Long-Term Management of Patients at Risk of Atherothrombosis.

Long-Term Management of Patients at Risk of Atherothrombosis

What is Atherothrombosis?

• Atherothrombosis is characterized by a sudden (unpredictable) atherosclerotic plaque disruption (rupture or erosion) leading to platelet activation and thrombus formation

• Atherothrombosis is the underlying condition that results in events leading to myocardial infarction, ischemic stroke, and vascular death

Plaque rupture1 Plaque erosion2

1. Falk E et al. Circulation 1995; 92: 657–71. 2. Arbustini E et al. Heart 1999; 82: 269–72.

NormalFatty

streakFibrousplaque

Athero-scleroticplaque

Plaquerupture/fissure &

thrombosisMyocardial infarction

Ischemicstroke/TIA†

Critical leg ischemia

Clinically silent

Cardiovasculardeath

Increasing age

Stable anginaIntermittent claudication

Unstableangina }ACS*

The Development of Atherothrombosis – a Generalized and Progressive Process

Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6, and

Aronow WS, Ahn C. Am J Cardiol 194; 74: 64–5.

*ACS, acute coronary syndrome †TIA, transient ischemic attack

Atherothrombosis* is aLeading Cause of Death Worldwide¹†

28

19

12

9

6

5.1

0 5 10 15 20 25 30

Atherothrombosis*

Infectious Disease

Cancer

Injuries

Pulmonary Disease

AIDS

1. The World Health Report, 2002, WHO Geneva, 2002.

Mortality (%)

*Ischemic heart disease, cerebrovascular disease, inflammatory heart disease and hypertensive heart disease†Worldwide defined as Member States by WHO Region (African, Americas, Eastern Mediterranean, European, South-East Asia and Western Pacific)

Atherothrombosis Significantly Reduces Life Expectancy

• More than 60% of patients aged >40 develop cardiovascular disease

• Cardiovascular disease reduces life expectancy by 11–12 years for patients aged >50 12.3 History of CVD

10.8 History of AMI

7.98 History of stroke

20.0 Healthy

Average Life Expectancy

(Men) at Age 60 (years)

CVD = cardiovascular diseaseAMI = acute myocardial infarction

Analysis of data from the Framingham Heart Study

Source: Peeters et al. Eur Heart J 2002; 23: 458-466

Manifestations of Atherothrombosis are Commonly Found in More than One Arterial Bed

in the Individual Patient¹*

1. Coccheri S. Eur Heart J 1998; 19(suppl): P1268.

Coronary disease

Cerebrovascular disease

Peripheral arterial disease

24.7%

3.8% 11.8%

29.9%

3.3%

7.4%

19.2%

*Data from CAPRIE study (n=19,185)

Increasing Worldwide* Prevalence of Atherothrombotic Manifestations

Populations aged > 50 years old

205.0 million(5.1% since 1997)

222.2 million(13.9% since 1997)

Myocardial infarction

Ischemic stroke

*projected populations of people aged over 50 years, and estimated prevalence of myocardial infarction and ischemic stroke cumulated in 14 countries: Belgium, Canada, Denmark, Finland, France, Germany, Italy, Netherlands, Norway, Spain, Sweden, Switzerland, UK, USA

Prevalence* 2000 2005


1. Guillot F, Moulard O. Circulation 1998; 98(abstr suppl 1): 1421.




Hospitalizations in the US due to ACS1

1. Cairns J et al. Can J Cardiol 1996; 12: 1279–92.

Acute coronary syndromes

1.5 million hospital admissions per year

Unstable angina (UA) Myocardial infarction(Q-wave and non-Q-wave)

750,000 admissions 750,000 admissions

European Survey of Acute Coronary Syndromes:the ENACT Study1

Patient records from 3,092 ACS patients in the EU* (1999)

0

5

10

15

20

25

30

35

40

45

50

UA/non-ST elevation MI Definite MI Suspected ACS

Ho

spit

aliz

atio

ns

(%)

*17 Western European countries 1. Fox KA et al. Eur Heart J 2000; 21: 1440–9.

