Pharmacology

Administration of a Loading Dose Has No Additive Effect

on Platelet Aggregation During the Switch From Ongoing
Clopidogrel Treatment to Ticagrelor in Patients With Acute
Coronary Syndrome
Gianluca Caiazzo, MD, PhD*; Salvatore De Rosa, MD, PhD*; Daniele Torella, MD, PhD;
Carmen Spaccarotella, MD; Annalisa Mongiardo, MD; Salvatore Giampà, MD;
Mariella Micieli, PharmD, MD; Eleonora Palella, MD; Elio Gulletta, MD; Ciro Indolfi, MD

Background—Ticagrelor outperforms clopidogrel in preventing cardiovascular events in acute coronary syndrome. Despite
the inclusion of a loading dose in the Platelet Inhibition and Patient Outcomes (PLATO) trial for all patients randomized
to ticagrelor, it may not be necessary in patients receiving ongoing clopidogrel therapy. The aim of the present study
was to assess whether a ticagrelor loading dose is associated with a further platelet inhibition during the switch from
clopidogrel to ticagrelor in patients with acute coronary syndrome receiving ongoing antiplatelet treatment.
Methods and Results—Fifty patients with acute coronary syndrome receiving aspirin and clopidogrel treatment were
randomly assigned to a starting dose of ticagrelor (group 1, 90 mg; group 2, 180 mg). Platelet aggregation was measured
using multiple electrode aggregometry and standard light transmission aggregometry just before the switch and at 2,
6, 24, and 72 hours. No relevant difference in platelet aggregation was observed between the 2 study arms at baseline
(P=0.256). Residual platelet aggregation was significantly reduced in both arms 2 hours after the first administration
of ticagrelor (P<0.001 for both), with no difference in aggregation between groups (multiple electrode aggregometry,
17.6±7.2 versus 18.1±6 U; P=0.281). Similar results were observed with LTA.
Conclusions—Switching from clopidogrel to ticagrelor without a reloading dose is feasible, and it does not hinder platelet
aggregation inhibition in patients with acute coronary syndrome. Further prospective studies are needed to assess the
Downloaded from http://ahajournals.org by on July 17, 2021

clinical relevance of our findings.

Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT01795820.  
(Circ Cardiovasc Interv. 2014;7:104-112.)

Key Words: acute coronary syndrome ◼ platelet aggregation ◼ ticagrelor

D ual antiplatelet therapy is a cornerstone for the man-

agement of patients with acute coronary syndrome
(ACS).1 Recently, new and more powerful alternative anti-
platelet agents have been introduced into clinical practice.2,3
Among them, in the Platelet Inhibition and Patient Outcomes
(PLATO) trial, ticagrelor was found to be significantly more
effective than clopidogrel in preventing cardiovascular events
in patients with ACS (number needed to treat =53). However,
in the same study, treatment with ticagrelor was associated
with a higher incidence of nonprocedural-related bleedings
(number needed to harm =143).
The administration of a loading dose was scheduled in all
patients randomized to ticagrelor in the PLATO trial, indepen-
dent of any ongoing antiplatelet regimen, even those receiving
ongoing clopidogrel therapy. Currently, no direct evidence is
available on the need for a reload dose when switching from
an ongoing clopidogrel to a ticagrelor antiplatelet regimen. A
ticagrelor loading dose could be unnecessary for maintaining a
constant level of platelet inhibition in patients already receiv-
ing clopidogrel therapy. Thus, in the present study, we sought
to assess whether the administration of a ticagrelor loading
dose provides further inhibition of platelet aggregation during
the switch from ongoing clopidogrel–aspirin to ticagrelor–
aspirin double antiplatelet therapy in patients with ACS.
Methods
The Administration of a Loading Dose Has No Additive Effect on
Platelet Aggregation During the Switch From Ongoing Clopidogrel

Received May 4, 2013; accepted December 22, 2013.

From the Division of Cardiology, Department of Medical and Surgical Sciences (G.C., S.D.R., D.T., C.S., A.M., S.G., M.M., C.I.) and Clinical Pathology
Unit, Department of Health Sciences (E.P., E.G.), Magna Graecia University of Catanzaro, Catanzaro, Italy; and URT-CNR, Department of Medicine,
Consiglio Nazionale delle Ricerche, Catanzaro, Italy (C.I.).
*Drs Caiazzo and De Rosa contributed equally to this work.
The Data Supplement is available at http://circinterventions.ahajournals.org/lookup/suppl/doi:10.1161/CIRCINTERVENTIONS.113.000512/-/DC1.
Correspondence to Ciro Indolfi, MD, Department of Medical and Surgical Sciences, URT Consiglio Nazionale delle Ricerche (CNR), Magna Graecia
University, Catanzaro 88100, Italy. E-mail indolfi@unicz.it
© 2014 American Heart Association, Inc.
Circ Cardiovasc Interv is available at http://circinterventions.ahajournals.org DOI: 10.1161/CIRCINTERVENTIONS.113.000512

