Ticagrelor vs Prasugrel-Metaanalysis
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Transcript of Ticagrelor vs Prasugrel-Metaanalysis
ORIGINAL ARTICLE
High on-treatment platelet reactivity with ticagrelor versusprasugrel: a systematic review and meta-analysis
G. LEMESLE ,*†‡ G. SCHURTZ ,* C . BAUTERS*†‡ and M. HAMON§¶*Centre Hospitalier R�egional et Universitaire de Lille; †Inserm U744, Institut Pasteur de Lille; ‡Facult�e de M�edecine de l’Universit�e de Lille,
Lille; §Centre Hospitalier Universitaire de Caen; and ¶Facult�e de M�edecine de Caen, Caen, France
To cite this article: Lemesle G, Schurtz G, Bauters C, Hamon M. High on-treatment platelet reactivity with ticagrelor vs. prasugrel: a systematic
review and meta-analysis. J Thromb Haemost 2015; 13: 931–42.
Summary. Background: Ticagrelor and prasugrel have
shown superiority over clopidogrel. However, it remains
unclear if one is superior to another regarding on-treat-
ment platelet reactivity. Objectives: To compare the
impact of ticagrelor and prasugrel on high on-treatment
platelet reactivity (HTPR). Methods: The PubMed and
Cochrane databases were searched for eligible studies in
December 2014. Studies were eligible if they compared
ticagrelor and prasugrel regarding high on-treatment
platelet reactivity (HTPR). Pooled estimates were calcu-
lated by using a random-effects model with 95% confi-
dence intervals. Results: We included 14 studies and 1822
patients: 805 and 1017 in the ticagrelor and prasugrel
groups, respectively. The rate of HTPR was significantly
lower in the ticagrelor group: 1.5% vs. 9.8% (RR = 0.27
[0.14–0.50]). The pre-specified analysis focusing on ran-
domized trials (n = 10) showed consistent results
(RR = 0.27 [0.12–0.60]). Conclusion: Our results suggest
that ticagrelor allows a higher platelet reactivity inhibition
as compared with prasugrel and leads to a further
decrease in the rate of HTPR.
Keywords: acute coronary syndrome; antiplatelet agents;
coronary artery disease; percutaneous coronary
intervention; platelet function tests.
Introduction
There is a wide variability in inhibition of platelet reactiv-
ity after exposure to P2Y12 receptor inhibitors and high
on-treatment platelet reactivity (HTPR) has been associ-
ated with poor outcomes, especially with clopidogrel but
also with new antiplatelet agents [1–7]. The most recent
antiplatelet agents, ticagrelor and prasugrel, have both
been shown to induce higher levels of platelet reactivity
inhibition as compared with clopidogrel and to decrease
the proportion of patients with HTPR [8–13]. Impor-
tantly, these two drugs have also been shown to be supe-
rior for reduction of major cardiovascular and cerebral
events (MACCE) in the context of acute coronary syn-
drome (ACS) when compared with clopidogrel [14,15].
Consequently, these two drugs are now recommended as
the treatment of choice for ACS management in Euro-
pean and American guidelines [16,17].
Ticagrelor and prasugrel have, however, different mecha-
nisms of action that may lead to significant differences in
terms of biological and clinical outcomes. Prasugrel is a
third generation thienopyridine that irreversibly inhibits the
platelet P2Y12 receptors while ticagrelor is a cyclopenthyl-
triazolo-pyrimidine and a reversible antagonist of this recep-
tor. To date, no study has directly compared ticagrelor and
prasugrel regarding clinical outcomes, and small biological
studies comparing the effect of both treatments on platelet
reactivity have shown contradictory results [8,18–31]. Thus,it remains uncertain whether or not one agent is superior to
another regarding on-treatment platelet reactivity.
We therefore conducted this systematic review and
meta-analysis to compare the impact of ticagrelor and
prasugrel on high on-treatment platelet reactivity
(HTPR).
Methods
Study objectives
The primary objective of this systematic review and meta-
analysis was to compare the impact of the two recently
Correspondence: Gilles Lemesle, Centre H�emodynamique et Unit�e
de Soins Intensifs de Cardiologie, Hopital Cardiologique, Bd du Pr
Jules Leclercq, Centre Hospitalier R�egional et Universitaire de Lille,
59037 Lille Cedex, France.
Tel: +33 320445301; fax: +33 320444898.
E-mail: [email protected]
Received 6 January 2015
Manuscript handled by: J.-B. Hansen
Final decision: F. R. Rosendaal, 16 March 2015
© 2015 International Society on Thrombosis and Haemostasis
Journal of Thrombosis and Haemostasis, 13: 931–942 DOI: 10.1111/jth.12907
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introduced antiplatelet agents, ticagrelor and prasugrel,
on HTPR. The primary endpoint was HTPR as defined
in original included studies, either as platelet reactivity
units (PRU) as assessed by the VerifyNow-P2Y12 (VN)
function assay or as platelet reactivity index (PRI) as
assessed by the vasodilator stimulated phosphoprotein
(VASP) test. When both biological tests were performed,
we used for the principal analysis the test that served to
define the primary endpoint in the original study.
