Anti-platelet therapy and
Peripheral Arterial Disease
K Cassar MD(Malta), M MEd(Dundee), FRCS (Edin),
MD (Aberdeen), FRCS (Gen Surg)
University of Aberdeen
Peripheral Arterial Disease
Peripheral Arterial Disease
Mortality
Population above 62 years
(63% had one or more)
CerebroVascular
Disease
9%
8%
Coronary
Heart
Disease
21%
5%
3%
9%
PAOD
8%
1
PLATELETS
Rudolf Virchow
1821-1902
Endothelial Denudation
Endothelium
Sub-endothelium
Endothelial Denudation
vWF
Collagen
Platelet Adhesion
GPIIb/IIIa
Endothelium
Sub-endothelium
GPIa/IIa
GPIb/IX
Collagen
vWF
Endothelium
Collagen
vWF
Sub-endothelium
2
Platelet Aggregation
Platelet adhesion and aggregation
Platelet-rich
Thrombus
GPIIb/IIIa
Endothelium
INTIMA
GPIa/IIa
GPIb/IX
Endothelium
IEL
Sub-endothelium
Collagen
Vessel occlusion
Angioplasty
vWF
MEDIA
Graft
Occlusion
Platelet-Induced Smooth Muscle
Proliferation
Platelet-rich
Thrombus
Endothelium
INTIMA
IEL
PDGF
MEDIA
3
Platelet-Induced Smooth Muscle
Proliferation
Platelet-Induced Smooth Muscle
Proliferation
Platelet-rich
Thrombus
Endothelium
Endothelium
INTIMA
INTIMA
IEL
IEL
MEDIA
MEDIA
P-selectin
• Observational study: controls, claudicants,
criticals – 100 subjects
• P-selectin – marker of platelet activation
P-selectin
Flow Cytometer
4
Platelet activation- P-selectin
Results:P-selectin expression
2.00
=
=
1.50
Psel
(%) 1.00
=
==
=
==
==
=
=
=
0.50
=
=
==
=
=
==
=
==
=
==
=
=
=
=
=
P-selectin expression (%)
=
=
=
==
=
=
==
=
==
==
==
=
= =
=
= =
=
=
==
=
=
=
=
=
==
=
=
=
=
=
=
=
=
==
=
=
==
=
=
=
Controls
0.59
Claudicants
0.85 (p=0.023)
Criticals
1.11 (p=0.028)
=
0.00
controls
claudicants
criticals
Antiplatelet Drugs
ASPIRIN
Arachidonic Acid
Cyclooxygenase
THROMBOXANE
GPIIb/IIIa
SIGN
1998
Joint British recommendations:
1998
• Patients with PAD should be managed in
the same way as those with established
coronary heart disease
5
Anti-thrombotic Trialists’
Collaboration Meta-analyses
(2002)
• 3123 patients with intermittent claudication
in 26 trials
K Cassar, R Coull, P Bachoo, E Macaulay, J Brittenden
European Journal of Vascular and Endovasc Surgery 26:262-66 (2003)
K Cassar, R Coull, P Bachoo, E Macaulay, J Brittenden
European Journal of Vascular and Endovasc Surgery 26:262-66 (2003)
Patient self-medicated
Patient prescribed
GP prescribe
90
Percentage
Management of secondary risk factors in patients with
intermittent claudication
Percentage
Management of secondary risk factors in patients with
intermittent claudication
7
90
Patient self-medicated
Patient prescribed
GP prescribe
59
GP response (%)
Patient response (%)
GP response (%)
Patient response (%)
6
Antiplatelet Drugs
ASPIRIN
ADP
Clopidogrel
Arachidonic Acid
Cyclooxygenase
THROMBOXANE
CLOPIDOGREL
ADP
receptor
GPIIb/IIIa
The CAVA Study
Restenosis and reocclusion
A randomised, double-blind, placebo
controlled trial of clopidogrel and aspirin
versus aspirin alone in patients undergoing
endovascular intervention for claudication
K Cassar, I Ford, M Greaves, P Bachoo, J Brittenden
Departments of Medicine and Therapeutics, and
Vascular Surgery, University of Aberdeen; Vascular
Unit, Aberdeen Royal Infirmary
Hypothesis
• In patients undergoing PTA/stenting
clopidogrel and aspirin in combination reduce
platelet activation and platelet responsiveness
more effectively than aspirin alone
%
Patency after SFA/pop PTA
100
90
80
70
60
50
40
30
20
10
0
Immediate Success
Rate
1 year patency
94
74
62
