Transcript Acute Coronary Syndrome: An Overview

Up-to-date :
Antiplatelet
Therapy for Acute
Coronary
Syndrome
นพ. ภาวิทย์ เพียรวิจิตร
หน่ วยโรคหัวใจ
คณะแพทยศาสตร์ โรงพยาบาลรามาธิบดี
มหาวิทยาลัยมหิดล
Increasing CV Mortality
90
CVD
Accident
Cancer
AIDS
Pneumonia
Diarrhea
70
60
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40
30
20
10
0
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Year
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67
Death rare per 100,000 populations
80
Bureau of Health Policy and Plan and Division of Epidemiology, MOPH
CAD: 2 Major Presentations
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Stable angina
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Unstable angina / ACS
Case # 1: อาการคงที่ (stable angina)
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Age: 55
Sex: Male
Past History: HTN
Occupation: High stress
Complaint:
 Chest pain when he runs
about 500 meters.
 Relieved with rest in 3
minutes.
 Occasional chest pain
with stress
‘Stable’ Angina: Predictable Disease
ไขมัน พังผืด เซล
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Age: 50
Sex: Male
Habit: non-smoker
Past History: Complaint:
 Sudden onset of chest pain
while resting
 No improvement after
15minutes
What causes ‘unstable’ symptom?
?
Acute Coronary Syndrome
ลิม่ เลือด
Truths about Plaque Rupture
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No warning.
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Can occur after ‘normal’ EST.
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No precipitating cause: ?↑BP,
?activitiy
Spectrum of ACS
Accelerating/ New onset Angina
Unstable Angina, EKG-, TropUA with Trop+ / NSTEMI / NQWMI
STEMI / QWMI
Non ST Elevation MI
ST Elevation MI
แนวทางการรักษาคนไข้ ACS

Prevent plaque rupture
 Statins
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Decrease O2 need
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Decrease platelet activation and
aggregation
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Open blocked vessel
ยาที่ควรให้ ใน ACS
(NSTEMI and STEMI)
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ยาต้ านเกล็ดเลือด
B-blockers* (? mode of administration)
 Ca blockers as alternatives
Class I
Nitrates
O2
Recommendation
Morphine
If no contra-indications!
Anti-coagulation
ACEI*
Aspirin

Mechanism of action:
 Irreversible COX inhibitor
 Prevents thromboxane A2 formation
 Diminishing platelet aggregation
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Indication: Class IA
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Dosage: 160-300mg
Efficacy of ASA: Reduction of
Death or MI in Unstable Angina
Probability of death or MI
0.25
Placebo
0.20
Risk ratio after 1 year 0.52
95% Cl 0.37–0.72 (p=0.0001)
0.15
0.10
ASA 75 mg
0.05
0.00
0
3
6
9
12
Months
Wallentin LC et al JACC 1991;18:1587–1593
Lytics & ASA in STEMI: ISIS-2
25%*
14
5-week mortality (%)
12
10
p <0.00001
12.0%
23%*
p <0.00001
42%*
p <0.00001
13.2%
11.8%
9.2%
9.4%
8.0%
8
6
4
2
0
Placebo versus
streptokinase
1. ISIS-2 Collaborative Group. Lancet 1988; 2: 349360.
Placebo versus
ASA 162 mg
Neither
versus both
*Odds reduction
ADP Antagonist
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Thienopyridine derivative
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Mechanism of action:

