Acute Coronary Syndromes: Management of UANSTEMI

1
Acute Coronary Syndromes Management of
UA/NSTEMI
2
Overview of 2003 Updates to the ACC/AHA
Guideline for UA/NSTEMI

• Assess likelihood of CAD
• Risk stratification
• Target therapy more aggressive treatment in
  higher-risk patients
• Anti-ischemic, antithrombotic therapy
• Invasive vs conservative strategy
• Discharge planning (risk factor modification and
  long-term medical therapy)

ACC/AHA, American College of Cardiology/American
Heart Association UA, unstable angina NSTEMI,
nonST-segment elevation myocardial
infarction.Braunwald E, et al. J Am Col.
Cardiol. 200036970-1062.
3
Acute Management of UA/NSTEMI

• Anti-Ischemic Therapy
• Oxygen, bed rest, ECG monitoring
• Nitroglycerin
• ?-Blockers
• ACE inhibitors

• Antithrombotic Therapy
• Antiplatelet therapy
• Anticoagulant therapy

UA, unstable angina NSTEMI, non-ST-segment
elevation myocardial infarction ECG,
electrocardiogram ACE, angiotensin-converting
enzyme. Braunwald E, et al. J Am Coll Cardiol.
200036970-1062.
4
ACC/AHA Class I Recommendations for
Antithrombotic Therapy
Definite ACS With Invasive Strategy
(Catheterization/PCI) or High Risk (IIa)
Possible ACS
Likely/Definite ACS
Aspirin
Aspirin IV Heparin IV Platelet GP IIb/IIIa
Antagonist
Aspirin SQ LMWH or IV Heparin
Clopidogrel
Clopidogrel
Class IIa enoxaparin preferred over UFH unless
CABG planned within 24 hours. ACC, American
College of Cardiology AHA, American Heart
association ACS, acute coronary syndrome PCI,
percutaneous coronary intervention SQLMWH,
subcutaneous low molecular-weight heparin IV,
intravenous. Braunwald E, et al. J Am Coll
Cardiol. 200036970-1062.
5
Aspirin in Acute Coronary Syndromes
Unstable Angina
Acute MI
Plt.0001 Death or MI
P.003 Reocclusion
P.012 MI
Plt.001 Death
20
30
4
15
17.1
25.0
3.3
11.8
15
3
9.4
20
10
1.9
Patients ()
10
2
11.0
6.5
10
5
5
1
0
0
0
0
Placebo
ASA
Placebo
Placebo
Placebo
ASA
ASA
ASA
N 397 399 513 419 8587 8600 8587 8600
MI, myocardial infarction ASA, acetylsalicylic
acid RISC, Research on InStability in Coronary
artery disease. RISC Group. Lancet.
1990336827-830. Roux S, et al. J Am Coll
Cardiol. 199219671-677. ISIS-2. Lancet.
19882349-360.
6
Aspirin in Acute Coronary Syndromes
Primary Prevention
Stable Angina
UA/NSTEMI
Plt.0001MI
P.0003MI
P.008Death or MI
P.012Death or MI
15
12.9
15
15
2.2
2.5
12.9
11.9
2
10
10
10
1.3
1.5
6.2
Patients ()
1
3.9
3.3
5
5
5
0.5
0
0
0
0
ASA
ASA
ASA
ASA
Placebo
Placebo
Placebo
Placebo
N 11034 11037 155 178 279 276 118 121
MI, myocardial infarction ASA, acetylsalicylic
acid RISC, Research on InStability in Coronary
artery disease ISIS-2, Second International
Study of Infarct Survival. PHS. N Engl J Med.
1989321129-35. Ridker PM, et al. AJC.
1991114835-839. Cairns JA, et al. N Engl J Med.
19853131369-1375. Theroux P, et al. N Engl J
Med. 19883191105-1111.
7
Indirect Comparisons of ASA Doses on Vascular
Events in High-Risk Patients
OR
Aspirin Dose No. of Trials ()
Odds Ratio
500-1500 mg 34 19
160-325 mg 19 26
75-150 mg 12 32
lt75 mg 3 13
Any aspirin 65 23
0.5
1.0
1.5
2.0
0
Odds reduction. Treatment
effect Plt.0001. ASA, acetylsalicylic
acid. Adapted with permission from BMJ
Publishing Group. Antithrombotic Trialists
Collaboration. BMJ. 200232471-86.
Antiplatelet Better
Antiplatelet Worse
8
BRAVO Bleeding By ASA dose
Outcomes by Aspirin Dose in Placebo Study Drug
Patients
Low Dose,75-162 mg/d(n2410)
Higher Dose,gt162 mg/d(n2179)
Primary end point 16.4 18.6 Death, MI,
stroke 6.2 6.1 Death 2.8 1.7 MI 2.0 2.1 Stroke 2.1
2.8 Urgent hospital care 9.5 10.6 Urgent
resuscitation 7.3 10.0 Internal
bleeding 2.4 3.3 Any bleeding 11.1 15.4 Transfusio
n 1.0 2.0
Topol EJ, et al. Circulation. 2003108399-406.
(with permission)
9
CURE Major Bleeding at 1 year by ASA Dose
Clopidogrel ASA (N6259)
Placebo ASA (N6303)
ASA Dose

