Transcript Non ST Elevation - Acute Coronary Syndrome

Early And Long Term Treatment
With Clopidogrel In Coronary
Artery Disease
‫פרופ’ יוסף רוזנמן‬
‫ בי"ח וולפסון‬,‫מכון הלב‬
2005 ‫דצמבר‬
Acute Coronary Syndromes
Acute Coronary Syndrome
No ST Elevation
ST Elevation
Non ST Elevation MI
Unstable Angina
Myocardial Infarction
Non Q MI
Q wave MI
Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062.
Initial Treatment Strategy
ACS
ST Elevation
Reperfusion and culprit
plaque stabilization
1. Anti-thrombotic Rx (+ Fibrinolysis)
2. Early / Primary PCI
Non ST Elevation
Culprit plaque
stabilization
1. Anti-thrombotic Rx
2. Early PCI
The best way to stabilize a culprit plaque is with a stent
Goals of Peri – PCI Medical Treatment
(short and long term)
1
2
Minimize peri-procedural
complications (related to the
treated plaque)
Thrombosis etc
 Stabilize the rest of the nonocclusive narrowings
Prevent progression
Prevent atherothrombosis
The Clinical Questions
Combination Rx. (ASA + Clopidogrel)
When angiography / PCI is planned in a
patient already treated with ASA:
1
2
Is additional pre-treatment with
clopidogrel improving outcome (until
angiography / PCI, at 1 month – or longer)
Is continuation of clopidogrel beyond 1
month improving long-term outcome
1
Clopidogrel before coronary
angiography - Patients with ACS
 Goals of therapy
1. Prevent ischemic events until coronary
angiography / PCI
 Before plaque stabilization was achieved
2. Prevent PCI / stent related ischemic
complications
1
Clopidogrel before coronary
angiography - Patients with ACS
• ST Elevation
–CLARITY
• Non ST Elevation
–CURE
Clopidogrel before coronary
1 angiography - Patients with ACS
• ST Elevation
–CLARITY
• Non ST Elevation
–CURE
Study Design
Double-blind, randomized, placebo-controlled trial in
3491 patients, age 18-75 yrs with STEMI < 12 hours
Fibrinolytic, ASA, Heparin
randomize
Clopidogrel
300 mg + 75 mg qd
Placebo
Study
Drug
Coronary Angiogram
(2-8 days)
Open-label
clopidogrel
per MD in
both groups
30-day clinical follow-up
Primary endpoint:
Occluded
artery (TIMI Flow
Grade 0/1)
or D/MI by time
of angio
Primary Endpoint:
Occluded Artery or Death/MI (%)
Occluded Artery (or D/MI by time of angio)
25
36%
21.7
Odds Ratio 0.64
(95% CI 0.53-0.76)
Odds Reduction
20
P=0.00000036
15.0
15
10
5
0.4
0
Clopidogrel
n=1752
Placebo
n=1739
0.6
0.8
Clopidogrel
better
1.0 1.2
1.6
Placebo
better
Need for Urgent or
Additional Treatment
16% 
P=0.07
35
30
25 21% 
21% 
P=0.005
(%)
P=0.01
15
29.3
Clopidogrel
Placebo
23.3
20
18.6
33.0
19.5
15.4
10
5
0
Early Angio
(w/in 48 hrs)
Urgent Revasc
(index hosp)
GP IIb/IIIa
if PCI
Placebo
10
20%
Clopidogrel
5
Odds Ratio 0.80
(95% CI 0.65-0.97)
P=0.026
1
0
Percentage with endpoint (%)
15
CV Death, MI, RI  Urg Revasc
0
5
10
15
days
20
25
30
CLARITY: Patient Management
Parameter
Symptom onset to fibrinolytic (hours)
Fibrinolytic to study drug (minutes)
Median doses of study medication
Angiography performed (%)
Study drug to angiography (hours)
Coronary revascularization (%):
PCI
CABG
Clopidogrel
(n=1,752)
Placebo
(n=1,739)
2.7
10
4
94
84
63
57.2
5.9
2.6
10
4
94
84
63
56.6
6.0
Sabatine M et al. New Engl J Med 2005; 352: 1179–1189.
