Transcript Clopidogrel in the long-term management of patients at

Clinical Efficacy of Clopidogrel
in
CVA, ACS, PAD
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.
Synergistic Mode of Action with
Clopidogrel and ASA1
CLOPIDOGREL
C
ADP
ADP
GPllb/llla
Activation
(Fibrinogen receptor)
ASA
ASA
COX
TXA2
COX (cyclo-oxygenase)
ADP (adenosine diphosphate)
TXA2 (thromboxane A2)
1. Schafer AI. Am J Med 1996; 101: 199–209.
Collagen thrombin
TXA2
CAPRIE: Long-Term Benefit of
Clopidogrel Compared with ASA1
Cumulative Event Rate
(Myocardial Infarction, Ischemic Stroke or Vascular Death)
ASA
Cumulative event rate (%)
16
8.7%*
Overall
relative
risk
reduction
Clopidogrel
12
8
4
p = 0.043, n = 19,185
0
0
3
6
9
12
15
18
21
24
Months of follow-up
*ITT analysis
1. CAPRIE Steering Committee. Lancet 1996; 348: 1329–39.
27
30
33
36
CAPRIE: Benefit of Clopidogrel over ASA in the
Reduction of Myocardial Infarction1
ASA
19.2%*
Relative
risk
reduction
Clopidogrel
Cumulative event rate (%)
5
ASA 3.6%
4
3
Clopidogrel 2.9%
2
1
p = 0.008, n = 19,185
0
0
3
6
9
12
15
18
21
24
Months of follow-up
*ITT analysis
1. Gent M. Circulation 1997; 96(suppl 8): I-467.
27
30
33
36
CAPRIE: Amplified Benefit of Clopidogrel
in Patients with Higher Vascular Risk
Event Rate
(Myocardial Infarction, Ischemic Stroke, or Vascular Death)
30%
34
28
Event rate (%)
25%
*
11
20%
*
15.2%
15%
20.0%
17.2%
23.8%
*
20.4%
14.1%
10%
5%
0
All CAPRIE patients†1
(n = 19,185)
Prior history of any
Prior history of major
‡2
ischemic event
acute event (MI or stroke)‡2
(n = 8,854)
(n = 4,496)
*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: 1329–39. 2. Jarvis B, Simpson K. Drugs
2000; 60: 347–77.
ASA
Clopidogrel
CAPRIE: Amplified Benefit of Clopidogrel
in Patients with Diabetes
Event Rate
(Myocardial Infarction, Stroke, Vascular Death, or Hospitalization*)
38
25%
†
Annual event rate (%)
21
†
20%
11
†
15%
21.5%
13.7%
17.7%
15.6%
17.7%
ASA
Clopidogrel
12.6%
10%
5%
0
All CAPRIE patients¹
Diabetes²
Diabetes treated with
insulin²
*For ischemic events or bleeding
†Number of events prevented/1,000 patients/year over ASA
1. Bhatt DL et al. Am Heart J 2000; 140: 67–73. 2. Jarvis B, Simpson K. Drugs 2000; 60: 347–77.
CAPRIE: Amplified Benefit of Clopidogrel
in Patients with Prior CABG1
Event Rate
(Myocardial Infarction, Stroke, Vascular Death, or Hospitalization*)
Annual event rate (%)
