Ticagrelor Vs Prasugrel-Metaanalysis

Journal of Thrombosis and Haemostasis, 13: 931942
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DOI: 10.1111/jth.12907
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ORIGINAL ARTICLE
High on-treatment platelet reactivity with ticagrelor versus

prasugrel: a systematic review and meta-analysis
G . L E M E S L E , * G . S C H U R T Z , * C . B A U T E R S * and M . H A M O N
se
*Centre Hospitalier Regional et Universitaire de Lille; Inserm U744, Institut Pasteur de Lille; Faculte de Medecine de lUniversite de Lille,
Lille; Centre Hospitalier Universitaire de Caen; and Faculte de Medecine de Caen, Caen, France
review and meta-analysis. J Thromb Haemost 2015; 13: 93142.
Introduction
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There is a wide variability in inhibition of platelet reactivity after exposure to P2Y12 receptor inhibitors and high
on-treatment platelet reactivity (HTPR) has been associated with poor outcomes, especially with clopidogrel but
also with new antiplatelet agents [17]. 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 [813]. Importantly, these two drugs have also been shown to be superior for reduction of major cardiovascular and cerebral
events (MACCE) in the context of acute coronary syndrome (ACS) when compared with clopidogrel [14,15].
Consequently, these two drugs are now recommended as
the treatment of choice for ACS management in European and American guidelines [16,17].
Ticagrelor and prasugrel have, however, different mechanisms 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 cyclopenthyltriazolo-pyrimidine and a reversible antagonist of this receptor. 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 [8,1831]. 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).
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Summary. Background: Ticagrelor and prasugrel have

shown superiority over clopidogrel. However, it remains
unclear if one is superior to another regarding on-treatment 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 calculated by using a random-effects model with 95% confidence 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
[0.140.50]). The pre-specified analysis focusing on randomized trials (n = 10) showed consistent results
(RR = 0.27 [0.120.60]). 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.
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To cite this article: Lemesle G, Schurtz G, Bauters C, Hamon M. High on-treatment platelet reactivity with ticagrelor vs. prasugrel: a systematic
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Keywords: acute coronary syndrome; antiplatelet agents;

coronary
artery
disease;
percutaneous
coronary
intervention; platelet function tests.
Correspondence: Gilles Lemesle, Centre Hemodynamique et Unite

de Soins Intensifs de Cardiologie, H^
opital Cardiologique, Bd du Pr
Jules Leclercq, Centre Hospitalier Regional et Universitaire de Lille,
59037 Lille Cedex, France.
Tel: +33 320445301; fax: +33 320444898.
E-mail: gilles_lemesle@yahoo.fr
Methods
Study objectives
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
The primary objective of this systematic review and metaanalysis was to compare the impact of the two recently
932 G. Lemesle et al
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Data synthesis and statistical analysis
Pooled estimates were calculated by using a randomeffects 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 performed 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 standard 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.
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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 systematically 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.
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Search strategy
and type of CAD (stable CAD or ACS); relative timing

of HTPR assessment after treatment initiation; definitions
of HTPR; technical characteristics of the platelet reactivity 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) performed 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; minimization of selection bias with a clear description of
inclusion and exclusion criteria; description of the baseline characteristics of the cohort; completeness of the follow-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 characteristics, clinical course and treatment allocation. Disagreements were solved by consensus.
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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.
Study eligibility
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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 follow-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 ticagrelor [32].
Data extraction
The following information was extracted from each study:

first author; year of publication; period of patient inclusion; journal; type of comparison (randomized or not);
study population characteristics, including sample size,
number of patients, gender, mean age, diabetes mellitus
HTPR with ticagrelor vs. prasugrel 933
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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 assessment of the full-text was performed. We finally included
14 studies and excluded 17 others. The reasons for exclusion 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.
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Search results and study selection
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 maintenance 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 summarized 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 analyzed exclusively patients with stable CAD. Among the 13
other studies, which tested patients with ACS, the percentage of patients with STEMI varied between 23.3%
and 100%. There were four studies that focused on
STEMI patients exclusively.
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Results
Effect of ticagrelor and prasugrel on HTPR

