Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease

1
Early And Long Term Treatment With Clopidogrel In
Coronary Artery Disease
???? ???? ?????? ???? ???, ??"? ???????
????? 2005
2
Acute Coronary Syndromes
Acute Coronary Syndrome
No ST Elevation
ST Elevation
Non ST Elevation MI
Myocardial Infarction Non Q MI Q wave MI
Unstable Angina
Braunwald E et al. J Am Coll Cardiol
2000369701062.
3
Initial Treatment Strategy
ACS ST Elevation
Non ST Elevation
Culprit plaque stabilization
Reperfusion and culprit plaque stabilization

• Anti-thrombotic Rx ( Fibrinolysis)
• 2. Early / Primary PCI

1. Anti-thrombotic Rx
2. Early PCI

The best way to stabilize a culprit plaque is
with a stent
4
Goals of Peri PCI Medical Treatment (short and
long term)

• Minimize peri-procedural complications (related
  to the treated plaque)
• Thrombosis etc
• Stabilize the rest of the non-occlusive
  narrowings
• Prevent progression
• Prevent atherothrombosis

1
2
5
The Clinical QuestionsCombination Rx. (ASA
Clopidogrel)

• When angiography / PCI is planned in a patient
  already treated with ASA
• 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
2
6
Clopidogrel before coronary angiography -
Patients with ACS
1

• Goals of therapy
• Prevent ischemic events until coronary
  angiography / PCI
• Before plaque stabilization was achieved
• Prevent PCI / stent related ischemic complications

7
Clopidogrel before coronary angiography -
Patients with ACS
1

• ST Elevation
• CLARITY
• Non ST Elevation
• CURE

8
Clopidogrel before coronary angiography -
Patients with ACS
1

• ST Elevation
• CLARITY
• Non ST Elevation
• CURE

9
Study Design
Double-blind, randomized, placebo-controlled
trial in3491 patients, age 18-75 yrs with STEMI
lt 12 hours
Fibrinolytic, ASA, Heparin
randomize
Clopidogrel 300 mg 75 mg qd
Placebo
Study Drug
Primary endpoint Occludedartery (TIMI Flow
Grade 0/1) or D/MI by timeof angio
Coronary Angiogram (2-8 days)
Open-label clopidogrel per MD inboth groups
30-day clinical follow-up
10
Primary EndpointOccluded Artery (or D/MI by
time of angio)
Odds Ratio 0.64(95 CI 0.53-0.76)
36 Odds Reduction
P0.00000036
1.0
0.4
0.6
0.8
1.2
1.6
Clopidogrel better
Placebo better
Placebo
Clopidogrel
n1752
n1739
11
Primary Angiographic Outcomes (median 3.5 days)
Outcome Clopidogrel Placebo OddsRatio P value
Primary End Point () 15.0 21.7 0.64 lt0.001
TIMI Flow Grade 0/1 11.7 18.4 0.59 lt0.001
MI 2.5 3.6 0.70 0.08
Death 2.6 2.2 1.17 0.49
Angiographic ()
TIMI Flow Grade 3 67.8 60.8 1.36 lt0.001
TIMI Myocardial Perfusion 3 55.8 51.2 1.21 0.008
Thrombus 43.0 50.8 0.73 lt0.001
12
Need for Urgent orAdditional Treatment
16 ? P0.07
21 ? P0.005
21 ? P0.01
Early Angio(w/in 48 hrs)
Urgent Revasc(index hosp)
GP IIb/IIIaif PCI
13
CV Death, MI, RI ? Urg Revasc
15
Placebo
20
10
Clopidogrel
Percentage with endpoint ()
Odds Ratio 0.80 (95 CI 0.65-0.97) P0.026
5
1
0
0
5
10
15
20
25
30
days
14
CLARITY Patient Management

• Clopidogrel Placebo
• Parameter (n1,752) (n1,739)
• Symptom onset to fibrinolytic (hours) 2.7 2.6
• Fibrinolytic to study drug (minutes) 10 10
• Median doses of study medication 4 4
• Angiography performed () 94 94
• Study drug to angiography (hours) 84 84
• Coronary revascularization () 63 63
• PCI 57.2 56.6
• CABG 5.9 6.0

Sabatine M et al. New Engl J Med 2005 352
11791189.
15
PCI-CLARITY Reduction in CV Death, MI, Stroke
from PCI to 30 Days