• lt100 mg (N5320) 1.9 3.0
• 100-199 mg (N3109) 2.8 3.4 gt200 mg
  (N4110) 3.7 4.9
• P value for trend .0001 .0009

P.0001. P.0009. Adapted from Peters RJG, et
al. Circulation. 20031081682-1687.
10
Comparison of Heparin ASA vs ASA Alone
B
Theroux
B
RISC
B
Cohen 1990
B
ATACS
B
Holdright
B
Gurfinkel
Summary Relative Risk
B
0.67 (0.44-0.1.02)
0.1
1
10
RR Death/MI
ASA Alone 68/65510.4
Heparin ASA 55/6987.9
ASA, acetylsalicylic acid RISC, Research on
InStability in Coronary artery disease ATACS,
Antithrombotic Therapy in Acute Company
Syndromes RR, relative risk MI, myocardial
infarction. Oler A, et al. JAMA.
1996276811-815. (with permission)
11
TIMI IIB/ESSENCE MetanalysisEnoxaparin vs
Unfractionated Heparin
TIMI, Thrombosis in Myocardial Infarction
ESSENCE, Efficacy and Safety of Subcutaneous
Enozapam in NonQ-Wave Coronary Events UHF,
unfractionated heparin ENOX, enoxaparin MI,
myocardial infarction OR, odds ratio. Antman EM,
et al. Circulation. 19991001602-1608. (with
permission)
12
TIMI IIB Early Phase Death/MI/Urgent Revasc
UHF, unfractionated heparin ENOX, enoxaparin
RRR, relative risk ratio. Antman EM. Circulation.
19991001593-1601. (with permission)
13
INTERACT Enoxaparin vs Unfractionated Heparin
With GP IIb/IIIa Inhibitors
Major Bleeds96 Hours
Death/MI30 Days
P.03
P.031
Percent
Enoxaparin
UFH
UFH
Enoxaparin
Goodman SG, et al. Circulation. 2003107238-244.
14
A-Phase Study Design
1? endpoint 7 days
ENOX 1mg/kg q12 hr
2018
2026
Z
UA/ NSTEMI
3987
Tirofiban ASA
Treat Evaluate for Z-Phase
Z
UFH Weight-adjusted
1961
1952
Aggressive or conservative care per local practice
Randomize
Chest pain
- 24 hours
Hour 0
Final A visit 30 days
Min 0 hour Max 120 hour
Blazing M. presented at ACC 2003.
15
7- and 30-Day Primary EndpointComposite Death,
MI and Refractory Ischemia
UFH
9.4 (184 events)
12
ENOX
10
8
8.4 (169 events)
Event Rates ()
6
4
UFH
Day 7
Enoxaparin
2
0
0
10
20
30
Days From Randomization
Blazing M. presented ACC 2003.
16
Enox Test vs Outcomes
Death/MI/Urg TVR Bleeding
30
30
25
25
20
20
Probability of Any Bleeding ()
15
15
Probability of MACE ()
10
10
5
5
0
0
200
250
300
350
400
450
500
550
600
200
250
300
350
400
450
500
550
600
ENOX Time (sec)
ENOX Time (sec)
Moliterno DJ, et al. JACC. 2003421132-1139.
(with permission)
17
Direct Thrombin Inhibitor Trialists' Collaboration
Death orMyocardialInfarction
Direct ThrombinInhibitor Heparin(N18,736)