Study and patient characteristics
The overall rate of HTPR was 6.1% in the present metaanalysis. As shown in Fig. 2, the rate of HTPR was significantly lower in the ticagrelor group as compared with
the prasugrel group: 1.5% vs. 9.8%, risk ratio
(RR) = 0.27 [0.140.50] (P < 0.0001). The analysis excluding 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
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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 studies, 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
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n = 434 articles identified
As
n = 403 articles excluded on the basis of title and abstract
n = 31 relevant studies
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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 data
n = 3 studies not reporting data on HTPR
n = 2 studies reporting animal data only
n = 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

Fig. 1. Flow chart of the study selection process.
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50/25/25
30/15/15
Randomized
Single blind
Monocenter
Crossover
Randomized
Single blind
Monocenter
Randomized
Open label
Monocenter
Randomized
Single blind
Monocenter
Crossover
Randomized
Open label
Monocenter
Randomized
Open label
Monocenter
Randomized
Open label
Multicenter
Alexopoulos
et al. (2012) [18]
Alexopoulos
et al. (2012) [20]
Parodi et al.
(2013) [29]
Alexopoulos
et al. (2013) [21]
Deharo et al.
(2013) [22]
Laine et al.
(2014) [26]
Angiolillo
et al. (2014)
[31]
er
110/35/75
Patients with
completed
biological
data 98/33/65
100/50/50
96/48/48
55/27/27
44/22/22
Design
Author (Year)
Number of
patients
Total/Ticagrelor/
Prasugrel
Ticagrelor 90 mg bid vs.

Prasugrel 10 od for 7 days
Ticagrelor 180 mg
then 90 mg bid
vs. Prasugrel 60 mg then 10
mg od for 30 days
Ticagrelor 180 mg vs.
Prasugrel 60 mg
Ticagrelor 90 mg bid
vs. Prasugrel
10 mg od for 15 days then
crossover for 15 days

Prasugrel 60 mg
VN and VASP at baseline,

2, 4, 24, 48 h and 7 days
VASP between 6 and

18 h after LD
VASP at 30 days
VN at the end of each

15-day period
VN at baseline, 2, 4, 8
and 12 h after LD
PRU > 208

PRI > 50%
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PRI > 50%
PRI > 50%
PRU > 230
PRU > 240
PRU > 208
PRU > 235
Definition
of HTPR used
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VN at Baseline, 1, 2, 6,
24 h and 5 days
VN at the end of
each 15-day period
Biological test used

and timing
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Ticagrelor 180 mg then
90 mg bid vs. Prasugrel
60 mg then 10 mg od
for 5 days
Ticagrelor 90 mg bid
vs. Prasugrel 10 mg
od for 15 days then
crossover for 15 days
Treatment tested
Table 1 Description of the studies included in the present meta-analysis. Biological test and definition of HTPR used
se
At 15 days
PRU 32.9 [95%CI 18.747.2] vs 101.3
[86.8115.7] P < 0.001
HTPR
0/43 = 0% vs. 1/42 = 2.4%
At 24 h
HTPR
0/26 = 0% vs. 1/24 = 4.2%
At 5 days
PRU 25.6 [95%CI 12.338.9]
vs. 50.3 [36.464.1] P = 0.01
HTPR
0/27 = 0% vs. 0/24 = 0%
At 2 h
PRU median 275 [quartiles 88305] vs. 217
[12279] P = 0.207
HTPR at 12 h
1/25 = 4% vs. 0/25 = 0%
At 15 days
PRU 45.2 [95%CI 27.463.1] vs. 80.8
[6398.7] P = 0.001
HTPR
0/30 = 0% vs. 1/30 = 3.3%
At 30 days
PRI 20.2 9.9% vs. 25.8 11.5% P = 0.01
HTPR
0/48 = 0% vs. 0/48 = %
Between 6 and 18 h
PRI 17.3 14.2% vs. 27.7 23.3% P = 0.009
HTPR
3/50 = 6% vs 8/50 = 16%
At 24 h
data not reported
At 7 days
PRU 47.9 47.6 vs. 95.6 54.1 P < 0.001
PRI 20.1 17.8% vs. 32.4 18.6% P = 0.004
HTPR
PRU 1/33 = 3% vs. 1/65 = 1.5%
PRI 1/33 = 3% vs. 10/65 = 15.3%
Results Ticagrelor vs. Prasugrel
Registry
Monocenter
No adjustment
Registry
Monocenter
Propensity
matching
Randomized
Open label
Monocenter
Registry
Monocenter
No adjustment
Randomized
Open label
Monocenter
Registry
Monocenter
No adjustment
Randomized
Open label
Monocenter
Ibrahim et al.
(2014) [25]
Alexopoulos et al.
(2014) [19]
Lhermusier et al.
(2014) [28]
Dillinger et al.
(2014) [24]
Deharo et al.
(2014) [23]
Perl et al.
(2014) [30]
Laine et al.
(2014) [27]
er
VN at 30 days
VASP at 24 h after LD
Biological test used

