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Clopidogrel

(PLAVIX)
In the Management of Unstable Angina /
NSTEMI in the light of Clinical Trials

Presented By:
Pharmacology of Clopidogrel
(PLAVIX)
– a Unique Antiplatelet Agent
Molecular Structure

• Generic: clopidogrel bisulfate


• Class: ADP-receptor antagonist
• Molecular weight = 419.9

1. Clopidogrel Prescribing Information, US, February 2002.


Mode of Action of Clopidogrel
(PLAVIX)1

CLOPIDOGREL C

ADP

ADP

GPllb/llla Collagen thrombin


Activation
(Fibrinogen receptor) TXA 2

ASA COX

TXA2

COX (cyclo-oxygenase)
ADP (adenosine diphosphate)
TXA2 (thromboxane A2)
1. Jarvis B, Simpson K. Drugs 2000; 60: 347–77.
Effects of ADP-Receptor Activation
ADP / ATP

P2Y1
P2X1 P2T12

Gq coupled
Gi2 coupled
Cation influx Calcium mobilization

Ca2+ Ca2+ cAMP

No effect on Platelet shape change Fibrinogen receptor activation


fibrinogen Transient aggregation Thromboxane A2 generation
receptor
Sustained aggregation response

Adapted from Savi P et al. Biochem Biophys Res Commun 2001; 283: 379–83, and Ferguson JJ.
The Physiology of Normal Platelet Function. In: Ferguson JJ, Chronos N, Harrington RA (Eds).
Antiplatelet Therapy in Clinical Practice. London: Martin Dunitz; 2000: pp.15–35.
Pharmacology of Clopidogrel
(PLAVIX) (I)1
• Absorption (oral): rapid, not affected by food or antacids
• Metabolism: rapid and extensive hepatic metabolism
• Half-life: 8 hours (but has an irreversible effect on
platelets, with a lifespan of approximately 7–10 days)
• Excretion: 50% in urine and 46% in feces, after 5 days
• Standard dosing: 75 mg once daily
• Rapid onset of action with a loading dose of 300 mg
– provides full antiplatelet effect within 3 hours

1. Jarvis B, Simpson K. Drugs 2000; 60: 347–77.


Pharmacology of Clopidogrel
(PLAVIX) (II)1
• No significant adverse drug–drug interaction with any
frequently prescribed medication in cardiovascular
patients; benefit of clopidogrel over ASA maintained in
patients taking concomitant medications
• Care should be exercised when used in combination
with other antithrombotic medications (warfarin,
heparin etc.)

1. Jarvis B, Simpson K. Drugs 2000; 60: 347–77.


A Loading Dose of Clopidogrel (PLAVIX)
Provides Rapid and Full Effect by 3 Hours1
Healthy Volunteers

100
* *
80
* *
Mean inhibition (%)

*
60

40 * Clopidogrel
75 mg
20 Clopidogrel
300 mg
0

-20
(n = 20/group)
1.5 3 6 24 27 48
Time (hours)
*p < 0.002 vs clopidogrel 75 mg

1. Data on file, Sanofi-Synthélabo, 1999, internal report PDY 3494.


Effects of Clopidogrel (PLAVIX) on a
Key Inflammatory Modulator (CD40L)1
Effects ex vivo in healthy volunteers

0.5

0.4 Control
CD40L (Mn X)

0.3 ADP, 30µM

0.2
* *
0.1

0
Control ASA Clopidogrel Clopidogrel
plus ASA

*p < 0.05 versus ADP-stimulated controls

1. Hermann A et al. Platelets 2001; 12: 74–82.


Effects of Clopidogrel (PLAVIX) on Platelet-
Dependent Mitogenesis of Smooth Muscle Cells1,2

40
DNA synthesis (x fold increase)

30

20

10 *
*
0
Control ASA Clopidogrel Clopidogrel
plus ASA

*p < 0,05 versus control

1. Hermann A et al. Thromb Res 2002; 105: 173–5. 2. Hermann A et al. Arch Pharmacol 2001;
363(suppl 4): 442.
Clinical Efficacy of
Clopidogrel (PLAVIX)

