Thrombolysis assisted PCIThrombolysis assisted PCI

Bonnie H. Weiner MD MSEC MBA FSCAIPast President SCAI

Professor of MedicineDirector Interventional Cardiology Research

St Vincent Hospital @ Worcester Medical Center

Bonnie H. Weiner MD MSEC MBA FSCAIPast President SCAI

Professor of MedicineDirector Interventional Cardiology Research

St Vincent Hospital @ Worcester Medical Center

DisclosureDisclosure

I am an Interventional Cardiologist I believe every STEMI patient should have PCI I deal with reality and recognize that this may not be possible everywhere today General Disclosures

Ownership Imaging Core Lab Services Davol AtheroMed

Consulting Boston Biomedical Associates

CR Bard Labcoat Therox

Cormend Research

Medtronic Boston Scientific Abbott

Honoraria SCAI

I am an Interventional Cardiologist I believe every STEMI patient should have PCI I deal with reality and recognize that this may not be possible everywhere today General Disclosures

Ownership Imaging Core Lab Services Davol AtheroMed

Consulting Boston Biomedical Associates

CR Bard Labcoat Therox

Cormend Research

Medtronic Boston Scientific Abbott

Honoraria SCAI

PCI in STEMIPCI in STEMI

Primary PCI PCI immediately following successful

fibrinolysis Rescue PCI in failed fibrinolysis Facilitated PCI

Primary PCI PCI immediately following successful

fibrinolysis Rescue PCI in failed fibrinolysis Facilitated PCI

Repeat ThrombolysisAccelerated tPA or

reteplase

n=142

Primary Endpoint:Composite of death, reinfarction, CVA, or severe heart failure at 6 months

REACT: 6 month resultsREACT: 6 month results

NEJM 2005;353:2758

427 Acute MI patients with failed thrombolysisaspirin thrombolytic therapy (60% received streptokinase) within 6 hours of

chest pain onset, <50% resolution of ST changes on ECG at 90 minutes

42% anterior infarctions

Conservative Treatment

IV Unfractionated Heparinfor 24 hours

n=141

Rescue PCI

Angiography with or without Revascularization

n=144

REACT: 6 Month ResultsREACT: 6 Month ResultsPrimary Composite Endpoint at

6Months(Death, MI, CVA, or severe heart failure) The primary composite

endpoint of death, MI, CVA or severe heart failure at 6 months was significantly lower in the rescue PCI group compared with either the repeat thrombolysis group or the conservative management group

RepeatThrombolysis

Rescue PCI ConservativeManagement

•p<0.001 •p=0.002

Facilitated PCIFacilitated PCI

a strategy of planned immediate PCI after administration of an initial pharmacological regimen intended to improve coronary patency before the procedure. These regimens have included high-dose heparin, platelet glycoprotein (GP) IIb/IIIa inhibitors, full-dose or reduced dose fibrinolytic therapy, and the combination of a GP IIb/IIIa inhibitor with a reduced-dose fibrinolytic agent (e.g., fibrinolytic dose typically reduced 50%).

a strategy of planned immediate PCI after administration of an initial pharmacological regimen intended to improve coronary patency before the procedure. These regimens have included high-dose heparin, platelet glycoprotein (GP) IIb/IIIa inhibitors, full-dose or reduced dose fibrinolytic therapy, and the combination of a GP IIb/IIIa inhibitor with a reduced-dose fibrinolytic agent (e.g., fibrinolytic dose typically reduced 50%).

*ACC/AHA 2007 Focused update STEMI Guidelines

RationalRational

Primary PCI appears superior to thrombolysis but not all patients have the required prompt (DTB < 90 minutes) access to the cath lab.

Treatment delays are common and reduce the true benefit of PCI

TIMI 3 flow prior to PCI is an important predictor of success and clinical outcome

Primary PCI appears superior to thrombolysis but not all patients have the required prompt (DTB < 90 minutes) access to the cath lab.

