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Thrombolytics vs Primary

Intervention vs Facilitated
Intervention
Alexandra Lansky, MD
The Cardiovascular Research Foundation
Lenox Hill Heart and Vascular Institute

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Thrombolytics for AMI


Benefits
Widespread availablity
12-17% survival benefit
Preserves LVEF
Limitations
20% of vessels remain occluded
45% have TIMI flow< 3
Median time to reperfusion is 45 minutes
No reliable marker of reperfusion
Recurrent ischemia occurs in 15-30%
Intracranial bleeds occur in 0.5-1.5%
The Cardiovascular
Research Foundation

Lenox Hill Heart and Vascular


Institute of New York

Only ~20% of U.S. Hospitals Have


Angioplasty Services
US Hospitals with Angioplasty Services

The Cardiovascular
Research Foundation

Lenox Hill Heart and Vascular


Institute of New York

Twenty-Two Year (1975-1997) Trends in the Case Fatality


Rates From Initial QMI and NQMI
Hospital records of 5,832 residents of Worcester, MA admitted with QMI
and NQMI between 1975 and 1997 were compared to determine
differences in incidence of in-hospital and long-term mortality.

QWMI

NQWMI

19.5%

12.5%

1978

24%

12%

1997

14%

12%

1 year

91%

85%

2 years

86%

80%

Overall Outcomes
Hospital death rates

(n=3,396)

(n=2,436)

Hospital mortality

Survival after discharge

5 years Between 1975 and 1997, QWMI-associated


75%
65%
Conclusion:
mortality
decreased,
whereas NQWMI-associated mortality
constant.
10 years
56% remained
47%
The Cardiovascular
Research Foundation

Furman MI, et al, J Am


5 Coll Cardiol
2001;37:1571-1580.

Lenox Hill Heart and Vascular


Institute of New York

Trends in Hospital Mortality in AMI


- From 1,514,292 pts in NRMI 1-3 All pts

12%
10%
8%

Thrombolytic therapy

11.2%
P=0.0001

8.4%

9.4%

P=0.0001

5.9%

6%
4%

Primary PTCA

5.7%

P=0.01

5.3%

2%
0%
1990 1991 1992 1993 1994 1995 1996 1997 1998 1999
The Cardiovascular
Research Foundation

Lenox Hill Heart and Vascular


Institute of New York

30 Day Mortality with Reperfusion Therapy in AMI


Meta-Analysis Comparison
Death, %

17% ; p<0.0001
34% ; p=0.02

Placebo Lytic

Lytic

FTT: 9 placebo controlled

lytic trials (n=58,800)

The Cardiovascular
Research Foundation

PTCA

11 PTCA-lytic trials
(n=2,606) - PCAT
Lenox Hill Heart and Vascular
Institute of New York

The PCAT Collaboration


The Primary Coronary Angioplasty
Trialists
11 prospective, randomized trials of
thrombolytic therapy vs. primary PTCA
2,725 patients randomized
streptokinase trials, 699 rand. pts
3 t-PA trials with 3-4 dosing, 588 rand. pts
3 accelerated t-PA trials, 1437 rand. pts
All study data pooled for true meta-analysis
The Cardiovascular
Research Foundation

Lenox Hill Heart and Vascular


Institute of New York

PCAT (11 studies, n=2,725): Mortality


Lytic (n=1377)

10.0

PTCA (n=1348)
7.5%
7.5%

8.0
6.0

4.0

5.1%
5.1%

2.0

P=0.039
P=0.039

0.0

0
The Cardiovascular
Research Foundation

3
Months
9

Lenox Hill Heart and Vascular


Institute of New York

PCAT: Reinfarction
Lytic (n=1377)

10.0

PTCA (n=1348)