From CAPRIE to CURE


Clinical Efficacy of Clopidogrel
(PLAVIX)
Clinical Benefit of Clopidogrel in more than
30,000 Patients – from CAPRIE to CURE

Trial Patients Design Maximum Number of


follow-up patients

CAPRIE1 Myocardial infarction, Clopidogrel 3 years 19,185


stroke, peripheral vs ASA
arterial disease

CLASSICS2 Coronary stenting Clopidogrel* 4 weeks 1,020


vs ticlopidine*

CURE3 Acute coronary Clopidogrel* 1 year 12,562


syndrome† vs placebo*

*
On top of standard therapy (including ASA)

Without ST segment elevation
1. CAPRIE Steering Committee. Lancet 1996; 348: 1329–39. 2. Bertrand NE et al. Circulation
2000; 102: 624–9 3. The CURE Trial Investigators. N Engl J Med 2001; 345: 494–502.
CAPRIE: Design1

• Objective: to compare the efficacy and safety of


clopidogrel 75 mg with active control – ASA 325 mg
• Double-blind, randomized, prospective trial
• Multicenter (384 centers in 16 countries)
• Follow-up of 19,185 patients from 1 to 3 years with:
– Ischemic atherothrombotic stroke
– Myocardial infarction (MI)
– Peripheral arterial disease
• Combined primary endpoint: cluster of ischemic
stroke, MI, and vascular death

1. CAPRIE Steering Committee. Lancet 1996; 348: 1329–39.


CAPRIE: Long-Term Benefit of
Clopidogrel (PLAVIX) Compared with ASA1
Cumulative Event Rate
(Myocardial Infarction, Ischemic Stroke or Vascular Death)
ASA 8.7%*
Overall
16
relative
risk
Cumulative event rate (%)

reduction
12 Clopidogrel

p = 0.043, n = 19,185
0
0 3 6 9 12 15 18 21 24 27 30 33 36

Months of follow-up
*ITT analysis

1. CAPRIE Steering Committee. Lancet 1996; 348: 1329–39.


CAPRIE: Benefit of Clopidogrel (PLAVIX) over
ASA in the Reduction of Myocardial Infarction1
ASA 19.2%*
5 Relative
risk
ASA 3.6%
Cumulative event rate (%)

reduction
4 Clopidogrel

2 Clopidogrel 2.9%

1
p = 0.008, n = 19,185
0
0 3 6 9 12 15 18 21 24 27 30 33 36

Months of follow-up

*ITT analysis

1. Gent M. Circulation 1997; 96(suppl 8): I-467.


Synergistic Mode of Action with
Clopidogrel (PLAVIX) and ASA1

CLOPIDOGREL C

ADP

ADP

GPllb/llla Collagen thrombin


Activation
(Fibrinogen receptor) TXA2

ASA
ASA COX

TXA2

COX (cyclo-oxygenase)
ADP (adenosine diphosphate)
TXA2 (thromboxane A2)
1. Schafer AI. Am J Med 1996; 101: 199–209.
Synergistic Action of Clopidogrel (PLAVIX) on
top of ASA in Thrombus Formation1
Experimental model
Clopidogrel (10 mg/kg) Clopidogrel plus ASA
0 (10 mg/kg plus 10 mg/kg)
ASA (10 mg/kg) Placebo
Blood flow (% decrease)

-20

-40

-60

-80

-100
0 5 10 15 20 25 30 35 40 45 50
Time (minutes)

1. Herbert JM et al. Thromb Haemost 1998; 80: 512–18.


Synergistic Action of Clopidogrel (PLAVIX)
on top of ASA in Thrombosis1
Stent model