PCI-CLARITY: MI, Stroke, or CV Death
Events pre and post PCI
41%
Patients with endpoint (%)
15
p=0.001
No Pretreatment (n=930)
Clopidogrel Pretreatment (n=933)
12.0
38%
46%
p=0.03
p=0.008
10
7.5
6.2
6.2
4.0
5
3.6
0
Overall
Events*
***MI or Stroke
Pre-PCI
Events**
Post-PCI
Events*
M Sabatine, et al. JAMA 2005,
Prehospital Fibrinolysis with Double Antiplatelet Therapy in
Acute ST-Elevation Myocardial Infarction:
The Clarity Ambulance Substudy
Substudy Sites and
Patient Numbers
France: 172 patients
L Soulat: 57
Y Lambert: 48
F Lapostolle: 28
F Thieuleux: 21
C Gully: 10
D Pollet: 5
D Galley: 2
L Olliver: 1
UK: 40 patients
J Adgey: 27
J Purvis: 13
Sweden: 5 patients
J-E Karlsson: 5
217 patients in total
Montalescot G. ESC, September 2005
Angiographic & ECG Parameters:
Ambulance vs. Non-Ambulance
Odds ratio
(95% CI)
TFG 3
Event rate (%)
Ambulance
Nonp value
ambulance
64.4
64.4
NS
90 min
47.2
37.0
0.02
180 min
63.2
52.7
0.05
Complete* ST resolution at ECG
0
0.5
1.0
1.5
2.0
2.5 3.0
Ambulance better
Non-ambulance better
*Complete considered to be >70%; ECG=electrocardiogram
Montalescot G. ESC, September 2005
Primary Endpoint of
TIMI Flow Grade 0/1, MI or Death
Odds ratio (95% CI)
Ambulance
0.60 (0.301.17)
Non-ambulance
0.65 (0.540.77)
Overall
0.64 (0.530.76)
0
0.5
Clopidogrel better
1.0
1.5
2.0
Placebo better
Montalescot G. ESC, September 2005
Clopidogrel before coronary
1 angiography - Patients with ACS
• ST Elevation
–CLARITY
• Non ST Elevation
–CURE
CURE
Study Design
Clopidogrel 300 mg
loading dose
Clopidogrel 75mg q.d.
+ ASA 75-325 mg q.d.*
(6259 patients)
Patients with
Acute Coronary
Syndrome
(unstable angina or
non-ST-segment
elevation MI)
R
3 months  double-blind treatment  12 months
R = Randomization
* In combination with other standard therapy
Placebo + ASA
75-325 mg q.d.*
(6303 patients)
The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.
CURE
Primary End Point - MI/Stroke/CV Death
Cumulative Hazard Rate
0.14
11.4%
Placebo
+ ASA*
0.12
9.3%
0.10
0.08
Clopidogrel
+ ASA*
0.06
0.04
20% RRR
P < 0.001
N = 12,562
0.02
0.00
0
3
6
9
Months of Follow-Up
* In combination with standard therapy
The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.
12
CURE
MI/Stroke/CV Death within 30 Days
1
Cumulative Hazard Rate
0.06
Placebo
+ ASA*
0.05
0.04
Clopidogrel
+ ASA*
0.03
0.02
21% RRR
P = 0.003
N = 12,562
0.01
0.00
0
10
20
Days of Follow-Up
* In combination with standard therapy
The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.
30
CURE
1
MI/Stroke/CV Death or severe Ischemia
at 24 hours
CV death, nonfatal MI,
stroke or refractory or
severe ischemia
2.5
34%
2.1%
2
1.5%
1.5
1
0.5
0
Placebo + aspirin
Clopidogrel + aspirin
NEJM 2001; 345:495-502
CURE
1
Need for Additional Anti-Thrombotic After
Randomization
GP IIb/IIIa Inhibitor
Thrombolysis
P= 0.003
P< 0.001
2
2%
1.5
43%
1.1%
1
0.5
0
Placebo +
aspirin
Clopidogrel +
aspirin
% patients requiring
GP IIb/IIIa inhibitors
% patients requiring
thrombolytic therapy
2.5
8
7
6
5
4
3
2
1
0
18%
7.2%
5.9%
Placebo +
aspirin
Clopidogrel +
aspirin
NEJM 2001; 345:495-502
Should clopidogrel be added GP IIb/IIIa
antagonists as pretreatment before
coronary angiography (“upstream”) ?
Is there additional benefit to
clopidogrel that would justify:
Increased CABG bleeding
or alternatively
Need to postpone CABG for 3-5 days
No data in the literature however
The Role of Platelets in Atherothrombosis
1
2
Adhesion
3
Aggregation
Activation
Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org.