8.4%
8.4%

8.0
6.0

4.0
4.2%
4.2%

2.0
0.0

P<0.0001
P<0.0001

The Cardiovascular
Research Foundation

3
Months
10

Lenox Hill Heart and Vascular


Institute of New York

PCAT: Stroke
2.5

P=0.02
P=0.002

2
1.5

P=0.02

P=0.01

1.45

1.09

0.80

0.66

0.5
0

1.88

0.07
In-hospital

0.07
30 days

Hemorrhagic stroke
The Cardiovascular
Research Foundation

11

0.22
In-hospital

30 days

All stroke
Lenox Hill Heart and Vascular
Institute of New York

PCAT Subgroup Analyses: 30 Day Death or ReMI


Subgroup

Lytic

Age
<60
60-70
>70

8.2%
12.8%
23.6%

Male
Female

Events prevented
per 1000 pts

PTCA

4.3%
6.3%
13.3%

OR
48%
51%
43%

41
64
118

12.2%
16.4%

5.7%
11.7%

53%
29%

61
82

No Diabetes
Diabetes

11.8%
19.3%

6.5%
9.2%

45%
52%

59
97

No Prior MI
Prior MI

11.5%
22.7%

6.6%
9.7%

43%
57%

58
114

Oddsratio[95%CI]:00.511.52
The Cardiovascular
Research Foundation

12

Lenox Hill Heart and Vascular


Institute of New York

PCAT: Effect of Age on Mortality


30

28.6

Lytic (n=1377)

25

22.8

PTCA (n=1348)

20

15.8

% 15
10
5
0

5.9
3.6
1.3
0.0

<40

2.3

1.0

2.4

40-49

50-59

6.4
4.1

60-69

70-79

>80

Age group (years)


The Cardiovascular
Research Foundation

13

Lenox Hill Heart and Vascular


Institute of New York

NRMI-2: Primary PCI


P=NS

MV adjusted odds of death

2.2

P=NS

P=0.01

P=0.0007

P=0.0003

N=27,080
1.8
1.62

1.4

1.61

1.41
1.14

1.15

1
0.6
0.2

N=2,230

0-60

5,734

6,616

4,461

2,627 5,412

61-90
91-120
121-150
151-180
Door-to-Balloon Time (minutes)

>180

Cannon CP, et al Circulation 1999;100:I-360


The Cardiovascular
Research Foundation

14

Lenox Hill Heart and Vascular


Institute of New York

Limitations of Primary PTCA


In-hospital and late restenosis and reocclusion
Inadequate reperfusion success
TIMI-3 flow in only 75%-95% of pts

lower in SVG and cardiogenic shock


technique and operator dependent
Adequate tissue perfusion in ~30%
Inherent logistical delays to reperfusion
2 hours or longer!
Reduced myocardial salvage,
increased mortality, morbidity and cost
The Cardiovascular
Research Foundation

15

Lenox Hill Heart and Vascular


Institute of New York

The Stent PAMI Randomized Trial


AMI <12 hours, any age, cardiogenic shock excluded
- n=1,458 at 62 centers in N.A., S.A. and Europe ASA, Ticlid

Angiographic criteria for stent?


yes

Abciximab
5.4%

Registry
n=558 (38%)

N=900 (62%)
Randomize

PTCA
(n=448; X/O stent in 15%)
The Cardiovascular
Research Foundation

no

Palmaz Schatz Stent


(n=452; 99% stented)
16

Lenox Hill Heart and Vascular


Institute of New York

Stent PAMI: 6 Month Outcomes


900 pts with AMI randomized to stent vs. PTCA
40%

P=0.0002
33.5%

Stent

PTCA

P<0.0001

30%
20%

20.6%

10%

21.0%

P=0.03
5.1%

9.3%

10.6%

0%

Angiographic
restenosis
The Cardiovascular
Research Foundation

Infarct artery
reocclusion
17

Ischemic TVR

Lenox Hill Heart and Vascular


Institute of New York

Stent PAMI: Myocardial Recovery


Paired acute and 6 month follow-up LVEF
100%

P<0.0001
P<0.0001

Stent
PTCA

75%

P<0.0001
P<0.0001

53.8% 54.8%

58.9%

58.8%

50%
25%
0%

The Cardiovascular
Research Foundation

P=NS
P=NS

P=NS
P=NS

Acute

6 Month

18

Lenox Hill Heart and Vascular


Institute of New York

Stent PAMI: 1 Year Survival


97.0%
97.0%

100%

95%

94.6%
94.6%

90%

PTCA
Stent

85%

p=0.054

80%
0

25

50

75

100 125

150 175 200 225 250 275 300 325 350

Days
The Cardiovascular
Research Foundation

19

Lenox Hill Heart and Vascular


Institute of New York

PAMI Stent: Final TIMI Flows


Operator assessment (N)
TIMI flow
- 0/1
-2
-3
Core Lab assessment (N)
TIMI flow
- 0/1
-2
-3
The Cardiovascular
Research Foundation

