inhibitory effects of ticagrelor compared to clopidogrel on platelet function in patients with acute...
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Inhibitory Effects of Ticagrelor Compared to Clopidogrel on Platelet Function in Patients
with Acute Coronary Syndromes The PLATO PLATELET Substudy
Storey RF1, Angiolillo DJ2, Patil SB1, Desai B2, Ecob R1, Husted S3, Emanuelsson H4, Cannon CP5, Becker RC6, Wallentin L7
1Department of Cardiovascular Science, University of Sheffield, and NIHR Cardiovascular Biomedical Research Unit, Sheffield, UK2University of Florida College of Medicine-Jacksonville, Jacksonville, FL, USA3Århus University Hospital, Århus, Denmark4AstraZeneca, Mölndal, Sweden5TIMI Study Group, Brigham and Women’s Hospital, Boston, USA6Duke Clinical Research Institute, Durham, USA7Uppsala Clinical Research Center and Department of Medical Sciences Cardiology,
Uppsala University, Uppsala, Sweden
J. Am. Coll. Cardiol 2010;56(18):1456-62
PLATO PLATELET
• Objectives: The PLATO (PLATelet inhibition and patient Outcomes) PLATELET substudy aimed to compare the antiplatelet effects of clopidogrel and ticagrelor in patients with acute coronary syndromes.
• Background: The PLATO study demonstrated superiority of ticagrelor over clopidogrel in the prevention of ischemic events in patients with acute coronary syndromes.
Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62
PLATO PLATELET
• Methods: • Patients were randomized to receive either clopidogrel
(300- to 600-mg loading dose [LD], 75 mg/day) or ticagrelor (180-mg LD, 90 mg twice daily).
• The effects of maintenance therapy were studied in 69 patients pre- and 2 to 4 h post-dose after at least 28 days.
• The LD effect was studied in 24 clopidogrel-naive patients. Light transmittance aggregometry (adenosine diphosphate 5 to 20 M), VerifyNow P2Y12, and VASP phosphorylation assays were performed.
Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62
PLATO PLATELET
• Results: • During maintenance therapy, ticagrelor achieved greater
suppression of platelet reactivity compared with clopidogrel.
• The mean maximum light transmittance aggregometry responses (adenosine diphosphate 20 M) post maintenance dose were 44 ± 15% for clopidogrel and 28 ± 10% for ticagrelor (p<0.001).
• High platelet reactivity was seen more frequently in the clopidogrel group. Proton pump inhibitor use was associated with higher platelet reactivity with clopidogrel but not ticagrelor.
• The ticagrelor LD also achieved greater inhibition of platelet aggregation compared with the clopidogrel LD.
Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62
Figure 1A. Responses to maintenance doses of clopidogrel (C) and ticagrelor (T): maximum LTA response (ADP 20μM)
LTA = light transmittance aggregometry; SE = standard error
Trough Peak
100
80
60
40
20
0C T C T
% P
late
let
agg
reg
atio
n, m
ean
(S
E)
p <0.001 p <0.001
Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62
Figure 1B. Responses to maintenance doses of clopidogrel (C) and ticagrelor (T):
final LTA response (ADP 20μM)
LTA = light transmittance aggregometry; SE = standard error
C T C T
100
80
60
40
20
0
Trough Peak
p <0.01 p <0.01
% P
late
let
agg
reg
atio
n, m
ean
(S
E)
Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62
Figure 1C. Responses to maintenance doses of clopidogrel (C) and ticagrelor (T): maximum LTA response (ADP 5μM)
LTA = light transmittance aggregometry; SE = standard error
C T C T
100
80
60
40
20
0
Trough Peak
p <0.01 p <0.001
% P
late
let
agg
reg
atio
n, m
ean
(S
E)
Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62
Figure 1D. Responses to maintenance doses of clopidogrel (C) and ticagrelor (T):
final LTA response (ADP 5μM)
LTA = light transmittance aggregometry; SE = standard error
C T C T
100
80
60
40
20
0
Trough Peak
p <0.001 p <0.001
% P
late
let
agg
reg
atio
n, m
ean
(S
E)
Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62
Figure 1E. Responses to maintenance doses of clopidogrel (C) and ticagrelor (T):
VerifyNow P2Y12 assay
SE = standard error