ADP receptor antagonist
Mode of Action
COX, cyclooxygenase; ADP, adenosine diphosphate; TxA2, thromboxane A2
Schafer AI Am J Med 1996;101:199–209
Clopidogrel in Unstable Angina to Prevent
Recurrent Events : CURE Design
N 12 500
28 countries
ACS
without ST
elevation
•Presented within 24hrs
•Clinical symptoms
•Ischemic EKG change
Clopidogrel
300 mg loading dose
Clopidogrel
75 mg o.d.
(~6250 patients)
ASA 75–325 mg
R
Double-blind treatment 3 to 12 months
ASA 75–325 mg
Placebo
1 tab o.d.
(~6250 patients)
CURE Study Investigators Eur Heart J 2000;21:2033–2041
CURE : Primary Endpoint
% of patients with recurrent ischemic event (cardiovascular death, MI, or stroke)
14
*
11.4%
Benefits were seen within hours and continued
to increase over the 12 months
12
9.3%
10
20% RRR
p=0.00009
n=12,562
8
6
4
Standard therapy‡
Clopidogrel + standard therapy‡
2
0
0
‡including
1
ASA
2
3
4
5
6
7
Months of follow-up
8
9
10
11
12
The CURE Investigators. N Eng J Med August 2001
Primary Outcome : Subgroups
2N
Standard
therapy‡
Patient characteristics
Overall
% events
Clopidogrel +
Standard therapy‡
12 562
11.4
9.3
ST deviation +
ST deviation -
6275
6287
14.3
8.6
11.5
7.0
Entry enzymes elevated +
Entry enzymes elevated -
3176
9386
13.0
10.9
10.9
8.8
Diabetes +
Diabetes -
2840
9722
16.7
9.9
14.2
7.9
Risk
4187
4185
4184
6.7
9.4
18.0
5.1
6.5
16.3
4577
7985
13.9
10.0
11.5
8.1
2246
10 316
14.4
10.7
8.4
9.5
Low
Intermediate
High
Rev after randomization +
Rev after randomization History of rev +
History of rev + with condition
‡including
- without condition
ASA
The CURE Investigators. N Eng J Med August 2001
Rev, revascularization
0.4
RR (95% CI)
0.6
0.8
1.0
1.2
PCI-CURE :
Long-term Efficacy
Cumulative hazard rates
Composite of CV-death or MI from randomization to end of follow-up†
12.6%
Placebo‡
Clopidogrel‡
0.15
8.8%
0.10
0.05
0.0
0
10 40
a b
100
200
Days of follow-up
a = median time from randomization to PCI (10 days)
b = 30 days after median time of PCI
†up to 12 months ‡on top of standard therapy including ASA
The CURE Investigators. Lancet August 2001
300
400
31% RRR
p=0.002
n=2658
CURE: Major Bleeding by ASA
Dose
Peters RJ et al. Circulation 2003;108:1682
2002 ACC/AHA UA/NSTEMI
Guidelines Update
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Class I:
•
ASA should be administered as soon as possible after
presentation and continued indefinitely (IA)
Clopidogrel 75 mg daily (in the absence of
contraindications) when ASA is not tolerated (IA)
If early non-interventional approach is planned,
clopidogrel should be added to ASA as soon as possible
on admission and administered for at least 1 month (IA)
and for up to 9 months (IB)
If PCI planned, clopidogrel should be started and
continued for at least 1 month (IA) and up to 9 months in
patients who are not at high risk for bleeding (IB)
•
•
•
1. Braunwald E et al.
FOR INTERNAL USE ONLY
ALBION
Assessment of best Loading dose of clopidogrel to Blunt
platelet activation, Inflammation and Ongoing Necrosis
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103 patients aged 18 to 85 years
UA NSTEMI within the 48 hours prior to randomisation.
300mg, 600mg and 900mg
Blood monitored every hour during the first 6 hours then
at 24 hours to determine the kinetics of inhibition of
platelet aggregation.
Within the first 24 hours, higher loading doses of
clopidogrel induced faster onset of action and higher
levels of inhibition of platelet aggregation than the
indicated loading dose of 300mg, in patients with ACS
Similar safety profile among different dosage groups.
EuroPCR Congress in Paris on May 24
Faster Onset of Action and
Higher Level of Platelet Inhibition
Maximum Inhibition of Platelet Aggregation (5 µM ADP)
45
(%) Inhibition
40
35
30
25
20
15
Shortened time to reach the highest
level of inhibition of the 300 mg LD
10
5
300 mg LD
600 mg LD
900 mg LD
 p< 0.05 vs. 300 mg LD
0
1
2
3
4
5
6
24
Time (h)
Faster Onset of Action and Higher
Level of Platelet Inhibition
Maximum Inhibition of Platelet Aggregation (20 µM ADP)
40
(%) Inhibition
35
30
25
20
15