Stent
451

PTCA
447

0.2%
6.9%
92.9%

0.4%
3.1%
96.4%

446

441

0.7%
9.9%
89.5%

0.6%
6.8%
92.7%

20

0.02

0.046

Lenox Hill Heart and Vascular


Institute of New York

Relationship Between Early TIMI-3 Flow


and Short-term Mortality After Reperfusion Rx
Thrombolytic therapy

Primary PTCA

10

Death (%)

8
6
4

r 2 =0.83; p<0.0001
2 slope = -0.08
-.08
intercept = 10.3%
0
0
10
20
30
40

50

60

70

80

90

100

TIMI-3 flow (%)


The Cardiovascular Research Foundation

21

Transcatheter Cardiovascular Therapeutics

Beyond TIMI-3 Flow: ST Segment Resolution


403 consecutive pts with ST AMI achieving TIMI-3 flow
after primary PTCA with EKGs 1 before and after
Partial ST segment
Resolution
(30% - 70%)

34%

15%

No ST segment
resolution (<30%)

51%
Complete ST segment
resolution
Vant Hof AW et al. Lancet 1997;350:615-9
The Cardiovascular
Research Foundation

22

Lenox Hill Heart and Vascular


Institute of New York

Survival as a Function of ST Seg. Resolution


In403ptswithTIMI3flowafterprimaryPTCA
1 yr
MR

Complete

100%

Partial

90%
80%

5%

MV
MV risk
risk of
of death
death == 3.5
3.5 [1.5,
[1.5, 8.0]
8.0] 16%
None

70%
60%

MV
MV risk
risk of
of death
death == 6.4
6.4 [2.7,
[2.7, 15.3]
15.3] 31%

P<0.001
0

The Cardiovascular
Research Foundation

6
Months
23

Lenox Hill Heart and Vascular


Institute of New York

12

Causes of Decreased Myocardial Perfusion


With Normal Epicardial Coronary Flow
Microvascular spasm or stunning
Endothelial cell swelling
Microvascular compression
- myocyte and interstitial edema
- elevated L VEDP
Loss of microvascular integrity
Platelet, wbc plugging of small vessels
- embolization or in situ thrombosis
The Cardiovascular Research Foundation

24

Transcatheter Cardiovascular Therapeutics

Enhancing Myocardial Recovery


Pharmacologicadjunctstomechanicalreperfusion
Reduce/eliminate distal embolization/platelet plugging
- IIb/IIIa inhibitors
- adenosine (P-selectin dependent)
Decrease microvascular resistance
- papaverine, nicorandil, verapamil, adenosine
Prevent reperfusion injury
- free-radical scavengers (SOD, adenosine, etc.)
- leukocyte depletion or inhibitors (CD18)
- GIK
The Cardiovascular
Research Foundation

25

Lenox Hill Heart and Vascular


Institute of New York

IIb/IIIa Inhibitors During Primary PTCA


Placebo

GP IIb/IIIa
RESTORE AMI Subset
30 day Events
(Tirofiban; n=134)

RAPPORT
6 month Events
(Abciximab; n=483)
20%
15%
10%
5%

20%

P=NS
P=0.006

16.1%
13.3%

15%
10%

6.6%

P=NS
12.7%
9.9%

5%

1.7%

0%

0%
Urgent TVR

The Cardiovascular
Research Foundation

Death, ReMI,
Any TVR

Death, ReMI, Any TVR

26

Lenox Hill Heart and Vascular


Institute of New York

IIb/IIIa Inhibitors During 1o Stenting


- 30 day events -

Placebo

ISAR-2
(Abciximab; n=401)