• Ratio of unstable angina (UA) to MI was 1.2:1.0 overall and was similar in all European countries

• In patients with diagnosis of UA on admission, 9% evolved to definite MI despite current treatment

Epidemiology and Long-term Outcome of Cerebrovascular Disease

• Incident cases/year (per 1 million inhabitants)1

– 500 transient ischemic attacks– 2,400 strokes (75%: first ever strokes)

• in 3 months: 480 (20%) deaths

• in 1 year: 700 (29%) deaths600 (25%) dependent survivors

1,100 (46%) independent survivors

• Prevalent cases (per 1 million inhabitants)1

– 12,000 patients, of whom 800 (7%) have recurrent stroke every year

1. Hankey GJ, Warlow C. Lancet 1999; 354: 1457–63.

5-Year Mortality Risk in Cerebrovascular Patients1

0 5 10 15 20 25 30 35 40 45

Cerebrovasculardisease (CVD)

Cardiovasculardisease (CAD)

5-year mortality (%)

39%

18%

1. Sacco RL et al. Neurology 1994; 44: 626–34.

Long-term Outcome of Peripheral Arterial Disease (PAD)1

1. Ouriel K. Lancet 2001; 358: 1257–64.

0

20

40

60

80

100

0 1 2 3 4 5 6 7 8 9 10

Time (years)

Pat

ien

ts (

%) Survival

Myocardialinfarction

Intervention

Amputation

Causes of death: • 55% coronary artery disease• 10% cerebrovascular disease• 25% non-vascular• < 10% other vascular

1. Adult Treatment Panel II. Circulation 1994; 89:1333–63. 2. Kannel WB. J Cardiovasc Risk 1994; 1: 333–9. 3. Wilterdink JI, Easton JD. Arch Neurol1992; 49: 857–63. 4. Criqui MH et al. N Engl J Med 1992; 326: 381–6.

*Sudden death defined as death documented within 1 hour and attributed to coronary heart disease (CHD)†Includes only fatal MI and other CHD death; does not include non-fatal MI

Increased risk vs general population (%)

Original event Myocardial infarction Stroke

Myocardial infarction

Stroke

Peripheral arterial disease

5–7 x greater risk1

(includes death)3–4 x greater risk2

(includes TIA)


(includes angina and sudden death*)

9 x greater risk3

4 x greater risk4

(includes only fatal MI and other CHD death†)


(includes TIA)

Risk of a Second Vascular Event

Plaque Disruption Leading to Atherothrombosis Formation

1. Falk E et al. Circulation 1995; 92: 657–71.

Macrophage Tissue factor

Fibrin

Aggregated plateletsBLOODFLOW

1. Kuwahara M et al. Arterioscler Thromb Vasc Biol 2002; 22: 329–34.

Platelet Aggregation

FIRM, BUT REVERSIBLEADHESION

IRREVERSIBLEADHESION

Scanning electron micrograph of discoid, dormant platelets

Activated, aggregating platelets illustrating fibrin strands

Flowingdisc-shaped

platelet

Rollingball-shaped

platelet

Hemisphere-shapedplatelet

Spreadingplatelet

Inflammatory Modulators Produced by Platelets

1. Libby P, Simon DI. Circulation 2001; 103: 1718–20. 4. Hermann A et al. Platelets 2001; 12: 74–82. 2. von Hundelshausen P et al. Circulation 2001; 103: 1772–77. 5. Robbie L, Libby P. Ann N Y Acad Sci 2001; 947: 167–79.3. Wever RMF et al. Circulation 1998; 97: 108–12.

Transforming growthfactor-ß5

• Stimulate smooth muscle cell biosynthesis

Nitric oxide3

• Effects on monocyte, leucocyte, endothelium, and smooth muscle cells

CD154 (CD40 ligand)1,4

• Regulates macrophage and smooth muscle cell functions

RANTES2

• Influences macrophage adhesion to endothelial cell

Platelet-factor 41

• Mediates shear-resistant arrest of monocytes to endothelium

PLATELET

Platelet-derived growthfactor (PDGF)1 • Induces proliferation of

smooth muscle cells

Thrombospondin1

• Interacts with cell surface receptors

COX = cyclo-oxygenaseADP = adenosine diphosphateTxA2 = thromboxane A2

CLOPIDOGREL

ASA COX

ADP

ADP

C

GPllb/llla(Fibrinogen receptor)