Search strategy
The PubMed and Cochrane databases were searched for
eligible studies with no restriction of time in December
2014 by using the combined medical subject headings for
‘ticagrelor and prasugrel’. The complete search used for
PubMed was: (ticagrelor[All fields] AND prasugrel[All
fields] AND English[language]). Two investigators (GL
and GS) independently checked retrieved titles and
abstracts for eligibility and relevant full texts were system-
atically retrieved for further detailed assessment. Major
reviews regarding platelet inhibition under P2Y12 receptor
inhibitors were also hand-searched. Cross-references and
quoted papers were checked, and experts were contacted
to identify other relevant studies. The retrieved studies
were examined to exclude duplicate or overlapping data.
Unpublished data were not considered for the present
analysis because results could not be considered as certain
and definitive. Meeting abstracts were also excluded
because they could not provide adequately detailed data
and their results might not be final.
Study eligibility
Studies were eligible only if they compared ticagrelor and
prasugrel regarding HTPR and referred to subjects with
coronary artery disease (CAD). Inclusion criteria were (i)
comparison of ticagrelor and prasugrel, (ii) in patients
identified with CAD (iii) with a reported HTPR measured
during initial hospitalization or at least at 1 month fol-
low-up. Studies were excluded if (i) they were performed
without assessment of HTPR, (ii) were performed with
no final report and only abstracts available, (iii) they
tested unusual dosage of either ticagrelor or prasugrel, or
(iv) they were performed in animals. In addition, one
study that included only patients with HTPR taking
prasugrel was also excluded in order to not favour ticagr-
elor [32].
Data extraction
The following information was extracted from each study:
first author; year of publication; period of patient inclu-
sion; journal; type of comparison (randomized or not);
study population characteristics, including sample size,
number of patients, gender, mean age, diabetes mellitus
and type of CAD (stable CAD or ACS); relative timing
of HTPR assessment after treatment initiation; definitions
of HTPR; technical characteristics of the platelet reactiv-
ity test and threshold, including type and brand of assay;
and rate of patients with HTPR in each group (ticagrelor
vs. prasugrel). Three investigators (GL, CB and MH) per-
formed the data extraction independently. Discrepancies
were solved by consensus.
Specific quality aspects such as the following were used
to assess the studies: control of confounding factors; min-
imization of selection bias with a clear description of
inclusion and exclusion criteria; description of the base-
line characteristics of the cohort; completeness of the fol-
low-up; clear definition of study outcomes; relative timing
of the HTPR assessment after patient admission; and
whether or not the investigator responsible for the HTPR
measurements was unaware of the patients’ baseline char-
acteristics, clinical course and treatment allocation. Dis-
agreements were solved by consensus.
Data synthesis and statistical analysis
Pooled estimates were calculated by using a random-
effects model with 95% confidence intervals (CI).
Between-study statistical heterogeneity was assessed by
using the Cochran Q chi-square test and the I2 test.
For the pooled principal analysis, the later biological
data on HTPR available in each selected study were used.
In the case of multiple assessments of residual platelet
reactivity, we used for the principal analysis the test that
served to define the primary endpoint in the original
study. Separate pre-specified subgroup analyses were per-
formed in randomized studies excluding registries, in
studies that used the VASP test and studies that used the
VN assay, in studies testing the effect of the loading dose
of each treatment (biological data available within 12–24 h after the loading dose) and studies testing the effect
of the maintenance dose of each treatment (between 5
and 30 days after initiation of treatment), in studies
focusing on ST elevation myocardial infarction (STEMI)
patients, in studies focusing on diabetic patients, and
without the study published by Dillinger et al. [24] that
did not report a precise timing for platelet function
assessment.
Publication bias was assessed visually by examination
of funnel plots of each trial effect size against the stan-
dard error (SE).
Statistical computations were performed with SPSS
11.0 (SPSS Inc., Chicago, IL, USA) and Review Manager
4.2 and significance testing was at the two-tailed 0.05
level. This study was performed according to established
methods and in compliance with the quality of reporting
of meta-analyses (QUORUM) guidelines [33].
The authors are solely responsible for the design of this
study, all analyses, the editing of the paper and its final
content.
© 2015 International Society on Thrombosis and Haemostasis
932 G. Lemesle et al
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Results
Search results and study selection
We found 434 citations in PubMed and other data
sources. There were 31 studies that compared the effect
of ticagrelor and prasugrel for which a detailed assess-
ment of the full-text was performed. We finally included
14 studies and excluded 17 others. The reasons for exclu-
sion were: studies testing unusual dosage of ticagrelor or
prasugrel (n = 2), studies not assessing biological data
(n = 7), studies not reporting data on HTPR (n = 3),
studies not performed in humans (n = 2), and studies with
duplicate data (n = 2). One additional study that included
only patients with HTPR taking prasugrel was also
excluded in order to not favour ticagrelor (atypical
design) [32]. The study selection process is summarized in
Fig. 1.
Study and patient characteristics
The final analysis included 1822 patients with CAD and
biological data on HTPR: 805 in the ticagrelor group and
1017 in the prasugrel group. Among the 14 included stud-
ies, there were 10 randomized trials and four registries,
including one with a propensity matching analysis.