ADMIRAL
(Abciximab; n=300)
P<0.03

The Cardiovascular
Research Foundation

GP IIb/IIIa

P<0.05

27

Lenox Hill Heart and Vascular


Institute of New York

ADMIRAL
300 pts with AMI <12
randomized to abciximab vs. placebo before primary stenting

P=NS
P<0.05

P<0.05

Study drug initiation


In ambulance or ER
The Cardiovascular
Research Foundation

P=NS

28

Study drug initiation


In cath lab or CCU
Lenox Hill Heart and Vascular
Institute of New York

CADILLAC: Enrollment
AMI
AMI <12
<12 hours,
hours, any
any age,
age, cardiogenic
cardiogenic shock
shock excluded
excluded
n=2,677
n=2,677 at
at 76
76 centers
centers in
in N.A.,
N.A., S.A.
S.A. and
and Europe
Europe
Angiography

Ye
s

?? met
met angiographic
angiographic criteria
criteria

n=2,082 (78%)

No

Registry
Registry (n=595)
(n=595)
PTCA
PTCA-- 126
126 (5%)
(5%)
Stent
Stent -- 142
142 (5%)
(5%)
CABG
CABG -- 139
139 (5%)
(5%)
Med
Med Rx
Rx -- 188
188 (7%)
(7%)
Randomized:
Randomized:
89%
89% of
of all
all PCI
PCI
94%
94% of
of all
all stent
stent

Randomize
Randomize
Primary
Primary PTCA
PTCA
(n=515)
(n=515)
The Cardiovascular
Research Foundation

MultiLink
MultiLink stent
stent
(n=513)
(n=513)

Primary
Primary PTCA
PTCA
++Abciximab
Abciximab
(n=529)
(n=529)
29

MultiLink
MultiLink stent
stent
++Abciximab
Abciximab
(n=525)
(n=525)

Lenox Hill Heart and Vascular


Institute of New York

CADILLAC: TIMI Flows


TIMI 3

TIMI 2

TIMI 0/1

100%

P=NS

80%

96.1%
96.1%

60%

94.6%
94.6%

96.4%
96.4%

93.9%
93.9%

40%
20%
0%

P
The Cardiovascular
Research Foundation

P/A S
Baseline

S/A
30

P/A S S/A
Final Procedure
Lenox Hill Heart and Vascular
Institute of New York

Subacute Thrombosis
- 30 days 5%

P=0.02
P=0.02

4%

P=0.06

3%
2%

P=0.03

1.8%
1.0%

0.6%

1%

0.0%

0%

PTCA

PTCA +
Abciximab

Stent

Stent +
Abciximab
Kaplan Meier estimates

The Cardiovascular
Research Foundation

31

Lenox Hill Heart and Vascular


Institute of New York

Mortality - 12 Months
PTCA, no abciximab
PTCA, abciximab
Stent, no abciximab
Stent, abciximab

6%

4%

5.3%
5.0%
3.2%
2.9%

2%

P=0.11
0%
0

10

12

Months to event
The Cardiovascular
Research Foundation

32

Lenox Hill Heart and Vascular


Institute of New York

MACE - 12 Months
PTCA, no abciximab
PTCA, abciximab
Stent, no abciximab

25%
20%

21.2%
19.8%

Stent, abciximab

15%

13.1%
12.5%

10%
5%
0%

P<0.000001
0

10

12

Months to event
The Cardiovascular
Research Foundation

33

Lenox Hill Heart and Vascular


Institute of New York

SHOCK Trial
302 pts with cardiogenic shock within 36 of AMI
ST /new LBBB randomized to emergency
revasc. (n=152) or initial medical care (n=150)

p=NS

The Cardiovascular
Research Foundation

P<0.05

34

P<0.05

Lenox Hill Heart and Vascular


Institute of New York

&

Thrombin Inhibition During 1o PTCA


Heparin

Hirudin

GUSTO 2B AMI pts Rxed


with PTCA Subset
30 day Events
(n=465)
P=0.37

GUSTO 2B AMI Subset


N=1138
Front loaded tPA 15mg
bolus+0.75mg/kg over 30
min+0.50mg/kg over 60min
vs Primary PTCA
1o Endpoint: 30 day
death, MI, Stroke
Further randomized in
2x2 factorial to heparin vs
Hirudin for 3 to 5 days
NEJM 1997;336:1621-28

