Case Studies in The Management of Acs With GP Iib/Iiia Inhibitors

Case Studies in the Management of ACS
With GP IIb/IIIa Inhibitors
Medical Editors
H. Vernon Anderson, MD
Cardiology Division
University of Texas Health Sciences Center
Houston, TX
James J. Ferguson III, MD
Cardiology Research
Texas Heart Institute
Houston, TX
Jonathan D. Marmur, MD
Interventional Cardiology
Mount Sinai Medical Center
New York, NY
E. Magnus Ohman, MD
Duke University Medical Center
Durham, NC
2000 Academy for Healthcare Education. No material may be reproduced in whole or in part without
written permission from the Academy for Healthcare Education
Case 1: Presentation
64-year-old woman with

typical chest pain,
shortness of breath,
diaphoresis at rest
Current
medications: HRT
Hemodynamically stable
Physical exam
unremarkable
Treated with rt-PA,
heparin, and aspirin
Resolution of chest
discomfort over
next hour
ECG on arrival to ED
Repeat ECG
Case 1: Recurrent Chest Pain
One hour later patient develops recurrent

chest pain and ECG is repeated
Patient is given tirofiban and ECG is
repeated hour later
Patient taken to cath lab
Case 1: Post-Intervention
Stent placed in RCA
Final ECG demonstrates no

progression to Q-wave MI
Case 1: Lessons Learned
Reocclusion After Thrombolysis Is a

Relatively Common Phenomenon
90-Minute Patency
85%
60-Minute Patency
75%
TIMI Grade 3 Flow
57%
No Myocardial Perfusion
Intermittent Patency
Reocclusion
25%
34%
13%
Optimal Reperfusion
Moliterno DJ, Topol EJ. Thromb Haemostasis. 1997;78:214-219.
44%
29%
25%
Use of GP IIb/IIIa Inhibitors With Reduced

Dose Thrombolytic Improves Reperfusion
% of Patients
60 Minutes
100
91%
80
19
60
70%
t-PA
Abciximab
N=
78%
94%
TIMI 2
17
TIMI 3
16
27
40
20
90 Minutes
72
*P=0.009
62
77
43
100 mg
117
50 mg
+
53
Cannon. J Am Coll Cardiol. 1999;34:1395-1402.
100 mg
215
50 mg
+
97
P=0.01
Use of GP IIb/IIIa Inhibitors With Reduced

Dose Thrombolytic Benefits Safety
10
Major Hemorrhage
% of Patients
8
6
N=103
N=235
Instrument
Spontaneous
Intracranial
t-PA (mg)
Abciximab
Heparin
8
6
N=70
100
STD
Mortality
10
50
+
Low
50
+
Very Low
Antman et al. Circulation. 1999;99:2720-2732.
N=103
N=235
2
0
N=70
100
STD
50
+
Low
50
+
Very Low
76-year-old man presents with crescendo

angina over past 2 weeks
Hx of inferior nonQ-wave MI 6 months ago,
medically managed
Treated with aspirin and heparin in the ED
Chest discomfort persists and patient taken
to cath lab
Case 2: Post-Stent
Stent placed in area of lesion

No reflow seen distal to stent
Post-GP IIb/IIIa
Patient given abciximab

Reinjection of RCA after
5 minutes of therapy
Thrombus Is Less Common and Flow Is

Better With Early GP IIb/IIIa Use
% Patients
100
100
80
Fresh occlusion
80
60
Medium or
large thrombus
60
40
Possible or
small thrombus
40
20
20
Heparin
Alone
Tirofiban +
Heparin
Zhao et al. Circulation. 1999;100:1609-1615.
TIMI Flow
Grade 2
Grade 1
Grade 0
Heparin
Alone
Tirofiban +
Heparin
Long-Term Benefit of Reduced Thrombus

and TIMI 3 Flow
Events at 30 Days
Patients With Event (%)
30
Thrombus (n=643)
No thrombus (n=784)
25
20
20%
10%
Odds ratio
P value
15
12%
9%
6%
5
0
25
20
15
10
30
Composite
1.72
<0.001
Zhao et al. Circulation. 1999;100:1609-1615.
12%
10
5%
MI/Death Refract Isch

1.44
<0.001
20%
1.68
0.002
TIMI 0-2 (n=298)

