Plavix UA-NSTEMI Slidekit 2010(2)

8/7/2019 Plavix UA-NSTEMI Slidekit 2010(2)

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Clopidogrel(PLAVIX)

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

Presented By:


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Pharmacology of Clopidogrel(PLAVIX) a Unique Antiplatelet Agent


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Molecular Structure

Generic: clopidogrel bisulfate

Class: ADP-receptor antagonist

Molecular weight = 419.9

1. Clopidogrel Prescribing Information, US, February 2002.


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COX (cyclo-oxygenase)ADP (adenosine diphosphate)TXA2 (thromboxane A 2)

CLOPIDOGREL

ASA COX

ADP

ADP

C

GPllb/llla(Fibrinogen receptor)

Collagen thrombinTXA 2Activation

TXA2

Mode of Action of Clopidogrel(PLAVIX) 1

1. Jarvis B, Simpson K. Drugs 2000; 60: 34777.


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Effects of ADP-Receptor Activation

Adapted from Savi P et al. Biochem Biophys Res Commun 2001; 283: 37983, 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.1535.

ADP / ATP

P2Y 1P2X 1 P2T 12

Gi2 coupledGq coupled

Ca 2+ Ca 2+ cAMP

Platelet shape changeTransient aggregation

No effect onfibrinogen

receptor

Cation influx Calcium mobilization

Fibrinogen receptor activationThromboxane A 2 generation

Sustained aggregation response


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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 onplatelets, with a lifespan of approximately 710 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



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Pharmacology of Clopidogrel(PLAVIX) (II) 1

No significant adverse drugdrug interaction with anyfrequently prescribed medication in cardiovascular patients; benefit of clopidogrel over ASA maintained inpatients taking concomitant medications

Care should be exercised when used in combinationwith other antithrombotic medications (warfarin,heparin etc.)



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A Loading Dose of Clopidogrel (PLAVIX)Provides Rapid and Full Effect by 3 Hours 1

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

100

-20

0

20

40

60

80

1.5 3 6 24 27 48

Time (hours)

Me a n in hib it io n ( % )

Clopidogrel75 mg

Clopidogrel300 mg

*

*p < 0.002 vs clopidogrel 75 mg

(n = 20/group)

** *

**

Healthy Volunteers


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Effects of Clopidogrel (PLAVIX) on aKey Inflammatory Modulator (CD40L) 1

1. Hermann A et al . Platelets 2001; 12: 7482.

Effects ex vivo in healthy volunteers

*p < 0.05 versus ADP-stimulated controls

0

0.1

0.2

0.3

0.4

0.5

Control ASA Clopidogrel Clopidogrelplus ASA

C D40 L ( Mn X)

* *

Control

ADP, 30M


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Effects of Clopidogrel (PLAVIX) on Platelet-Dependent Mitogenesis of Smooth Muscle Cells 1,2

1. Hermann A et al . Thromb Res 2002; 105: 1735. 2. Hermann A et al . Arch Pharmacol 2001;363(suppl 4): 442.

*p < 0,05 versus control

0

10

20

30

40

Control ASA Clopidogrel Clopidogrelplus ASA

DN

A s y n t he s is ( x fo ld i nc re a s e )

**


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Clinical Efficacy of Clopidogrel (PLAVIX)

From CAPRIE to CURE


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Clinical Efficacy of Clopidogrel(PLAVIX)

Trial Patients Design Maximumfollow-up

Number of patients

CAPRIE 1 Myocardial infarction,stroke, peripheralarterial disease

Clopidogrelvs ASA

3 years 19,185

CURE 3 Acute coronarysyndrome

Clopidogrel *vs placebo *

1 year 12,562

CLASSICS 2 Coronary stenting Clopidogrel * vs ticlopidine *

4 weeks 1,020

1. CAPRIE Steering Committee. Lancet 1996; 348: 132939. 2. Bertrand NE et al. Circulation 2000; 102: 6249 3. The CURE Trial Investigators. N Engl J Med 2001; 345: 494502.

Clinical Benefit of Clopidogrel in more than30,000 Patients from CAPRIE to CURE

*On top of standard therapy (including ASA)Without ST segment elevation


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CAPRIE: Design 1

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: 132939.