The definition of HTPR used in the different studies is
described in Table 1. Altogether, seven studies used the
VN assay, six used the VASP test and one used both. An
assessment of the effect of the loading dose was available
for six studies (dosage between 12 and 24 h after the
loading dose) and an assessment of the effect of the main-
tenance dose was available in nine studies (data available
for between 5 and 30 days after treatment initiation). The
overall quality assessment of the different studies is sum-
marized in Table 2.
As shown in Table 3, the mean age varied between 54
and 69.5 years and the proportion of men varied between
72.4% and 95%. The proportion of patients with diabetes
mellitus varied between 9% and 100%, including two
studies focusing only on diabetics. Only one study ana-
lyzed exclusively patients with stable CAD. Among the 13
other studies, which tested patients with ACS, the per-
centage of patients with STEMI varied between 23.3%
and 100%. There were four studies that focused on
STEMI patients exclusively.
Effect of ticagrelor and prasugrel on HTPR
The overall rate of HTPR was 6.1% in the present meta-
analysis. As shown in Fig. 2, the rate of HTPR was sig-
nificantly lower in the ticagrelor group as compared with
the prasugrel group: 1.5% vs. 9.8%, risk ratio
(RR) = 0.27 [0.14–0.50] (P < 0.0001). The analysis exclud-
ing the study published by Dillinger et al. [24] showed
similar results (data not shown).
The prespecified analysis of randomized studies
excluding registries showed consistent results; the rate of
n = 434 articles identified
n = 31 relevant studies
retrieved for detailed assessment
n = 17 studies excluded
n = 2 studies not using recommended dosage of either ticagrelor or prasugrel
n = 7 studies not reporting biological datan = 3 studies not reporting data on HTPRn = 2 studies reporting animal data onlyn = 2 studies with duplicate data n = 1 study with atypical design (only patient with high HTPR
under prasugrel included)
n = 14 studies included in final analysis
n = 403 articles excluded on the basis of title and abstract
Fig. 1. Flow chart of the study selection process.
© 2015 International Society on Thrombosis and Haemostasis
HTPR with ticagrelor vs. prasugrel 933
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Table
1Descriptionofthestudiesincluded
inthepresentmeta-analysis.Biologicaltest
anddefinitionofHTPR
used
Author(Y
ear)
Design
Number
of
patients
Total/Ticagrelor/
Prasugrel
Treatm
enttested
Biologicaltest
used
andtiming
Definition
ofHTPR
used
ResultsTicagrelorvs.Prasugrel
Alexopoulos
etal.(2012)[18]
Randomized
Single
blind
Monocenter
Crossover
44/22/22
Ticagrelor90mgbid
vs.Prasugrel10mg
odfor15daysthen
crossover
for15days
VN
attheendof
each
15-dayperiod
PRU
>235
At15days
PRU
32.9
[95%
CI18.7–4
7.2]vs101.3
[86.8–1
15.7]P
<0.001
HTPR
0/43=0%
vs.1/42=2.4%
Alexopoulos
etal.(2012)[20]
Randomized
Single
blind
Monocenter
55/27/27
Ticagrelor180mgthen
90mgbid
vs.Prasugrel
60mgthen
10mgod
for5days
VN
atBaseline,
1,2,6,
24hand5days
PRU
>208
At24h
HTPR
0/26=0%
vs.1/24=4.2%
At5days
PRU
25.6
[95%
CI12.3–3
8.9]
vs.50.3
[36.4–6
4.1]P
=0.01
HTPR
0/27=0%
vs.0/24=0%
Parodiet
al.
(2013)[29]
Randomized
Open
label
Monocenter
50/25/25
Ticagrelor180mgvs.
Prasugrel60mg
VN
atbaseline,
2,4,8
and12hafter
LD
PRU
>240
At2h
PRU
median275[quartiles
88–305]vs.217
[12–279]P
=0.207
HTPR
at12h
1/25=4%
vs.0/25=0%
Alexopoulos
etal.(2013)[21]
Randomized
Single
blind
Monocenter
Crossover
30/15/15
Ticagrelor90mgbid
vs.Prasugrel
10mgodfor15daysthen
crossover
for15days
VN
attheendofeach
15-dayperiod
PRU
>230
At15days
PRU
45.2
[95%
CI27.4–6
3.1]vs.80.8
[63–98.7]P
=0.001
HTPR
0/30=0%
vs.1/30=3.3%
Deharo
etal.
(2013)[22]
Randomized
Open
label
Monocenter
96/48/48
Ticagrelor180mg
then
90mgbid
vs.Prasugrel60mgthen
10
mgodfor30days
VASPat30days
PRI>50%
At30days
PRI20.2
�9.9%
vs.25.8
�11.5%
P=0.01
HTPR
0/48=0%
vs.0/48=%
Laineet
al.
(2014)[26]
Randomized
Open
label
Monocenter
100/50/50
Ticagrelor180mgvs.