1
Conclusions: Early Clopidogrel Therapy
Treatment with clopidogrel is indicated
as soon as possible in patients with acute
coronary syndrome
 ST elevation and non ST elevation
Treatment is effective to reduce
ischemic complications
 Before coronay angiography
 During and after PCI
1
Conclusions: Early Clopidogrel Therapy
Loading dose should be 600mg to achieve early
optimal antiplatelet effect
 ?? 300mg in patients after fibrinolytic therapy
It is unclear whether therapy should be added to
“upstream” GP IIb/IIIa antagonists
 Especially in high risk patients in whom the likelihood
for CABG is high
Goals of Peri – PCI Medical Treatment
(short and long term)
1
Minimize peri-procedural
complications (related to the treated
plaque)
Thrombosis etc
 Stabilize the rest of the non-
2
occlusive narrowings
Prevent progression
Prevent atherothrombosis
The Clinical Questions
Combination Rx. (ASA + Clopidogrel)
When PCI is planned in a patient
already treated with ASA:
1
Is additional pre-treatment with clopidogrel
improving outcome (until PCI, at 1 month –
or longer)
2
Is continuation of clopidogrel
beyond 1 month after PCI / stent
improving long-term outcome
Discharge/Post-Discharge
2
Medications - Guidelines
I IIa IIb III
ASA, if not contraindicated
Clopidogrel, when ASA contraindicated
Aspirin + Clopidogrel for up to 9 months
-blocker, if not contraindicated
Lipid  agents + diet, if LDL >130 mg/dL
ACE Inhibitor: CHF, EF < 40%, DM, or HTN
PCICURE
Overall Study Design: PCI-CURE
PCI-CURE
Pretreatment
N = 2,658 patients undergoing PCI
Open-label thienopyridine
PLACEBO
+ ASA *
N = 1345
Question 2
Question
1
R
PCI
30 days post PCI
N = 1313
CLOPIDOGREL
+ ASA *
Open-label thienopyridine
Pretreatment
Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502.
End of follow-up
Up to 12 months
after randomization
Overall Study Design: CREDO
PCI*
Clopidogrel
Arm
Randomization Pre-treatment
28 Days
Open label
clopidogrel
Clopidogrel 300 mg
+ ASA† (325 mg)
12 Months
continuation
Clopidogrel 75 mg QD
+ ASA† 325 mg QD
Clopidogrel 75 mg QD
+ ASA† (81-325 mg) QD
Clopidogrel 75 mg QD
+ ASA† 325 mg QD
Placebo QD
+ ASA† (81-325 mg) QD
Placebo
Arm
R
Placebo +
ASA† (325 mg)
Question 1
Question 2
1
Steinhubl S, Berger P, Tift Mann III J et al. JAMA. 2002;Vol 288,No 19:2411-2420.
2
Methodological Pitfall
Can a study with a single randomization
provide an answer to two questions?
Alternatively
Should a second randomization be done
in order to answer the second question?
Study Design
single randomization
PCICURE
PCI-CURE
Continuation
Pretreatment
Open-label thienopyridine
PLACEBO
+ ASA *
R
N = 1345
PCI
30 days post PCI
End of follow-up
Up to 12 months
after randomization
N = 1313
CLOPIDOGREL
+ ASA *
Open-label thienopyridine
Pretreatment
Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502.
Continuation
PCICURE
Alternative Study Design
two randomizations
PCI-CURE
Continuation
Pretreatment
Open-label thienopyridine
PLACEBO
+ ASA *
N = 1345
R2
Clop.
R1
2
PCI
Question 2
Placebo
N = 1313
CLOPIDOGREL
+ ASA *
R2
Open-label thienopyridine
Pretreatment
Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502.
Continuation
Is it just methodology?
Can we really expect long
term benefit from early
antiplatelet therapy?
Adjunct antiplatelet therapy for PCI
 EPISTENT
– Randomized study designed to determine the effect
of treatment with abciximab
 TARGET
– Randomized study designed to show that tirofiban is
not inferior to abciximab
– Post-hoc nonrandomized comparison among those
who were or were not pre-treated with clopidogrel
 PCI-CURE
– Subgroup of CURE patients who underwent PCI
– Randomized comparison of pre-treatment and
continued clopidogrel therapy vs. placebo
Early and long term reduction of death or MI from
antiplatelet therapy in patients with ACS
Absolute reduction of Death or MI at 1 month and 1 year
5
4.8
EPISTENT
% reduction
3.9
TARGET
3
PCI-CURE
-Abciximab
-Early clopidogrel
-Early and continued
clopidogrel
1.3
0.9
0
1 month
* 6 month data in TARGET
0.8
1 month to 1 year *
2
Long Term Clopidogrel Post PCI
Clinical guidelines: 9 months to 1
year in patients with ACS
However, current data does not
fully support this recommendation
What should we do?