TIMI 3 (n=1095)
10%
7.4%
5
0
Composite
1.72
<0.001
9%
5.5%
MI/Death Refract Isch

1.44
0.08
1.68
0.02
Better Coronary Flow Reserve

With GP IIb/IIIa Use
Cardiac Events
at 30 Days
15
10
5
P=0.007
P=0.024
0.5
P=0.15
0.4
0.3
0.2
0.1
0.0
0
Basal
Peak
Neumann et al. Circulation. 1998;98:2695-2701.
20
% Patients With Events
20
Heparin
Abciximab
Wall Motion Index
Coronary Flow Velocity (cm/s)
Difference From Baseline to 14 Days
15
10
5
0
OR =0.2
P=0.031
58-year-old man with

diabetes presents to the
ED with crescendo angina
culminating in rest pain
History of elevated
cholesterol, smoking,
hypertension, and LVH
Current meds: aspirin,
ACE inhibitor, insulin
Given heparin, IV NTG, Ca
channel blocker, admitted
to CCU
Developed recurrent chest
pain
Eptifibatide added
TnI elevated to 1.4
Case 3: Pre- and Post-Stent
Left coronary angiogram

preintervention with severe
proximal OM1 stenosis
Stent placed in OM1

Patient did well post-stent with no
recurrence of chest pain
Risk Stratification: Diabetes
20
% Patients
15
Heparin
(n=193)
Tirofiban + heparin
(n=169)
P=0.044
P=0.002
19.2%
15.5%
P=0.004
11.2%
10
9.3%
4.7%
5
1.2%
0
Day 7
Throux et al. Circulation. 1998;98:I-359.
Day 30
Day 180
Risk Stratification: Rest Pain

Death/MI at 42 Days
Death/MI at 1 Year
30
25
18.4
20
15
10
5
4.2
Rest Pain
<48 h
n=1091
1.4
0.0
No Rest
Pain
n=261
Cannon et al. Circulation. 1995;92:I-19. Abstract.
Death/MI, % of Patients
Death/MI, % of Patients
Unstable angina patients

Post-MI patients
30
26.3
25
20
15
10
10.9
7.3
0.0
Rest Pain
<48 h
No Rest
Pain
Risk Stratification: Troponin

Braunwald Class III Patients With Pos ECG
AMI Ruled Out by CK-MB at 16 Hours
Composite Endpoint
(30 days MI, Death)
25
20
23%
P=0.02
15
10
5
0
5.8%
TnIn = 69
Galvani. Circulation. 1997;95:2053-2059.
TnI+
n = 22
Patients With Elevated Troponin-I

Benefit From GP IIb/IIIa Addition
TnI positive with heparin
TnI positive with tirofiban
Event Rate (%)
15
10
0
0
Heeschen et al. Lancet. 1999;354:1757-1762.
10
15
20
Follow-up (days)
25
30
Risk Stratification: Aspirin Failure

25
No prior aspirin, n=3422

Prior aspirin, n=6039
% Patients
20
15
10
5
0
4-Day Death
30-Day Death/MI
Alexander et al. Am J Cardiol. 1999;83:1147-1151.
6-Month
Death/MI
Cardiogenic
Shock
Heart Failure
Risk Stratification: Refractory Angina

Myocardial Infarction or Death
%
P value
ST depression
13.3
0.004
>3 Pain episodes

in previous 48 h
10.6
0.01
Refractory angina
22.27
(proced and non-proced)
0.0001
Refractory angina
(non-proced)
0.0001
10.3
0
Odds Ratio
Bazzino. Am Heart J. 1999;137:322-331.
9 10 11 12 13 14
Indications for Initiation of GP IIb/IIIa Therapy

Ischemic Chest Pain
NonST-Elevation ACS High-Risk Indicators
Consider Treatment
Definitely Treat
ST Depression 1 mm
or
Positive Markers
or
Dynamic ECG
LV Dysfunction - HF
Diabetic - Elderly
Prior MI
Refractory Symptoms
Heparin and Aspirin

Glycoprotein IIb/IIIa Inhibitor
Nitrates
-Blocker
63 y/o male admitted to a

community hospital with chest
discomfort and epigastric pain
persisting for 8 hours
Hx smoking, chol, GERD
ECG: ST depressions V5-V6, T
wave changes V2-V4
Started on -blocker, nitrates, ASA

and heparin
No relief of Sx
CK 891; CK-MB 102; TnI 5.8
Tirofiban added
Pt became pain free 3 hours later
Transferred to tertiary center
Case 4: Angiography
Pt maintained on
tirofiban x 3 d w no Sx
Cath: Nl EF,
posterolateral hypo
Significant LAD, Cx,
RCA lesions
Decision to perform
CABG
Sheath removed on
tirofiban
Tirofiban contd until
8 hours prior to surgery
LIMA to LAD; SVG to
OM2, RCA
D/Cd day 5 post-op
Use of GP IIb/IIIa in Interventions