Control (unperfused)
Thrombus weight 20 mg

ASA 10 mg/kg IV
Thrombus weight 18 mg

Clopidogrel 5 mg/kg IV
Thrombus weight 8 mg

Clopidogrel 5 mg/kg IV plus ASA


10 mg/kg IV Thrombus weight 1 mg

1. Makkar RR et al. Eur Heart J 1998; 19: 1538–46.


Synergistic Action of Clopidogrel (PLAVIX)
*
and ASA in Healthy Volunteers1
Mean Reduction of Platelet Deposition vs ASA Alone
p = NS
p = 0.01
80 p < 0.001 p < 0.001
vs ASA vs ASA
70 p < 0.001
vs ASA
60
Mean reduction (%)

Clopidogrel 300 mg
plus ASA
50
vs ASA alone
p = 0.03
40 p = 0.03 vs ASA
Clopidogrel 75 mg
30 p = 0.04 plus ASA
vs ASA
20 vs ASA alone

10
0
Day 1, 1.5 hrs Day 1, 6 hrs Day 6, 6 hrs
-10
*With or without loading dose n = 18 for all comparisons
1. Cadroy Y et al. Circulation 2000; 101: 2823–8.
Acute Coronary Syndrome (ACS) is a
Classic Manifestation of Atherothrombosis
Unstable
Non-Q-W MI Q-W MI Stroke PAD
angina

Common underlying
atherothrombosis

Plaque rupture Platelet activation Thrombus formation


and aggregation

Atherothrombotic event
(MI, stroke, vascular death)
Atherothrombosis: A Generalized
and Progressive Process
Unstable
angina ACS
MI
Ischemic
stroke/TIA
Critical leg
ischemia
Cardiovascularde
ath

Atherosclerosis Atherothrombosis

Stable angina
Intermittent claudication

Adapted from Stary HC et al. Circulation. 1995; 92: 1355–74, and Fuster V et al. Vasc Med.
1998; 3: 231–9.
CURE: Design1
• Objective: to evaluate the early and long-term efficacy and safety
of clopidogrel (300/75 mg) on top of standard therapy (including
ASA)
• Double-blind, randomized, prospective trial
• Multicenter (482 centers in 28 countries)
• Follow-up of 12,562 patients from 3 months to 1 year with acute
coronary syndromes (without ST segment elevation)
• Primary endpoint: first occurrence of any component of the
cluster of:
– cardiovascular death
– myocardial infarction
– stroke (ischemic, hemorrhagic, or of uncertain type)

1. The CURE Trial Investigators. N Engl J Med 2001; 345: 494–502.


CURE: Design1

g
ad l
in
lo re
se g og
n = 12,562

do 0m id
30 lop
28 countries

C
Clopidogrel
75mg o.d.
ASA 75–325 mg o.d. (n = 6,259)
Patients with
acute coronary
syndrome

(unstable angina
R Double-blind treatment up to 12 months

or non-Q-wave
myocardial ASA 75–325 mg o.d.
infarction)
Placebo
e v ose

1 tab o.d.

al nth
it

it

it

it
sc adin 1
d

(n = 6,303)
t

vis

vis
isi

vis

vis

it
lo Day
g

vis
fin o
or 12 m
th

th

th

th
rg

on

on

on

on
ha

1m

3m

6m

9m
o
eb
Di
ac

R = Randomization
Pl

1. The CURE Study Investigators. Eur Heart J 2000; 21: 2033–41.


CURE: Early and Long-Term Benefits
of Clopidogrel1,2
Cumulative Events
(Myocardial Infarction, Stroke, or Cardiovascular Death)

0.14
Placebo*
Cummulative hazard rate

0.12 (n = 6,303)
0.10

0.08 Clopidogrel* 20% Relative


(n = 6,259) risk reduction
0.06
p = 0.00009
0.04

0.02

0.00
0 3 6 9 12
Months of follow-up
*On top of standard therapy (including ASA)

1. The CURE Trial Investigators. N Engl J Med 2001; 345: 494–502. 2. Data on file, 2002,
p73 internal CSR-EFC 3307.
CURE: Consistent Benefit Independent
of Patient History1
Baseline Percent events
characteristics N Clopidogrel* Placebo* Clopidogrel better Placebo better