8
No Pretreatment (6.2)
6
46 p0.008
4
Percentage with Outcome ()
Clopidogrel Pretreatment (3.6)
2
0
0
5
10
15
20
25
30
Days Post PCI
M Sabatine, et al. JAMA 2005
16
PCI-CLARITY MI, Stroke, or CV DeathEvents pre
and post PCI
MI or Stroke
M Sabatine, et al. JAMA 2005,
17
Prehospital Fibrinolysis with Double Antiplatelet
Therapy in Acute ST-Elevation Myocardial
Infarction The Clarity Ambulance Substudy
18
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
19
Angiographic ECG Parameters Ambulance vs.
Non-Ambulance
Event rate ()
Odds ratio (95 CI)
p value
Ambulance
Non-ambulance
TFG 3 64.4 64.4 NS
Complete ST resolution at ECG 90 min 180 min 47.2 63.2 37.0 52.7 0.02 0.05
Ambulance better
Non-ambulance better
Complete considered to be gt70
ECGelectrocardiogram
20
Primary Endpoint of TIMI Flow Grade 0/1, MI or
Death
Odds ratio (95 CI)
0.60 (0.30?1.17)
Ambulance
0.65 (0.54?0.77)
Non-ambulance
Overall
0.64 (0.53?0.76)
0
0.5
1.0
1.5
2.0
Clopidogrel better
Placebo better
21
Clopidogrel before coronary angiography -
Patients with ACS
1

• ST Elevation
• CLARITY
• Non ST Elevation
• CURE

22
Study Design
CURE
Clopidogrel 300 mg loading dose
Clopidogrel 75mg q.d. ASA 75-325 mg q.d.
(6259 patients)
Patients with Acute CoronarySyndrome
R
3 months double-blind treatment 12 months
(unstable angina or non-ST-segment elevation MI)
Placebo ASA 75-325 mg q.d. (6303 patients)
Day 1
3 m. Visit
6 m. Visit
9 m. Visit
1 m. Visit
12 m.or Final Visit
Discharge Visit
Placebo loading dose
The CURE Trial Investigators. N Engl J Med.
2001345494-502.
R Randomization In combination with other
standard therapy
23
Primary End Point - MI/Stroke/CV Death
CURE
11.4
Placebo ASA
9.3
Clopidogrel ASA
20 RRR P lt 0.001 N 12,562
3
6
9
0
12
Months of Follow-Up
In combination with standard therapy The CURE
Trial Investigators. N Engl J Med.
2001345494-502.
24
MI/Stroke/CV Death within 30 Days
CURE
1
Placebo ASA
Clopidogrel ASA
21 RRR P 0.003 N 12,562
10
20
30
0
Days of Follow-Up
In combination with standard therapy The CURE
Trial Investigators. N Engl J Med.
2001345494-502.
25
MI/Stroke/CV Death or severe Ischemia at 24 hours
CURE
1
34
CV death, nonfatal MI,stroke or refractory
orsevere ischemia
NEJM 2001 345495-502
26
Need for Additional Anti-Thrombotic After
Randomization
CURE
1
GP IIb/IIIa Inhibitor
Thrombolysis
P 0.003
Plt 0.001
18
43
patients requiringthrombolytic therapy
patients requiringGP IIb/IIIa inhibitors
NEJM 2001 345495-502
27
Should clopidogrel be added GP IIb/IIIa
antagonists as pretreatment before coronary
angiography (upstream) ?

• GP IIb/IIIa receptor is the final common pathway
  in platelet aggregation.
• GP IIb/IIIa blockade is the most effective
  antiplatelet aggregation therapy.
• Bleeding risk is not increased if therapy is
  stopped 2-4 hours prior to CABG.
• Bleeding risk is markedly increased unless
  clopidogrel is stopped 3-5 days prior to CABG.

28
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
29
The Role of Platelets in Atherothrombosis
Adhesion
Aggregation
1
3
Activation
2
Reproduced with permission from Cannon CP.
Atherothrombosis slide compendium. Available at
www.theheart.org.
30
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31
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Conclusions Early Clopidogrel Therapy
1

• 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

33
Conclusions Early Clopidogrel Therapy
1

• 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

34
Goals of Peri PCI Medical Treatment (short and
long term)

• Minimize peri-procedural complications (related
  to the treated plaque)
• Thrombosis etc
• Stabilize the rest of the non-occlusive
  narrowings
• Prevent progression
• Prevent atherothrombosis

1
2
35
The Clinical QuestionsCombination Rx. (ASA
Clopidogrel)

• When PCI is planned in a patient already treated
  with ASA
• Is additional pre-treatment with clopidogrel
  improving outcome (until PCI, at 1 month or
  longer)
• Is continuation of clopidogrel beyond 1 month
  after PCI / stent improving long-term outcome