Treatment delays are common and reduce the true benefit of PCI

TIMI 3 flow prior to PCI is an important predictor of success and clinical outcome

Facilitated PCIFacilitated PCI

A number of small studies suggested a benefit to several approaches

CAPITAL-AMI 170 patients with STEMI randomized to TNK

vs. TNK facilitated PCI Primary endpoint: death, re MI, recurrent

unstable ischemia or stroke at 6 months

A number of small studies suggested a benefit to several approaches

CAPITAL-AMI 170 patients with STEMI randomized to TNK

vs. TNK facilitated PCI Primary endpoint: death, re MI, recurrent

unstable ischemia or stroke at 6 months

CAPITAL-AMICAPITAL-AMI

% W

ith C

ompo

site

End

poin

t

Days form Randomization

JACC 2005;46:417

p=0.04

24.4%

11.6%

•A

•D

•M

•I

•R

•A

•L

bciximab before

irect Angioplasty and Stenting in

yocardial

nfarction

egarding

cute and

ong term follow-up

ADMIRAL StudyADMIRAL Study

NEJM 2001;334:1895

Aim of the StudyAim of the Study•To demonstrate the superiority of abciximab over placebo in primary PTCA with stenting in acute myocardial infarction

•ESC

DesignDesign•AMI < 12 hours

randomized

•Abciximab

+

•Heparin, ASA, Ticlopidine

•Placebo

+

•Heparin, ASA, Ticlopidine

•First Coronary Angiography

PTCA + Stent

•First Coronary Angiography

PTCA + Stent

•Coronary Angiography

at 24 h and 6 Months

•Coronary Angiography

at 24 h and 6 Months

•Clinical evaluation

(24 h, 30 Days and 6 Months

Primary Endpoint (6 months)Primary Endpoint (6 months)

7.4

15.9

•0

•5

•10

•15

•20

% o

f P

atie

nts

p = 0.02

- 52.3 %

Death, Recurrent MI, Urgent TVRDeath, Recurrent MI, Urgent TVR

Placebo

n = 150

Abciximab

n = 150

Primary Endpoint Components (6 Months)Primary Endpoint Components (6 Months)

7.3

3.4

4.0

6.6

2.02.0

0

5

10

Death Recurrent MI Urgent TVR

% o

f P

atie

nts

Placebo Abciximab

p = 0.33

- 54.8%

- 35.0%

p = 0.02

Secondary Endpoint (6 Months)Secondary Endpoint (6 Months)Death, Recurrent MI, Any RevascularizationDeath, Recurrent MI, Any Revascularization

22.8

33.8

•0

20

30

40

% o

f P

atie

nts

p = 0.03

- 39.5 %

Placebo

n = 150

Abciximab

n = 150

Bleeding Events (30 Days)Bleeding Events (30 Days)

3.3

12.1

00.7

0

2

4

6

8

12

Major Minor

% o

f P

atie

nts

Placebo Abciximab

p = 0.50

p = 0.004

Facilitated PCI: Limits of the DataFacilitated PCI: Limits of the Data

Conflicting studies: Currently is Class IIb, abciximab, anterior location, < 75 years old, no risk factors for bleeding, + planned PCI* Most show improved TIMI flow rates or less

reinfarction Other harder endpoints such as death have been

harder to prove Several recently presented larger trials:

ASSENT 4: Negative study, stopped prematurely FINESSE: Reported at the ESC 2007

Conflicting studies: Currently is Class IIb, abciximab, anterior location, < 75 years old, no risk factors for bleeding, + planned PCI* Most show improved TIMI flow rates or less

reinfarction Other harder endpoints such as death have been

harder to prove Several recently presented larger trials:

ASSENT 4: Negative study, stopped prematurely FINESSE: Reported at the ESC 2007

*ACC/AHA 2004 STEMI Guidelines

ASSENT-4: Full Dose Fibrinolytic with PCI vs. PCI Alone

ASSENT-4: Full Dose Fibrinolytic with PCI vs. PCI Alone

Full dose tenecteplase N=4000 Primary endpoint: death or CHF or

cardiogenic shock at 90 days Study stopped at 1667 patients by the

DSMB due to superiority of the PCI only arm

Full dose tenecteplase N=4000 Primary endpoint: death or CHF or

cardiogenic shock at 90 days Study stopped at 1667 patients by the

DSMB due to superiority of the PCI only arm

Lancet 2006;367:569

ASSENT- 4: Outcomes at 90 days (primary end point)

ASSENT- 4: Outcomes at 90 days (primary end point)

End point TNK+PCI (%)

PCI alone (%)

p

Death/CHF/cardiogenic shock

18.8 13.7 0.0055

ASSENT- 4: Outcomes at 90 days

ASSENT- 4: Outcomes at 90 days

Lancet 2006;367:569

End point TNK+PCI (%)

PCI alone (%)

p

Death 6.7 5.0 0.141

Cardiogenic shock

6.1 4.8 0.273

CHF 12.1 9.4 0.078

ASSENT- 4 secondary end points at 90 days

ASSENT- 4 secondary end points at 90 days

Lancet 2006;367:569

End point TNK+PCI (%)

PCI alone (%)

p

Re-MI 6.1 3.5 0.020

Repeat TVR 6.6 3.6 0.006

Stroke 2.65 0.10 <0.0001

Intracranial hemorrhage

1.09 0.10 <0.05

Major bleeds (in hospital)

5.6 4.4 0.3118

•3000 pts STEMI•Chest pain <6 h•ASA (150-325 mg)•Heparin (40 U/kg, 3000) or•Enoxaparin (.5/.3 mg/kg iv/sc)

FACILITATED PCI•Abciximab (.25/.125)•Reteplase (5 IU + 5 IU)

in the ED• (single bolus for age>75)•PCI 60-120 mins

PRIMARY PCI•Angio/PCI •60-120 minutes•Abciximab during

PCI in CCL

1° Endpoint 90 day death, CHF,VF, shock

Double-blind, randomized, triple-dummy placebo-controlled

ABCIXIMAB

FACILITATED PCI•Abciximab in ER•Angio/PCI •60-120 minutes

Ellis S. European Society of Cardiology Congress 2007; September 3, 2007; Vienna, Austria.

•*All-cause mortality; rehospitalization or emergency department treatment for CHF; resuscitated ventricular fibrillation occurring >48 hours after randomization; cardiogenic shock•ED=emergency department

FINESSEFINESSE

End point Primary PCI (%)

Abciximab-facilitated (%)

Combination (abciximab/reteplase)-facilitated (%)

p, combination-facilitated vs primary PCI

p, combination-facilitated vs abciximab-facilitated

Primary end point*

10.7 10.5 9.8 NS NS

All-cause mortality

4.5 5.5 5.2 NS NS

Complications of MI

8.9 7.5 7.4 NS NS

CHF requiring hospital/ED visit

2.2 2.9 1.9 NS NS

Death 4.5 5.5 5.2 NS NS

Ellis S. European Society of Cardiology Congress 2007; September 3, 2007; Vienna, Austria.

Primary, Secondary, and Bleeding End Points in FINESSE

Primary, Secondary, and Bleeding End Points in FINESSE

End point Primary PCI (%)

Abciximab-facilitated (%)

Combination (abciximab/reteplase)-facilitated (%)

p, combination-facilitated vs primary PCI

p, combination-facilitated vs abciximab-facilitated

Cardiogenic shock

6.8 4.8 5.3 NS NS

VF 0.4 0.2 0.6 NS NS

TIMI major bleeding

2.6 4.1 4.8 0.025 NS

TIMI minor bleeding

4.3 6.0 9.7 <0.001 0.006

TIMI major or minor bleeding

6.9 10.1 14.5 <0.001 0.008

*All-cause mortality; rehospitalization or emergency department treatment for CHF; resuscitated ventricular fibrillation occurring >48 hours after randomization; cardiogenic shock•VF=ventricular fibrillation