Overall 12,562 9.3 11.4


Diagnosis Non-Q-W MI 3,295 12.7 15.5
Unstable angina 8,298 7.3 8.7
Other 968 15.1 19.7
Elev card enzy No 9,381 8.8 10.9
Yes 3,176 10.7 13.0
ST depr >1.0 mm No 7,273 7.5 8.9
Yes 5,288 11.8 14.8
Diabetes No 9,721 7.9 9.9
Yes 2,840 14.2 16.7
Previous myocardial No 8,517 7.8 9.5
infarction
Yes 4,044 12.5 15.4
No 12,055 8.9 11.0
Previous stroke
Yes 506 17.9 22.4

0.4 0.6 0.8 1.0 1.2

*On top of standard therapy (including ASA)


1. Clopidogrel Prescribing Information, US, February 2002.
CURE: Consistent Benefit on Top of
Various Standard Therapies1
Concomitant Events (%)
medication/therapy N Clopidogrel* Placebo* Clopidogrel better Placebo better

Heparin/LMWH No 951 4.9 7.7


Yes 11611 9.7 11.7
ASA < 100 mg 1927 8.5 9.7
100–200 7428 9.2 10.9
mg
3201 9.9 13.7
> 200 mg
GPIIb/IIIa Antag 11739 8.9 10.8
No
823 15.7 19.2
Yes
Beta-blocker 2032 9.9 12.0
No
10530 9.2 11.3
Yes
ACEI 4813 6.3 8.1
No
7749 11.2 13.5
Yes
Lipid-lowering 4461 10.9 13.1
No
8101 8.4 10.5
Yes
PTCA/CABG 7977 8.1 10.0
No
4585 11.4 13.8
Yes
0.4 0.6 0.8 1.0 1.2
*On top of standard therapy (including ASA) Hazard ratio (95% CI)
1. Clopidogrel Prescribing Information, US, February 2002.
CURE: Effects of Clopidogrel (PLAVIX)
Stratified by TIMI Risk Score at 12 Months
ARR* 1.6 1.6 4.8
RRR† 29% 15% 27%
MI, stroke or vascular death (%)

25 n = 1,989
20.7
20
15.9
15 n = 7,297 Placebo
11.4 p = 0.003 Clopidogrel
9.8
10 n = 3,276
5.7 p = 0.02
5 4.1
p = 0.03
0
Low risk Moderate risk High risk
*Absolute risk reduction

Relative risk reduction
1. The CURE Trial Investigators. N Engl J Med 2001; 345: 494–502. 2. Budaj AJ et al J Am Coll
Cardiol 2002; 39, (suppl B): 441B.
ACC/AHA 2007
Guidelines for the
Management of
Patients With Unstable
Angina/Non–ST-Elevation
Myocardial Infarction
3.2.1. Antiplatelet Therapy
Recommendations
CLASS I
1. Aspirin should be administered to UA/NSTEMI patients as soon as
possible after hospital presentation and continued indefinitely in
patients not known to be intolerant of that medication. (Level of
Evidence: A)
2. Clopidogrel (loading dose followed by daily maintenance dose)
should be administered to UA/NSTEMI patients who are unable to
take ASA because of hypersensitivity or major gastrointestinal
intolerance. (Level of Evidence: A)
3. In UA/NSTEMI patients with a history of gastrointestinal bleeding,
when ASA and clopidogrel are administered alone or in combination,
drugs to minimize the risk of recurrent gastrointestinal bleeding
(e.g., proton-pump inhibitors) should be prescribed concomitantly.
(Level of Evidence: B)
4. For UA/NSTEMI patients in whom an initial invasive strategy is
selected, antiplatelet therapy in addition to aspirin should be
initiated before diagnostic angiography (upstream) with either
Clopidogrel (loading dose followed by daily maintenance dose)* or
An intravenous GP IIb/IIIa inhibitor. (Level of Evidence: A)
Abciximab as the choice for upstream GP IIb/IIIa therapy is
indicated only if there is no appreciable delay to angiography and
PCI is likely to be performed; otherwise, IV eptifibatide or tirofiban is
the preferred choice of GP IIb/IIIa inhibitor. (Level of Evidence: B)