and timing

Prasugrel 60 mg
Ticagrelor 180 mg then 90

mg bid vs. Prasugrel 60
mg then 10 mg
od for 30 days
Ticagrelor 180 mg
then 90 mg
bid vs. Prasugrel 60 mg
then 10 mg od for 30 days
Ticagrelor 180 mg then

90 mg bid vs. Prasugrel
60 mg then 10 mg od
until discharge
Ticagrelor 90 mg bid vs.

Prasugrel 10 mg od
for 24 h
VASP between 6 and

12 h after LD
VN between 24 days
and at 30 days
VASP at 30 days
PRI > 50%
PRU > 208

PRI > 50%
PRU > 208
PRI > 50%
Definition
of HTPR used
PRI > 50%
PRU > 208
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PRI > 50%
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VASP before discharge

( at 4 days, no
exact timing)
VN and VASP at 4 and 24 h
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Ticagrelor 180 mg then 90 mg

bid vs. Prasugrel 60 mg
then 10 mg od for 30 days
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Prasugrel 60 mg
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114/52/62
Patients with
completed
biological data
at 30 days 86/40/46
88/44/44
186/93/93
387/119/268
20/10/10
512/278/234
Propensity
matched
442/221/221
164/22/51
Patient under
clopidogrel
(n = 91)
Treatment tested
Between 6 and 12 h
PRI 17 10.5% vs. 19.5 19.2% P = 0.5
HTPR
0/44 = 0% vs. 4/44 = 9.1%
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At 24 h
HT group: PRI 41.5 21 vs. 37.6 25
NT group: PRI 17.8 14.5 vs. 27 25.5
HTPR
HT 3/10 = 30% vs. 8/25 = 32%
NT 1/12 = 8% vs. 6/26 = 23%
Total 4/22 = 18.2% vs. 14/51 = 27.4%
At 30 days
PRU 33.3 [95%CI 29.337.3] vs.
84.6 [73.695.6] P < 0.001
HTPR
0/278 = 0% vs. 13/234 = 5.5%
Propensity matched
0/221 = 0% vs. 12/221 = 5.4%
At 24 h
PRI 4 [211] vs. 21 [1958]
PRU 9 [510] vs. 97 [41145]
HTPR
PRU 0/10 = 0% vs. 0/10 = 0%
No data for PRI
At discharge
PRI 14% [95%CI 923] vs. 25% [1438]
P < 0.0001
HTPR
2/119 = 1.7% vs. 33/268 = 12.3%
At 30 days
PRI 18.7 11.5% vs. 34 15.3%
HTPR
1/93 = 1.1% vs. 13/93 = 13.9%
At 30 days
PRU 21.1 26.1 vs. 67.3 62.5 P < 0.001
HTPR
0/40 = 0% vs. 4/46 = 8.7% 0.056
Results Ticagrelor vs. Prasugrel
Bid, bi-daily; od, once daily; LD, loading dose; VASP, vasodilator stimulated phosphoprotein; VN, VerifyNow-P2Y12; PRI, platelet reactivity index; PRU, platelet reactivity unit; HTPR, high
on-treatment platelet reactivity.
Design
Number of
patients
Total/Ticagrelor/
Prasugrel
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Author (Year)
Table 1 (Continued)
Table 2 Quality assessment of the studies included in the principal pooled analysis
Period of
inclusion
Control of
confounding
factors
Clear description
of inclusion/exclusion
criteria
Clear
definition
of the
primary
endpoint
Minimization of
selection bias
Design
Alexopoulos
et al. (2012) [18]
Randomized
Single blind
Monocenter
Crossover
Not reported
Adequate
Yes
Yes
Alexopoulos
et al. (2012) [20]
Randomized
Single blind
Monocenter
Randomized
Open label
Monocenter
Randomized
Single blind
Monocenter
Crossover
Randomized
Open label
Monocenter
Randomized
Open label
Monocenter
Randomized
Open label
Multicenter
Registry
Monocenter
No adjustment
Sept 2011 to
Apr 2012
Adequate
Yes
Yes
All patients with PCI