104

What Is Known
• Ticagrelor had higher efficacy on clinical end points
when compared with clopidogrel in patients with
acute coronary syndrome in the Platelet Inhibition
and Patient Outcomes (PLATO) trial.
• In the PLATO trial, the switch from ongoing clopi-
dogrel therapy to ticagrelor was performed with the
administration of a ticagrelor loading dose.
• It is unknown whether the administration of a ti-
cagrelor loading dose is essential during the thera-
peutic switch from ongoing dual antiplatelet therapy,
including clopidogrel to ticagrelor.
What the Study Adds
• Avoidance of the ticagrelor loading dose at the
switch from ongoing clopidogrel does not signifi-
cantly influence the level of platelet aggregation in
patients with acute coronary syndrome.
• These results may be of practical interest for the
management of high bleeding-risk patients, such as
older patients or those with chronic kidney disease,
encountered in the daily clinical routine.
Treatment to Ticagrelor in Patients With Acute Coronary Syndrome
(SHIFT-OVER) study is a randomized, single-blinded, single-­center
trial. Consecutive patients diagnosed with ACS, and who were re-
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ceiving clopidogrel treatment, were screened. All suitable patients
who accepted to participate provided written informed consent and
were randomly assigned to either a ticagrelor 90 mg (no loading dose,
group 1) plus 90 mg bis in die (maintenance) or a 180 mg (loading
dose, group 2) plus 90 mg bis in die (maintenance) in addition to as-
pirin treatment. None of the enrolled patients were actively receiving
oral anticoagulation therapy; all patients were treated with a load-
ing dose of aspirin (500 mg) at the moment of the acute event and
were then administered aspirin (100 mg) once a day as a maintenance
dose. The evening dose of ticagrelor was administered to all patients
randomized in the SHIFT-OVER study starting on the day the thera-
peutic shift was performed. A high maintenance dose of clopidogrel
(150 mg/die) was not allowed in the present study. The time from the
initiation of clopidogrel to the therapeutic shift to ticagrelor, as well
as the time interval from the index event to the shift to ticagrelor, was
registered and reported (mean±SD).
All patients starting ticagrelor treatment during the study pro-
tocol continued to receive dual antiplatelet treatment with aspirin
and ticagrelor beyond the end of the study and up to months after
the acute event, according to the current treatment guidelines for
ACS.4,5 Random allocation of patients was performed on the basis
of a concealed randomization table that was previously generated
using Research Randomizer (http://www.randomizer.org/form.htm).
The study protocol was approved by the local institutional Ethics
Committee. The trial protocol is registered within ClinicalTrials.gov.
Platelet aggregation was measured using point-of-care mul-
tiple electrode aggregometry (MEA; Dynabyte Medical, Munich,
Germany) at multiple time-points (just before the first administra-
tion of ticagrelor and at 2, 6, 24, and 72 hours after the therapeutic
switch to ticagrelor). Platelet aggregation was additionally mea-
sured at baseline and at 2 and 24 hours after the therapeutic switch
using traditional light transmission aggregometry (LTA; AggRAM
Analyzer System; Helena Laboratories Inc, Beaumont, TX) to verify
the reproducibility of the results. The 24- and 72-hour measurements
were performed in the morning, just before the administration of the
morning ticagrelor dose. Hence, the time between the last ticagrelor
Caiazzo et al   SHIFT-OVER Study   105
maintenance dose and the platelet function test was 12 hours for these
measurements. The following exclusion criteria were applied: age
<18 and >80 years, percutaneous coronary intervention in the previ-
ous 6 months, ongoing ticagrelor, prasugrel or ticlopidine therapy,
contraindication to ticagrelor therapy, reloading with clopidogrel
after the initial loading dose, administration of glycoprotein IIb/IIIa
inhibitors until 6 days before the treatment randomization, resistance
to clopidogrel, concomitant neoplastic or immune-mediated patholo-
gies, liver cirrhosis, severe pulmonary pathologies, hemorrhagic dia-
thesis, previous stroke, actual pregnancy, ongoing pharmacological
treatment with p450 cytochrome inhibitors until 15 days before the
randomization, thrombocytopenia, or anemia (hemoglobin, <10 g/
dL). The inclusion/exclusion criteria used in the SHIFT-OVER study
are listed in the Table I in the Data Supplement.
The primary end point of the SHIFT-OVER study was the difference
in residual platelet aggregation levels, as determined by MEA, 2 hours
after the therapeutic shift from clopidogrel to ticagrelor between the
2 study arms (loading dose and no loading dose groups). Secondary
study end points included platelet aggregation results across all time-­
points and the occurrence of clinical events within 30 days.
Blood Sampling
Blood samples were obtained through venous puncture. All
blood samples were analyzed after a resting phase of 30 minutes.
Hemoglobin levels, hematocrit values, platelet counts, and white
blood cell counts were measured in 2.7-mL tubes containing 1.6
mg EDTA/mL blood. For MEA, blood samples were collected in
3-mL hirudin tubes (Verum Diagnostica GmbH, Munich, Germany),
whereas LTA blood samples were collected in 0.35-mL sodium ci-
trate (3.8%) Vacutainer Blood Collection Tubes (Becton; Dickinson
and Company, Franklin Lakes, NJ).
Assays for Platelet Function
Point-of-Care Whole Blood MEA
Whole blood platelet aggregometry was performed using a Multiplate
platelet analyzer, which provides 2 independent measuring units, each
consisting of 2 conductive wires. During analysis, the sample–reagent
mixture is automatically stirred using a discardable PTFE-coated mag-
netic stirrer (800 U/min). The instrument continuously measures the
change in resistance, which is proportional to the amount of platelets
adhering to the electrodes and transforms it to arbitrary aggregation
units (AU); these values are plotted against time (min), and the area
under the aggregation curve (AUC=AU×min) is calculated from the
mean values of the 2 curves. To simplify the numbers, AU×min were fi-
nally converted to units (U), where 10 AU×min correspond to 1 U (U).
ΔU indicates the difference between aggregation levels measured at T0
(before the first administration of ticagrelor) and T2 (2 hours after the
first ticagrelor administration). The result was considered acceptable
when the difference between the 2 curves is <20%. Briefly, 300 μL of
saline were added to whole blood at 37°C. After a 3-minute incuba-
tion, 20 μL of the selected agonist solution was added to obtain a final
concentration of 0.5 mmol/L arachidonic acid (ASPITEST; Dynabyte,
Munich, Germany), 6.4 μmol/L ADP (ADP-Test; Dynabyte), or 32
μmol/L thrombin receptor-activating peptide (TRAP-Test; Dynabyte).
Light Transmission Aggregometry
Platelet aggregation was also measured by LTA using the AggRAM
Analyzer System. To avoid trauma, blood samples were collected in
0.35-mL sodium citrate (3.8%) Vacutainer Blood Collection Tubes.
Platelets were prepared according to a standard procedure.6 Briefly,
samples were centrifuged for 15 minutes at 1000 RPM to obtain
platelet-­rich plasma. Platelet-poor plasma was obtained via further cen-
trifugation for 10 minutes at 3500 RPM, and it was used as blank refer-
ence. Platelet aggregation was evaluated using 450 μL of platelet-rich
plasma after stimulation with 20 mmol/L ADP (Helena BioSciences
Europe, Tyne and Wear, United Kingdom). All measurements were ob-
tained within 2 hours of sample collection, and the results are reported
as maximal aggregation. Δ represents the mean difference between the
aggregation levels measured at T0 (before the first administration of
ticagrelor) and T2 (2 hours after the first ticagrelor administration).
 106  Circ Cardiovasc Interv  February 2014

