

P value

Through angiography

TIMI major (Hgb >5 g/dL or ICH) 1.3 1.1 NS

TIMI minor (Hgb 3-5 g/dL) 1.0 0.5 NS

Intracranial hemorrhage 0.5 0.7 NS

Through 30 days

TIMI major 1.9 1.7 NS

In those undergoing CABG 7.5 7.2 NS

CABG w/in 5 d of study med 9.1 7.9 NS

TIMI minor 1.6 0.9 NS

CV Death, MI, or Strokefollowing PCI

CV Death, MI, or Strokefollowing PCI

02

46

8

0 10 20 30Days post PCI

Per

cen

tag

e w

ith

ou

tco

me

(%) No PretreatmentNo Pretreatment

Clopidogrel Clopidogrel PretreatmentPretreatment

46%46%46%46%

Odds Ratio 0.54Odds Ratio 0.54(95% CI 0.35-0.85)(95% CI 0.35-0.85)

P=0.008P=0.008

Odds Ratio 0.54Odds Ratio 0.54(95% CI 0.35-0.85)(95% CI 0.35-0.85)

P=0.008P=0.008

Conclusions: Clopidogrel in STEMIConclusions: Clopidogrel in STEMI

Addition of Clopidogrel to ED treatment of STEMI with fibrinolytics is useful and effective

In patients going to PCI, early treatment with clopidogrel is effective as well.

Addition of Clopidogrel to ED treatment of STEMI with fibrinolytics is useful and effective

In patients going to PCI, early treatment with clopidogrel is effective as well.

Reperfusion Guidelines:Fibrinolytics Versus PCIReperfusion Guidelines:Fibrinolytics Versus PCI

Reperfusion guidelinesReperfusion guidelines Comparing PCI to fibrinolysis*:

PCI demonstrates lower mortality PCI demonstrates lower reinfarction

rate PCI has a lower hemorrhagic stroke

rate

However, this is only likely to be significant if PCI can be performed within 90 minutes in a high volume center If there is greater than a 60 minute

delay, fibrinolysis is likely superior**

Comparing PCI to fibrinolysis*: PCI demonstrates lower mortality PCI demonstrates lower reinfarction

rate PCI has a lower hemorrhagic stroke

rate

However, this is only likely to be significant if PCI can be performed within 90 minutes in a high volume center If there is greater than a 60 minute

delay, fibrinolysis is likely superior***Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials. The Lancet. 2003;361:13-20.

**Nallamothu BK, Bates ER. Percutaneous coronary intervention versus fibrinolytic therapy in acute myocardial infarction: is timing (almost) everything? Am J Cardiol. 2003;92:824-6.

Symptoms – balloon inflation (min)

On

e-ye

ar m

ort

alit

y (%

)

6 RCTs of 1° PCI by Zwolle Group 1994 – 2001N = 1,791

RR = 1.08 [1.01 – 1.16] for each 30 min delay(P = 0.04)

P < 0.000112

10

8

6

4

2

00 60 120 180 240 300 360

Time-delay to Treatment and MortalityTime-delay to Treatment and Mortality in 1 in 1°° Angioplasty for Acute MI: Angioplasty for Acute MI:

Every Minute Delay CountsEvery Minute Delay Counts

DeLuca G, et al. DeLuca G, et al. CirculationCirculation. 2004;109:1223.. 2004;109:1223.

PCI-related Time Delay (Door-to-balloon − Door to-needle)PCI-related Time Delay (Door-to-balloon − Door to-needle)

CircleCircle sizessizes = = sample size of the sample size of the individual study individual study

Solid lineSolid line = = weighted meta-regressionweighted meta-regression

Favors PCIFavors PCI

Favors LysisFavors Lysis

Benefits of PCI are LOST if PCI COSTS TOO MUCH TIME vs. Benefits of PCI are LOST if PCI COSTS TOO MUCH TIME vs. lytic therapylytic therapy

PP = 0.006 = 0.006

62 min62 min

Ab

solu

te R

isk

Dif

fere

nce

in

Dea

th (

%)

Ab

solu

te R

isk

Dif

fere

nce

in

Dea

th (

%)

1515

1010

55

00

-5-500 2020 4040 6060 8080 100100

PCI vs. Lysis: Is Timing (Almost) Everything ?PCI vs. Lysis: Is Timing (Almost) Everything ?

