Clinical Efficacy of Clopidogrel in CVA, ACS, PAD

1
Clinical Efficacy of Clopidogrelin CVA, ACS,
PAD
2
Atherothrombosis A Generalized and Progressive
Process
Unstable angina MI Ischemic stroke/TIA Critical
leg ischemia Cardiovasculardeath
ACS
Atherosclerosis
Atherothrombosis
Stable angina Intermittent
claudication
Adapted from Stary HC et al. Circulation. 1995
92 135574, and Fuster V et al. Vasc Med. 1998
3 2319.
3
Synergistic Mode of Action with Clopidogrel and
ASA1
CLOPIDOGREL
C
ADP
ADP
GPllb/llla (Fibrinogen receptor)
Activation
ASA
COX
ASA
COX (cyclo-oxygenase) ADP (adenosine
diphosphate) TXA2 (thromboxane A2)
1. Schafer AI. Am J Med 1996 101 199209.
4
CAPRIE Long-Term Benefit of Clopidogrel
Compared with ASA1
Cumulative Event Rate (Myocardial Infarction,
Ischemic Stroke or Vascular Death)
8.7Overallrelativeriskreduction
ASA
Clopidogrel
Cumulative event rate ()
p 0.043, n 19,185
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
132939.
5
CAPRIE Benefit of Clopidogrel over ASA in the
Reduction of Myocardial Infarction1
Months of follow-up
ITT analysis
1. Gent M. Circulation 1997 96(suppl 8) I-467.
6
CAPRIE Amplified Benefit of Clopidogrel in
Patients with Higher Vascular Risk
Event Rate(Myocardial Infarction, Ischemic
Stroke, or Vascular Death)
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
1. CAPRIE Steering Committee. Lancet 1996 348
132939. 2. Jarvis B, Simpson K. Drugs 2000 60
34777.
7
CAPRIE Amplified Benefit of Clopidogrel in
Patients with Diabetes
Event Rate(Myocardial Infarction, Stroke,
Vascular Death, or Hospitalization)
25
For ischemic events or bleedingNumber of
events prevented/1,000 patients/year over ASA
1. Bhatt DL et al. Am Heart J 2000 140 6773.
2. Jarvis B, Simpson K. Drugs 2000 60 34777.
8
CAPRIE Amplified Benefit of Clopidogrelin
Patients with Prior CABG1
Event Rate(Myocardial Infarction, Stroke,
Vascular Death, or Hospitalization)
For ischemic events or bleedingNumber of
events prevented/1,000 patients/year over ASA
1. Bhatt DL et al. J Am Coll Cardiol 2000
35(suppl A) 383.
9
CAPRIE Favorable Safety for Clopidogrel Compared
ASA
Patients with ASA intolerance were
excluded Clinically severe or resulting in early
drug discontinuation
1. CAPRIE Steering Committee. Lancet 1996 348
132939. 2. Harker LA et al. Drug Safety 1999
21 32535.
10
CURE Design1
Clopidogrel 300mg loadingdose
n 12,562 28 countries
Clopidogrel75mg o.d.(n 6,259)
ASA 75325 mg o.d.
Patients with acute coronarysyndrome
R
Double-blind treatment up to 12 months
(unstable angina or non-Q-wavemyocardial
infarction)
ASA 75325 mg o.d.
Placebo 1 tab o.d.(n 6,303)
Day 1
12 monthor final visit
3 month visit
1 month visit
6 month visit
9 month visit
Placebo loading dose
Discharge visit
R Randomization
1. The CURE Study Investigators. Eur Heart J
2000 21 203341.
11
CURE Early and Long-Term Benefits of
Clopidogrel1,2
Cumulative Events (Myocardial Infarction, Stroke,
or Cardiovascular Death)
On top of standard therapy (including ASA)
1. The CURE Trial Investigators. N Engl J Med
2001 345 494502. 2. Data on file, 2002, p73
internal CSR-EFC 3307.
12
PCI-CURE 31 Relative Risk Reduction at
Long-Term1
Endpoint Myocardial Infarction or Vascular Death
On top of standard therapy (including ASA)
1. Mehta SR et al. Lancet 2001 358 52733.
13
CURE Bleeding Episodes
On top of standard therapy (including ASA)
1. The CURE Trial Investigators. N Engl J Med
2001 345 494502. 2. Chesebro JH et al.
Circulation 1987 76 14254. 3. The GUSTO
Investigators. N Engl J Med 1993 329 67382.
14
CURE Relation Between Safety and ASA Dosage1
6.0
4.9
5.0
4.0
4.0
3.5
Bleeding rate ()
3.0
2.6
Placebo
2.3
2.0
Clopidogrel
2.0
1.0
0.0
100200 mg
gt 200 mg
lt 100 mg
ASA dose 75325 mg
On top of standard therapy (including ASA)
1. Clopidogrel Prescribing Information, US,
February 2002.
15
ACC/AHA 2002 Guidelines Update for UA and NSTEMI1
Class I Recommendations for Long Term Therapy
ASA