Bleeding Assessment and Classification Table 1.  Patient Baseline Characteristics

Bleeding events were classified according the Bleeding Academic
Group 1 Group 2
Research Consortium classification. Briefly, bleedings were consid-
(No Loading Dose) (Loading Dose)
ered minor if classified as type 1 to type 2, and they were considered
major if classified as type 3 to type 5.7 N=25 N=25 P Value
Age, y 61±9 62±10 0.725
Statistical Methods Men, % 88 83 0.641
Continuous variables are presented as the mean±SD unless other- Hypertension 13 (52%) 14 (56%) 0.897
wise noted. Categorical variables were compared using the χ2 test.
­One-way ANOVA testing was used to compare approximately normal Dyslipidemia 5 (20%) 11(44%) 0.069
distributed variables. Lin concordance correlation was used to com- Diabetes mellitus 6 (24%) 10 (40%) 0.263
pare results from MEA and LTA. The Mann–Whitney U test was used
Current smokers 12 (48%) 6 (24%) 0.077
to compare between 2 groups with non-normally distributed vari-
ables. The Wilcoxon rank test was used to compare paired groups. On Previous MI 3 (12%) 4 (16%) 0.726
the basis of previously published platelet aggregation results, we de- Previous stroke 0 0 …
termined that a sample size of 24 subjects for each group was needed
to achieve 80% power and to detect a 20% difference in aggregation Left ventricle ejection 48±8 51±6 0.217
levels between the experimental groups, with a type I error of 5%.8–10 fraction, %
To account for patients who, despite being randomly assigned to 1 Creatinine, mg/dL 0.8±0.2 0.9±0.2 0.225
group, could change the treatment group for any reason, we added 1 hsTrop T peak, μg/L 1.9±2.8 2.6±4.2 0.638
additional subject to each group, resulting in a final sample size of 25
subjects per experimental group. CK peak, UI/L 1761±4053 908±1492 0.341
Because platelet aggregation was repeatedly measured within the Hemoglobin, g/dL 14.2±1.3 14.3±1.1 0.809
same subjects, a repeated measure fixed effects model was used to
Hematocrit, % 43.2±3.5 41.7±8.7 0.448
account for time-correlation and modified treatments over time in the
primary analysis. In this model, MEA aggregation levels were used as Platelet count, ×103/μL 220±23 233±84 0.576
the within-subject factor, and 5 time-points were considered (0, 2, 6, NT-pro-BNP, pg/mL 1880±2014 762±965 0.225
24, and 72 hours). The treatment group (loading dose versus no load-
ing dose) was selected as the between-subjects factor. All additional Unstable angina 3 (12%) 3 (12%) 0.999
variables were treated as covariates. The Mauchly test was used to NSTEMI 10 (40%) 13 (52%) 0.395
measure the assumption of sphericity, whereas multivariate tests were STEMI 12 (48%) 9 (36%) 0.390
conducted using the Pillai trace test and further validated with the fol-
lowing additional tests: Wilks lambda, Hotelling trace, and Roy larg- CK indicates creatine phosphokinase; hsTrop T, high sensitivity T troponin;
est root. The same statistical analyses were applied to the LTA results. MI, myocardial infarction; NSTEMI, non–ST-segment–elevation myocardial
infarction; and NT-pro-BNP, N-terminal-pro-brain natriuretic peptide.
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Statistical significance was assumed at P<0.05. All statistical analy-

