Clinical Efficacy of Clopidogrelin

CVA, ACS, PAD

Atherothrombosis: A Generalized and Progressive Process

Unstable angina MI Ischemic stroke/TIACritical leg ischemiaCardiovasculardeath

ACS

Atherosclerosis

Adapted from Stary HC et al. Circulation. 1995; 92: 1355–74, and Fuster V et al. Vasc Med. 1998; 3: 231–9.

Stable angina Intermittent claudication

Atherothrombosis

COX (cyclo-oxygenase)ADP (adenosine diphosphate)TXA2 (thromboxane A2)

CLOPIDOGREL

ASA COX

ADP

ADP

C

GPllb/llla(Fibrinogen receptor)

Collagen thrombinTXA2

Activation

TXA2

ASA

Synergistic Mode of Action with Clopidogrel and ASA1

1. Schafer AI. Am J Med 1996; 101: 199–209.

CAPRIE: Long-Term Benefit of Clopidogrel Compared with ASA1

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

*ITT analysis

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

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

Cu

mu

lati

ve e

ven

t ra

te (

%)

ASA

p = 0.043, n = 19,185

Clopidogrel

CAPRIE: Benefit of Clopidogrel over ASA in the Reduction of Myocardial Infarction1

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

Cu

mu

lati

ve e

ven

t ra

te (

%)

p = 0.008, n = 19,185

ASA 3.6%

Clopidogrel 2.9%

Clopidogrel

ASA 19.2%*

Relativerisk

reduction

*ITT analysis

CAPRIE: Amplified Benefit of Clopidogrel in Patients with Higher Vascular Risk

1. CAPRIE Steering Committee. Lancet 1996; 348: 1329–39. 2. Jarvis B, Simpson K. Drugs 2000; 60: 347–77.

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

(n = 8,854) (n = 4,496)

15.2%

20.0%

23.8%

14.1%

17.2%

20.4%

0

5%

10%

15%

20%

25%

30%

All CAPRIE patients†1

(n = 19,185)Prior history of any

ischemic event‡2

Prior history of majoracute event (MI or stroke)‡2

Eve

nt

rate

(%

)

ASAClopidogrel

11*

28*

34*

*Number of events prevented/1,000 patients/year over ASA†Cumulative proportion of patients experiencing event over 3 years (mean follow-up, 2 years) ‡3-year event rate

CAPRIE: Amplified Benefit of Clopidogrel in Patients with Diabetes

1. Bhatt DL et al. Am Heart J 2000; 140: 67–73. 2. Jarvis B, Simpson K. Drugs 2000; 60: 347–77.

25%

13.7%

17.7%

21.5%

12.6%

15.6%17.7%

0

5%

10%

15%

20%

All CAPRIE patients¹ Diabetes² Diabetes treated withinsulin²

An

nu

al e

ven

t ra

te (

%)

ASA

Clopidogrel

11†

21†

38†

Event Rate(Myocardial Infarction, Stroke, Vascular Death, or Hospitalization*)

*For ischemic events or bleeding†Number of events prevented/1,000 patients/year over ASA

CAPRIE: Amplified Benefit of Clopidogrelin Patients with Prior CABG1

1. Bhatt DL et al. J Am Coll Cardiol 2000; 35(suppl A): 383.

*For ischemic events or bleeding†Number of events prevented/1,000 patients/year over ASA

Event Rate(Myocardial Infarction, Stroke, Vascular Death, or Hospitalization*)

25%

Overall benefit: p = 0.001; multivariate analysis

13.7%

22.3%

12.6%

15.9%

0

5%

10%

15%

20%

All CAPRIE Prior CABG

ASAClopidogrel

An

nu

al e

ven

t ra

te (

%)

11†

64†

1. CAPRIE Steering Committee. Lancet 1996; 348: 1329–39. 2. Harker LA et al. Drug Safety 1999; 21: 325–35.

*Patients with ASA intolerance were excluded†Clinically severe or resulting in early drug discontinuation