Heparin
Tirofiban + heparin
% Death/MI/RI/UAP Readmit
(30 Days)
40
30
20
OR=0.80
95% CI=0.40-1.0
OR=0.65
95% CI=0.42-1.01
OR=0.84
95% CI=0.56-1.27
16.8
14.8
32.9
26.7
24.7
18.1
10
Medical Rx
Barr et al. Circulation. 1998;98:I-504. Abstract.
PCI
CABG
% Death or MI (30 Days)
25
20
15
Heparin
Eptifibatide + heparin
RR=31%
P=0.01
RR=7%
P=0.23
16.7
15.6
14.5
11.6
10
5
0
Early PCI
(Within 72 h After Randomization)
Med Rx, Late PCI, CABG
The PURSUIT Trial Investigators. N Engl J Med. 1998;339:436-443.

Probability of Death or MI
All 1570 Patients Evaluated

0.12
0.08
475 Patients Undergoing PTCA

0.12
RR=44%
0.08
RR=66%
Tirofiban +
Heparin
0.04
Heparin Only
Tirofiban + Heparin
0.04
Heparin Only
0.00
0 6 12 18 24 30 36 42 48
0.00
2 4 7
Hours
Drug
Infusion
PTCA
The PRISM-PLUS Study Investigators. N Engl J Med. 1998;338:1488-1497.
14
Days
21
28
Inhibition of Aggregation (%)
Advantages of Short-Acting Agents

100
75
50
25
Eptifibatide
Abciximab
Tirofiban
0
24
0
Infusion Time
24
Postinfusion
Time (h)
Scarborough et al. Circulation. 1999;100:437-444.
48
Additional Benefit of GP IIb/IIIa in Patients

Already on Aspirin and Ticlopidine
% of Patients Death/MI
Death, MI at 1 Year
20
Pretreatment
20
P=0.021
No Pretreatment
15.8
15
P<0.001
15
11.2
10
10
6.9
6.7
Stent +
Placebo
N=466
Stent +
Abciximab
N=466
Steinhubl et al. Circulation. 1998;98(suppl):I-573.
Stent +
Placebo
N=343
Stent +
Abciximab
N=328
Case 5: Presentation and Pre-Stent
68-year-old man s/p stent to RCA

3 years ago
Prolonged chest pain at home
Troponin is elevated
Patient is stable over weekend
Current meds: aspirin

In ED recurrent chest pain
relieved with NTG
In ED patient is given eptifibatide
for 48 hours
Patient is brought to cath lab on
Monday
Case 5: Post-Stent
LAD stent placed
Patient discharged on
aspirin, clopidogrel,
statin
Patient does well with no

recurrence of symptoms
Eptifibatide continued for

24 hours
Benefits of Early Use of GP IIb/IIIa

Include Cool Down and Stabilization
Cumulative Incidence
of Death/Nonfatal MI (%)
During Initial Pharmacologic

Treatment
10
8
N=12,296
P=0.001
During 48 Hours After PCI
Control
GP IIb/IIIa inhibitor
N=2754
P=0.001
8.0%
6
4.9%
4.3%
2.9%
2
0
+24 h
+48 h
+72 h
+24 h
Start GP IIb/IIIa Inhibitor/Placebo
PCI
Boersma et al. Circulation. 1999;100:2045-2048.
+48 h
Pretreatment With GP IIb/IIIa Inhibitor

Reduces Adverse Events
= -4.4%, RR=19%, P=0.02
35
Heparin
With Endpoint (%)
30
25
Tirofiban + Heparin
20
15
= -3.8%, RR=22%, P=0.029
10
5
= -5.0%, RR=32%, P=0.004
0 7
30
60
90
Day
120
The PRISM-PLUS Investigators. N Engl J Med. 1998;338:1488-1497.
150
180
100
30
80
Bleeding time (min)
% Inhibition of Platelet Aggregation
Use of GP IIb/IIIa Inhibitors with LMWH
60
40
20
Tirofiban/enoxaparin
Tirofiban/enoxaparin
Tirofiban/unfrac heparin
P=0.02
24
24.9
18
19.6
12
6
Tirofiban/unfrac heparin
0
Hour 24
Hour 30
Cohen et al. International J Cardiol. 1999;71:273-281.
Hour 48
Adjusted Mean
Adverse Events: No Significant Rise in