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CAPRIE: Long-Term Benefit of Clopidogrel (PLAVIX) Compared with ASA 1

Cumulative Event Rate(Myocardial Infarction, Ischemic Stroke or Vascular Death)

*ITT analysis

1. CAPRIE Steering Committee. Lancet 1996; 348: 132939.

Months of follow-up

8.7% *Overallrelative

riskreduction

0

4

8

12

16

0 3 6 9 12 15 18 21 24 27 30 33 36

C u mu la t ive e ve nt ra t e ( % )

ASA

p = 0.043, n = 19,185

Clopidogrel


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CAPRIE: Benefit of Clopidogrel (PLAVIX) over ASA in the Reduction of Myocardial Infarction 1

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

Months of follow-up

0

1

2

3

4

5

0 3 6 9 12 15 18 21 24 27 30 33 36

C u mu la t ive e ve nt ra t e ( % )

p = 0.008, n = 19,185

ASA 3.6%

Clopidogrel 2.9%

Clopidogrel

ASA 19.2% *Relative

riskreduction

*ITT analysis


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COX (cyclo-oxygenase)ADP (adenosine diphosphate)TXA2 (thromboxane A 2)

CLOPIDOGREL

ASA COX

ADP

ADP

C

GPllb/llla(Fibrinogen receptor)

Collagen thrombinTXA2

Activation

TXA2

ASA

Synergistic Mode of Action withClopidogrel (PLAVIX) and ASA 1

1. Schafer AI. Am J Med 1996; 101: 199209.


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Synergistic Action of Clopidogrel (PLAVIX) ontop of ASA in Thrombus Formation 1

1. Herbert JM et al. Thromb Haemost 1998; 80: 51218.

-100

-80

-60

-40

-20

0

0 5 10 15 20 25 30 35 40 45 50

Time (minutes)

Blo o d flo w ( % d e c re a s e )

Clopidogrel plus ASA(10 mg/kg plus 10 mg/kg)

Clopidogrel (10 mg/kg)

ASA (10 mg/kg) Placebo

Experimental model


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Synergistic Action of Clopidogrel (PLAVIX)on top of ASA in Thrombosis 1

1. Makkar RR et al. Eur Heart J 1998; 19: 153846.

Control (unperfused)Thrombus weight 20 mg

ASA 10 mg/kg IVThrombus weight 18 mg

Clopidogrel 5 mg/kg IV

Thrombus weight 8 mg

Clopidogrel 5 mg/kg IV plus ASA10 mg/kg IV Thrombus weight 1 mg

Stent model


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Synergistic Action of Clopidogrel (PLAVIX)* and ASA in Healthy Volunteers 1Mean Reduction of Platelet Deposition vs ASA Alone

1. Cadroy Y et al. Circulation 2000; 101: 28238.

n = 18 for all comparisons

-10

0

1020

30

40

5060

70

80

Day 1, 1.5 hrs Day 1, 6 hrs Day 6, 6 hrs

Me a n re d u c t io n ( % ) Clopidogrel 300 mg

plus ASAvs ASA alone

Clopidogrel 75 mgplus ASAvs ASA alone

p = 0.03vs ASA

p < 0.001vs ASA

p = 0.04vs ASA

p < 0.001vs ASA

p < 0.001vs ASA

p = 0.03

p = 0.01

p = NS

*With or without loading dose


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Acute Coronary Syndrome (ACS) is aClassic Manifestation of Atherothrombosis

Unstableangina Non-Q-W MI Q-W MI Stroke PAD

Common underlying

atherothrombosis

Atherothrombotic event(MI, stroke, vascular death)

Plaque rupture Platelet activationand aggregation

Thrombus formation


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Atherothrombosis: A Generalizedand Progressive Process

UnstableanginaMIIschemicstroke/TIACritical legischemiaCardiovasculardeath

ACS

Atherosclerosis

Adapted from Stary HC et al. Circulation . 1995; 92: 135574, and Fuster V et al . Vasc Med .1998; 3: 2319.

Stable anginaIntermittent claudication

Atherothrombosis


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CURE: Design 1

Objective: to evaluate the early and long-term efficacy and safetyof clopidogrel (300/75 mg) on top of standard therapy (includingASA)

Double-blind, randomized, prospective trial

Multicenter (482 centers in 28 countries)

Follow-up of 12,562 patients from 3 months to 1 year with acutecoronary syndromes (without ST segment elevation)

Primary endpoint: first occurrence of any component of thecluster of:

cardiovascular death myocardial infarction

stroke (ischemic, hemorrhagic, or of uncertain type)

1. The CURE Trial Investigators. N Engl J Med 2001; 345: 494502.


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1. The CURE Study Investigators. Eur Heart J 2000; 21: 203341.

CURE: Design 1

Double-blind treatment up to 12 months

ASA 75325 mg o.d.

Clopidogrel75mg o.d.(n = 6,259)

Placebo1 tab o.d.

(n = 6,303)

ASA 75325 mg o.d.