ses were performed using SPSS software (version 20.0; Chicago, IL).
In this study, 21 patients presented a ST-segment–elevation
Results myocardial infarction, 23 presented a non–ST-segment–
elevation myocardial infarction, and 6 presented an unstable
Patient Population
angina (Table 1).
A total of 50 patients were consecutively randomized in a 1:1
fashion to either group 1 (switch to ticagrelor [90 mg BID] Platelet Aggregation Analysis
without loading dose) or group 2 (switch to ticagrelor [180 Platelet aggregation was evaluated using 2 different tech-
mg] with loading dose). No statistically significant differences niques: whole blood MEA and traditional LTA. We observed
were observed in demographic variables, baseline routine lab- a significant concordance between the ADP-induced
oratory variables, or medications between the 2 study arms aggregometry obtained with the MEA (ADP-MEA) and
(Tables 1 and 2).
In addition, mean platelet count at baseline was similar Table 2.  Baseline Medical Therapy
between the 2 study arms (220±73×103/μL in group 1 versus
233±84×103/μL in group 2; P=0.576). Group 1 Group 2
(No Loading Dose) (Loading Dose)
The mean time from the index event to enrollment was of
N=25 N=25 P Value
115±151 hours, and the time interval for which patients were
on clopidogrel therapy before switching to ticagrelor was ASA 25 (100%) 25 (100%) …
110±147 hours. Clopidogrel 25 (100%) 25 (100%) …
The mean time from the last maintenance dose of clopido- ACE-inhibitors 18 (72%) 22 (87.5%) 0.178
grel to the first platelet function test (the baseline T0 evalu- β-blockers 17 (68%) 15 (60.9%) 0.606
ation) was 22±4.9 hours. The time from the last ticagrelor Ca-antagonists 2 (8%) 5 (20%) 0.199
maintenance dose and the 24- and 72-hour platelet function Statins 21 (83.3%) 20 (79.2%) 0.712
tests was 12 hours because the tests were performed just before
GP IIb/IIIa inhibitors 0 0 …
the administration of the morning ticagrelor dose, as described
in the protocol. Diuretics 1 (4%) 3 (12.5%) 0.277
Of the 50 randomized patients, 48 underwent coronary Insulin 1 (4%) 2 (8.3%) 0.527
revascularization (45 percutaneous coronary intervention Oral antidiabetics 4 (16%) 5 (20%) 0.662
and 3 coronary artery bypass grafting) and 2 patients did not ACE indicates angiotensin-converting enzyme; ASA, aspirin; and GP IIb/IIIa,
receive any revascularization. glycoprotein IIb/IIIa.
 Caiazzo et al   SHIFT-OVER Study   107

that measured with LTA (ADP-LTA; r=0.40; Lin coefficient, Table 3.  Results of Platelet Aggregation by MEA and LTA
0.014) at baseline. Tests at Different Time-Points
Results of platelet aggregation test for both MEA and LTA Group 1 Group 2
are displayed in Figure 1 and Table 3. No relevant difference (No Loading Dose) (Loading Dose)
in platelet aggregation was observed between the 2 study arms N=25 N=25 P Value
at baseline, as determined by MEA (34.4±12.9 U in group 1 Platelet aggregation with MEA, U
versus 41.7±20 U in group 2; P=0.256) or LTA (24±17% in
 ADP T0 34.4±1.3 41.7±2 0.256
group 1 versus 25±14% in group 2; P=0.535).
 ADP T2 17.6±7.2 18.1±6 0.281
Residual platelet aggregation was significantly reduced in
both arms 2 hours after the first administration of ticagrelor  ADP T6 15±5.3 14.6±6 0.756
(ΔU 16.8±11; P<0.001 in group 1 and ΔU 23.6±19.9; P<0.001  ADP T24 17.4±1 18.8±5.6 0.165
in group 2), as determined using MEA. Similar results were  ADP T72 19.1±8.1 (n=20) 22.9±6.1 (n=17) 0.117
obtained with LTA (Δ 15±15%; P<0.001 in group 1 and Δ Platelet aggregation with LTA, %
16±14%; P<0.001 in group 2). Interestingly, no difference was  MAX T0 24±17 25±14 (n=24) 0.535
observed in residual platelet aggregation after the therapeutic  MAX T2 9±4 9±3 0.698
switch to ticagrelor between group 1 (no ticagrelor loading
 MAX T24 9±4 9±3 0.600
dose) and group 2 (ticagrelor loading dose). Indeed, residual
platelet aggregation 2 hours after the switch to ticagrelor was LTA indicates light transmission aggregometry; MAX, maximal platelet
aggregation; and MEA, multiple electrode aggregometry.
17.6±7.2 U in group 1 versus 18.1±6 U in group 2 (P=0.281)
using MEA and 9±4% in group 1 versus 9±3% in group 2
(P=0.698) using LTA. Similar levels of residual platelet aggre- were 17.4±10.5 U in group 1 versus 18.8±5.6 U in group 2
gation were observed throughout the time course of the study. (P=0.165) using MEA and 9±4% in group 1 versus 9±3% in
In particular, residual platelet aggregation at 6 hours was group 2 (P=0.600) using LTA. The same trend was maintained
15±5.3 U in group 1 versus 14.6±6 U in group 2 (P=0.756) at 72 hours after the shift to ticagrelor because residual plate-
using MEA. Similarly, residual aggregation levels at 24 hours let aggregation was 19.1±8.1 U in group 1 versus 22.9±6.1 U
in group 2 using MEA (P=0.117).
Because platelet aggregation was repeatedly measured in
ADP-induced PLT-aggregation the same subjects, statistical analysis was performed using
80 a repeated-measures ANOVA. This analysis confirmed that
no load
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the study treatment (loading dose versus no loading dose)

Platelet Aggregation

load
60 had no effect on platelet aggregation. In addition, neither the
time interval from initiation of clopidogrel administration to
U (MEA)

40 the shift to ticagrelor nor pretreatment aggregation level had

any statistically significant effect (P>0.05 for all variables;
20 Table 4). Notably, the assumption of sphericity was met at
the Mauchly test of sphericity, and the results were consis-
0 tent across 4 different test used (Pillai trace, Wilks lambda,
Hotelling trace, and Roy largest root).
e

h
2h

6h
in

24

72

In addition, the same analysis was repeated after the addi-

el
as
B

Time Course tion of the following covariates: time interval from the acute
event to shift to ticagrelor, presence of hypertension, and pres-
ADP-induced PLT-aggregation ence of diabetes mellitus. These additional analyses provided
50
similar results, confirming that these covariates did not influ-
no load ence the study outcome (Table 5).
Max Aggregation (%)