1
2
36
Discharge/Post-Discharge Medications - Guidelines
2

• ASA, if not contraindicated
• Clopidogrel, when ASA contraindicated
• Aspirin Clopidogrel for up to 9 months
• ?-blocker, if not contraindicated
• Lipid ? agents diet, if LDL gt130 mg/dL
• ACE Inhibitor CHF, EF lt 40, DM, or HTN

37
Initial Treatment Strategy
ACS ST Elevation
Non ST Elevation
Culprit plaque stabilization
Reperfusion and culprit plaque stabilization

• Anti-thrombotic Rx ( Fibrinolysis)
• 2. Early / Primary PCI

1. Anti-thrombotic Rx
2. Early PCI

The best way to stabilize a culprit plaque is
with a stent
38
Overall Study Design PCI-CURE
PCI-CURE
PCI-CURE
N 2,658 patients undergoing PCI
Pretreatment
Open-label thienopyridine
PLACEBO ASA
N 1345
Question 2
End of follow-up Up to 12 months after
randomization
Question 1
PCI
30 days post PCI
R
N 1313
CLOPIDOGREL ASA
Open-label thienopyridine
Pretreatment
Mehta, SR. et al for the CURE Trial
Investigators. N Engl J Med. 2001345494-502.
39
Overall Study Design CREDO
PCI
28 Days
12 Months
Randomization - Pre-treatment
Open label clopidogrel
continuation
Clopidogrel Arm
Clopidogrel 300 mg ASA (325 mg)
Clopidogrel 75 mg QD ASA 325 mg QD
Clopidogrel 75 mg QD ASA (81-325 mg) QD
R
Clopidogrel 75 mg QD ASA 325 mg QD
Placebo QD ASA (81-325 mg) QD
Placebo Arm
Placebo ASA (325 mg)
Question 1
Question 2
1
2
Steinhubl S, Berger P, Tift Mann III J et al.
JAMA. 2002Vol 288,No 192411-2420.
40
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?

41
Study Designsingle randomization
PCI-CURE
PCI-CURE
Continuation
Pretreatment
Open-label thienopyridine
PLACEBO ASA
N 1345
End of follow-up Up to 12 months after
randomization
PCI
30 days post PCI
R
N 1313
CLOPIDOGREL ASA
Open-label thienopyridine
Continuation
Pretreatment
Mehta, SR. et al for the CURE Trial
Investigators. N Engl J Med. 2001345494-502.
42
Alternative Study Designtwo randomizations
PCI-CURE
PCI-CURE
Continuation
Pretreatment
Open-label thienopyridine
PLACEBO ASA
N 1345
R2
Clop.
2
Question 2
PCI
R1
Placebo
R2
N 1313
CLOPIDOGREL ASA
Open-label thienopyridine
Continuation
Pretreatment
Mehta, SR. et al for the CURE Trial
Investigators. N Engl J Med. 2001345494-502.
43
Is it just methodology?

• Can we really expect long term benefit from early
  antiplatelet therapy?

44
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

45
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

• Abciximab
• Early clopidogrel
• Early and continued
• clopidogrel

reduction

6 month data in TARGET
46
Long Term Clopidogrel Post PCI
2

• Clinical guidelines 9 months to 1 year in
  patients with ACS
• However, current data does not fully support this
  recommendation
• What should we do?

47
Comulative event rate in primary prevention
stable CAD and ACS
ACS
Stable
Primary
48
Risk of vascular event after ACS
Commulative risk
Risk of event
Risk per time
Stable CAD
Time after ACS
49
Risk of vascular event after ACShigh and low risk
High risk
Risk of event
Low risk
Time after ACS
50
Risk of bleeding after initiation of clopidogrel
(high and low risk)

• Fixed, except for the initial few days
• heparin, catheterization

Risk of event
High risk
Low risk
Time after clopidogrel
51
Risk of event (vascular/bleeding) after ACS and
clopidogrel
vascular
Risk of event
bleeding
3 months ??
Time after ACS
52
Risk of event (vascular/bleeding) after ACS and
clopidogrel
vascular
High vascular risk
Risk of event
bleeding
3 months ??
gt 1 year
Time after ACS
53
Risk of event (vascular/bleeding) after ACS and
clopidogrel
vascular
High bleeding risk e.g. coumadin
Risk of event
bleeding
3 months ??
lt 1 months
Time after ACS
54
Risk of event (vascular/bleeding) after ACS and
clopidogrel

• 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

vascular
Risk of event
bleeding
3 months ??
Time after ACS
55
Who is High RiskPatients in whom long term
clopidogrel should be considered