Comulative event rate in primary
prevention stable CAD and ACS
ACS
Stable
Primary
Risk of vascular event after ACS
Risk of event
Commulative risk
Stable CAD
Risk per time
Time after ACS
Risk of event
Risk of vascular event after ACS
high and low risk
High risk
Low risk
Time after ACS
Risk of bleeding after initiation of
clopidogrel (high and low risk)
Risk of event
Fixed, except for the initial few days
 heparin, catheterization
High risk
Low risk
Time after clopidogrel
Risk of event (vascular/bleeding) after
ACS and clopidogrel
Risk of event
vascular
bleeding
3 months ??
Time after ACS
Risk of event (vascular/bleeding) after
ACS and clopidogrel
vascular
Risk of event
High vascular risk
bleeding
3 months ??
Time after ACS> 1 year
Risk of event (vascular/bleeding) after
ACS and clopidogrel
vascular
Risk of event
High bleeding risk
e.g. coumadin
bleeding
< 1 months
3 months ??
Time after ACS
Risk of event (vascular/bleeding) after
ACS and clopidogrel
Risk of event
vascular
Long term clopidogrel for patients with
High risk for vascular event
Low bleeding risk
Short term clopidogrel for patients with
Low risk for vascular event
High bleeding risk
bleeding
3 months ??
Time after ACS
Who is ”High Risk”
Patients in whom long term clopidogrel
should be considered
 The
vulnerable patient
 TIMI risk score
 Aspirin Failure
 Others
Who is ”High Risk”
Patients in whom long term clopidogrel
should be considered
 The
vulnerable patient
 TIMI risk score
 Aspirin Failure
 Others
ACS Pathophysiology
Inflammation, Plaque Rupture, Thrombosis, and Microembolization
Quiescent plaque
Lipid core
Plaque formation
Lipids, other risk factors
Vulnerable plaque
TF  Clotting Cascade
Inflammation
Collagen 
platelet activation
Macrophages
Foam Cells
Metalloproteinases
Culprit plaque
Plaque rupture
Inflammation
LDL, others, Infection?
Plaque rupture (erosion)
? Macrophages, metalloproteinases
Platelet-thrombin micro-emboli
Thrombosis
Platelet Activation, Thrombin
Courtesy of David Kandzari.
Atherosclerotic Plaques Terminology
• Culprit
– Responsible for the clinical event
• Vulnerable
– High risk to become culprit (cause
clinical event)
• Quiescent (Stable)
– Primary or healed (vulnerable or culprit)
Culprit and healed plaques in a coronary bifurcation
Coronary Artery Disease: Diffuse disease with a
variable mix of stable, vulnerable and culprit plaques
Fuster, V. et al. J Am Coll Cardiol 2005;46:937-954
Angiograms of 253
patients with acute MI
Complex Plaques:
Single: 153 - 60.5%
Multiple: 100 – 39.5%
N Engl J Med 2000;343:915-22
Clinical Outcome at 1 Year –
Single vs. Multiple Complex Plaques
Similar results when
analysis was
restricted to patients
with multivessel
coronary disease:
74.5% of single
91.0% of multiple
Characteristics of Carotid Plaques: Patients
with Unstable versus Stable Angina
Multivariate analysis: UA and CRP >3 mg/l were independently
and strongly associated with complex carotid plaques
Vulnerable Patient – at high risk for
vascular event
coronary
elsewhere
Who is the vulnerable patient?
Patient with current multiple complex
plaques
– Coronary, carotid etc
Patient with multiple uncontrolled
risk factors
– At risk to develop new complex plaques
Vulnerability
cutoff value ?
Who is ”High Risk”
Patients in whom long term clopidogrel
should be considered
 The
vulnerable patient
 TIMI risk score
 Aspirin Failure
 Others
TIMI Risk Score and Outcome
Excess major bleeding risk with clopidogrel is
independent of the TIMI risk – it is 1%
Budaj et al. circulation 2002
TIMI Risk Score and Absolute Reduction
of death/MI/Stroke with Clopidogrel
Percent reduction
8
7.1
Majority of patients
6
4.2
4
2.1
2
1.3
Major bleeding – 1%
0.1
0
0-1
N=
1.9
752
2
2524
3
3730
4
3567
TIMI Risk Score
5
1593
>5
396
Who is ”High Risk”
Patients in whom long term clopidogrel
should be considered
 The
vulnerable patient
 TIMI risk score
 Aspirin Failure
 Others
Aspirin Failure – Patient with acute
vascular event (coronary, cerebral)
while being treated with aspirin

Aspirin was not enough to prevent the
event
Aspirin is ineffective as an antiplatelet
agent – resistance?