C T C T
500
400
300
200
100
0Pla
tele
t re
acti
on
un
its
(PR
U),
mea
n (
SE
)
235 PRU
Trough Peak
p <0.001 p <0.001
Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62
Figure 1F. Responses to maintenance doses of clopidogrel (C) and ticagrelor (T):
VASP assay
SE = standard error
C T C T
100
90
80
70
60
50
40
30
20
10
0
Pla
tele
t re
acti
vity
ind
ex (
%),
mea
n (
SE
)
Trough Peak
p <0.001 p <0.001
Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62
Figure 2. VerifyNow responses to maintenance doses of clopidogrel (C) and ticagrelor (T)
according to geographic location (UK or US)
500
400
300
200
100
0
Pla
tele
t re
acti
on
un
its
(PR
U),
mea
n (
SE
)
UK US UK US UK US UK USTrough Peak Trough Peak
C TSE = standard error
All p = NSStorey RF et al. J Am Coll Cardiol 2010;56(18):1456-62
Figure 3A. Responses to loading doses of clopidogrel (C) and ticagrelor (T): maximum LTA response (ADP 20μM)
LTA = light transmittance aggregometry
Pre 1h 2h 4h 8h 12hC T C T C T C T C T C T
100
80
60
40
20
0
% P
late
let
agg
reg
atio
n, m
ean p <0.01p <0.001 p <0.01
Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62
Figure 3B. Responses to loading doses of clopidogrel (C) and ticagrelor (T):
final LTA response (ADP 20μM)
LTA = light transmittance aggregometry
Pre 1h 2h 4h 8h 12hC T C T C T C T C T C T
100
80
60
40
20
0
p <0.001
% P
late
let
agg
reg
atio
n, m
ean
Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62
Figure 3C. Responses to loading doses of clopidogrel (C) and ticagrelor (T): maximum LTA response (ADP 5μM)
LTA = light transmittance aggregometry
Pre 1h 2h 4h 8h 12hC T C T C T C T C T C T
100
80
60
40
20
0
p <0.01
% P
late
let
agg
reg
atio
n, m
ean
Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62
Figure 3D. Responses to loading doses of clopidogrel (C) and ticagrelor (T):
final LTA response (ADP 5μM)
LTA = light transmittance aggregometry
Pre 1h 2h 4h 8h 12hC T C T C T C T C T C T
100
80
60
40
20
0
p <0.01
% P
late
let
agg
reg
atio
n, m
ean
Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62
Figure 3E. Responses to loading doses of clopidogrel (C) and ticagrelor (T):
VerifyNow P2Y12 assay
C T C T
500
400
300
200
100
0
Pla
tele
t re
acti
on
un
its
(PR
U),
mea
n
Pre 4h
p <0.01
Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62
Figure 3F. Responses to loading doses of clopidogrel (C) and ticagrelor (T):
VASP assay
C T C T
100
80
60
40
20
0
Pla
tele
t re
acti
vity
ind
ex (
%),
mea
n
Pre 4h
Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62
Figure 4A. IPA following loading doses of clopidogrel (C) and ticagrelor (T): inhibition of
maximum LTA response (ADP 5μM)
LTA = light transmittance aggregometryP values determined by unpaired t test or Mann Whitney test
1h 2h 4h 8h 12hC T C T C T C T C T
100
80
60
40
20
0
% In
hib
itio
n, m
ean
p <0.01p <0.01p <0.001
Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62
Figure 4B. IPA following loading doses of clopidogrel (C) and ticagrelor (T): inhibition of
final LTA response (ADP 5μM)
LTA = light transmittance aggregometryP values determined by unpaired t test or Mann Whitney test
1h 2h 4h 8h 12hC T C T C T C T C T
100
80
60
40
20
0
p <0.01 p <0.001 p <0.01 p <0.01 p <0.01
% In
hib
itio
n, m
ean
Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62
Suppl. Figure 1A. Responses to maintenance doses of clopidogrel (C) and ticagrelor (T):
maximum LTA response (ADP 20μM)
Data are mean, interquartile range (boxes), 10–90 percentile (whiskers) and outlying data points (dots); LTA = light transmittance aggregometry
C T C T
100
80
60
40
20
0
% P
late
let
agg
reg
atio
n
Trough Peak
p <0.001 p <0.0001
Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62
Suppl. Figure 1B. Responses to maintenance doses of clopidogrel (C) and ticagrelor (T):
final LTA response (ADP 5μM)
Data are mean, interquartile range (boxes), 10–90 percentile (whiskers) and outlying data points (dots); LTA = light transmittance aggregometry
C T C T
100
80
60
40
20
0
Trough Peak
p <0.001 p <0.001
% P
late
let
agg
reg
atio
n
Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62
Suppl. Figure 1C. Responses to maintenance doses of clopidogrel (C) and ticagrelor (T):
VerifyNow P2Y12 assay
Data are mean, interquartile range (boxes), 10–90 percentile (whiskers) and outlying data points (dots)
C T C T
500
400
300
200
100
0
Trough Peak
p <0.0001 p <0.0001
Pla
tele
t re
acti
on
un
its
(PR
U)
Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62
Suppl. Figure 1D. Responses to maintenance doses of clopidogrel (C) and ticagrelor (T):
VASP assay
Data are mean, interquartile range (boxes), 10–90 percentile (whiskers) and outlying data points (dots)
C T C T
100
90
80
70
60
50
40
30
20
10
0
Trough Peak
p <0.0001 p <0.0001
Pla
tele
t re
acti
vity
ind
ex (
%)
Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62
Proportion of platelet function responses greater than risk thresholds for ischemic
events: pre-maintenance dose
LTA = light transmittance aggregometry
100
80
60
40
20
0
% a
bo
ve t
hre
sho
ld
Maximum LTA response to ADP
20μm >50%
Final LTA response to ADP
5μm >14%
VerifyNow P2Y12 >235 PRU
VASP PRI >50%
p <0.0001
p <0.0001
p=0.02p=0.0001
Ticagrelor
Clopidogrel
Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62
Proportion of platelet function responses greater than risk thresholds for ischemic events: 2–4 hours post-maintenance dose
LTA = light transmittance aggregometry
100
80
60
40
20
0
% a
bo
ve t
hre
sho
ld
Maximum LTA response to ADP
20μm >50%
Final LTA response to ADP
5μm >14%
VerifyNow P2Y12 >235 PRU
VASP PRI >50%
p=0.0001
p <0.0001
p=0.01
p <0.0001
Ticagrelor
Clopidogrel
Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62
LTA responses during maintenance therapy according to treatment with PPIs:
pre-maintenance dose100
80
60
40
20
0
% P
late
let
agg
reg
atio
n, m
ean
Ticagrelor Clopidogrel Ticagrelor Clopidogrel
p=0.59
p=0.054
p=0.04
p=0.21
LTA = light transmittance aggregometry; PPI = proton pump inhibitor
Maximum LTA response to ADP 20μm
Final LTA response to ADP 5μm
PPI
No PPI
Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62
LTA responses during maintenance therapy according to treatment with PPIs: 2–4 hours post-maintenance dose
100
80
60
40
20
0
% P
late
let
agg
reg
atio
n, m
ean
Ticagrelor Clopidogrel Ticagrelor Clopidogrel
p=0.68
p=0.013
p=0.007
p=0.73
LTA = light transmittance aggregometry; PPI = proton pump inhibitor
Maximum LTA response to ADP 20μm
Final LTA response to ADP 5μm
PPI
No PPI
Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62
VerifyNow P2Y12 responses during maintenance therapy according to treatment
with PPIs: pre-maintenance dose
Ticagrelor Clopidogrel
p=0.56
p=0.005
PPI = proton pump inhibitor
VerifyNow P2Y12 response
PPI
No PPI300
250
200
150
100
50
0
Pla
tele
t re
acti
on
un
its
(PR
U),
mea
n
Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62
VerifyNow P2Y12 responses during maintenance therapy according to treatment with PPIs: 2–4 hours post-maintenance dose
Pla
tele
t re
acti
on
un
its
(PR
U),
mea
n
Ticagrelor Clopidogrel
p=0.98
p=0.005
PPI = proton pump inhibitor
VerifyNow P2Y12 response
PPI
No PPI300
250
200
150
100
50
0
Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62
VASP responses during maintenance therapy according to treatment with PPIs:
pre-maintenance dose
PPI = proton pump inhibitor
VASP response
100
80
60
40
20
0
Pla
tele
t re
acti
vity
ind
ex (
%),
mea
n
Ticagrelor Clopidogrel
p=0.43
p=0.47
PPI
No PPI
Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62
VASP responses during maintenance therapy according to treatment with PPIs:
2–4 hours post-maintenance dose
PPI = proton pump inhibitor
100
80
60
40
20
0
Pla
tele
t re
acti
vity
ind
ex (
%),
mea
n
Ticagrelor Clopidogrel
p=0.32
p=0.23
PPI
No PPI
VASP response
Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62
PLATO PLATELET
• Conclusions:
• Ticagrelor achieves greater antiplatelet effect than clopidogrel in patients with acute coronary syndromes, both in the first hours of treatment and during maintenance therapy.
Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62