Bleeding Rates
Tirofiban + Heparin
n=773
Heparin
n=797
P Value
1.4%
0.0%
0.8%
0.0%
NS
NS
10.5%
8.0%
NS
Transfusions
(all blood products)
4.0%
2.8%
NS
Platelets 90,000/mm3
1.9%
0.8%
NS
Major Bleeding (TIMI)

Intracranial bleeding
Minor Bleeding (TIMI)
The PRISM-PLUS Investigators. N Engl J Med. 1998;338:1488-1497.

AGGRASTAT package insert.
65-year-old man presents to ED with angina at rest
Meds: aspirin, beta blocker, NTG, statin, insulin
Patient has history of claudication, stroke 1 year ago with no residual deficit,
MI 5 y ago, CABG 3, diabetes, hypertension
Patient presents to community hospital
ECG shows new ST laterally
Patient is given enoxaparin, IV NTG
Case 6: Pre- and Post-Stent
Recurrent chest
pain
Tirofiban started
Patient is taken to
cath lab next day
Stent placed in
SVG to LAD
Patient
transferred to
tertiary care
center;
enoxaparin and
tirofiban continued
Adverse Events in Patients

Transferred to a Referral Center
Heparin alone
% Patients With Events
20
17.4
15
10.8
10.3*
10
5
0
20
15.4
13.8
15
Tirofiban + heparin
10
7.1*
10.3
8.1
5.4
3.9*
7
Days
12.0
30
Days
180
Days
Community Hospital
2.7
7
Days
30
Days
180
Days
Transfer
* P<0.04 vs. heparin.

P values for transfer subgroup were not calculated, as this group was defined by postrandomization events.
Throux et al. Eur Heart J. 1998;19(suppl):50. Abstract.
TnI Levels in UA/NQWMI Patients Treated

With Tirofiban: PRISM-PLUS
18
Heparin (n=52)
Troponin I (ng/mL)
Tirofiban + heparin (n=53)
P=0.017
15.5
12
P=NS
5.2
3.1
1.6
0
Baseline Levels
Hahn et al. J Am Coll Cardiol. 1998;31(suppl A):229A.
Peak Levels
Unfractionated Heparin Versus Enoxaparin in UA

(ESSENCE/TIMI 11B Pooled Analysis)
Day
UFH
(%)
Enox
(%)
1.8
Death/MI
OR
(95% CI)
1.4
0.80 (0.55-1.16)
20
0.24
5.3
4.1
0.77 (0.62-0.95)
23
0.02
14
6.5
5.2
0.79 (0.65-0.96)
21
0.02
43
8.6
7.1
0.82 (0.69-0.97)
18
0.02
0.5
1
2
Odds Ratio
Favors
Favors
Enoxaparin
UFH
Antman et al. Circulation. 1999;100:1602-1608.
GP IIb/IIIa Blockers and Platelet Count:

Relation to Unfractionated Heparin Use
6
NICE 4
EPIC B+I
EPILOG(SD)
EPILOG (LD)
EPISTENT (PTCA)
EPISTENT (Stent)
% Patients
5
4
3
2
1
0
<100,000
<50,000
Platelet Count
Kereiakes et al. Am J Cardiol. 1999;84 (suppl 6A):67P.
<20,000
85-year-old man presents with recurrent

pulmonary edema in acute respiratory
distress
Hx DM, moderate AS, 3VD, EF 30%,

COPD, AAA repair 10 y ago
Current meds: aspirin, beta blocker,

furosemide, glyburide, bronchodilators,
nitrates
Intubated in ED, taken to CCU

Heparin added, further diuresis
Tirofiban added
CK peak 312 (<3ULN)
MB peak 3.9 (<3ULN)
TnI 2.3
Case 7: Pre-Intervention
Taken to cath lab: IABP, temp pacemaker, dopamine added

Severe 3VD with significant LM and LAD lesions; RCA occluded
Declined by CV surgery as too high risk
RCA
LCA
Case 7: Post-Intervention
Rotablator
Stent (1 of 3)
Rotational atherectomy LM and LAD, 1.5 mm burr