Nallamothu BK, Bates ER. Nallamothu BK, Bates ER. Am J CardiolAm J Cardiol. 2003:92:824.. 2003:92:824.

Actual time of inter-hospital transfer in the USActual time of inter-hospital transfer in the US

NRMI-4 data from 2002: Door to balloon time for STEMI

patients in the US, when transferred from a non-PCI center to a PCI center:

185 minutes Only 3% of patients received PCI in

less than 90 minutes!

NRMI-4 data from 2002: Door to balloon time for STEMI

patients in the US, when transferred from a non-PCI center to a PCI center:

185 minutes Only 3% of patients received PCI in

less than 90 minutes!Antman EM, Anbe DT, Armstrong PW et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction; A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines for the Management of patients with acute myocardial infarction). J Am Coll Cardiol. 2004;44:E1-E211.

Reperfusion guidelinesReperfusion guidelines

STEMI patients who have contraindications to fibrinolysis presenting within 12 hours of onset should undergo primary PCI (class I)

Class III (harmful) recommendations ST depression (unless posterior MI

suspected) Symptoms began > 24h prior

STEMI patients who have contraindications to fibrinolysis presenting within 12 hours of onset should undergo primary PCI (class I)

Class III (harmful) recommendations ST depression (unless posterior MI

suspected) Symptoms began > 24h prior

Reperfusion guidelinesReperfusion guidelines

Thrombolysis failure Rescue PCI is recommended for patients

experiencing cardiogenic shock after failed fibrinolysis

< 75 yo (class I)> 75 yo (class IIa)

Rescue PCI is recommended for patients experiencing hemodynamic or electrical instability, or continued ischemic symptoms after fibrinolysis (class IIa)

Rationale for Early Transfer to PCI capable hospital

Thrombolysis failure Rescue PCI is recommended for patients

experiencing cardiogenic shock after failed fibrinolysis

< 75 yo (class I)> 75 yo (class IIa)

Rescue PCI is recommended for patients experiencing hemodynamic or electrical instability, or continued ischemic symptoms after fibrinolysis (class IIa)

Rationale for Early Transfer to PCI capable hospital

Facilitated PCI Facilitated PCI Can the use of early antiplatelet and

antithrombin agents make PCI easier? Can the use of early antiplatelet and

antithrombin agents make PCI easier?

8%8%

23%23%

18%18%

32%32%

Gold et al 10 minCirculation. 1997; 95: 1755-1959.

GRAPE 45 minJACC. 1999; 33:1528-1532.

SPEED 60 minEHJ. 1999; 20:616 (3336).

TIMI-14 90 minCirculation. 1999; 99:2720-2732.

Fribrinolytic Effect of Abciximab Fribrinolytic Effect of Abciximab

TIMI Grade 3 Flow25% 50%

Study Time0

Experience Over Several Clinical TrialsExperience Over Several Clinical Trials

Cutlip, et al: ED Administration of Eptifibatide Prior to Primary PTCA in the Treatment of STEMI Am J Cardiol 2001;88:62-64

0

10

20

30

40

50

60

TIMI 2 TIMI 3 TIMI 2/3

PlaceboIntegrilin

56.7%

13.3%

Primary PCIPrimary PCIPrimary PCIPrimary PCI

STEMI < 6 HRS Undergoing Primary PCI STEMI < 6 HRS Undergoing Primary PCI (n=343)(n=343)

TITAN TIMI 34: Study DesignTITAN TIMI 34: Study Design

RANDOMIZERANDOMIZEOpen LabelOpen Label

RANDOMIZERANDOMIZEOpen LabelOpen Label

ASA 160-325 mg po ASA 160-325 mg po HEPARIN 60 U/kg bolus (Max 4000U) and 7U/kg HEPARIN 60 U/kg bolus (Max 4000U) and 7U/kg

infusion (Max 800 U/hr)infusion (Max 800 U/hr)