Clopidogrel for 9 months

Beta-blockers

Lipid lowering therapy

ACE I
At hospital discharge and post-hospital
dischargeIn the absence of contraindications Cl
opidogrel should be administered to hospitalized
patients who are unable to take ASA because of
hypersensitivity or major GI intolerance
1. Braunwald E et al. American College of
Cardiology (ACC) and the American Heart
Association (AHA) Guidelines, USA ACC/AHA 2002.
16
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 models25
• 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 study6
• 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
132939. 2. Cadroy Y et al. Circulation 2000
101 28238. 3. Herbert JM et al. Thromb Haemost
1998 80 5128. 4. Harker LA et al. Circulation
1998 98 24619. 5. Makkar RR et al. Eur Heart J
1998 19 153846. 6. The CURE Trial
Investigators. N Engl J Med 2001 345 494502.
7. Data on file, 2002, p73internal CSR-EFC 3307.
17
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18
What is PAD?
PAD is an atherothrombotic disorder affecting the
peripheral arteries and it is associated with a
high risk of MI, stroke and vascular death1

• The major risk factors for PAD are2
• smoking
• diabetes
• age gt55 years (men) or gt65 years (women)
• hyperlipidemia
• hypertension
• history of cardiovascular disease

1. Hiatt WR. J Vasc Surg. 2002 361283-1291. 2.
Belch JJ et al. Arch Intern Med 2003 163
884-892.
19
Only 1 in 10 patients with PAD has classical
symptoms of intermittent claudication
1 in 5 people over 65 has PAD
Only 1 in 10 of these patients has classical
symptoms of intermittent claudication (IC)
ABIlt0.9
Diehm C et al. Atherosclerosis 2004 172 95-105.
20
Platelets are activated following the rupture of
an atherosclerotic plaque
Platelet aggregation
Normal platelets
Activated platelets
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 1535.
21
Prevalence of PAD increases with age
Rotterdam Study (ABI Test lt0.9)1 San Diego
Study (PAD by noninvasive tests)2
Patients with PAD ()
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.
22
Measuring Ankle-Brachial Index (ABI)
Video courtesy of Professor Curt Diehm,
Karlsbad-Clinic, Academic Teaching Hospital of
the University of Heidelberg, Germany.
23
Association of low ankle brachial index with
highmortality in primary care
European Heart Journal (2006) 27, 17431749
24
How is Ankle-Brachial Index (ABI) measured?
ABI

• Measure ankle and brachial systolic pressures
  with Doppler1,2
• Use highest arm and each ankle pressures1,2

ABI Interpretation3 gt
0.90 Normal 0.41 0.90
Mild-to-moderate peripheral arterial disease
0.00 0.40 Severe peripheral arterial
disease
1. TASC Working Group. Int Angiol 2000 19
(suppl) 5-34. 2. Vascular Disease Foundation,
2003. Available athttp//www.vdf.org/ABI.htm. 3.
Hiatt WR. N Engl J Med 2001 344 1608-1621.
25
There is a strong two way association between
decreased ABI and increased risk for
cardiovascular death1
70
60
All-cause mortality CVD mortality
50
40
Percent ()

30

20

10
0
lt0.60 (n25)
1.0-lt1.10 (n980)
0.90-lt1.0 (n195)
0.60-lt0.70 (n21)
0.70-lt0.80 (n40)
0.80-lt0.90 (n130)
Baseline ABI
Mean participant follow-up 8.3 years
Resnick HE et al. Circulation 2004 109
733-739.
26
Patients with PAD are at high risk of MI and
stroke
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.
27
Risk of death is increased in patients with both
symptomatic and asymptomatic PAD
100
Normal subjects
75
Asymptomatic PAD
50
Survival ( of patients)
Symptomatic PAD
25
Severe symptomatic PAD
0
0
2
4
6
8
10
12
Year
Kaplan-Meier survival curves based on mortality
from all causes.Large-vessel PAD.
Criqui MH et al. N Engl J Med 1992 326 381-386.
28
The American Diabetes Association recommends
screening for PAD in patients with diabetes1

• A screening ABI should be performed in patients
  with diabetes

• Those lt50 years of age who have other risk
  factors associated with PAD
• Smoking
• Hypertension
• Hyperlipidemia
• Duration of diabetes
• gt10 years

• Those gt50 years of age
• If normal an exercise
• test should be
• carried out
• The ABI test
• should be repeated
• every 5 years

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

1. American Diabetes Association. Diabetes Care
2003 26 33333341. 2. Estes JM, Pomposelli FB
Jr. Diabet Med 1996 13 S43S57.
29
Patients with PAD are at risk of MI, ISand death
CAPRIE data
Coronaryoutcome
Cerebrovascularoutcome
6
5.2
5.1
5
4.2
3.6
4
Clopidogrel
3
3-year cumulative event rate ()
Aspirin
2
1
0
Patients qualifying for CAPRIE on the basis of PAD
Dormandy JA, Creager MA. Cerebrovasc Dis
19999(Suppl 1)1128 (Abstr 4).
30
American Diabetes Association Consensus
Statement 2003 PAD in people with diabetes

• It is recommended that patients with diabetes
  who are gt50 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
31
The Call to Action Paper highlighted 5 key action
items
Increase awareness of PAD and its consequences
Improve treatment rates among patients who have
been diagnosed with symptomatic PAD
Call to action Paper
Improve the identification of patients with
symptomatic PAD
60
Increase the rates of early detection among the
asymptomatic population
Initiate a screening protocol for patients at
high risk for PAD
Belch JJF et al. Arch Intern Med 2003 163
884-892.