Prasugrel60mg
VASPbetween6and
18hafter
LD
PRI>50%
Between6and18h
PRI17.3
�14.2%
vs.27.7
�23.3%
P=0.009
HTPR
3/50=6%
vs8/50=16%
Angiolillo
etal.(2014)
[31]
Randomized
Open
label
Multicenter
110/35/75
Patients
with
completed
biological
data
98/33/65
Ticagrelor90mgbid
vs.
Prasugrel10odfor7days
VN
andVASPatbaseline,
2,4,24,48hand7days
PRU
>208
PRI>50%
At24h
data
notreported
At7days
PRU
47.9
�47.6
vs.95.6
�54.1
P<0.001
PRI20.1
�17.8%
vs.32.4
�18.6%
P=0.004
HTPR
PRU
1/33=3%
vs.1/65=1.5%
PRI1/33=3%
vs.10/65=15.3%
© 2015 International Society on Thrombosis and Haemostasis
934 G. Lemesle et al
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Table
1(C
ontinued)
Author(Y
ear)
Design
Number
of
patients
Total/Ticagrelor/
Prasugrel
Treatm
enttested
Biologicaltest
used
andtiming
Definition
ofHTPR
used
ResultsTicagrelorvs.Prasugrel
Ibrahim
etal.
(2014)[25]
Registry
Monocenter
Noadjustment
164/22/51
Patientunder
clopidogrel
(n=91)
Ticagrelor180mgvs.
Prasugrel60mg
VASPat24hafter
LD
PRI>50%
At24h
HTgroup:PRI41.5
�21vs.37.6
�25
NTgroup:PRI17.8
�14.5
vs.27�
25.5
HTPR
HT3/10=30%
vs.
8/25=32%
NT1/12=8%
vs.6/26=23%
Total4/22=18.2%
vs.14/51=27.4%
Alexopouloset
al.
(2014)[19]
Registry
Monocenter
Propensity
matching
512/278/234
Propensity
matched
442/221/221
Ticagrelor180mgthen
90mg
bid
vs.Prasugrel60mg
then
10mgodfor30days
VN
at30days
PRU
>208
At30days
PRU
33.3
[95%
CI29.3–37.3]vs.
84.6
[73.6–95.6]P
<0.001
HTPR
0/278=0%
vs.13/234=5.5%
Propensity
matched
0/221=0%
vs.12/221=5.4%
Lhermusier
etal.
(2014)[28]
Randomized
Open
label
Monocenter
20/10/10
Ticagrelor90mgbid
vs.
Prasugrel10mgod
for24h
VN
andVASPat4and24h
PRU
>208
PRI>50%
At24h
PRI4[2–11]vs.21[19–58]
PRU
9[5–1
0]vs.97[41–145]
HTPR
PRU
0/10=0%
vs.0/10=0%
Nodata
forPRI
Dillinger
etal.
(2014)[24]
Registry
Monocenter
Noadjustment
387/119/268
Ticagrelor180mgthen
90mgbid
vs.Prasugrel
60mgthen
10mgod
untildischarge
VASPbefore
discharge
(�at4days,no
exact
timing)
PRI>50%
Atdischarge
PRI14%
[95%
CI9–23]vs.25%
[14–38]
P<0.0001
HTPR
2/119=1.7%
vs.33/268=12.3%
Deharo
etal.
(2014)[23]
Randomized
Open
label
Monocenter
186/93/93
Ticagrelor180mgthen
90
mgbid
vs.Prasugrel60
mgthen
10mg
odfor30days
VASPat30days
PRI>50%
At30days
PRI18.7
�11.5%
vs.34�
15.3%
HTPR
1/93=1.1%
vs.13/93=13.9%
Perlet
al.
(2014)[30]
Registry
Monocenter
Noadjustment
114/52/62
Patients
with
completed
biologicaldata
at30days86/40/46
Ticagrelor180mg
then
90mg
bid
vs.Prasugrel60mg
then
10mgodfor30days
VN
between2–4
days
andat30days
PRU
>208
At30days
PRU
21.1
�26.1
vs.67.3
�62.5
P<0.001
HTPR
0/40=0%
vs.4/46=8.7%
0.056
Laineet
al.
(2014)[27]
Randomized
Open
label
Monocenter
88/44/44
Ticagrelor180mgvs.
Prasugrel60mg
VASPbetween6and
12hafter
LD
PRI>50%
Between6and12h
PRI17�
10.5%
vs.19.5
�19.2%
P=0.5
HTPR
0/44=0%
vs.4/44=9.1%
Bid,bi-daily;od,once
daily;LD,loadingdose;VASP,vasodilatorstim
ulatedphosphoprotein;VN,VerifyNow-P2Y
12;PRI,
plateletreactivityindex;PRU,plateletreactivityunit;HTPR,high
on-treatm
entplateletreactivity.
© 2015 International Society on Thrombosis and Haemostasis
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Table 2 Quality assessment of the studies included in the principal pooled analysis
Author (Year) Design
Period of
inclusion
Control of
confounding
factors
Clear description
of inclusion/exclusion
criteria
Clear
definition
of the
primary
endpoint
Minimization of
selection bias
Alexopoulos
et al. (2012) [18]
Randomized
Single blind
Monocenter
Crossover
Not reported Adequate Yes Yes All patients with PCI
for ACS and
residual HTPR after
600 mg loading dose
of clopidogrel 24 h
after PCI
Alexopoulos
et al. (2012) [20]
Randomized
Single blind
Monocenter
Sept 2011 to
Apr 2012
Adequate Yes Yes All patients with STEMI
Parodi et al.