CAPRIE: Favorable Safety for Clopidogrel Compared ASA*

Adverse experiences†

Diarrhea (severe)1

Gastritis2

Gastro-intestinal ulcer2

Gastro-intestinal hemorrhage(severe)1

Intracranial hemorrhage1

Rash (severe)1

Neutropenia2

ASA(n = 9,586)

Clopidogrel(n = 9,599)

p value

NS< 0.001

0.001

< 0.05

NS

< 0.05

NS

0.11%1.32%1.15%

0.71%

0.49%

0.10%

0.17%

0.23%0.75%0.68%

0.49%

0.35%

0.26%

0.10%

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

CURE: Design1

Double-blind treatment up to 12 months

ASA 75–325 mg o.d.

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

Placebo1 tab o.d.(n = 6,303)

ASA 75–325 mg o.d.D

ay 1

6 m

onth

vis

it9

mon

th v

isit

12 m

onth

or fi

nal v

isit

Clopid

ogrel

300m

g load

ing

dose

3 m

onth

vis

it

Dis

char

ge v

isit

1 m

onth

vis

it

Patients withacute coronary

syndrome

(unstable angina or non-Q-wave

myocardial infarction)

Plac

ebo

load

ing

dose

R = Randomization

n = 12,562

28 countries

R

CURE: Early and Long-Term Benefits of Clopidogrel1,2

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

Cu

mm

ula

tive

haz

ard

rat

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)

*On top of standard therapy (including ASA)

PCI-CURE: 31% Relative Risk Reduction at Long-Term1

1. Mehta SR et al. Lancet 2001; 358: 527–33.

0.00

0.05

0.10

0.15

0 100 200 300 400

Days of follow-up

Cu

mu

lati

ve h

azar

d r

ate

Placebo*

(n = 1,345)

31% Relativerisk reduction

p < 0.002

Clopidogrel*

(n = 1,313)

Median time to PCI

10

Endpoint: Myocardial Infarction or Vascular Death

CURE: Bleeding Episodes

1. The CURE Trial Investigators. N Engl J Med 2001; 345: 494–502. 2. Chesebro JH et al. Circulation 1987; 76: 142–54. 3. The GUSTO Investigators. N Engl J Med 1993; 329: 673–82.

Event

Major bleeding1

• Life-threatening

• Other major bleeding

Transfusions of 2 units of blood1

Minor bleeding1

Major bleeding byTIMI definition2

Major bleeding byGUSTO definition3

Placebo*

(n = 6,303)Clopidogrel*

(n = 6,259) p value

2.7%

1.8%

0.9%

2.2%

2.4%

1.2%

1.1%

3.7%

2.2%

1.5%

2.8%

5.1%

1.1%

1.2%

0.001

NS

0.002

0.02

< 0.001

0.70

0.48

*On top of standard therapy (including ASA)

CURE: Relation Between Safety and ASA Dosage1

1. Clopidogrel Prescribing Information, US, February 2002.

0.0%

1.0%

2.0%

3.0%

4.0%

5.0%

6.0%

Ble

edin

g r

ate

(%)

2.0%

2.6%2.3%

3.5%

4.0%

4.9%

ASA dose 75–325 mg

100–200 mg > 200 mg< 100 mg

Placebo*

Clopidogrel*

*On top of standard therapy (including ASA)

ASA†

Clopidogrel†‡ for 9 months

Beta-blockers†

+

+

Lipid lowering therapy+

ACE I+

Class I Recommendations for Long Term Therapy*

ACC/AHA 2002 Guidelines Update for UA and NSTEMI1

1. Braunwald E et al. American College of Cardiology (ACC) and the American Heart Association (AHA) Guidelines, USA: ACC/AHA; 2002.

*At hospital discharge and post-hospital discharge†In the absence of contraindications‡Clopidogrel should be administered to hospitalized patients who are unable to take ASA because of hypersensitivity or major GI intolerance

From CAPRIE to CURE – Conclusions

• In CAPRIE, clopidogrel was more effective than ASA in reducing the combined risk of myocardial infarction, ischemic stroke, or vascular death1

• Synergistic effects of clopidogrel and ASA have been demonstrated in ex vivo platelet studies and animal models2–5

• Clopidogrel 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, p73internal CSR-EFC 3307.