””EPTIFIBATIDE EPTIFIBATIDE

180/2.0/180180/2.0/180TRANSFER TO CATH TRANSFER TO CATH

LABLAB

DIAGNOSTIC ANGIODIAGNOSTIC ANGIO

PRIMARY ENDPOINT: Pre PCI TIMI Frame CountPRIMARY ENDPOINT: Pre PCI TIMI Frame CountPRIMARY ENDPOINT: Pre PCI TIMI Frame CountPRIMARY ENDPOINT: Pre PCI TIMI Frame Count

EPTIFIBATIDE EPTIFIBATIDE 180/2.0/180180/2.0/180

TRANSFER TO CATH TRANSFER TO CATH LABLAB

DIAGNOSTIC ANGIODIAGNOSTIC ANGIO

© © TIMI 2005. Duplication prohibited by lawTIMI 2005. Duplication prohibited by law

© © TIMI 2005. Duplication prohibited by lawTIMI 2005. Duplication prohibited by law

0

5

10

15

20

25

30

0

5

10

15

20

25

30

Pre

- P

CI

TM

PG

3 (

%)

Pre

- P

CI

TM

PG

3 (

%)

EREREptifibatideEptifibatide

Cath Lab Cath Lab EptifibatideEptifibatide

24.3%24.3%

14.2%14.2%

p = 0.026p = 0.026

(41/169)(41/169) (20/141)(20/141)

p=0.025 adjusting for infarct locationp=0.025 adjusting for infarct location

Primary Analysis: Modified Intent-to-TreatPrimary Analysis: Modified Intent-to-Treat

TITAN-TIMI 34: Secondary Angiographic Endpoint TIMI Flow Grades

TITAN-TIMI 34: Secondary Angiographic Endpoint TIMI Flow Grades

0

5

10

15

20

25

30

35

40

45

50

0

5

10

15

20

25

30

35

40

45

50

Pre

- P

CI

TIM

I 2

or

3 F

low

(%

)P

re -

PC

I T

IMI

2 o

r 3

Flo

w (

%)

EREREptifibatideEptifibatide

Cath Lab Cath Lab EptifibatideEptifibatide

46.2%46.2%

36.6%36.6%

(79/171)(79/171) (52/142)(52/142)

TIMI 2 or 3TIMI 2 or 3p = 0.087p = 0.087

24%19%p=NSp=NS

TIMI 3TIMI 3

TITAN-TIMI 34: Angiographic Perfusion ScoreTITAN-TIMI 34: Angiographic Perfusion Score

Integrates epicardial and myocardial perfusion

Integrates flow before and after PCI

Sum of the following:

TIMI Flow Grade Before PCI (0-3)

TIMI Myocardial Perfusion Grade Before PCI (0-3)

TIMI Flow Grade After PCI (0-3)

TIMI Myocardial Perfusion Grade After PCI (0-3)

Integrates epicardial and myocardial perfusion

Integrates flow before and after PCI

Sum of the following:

TIMI Flow Grade Before PCI (0-3)

TIMI Myocardial Perfusion Grade Before PCI (0-3)

TIMI Flow Grade After PCI (0-3)

TIMI Myocardial Perfusion Grade After PCI (0-3)

Total Angiographic Perfusion Score: 0 - 12Total Angiographic Perfusion Score: 0 - 12

Gibson CM. Am Heart J. 2004 Aug;148(2):336-40. Gibson CM. Am Heart J. 2004 Aug;148(2):336-40.

Failed 0-3; Partial 4-9; Failed 0-3; Partial 4-9; Full 10-12Full 10-12Failed 0-3; Partial 4-9; Failed 0-3; Partial 4-9; Full 10-12Full 10-12

© © TIMI 2005. Duplication prohibited by lawTIMI 2005. Duplication prohibited by law

TITAN-TIMI 34: Full Angiographic PerfusionTITAN-TIMI 34: Full Angiographic Perfusion

© © TIMI 2005. Duplication prohibited by lawTIMI 2005. Duplication prohibited by law