300 mg LD
10
 p< 0.05 vs. 300 mg LD
5
600 mg LD
900 mg LD
0
1
2
3
4
5
6
24
Time (h)
Major Adverse Cardiac
Events
300 mg
n = 35
600 mg
n = 34
900 mg
n = 34
Death (n)
0
0
0
Non-fatal MI*(n)
1
2
0
Unplanned PCI (n)
1
0
0
Hospitalization for recurrent angina (n)
2
0
0
4 (11.4)
2 (5.9)
0
TOTAL – n (%)
* New Q wave or CK > 3 times the ULN
Safety
300 mg
n = 35
600 mg
n = 34
900 mg
n = 34
Severe
0
0
0
Moderate
1
0
1
10
10
13
11
10
14
Bleeding* Day 1- Discharge (n)
Mild
TOTAL
*GUSTO Classification
Study Design
Double-blind, randomized, placebo-controlled trial in
patients aged 1875 years with STEMI ≤12 hours
Clopidogrel 300 mg loading dose / 75 mg QD†
n=1752
Thrombolysis,
heparin and ASA*
R
Study treatment until
angiography (28 days) or
hospital discharge
(maximum 8 days)
Clinical
Follow-up
at 30 days
n=1739
Placebo†
Primary endpoint: occluded artery (TIMI flow grade [TFG] 0/1),
death/MI by time of angiography
*ASA=150–325 mg (if no ASA within prior 24 hours) as loading dose. Patients received
heparin if they received a fibrin specific thrombolytic
†All patients received ASA 75–162 mg/day plus other standard care
1. Sabatine MS et al. New Engl J Med 2005; 352 (available at www.nejm.org)
Angiographic Outcomes and
Long-term Mortality
HR: 0.41 (p=0.001)
16
HR: 0.51 (p=0.038)
14.5%
2-year mortality (%)
14
12
9.1%
10
8
6.4%
6
4.8%
4
2
0
TFG 0/1
TFG 2/3
TIMI flow grade
TMPG 0/1
TMPG 2/3
TIMI myocardial
perfusion grade*
*90 minute angiogram in TIMI 10b trial; HR=hazard ratio
1. Gibson CM et al. Circulation 2002; 105: 19091913.
Study Endpoints
Primary endpoint:
• Composite
• % of occluded infarct related artery (TFG 0/1) on predischarge angiogram
• Death or MI before CAG
• Death or MI by hospital discharge (maximum 8 days) if no
angiography performed
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*CV death, MI, stroke or recurrent ischemia leading to
urgent target vessel revascularization
1. Sabatine MS et al. New Engl J Med 2005; 352
FOR INTERNAL USE ONLY
Clopidogrel Improved Perfusion
Primary endpoint* (%)
25
36% reduction*
p <0.001
21.7
20
15
15.0
10
5
Clopidogrel
(n=1752)
Placebo
(n=1739)
*Based on odds of an occluded infarct-related artery (TFG 0/1), death or MI by angiography for
clopidogrel versus placebo (OR: 0.64 [0.53 to 0.76]; p <0.001)
1. Sabatine MS et al. New Engl J Med 2005; 352 (available at www.nejm.org)
CLARITY:
Reduction of Primary Endpoint by 36%
Clopidogrel Placebo
(n=1752) (n=1739)
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Odds ratio
(95% CI)
p value
Primary endpoint (%)
 TFG 0/1, MI/death 15.0
21.7
0.64 (0.530.76) <0.001
Components (%)
 TFG 0/1
 Recurrent MI
 Death
18.4
3.6
2.2
0.59 (0.480.72) <0.001
0.70 (0.471.04) 0.08
1.17 (0.751.82) 0.49
11.7
2.5
2.6
1. Sabatine MS et al. New Engl J Med 2005; 352
FOR INTERNAL USE ONLY
Primary Endpoint: Subgroups
Characteristic
Number of
patients
Odds
reduction
3491
36
15.0
21.7
2466
1015
42
22
13.2
19.0
21.0
23.1
2796
685
35
38
14.5
16.9
20.8
24.7
1416
2065
33
38
15.0
15.0
20.7
22.2
2397
1084
31
44
14.7
15.7
20.1
24.9
1429
1431
621
31
42
26
11.4
17.8
17.1
15.7
27.1
21.9
OVERALL
Age
<65 years
65 years
Gender
Male
Female
Infarct location
Anterior
Non-anterior
Fibrinolytic
Fibrin-specific
Non-fibrin specific
Predominant heparin
LMWH
UFH
None
0.4
0.6
0.8 1.0 1.2
Clopidogrel better
1. Sabatine MS et al. New Engl J Med 2005; 352
1.6
Placebo better
Event rates (%)
Clopidogrel Placebo
CLARITY :
Clinical Events at 30 Days
Incidence of clinical endpoints (%)
15
Placebo
Clopidogrel
20%*
p=0.03
10
CV death, MI or
recurrent ischemia
leading to urgent
revascularization
5
0
0
5
1. Sabatine MS et al. New Engl J Med 2005
10
15
20
Time (days)
25
30
Safety
Primary
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
TIMI major
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
p value
23 (1.3)
19 (1.1)
0.64
17 (1.0)
40 (2.3)
8 (0.5)
9 (0.5)
28 (1.6)
12 (0.7)
0.17
0.18
0.38
33 (1.9)
27 (1.6)
59 (3.4)
30 (1.7)
16 (0.9)
46 (2.7)
0.80
0.12
0.24
bleeding endpoints (%)
TIMI minor
TIMI major or minor
Intracranial hemorrhage
Bleeding