for ACS and
residual HTPR after
600 mg loading dose
of clopidogrel 24 h
after PCI
All patients with STEMI
Not reported
Adequate
Yes
Yes
June 2012 to
Sept 2012
Adequate
Yes
Yes
Mar 2013 to
June 2013
Adequate
No
Not reported
Adequate
Laine et al.
(2014) [26]
Angiolillo et al.
(2014) [31]
Ibrahim et al.
(2014) [25]
Registry
Monocenter
Propensity
matching
Not reported
Mar 2012 to
Oct 2013
All consecutive patients

with ACS
Yes
Yes
All patients with ACS and

diabetes
Adequate
Yes
Yes
Stable CAD patients
Poor
Yes
No
No
Yes
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)
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)
ACS within 4 h after 600 mg
loading dose of clopidogrel
and irrespective of platelet reactivity
after clopidogrel
Unclear, all consecutive
patients with ACS
Good
er
Randomized
Open label
Monocenter
Nov 2012 to
May 2013
Adequate
Yes
No
Registry
Monocenter
No adjustment
Randomized
Open label
Monocenter
Registry
Monocenter
No adjustment
Randomized
Open label
Monocenter
Not reported
Poor
Yes
No
Mar 2013 to
Dec 2013
Adequate
Yes
Yes
All consecutive patients with

PCI for ACS
Not reported
Poor
Yes
No
Unclear, all consecutive

patients with STEMI
Aug 2012 to
June 2013
Adequate
Yes
Yes
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nd
Lhermusier et al.
(2014) [28]
Dillinger et al.
(2014) [24]
Deharo et al.
(2014) [23]
Perl et al.
(2014) [30]
Laine et al.
(2014) [27]
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No
As
Alexopoulos
et al. (2014) [19]
Not reported
All patients with ACS

and Diabetes
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Deharo et al.
(2013) [22]
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Alexopoulos
et al. (2013) [21]
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Parodi et al.
(2013) [29]
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Author (Year)
PCI, percutaneous coronary intervention; ACS, acute coronary syndrome; STEMI, ST elevation myocardial infarction; HTPR, high on-treatment platelet reactivity.