Aspirin is effective as an antiplatelet agent
but the disease risk is high and there is a
need for more aggressive antiplatelet
therapy
Aspirin Resistance
Cellular Factors
Genetic
Polymorphisms
Insufficient suppression
of COX-1
Clinical Factors
Failure to prescribe
Overexpression
of COX-2 mRNA
Noncompliance
Collagen receptor
Erythrocyte-induced
platelet activation
Interaction with ibuprofen
vWF receptor
Increased norepinephrine
Can be intermittent
COX-1
GP IIIa receptor
Generation of 8-iso-PGF2
Aspirin Resistance
Adapted with permission from Bhatt DL. J Am Coll Cardiol. 2004;43:1127-1129.
Nonabsorption
Unfortunately (surprisingly)
there is no subgroup analysis
of CAPRIE or CURE for patients
who were on prior aspirin
However
There are other subgroup
analyses
Clopidogrel in patients with prior CABG
CAPRIE substudy (N=1480)
Combined endpoint: Vascular
Vascular death
10
9.7%
9
8.1%
8
7
6
5
4 Aspirin
3
Clopidogrel
2
p = 0.03
1
0
0 6 12 18 24 30 36
Months of Follow-up
death, MI, stroke or hospitalization
for ischemia or bleeding
50
43%
46.1%
45
31%
40
36.7%
35
30
25
Aspirin
20
Clopidogrel
15
10
p = 0.001
5
0
0
6
12
18
24
30
36
Months of Follow-up
Circulation 2001; 103: 363-368
Clopidogrel in patients with history of prior
ischemic event - CAPRIE substudy (N=4496)
Ringleb, P. A. et al. Stroke 2004;35:528-532
CURE
Beneficial Outcomes with Clopidogrel in Various Subgroups
Percentage of Patients with Event
Characteristic
Overall
Associated MI
No associated MI
Male sex
Female sex
65 yr old
> 65 yr old
ST-segment deviation
No ST-segment deviation
Enzymes elevated at entry
Enzymes not elevated at entry
Diabetes
No diabetes
Low risk
Intermediate risk
High risk
History of revascularization
No history of revascularization
Revascularization after randomization
No revascularization after randomization
No. of
Patients
Clopidogrel
+ ASA*
Placebo
+ ASA*
12562
3283
9279
7726
4836
9.3
11.3
8.6
9.1
9.5
11.4
13.7
10.6
11.9
10.7
6354
6208
6275
6287
3176
9386
2840
9722
5.4
13.3
11.5
7.0
10.7
8.8
14.2
7.9
7.6
15.3
14.3
8.6
13.0
10.9
16.7
9.9
4187
4185
4184
2246
10316
4577
7985
5.1
6.5
16.3
8.4
9.5
11.5
8.1
6.7
9.4
18.0
14.4
10.7
13.9
10.0
* In combination with standard therapy
The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.
0.4
0.6
0.8
Clopidogrel Better
1.0
1.2
Placebo Better
Relative Risk (95% CI)
CURE: Impact of History of
Revascularization
Percent of Patients with an Event
14.4
15
Clopidogrel
Placebo
6.0%
1.2%
10.7
9.5
10
8.4
5
Yes (N=2246)
No (N=10316)
History of Revascularization
Conclusions – early treatment
Clopidogrel loading should be given to
patients with ACS (both STE and NonSTE) as soon as possible regardless* of
the timing of the planned coronary
angiography
– * It is still unclear whether treatment can be
postponed when “upstream” GP IIb/IIIa is
being used (especially when the likelihood of
CABG is high).
• will be clarified by ongoing trial – “early ACS”
Conclusions – long term treatment
Clinical guidelines recommend 9-12 months
clopidogrel to all patients with non-STE ACS
Treatment should be definitely continued as
long as there is a risk for stent thrombosis
– Longer duration
• high risk subset (multiple complex plaques, TIMI risk
score >5, continuously elevated CRP?)
• Aspirin failure ?
– Shorter duration
• High bleeding risk (e.g. coumadin etc)