0

5

10

15

20

25

0

5

10

15

20

25

Fu

ll A

ng

iog

rap

hic

F

ull

An

gio

gra

ph

ic

Per

fusi

on

(A

PS

10-

12)

%

Per

fusi

on

(A

PS

10-

12)

%

EREREptifibatideEptifibatide

Cath Lab Cath Lab EptifibatideEptifibatide

21.1%21.1%

12.5%12.5%

p = 0.059p = 0.059

(32/152)(32/152) (16/128)(16/128)

Primary Analysis: Modified Intent-to-TreatPrimary Analysis: Modified Intent-to-Treat

Full Angiographic Perfusion previously defined in Gibson CM. Am Heart J. 2004 Aug;148(2):336-40. Full Angiographic Perfusion previously defined in Gibson CM. Am Heart J. 2004 Aug;148(2):336-40.

© © TIMI 2005. Duplication prohibited by lawTIMI 2005. Duplication prohibited by law

2.32.1

0

1

2

3

2.32.1

0

1

2

3

Dea

th (

%)

Dea

th (

%)

EREREptifibatideEptifibatide

Cath Lab Cath Lab EptifibatideEptifibatide

DeathDeathp = NSp = NS

2.9

7.1

0

2

4

6

8

2.9

7.1

0

2

4

6

8

CH

F

(%)

CH

F

(%)

EREREptifibatideEptifibatide

Cath Lab Cath Lab EptifibatideEptifibatide

n=173n=173 n=142n=142

Primary Analysis: Modified Intent-to-TreatPrimary Analysis: Modified Intent-to-Treat

TITAN-TIMI 34 Clinical Endpoints at Discharge/Day 5

TITAN-TIMI 34 Clinical Endpoints at Discharge/Day 5

CHFCHFp = 0.082p = 0.082

n=173n=173 n=142n=142

© © TIMI 2005. Duplication prohibited by lawTIMI 2005. Duplication prohibited by law

OutcomeER

Eptifibatide (n=174)

Cath Lab Eptifibatide (n=142)

P-value

TIMI Major (Hgb >5 g/dL or ICH)

1.7% 3.5% NS

TIMI Minor (Hgb 3-5 g/dL) 5.2% 4.2% NS

TIMI Major or Minor 6.9% 7.8% NS

Transfusion PRBC 9.8% 7.0% NS

Stroke or ICH 0.0% 0.0% NS

Thrombocytopenia (Plt. < 100K)

2.3% 1.4% NS

TITAN-TIMI 34: Bleeding EventsTITAN-TIMI 34: Bleeding Events

Non CABG Through Discharge; Site AssessmentNon CABG Through Discharge; Site AssessmentPrimary Analysis: Modified Intent-to-TreatPrimary Analysis: Modified Intent-to-Treat

Facilitated PCIFacilitated PCI For Fibrinolytic Ineligible Patients

Cardiogenic Shock

Time to Balloon <90 minutes

ASA, NTG, BB

Heparin 4000/1000

Integrelin Bolus and Infusion

Clopidogrel 300 mg po

Rapid Transfer to Cath Lab

For Fibrinolytic Ineligible Patients

Cardiogenic Shock

Time to Balloon <90 minutes

ASA, NTG, BB

Heparin 4000/1000

Integrelin Bolus and Infusion

Clopidogrel 300 mg po

Rapid Transfer to Cath Lab

Facilitated PCIFacilitated PCI

Primary angioplasty or stent placement is the gold standard treatment of STEMI in cath lab centers.

ASA, NTG, Heparin weight based dosing

IIb/IIIa inhibitor either prior to or at the same time as PCI decreases reocclusion and has some fibrinolytic effects equal to streptokinase.

Benefits of cath over thrombolytics lost if time from door to cath lab greater than 90 minutes.

Primary angioplasty or stent placement is the gold standard treatment of STEMI in cath lab centers.

ASA, NTG, Heparin weight based dosing

IIb/IIIa inhibitor either prior to or at the same time as PCI decreases reocclusion and has some fibrinolytic effects equal to streptokinase.

Benefits of cath over thrombolytics lost if time from door to cath lab greater than 90 minutes.

QUESTIONS??QUESTIONS??