3.0 15 mm balloon to 12 atm 3.0 16 mm GFX
stents (3 deployed)
Tirofiban continued for 12 hours post-procedure
Extubated on 3rd day; discharged home on 8th day
Proportion of Deaths (%)
Mortality Benefits With Use of GP IIb/IIIa

Inhibitors With Stents
Stent + placebo (n=809)
Stent + abciximab (n=794)
Balloon angioplasty + abciximab (n=796)
3.0
2.5
2.4%
2.0
2.1%
1.5
1.0
1.0%
0.5
0.0
0
60
120
180
240
Time Since Randomization (days)

Topol et al. Lancet. 1999;354:2019-2024.
300
360
P <0.037
Early Use of GP IIb/IIIa Results in Lower

Event Rate in High-Risk Interventions
Re-analysis
(Death, MI, all revascularization)
(Death, MI, urgent revascularization)
=-2.8%
RR = 27% Placebo + Heparin
P = 0.022
12
= -1.9%
RR =16%
P = 0.16
9
Tirofiban + Heparin
6
=-3.3%
RR = 38%
P < 0.005
3
0
0
10
15
Day
20
25
30
% With Composite Endpoint
Composite
12
10
= -2.5%
RR = 24%
P = 0.052
2.9%
RR = 30%
P = 0.016 Placebo + Heparin
8
6
Tirofiban + Heparin
= -3.5%
RR = 40%
P = 0.002
2
0
The RESTORE Investigators. Circulation. 1997;96:1445-1453.
10
15
Day
20
25
30
Case Studies: Conclusions
If there are no contraindications, GP IIb/IIIa inhibitors should

be incorporated into early medical management of these
patients with ACS:
All NQWMI patients
UA patients if they have high-risk features
If not already started, and there are no contraindications,

GP IIb/IIIa inhibitors should be used in all patients with ACS
undergoing percutaneous interventions

Case Studies in The Management of Acs With GP Iib/Iiia Inhibitors

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Case Studies in The Management of Acs With GP Iib/Iiia Inhibitors

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Case Studies in the Management of ACS

With GP IIb/IIIa Inhibitors

64-year-old woman with

Case 1: Recurrent Chest Pain

One hour later patient develops recurrent

Patient taken to cath lab

Stent placed in RCA

Final ECG demonstrates no

Case 1: Lessons Learned

Reocclusion After Thrombolysis Is a

TIMI Grade 3 Flow

Case 1: Lessons Learned

Use of GP IIb/IIIa Inhibitors With Reduced

Cannon. J Am Coll Cardiol. 1999;34:1395-1402.

Case 1: Lessons Learned

Use of GP IIb/IIIa Inhibitors With Reduced

Antman et al. Circulation. 1999;99:2720-2732.

76-year-old man presents with crescendo

Stent placed in area of lesion

Patient given abciximab

Case 2: Lessons Learned

Thrombus Is Less Common and Flow Is

Zhao et al. Circulation. 1999;100:1609-1615.

Case 2: Lessons Learned

Long-Term Benefit of Reduced Thrombus

Zhao et al. Circulation. 1999;100:1609-1615.

MI/Death Refract Isch

TIMI 0-2 (n=298)

MI/Death Refract Isch

Case 2: Lessons Learned

Better Coronary Flow Reserve

Neumann et al. Circulation. 1998;98:2695-2701.

% Patients With Events

Wall Motion Index

Coronary Flow Velocity (cm/s)

Difference From Baseline to 14 Days

58-year-old man with

Case 3: Pre- and Post-Stent

Left coronary angiogram

Stent placed in OM1

Case 3: Lessons Learned

Risk Stratification: Diabetes

Throux et al. Circulation. 1998;98:I-359.

Case 3: Lessons Learned

Risk Stratification: Rest Pain

Cannon et al. Circulation. 1995;92:I-19. Abstract.

Unstable angina patients

Case 3: Lessons Learned

Risk Stratification: Troponin

Galvani. Circulation. 1997;95:2053-2059.

Case 3: Lessons Learned

Patients With Elevated Troponin-I

Event Rate (%)

Heeschen et al. Lancet. 1999;354:1757-1762.

Case 3: Lessons Learned

Risk Stratification: Aspirin Failure

No prior aspirin, n=3422

Alexander et al. Am J Cardiol. 1999;83:1147-1151.

Case 3: Lessons Learned

Risk Stratification: Refractory Angina

>3 Pain episodes

Case 3: Lessons Learned

Indications for Initiation of GP IIb/IIIa Therapy