Table 3 Description of the baseline characteristics of the populations of the different studies included in the principal pooled analysis
Type of patients
Mean
age (years)
Sex male
Diabetes
mellitus
59.6
84.1%
22.7%
STEMI = 43.2%
NSTEMI = 22.7%
UA = 34.1%
Stable angina = 0%
59.5
80%
9%
STEMI = 100%
NSTEMI = 0%
UA = 0%
Stable angina = 0%
STEMI = 100%
NSTEMI = 0%
UA = 0%
Stable angina = 0%
STEMI = 23.3%
NSTEMI = 36.7%
UA = 40%
Stable angina = 0%
No precision
44/22/22
Alexopoulos
et al. (2012) [20]
55/27/27
ACS only
HTPR after
600 mg
loading dose of
clopidogrel 24 h
after PCI
STEMI only
Parodi et al.
(2013) [29]
50/25/25
STEMI only
67
78%
18%
Alexopoulos et al.
(2013) [21]
30/15/15
ACS
Diabetics only
63.1
93.3%
100%
Deharo et al.
(2013) [22]
Laine et al.
(2014) [26]
96/48/48
ACS
60.8
81%
22%
100/50/50
ACS
Diabetics only
63.8
76%
100%
Angiolillo et
al. (2014) [31]
110/35/75
Ibrahim et al.
(2014) [25]
164/22/51
Patient under
clopidogrel (n = 91)
Alexopoulos et al.
(2014) [19]
512/278/234
Propensity
matched 442/221/221
Stable CAD
Under ticagrelor
for 3 to 5 days
Irrespective of
platelet reactivity
ACS
Hypothermia
(cardiac arrest) vs.
normothermia
(no cardiac arrest)
ACS
Lhermusier et al.
(2014) [28]
20/10/10
Deharo et al.
(2014) [23]
Perl et al.
(2014) [30]
Laine et al.
(2014) [27]
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72.4%
31.6%
61.5
82%
62%
No precision
59.6
84.1%
22%
ACS
After 600 mg
loading dose of
clopidogrel
Irrespective of
platelet reactivity
ACS
69.5
95%
30%
STEMI = 55.5%
NSTEMI = 25.8%
UA = 18.7%
Stable angina = 0%
STEMI = 0%
NSTEMI or UA = 100%
Stable angina = 0%
54
84.5%
20.4%
186/93/93
ACS
STEMI only
Not
reported
79.8%
Not reported
114/52/62
Not
reported
60
31.6%
88/44/44
STEMI only
56
87.5%
11.4%
er
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59.4
STEMI or NSTEMI = 81%

UA = 19%
Stable angina = 0%
STEMI = 0%
NSTEMI = 0%
UA = 0%
Stable angina = 100%
387/119/268
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nd
Dillinger et al.
(2014) [24]
en
Alexopoulos
et al. (2012) [18]
Clinical presentation
se
Number of patients
Total/Ticagrelor/Prasugrel
Author (Year)
STEMI = 28.9%
NSTEMI = 71.1%
UA = 0%
Stable angina = 0%
No precision
STEMI = 100%
NSTEMI = 0%
UA = 0%
Stable angina = 0%
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-treatment platelet reactivity; CAD, coronary artery disease; UA, unstable angina.
805
Total (95% Cl)
1017
100.0%
0.27 [0.14, 0.50]
Risk ratio
M-H, Random, 95% Cl
se
Risk ratio
Ticagrelor
Prasugrel
Events Total Events Total Weight M-H, Random, 95% Cl
24
Not estimable
0
27
0
0
1
30
3.7%
0.33 [0.01, 7.87]
30
3.7%
0
1
42
0.33 [0.01, 7.78]
43
4.6%
0
12
221
0.04 [0.00, 0.67]
221
8.5%
10
65
1
0.20 [0.03, 1.47]
33
0
48
0
Not estimable
48
1
8.4%
13
93
0.08 [0.01, 0.58]
93
2
15.3%
33
268
0.14 [0.03, 0.56]
119
4
25.4%
14
51
0.66 [0.25, 1.79]
22
4.4%
4
44
0
0.11 [0.01, 2.00]
44
3
18.1%
8
50
0.38 [0.11, 1.33]
50
0
10
0
Not estimable
10
0
25
1
3.7%
25
3.00 [0.13, 70.30]
4
46
4.4%
0
40
0.13 [0.01, 2.30]
en
Study or subgroup
Alexopoulos CircCI 2012
Alexopoulos DiabCare 2013
Alexopoulos JACC 2012
Alexopoulos TH 2014
Angiolillo JACC 2014
Deharo IJC 2013
Deharo IJC 2014
Dilliger IJC 2014
Ibrahim Resuscit. 2014
Laine Platelets 2014
Laine TH 2014
Lhermusier IJC 2014
Parodi JACC 2013
Perl JTT 2014
12
100
Total events
Heterogeneity: 2 = 0.14; 2 = 11.49, df = 10 (P = 0.32); I 2 = 13%
0.01
0.1
Ticagrelor
Li
c
Test for overall effect: Z = 4.13 (P < 0.0001)
10
100
Prasugrel
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.
The funnel plots (Fig. 4) including all studies did not