40 load The same repeated-measures analysis was performed

for LTA results, confirming that the study treatment (load-
30
ing dose versus no loading dose) did not influence platelet
(LTA)

20 aggregation, as measured using LTA. In addition, neither the

10 Table 4.  Repeated-Measures ANOVA: Model 1

0 Effect Size Estimate

F (Partial η2) P Value
2h
e

h
in

24

MEA 0.781 0.072 0.514

el
as
B

Time Course MEA×study group 0.822 0.076 0.492

Figure 1. Aggregation curves measured by multielectrode (MEA) MEA×ADP pre-shift 0.475 0.045 0.702
and light transmission aggregometry (LTA). No relevant differ- MEA×time from clopidogrel to shift 2.646 0.209 0.067
ence was observed in platelet (PLT) aggregation between the 2
MEA×time from event to shift 2.663 0.210 0.066
study arms at any time point during this study (top). The same
results were obtained using MEA or LTA (bottom). MEA indicates multiple electrode aggregometry.
 108  Circ Cardiovasc Interv  February 2014

time interval from initiation of clopidogrel administration Table 6.  Repeated-Measures ANOVA: LTA Results
to the shift to ticagrelor nor pretreatment aggregation level
Effect Size Estimate
had a statistically significant effect (P>0.05 for all variables; F (Partial η2) P Value
Table 6). Because the assumption of sphericity was not met
LTA 0.115 0.003 0.737
using the Mauchly test of sphericity, the statistics were recal-
culated after adjusting the degrees of freedom of the F test LTA×study group 0.173 0.004 0.680
by means of the following 3 methods: the lower-bound test, LTA×baseline aggregation 0.213 0.005 0.647
the Greenhouse–Geisser test, and the Huynh–Feldt test. These LTA×time from clopidogrel to shift 0.012 <0.001 0.914
corrections provided similar results, confirming that there was LTA×time from event to shift 0.008 <0.001 0.931
no influence on the study outcome (P>0.05 for all analyses). LTA indicates light transmission aggregometry.
Furthermore, there was no evidence of nonlinear effects.
In line with previous reports, baseline platelet aggregation
Accordingly, receiver operating curve analysis revealed that
was slightly higher in patients with diabetes mellitus when
residual platelet aggregation was unable to identify patients
compared with those with non–diabetes mellitus (41.4±16.5
who had received a loading dose of ticagrelor (Figure 3) at
U versus 36.5±17.3 U) although this difference was not sta-
either 2 hours after the first administration (AUC, 0.589;
tistically significant (P=0.253). Accordingly, the time course
P=0.282 for MEA and AUC, 0.468; P=0.698 for LTA) or after
of platelet aggregation in the subgroup with diabetes mellitus
24 hours (AUC, 0.614; P=0.165 for MEA and AUC, 0.543;
displayed a similar trend to that of the general study popula-
P=0.600 for LTA). No significant difference in residual plate-
tion (Table 7; Figure 2), confirming that ticagrelor maintains
let aggregation was observed between men and women at
its efficiency in inhibiting platelet aggregation in patients with
baseline (P=0.685), as well as 2 hours (P=0.122) and 24 hours
diabetes mellitus. Repeated-measures ANOVA confirmed that
after the switch (P=0.375), as measured using MEA. Similar
the study treatment (loading dose versus no loading dose)
results were confirmed using LTA.
did not influence platelet aggregation. Moreover, neither the
time interval from initiation of clopidogrel administration
to the shift to ticagrelor nor pretreatment aggregation levels
Differences in Platelet Aggregation Depend on
had a statistically significant effect (P>0.05 for all variables;
P2Y12 Inhibition
To confirm that the observed results were related to P2Y12
Table 8). Similar results were found using LTA. However,
inhibition and not to other platelet anomalies, we measured
because the assumption of sphericity was not met in the latter
TRAP-2–induced platelet aggregation. There was no differ-
case using the Mauchly test of sphericity, the statistics were
ence in TRAP-2–induced platelet aggregation between the 2
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recalculated after adjusting the degrees of freedom of the F

study arms throughout the course of the study. In fact, residual
test, as described above (Table 9).
TRAP-2–induced platelet aggregation was 95.2±23.8 U in
No statistically significant differences were observed after
group 1 versus 92.7±20.1 U in group 2 at baseline (P=0.900),
comparing the platelet aggregation results between the 2 treat-
89.3±27 U in group 1 versus 75.1±26.8 U in group 2 at 2
ment groups (ticagrelor loading versus no loading) within the
hours (P=0.091), 88.8±79.2 U in group 1 versus 79.1±31.4
3 subgroups (ST-segment–elevation myocardial infarction,
U in group 2 at 6 hours (P=0.204), 82.8±26.8 U in group 1
non–ST-segment–elevation myocardial infarction, or unstable
versus 84.2±22.3 U in group 2 at 24 hours (P=0.555), and
angina; Table 10), with the exception of the 72-hour platelet
95.3±25.1 U in group 1 versus 94.4±20.2 U in group 2 at 72
function test by MEA. However, this difference was not con-
hours (P=0.987). Arachidonic acid–induced platelet aggrega-
firmed by repeated-measures analysis (P>0.05).
tion was measured as an internal control (Table 11).
Next, we performed a multivariate analysis to test for pre-
dictors of ticagrelor response at 72 hours, including age, sex,
Table 7.  Results of Platelet Aggregation in Patients With
body mass index, diabetes mellitus, hypertension, smoking, Diabetes Mellitus
creatinine, and administration of a ticagrelor loading dose.
Interestingly, hypertension was the only independent predic- Group 1 Group 2
tor of the response to ticagrelor (P=0.002). (No Loading Dose) (Loading Dose)
N=6 N=10 P Value
Platelet aggregation with MEA, U
Table 5.  Repeated-Measures ANOVA: Model 2
 ADP T0 41.2±14.9 41.4±18.3 >0.999
Effect Size Estimate  ADP T2 20.2±8.4 17.7±3.2 0.958
F (Partial η2) P Value
 ADP T6 14.6±5.8 16.6±5.5 0.875
MEA 0.770 0.076 0.521  ADP T24 14.4±7.3 21.3±6.1 0.118
MEA×study group 0.804 0.079 0.502  ADP T72 17.8±4 (n=4) 22.6±7 (n=8) 0.073
MEA×ADP pre-shift 0.470 0.048 0.706 Platelet aggregation with LTA, %
MEA×time from clopidogrel to shift 2.829 0.233 0.057  MAX T0 29±16 26±12 (n=9) 0.776
MEA×time from event to shift 2.843 0.233 0.056  MAX T2 10±3 8±2 0.093
MEA×hypertension 0.390 0.040 0.761  MAX T24 11±5 11±3 0.875
MEA×diabetes mellitus 0.076 0.008 0.972 LTA indicates light transmission aggregometry; MAX, maximal platelet
MEA indicates multiple electrode aggregometry. aggregation; and MEA, multiple electrode aggregometry.
 Caiazzo et al   SHIFT-OVER Study   109

