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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info:doi/10.1111/jth.12907

info:doi/10.1111/jth.12907

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Text Box

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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.


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.


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%



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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.



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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.



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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


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.



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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


10 100

0.01 0.1 1


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.



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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.


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.


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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Ticagrelor vs Prasugrel-Metaanalysis