detect asymmetry along the treatment effect axis, indicating similar results in larger and smaller studies with unlikely publication bias.
U
nd
er
As
tra
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ca
HTPR was 1.5% in the ticagrelor group and 8.6% in

the prasugrel group (RR = 0.27 [0.120.60], 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 consistent 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 [0.130.56],
P = 0.0005). The rate of HTPR was 0.5% vs. 4.1%
(RR = 0.37 [0.091.52], 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 1224 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 [0.251.05], 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
[0.070.39], 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 prasugrel group (RR = 0.32 [0.042.49], 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).
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 exceptionally reported residual HTPR after ticagrelor or prasugrel initiation [813,34]. 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 acknowledged 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 additional 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
Ticagrelor
Prasugrel
Risk ratio
Events Total Events Total Weight M-H, Random, 95% CI
0
27
0
24
Not estimable
1
6.5%
0.33 [0.01, 7.87]
30
0
30
0
1
6.5%
0.33 [0.01, 7.78]
42
43
1
10
16.1%
65
0.20 [0.03, 1.47]
33
0
Not estimable
48
48
0
1
13
16.1%
93
0.08 [0.01, 0.58]
93
0
7.8%
0.11 [0.01, 2.00]
44
44
4
3
40.5%
0.38 [0.11, 1.33]
50
50
8
0
Not estimable
10
10
0
1
6.5%
3.00 [0.13, 70.30]
25
25
0
100.0%
0.27 [0.12, 0.60]
0.01
se
Total (95% CI)

403
431
Total events
6
37
Test for overall effect: Z = 3.19 (P = 0.001)
Risk ratio
M-H, Random, 95% CI
0.1
10
100
en
A
Study or subgroup
Alexopoulos CircCI 2012
Alexopoulos DiabCare 2013
Alexopoulos JACC 2012
Angiolillo JACC 2014
Deharo IJC 2013
Deharo IJC 2014
Laine Platelets 2014
Laine TH 2014
Lhermusier IJC 2014
Parodi JACC 2013
Ticagrelor Prasugrel
Weight
15.7%
31.4%
37.8%
15.2%
Total (95% CI)

402
586 100.0%
6
Total events
63
Test for overall effect: Z = 2.29 (P = 0.02)
Risk ratio
M-H, Random, 95% CI
0.04 [0.00, 0.67]
0.14 [0.03, 0.56]
0.66 [0.25, 1.79]
0.13 [0.01, 2.30]
Ze
ne
ca
Ticagrelor
Prasugrel
Events Total Events Total
0
221
12
221
2
119
33
268
4
22
14
51
0
40
4
46
Study or subgroup
Alexopoulos TH 2014
Dilliger IJC 2014
Ibrahim Resuscit. 2014
PerI JTT 2014
Risk ratio
M-H, Random, 95% CI
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0.20 [0.05, 0.79]
0.01
0.1
10
100
Ticagrelor Prasugrel
Fig. 3. Impact of ticagrelor and prasugrel on the rate of high on-treatment platelet reactivity (HTPR). A: analysis restricted to randomized trials. B: analysis restricted to registries. Abbreviations as in Fig. 2.
SE(log[RR])
tra
As
0.5
er
U
nd
1.5
2
0.01
RR
0.1
10
100
Fig. 4. Funnel plots of studies included in the principal pooled analysis. SE, standard error; RR, risk ratio.
red blood cells and subsequently increases plasma adenosine