Collagen thrombinTXA2

Activation

TXA2

Mode of Action of Antiplatelet Agents¹

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

Strong Evidence Base:Antithrombotic Trialists’ Collaboration1

• Objective:– to determine the effects of antiplatelet therapy among

patients at high risk of occlusive vascular events

• Data reviewed:– 287 studies involving:

• 135,000 patients in comparisons of antiplatelet therapy vs control

• 77,000 patients in comparisons of different antiplatelet regimens

• Main outcome measure:– ‘serious vascular event’: non-fatal myocardial infarction,

non-fatal stroke, or vascular death

1. Antithrombotic Trialists’ Collaboration. BMJ 2002; 324: 71–86.

Antithrombotic Trialists’ Collaboration: Efficacy of Antiplatelet Therapy on Vascular Events1*


*Vascular events = MI, stroke or vascular death

Category % odds reduction

Acute myocardial infarction

Acute stroke

Prior myocardial infarction

Prior stroke/transient ischemic attack

Other high risk

• CAD (e.g. unstable angina, heart failure)

• PAD (e.g. intermittent claudication)

• Risk of embolism (e.g. atrial fibrillation)

• Other (e.g. diabetes)

All trials 22 ± 2

1.00.50.0 1.5 2.0

Control betterAntiplatelet better

Antithrombotic Trialists’ Collaboration: Evidence Supports Low Dose ASA (75–150mg)1


ASA dose % odds reduction

500–1500 mg daily

160–325 mg daily

75–150 mg daily

< 75 mg daily

Any ASA dose 23 ± 2

(p < 0.0001)

1.00.50.0 1.5 2.0

Control betterASA better

Effects of Antiplatelet Therapy on Vascular Events in High Risk Patients

1. Antithrombotic Trialists’ Collaboration. BMJ 2002; 324: 71–86.2. Fisher LD et al. Am Heart J 2001; 141: 26–32.

All trials 195 144,051 251

Any ASA 64 59,395 231

Dipyridamole 15 5,430 161

Ticlopidine 42 5,430 321

Clopidogrel* 1 19,185 302

No. of trials with data

No. of patients

% odds reduction(MI, stroke, or

vascular death)Treatment

*The % odds reduction for clopidogrel is the result of a statistical analysis that uses data from the Antithrombotic Trialists’ Collaboration and the CAPRIE trial to estimate the effect of clopidogrel vs placabo


Antithrombotic Trialists’ Collaboration: Efficacy of Different Oral Antiplatelet Agents Relative to ASA1

Antiplatelet agent % odds reduction p value

Dipyridamole -2% NS

Ticlopidine 12% NS

Clopidogrel 10% 0.03

All agents 8%

0.0001

1.00.50.0 1.5 2.0ASA betterOther antiplatelet better

ASA alone betterCombined with ASA

Antithrombotic Trialists’ Collaboration1

Dipyridamole 6% NS

Ticlopidine 20% NS

iv GPIIb/IIIa-inhibitor 19% p < 0.0001

Subtotal 15% p < 0.0001

Comparison* % odds reduction p value

CURE 2

Clopidogrel 20% p = 0.000093

1.00.50.0 1.5 2.0

1. Antithrombotic Trialists’ Collaboration. BMJ 2002; 324: 71–86. 2. The CURE Trial Investigators. N Engl J Med 2001; 342: 494–502. 3. Clopidogrel Prescribing Information, US, 2002.

*In combination with ASA vs ASA alone

Effects of Different Antiplatelet Agents Combined with ASA vs ASA Alone

Antithrombotic Trialists’ Collaboration: Conclusion (I)

• Antiplatelet therapy should be considered routinely for all patients at risk

• Antiplatelet therapy reduces serious vascular events in a wide range of high-risk patients:– acute myocardial infarction (MI) and acute stroke

– prior MI and prior stroke/transient ischemic attack

– coronary artery disease (e.g. unstable angina, heart failure)

– peripheral arterial disease (e.g. intermittent claudication)

– high risk of embolism (e.g. atrial fibrillation)

– Other high risk factors (e.g diabetes)1

• Antiplatelet therapy should be continued long-term2,3

1. Antithrombotic Trialists’ Collaboration. BMJ 2002; 324: 71–86. 2. Braunwald E et al. J Am Coll Cardiol 2000; 36: 970–1062. 3. Bertrand ME et al. Eur Heart J 2000; 21: 1406–32.