• The vulnerable patient
• TIMI risk score
• Aspirin Failure
• Others

56
Who is High RiskPatients in whom long term
clopidogrel should be considered

• The vulnerable patient
• TIMI risk score
• Aspirin Failure
• Others

57
ACS PathophysiologyInflammation, Plaque Rupture,
Thrombosis, and Microembolization
Quiescent plaque
Plaque formation Lipids, other risk
factors InflammationLDL, others,
Infection? Plaque rupture (erosion) ?
Macrophages, metalloproteinases ThrombosisPlate
let Activation, Thrombin
Lipid core
Vulnerable plaque
TF ? Clotting Cascade
Inflammation
Collagen ? platelet activation
Foam Cells
Metalloproteinases
Macrophages
Culprit plaque
Plaque rupture
Platelet-thrombin micro-emboli
Courtesy of David Kandzari.
58
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)

59
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
200546937-954
60

• Angiograms of 253 patients with acute MI
• Complex Plaques
• Single 153 - 60.5
• Multiple 100 39.5

N Engl J Med 2000343915-22
61
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

62
Characteristics of Carotid Plaques Patients with
Unstable versus Stable Angina
Multivariate analysis UA and CRP gt3 mg/l were
independently and strongly associated with
complex carotid plaques
63
Vulnerable Patient at high risk for vascular
event
coronary
elsewhere
64
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

65
Vulnerability cutoff value ?
66
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67
Who is High RiskPatients in whom long term
clopidogrel should be considered

• The vulnerable patient
• TIMI risk score
• Aspirin Failure
• Others

68
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
69
TIMI Risk Score and Absolute Reduction of
death/MI/Stroke with Clopidogrel
Majority of patients
Percent reduction
Major bleeding 1
N 752 2524 3730 3567
1593 396
TIMI Risk Score
70
Who is High RiskPatients in whom long term
clopidogrel should be considered

• The vulnerable patient
• TIMI risk score
• Aspirin Failure
• Others

71
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

72
Aspirin Resistance
Cellular Factors Insufficient suppression of
COX-1 Overexpression of COX-2 mRNA Erythrocyte-in
duced platelet activation Increased
norepinephrine Generation of 8-iso-PGF2?
Clinical Factors Failure to prescribe Noncomplian
ce Nonabsorption Interaction with ibuprofen Can
be intermittent
Genetic Polymorphisms COX-1 GP IIIa
receptor Collagen receptor vWF receptor
Aspirin Resistance
Adapted with permission from Bhatt DL. J Am Coll
Cardiol. 2004431127-1129.
73
Unfortunately (surprisingly) there is no subgroup
analysis of CAPRIE or CURE for patients who were
on prior aspirin HoweverThere are other
subgroup analyses
74
Clopidogrel in patients with prior CABG CAPRIE
substudy (N1480)
Combined endpoint Vascular death, MI, stroke or
hospitalization for ischemia or bleeding
Vascular death
Circulation 2001 103 363-368
75
Clopidogrel in patients with history of prior
ischemic event - CAPRIE substudy (N4496)
Ringleb, P. A. et al. Stroke 200435528-532
76
Beneficial Outcomes with Clopidogrel in Various
Subgroups
CURE
Percentage of Patients with Event
Placebo ASA
No. ofPatients
Clopidogrel ASA
Characteristic
Overall 12562 9.3 11.4 Associated
MI 3283 11.3 13.7 No associated
MI 9279 8.6 10.6 Male sex 7726 9.1 11.9 Female
sex 4836 9.5 10.7 65 yr old 6354 5.4 7.6 gt 65
yr old 6208 13.3 15.3 ST-segment
deviation 6275 11.5 14.3 No ST-segment
deviation 6287 7.0 8.6 Enzymes elevated at
entry 3176 10.7 13.0 Enzymes not elevated at
entry 9386 8.8 10.9 Diabetes 2840 14.2 16.7 No
diabetes 9722 7.9 9.9 Low risk 4187 5.1 6.7 Inte
rmediate risk 4185 6.5 9.4 High
risk 4184 16.3 18.0 History of
revascularization 2246 8.4 14.4 No history of
revascularization 10316 9.5 10.7 Revascularizatio
n after randomization 4577 11.5 13.9 No
revascularization after randomization 7985 8.1 10.
0
1.2
1.0
0.8
0.6
0.4
Placebo Better
Clopidogrel Better
In combination with standard therapy The CURE
Trial Investigators. N Engl J Med.
2001345494-502.
Relative Risk (95 CI)
77
CURE Impact of History of Revascularization
Percent of Patients with an Event
6.0
1.2
(N2246)
(N10316)
History of Revascularization
78
Conclusions early treatment

• Clopidogrel loading should be given to patients
  with ACS (both STE and Non-STE) 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

79
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 gt5, continuously elevated CRP?)
• Aspirin failure ?
• Shorter duration
• High bleeding risk (e.g. coumadin etc)