(2013) [29]
Randomized
Open label
Monocenter
Not reported Adequate Yes Yes All patients with STEMI
Alexopoulos
et al. (2013) [21]
Randomized
Single blind
Monocenter
Crossover
June 2012 to
Sept 2012
Adequate Yes Yes All patients with ACS
and Diabetes
Deharo et al.
(2013) [22]
Randomized
Open label
Monocenter
Mar 2013 to
June 2013
Adequate No No All consecutive patients
with ACS
Laine et al.
(2014) [26]
Randomized
Open label
Monocenter
Not reported Adequate Yes Yes All patients with ACS and
diabetes
Angiolillo et al.
(2014) [31]
Randomized
Open label
Multicenter
Not reported Adequate Yes Yes Stable CAD patients
Ibrahim et al.
(2014) [25]
Registry
Monocenter
No adjustment
Not reported Poor Yes No Patients with ACS
84 out of the 164 patients
underwent hypothermia in the context
of cardiac arrest
and exclusion of patients who received
clopidogrel (n = 91)
Alexopoulos
et al. (2014) [19]
Registry
Monocenter
Propensity
matching
Mar 2012 to
Oct 2013
Good No Yes Consecutive patients with PCI for ACS
512 out of 937 patients, exclusion of
patients discharged under clopidogrel
or switched to clopidogrel within the
first month (n 235), who died within
the first month (n = 22), who had no
biological assessment available at 1
month (n = 5) and those who refused
to participate (n = 157)
Lhermusier et al.
(2014) [28]
Randomized
Open label
Monocenter
Nov 2012 to
May 2013
Adequate Yes No ACS within 4 h after 600 mg
loading dose of clopidogrel
and irrespective of platelet reactivity
after clopidogrel
Dillinger et al.
(2014) [24]
Registry
Monocenter
No adjustment
Not reported Poor Yes No Unclear, all consecutive
patients with ACS
Deharo et al.
(2014) [23]
Randomized
Open label
Monocenter
Mar 2013 to
Dec 2013
Adequate Yes Yes All consecutive patients with
PCI for ACS
Perl et al.
(2014) [30]
Registry
Monocenter
No adjustment
Not reported Poor Yes No Unclear, all consecutive
patients with STEMI
Laine et al.
(2014) [27]
Randomized
Open label
Monocenter
Aug 2012 to
June 2013
Adequate Yes Yes All patients with STEMI
PCI, percutaneous coronary intervention; ACS, acute coronary syndrome; STEMI, ST elevation myocardial infarction; HTPR, high on-treat-
ment platelet reactivity.
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Table 3 Description of the baseline characteristics of the populations of the different studies included in the principal pooled analysis
Author (Year)
Number of patients
Total/Ticagrelor/Prasugrel Type of patients
Mean
age (years) Sex male
Diabetes
mellitus Clinical presentation
Alexopoulos
et al. (2012) [18]
44/22/22 ACS only
HTPR after
600 mg
loading dose of
clopidogrel 24 h
after PCI
59.6 84.1% 22.7% STEMI = 43.2%
NSTEMI = 22.7%
UA = 34.1%
Stable angina = 0%
Alexopoulos
et al. (2012) [20]
55/27/27 STEMI only 59.5 80% 9% STEMI = 100%
NSTEMI = 0%
UA = 0%
Stable angina = 0%
Parodi et al.
(2013) [29]
50/25/25 STEMI only 67 78% 18% STEMI = 100%
NSTEMI = 0%
UA = 0%
Stable angina = 0%
Alexopoulos et al.
(2013) [21]
30/15/15 ACS
Diabetics only
63.1 93.3% 100% STEMI = 23.3%
NSTEMI = 36.7%
UA = 40%
Stable angina = 0%
Deharo et al.
(2013) [22]
96/48/48 ACS 60.8 81% 22% No precision
Laine et al.
(2014) [26]
100/50/50 ACS
Diabetics only
63.8 76% 100% STEMI or NSTEMI = 81%
UA = 19%
Stable angina = 0%
Angiolillo et
al. (2014) [31]
110/35/75 Stable CAD
Under ticagrelor
for 3 to 5 days
Irrespective of
platelet reactivity
59.4 72.4% 31.6% STEMI = 0%
NSTEMI = 0%
UA = 0%
Stable angina = 100%
Ibrahim et al.
(2014) [25]
164/22/51
Patient under
clopidogrel (n = 91)
ACS
Hypothermia
(cardiac arrest) vs.
normothermia
(no cardiac arrest)
61.5 82% 62% No precision
Alexopoulos et al.
(2014) [19]
512/278/234
Propensity
matched 442/221/221
ACS 59.6 84.1% 22% STEMI = 55.5%
NSTEMI = 25.8%
UA = 18.7%
Stable angina = 0%
Lhermusier et al.