Antithrombotic Trialists’ Collaboration: Conclusion (II)

• Low dose ASA (75–150 mg daily) is as effective as higher ASA doses for long-term use1

• ADP-receptor antagonists are the only antiplatelet agents to have been shown to be superior to ASA in % odds reduction1,2

• Adding a second antiplatelet drug (e.g. clopidogrel* or a GPIIb/IIa antagonist) to ASA may produce additional benefits1

1. Antithrombotic Trialists’ Collaboration. BMJ 2002; 324: 71–86.2. Antiplatelet Trialists’ Collaboration. BMJ 1994; 308: 81–106.

* CURE results were not available at the time of this review

Clopidogrel in the Long-Term Management of Patients at Risk

of Atherothrombosis

Clinical Efficacy of Clopidogrel

Trial Patients Design Maximum follow-up

Number of patients

CAPRIE1 MI, stroke, PAD Clopidogrelvs ASA

3 years 19,185

CURE3 Acute coronarysyndrome (UA or NSTEMI)

Clopidogrel*vs placebo*

1 year 12,562

CLASSICS2 Coronary stenting Clopidogrel* vs ticlopidine*

1 month 1,020

1. CAPRIE Steering Committee. Lancet 1996; 348: 1329–39. 2. Bertrand NE et al. Circulation 2000; 102: 624–29 3. The CURE Trial Investigators. N Engl J Med 2001; 345: 494–502.4. Steinhubl et al.JAMA 2002;288: 2411-20

Clinical Benefit of Clopidogrel in more than 30,000 Patients – from CAPRIE to CREDO

*In addition to standard therapy (including ASA)

CREDO4Coronary Stenting

Clopidogrel*vs placebo*

1 year 2,116

CAPRIE: Long-Term Benefit of Clopidogrel Compared to ASA¹

*ITT analysis1. CAPRIE Steering Committee. Lancet 1996; 348: 1329–39.

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

p = 0.043, n = 19,185

ASA

Clopidogrel

Clopidogrel

0

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

Months of follow-up

Cu

mu

lati

ve

ev

en

t ra

te (

%)

ASA 8.7%*Overallrelative

riskreduction

4

8

12

16

CAPRIE: Consistent Benefit of Clopidogrel over ASA in Both Low- and High-Risk Patients

1. Cannon C. J Am Coll Cardiol 2002; 39 (abstr suppl): 290A.

17.2%

7.9%6.8%

4%4.2%

7.8%

6.0%

2.9%2.9%

12.0%

0

2

4

6

8

10

12

14

16

18

20

1 2 3 4 5+

Number of risk factors

MI

to 3

ye

ars

(%

)

ASAClopidogrel31%*

30%*

Event Rate (Fatal or Non-Fatal Myocardial Infarction)

*Relative risk reduction

CAPRIE: Amplified Benefit of Clopidogrel in Patients with Higher Vascular Risk1–3

1. CAPRIE Steering Committee. Lancet 1996; 348: 1329–39.2. Jarvis B, Simpson K. Drugs 2000; 60: 347–77. 3. Ringleb PA et al. Eur Heart J 1999; 20: 666.

Events Prevented/1,000 Patients/Year over ASA

152

200

238

141

172

204

0

50

100

150

200

250

300

All CAPRIE patients¹(n=19,825)

Prior history of anyischemic event²

(n=8,854)

Prior history of majoracute event (MI or stroke)

(n=4,496)

Eve

nt

rate

* /100

0 p

atie

nts

(av

era

ge

foll

ow

-up

, 2

ye

ars)

ASAClopidogrel

11

2834

3

*Event rate of myocardial infarction, ischemic stroke, or vascular death

CAPRIE: Amplified Benefit of Clopidogrel in Patients with Diabetes1,2

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

Events Prevented/1,000 Patients/Year over ASA

137

177

215

126

156

177

0

50

100

150

200

250

All CAPRIE patients¹ Diabetes² Diabetes treated withinsulin²

Eve

nt

rate

* /100

0 p

atie

nts

/ye

ar

ASA

Clopidogrel

11

21

38

*Event rate of myocardial infarction, stroke, vascular death, or hospitalization

CAPRIE: Enhanced Benefit with Clopidogrel in High-risk Patients1–3

NNT = number of patients needed to treat to prevent an event MI = Myocardial infarction ARR = absolute risk reduction CABG = coronary artery bypass grafting* followed for an average of 1.9 years 1. CAPRIE Steering Committee. Lancet 1996; 348: 1329–1339