ADP-induced PLT-aggregation Table 9.  Repeated-Measures ANOVA: Patients With Diabetes

(Diabetics subgroup) Mellitus (With LTA)
80
no load Effect Size Estimate
F (Partial η2) P Value
Platelet Aggregation

load
60
LTA 3.492 0.259 0.091
U (MEA)

40
LTA×study group 0.509 0.048 0.492
LTA×baseline platelet aggregation 2.285 0.186 0.162
20 LTA×time from clopidogrel to shift 0.132 0.013 0.724
LTA×time from event to shift 0.129 0.013 0.727
0
LTA indicates light transmission aggregometry.
2h

6h

h
e
in

24

72
el

One additional patient was readmitted beyond the 30-day

as
B

Time Course observational period for a planned coronary revascularization

(coronary artery bypass grafting), which was successfully per-
ADP-induced PLT-aggregation
(Diabetics subgroup) formed without procedural complications. Importantly, no major
bleedings were observed in either group. Few minor bleedings
50
were reported within 30 days (n=9), but there was no statisti-
no load cally significant difference between the groups (P=0.064). The
Max Aggregation (%)

40 load observed minor bleedings included epistaxis in 2 patients, gin-

gival bleeding in 2 patients, minor subcutaneous ecchymosis in
30
3 patients, slight hematuria in 1 patient, and small blood loss
(LTA)

20 from preexisting hemorrhoids in 1 patient. Spontaneous resolu-

tion was observed in all the reported cases, and no interruption or
10 modification of dual antiplatelet therapy was necessary. Table 12
displays a complete list of all 30-day clinical events.
0

Discussion
2h

h
e
in

24
el
as

The major finding of this randomized, single-blinded study

B
Downloaded from http://ahajournals.org by on July 17, 2021

Time Course
Figure 2. Aggregation curves measured by multielectrode (MEA)
and light transmission aggregometry (LTA) in patients with dia-
betes mellitus. Baseline platelet (PLT) aggregation was slightly
higher in patients with diabetes mellitus when compared with
those with non–diabetes mellitus, and a time course of platelet
aggregation in the subgroup with diabetes mellitus displayed a
similar trend as was observed in the general study population.
Clinical Events at 30-Day Follow-Up
Clinical follow-up at 30 days after the switch from clopidogrel
to ticagrelor was available for 48 of the 50 enrolled patients. No
deaths nor strokes were reported during the follow-up period.
A total of 2 patients underwent a new hospitalization within
30 days of the shift to ticagrelor. Among these, 1 patient was
referred to the hospital by the general practitioner because of
the onset of atrial fibrillation; he was successfully cardioverted
to sinus rhythm and discharged the day after. One patient was
hospitalized for a planned cardiovascular rehabilitation program.
Table 8.  Repeated-Measures ANOVA: Patients With Diabetes
Mellitus (With MEA)
Effect Size Estimate
F (Partial η2)
MEA 3.541
MEA×study group 1.503
MEA×ADP pre-shift 4.590
MEA×time from clopidogrel to shift 4.659
MEA×time from event to shift 4.643
MEA indicates multiple electrode aggregometry.
was that the therapeutic switch from ongoing clopidogrel to
ticagrelor treatment without the administration of a loading
dose of ticagrelor seems to be safe and yields a similar level
of residual platelet aggregation when compared with patients
who received a ticagrelor loading dose.
Our results are based on the point-of-care MEA test, and tra-
ditional LTA was performed at baseline and after 2 and 24 hours
as a methodological control. All results were obtained in a pop-
ulation of patients with ACS, the only clinical setting in which
ticagrelor treatment is currently approved.4,5 Our results have
important clinical implications for the management of anti-
platelet therapy in patients with ACS. Indeed, at present, a load-
ing dose of ticagrelor is administered in most centers because
all patients enrolled in the large PLATO trial received a loading
dose of the new drug, regardless of the previous antiplatelet reg-
imen.2 However, there is no direct evidence supporting the need
to reload patients when switching from an ongoing clopidogrel
to the ticagrelor antiplatelet regimen. This study is the first to
address whether a loading dose should be administered when
switching from ongoing clopidogrel to ticagrelor treatment. In
particular, avoiding the administration of the loading dose of
P ticagrelor could limit bleeding events, especially during the crit-
Value ical periprocedural phase, in which the patient is already treated
0.680 0.104 with several anticoagulants and antiplatelet agents. In fact, in-
depth analysis of the results from PLATO revealed that a higher
0.474 0.321
number of bleeding events were reported within 30 days in the
0.734 0.067
ticagrelor-treatment group (2.45%; 229 bleeding events) when
0.737 0.065 compared with that in the comparator group (2.0%; 186 bleed-
0.736 0.067 ing events) although this difference was not statistically signifi-
cant. In fact, even after adjusting for several baseline variables,
 110  Circ Cardiovasc Interv  February 2014