Day 1

6 mon

th visit

9 mon

th visit

12 m

onth

or fina

l visit

Clop

idog re

l

300m

g loadin

g

dose

3 mon

th visit

Disc

harg

e visit

1 mon

th visit

Patients withacute coronary

syndrome

(unstable anginaor non-Q-wave

myocardialinfarction)

Plac

ebo

load

ing dos

e

R = Randomization

n = 12,562

28 countries

R


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CURE: Early and Long-Term Benefitsof Clopidogrel 1,2

1. The CURE Trial Investigators. N Engl J Med 2001; 345: 494502. 2. Data on file, 2002,p73 internal CSR-EFC 3307.

0.00

0.02

0.04

0.06

0.08

0.10

0.12

0.14

0 3 6 9 12

Months of follow-up

C u mmu la t ive ha za rd ra t e Placebo *

(n = 6,303)

Clopidogrel * (n = 6,259)

20% Relativerisk reduction

p = 0.00009

Cumulative Events(Myocardial Infarction, Stroke, or Cardiovascular Death)

*On top of standard therapy (including ASA)


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CURE: Consistent Benefit Independentof Patient History 1


Baseline

characteristics

Overall

Diagnosis

Elev card enzy

ST depr >1.0 mm

Diabetes

Previous myocardialinfarction

Previous stroke

Non-Q-W MI

Unstable angina

Other

No

Yes

No

Yes

No

Yes

No

Yes

No

Yes

12,562

3,295

8,298

968

9,381

3,176

7,273

5,288

9,721

2,840

8,517

4,044

12,055

506

9.3

12.7

7.3

15.1

8.8

10.7

7.5

11.8

7.9

14.2

7.8

12.5

8.9

17.9

11.4

15.5

8.7

19.7

10.9

13.0

8.9

14.8

9.9

16.7

9.5

15.4

11.0

22.4

N Clopidogrel * Placebo *

Percent events

Clopidogrel better Placebo better

0.4 0.6 0.8 1.0 1.2



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CURE: Consistent Benefit on Top of Various Standard Therapies 1



0.4 0.6 0.8 1.0 1.2Hazard ratio (95% CI)

Concomitantmedication/therapy

Heparin/LMWH

ASA

GPIIb/IIIa Antag

Beta-blocker

ACEI

Lipid-lowering

PTCA/CABG

No

Yes

< 100 mg

100200mg

> 200 mgNo

Yes

No

Yes

No

Yes

No

Yes

No

Yes

951

11611

1927

7428

3201

11739

823

2032

10530

4813

7749

4461

8101

7977

4585

4.9

9.7

8.5

9.2

9.9

8.9

15.7

9.9

9.2

6.3

11.2

10.9

8.4

8.1

11.4

7.7

11.7

9.7

10.9

13.7

10.8

19.2

12.0

11.3

8.1

13.5

13.1

10.5

10.0

13.8

N Clopidogrel*

Placebo*

Events (%)

Clopidogrel better Placebo better


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5.7

11.4

20.7

4.1

9.8

15.9

0

5

10

15

20

25

Low risk Moderate risk High risk

MI, s t ro k e o r va s c u la r d e a t h ( % )

Placebo

Clopidogrel

p = 0.03

p = 0.02

p = 0.003

n = 3,276

n = 7,297

n = 1,989

CURE: Effects of Clopidogrel (PLAVIX)Stratified by TIMI Risk Score at 12 Months

1. The CURE Trial Investigators. N Engl J Med 2001; 345: 494502. 2. Budaj AJ et al J Am Coll Cardiol 2002; 39, (suppl B): 441B.

ARR * 1.6 1.6 4.8RRR 29% 15% 27%

*Absolute risk reductionRelative risk reduction


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ACC/AHA 2007Guidelines for the

Management of Patients With UnstableAngina/NonST-Elevation

Myocardial Infarction


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3.2.1. Antiplatelet TherapyRecommendations

CLASS I1. Aspirin should be administered to UA/NSTEMI patients as soon aspossible after hospital presentation and continued indefinitely inpatients 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 totake ASA because of hypersensitivity or major gastrointestinalintolerance. (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)


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4. For UA/NSTEMI patients in whom an initial invasive strategy isselected, antiplatelet therapy in addition to aspirin should beinitiated 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 isindicated only if there is no appreciable delay to angiography andPCI 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)


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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 angiographyshould 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 ASAAnd anticoagulant therapy before diagnostic angiography

(upstream). (Level of Evidence: C)

CLASS IIa


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1. For UA/NSTEMI patients in whom an initial conservative strategy isselected and who have recurrent ischemic discomfort with clopidogrel,ASA, and anticoagulant therapy, it is reasonable to add a GPIIb/IIIa antagonist before diagnostic angiography. (Level of Evidence: C)

2. For UA/NSTEMI patients in whom an initial invasive strategy isselected, it is reasonable to initiate antiplatelet therapy with bothclopidogrel (loading dose followed by daily maintenance dose)* andan intravenous GP IIb/IIIa inhibitor. (Level of Evidence: B) Abciximabas the choice for upstream GP IIb/IIIa therapy is indicated only if there is no appreciable delay to angiography and PCI is likely to beperformed; otherwise, IV eptifibatide or tirofiban is the preferredchoice 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 anintravenous 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 plannedcatheterization or PCI. (Level of Evidence: B)


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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)

L T A ti l t Th t


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Long-Term Anticoagulant Therapy atHospital Discharge After UA/NSTEMI


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Documents

Plavix UA-NSTEMI Slidekit 2010(2)