(2014) [28]
20/10/10 ACS
After 600 mg
loading dose of
clopidogrel
Irrespective of
platelet reactivity
69.5 95% 30% STEMI = 0%
NSTEMI or UA = 100%
Stable angina = 0%
Dillinger et al.
(2014) [24]
387/119/268 ACS 54 84.5% 20.4% STEMI = 28.9%
NSTEMI = 71.1%
UA = 0%
Stable angina = 0%
Deharo et al.
(2014) [23]
186/93/93 ACS Not
reported
Not
reported
Not reported No precision
Perl et al.
(2014) [30]
114/52/62 STEMI only 60 79.8% 31.6% STEMI = 100%
NSTEMI = 0%
UA = 0%
Stable angina = 0%
Laine et al.
(2014) [27]
88/44/44 STEMI only 56 87.5% 11.4% STEMI = 100%
NSTEMI = 0%
UA = 0%
Stable angina = 0%
PCI, percutaneous coronary intervention; ACS, acute coronary syndrome; STEMI, ST elevation myocardial infarction; HTPR, high on-treat-
ment platelet reactivity; CAD, coronary artery disease; UA, unstable angina.
© 2015 International Society on Thrombosis and Haemostasis
HTPR with ticagrelor vs. prasugrel 937
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HTPR was 1.5% in the ticagrelor group and 8.6% in
the prasugrel group (RR = 0.27 [0.12–0.60], P = 0.001)
(Fig. 3).
As shown in Fig. S1, the rate of HTPR was almost
four times higher in studies that used the VASP test as
compared with studies that used the VN assay: 9% vs.
2.4%. Both techniques of HTPR assessment showed con-
sistent results regarding the impact of ticagrelor and
prasugrel on HTPR even if it does not reach statistical
significance for the VN assay. Using the VASP test, the
rate of HTPR was 2.7% in the ticagrelor group vs.
13.2% in the prasugrel group (RR = 0.26 [0.13–0.56],P = 0.0005). The rate of HTPR was 0.5% vs. 4.1%
(RR = 0.37 [0.09–1.52], P = 0.17) when using the VN
assay.
In addition, similar results were observed in studies
testing the effect of the loading dose (biological data
available within 12–24 h after the loading dose) and in
studies testing the effect of the maintenance dose
(between 5 and 30 days after treatment initiation). In
studies that tested the impact of the loading dose, the rate
of HTPR was 4.5% in the ticagrelor group and 13.2% in
the prasugrel group (RR = 0.52 [0.25–1.05], P = 0.07).
The rate of HTPR was 0.6% vs. 7.8% in studies that
tested the impact of the maintenance dose (RR = 0.16
[0.07–0.39], P < 0.0001) (Fig. S2).
In studies focusing exclusively on STEMI patients
(n = four studies and 275 patients), the rate of HTPR
was 0.7% in the ticagrelor group and 5.8% in the prasu-
grel group (RR = 0.32 [0.04–2.49], P = 0.28) (Fig. S3).
The impact of ticagrelor as compared with prasugrel in
studies focusing on diabetic patients was not interpretable
due to the small sample size (n = two studies only and
130 patients).
The funnel plots (Fig. 4) including all studies did not
detect asymmetry along the treatment effect axis, indicat-
ing similar results in larger and smaller studies with unli-
kely publication bias.
Discussion
If both ticagrelor and prasugrel have shown superiority
compared with clopidogrel, it remains uncertain whether
or not one is superior to the other regarding on-treatment
platelet reactivity. Interestingly, the overall rate of HTPR
was 6.1% in the present study, which is clearly higher
than the rate observed in previous studies performed in
healthy volunteers and stable CAD patients that excep-
tionally reported residual HTPR after ticagrelor or prasu-
grel initiation [8–13,34]. More importantly, the present
meta-analysis including 1822 patients with CAD disease
(mainly in the post-ACS setting) indicates that ticagrelor
significantly decreases the rate of patients with HTPR
during treatment as compared with prasugrel and may
further inhibit platelet reactivity. Indeed, the rate of
HTPR was six times lower in the ticagrelor group than in
the prasugrel group in the pooled principal analysis and
these results were consistent when restricting the analysis
to randomized trials. It should, however, be acknowl-
edged that the difference in HTPR definition across the
studies is a limitation of the present analysis.