Ellis S et al. N Engl J Med 2008;358:2205-2217

FINESSEFINESSE

Transfer-MITransfer-MI

Randomized trial of pharmacoinvasivestratagy Routine transfer within 6 hours

vs Rescue PCI for high risk STEMI

Randomized trial of pharmacoinvasivestratagy Routine transfer within 6 hours

vs Rescue PCI for high risk STEMI

ResultsResults

ResultsResults

ResultsResults

Level 1 MI Treatment TimesLevel 1 MI Treatment Times

Minutes (median)

In door 1 outdoor 1

Transport time

In door 2 - balloon

Total In door to balloon

Zone I(n=775)

Zone II(n=557)

AN(n=360)

DANAMI(n=567)

49(36,66)

60(48,83)

NA

50(39-65)

22(16,31)

35(26,49)

NA

32(20-45)

21(16,28)

19(15,25)

65(47,83)

26(20-38)

95(82,116)

122(101,151)

65(47,83)

108

•Adair

•Adams

•Allamakee

•Appanoose

•Audubon

•Benton

•Black Hawk

•Boone

•Bremer

•Buchanan

•Buena Vista •Butler

•Calhoun

•Carroll

•Cass

•Cedar

•Cerro Gordo

•Cherokee

•Chickasaw

•Clarke

•Clay

•Clayton

•Clinton

•Crawford

•Dallas

•Davis•Decatur

•Delaware

•Des Moines

•Dickinson

•Dubuque

•Emmet

•Fayette

•Floyd

•Franklin

•Fremont

•Greene

•Grundy

•Guthrie

•Hamilton

•Hancock

•Hardin

•Harrison

•Henry

•Howard

•Humboldt

•Ida

•Iowa

•Jackson

•Jasper

•Jefferson

•Johnson

•Jones

•Keokuk

•Kossuth

•Lee

•Linn

•Louisa

•Lucas

•Lyon

•Madison •Mahaska•Marion

•Marshall

•Mills

•Mitchell

•Monona

•Monroe•Montgomery

•Muscatine

•O'Brien

•Osceola

•Page

•Palo Alto

•Plymouth •Pocahontas

•Polk

•Pottawattamie

•Poweshiek

•Ringgold

•Sac

•Scott•Shelby

•Sioux

•Story•Tama

•Taylor

•Union

•Van Buren

•Wapello

•Warren •Washington

•Wayne

•Webster

•Winnebago

•Winneshiek

•Woodbury

•Worth

•Wright

•Primary •Secondary •Tertiary

•Level 1 Heart Attack Program

•Report Card – February 1, 2004 to June 30, 2007Report Card – February 1, 2004 to June 30, 2007

Mercy Zone 1 Zone 2

N=848 N=509 N=187 N=152

Median D-B (min) 60 100 134

30 Day Mortality(4.2%) 4.5% 2.1% 5.9%

•Blue = 30 miles- 15 min flight time (each way)

•Red= 60 miles- 23 min flight time (each way)

•GEISINGER: RURAL PENNSYLVANIA

GEISINGER RESULTSGEISINGER RESULTS•Patients Transferred to GMC

2004(n = 110)

2005(n = 134)

2006(n = 143)

2007(n = 63)

D2B

(Minutes)

189 113 105 96

•10 PCI centers•16 Transfer for PCI•28 Lytics•11 Mixed

•RACE Centers and Regions65 hospitals (10 PCI, 55 non PCI)

•Asheville

•Winston-Salem•Durham-Chapel Hill-

•Greensboro

•Charlotte

•East Carolina

•Each non-PCI center was assessed for

•reperfusion designation based on resources, transfer ability, and transfer time to PCI center