(N17,184)
OR (95 Cl)
0.85 (0.77-0.94) 0.88 (0.80-0.96) 0.91 (0.84-0.9
9)
815 (4.3) 883 (5.1) 947 (5.0) 990
(5.8) 1399 (7.4) 1409 (8.2)
End of treatment 7 days 30 days
Death
355 (1.9) 346 (2.0) 422 (2.2) 395
(2.3) 685 (3.6) 642 (3.7)
0.97 (0.83-1.13) 1.00 (0.87-1.16) 1.01 (0.90-1.1
2)
End of treatment 7 days 3 days
11 RCTS 36,000 Pts ACS, PCI
MyocardialInfarction
522 (2.8) 596 (3.5) 601 (3.2) 672
(3.9) 876 (4.7) 917 (5.3)
0.80 (0.71-0.90) 0.81 (0.72-0.91) 0.87 (0.79-0.9
5)
End of treatment 7 days 30 days
Stroke
0.95 (0.66-1.35) 0.94 (0.68-1.31) 1.01 (0.78-1.3
1) 0.75 (0.65-0.87) 0.72 (0.42-1.23)
End of treatment 7 days 30 days
62 (0.33) 60 (0.35) 72 (0.38) 70
(0.41) 120 (0.64) 110 (0.64) 360 (1.90) 403
(2.30) 21 (0.11) 28 (0.16)
Major bleedingduring treatmentIntracranial
bleeding during treatment
Direct Thrombin Inhibitor Trialists
Collaborative Group. Lancet. 2002359294-302.
(with permission)
18
Expert Panel Consensus
UA/NSTEMI Identified, LMWH
Early invasive strategy
Catheterization within 8 hours of last
subcutaneous dose
Catheterization between 8-12 hours of last
subcutaneous dose
/- GP IIb/IIIa
- GP IIb/IIIa
GP IIb/IIIa
No additional UFH or LMWH
Additional Enoxaparin 0.3 mg/kg IV bolus
Supplement with UFH lt50 U/kg, aim for ACT 200-250
Supplement with UFH lt60 U/kg, aim for ACT 250-300
Additional Enoxaparin 0.3-0.5 mg/kg IV
Kereiakes DJ, et al. Am Heart J.
2002144615-624. (with permission)
19
GP IIb/IIIa Inhibitor During Medical Management
and After PCI CAPTURE, PURSUIT, PRISM-PLUS
Post PCI
Medical Rx
10
N2754 P.001
N12,296 P.001
Control GP IIb/IIIa inhibitor
8.0
8
6
Death or MI
4.9
4.3
4
2.9
2
0
24 h
48 h
72 h
24 h
48 h
0
PCI
Boersma E, et al. Circulation. 19991002045-2048.
(with permission)
20
Meta-analysis of IIb/IIIa Inhibition in PCI for
30-Day Mortality
IIb/IIIa Inhibitor Better
Placebo Better
N 2099 2792 483 1265 150 4010 2141 2399 2064 401 3
00 2082 20186
Trt 1.5 0.4 2.5 1.0 1.0 0.7 0.8 0.5 0.4 2.0 3.4 1.
9 0.9
Ctrl 1.7 0.7 2.1 1.3 2.0 1.1 0.7 0.6 0.6 4.5 6.6 2
.3 1.3
EPIC EPILOG RAPPORT CAPTURE Impact I Impact
II Restore Epistent Espirit ISAR
2 Admiral Cadillac Combined
0.73 (0.55,0.96)
P.024
0.1
1
10
OR
Kong DF, et al. Am J Cardiol. 200392651-655.
(with permission)
21
IV GP IIb/IIIa Inhibitors in ACS Death or MI at
30 Days (N31,402)
Placebo
IV Gp IIb/IIIa
Study
Odds Ratio
95 CI
PRISM 7.1 5.8 0.80 0.60-1.06 PRISM-PLUS 12.0