2. Jarvis B. Drugs 2000; 60 (1) : 1–313. Bhatt et al. Am Heart J 2000; 140: 67–73

CAPRIE Population EndpointARR (%) compared

with ASANNT

Total CAPRIE PopulationStroke, Myocardial

Infarction, Vascular Death0.51* 196

Total CAPRIE Population + rehospitalization 1.1* 91

Patients with diabetes + rehospitalization 2.1* 48

Patients with CABG + rehospitalization 6.4* 16

Patients with hypercholesterolemia

+ rehospitalization 2.7* 37

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 continuation

CAPRIE: Favorable Safety for Clopidogrel Compared to 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)

0.11%1.32%1.15%

0.71%

0.49%

0.10%

0.17%

clopidogrel(n = 9,599)

0.23%0.75%0.68%

0.49%

0.35%

0.26%

0.10%

p = ns p < 0.001 p = 0.001 p < 0.05

p = ns

p < 0.05

p = ns

Acute Coronary Syndrome (ACS) is a Classic Manifestation of Atherothrombosis

Unstable angina

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

Common underlyingatherothrombosis

Atherothrombotic event(MI, stroke, vascular death)

Plaque rupture Platelet activationand aggregation

Thrombus formation

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

0.00

0.02

0.04

0.06

0.08

0.10

0.12

0.14

0 3 6 9 12Months of follow-up

Cu

mu

lati

ve h

azar

d r

ate

1. The CURE Trial Investigators. N Engl J Med 2001; 345: 494–502.2. Data on file, 2002, p73 internal CSR-EFC 3307.

Placebo*(n = 6,303)

Clopidogrel* (n = 6,259)

20% relativerisk reduction

p = 0.00009

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


CURE: Consistent Benefit In addition to Various Standard Therapies1


1. Clopidogrel Prescribing Information, US, February 2002.

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

100–200 mg

> 200 mg

No

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

CURE: Consistent Benefit Independent of Patient History1


Baselinecharacteristics

Overall

Diagnosis

Elev card enzy

ST depr >1.0 mm

Diabetes

Previous MI

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


CURE: Clopidogrel in Patients with a Previous Stroke1

1. Data on file, 2002, p87 internal CSR-EFC 3307.

Event Rate(Myocardial Infarction, Stroke, or Cardiovascular Death)

*Number of events prevented/1,000 patients treated†In addition to standard therapy (including ASA)

11.0%

22.4%

17.9%

8.9%

0

5

10

15

20

25

No previous stroke Previous stroke

Ev

en

ts (

%)

45*

21*

Placebo†

Clopidogrel†

CURE : Early and Long-term Efficacy of Clopidogrel


5.4%

6.3%

4.3%

5.2%

0%

1%

2%

3%

4%

5%

6%

7%

8%

0 to 30 days >30 days to 1 year

Placebo*

Clopidogrel*

p < 0.001 p < 0.001

Primary endpoint (stroke, MI or cardiovascular death)

RRR 21% 18%

1. S. Yusuf, Circulation 2003; 107: 966-72

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


CURE: Life-Threatening Bleeding1

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

Event

Life-threatening bleeding

• Fatal

• Causing drop inhemoglobin 5 g/dl

• Requiring transfusion 4 units of blood

• Causing hemorrhagicstroke

• Requiring surgery

• Hypotension requiringintropic agents

Placebo*(n = 6,303)

Clopidogrel*(n = 6,259)

1.8%

0.2%

0.9%

1.0%

0.1%

0.7%

0.5%

2.2%

0.2%

0.9%

1.2%

0.1%

0.7%

0.5%


CURE: Relation Between Safety and ASA Dosage¹


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*


0.15

0.10

0.05

0.0100

040 100 200 300 400

Cu

mu

lati

ve h

azar

d r

ates

31% RRRp=0.002n=2658

Days of follow-upa b

Placebo‡ Clopidogrel‡

The CURE Investigators. Lancet August 2001

a = median time from randomization to PCI (10 days)b = 30 days after median time of PCI†up to 12 months ‡In addition to standard therapy including ASA