The Cardiovascular
Research Foundation

35

Lenox Hill Heart and Vascular


Institute of New York

Facilitated PCI: The PACT Trial


Lytic eligible AMI
< 6 hrs
(n=605)

Heparin,
ASA in ER

Randomize
t-PA bolus
50 mg
Re-cath
at 5-7 days
The Cardiovascular
Research Foundation

placebo

Cath, PTCA if TIMI <2


36

Ross, JACC 1999;34:1954


Lenox Hill Heart and Vascular
Institute of New York

Facilitated 1o PTCA for AMI: PACT


Plasminogen Activator Angioplasty Comparability Trial
Placebo

N=606
Reduced dose tPA 50mg/kg
vs Placebo prior to Primary
PTCA
1o Endpoint: TIMI on cath
lab arrival
Conclusions
Improved patency with tPA
Improved convalescent EF
among pts with TIMI-3 flow
on cath lab arrival (62.4%
vs 57.9%,p-0.004)

tPA 50mg

P<0.001

JACC 1999;34:1954-62
The Cardiovascular
Research Foundation

37

Lenox Hill Heart and Vascular


Institute of New York

The PRAGUE Study


17 hospitals without catheterization facilities participated
in a national study of reperfusion strategies in AMI
AMI <6, ST or new BBB
N = 300 pts

SK
No transfer
N = 100
The Cardiovascular
Research Foundation

SK + transfer
for cath PTCA
N = 100
38

Widimsky et al
Eur Heart J
2000;21:823-31

Transfer for
primary PTCA
N = 100
Lenox Hill Heart and Vascular
Institute of New York

PRAGUE 30 Day Primary Endpoint

P=0.11

P<0.02
P<0.03
P=NS

Widimsky et al;Eur Heart J 2000;21:823-31


The Cardiovascular
Research Foundation

39

Lenox Hill Heart and Vascular


Institute of New York

LIMI Trial
Lytic eligible AMI
Hospital without PTCA
(n=224)

Randomize

Transfer for
primary PTCA
(n=75)

t-PA
transfer
for PTCA

t-PA

(n=75)

(n=74)

Vermeer, Heart 1999;82:426-431


The Cardiovascular
Research Foundation

40

Lenox Hill Heart and Vascular


Institute of New York

LIMI Trial Primary Endpoints

Vermeer, Heart 1999;82:426-431


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Research Foundation

41

Lenox Hill Heart and Vascular


Institute of New York

Pharmacologic Facilitation of PCI


Potential Advantages
Advantages
Potential
Earlier reperfusion
reperfusion
Earlier
Thrombus burden
burden reduction
reduction
Thrombus
Myocardial salvage
salvage
?? Myocardial
CHF &
& Mortality
Mortality
?? CHF

CAVEATS
Bleeding compl.
Costs
Drugs require time
Small trials negative

Randomized Trials
ADVANCE MI
FINESSE
INTENT
TIGER
CADILLAC-II
ASSENT-IV
The Cardiovascular
Research Foundation

42

Lenox Hill Heart and Vascular


Institute of New York

ACC/AHA Indications
Class I Indication for Primary PTCA
<12 hours symptoms onset, ST elevation, new LBBB
>12 hours and persistent symptoms
>75 procedure per year
Cardiogenic shock and <75yrs old, within 18 hours of
shock
Failed lytics (recurrent Sx)
Prior to Surgical repair of mechanical complication (cath)
No recommendations
Adjunctive 2b/3a; LMWH; facilitated PCI with lytics
Contraindications
Routine post successful Lytics
PCI of non-infarct artery
If >12 hours post MI in abcence of symptoms
The Cardiovascular
Research Foundation

43

Lenox Hill Heart and Vascular


Institute of New York