•Adair

•Adams

•Allamakee

•Appanoose

•Audubon

•Benton

•Black Hawk

•Boone

•Bremer

•Buchanan

•Buena Vista •Butler

•Calhoun

•Carroll

•Cass

•Cedar

•Cerro Gordo

•Cherokee

•Chickasaw

•Clarke

•Clay

•Clayton

•Clinton

•Crawford

•Dallas

•Davis•Decatur

•Delaware

•Des Moines

•Dickinson

•Dubuque

•Emmet

•Fayette

•Floyd

•Franklin

•Fremont

•Greene

•Grundy

•Guthrie

•Hamilton

•Hancock

•Hardin

•Harrison

•Henry

•Howard

•Humboldt

•Ida

•Iowa

•Jackson

•Jasper

•Jefferson

•Johnson

•Jones

•Keokuk

•Kossuth

•Lee

•Linn

•Louisa

•Lucas

•Lyon

•Madison •Mahaska•Marion

•Marshall

•Mills

•Mitchell

•Monona

•Monroe•Montgomery

•Muscatine

•O'Brien

•Osceola

•Page

•Palo Alto

•Plymouth •Pocahontas

•Polk

•Pottawattamie

•Poweshiek

•Ringgold

•Sac

•Scott•Shelby

•Sioux

•Story•Tama

•Taylor

•Union

•Van Buren

•Wapello

•Warren •Washington

•Wayne

•Webster

•Winnebago

•Winneshiek

•Woodbury

•Worth

•Wright

•Primary •Secondary •Tertiary

•Level 1 Heart Attack Program

•Report Card – February 1, 2004 to June 30, 2007Report Card – February 1, 2004 to June 30, 2007

Mercy Zone 1 Zone 2

N=848 N=509 N=187 N=152

Median D-B (min) 60 100 134

30 Day Mortality(4.2%) 4.5% 2.1% 5.9%

•Blue = 30 miles- 15 min flight time (each way)

•Red= 60 miles- 23 min flight time (each way)

•GEISINGER: RURAL PENNSYLVANIA

GEISINGER RESULTSGEISINGER RESULTS•Patients Transferred to GMC

2004(n = 110)

2005(n = 134)

2006(n = 143)

2007(n = 63)

D2B

(Minutes)

189 113 105 96

•10 PCI centers•16 Transfer for PCI•28 Lytics•11 Mixed

•RACE Centers and Regions65 hospitals (10 PCI, 55 non PCI)

•Asheville

•Winston-Salem•Durham-Chapel Hill-

•Greensboro

•Charlotte

•East Carolina

•Each non-PCI center was assessed for

•reperfusion designation based on resources, transfer ability, and transfer time to PCI center

Focused UpdateFocused Update

Focused UpdateFocused UpdateAlready out of

sync with available

data

ConclusionsConclusions

Large randomized trials of facilitated PCI (fibrinolytics+IIb/IIIa agents) have failed to show a positive benefit and but recent data have at least shown no harm

The latest ACC/AHA (2007) consider facilitated PCI as a class IIb indication but with the more recent data from ASSENT-4 and FINESSE did not change substantially

New Class III recommendation is out of sync with Transfer-MI data and network data (which both AHA and ACCF endorse) and fails to provide an option for patients without access to Primary PCI within 90 minutes

Large randomized trials of facilitated PCI (fibrinolytics+IIb/IIIa agents) have failed to show a positive benefit and but recent data have at least shown no harm

The latest ACC/AHA (2007) consider facilitated PCI as a class IIb indication but with the more recent data from ASSENT-4 and FINESSE did not change substantially

New Class III recommendation is out of sync with Transfer-MI data and network data (which both AHA and ACCF endorse) and fails to provide an option for patients without access to Primary PCI within 90 minutes

Facilitated PCI should not be first line therapy if primary PCI is available within 90 minutes

It is a reasonable alternative however when it is not possible to provide primary PCI because of:

•Distances•Transfer times•Resources•Cost

If done correctly mortality may approach that seen for primary PCI and will provide more patients with reperfusion therapy

•Thank You