12.6%

8.8%

Composite of CV-death or MI from randomization to end of follow-up†

PCI-CURE –Long-term Efficacy of Clopidogrel

CREDO-Long-term Benefits of Clopidogrel in PCI Patients

27% RRR

p = 0.02

Clopidogrel*

Placebo*CO

MB

INE

D E

ND

PO

INT

O

CC

UR

RE

NC

E (

%)

MONTHS FROM RANDOMIZATION

0 3 6 9 12

8.5%

11.5%

(MI, Stroke, or Death)1 year results

JAMA, November 20, 2002 – Vol 288, No 19: 2411–20* Standard therapy including ASA

0.6 0.8 1.0 1.2

GPIIb/IIIa Inhibitor Yes (N=826) No (N=1289)

ACS Yes (N=1407) No (N=694)

Diabetes Yes (N=560) No (N=1556)

Stent Yes (N=1616) No (N=500)

Male (N=1510)

Female (N=606)

Overall (N=2116)

28.826.5

27.622.7

11.232.8

28.819.0

24.5

32.1

26.9

0.4

Hazard ratio (95% CI)

Placebo BetterClopidogrel Better RRR

(MI, Stroke, or Death at 1 year)

JAMA, November 20, 2002 – Vol 288, No 19: 2411–20

CREDO- Consistent Long-term Benefit of Clopidogrel

CREDO-Safety Outcomes: Major Bleeding Events-1 Year Results

Major Bleeding Clopidogrel* (n=1,053)

Placebo* (n=1,063)

P-value

Any 93 (8.8%) 71 (6.7%) 0.07

Non-procedural 13 (1.2%) 8 (0.8%) 0.28

Procedural 81 (7.7%)# 63 (5.9%)^ 0.12

CABG 64 55

Non-CABG 17 8


* In addition to background therapy including ASA

# 101 patients underwent CABG in the clopidogrel group

^ 99 patients underwent CABG in the placebo group

ITT=Intent-To-Treat population

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, In addition to 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.

CREDO - 1 Year Results Conclusions

• Long-term results at 1 year demonstrate a 27 % RRR (p=0.02) in the combined endpoint of MI, stroke, and death

• The benefit was consistent in all patient subgroups evaluated

• In the CREDO trial patients received the best standard of care in the US:– Almost half of patients received GPIIb/IIIa antagonists, and

clopidogrel showed an incremental benefit In addition to GPIIb/IIIa

– Short time to PCI: 3 to 24 hours (per protocol); mean=9.8 hours


Recognition of Clopidogrel as a Key Component of Long-term therapy in Unstable

Angina/NSTEMI Patients

• Recommendations in the 2002 ACC/AHA and ESC guidelines

• Class I Recommendation for ACC/AHA– Start clopidogrel as soon as possible on admission,

continue for at least one month and for up to 9 months1

• ESC Guidelines– Clopidogrel is recommended for acute and long-term

treatment for at least 9-12 months2

1Braunwald E et al. J Am Coll Cardiol 2002;40:1366–74.2Bertrand ME et al. Eur Heart J 2002; in press.

CURE Within Trial Economic Analysis Compares Favorably with Other Treatment Strategies

1. Lamy A et al. Paper presented at AHA, Chicago, Nov 20022. Hillegass Wb, Am Heart J 1999; 138 : S24–S32 3. McDonnagh, Health Technology Assessment 2000, vol 4, N° 304. Mark et al. Circulation 2000; 101: 366–371 5. (Abciximab in PCI) Reed S. Pharmacoeconomics 2000; 18(3): 265–74