2 year patency
57
52
3 year patency
4 year patency
Karch LA et al. J Vasc Surg 2000; 31:880-7
STUDY DESIGN
(double blind RCT)
100 CLAUDICANTS
randomisation
Intervention 1
50 ASPIRIN+PLACEBO
50 ASPIRIN + CLOPIDOGREL
• Power calculation: 100 patients p<0.05, α=0.8
(Moshfegh et al; 2000 J Am Coll Card 36:699-705)
ANGIOPLASTY
Intervention 2
7
Blood Samples
Outcome measures
*
• Primary
– Platelet activation
• Platelet P-selectin expression
• Platelet fibrinogen binding
– Platelet responsiveness to stimulation
• ADP-stimulated platelet fibrinogen binding
*=administration of loading dose
of clopidogrel or placebo
Statistical Analysis
Results: flow of participants
Randomised n=132
•
•
•
•
SPSS Version 10.1
ANOVA:mixed factorial
P<0.05 statistically significant
Chi-squared test/Fisher’s exact test:
differences in adverse events between the
two groups
65:
(75mg Aspirin +
Placebo)
65 allocated
to receive 75mg aspirin +
67:
(75mg Aspirin +
75mgto receive
Clopidogrel
67 allocated
75mg aspirin
-
-
-
-
-
-
-
49 Angioplasty
54 Angioplasty
No patients were lost to follow-up
Characteristic
Males:females
Placebo
(n=65)
50:15
Clopidogrel
(n=67)
52:15
Mean Age/years (Range)
65.4 (46-80) 66.1 (43-80)
Smoking (%)
never
ex-smoker > 1year
ex-smoker < 1 year
smoker
Diabetes (%)
3 (4.6)
27 (41.5)
13 (20.0)
22 (33.8)
11 (16.9)
Baseline demographics
Ankle Brachial Pressure Index
1.1
1.0
5 (7.5)
28 (41.8)
11 (16.4)
23 (34.3)
12 (17.9)
3.68 (2.23) 4.15 (2.02)
% P selectin expression
Mean Serum cholesterol
mmol/L (STD)
P-selectin expression
95% CI
Baseline
0.9
95% CI
0.8
1hr pre PTA
95% CI
0.7
1hr post PTA
0.6
95% CI
24hr post PTA
0.5
0.4
placebo
0.63
0.65
clopidogrel
group
95% CI
Betweeen subjects
30day post PTA
ANOVA P=0.03
(Drop in clopidogrel
group: 27-37%)
8
% Fibrinogen binding
ADP-stimulated fibrinogen binding
90
ADP stim % fibrinogen binding
4.5
4.0
% fibrinogen binding
95% CI
Baseline
3.5
95% CI
3.0
1hr pre PTA
95% CI
2.5
1hr post PTA
2.0
95% CI
24hr post PTA
1.5
95% CI
30day post PTA
1.0
placebo
clopidogrel
group
Betweeen subjects
ANOVA P=0.026
(Drop in clopidogrel
group: 31-40%)
Adverse Events
• No difference in bleeding complications
• No patients required surgical intervention
for bleeding
Conclusion
80
95% CI
Baseline
70
95% CI
60
1hr pre PTA
95% CI
50
1hr post PTA
40
95% CI
24hr post PTA
30
95% CI
30day post PTA
20
placebo
clopidogrel
Between subjects
ANOVA:
P<0.001
(Clopidogrel group:
drop 49-57%)
group
Results
• Clopidogrel-aspirin combination compared
to aspirin alone significantly reduces:
platelet activation and
platelet responsiveness to stimulation
Is the antiplatelet drug having an
antiplatelet effect in this patient?
• The combination of aspirin-clopidogrel may:
– reduce the risk of cardiovascular events
– reduce the incidence of restenosis and reocclusion after
peripheral angioplasty in claudicants
Aspirin Resistance
• Need for Randomised controlled trials with
clinical outcome measures
9
Clopidogrel resistance??
ADP stimulated fibrinogen binding %
100
75
?
?
???
??
?
?
?
?
???
?
?
??
?
??
?
??
??
?
??
?
??
???
?
?
??
??
50
?
??
??
?
?
?
25
Future research
• Development of reliable simple point-ofcare test of platelet function:
?
?
?
?
?
??
?
???
??
???
??
?
?
?
???
?
?
– To allow correlation between platelet activation
and risk of vascular events
– to guide use of antiplatelet treatment
?
???
??
?
???
?
???
?
?
?
?
?
???
?
0
Pre
Post
Loch Nagar
10