() 8.7 0.70 0.50-0.98 (
) 13.6 1.17 0.80-1.70 PARAGON-A 11.7 (l) 10.3
0.87 0.58-1.29 (h) 12.3 1.06 0.72-1.55
PURSUIT 15.7 (l) 13.4 0.83 0.70-0.99 (h) 14.2
0.89 0.79-1.00 PARAGON-B 11.4 10.6 0.92 0.77
-1.09 GUSTO-IV 8.0 (24h) 8.2 1.02 0.83-1.24
(48h) 9.1 1.15 0.94-1.39 Overall 11.8 10.8
t 0.91 0.85-0.98
0
1.0
2.0
Placebo Better
Gp IIb/IIIa Better
P.015
Without heparin. With/without heparin. (l),
Low dose (h), High-dose. Boersma E, et al.
Lancet. 2002359189-198.
22
Benefit of IIb/IIIa inhibitors in UA/NSTEMI by
Troponin
Death or MI at 30 days ()
TnI gt0.1 ?g/L
UA, unstable angina NSTEMI, nonST-segment
elevation myocardial infarction CAPTURE,
Chimeric-7E3 AntiPlatelet Therapy in Unstable
angina REfractory to standard treatment PRISM,
Platelet Receptor Inhibition for Ischemic
Syndrome Management Study TnT, tropponin T
level TnI, troponin I level. Hamm CW, et al. N
Engl J Med. 19993401623-1629. Heeschen C, et
al. Lancet. 19993541757-1762.
23
GP IIb/IIIa Inhibition in TnI Patients by
Revascularization PRISM Study
Death/MI at 30 Days
16
0.37 (0.15-0.93) P .02
12
0.30 (0.10-0.84) P .004
Revascularization
8
Event rate ()
No revascularization
Heparin Heparin Tirofiban Tirofiban
4
0
0
5
10
15
20
25
30
Follow-up (days)
TnI, troponin I PRISM, Platelet Receptor
Inhibition for Ischemic Syndrome Management
study MI, myocardial infarction. Heeschen C,
et al. Lancet. 19993541757-1762. (with
permission)
24
GP IIb/IIIa Inhibition in Diabetics
30-Day Mortality in Diabetic Patients
Trial N Odds Ratio 95 Cl Placebo IIb/IIIa
2163 687 362 1677 412 1157 6458
PURSUIT PRISM PRISM-PLUS GUSTO IV PARAGON
A PARAGON B Pooled
6.1 4.2 6.7 7.8 6.2 4.8 6.2
5.1 1.8 3.6 5.0 4.6 4.9 4.6
P.33 P.07 P.17 P.022 P.51 P.93 P.007
0 0.5 1 1.5 2
Breslow-Day P.50 IIb/IIIa Better Placebo
Better OR0.74
Roffi M, et al. Circulation. 20011042767-2771.
(with permission)
25
Intravenous GP IIb/IIIa Antagonists in ACS Death
or MI (at 30 Days) in PCI/CABG lt5 Days Cohort and
in Medical Treatment Cohort
P.001
20
Placebo
17.3
18
IV GP IIb/IIIa
PNS
16
14.3
14
12
10.5
10.1
Death or MI
10
8
6
Interaction Plt.02
4
2
0
Intervention
Medical Treatment
(N5847)
(N25,555)
ACS, acute coronary syndrome MI, myocardial
infarction PCI, percutaneous coronary
intervention CABG, coronary artery bypass
graft NS, not significant. Boersma E, et al.
Lancet. 2002359189-198.
26
GP Iib/IIIa Inhibitor NSTE ACS Trials Analysis