US$ per event avoided

0 20,000 40,000 60,000 80,000 100,000 120,000

Statin (WOSCOPS*), US/UK 7

Statin (4S), US, 6

TACTICS**, US, 5

TACTICS*, US, 5

GPIIb/IIIa abciximab US, 4

PURSUIT, GPIIb/IIIa, US, 2,3

PRISM, GPIIb/IIIa, US, 2

CURE, US, 1

*WOSCOPS is a primary prevention study

5. Mahoney. JAMA 2002; 288 : 1851–58. * endpoint: death or MI; ** endpoint: death, MI or rehospitalisation6. Johannesson et al. N Engl J Med 1997; 336: 332–367. Scandanavian Simvastatin Study Group. Lancet 1994; 344: 1383–89 8. Sheperd J. Am J Cardiol 2001; 87 (suppl): 19B–22B (Primary prevention trial)

Cost-effectiveness of Clopidogrel Compared with Other Cardiovascular Strategies

1. Lindgren, Jonsson et al. Paper to be presented at ACA, Chicago, March 2003 (data for Sweden)2. Jonsson B. Eur Heart J 1996; 17: 1001–07 (data for Sweden, 1995)3. Van Hout BA. Eur Heart J. 2001; 22: 751–61 (data for Netherlands)

*WOSCOPS is a primary prevention study

0 5,000 10,000 15,000 20,000 25,000 30,000

GPIIb/IIIa (PURSUIT), France 4

Statin (sec prev), UK 5

Statin (prim prev), UK 5

Statin (4S), Netherlands 3

Statin (WOSCOPS*) Netherlands 3

Statin (LIPID) Netherlands 3

CURE, Sweden 1

€ Per life year saved

Statin (4S), Sweden 2

Ramipril (HOPE population), UK 6

4. Brown RE et al. Eur Heart J 2002; 23(1): 50–58 5. Ebrahim S. Health Technology Assessment 1999, Vol 3: n 19 (data for UK) 6. Malik IS. Heart 2001; 85: 539–43

16,4915,400*3,758 †Cost per LYS

36,7396,600*21,423Cost per event avoided

8451,524*451Incremental cost

PURSUIT4 Eptifibatide

(1996 US$)

4S2,3

Simvastatin

(1995 US$)

CURE1

Clopidogrel

(2002 US$)

1. Lindgren, Jonsson et al. Paper to be presented at ACA, Chicago, March 2003 (data for Sweden)2. Johannesson et al. N Engl J Med. 1997; 336: 332–363. Scandinavian Simvastatin Study Group. Lancet 1994; 344: 1383–89

12,739

19,143

670

TACTICS5 Invasive vs

Conserv

(2002 US$)

CURE Cost-effectiveness Compared with Other Cardiovascular strategies

1,290

11,285

237

Sweden US

4. Mark et al. Circulation. 2000; 101: 366–71 5. Mahoney. JAMA 2002; 288 : 1851–58

*Calculations are based on 61-year-old male with pre-treatment total cholesterol level of 261 mg/dL†This figure is based on preliminary calculations

Clopidogrel: Indications and Usage1

Clopidogrel is indicated for reduction of atherothrombotic events in:

• recent myocardial infarction (MI), recent stroke or established peripheral arterial disease (PAD)

– For patients with a history of recent myocardial infarction (MI), recent stroke, or established peripheral arterial disease, PLAVIX has been shown to reduce the rate of a combined endpoint of new ischemic stroke (fatal or not), new MI (fatal or not), and other vascular death.

• acute coronary syndrome (ACS)– For patients with acute coronary syndrome (unstable angina/non-Q-wave

MI) including patients who are to be managed medically and those who are to be managed with percutaneous coronary intervention (with or without stent) or CABG, PLAVIX has been shown to decrease the rate of a combined endpoint of cardiovascular death, MI, or stroke as well as the rate of a combined endpoint of cardiovascular death, MI, stroke, or refractory ischemia.