25%
22.3%
64
†
20%
11
†
15%
13.7%
15.9%
ASA
Clopidogrel
12.6%
10%
5%
0
All CAPRIE
Prior CABG
Overall benefit: p = 0.001; multivariate analysis
*For ischemic events or bleeding
†Number of events prevented/1,000 patients/year over ASA
1. Bhatt DL et al. J Am Coll Cardiol 2000; 35(suppl A): 383.
CAPRIE: Favorable Safety for Clopidogrel
Compared ASA*
ASA
Clopidogrel
(n = 9,586)
(n = 9,599)
Diarrhea (severe)1
Gastritis2
Gastro-intestinal ulcer2
Gastro-intestinal hemorrhage
(severe)1
0.11%
1.32%
1.15%
0.23%
0.75%
0.68%
NS
< 0.001
0.001
0.71%
0.49%
< 0.05
Intracranial hemorrhage1
0.49%
0.35%
NS
Rash (severe)1
0.10%
0.26%
< 0.05
Neutropenia2
0.17%
0.10%
NS
Adverse experiences†
*Patients with ASA intolerance were excluded
†Clinically severe or resulting in early drug discontinuation
1. CAPRIE Steering Committee. Lancet 1996; 348: 1329–39. 2. Harker LA et al.
Drug Safety 1999; 21: 325–35.
p value
CURE: Design1
n = 12,562
28 countries
Clopidogrel
Patients with
acute coronary
syndrome
(unstable angina
or non-Q-wave
myocardial
infarction)
ASA 75–325 mg o.d.
R
75mg o.d.
(n = 6,259)
Double-blind treatment up to 12 months
ASA 75–325 mg o.d.
Placebo
1 tab o.d.
(n = 6,303)
R = Randomization
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)
Cummulative hazard rate
0.14
Placebo*
(n = 6,303)
0.12
0.10
Clopidogrel*
(n = 6,259)
0.08
0.06
20% Relative
risk reduction
p = 0.00009
0.04
0.02
0.00
0
3
6
9
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.
12
PCI-CURE: 31% Relative Risk Reduction
at Long-Term1
Endpoint: Myocardial Infarction or Vascular Death
Cumulative hazard rate
0.15
Placebo*
(n = 1,345)
Median time
to PCI
0.10
Clopidogrel*
(n = 1,313)
31% Relative
risk reduction
0.05
p < 0.002
0.00
0 10
100
200
Days of follow-up
*On top of standard therapy (including ASA)
1. Mehta SR et al. Lancet 2001; 358: 527–33.
300
400
CURE: Bleeding Episodes
Event
Major bleeding1
Placebo*
(n = 6,303)
Clopidogrel*
(n = 6,259)
p value
2.7%
3.7%
0.001
•
Life-threatening
1.8%
2.2%
NS
•
Other major bleeding
0.9%
1.5%
0.002
Transfusions of  2 units
of blood1
2.2%
2.8%
0.02
Minor bleeding1
2.4%
5.1%
< 0.001
Major bleeding by
TIMI definition2
1.2%
1.1%
0.70
Major bleeding by
GUSTO definition3
1.1%
1.2%
0.48
*On top of standard therapy (including ASA)
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.
CURE: Relation Between Safety
and ASA Dosage1
6.0%
4.9%
Bleeding rate (%)
5.0%
4.0%
4.0%
3.5%
3.0%
Placebo*
2.6%
2.3%
2.0%
Clopidogrel*
2.0%
1.0%
0.0%
< 100 mg
100–200 mg
ASA dose 75–325 mg
*On top of standard therapy (including ASA)
1. Clopidogrel Prescribing Information, US, February 2002.
> 200 mg
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 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
†
1. Braunwald E et al. American College of Cardiology (ACC) and the American Heart Association
(AHA) Guidelines, USA: ACC/AHA; 2002.
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, p73
internal CSR-EFC 3307.
‫סל הבריאות ‪2006‬‬
‫•‬
‫המטופל אינו יכול להשתמש באספירין בשל רגישות יתר או כל‬
‫הוריית נגד אחרת‬
‫•‬
‫המטופל פיתח תופעות לוואי לטיפול באספירין‬
‫•‬
‫לאחר צינתור לב טיפולי במשך ‪ 3‬חודשים‬
‫•‬
‫בחולים עם תסמונת כלילית חדה שלא ניתן לבצע בהם צנתור‬
‫כלילי או שמחלתם אינה ניתנת לטיפול על ידי צנתור כלילי טיפולי (‬
‫למשך ‪ 3‬חודשים)‬
‫•‬
‫לחולים שלקו בשבץ מוחי שני תוך כדי טיפול מונע באספירין‬
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 death
1
The major risk factors for PAD are:2
• smoking
• diabetes
• age >55 years (men) or >65 years (women)