Risk-Adjusted Mortality at 30 Days
Odds Ratio for Mortality at 30 Days
95 CI
Odds Ratio
0.79-0.97
0.88
NRMI1
0.83-1.01
0.91
Boersma2
0.5
2.0
1.0
GP IIb/IIIa Inhibitor Favored (aspirin heparin)
Control Arm Favored (aspirin heparin)
Peterson ED, et al. J Am Coll Cardiol.
20034245-53.Boersma E, et al. Lancet.
2002359189-198.
27
Mortality by Hospitals Use of Early GP IIb/IIIa
Inhibitors (N1189 Hospitals)
In-Hospital Mortality ()
14
12
10
8
In-Hospital Mortality ()
6
4
2
0
lt5
5-15
16-30
gt30
Hospital Use of Early GP IIb/IIIa inhibitors in
NRMI ()
NRMI, National Registry of Myocardial Infarction.
Peterson ED, et al. J Am Coll Cardiol.
20034245-53. (with permission)
28
Efficacy of Clopidogrel or Ticlopidine in
Reducing Coronary Events After Stenting
30-Day Major Adverse Cardiac Events
Odds Ratio 95 CI
Trial
Clopid. ()
Ticl. ()
N
CLASSICS
1020
1.3
0.9
TOPPS
1016
2.6
3.5
Müller
700
3.1
1.7
CCF
2369
5.7
8.9
Lenox Hill
2565
2.4
3.8
Mayo
2827
0.6
1.6
N. Memorial
1378
0.8
2.2
S. Illinois
875
2.1
1.4
Wash. Hosp.
844
2.0
0.5
Wessex
-361
3.4
5.2
Overall
13,955
2.0
3.9
OR.73, P.003
0.1
1
10
Ticlopidine Better
Clopidogrel Better
CLASSICS, Clopidogrel Aspirin Stent Intervention
Coopoerative Study. Bhatt DL, et al. J Am Coll
Cardiol. 2002399-14. (with permission)
29
CURE Primary End Point MI/Stroke/CV Death
CURE, Clopidogrel in Unstable Angina to Prevent
Recurrent Ischemic Events MI, myocardial
infarction CV, cardiovascular RRR, relative
risk reduction. Plavix package insert 2002.
Adapted with permission (2002) from the
Massachusetts Medical Society. Yusuf S, et al. N
Engl J Med. 2001345494-502.
30
CURE MI/Stroke/CV Death/Severe Ischemia Within
24 Hours of Randomization
CURE, Clopidogrel in Unstable Angina to Prevent
Recurrent Ischemic Events MI, myocardial
infarction CV, cardiovascular RRR, relative
risk reduction RR, relative risk. Adapted from
Yusuf S, et al. Circulation. 2003107966-972.
31
CURE Benefit of Clopidogrel Aspirin Across All
TIMI Risk Score Groups
Primary Composite End Point (CV Death, MI, Stroke)
CURE, clopidogrel in Unstable Angina to Prevent
Ischemic Events TIMI, Thrombosis in Myocardial
Infarction CV, cardiovascular MI, myocardial
infarction RRR, relative risk reduction ARR,
Absolute risk reduction. In addition to other
standard therapies. Budaj A, et al. Circulation.
20021061622-1626. (with permission)
32
PCI-CURE Study Design
CURE
PCI-CURE