Table 10.  Results of Platelet Aggregation by MEA and LTA Tests in Patients With UA, NSTEMI, and STEMI at Different Time-Points
UA NSTEMI STEMI
Group 1 (No Load) Group 2 (Load) Group 1 (No Load) Group 2 (Load) Group 1 (No Load) Group 2 (Load) P Value*
N=3 N=3 N=10 N=13 N=12 N=9 (Intergroup)
Platelet aggregation with MEA, U
 ADP T0 306±47.8 278±93 329.2±138.2 447.9±201.3 365.2±139.4 420±219.2 0.506
 ADP T2 232.3±100.3 198.3±61.6 154.3±65.6 191.8±70.9 179.2±68.8 159.9±39.6 0.446
 ADP T6 130.3±73.9 177±58.5 134.2±26.5 134.4±53.5 167.4±63 152.7±71.6 0.328
 ADP T24 193±127.1 189.7±8,6 139.9±40.2 188.5±55,6 197.6±134.6 186.4±68,7 0.618
 ADP T72 205 (n=1) 185.3±21.7 139.2±55.6 (n=8) 201.5±57.6 (n=6) 227.5±81.9 (n=11) 265.9±54.2 (n=8) 0.006
Platelet aggregation with LTA, %
 MAX T0 18.1±8.1 24±15.1 21.9±11.4 23.4±14.9 (n=12) 27.6±22.2 28.4±12.3 0.705
 MAX T2 14.1±8.3 7.6±0.4 8.9±2.9 8.6±3.8 8.7±3.9 9.5±3.4 0.737
 MAX T24 8.4±0.9 9.4±3.3 9.4±4.1 9.3±4.2 9.4±4.3 9.5±2.4 0.975
LTA indicates light transmission aggregometry; MAX, maximal platelet aggregation; MEA, multiple electrode aggregometry; NSTEMI, non–ST-segment–elevation
myocardial infarction; and UA, unstable angina.
*Indicates the statistical results of the comparison between the diagnosis groups (UA, NSTEMI, STEMI).

a clear trend toward a higher rate of non–coronary artery bypass
grafting-related major bleeding in ticagrelor-treatment arm was
evident within the first 30 days of treatment (hazard ratio, 1.23;
95% confidence interval, 0.98–1.54; P=0.073). The lack of a
statistically significant difference can be explained by the over-
all low bleeding event rate registered in PLATO. In fact, despite
the large number of patients enrolled in the PLATO trial, this
comparison was grossly underpowered (power, ≈60%). In addi-
tion, in the same study, ticagrelor was associated with a sig-
Downloaded from http://ahajournals.org by on July 17, 2021
comparable between the 2 groups, and these values were
maintained throughout the time course, up to 72 hours after
the switch. Moreover, a consensual reduction in TRAP-2–
induced aggregation was observed at 2 hours, confirming the
high efficacy of the antiplatelet action of ticagrelor.
The therapeutic switch from ongoing clopidogrel treatment to
a newer, more efficient antiplatelet agent was recently addressed
for prasugrel in 2 independent studies.12,13 In the SWitching Anti
Platelet (SWAP) study, although a similar level of platelet inhi-

nificant increase in non–coronary artery bypass grafting-related
major or minor bleeding during the first 30 days (5.11 versus
4.02%; hazard ratio, 1.28; 95% confidence interval, 1.10–1.501;
P=0.002); the latter comparison being significant with a higher
statistical power (power, ≈95%).2,11
Interestingly, in the present study, residual platelet aggre-
gation 2 hours after the first ticagrelor administration was
bition was observed in the 2 study arms after 7 days of mainte-
nance treatment, more pronounced inhibition was achieved at 2
hours and up to 7 days in patients who received a 60-mg prasu-
grel loading dose at therapeutic switch.12 Similarly, Lhermusier
et al13 observed significantly higher inhibition of platelet aggre-
gation in patients who received a loading dose. Moreover, they
found that a half-dose (30 mg) of prasugrel reload was sufficient

PLT-aggregation 2h after the switch PLT-aggregation 24h after the switch

1.0 1.0

0.8 0.8
Sensitivity
Sensitivity

0.6 0.6
MEA at 2h MEA at 24h
(ADP-induced) (ADP-induced)
AUC=0.589 AUC=0.614
0.4 p=0.282 0.4 p=0.165

LTA at 2h LTA at 24h

0.2 (ADP-induced) 0.2 (ADP-induced)
AUC=0.468 AUC=0.543
p=0.698 p=0.600
0.0 0.0
0.0 0.2 0.4 0.6 0.8 1.0 0.0 0.2 0.4 0.6 0.8 1.0

1 - Specificity 1 - Specificity
Figure 3. Receiver operating curves (ROC) for the identification of patients who received a loading dose. ROC analysis revealed that resid-
ual platelet (PLT) aggregation cannot identify patients who received a loading dose of ticagrelor at either 2 (left) or 24 hours (right) after the
first administration. AUC indicates area under the curve; LTA, light transmission aggregometry; and MEA, multielectrode aggregometry.
 Caiazzo et al   SHIFT-OVER Study   111