5. For UA/NSTEMI patients in whom an initial conservative (i.e.,


noninvasive) strategy is selected (see Section 3.3), clopidogrel
(loading dose followed by daily maintenance dose)* should be
added to ASA and anticoagulant therapy as soon as possible after
admission and administered for at least 1 month (Level of Evidence:
A) and ideally up to 1 year. (Level of Evidence: B)
6. For UA/NSTEMI patients in whom an initial conservative strategy
is selected, if recurrent symptoms/ischemia, HF, or serious
Arrhythmias subsequently appear, then diagnostic angiography
should be performed. (Level of Evidence: A) Either
an intravenous GP IIb/IIIa inhibitor (eptifibatide or tirofiban; Level of
Evidence: A) or clopidogrel (loading dose followed by daily
Maintenance dose; Level of Evidence: A)* should be added to ASA
And anticoagulant therapy before diagnostic angiography
(upstream). (Level of Evidence: C)
CLASS IIa
1. For UA/NSTEMI patients in whom an initial conservative strategy is
selected and who have recurrent ischemic discomfort with clopidogrel,
ASA, and anticoagulant therapy, it is reasonable to add a GP
IIb/IIIa antagonist before diagnostic angiography. (Level of Evidence: C)

2. For UA/NSTEMI patients in whom an initial invasive strategy is


selected, it is reasonable to initiate antiplatelet therapy with both
clopidogrel (loading dose followed by daily maintenance dose)* and
an intravenous GP IIb/IIIa inhibitor. (Level of Evidence: B) Abciximab
as the choice for upstream GP IIb/IIIa therapy is indicated only if
there is no appreciable delay to angiography and PCI is likely to be
performed; otherwise, IV eptifibatide or tirofiban is the preferred
choice of GP IIb/IIIa inhibitor.† (Level of Evidence: B)

3. For UA/NSTEMI patients in whom an initial invasive strategy is


selected, it is reasonable to omit upstream administration of an
intravenous GP IIb/IIIa antagonist before diagnostic angiography if
bivalirudin is selected as the anticoagulant and at least 300 mg of
clopidogrel was administered at least 6 h earlier than planned
catheterization or PCI. (Level of Evidence: B)
CLASS IIb
For UA/NSTEMI patients in whom an initial conservative (i.e.,
noninvasive) strategy is selected, it may be reasonable to add eptifibatide
Or tirofiban to anticoagulant and oral antiplatelet therapy. (Level of
Evidence: B)

CLASS III
Abciximab should not be administered to patients in whom PCI is not
planned. (Level of Evidence: A)
Long-Term Anticoagulant Therapy at
Hospital Discharge After UA/NSTEMI
From CAPRIE to CURE – Conclusions
• In CAPRIE, clopidogrel (PLAVIX) was more effective than ASA in
reducing the combined risk of myocardial infarction, ischemic stroke,
or vascular death1
• Synergistic effects of clopidogrel (PLAVIX) and ASA have been
demonstrated in ex vivo platelet studies and animal models2–5
• Clopidogrel (PLAVIX) on top of standard therapy (including ASA)
demonstrates an early effect (within hours) and sustained long-term
benefit throughout the entire 12 month study period in the CURE
study:6
– a 20% relative risk reduction in ischemic events with long-term use
(up to 12 months) (p = 0.00009)7
– the Kaplan-Meier curves began to diverge within hours and continued to
diverge over the 12-month period

1. CAPRIE Steering Committee. Lancet 1996; 348: 1329–39. 2. Cadroy Y et al. Circulation
2000; 101: 2823–8. 3. Herbert JM et al. Thromb Haemost 1998; 80: 512–8. 4. Harker LA et al.
Circulation 1998; 98: 2461–9. 5. Makkar RR et al. Eur Heart J 1998; 19: 1538–46. 6. The
CURE Trial Investigators. N Engl J Med 2001; 345: 494–502. 7. Data on file, 2002, p73
internal CSR-EFC 3307.
Thank You