N2658 patients undergoing PCI
Pretreatment
Open-label thienopyridine
PLACEBO ASA
N1345
End of follow-up up to 12 months after
randomization
30 days post-PCI
PCI
R
Open-label thienopyridine
CLOPIDOGREL ASA
N1313
Pretreatment
Mehta SR, et al. Lancet. 2001358527-533.
33
PCI CURE Benefit of Pretreatment With
Clopidogrel at 30 Days
Cardiovascular Death, MI, or Urgent
Revascularization
0.08
Placebo ASA
6.4
0.06
4.5
0.04
Cumulative Hazard Rate
Clopidogrel ASA
0.02
30 RRR P.03 N2658
0.0
0
5
10
15
20
25
30
Follow-up (days)
Mehta SR, et al. Lancet. 2001358527-533. (with
permission)
34
PCI-CURE Long-term Results
CV Death or MI From Randomization to End of
Follow-up
0.15
12.6
Placebo Aspirin
31 Relative RiskReduction
0.10
8.8
Cumulative Hazard Rates
Clopidogrel Aspirin
0.05
P.002N2658
0.0
0
100
200
300
400
Follow-up (days)
Adapted from Mehta SR, et al. Lancet.
2001358527-533. (with permission)
35
Credo Study Study Design
Objective To assess the benefit of 1 year vs 1
month of clopidogrel plus aspirin in patients
undergoing PCI
PCI
28 Days
12 Months
Pretreatment3-24 h before PCI
Clopidogrel Arm
Clopidogrel 300 mg aspirin (325 mg)
Clopidogrel 75 mg QD aspirin 325 mg QD
Clopidogrel 75 mg QD aspirin (81-325 mg) QD
R
Clopidogrel 75 mg QD aspirin 325 mg QD
Placebo QD aspirin (81-325 mg) QD
Placebo Arm
Placebo aspirin (325 mg)
Steinhubl S, et al. JAMA. 20022882411-2420.
36
Effect of Timing of Loading Dose28-Day
EndpointDeath, MI, UTVR
Events ()
No-PT Better
PT-Clopidogrel Better
N
PT-Clopidogrel
No-PT
3 to lt6 hrs 7.9 7.0 893 6 to 24 hr 5.8 9.4
851
RRR -13.4 PNS
RRR 38.6 P.05
Overall CREDO Results
RRR 18.5 P.23
0.4
0.6
0.8
1.0
1.2
Hazard ratio (95 CI)
PT, pretreatment UTVR, urgent target vessel
revascularization. Plus ASA and other standard
therapies. Steinhubl S, et al. JAMA.
20022882411-2420.
37
CREDO Benefits of Clopidogrel Plus Aspirin to 1
Year Following PCI
CV Death, MI or Stroke
15
Placebo Clopidogrel
11.5
27 RRR P.02
10
8.5
Combined Endpoint Occurrence ()
5
0
0
3
6
9
12
Months From Randomization
Plus ASA and other standard therapies
. Steinhubl S, et al. JAMA. 20022882411-2420.
(with permission)
38
CURE Bleeding Results
CURE, Clopidogrel in Unstable Angina to Prevent
Ischemic Events Other standard therapies were
used as appropriate. Life-threatening and other
major bleeding . Plavix package insert 2003.
39
PCI-CURE Bleeding Outcomes
Placebo ASA ()
Clopidogrel ASA ()