concentration, which could activate the A2 adenosine receptor on platelets, increase cAMP levels and induce phosphorylation 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.
Conclusion
en
se
Despite the higher degree of inhibition of platelet reactivity 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 studies. How these findings will translate into clinical practice remains uncertain regarding the benefit/risk ratio:
decreased risk of ischemic events vs. increased risk of
bleeding.
Li
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Addendum
All authors have actively contributed to the manuscript as

follows: G. Schurtz, C. Bauters, M. Hamon and G. Lemesle 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.
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In addition, because ticagrelor is an active drug by

itself and has a simple metabolism leading to the formation 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 interesting 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 loading dose of ticagrelor: 4.5% vs. 13.2% (RR = 0.52
[0.251.05], P = 0.07). Our results also support the suggestion 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 conclusions 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 provides 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 [17], 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 surrogate 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 significant 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 profiles 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.
Disclosure of Conflict of Interests

G. Lemesle has received fees from Astra Zeneca, Daiichi
Sankyo and Lilly as a speaker and member of the advisory 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.
high on-treatment platelet reactivity (HTPR). A: analysis
restricted to studies that tested the effect of the loading
dose (biological data available within 1224 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.
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.
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Jouve B, Wittenberg O, Laine M, Michelet P, Bessereau J, Lemesle G, Dignat-George F, Paganelli F, Camoin-Jau L. Relationship between post-treatment platelet reactivity and ischemic and
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Ticagrelor Vs Prasugrel-Metaanalysis

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Ticagrelor Vs Prasugrel-Metaanalysis

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Journal of Thrombosis and Haemostasis, 13: 931942

This document has been supplied under an AstraZeneca License.

High on-treatment platelet reactivity with ticagrelor versus

review and meta-analysis. J Thromb Haemost 2015; 13: 93142.

Summary. Background: Ticagrelor and prasugrel have

Keywords: acute coronary syndrome; antiplatelet agents;

Correspondence: Gilles Lemesle, Centre Hemodynamique et Unite

Received 6 January 2015

Data synthesis and statistical analysis

The PubMed and Cochrane databases were searched for

and type of CAD (stable CAD or ACS); relative timing

introduced antiplatelet agents, ticagrelor and prasugrel,

Studies were eligible only if they compared ticagrelor and

The following information was extracted from each study:

2015 International Society on Thrombosis and Haemostasis

HTPR with ticagrelor vs. prasugrel 933

We found 434 citations in PubMed and other data

Search results and study selection

assessment of the effect of the loading dose was available

Effect of ticagrelor and prasugrel on HTPR

The final analysis included 1822 patients with CAD and

n = 434 articles identified

n = 403 articles excluded on the basis of title and abstract

retrieved for detailed assessment

n = 14 studies included in final analysis

Ticagrelor 90 mg bid vs.

Ticagrelor 180 mg vs.

VN and VASP at baseline,

VASP between 6 and

VN at the end of each

PRU > 208

PRI > 50%

PRI > 50%

PRU > 230

PRU > 240

PRU > 208

PRU > 235

Biological test used

Results Ticagrelor vs. Prasugrel

2015 International Society on Thrombosis and Haemostasis

2015 International Society on Thrombosis and Haemostasis

Biological test used

Ticagrelor 180 mg vs.

Ticagrelor 180 mg then 90

Ticagrelor 180 mg then

Ticagrelor 90 mg bid vs.

VASP between 6 and

PRI > 50%

PRU > 208

PRU > 208

PRI > 50%

PRI > 50%

PRU > 208

PRI > 50%

VASP before discharge

VN and VASP at 4 and 24 h

Ticagrelor 180 mg then 90 mg

Ticagrelor 180 mg vs.

Results Ticagrelor vs. Prasugrel

HTPR with ticagrelor vs. prasugrel 935

All patients with PCI

All patients with STEMI

All consecutive patients