2006סל הבריאות

המטופל אינו יכול להשתמש באספירין בשל רגישות יתר או כל •הוריית נגד אחרת

המטופל פיתח תופעות לוואי לטיפול באספירין•

חודשים3לאחר צינתור לב טיפולי במשך •

בחולים עם תסמונת כלילית חדה שלא ניתן לבצע בהם צנתור •

כלילי או שמחלתם אינה ניתנת לטיפול על ידי צנתור כלילי טיפולי חודשים)3( למשך

לחולים שלקו בשבץ מוחי שני תוך כדי טיפול מונע באספירין•

1. Hiatt WR. J Vasc Surg. 2002; 36:1283-1291.2. Belch JJ et al. Arch Intern Med 2003; 163: 884-892.

What is PAD?What is PAD?

The major risk factors for PAD are:The major risk factors for PAD are:22

• smoking smoking

• diabetesdiabetes

• age >55 years (men) or >65 years (women)age >55 years (men) or >65 years (women)

• hyperlipidemiahyperlipidemia

• hypertension hypertension

• history of cardiovascular diseasehistory of cardiovascular disease

PAD is an atherothrombotic disorder affecting PAD is an atherothrombotic disorder affecting the peripheral arteries and it is associated with the peripheral arteries and it is associated with

a high risk of MI, stroke and vascular deatha high risk of MI, stroke and vascular death11

Only 1 in 10 patients with PAD has classical symptoms of intermittent claudication

Only 1 in 10 of these patients has classical

symptoms of intermittent claudication (IC)

1 in 5 people over 65

has PAD†

† ABI<0.9

Diehm C et al. Atherosclerosis 2004; 172; 95-105.

Platelet thrombus

Platelets adhering to subendothelial space

Platelet aggregation

Subendothelial spaceEndothelial cells

Platelets

Normal platelets Activated platelets

PlateletsPlatelets are activated following the rupture of are activated following the rupture of an atherosclerotic plaquean atherosclerotic plaque

Adapted from: 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: 15–35.

Prevalence of PAD increases with agePrevalence of PAD increases with age

0

10

20

30

40

50

60

55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age group (y)

Figure adapted from Creager M, ed. Management of Peripheral Arterial Disease. Medical, Surgical and Interventional Aspects. 2000. 1 Meijer WT et al. Arterioscler Thromb Vasc Biol 1998; 18: 185-192.2.Criqui MH et al. Circulation 1985; 71: 510-515.

Pat

ien

ts w

ith

PA

D (

%)

Pat

ien

ts w

ith

PA

D (

%)

Rotterdam Study (ABI Test <0.9)1 San Diego Study (PAD by noninvasive tests)2

Measuring Ankle-Brachial Index (ABI)

Video courtesy of Professor Curt Diehm, Karlsbad-Clinic, Academic Teaching Hospital of the University of Heidelberg, Germany.

Association of low ankle brachial index with high

mortality in primary care

European Heart Journal (2006) 27, 1743–1749

How is Ankle-Brachial Index (ABI) measured?

• Measure ankle and brachial systolic pressures with Doppler1,2

• Use highest arm and each ankle pressures1,2

1. TASC Working Group. Int Angiol 2000; 19 (suppl): 5-34.2. Vascular Disease Foundation, 2003. Available at:http://www.vdf.org/ABI.htm.3. Hiatt WR. N Engl J Med 2001; 344: 1608-1621.

Ankle systolic pressureBrachial systolic pressure

ABI =

ABI Interpretation3

> 0.90 Normal

0.41 – 0.90 Mild-to-moderate peripheral arterial disease

0.00 – 0.40 Severe peripheral arterial disease

Resnick HE et al. Circulation 2004; 109: 733-739.