• hyperlipidemia
• hypertension
• history of cardiovascular disease
1. Hiatt WR. J Vasc Surg. 2002; 36:1283-1291.
2. Belch JJ et al. Arch Intern Med 2003; 163: 884-892.
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)
† ABI<0.9
Diehm C et al. Atherosclerosis 2004; 172; 95-105.
Platelets are activated following the rupture of
an atherosclerotic plaque
Normal platelets
Activated platelets
Platelet aggregation
Platelet
thrombus
Platelets
Platelets adhering
to subendothelial
space
Endothelial cells
Subendothelial space
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 age
Rotterdam Study (ABI Test <0.9)1
San Diego Study (PAD by noninvasive tests)2
Patients with PAD (%)
60
50
40
30
20
10
0
55-59
60-64
65-69
70-74
75-79
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.
80-84
85-89
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?
ABI =
Ankle systolic pressure
Brachial systolic pressure
• Measure ankle and brachial systolic pressures with Doppler1,2
• Use highest arm and each ankle pressures1,2
ABI Interpretation3
> 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 at:http://www.vdf.org/ABI.htm.
3. Hiatt WR. N Engl J Med 2001; 344: 1608-1621.
There is a strong two way association between
decreased ABI and increased risk for cardiovascular
death1
70
60
Percent (%)
All-cause mortality
50
CVD mortality
40
30
20
10
0
Baseline ABI*
Resnick HE et al. Circulation 2004; 109: 733-739.
*Mean participant follow-up 8.3 years
Patients with PAD are at high risk of MI and
stroke
PAD
Post-MI
Increased risk of MI*
Increased risk of stroke*
4
2-3 
risk4
greater
(includes only fatal MI and other
CHD death)
greater risk3
(includes TIA)
5-7 
3-4 
greater risk2
(includes TIA)
greater risk1
(includes death)
9
2-3 
Post-stroke
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.
greater risk3
greater risk2
(includes angina
and sudden death†)
*
†
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.
Risk of death is increased in patients with both
symptomatic and asymptomatic PAD
Survival (% of patients)
100
Normal subjects*
75
Asymptomatic PAD†
50
Symptomatic PAD†
Severe symptomatic PAD†
25
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.
The American Diabetes Association
recommends screening for PAD in patients with
1
diabetes
A screening ABI should be performed in patients with diabetes
Those >50 years of age
• If normal an exercise
test should be
carried out
• The ABI test
should be repeated
every 5 years
•
Those <50 years of age who
have other risk factors
associated with PAD
• Smoking
• Hypertension
• Hyperlipidemia
• Duration of diabetes
>10 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: 3333–3341.
2. Estes JM, Pomposelli FB Jr. Diabet Med 1996: 13: S43–S57.
Patients with PAD are at risk of MI, IS
and death
CAPRIE data
3-year cumulative event rate (%)
6
5
4
Coronary
outcome
Cerebrovascular
outcome
5.2
5.1
4.2
3.6
Clopidogrel
3
Aspirin
2
1
0
Patients qualifying for CAPRIE on the basis of PAD
Dormandy JA, Creager MA. Cerebrovasc Dis 1999;9(Suppl 1):1–128 (Abstr 4).
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
1
ASA].”
1. American Diabetes Association. Diabetes Care: Vol 26: 12, Dec 2003
The Call to Action Paper highlighted 5 key
action 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
Belch JJF et al. Arch Intern Med 2003; 163: 884-892.
Call to action
Paper
60%
Improve
treatment rates
among patients
who have been
diagnosed with
symptomatic
PAD
Increase the
rates of early
detection
among the
asymptomatic
population