• From PCI to 30 days
• Major 1.4 1.6
• Life threatening 0.7 0.7
• Minor 0.7 0.9
• From PCI to end of follow-up
• Major 2.5 2.7
• Life threatening 1.3 1.2
• Minor 2.1 3.5

PNS, P0.03 Adapted from Mehta SR, et al.
Lancet. 2001358527-533.
40
Major/Life-Threatening Bleeds Within 7 Days of
CABG Surgery
CURE investigators. N Engl J Med. 2001 Fox KM.
Presented at ESC 2002.
41
CURE Outcomes by CABG in Initial
Hospitalization (CV death/MI/Stroke
CURE investigators. N Engl J Med. 2001 Fox KM.
Presented at ESC 2002.
42
Early Clopidogrel Timing in ACS

• PCI-CURE and CREDO Need to start clopidogrel
  early (gt6 h) to get post-PCI benefit
• 50-60 of patients get PCI, 8-20 get CABG
  (half of whom are gt5 d postcatheterization
  anyway)
• Tradeoff per 1000 UA/NSTEMI patient Rx
• Early Rx prevents additional 10 major cardiac
  events vs creating 1.5 TIMI minor bleed post-CABG

ACS, acute coronary syndrome PCI, percutaneous
coronary intervention CURE, Clopidogrel in
Unstable Angina to Prevent Recurrent Events
CREDO, Clopidogrel for Reduction of Events During
Observation CABG, coronary artery bypass graft
UA, unstable angina NSTEMI, nonST-segment
myocardial infarction TIMI Thrombosis in
Myocardial Infarction. Boersma E, et al. Lancet.
2002359189-198.
43
PRONTO Study Effect of Co-Administration of
Various Statins With Clopidogrel
PRONTO Study100 Patients Undergoing Elective
Stenting
Induced Platelet Aggregation ? SD(5 ?M ADP
induced Platelet Aggregation)
PRONTO, Plavix Reduction Of New Thrombus
Occurrence. Gurbel PA, et al. Am Heart J.
2003145239-247.
44
No Interaction of Clopidogrel and Atorvastatin
18 16 14 12 10 8 4 2 0
RRR 60.6P.11
RRR 26.9P.02
RRR 12.4P.51
RRR 38.6P.01
RRR 36.4P.03
RRR 49.8P.02
RRR 63.3P.13
1-Year Death/MI/Stroke Event Rate ()
All patients(n2116)
No statin(n944)
Any statin (n1172)
CYP3A4-MET statin (n1001)
Atorvastatin statin (n564)
Prevastatin (n142)
Non-CYP3A4-MET statin (n158)
Saw P, et al. Circulation. 2003108921-924.
(with permission)
45
ISAR-REACT Trial
2159 low-risk patients undergoing elective
stenting, excluding patients with

• Acute coronary syndrome
• Acute MI with 14 days
• ST-segment depression
• Positive biomarkers
• Insulin-dependent diabetes

• Chronic total occlusions
• EF lt30
• Thrombus presence
• Lesions in bypass grafts

Clopidogrel (600-mg loading dose, 2 x 75 mg/d
through discharge, 75 mg/d for 4 weeks)

• Endpoints
• Primary 30 day death/MI/urgent target vessel
  revascularization
• Secondary 30-day bleeding complications

ACC 2003, Late Breaking Trials.
46
ISAR-REACT 30 Day Endpoints
Death/MI/Urgent TVR () P.82
Death ()PNS
Urgent TVR ()PNS
6
6
6
4.2
4.0
4
4
4
2
2
2
0.9
0.7
0.3
0.3
0
0
0
Abciximab
Placebo
Abciximab
Placebo
Abciximab
Placebo
ACC 2003, Late Breaking Trials.
47
Clopidogrel Therapy May Reduce the Risk
Associated With Elevated Baseline CRP Status
Death or MI by Day 30 in Patients Undergoing PCI
With Stenting
24 (n74)
No Thienopyridinepretreatment
25
Thienopyridinepretreatment
20
13 (n295)
15
10 (n565)
10.2 (n136)
Percent
10
58 RRR P.002
5
0
Total Population0lt11 mg/L
Highest Quartilegt11 mg/L
CRP, C-reactive protein MI, myocardial
infarction PCI, percutaneous coronary
intervention RRR, relative risk ratio. Chew
DP, et al. Am J Cardiol. 200188672-674.
48
Clopidogrel Therapy Attenuates the Risk
Associated With Baseline CRP Status
30-Day Death or MI in Patients Undergoing PCI
with Stenting
24.0