There is a strong two way association between decreased ABI and increased risk for cardiovascular

death1

Baseline ABI*

Per

cen

t (%

)

0

20

40

60

<0.60 (n=25)

70

50

30

10

0.60-<0.70 (n

=21)

0.70-<0.80 (n

=40)

0.80-<0.90 (n

=130)

0.90-<1.0 (n

=195)

1.0-<1.10 (n

=980)

All-cause mortality

CVD mortality

*Mean participant follow-up 8.3 years

Patients with PAD are at high risk of MI and stroke

Increased risk of MI* Increased risk of stroke*

PAD

Post-MI

Post-stroke

4 greater risk4

(includes only fatal MI and other CHD death)

5-7 greater risk1

(includes death)

2-3 greater risk2

(includes anginaand sudden death†)

2-3 greater risk3

(includes TIA)

3- 4 greater risk2

(includes TIA)

9 greater risk3

* Over 10 years versus the general population except for stroke following stroke which measures subsequent risk per year

† Sudden death defined as death documented within 1 hour and attributed to coronary heart disease.

1. Adult Treatment Panel II. Circulation 1994; 89: 1333-1435.2. Kannel WB. J Cardiovasc Risk 1994; 1: 333-339.3. Wilterdink JI, Easton JD. Arch Neurol 1992; 49: 857-863.4. Criqui MH et al. N Engl J Med 1992; 326: 381-386.

Risk of death is increased in patients with both symptomatic and asymptomatic PAD

*Kaplan-Meier survival curves based on mortality from all causes.†Large-vessel PAD.

Normal subjects*Normal subjects*

Asymptomatic PADAsymptomatic PAD††

Symptomatic PADSymptomatic PAD††

Severe symptomatic PADSevere symptomatic PAD††

100100

7575

5050

2525

0000 22 44 66 88 1010 1212

Su

rviv

al (

% o

f p

atie

nts

)S

urv

ival

(%

of

pat

ien

ts)

YearYear

Criqui MH et al. N Engl J Med 1992; 326: 381-386.

A screening ABI should be performed in patients with diabetes

The American Diabetes Association recommends screening for PAD in patients with

diabetes1

1. American Diabetes Association. Diabetes Care 2003; 26: 3333–3341.

2. Estes JM, Pomposelli FB Jr. Diabet Med 1996: 13: S43–S57.

Those <50 years of age who Those <50 years of age who have other risk factors have other risk factors associated with PADassociated with PAD

• SmokingSmoking• HypertensionHypertension• HyperlipidemiaHyperlipidemia• Duration of diabetes Duration of diabetes >10 years>10 years

Those >50 years of ageThose >50 years of age

• If normal an exercise If normal an exercise test should be test should be carried out carried out

• The ABI test The ABI test should be repeated should be repeated every 5 yearsevery 5 years

• Foot care is also important in diabetic patients as PAD is a major contributor to diabetic foot problems2

CAPRIE data

Patients with PAD are at risk of MI, ISand death

Patients with PAD are at risk of MI, ISand death

Dormandy JA, Creager MA. Cerebrovasc Dis 1999;9(Suppl 1):1–128 (Abstr 4).

0

1

2

3

4

5

6

3-ye

ar c

umul

ativ

e ev

ent r

ate

(%)

Clopidogrel

Aspirin

4.24.2

5.15.1

3.63.6

5.25.2

Patients qualifying for CAPRIE on the basis of PAD

Coronaryoutcome

Cerebrovascularoutcome

American Diabetes Association Consensus Statement 2003: PAD in people with diabetes

• “It is recommended that patients with diabetes who are >50 years of age have an ABI performed. An ABI is also useful in patients with other PAD risk factors and in those with symptoms.”1

• “Patients with diabetes and PAD may benefit more by taking clopidogrel [than

ASA].”1

1. American Diabetes Association. Diabetes Care: Vol 26: 12, Dec 2003

60%

Call to action Paper

The Call to Action Paper highlighted 5 key The Call to Action Paper highlighted 5 key action itemsaction items

Increase awareness of PAD and its

consequences

Improve the identification of

patients with symptomatic

PAD

Initiate a screening

protocol for patients at high

risk for PAD

Improve treatment rates among patients who have been diagnosed with

symptomatic PAD

Increase the rates of early

detection among the

asymptomatic population

Belch JJF et al. Arch Intern Med 2003; 163: 884-892.