Placebo
(n=1719)
bleeding endpoint (%)
Secondary

Clopidogrel
(n=1733)
through 30 days (%)
TIMI major
TIMI minor
TIMI major or minor
1. Sabatine MS et al. New Engl J Med 2005; 352
FOR INTERNAL USE ONLY
COMMIT/CCS-2: ClOpidogrel
and Metoprolol in Myocardial
Infarction Trial
1. Chen ZM et al. ACC 2005.
Study Design
Clopidogrel 75 mg QD*
(n ~ 23,000)
Patients with
acute STEMI
 24 hours
R
n=~46,000
Double-blind treatment until hospital
discharge or for a maximum of 4 weeks
(n ~ 23,000)
Placebo*
(2  2 Factorial with metoprolol)
* All patients received a background of ASA 162mg/day during the study
1. Chen ZM et al. ACC 2005.
COMMIT: Composite Endpoint
(Death, MI, or Stroke)
Placebo
(10.1%)
RRR=9%
10
9
P=0.002
Clopidogrel
Events (%)
8
(9.3%)
7
6
5
4
3
2
1
0
0
1. Chen ZM et al. ACC 2005.
7
14
21
28
Days since randomization
(up to 28 days)
FOR INTERNAL USE ONLY
COMMIT: Mortality
Placebo
(8.1%)
9
8
RRR=7%
p=0.03
7
Clopidogrel
(7.5%)
Mortality (%)
6
5
4
3
2
1
0
0
1. Chen ZM et al. ACC 2005.
7
14
21
Days since randomization
(up to 28 days)
28
COMMIT: Summary
• For STEMI, ASA + clopidogrel 75mg OD + Lytic:
• 7% reduction mortality
• No significant excess in TIMI major bleeding or
ICH
FOR INTERNAL USE ONLY
GP IIb/IIIa Receptor Antagonists
 Eptifibatide
 Tirofiban
 Abciximab
A murine monoclonal
antibody that completely blocks the binding
of fibrinogen to platelets produces
a thrombasthenic-like state in normal
platelets and binds to glycoproteins
IIb and/or IIIa. J Clin Invest 1983
Coller BS, Peerschke EI, Scudder LE, Sullivan CA.

Fc fragment of murine monoclonal antibody against Gp2b3a, 7E3,
was removed to prevent immunogenicity and Fab fragments joined
with the constant regions of human immunoglobulin, forming a
chimeric compound (abciximab, or c7E3).
RGD sequence
Gp IIb/IIIa in ACS
Gp IIb/IIIa blockers are recommended
(Class I) for UA/NSTEMI treated with
interventional approach.
For non-interventional patients with
ongoing ischemia (Class II)
ISAR-REACT:
30-d adverse reactions in low-to-moderate risk undergoing
PCI after 600mg Clopidogrel loading dose
Conclusions

Antiplatelet therapy is essential in the management of
patients with ACS
 Medically treated
 Percutaneous intervention
 New studies support expanding role of ADP
antagonists in the management of STEMI
1. Chen ZM et al. ACC 2005.
FOR INTERNAL USE ONLY
Thank you for your
attention.