1. Clopidogrel Prescribing Information, US, January, 2003.

Major Clinical Trials with Clopidogrel

Published (Lancet, 1996)

Published (Circulation, 2000)

Published (JAMA, 2002)

Published (N EnglJ Med, 2001)


19,185

1,020

2,116

12,562

2,658

36 months

4 weeks

12 months

12 months

12 months

Stroke, MI or established PAD

Coronarystenting

Coronary stenting

Unstable angina or NQWMI

CURE patients undergoing PCI

CAPRIE2

CLASSICS3

CREDO3

CURE5

PCI-CURE*6

Planned (Q2 2006)

Ongoing (2005)

Planned (2005)

Ongoing (Q3 2005)

Ongoing (2005)

Ongoing (Q2 2004)

Ongoing (Q1 2004)

~14,000

~2,000

~1,600

~15,200

~45,000

~2,200

7,601

36 months

12 months

12 months

42 months

4 weeks

4 weeks

18 months

Atrialfibrillation

PAD (post-angioplasty)

PAD plus bypass grafting

Coronary, cerebrovascular,

PAD, or major risk factors

Acute MI

Acute MI

TIA or stroke

ACTIVE

CAMPER

CASPAR

CHARISMA

COMMIT

CLARITY

MATCH

Status of study (data expected)

Number of patients

Maximum follow-up

PatientsStudy


Published (Circulation, 2000)

Published (JAMA, 2002)

Published (N EnglJ Med, 2001)


19,185

1,020

2,116

12,562

2,658

36 months

4 weeks

12 months

12 months

12 months

Stroke, MI or established PAD

Coronarystenting

Coronary stenting

Unstable angina or NQWMI

CURE patients undergoing PCI

CAPRIE1

CLASSICS2

CREDO

CURE4

PCI-CURE*5

Ongoing (2005)

Planned (2005)

Ongoing (Q3 2005)

Ongoing (2005)

Ongoing (Q2 2004)

Ongoing (Q1 2004)

~14,000

~2,000

~1,600

~15,200

~45,000

~2,200

7,601

36 months

12 months

12 months

42 months

4 weeks

4 weeks

18 months

Atrialfibrillation

PAD (post-angioplasty)

PAD plus bypass grafting

Coronary, cerebrovascular,

PAD, or major risk factors

Acute MI

Acute MI

TIA or stroke

ACTIVE

CAMPER

CASPAR

CHARISMA

COMMIT

CLARITY

MATCH

Status of study (data expected)

Number of patients

Maximum follow-up

PatientsStudy

* PCI-CURE is a sub-study of the CURE studyTIA = Transient ischemic attackMI = Myocardial infarctionNQWMI = Non-Q wave myocardial infarctionPAD = Peripheral arterial diseasePCI = Percutaneous coronary intervention

References1. CAPRIE Steering Committee. Lancet 1996; 348: 1329–392. Bertrand NE et al. Circulation 2000; 102: 624–293. Steinhubl S et al. JAMA 2002; 288(19): 2411–204. The CURE Trial Investigators. N Engl J Med 2001; 345: 494–5025. Mehta SR et al. Lancet 2001; 358: 527–33

Conclusions• Clopidogrel is a potent platelet inhibitor with a mechanism of action

different from ASA (ADP-receptor antagonist)1–3

• The landmark CAPRIE study confirms that clopidogrel offers improved benefit over and above ASA in patients at risk of atherothrombosis and has a favorable overall safety and tolerability profile compared with ASA4

• The landmark CURE trial demonstrates that clopidogrel offers a highly significant 20% relative risk reduction In addition to standard therapy (including ASA) in the early and long-term reduction of myocardial infarction, stroke and cardiovascular death in patients with acute coronary syndrome5

• Clopidogrel is simple and easy to use3

• Clopidogrel is supported by an extensive clinical trial program to evaluate benefits when used in addition to standard therapy (including ASA)

1. Jarvis B, Simpson K. Drugs 3000; 60: 347–77. 2. Schafer Al. Am J Med 1999; 101: 199–209. 3. Clopidogrel Prescribing Information, February 2002. 4. CAPRIE Steering Committee. Lancet 1996; 348: 1329–39. 5. The CURE Trial Investigators. N Engl J Med 2001; 345: 494–502.

Disclaimer

• This slide kit presents data to support the rationale for the use of ADP-receptor antagonists in registered and non-registered indications

• The slide kit has been prepared for medical and scientific purposes, and cannot be considered as an inducement to use clopidogrel in non-registered indications

• Neither Sanofi-Synthélabo nor Bristol-Myers Squibb recommends the use of clopidogrel in any manner inconsistent with that described in the full prescribing information

INT.CLO.03.03.05

Long-Term Management of Patients at Risk of Atherothrombosis.

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Transcript of Long-Term Management of Patients at Risk of Atherothrombosis.