It has been shown that the rate of HTPR may be highly
influenced by the definition and the technique used to assess
it [35,36]. In addition, some have suggested that the addi-
tional adenosine-like effect of ticagrelor may overestimate
the level of platelet reactivity inhibition as assessed by the
VASP test when compared with prasugrel and clopidogrel
[24,37,38]. Indeed, ticagrelor inhibits adenosine re-uptake by
Study or subgroup
Ticagrelor Prasugrel
Events
0 0273043
221334893
119224450102540
000
01
0
0
0
12 100
805 1017 100.0% 0.27 [0.14, 0.50]
0.13 [0.01, 2.30]3.00 [0.13, 70.30]
0.38 [0.11, 1.33]0.11 [0.01, 2.00]0.66 [0.25, 1.79]0.14 [0.03, 0.56]0.08 [0.01, 0.58]
0.33 [0.01, 7.87]0.33 [0.01, 7.78]0.04 [0.00, 0.67]0.20 [0.03, 1.47]
Not estimable
Not estimable
Not estimable
0.01 0.1 1
Ticagrelor Prasugrel
10 100
1
11
1210
13331448004 46
2510504451
268934865
221423024
3.7%
3.7%
3.7%4.6%8.5%
8.4%15.3%25.4%4.4%
4.4%
18.1%
0124
3
EventsTotal Total Weight
Risk ratio
M-H, Random, 95% Cl
Risk ratio
M-H, Random, 95% Cl
Alexopoulos CircCI 2012Alexopoulos DiabCare 2013Alexopoulos JACC 2012Alexopoulos TH 2014Angiolillo JACC 2014Deharo IJC 2013Deharo IJC 2014Dilliger IJC 2014Ibrahim Resuscit. 2014Laine Platelets 2014Laine TH 2014Lhermusier IJC 2014Parodi JACC 2013Perl JTT 2014
Total (95% Cl)
Total events
Test for overall effect: Z = 4.13 (P < 0.0001)
Heterogeneity: τ2 = 0.14; χ2 = 11.49, df = 10 (P = 0.32); I 2 = 13%
Fig. 2. Impact of ticagrelor and prasugrel on the rate of high on-treatment platelet reactivity (HTPR): principal pooled analysis. RR, risk ratio;
CI, confidence interval.
© 2015 International Society on Thrombosis and Haemostasis
938 G. Lemesle et al
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red blood cells and subsequently increases plasma adenosine
concentration, which could activate the A2 adenosine recep-
tor on platelets, increase cAMP levels and induce phosphor-
ylation of VASP by cAMP-dependent protein kinases [38].
In contrast, the VN assay may not be influenced by this
effect, as suggested by the results of Jeong and colleagues
[39]. Interestingly and as previously reported [35], the rate of
HTPR in the present meta-analysis was much higher in
studies that used the VASP test than in studies that used the
VN assay. This finding was, however, similarly observed
with both drugs: HTPR = 0.5% vs. 2.7% in the ticagrelor
group and 4.1% vs. 13.2% in the prasugrel group using the
VN assay and the VASP test, respectively. Importantly, the
results observed in the pooled principal analysis were shown
to be consistent in studies that used the VASP test and in
studies that used the VN assay.
Alexopoulos CircCI 2012 0 0
0
00
48
27 24 Not estimable0 30
43
489344501025
33
3042
48
44501025
65
93
0.33 [0.01, 7.87] 0.33 [0.01, 7.78] 0.20 [0.03, 1.47]
0.08 [0.01, 0.58] 0.11 [0.01, 2.00] 0.38 [0.11, 1.33]
3.00 [0.13, 70.30]
0.04 [0.00, 0.67]0.14 [0.03, 0.56]0.66 [0.25, 1.79]0.13 [0.01, 2.30]
0.27 [0.12, 0.60] 431403Total (95% CI) 100.0%
Not estimable
Not estimable
6.5%6.5%
6.5%
7.8%
16.1%
16.1%
40.5%
11
10
13
0
0
0
01
4143312
4022
119221
4651
268221
15.2%37.8%31.4%15.7%
0
0
42
6 37
1
1
3
Alexopoulos DiabCare 2013Alexopoulos JACC 2012Angiolillo JACC 2014Deharo IJC 2013Deharo IJC 2014Laine Platelets 2014Laine TH 2014Lhermusier IJC 2014Parodi JACC 2013
Total events
PerI JTT 2014
Dilliger IJC 2014Alexopoulos TH 2014
Ibrahim Resuscit. 2014
Study or subgroupTicagrelor Prasugrel Risk ratio
Events Total Events Total Weight M-H, Random, 95% CIRisk ratio
M-H, Random, 95% CI
Study or subgroupTicagrelor Prasugrel Risk ratio
Events Total Events Total Weight M-H, Random, 95% CIRisk ratio
M-H, Random, 95% CI
Heterogeneity: τ2 = 0.00; χ2 = 4.60, df = 6 (P = 0.60); I 2 = 0%Test for overall effect: Z = 3.19 (P = 0.001)
0.20 [0.05, 0.79] 586402Total (95% CI) 100.0%6 63Total events
Heterogeneity: τ2 = 1.03; χ2 = 7.03, df = 3 (P = 0.07); I 2 = 57%
Test for overall effect: Z = 2.29 (P = 0.02) 0.01 0.1 1
Ticagrelor Prasugrel
10 100
0.01 0.1 1
Ticagrelor Prasugrel
10010
A
B
Fig. 3. Impact of ticagrelor and prasugrel on the rate of high on-treatment platelet reactivity (HTPR). A: analysis restricted to randomized tri-
als. B: analysis restricted to registries. Abbreviations as in Fig. 2.
0 SE(log[RR])
0.5
1
1.5
20.01 0.1 1 10 100
RR
Fig. 4. Funnel plots of studies included in the principal pooled analysis. SE, standard error; RR, risk ratio.