25
No pretreatment
58 RRR P.002
Clopidogrel pretreatment
20
15
12.5
12.3
11.8
Patients ()
10.2
10
7.9
7.7
5.7
5
0
1st Quartile
2nd Quartile
3rd Quartile
4th Quartile
n216
n218
n227
n216
CRP Quartiles (mg/dl)
Adapted from Chew DP, et al. Am J Cardiol.
200188672-674.
49
Invasive vs Conservative Strategy for UA/NSTEMI
ISAR-COOL
2003
RITA-3
VANQWISH
VINO
MATE
TRUCS
TIMI IIIB
TACTICS-TIMI 18
FRISC II
Conservative
Invasive
No. of Patients 920 1674 7018
UA, unstable angina, NSTEMI, nonST-segment
myocardial infarction ISAR, Intracoronary
Stenting and Antithrombic Regimen Trial RITA,
Randomized Intervention Treatment of Angina
VANQWISH, Veterans Affairs Non-Q-Wave Infarction
Strategies in Hospital study MATE, Medicine vs
Angioplasty for Thrombolytic Exclusions trial
TACTICS-TIMI18, Treat Angina with Aggrestat and
Determine Cost of Therpay with Invasive or
Conservative Strategy FRISC, Fragmin during
InStability in Coronary artery disease.
50
Benefit of Invasive Strategy by Troponin and ST
Changes
Death, MI, Rehosp ACS at 6 Months
Plt.001
Plt.001
30
30
25.0
PNS
PNS
24.5
25
25
20
20
16.4
16.6
16.0
15.3
15.1
CV Events ()
15
15
12.4
10
10
5
5
0
0
TnT -
TnT
No ST change
ST change
TnT, troponin T ST, ST segment. Morrow DA. JAMA.
20012862405-2412 Cannon CP. N Engl J Med.
20013441879-1887.
51
2000 ACC/AHA UA/NSTEMI GuidelinesEarly Invasive
Strategy
Class I Any of the high-risk indicators (Level of
Evidence A) a) Recurrent angina at
rest/low-level activity despite Rx b)
Elevated TnT or TnI c) New ST-segment
depression d) Rec. angina/ischemia with CHF
symptoms, rales, MR e) Positive stress test
f) EF lt0.40 g) ?BP h) Sustained
VT i) PCI lt6 mos, prior CABG
Braunwald E, et al. J Am Col Cardiol.
200036970-1062.
52
Long-Term Cost-Effectiveness Analysis
Framingham
PURSUIT
CE Ratio per life-year gained
? Life-years (I-C)
CE Ratio per life-year gained
? Life-years (I-C)
? Costs (I-C)
13,022
0.045
0.046
586
Overall population
12,739
3982
0.217
3806
0.227
864
ST changes
Troponin T ?0.01
13,266
0.079
10,175
0.103
1048
Adapted from Mahoney EM, et al. JAMA.
20022881851-1858.
53
SIRIUS Drug Eluting Stents
100
Sirolimus-stent group
91.1
90
Standard-stent group
Event-free Survival ()
80
78.6
0
0 30 60 90 120 150 180 210 240 270
Days After Initial Procedure
No. at Risk Sirolimus Stent Standard Stent
533 529 527 524 520 515 509 505 493 477 525 523 52
1 514 506 481 474 465 451 436
Actuarial Rate of Survival Free from
Target-Vessel FailureAmong Patients Who Received
Either a Sirolimus-Eluting Stent or a Standard
Stent The rate of event-free survival was
significantly higher in the sirolimus-stent group
than in the standard-stent group (Plt.001 by the
Wilcoxon and log-rank tests).
Moses, et al. N Engl J Med. 20033491315-1323.
(with permission)
54
TACTICS Primary Endpoint
Death, MI, Rehosp for ACS at 6 Months
19.4 15.9
20
16
Patients
12
O.R 0.78 95 CI (0.62, 0.97) P.025
8
4
CONS
INV
0
0
1
2
3
4
5
6
Time (months)
Cannon CP. N Engl J Med. 20013441879-1887.
(with permission)