© 2015 International Society on Thrombosis and Haemostasis
HTPR with ticagrelor vs. prasugrel 939
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In addition, because ticagrelor is an active drug by
itself and has a simple metabolism leading to the forma-
tion of an also active metabolite via CYP3A4 enzymes,
one would expect a faster onset of action as compared
with prasugrel. In the present meta-analysis, it is inter-
esting to note that results were consistent in studies that
tested the effect of the loading dose of the treatment
(between 12 and 24 h after the loading dose) and in
studies that tested the effect of the maintenance dose.
Indeed and even if not statistically significant, there was
a trend for less HTPR (three times less) after the load-
ing dose of ticagrelor: 4.5% vs. 13.2% (RR = 0.52
[0.25–1.05], P = 0.07). Our results also support the sug-
gestion that the maintenance dose of 90 mg twice a day
of ticagrelor provides a higher level of platelet reactivity
inhibition than the dose of 10 mg of prasugrel once a
day. However, it is impossible to definitely make conclu-
sions regarding the potentially shorter delay in onset of
action of ticagrelor compared with prasugrel because
only a few studies reported very early time-points after
treatment initiation (within first hours) and because both
drugs have usually reach their maximal efficacy 6 h after
the loading dose [12,13]. In the three studies that
reported early time-points in the literature (n = 215
patients altogether), no significant difference has been
observed between ticagrelor and prasugrel within the
first 6 h after treatment initiation, suggesting that both
treatments are equally rapid in reaching their maximal
activity.
To summarize, our results suggest that ticagrelor pro-
vides greater platelet inhibition than prasugrel. It should
nevertheless be emphasized that our results apply to the
doses of the two drugs used in the included studies. As
HTPR has been closely associated with poor outcomes
in the literature [1–7], our findings may be of interest in
clinical practice. However, further studies are required
before we can suggest that patients who experienced a
recurrent ischemic event on prasugrel may benefit from
the switch to ticagrelor. Indeed, HTPR remains a surro-
gate endpoint and it is very difficult to anticipate how
these results will translate to clinical events in practice:
one may speculate that ticagrelor may decrease the rate
of ischemic events but it could also be speculated that
ticagrelor may increase the risk of bleeding with no sig-
nificant benefit in terms of ischemic events as compared
with prasugrel. In keeping with the last statement, lower
on-treatment platelet reactivity has clearly been shown
to be associated with bleeding in the literature [1,40,41].
Finally and despite all their biological differences, both
treatments may also have similar benefit and risk pro-
files in terms of clinical events. Nevertheless, pending
the final results of the ISAR-REACT 5 trial (scheduled
for the end of 2018), which will compare the impact of
ticagrelor and prasugrel on clinical events in 4000
patients [42], these biological data may help physicians
in decision-making.
Conclusion
Despite the higher degree of inhibition of platelet reac-
tivity obtained as compared with clopidogrel, our results
suggest that some patients may still be low-responders
to ticagrelor and prasugrel. Our results also suggest that
ticagrelor allows a higher inhibition of platelet reactivity
as compared with prasugrel and leads to a further
decrease in the number of patients with HTPR. It
should nevertheless be emphasized that our results apply
to the doses of the two drugs used in the included stud-
ies. How these findings will translate into clinical prac-
tice remains uncertain regarding the benefit/risk ratio:
decreased risk of ischemic events vs. increased risk of
bleeding.
Addendum
All authors have actively contributed to the manuscript as
follows: G. Schurtz, C. Bauters, M. Hamon and G. Leme-
sle were responsible for the conception and design and the
analysis and interpretation of data. M. Hamon, C. Bauters
and G. Lemesle were responsible for drafting, or critically
revising, the manuscript. G. Lemesle gave final approval.
Disclosure of Conflict of Interests
G. Lemesle has received fees from Astra Zeneca, Daiichi
Sankyo and Lilly as a speaker and member of the advi-
sory board. The other authors state that they have no
conflict of interests.
Supporting Information
Additional Supporting Information may be found in the
online version of this article:
Fig. S1. Impact of ticagrelor and prasugrel on the rate of
high on-treatment platelet reactivity (HTPR). A: analysis
restricted to studies that used the vasodilator stimulated
phosphoprotein (VASP) test. B: analysis restricted to
studies that used the VerifyNow-P2Y12 (VN) assay. RR,
risk ratio; CI, confidence interval.
Fig. S2. Impact of ticagrelor and prasugrel on the rate of
high on-treatment platelet reactivity (HTPR). A: analysis
restricted to studies that tested the effect of the loading
dose (biological data available within 12–24 h after the
loading dose). B: analysis restricted to studies that tested
the effect of the maintenance dose (between 5 and
30 days after treatment initiation). RR, risk ratio; CI,
confidence interval.
Fig. S3. Impact of ticagrelor and prasugrel on the rate of
high on-treatment platelet reactivity (HTPR). Analysis
restricted to studies that included patients presenting with
STEMI, ST elevation myocardial infarction; RR, risk
ratio; CI, confidence interval.
© 2015 International Society on Thrombosis and Haemostasis
940 G. Lemesle et al
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