Table 11.  Results of Platelet Aggregation (ASPI×Test) concomitant bleeding risk. Of note, the rate of minor bleedings
registered in the present study is higher than that was reported
Platelet Aggregation Group 1 Group 2
With MEA, U N=25 N=25 P Value in the PLATO trial. However, this finding could be explained
by several mechanisms. First, this study used a different bleed-
ASPI T0 21.1±21.3 (n=22) 15.9±6.6 (n=17) 0.799
ing classification. In fact, several events were classified as minor
ASPI T2 14.2±18.5 (n=21) 9.8±7.3 (n=17) 0.394 bleedings in the SHIFT-OVER study, even those that did not
ASPI T6 12.1±11.7 (n=21) 9.8±6.2 (n=17) 0.988 require medical intervention by a healthcare professional. In
ASPI T24 10.4±6.9 (n=21) 11.1±5.8 (n=17) 0.692 contrast, such events were listed as minimal bleedings in the
ASPI T72 13.2±10.4 (n=17) 15±7.5 (n=13) 0.464 PLATO trial. Moreover, the present study enrolled a higher risk
ASPI indicates arachidonic acid–induced platelet aggregation; and MEA, patient group from a real-world population, which consequently
multiple electrode aggregometry. had a higher bleeding risk, when compared with the PLATO
trial. In fact, we registered a higher prevalence of diabetes mel-
litus in our study when compared with that in the PLATO trial
to obtain a similar level of platelet inhibition as the full load-
(33% versus 25%), and our study encompassed a large majority
ing dose (60 mg). In addition, in A Comparison of Prasugrel
of male patients (85% versus 72% in the PLATO).
at PCI or Time of Diagnosis of Non-ST–Elevation Myocardial
Notably, the baseline level of ADP-induced aggregation
Infarction (ACCOAST) trial, which compared a split loading
was low in this present study, which is not surprising given the
dose of prasugrel (30 mg immediately after non–ST-segment–
high variability of platelet aggregation levels reported in dif-
elevation myocardial infarction diagnosis and 30 mg at the time
of percutaneous coronary intervention) versus a single 60-mg ferent studies; this finding could be because of several reasons,
bolus administration at percutaneous coronary intervention, such as different patient baseline characteristics, concomitant
pretreatment with prasugrel did not reduce the rate of major medications, and treatment adherence. An additional source
ischemic events ≤30 days, but it increased the rate of major of variation is the methodological set up for platelet aggre-
bleeding complications.14 gation analysis. This last point is not trivial because minimal
Our findings demonstrate that the administration of a load- protocol variations may have major influences on test results.
ing dose of ticagrelor has virtually no additive effect on plate- Nevertheless, the baseline platelet aggregation observed in
let aggregation or the onset of drug action in patients with ACS our study is comparable with several other studies in patients
who were responders to dual antiplatelet therapy with aspirin with ACS, with some authors reporting even lower mean ADP-­
and clopidogrel. In fact, the same reduction in platelet aggre- induced platelet aggregation in response to clopidogrel treat-
gation was achieved within 2 hours in both groups, indepen- ment.8 Furthermore, Storey et al16 reported a 35±17% platelet
Downloaded from http://ahajournals.org by on July 17, 2021

dently of the administration of a ticagrelor loading dose. The inhibition with ongoing clopidogrel treatment. Such small dif-
latter point is important because a faster inhibition of platelet ferences can be explained by different patient baseline charac-
aggregation could be of pathophysiological relevance in the teristics between the studies. Nonetheless, the baseline levels
acute setting of coronary disease. Supporting this hypothesis, of platelet aggregation measured in this study did not affect
high on-treatment residual platelet reactivity is correlated with the comparison between the 2 treatment arms. Interestingly,
a substantial increase in the rate of clinical events, up to an a significant and early reduction in platelet aggregation after
absolute risk increase of 5.9%.15 administration of the first ticagrelor dose was evident, whereas
The excellent efficacy of ticagrelor is associated with a good aggregation levels at 2 hours correspond to those found in simi-
safety profile. Evaluating the net clinical benefit of ticagrelor lar studies with P2Y12 antagonists, as determined by both at
versus clopidogrel, taking into account the bleeding rate, yields LTA and MEA.9 Notably, after correcting platelet aggregation
a 3:1 likelihood of being helped versus harmed in the PLATO to baseline levels, no significant difference in platelet aggrega-
in favor of ticagrelor.2 Nevertheless, the higher incidence of tion was observed between groups 1 and 2 at any time point
nonprocedure-related bleedings associated with ticagrelor when (P=0.58 at 2 hours; P=0.61 at 6 hours; P=0.95 at 24 hours;
compared with the less effective thienopyridine clopidogrel P=0.24 at 72 hours). Accordingly, the addition of baseline
(number needed to harm, 143) creates the need to reduce the aggregation levels as a covariate to the repeated-­ measures
ANOVA model confirmed that baseline aggregation levels did
not influence downstream platelet aggregation levels (P>0.05).
Table 12.  Clinical Events at 30-Day Follow-Up
In conclusion, this study demonstrates for the first time
Group 1 Group 2 that the administration of a loading dose of ticagrelor has no
(No Loading Dose) (Loading Dose) additive effect on platelet aggregation in patients with ACS
N=24 N=24 P Value receiving ongoing treatment with clopidogrel when switching
Death 0 0 … to the more effective antiplatelet agent, ticagrelor. These find-
MI 0 0 … ings generate the intriguing hypothesis that avoiding the load-
Stroke 0 0 … ing dose of ticagrelor when switching the P2Y12 antiplatelet
agent in clopidogrel-treated patients could be associated with
Major bleedings 0 0 …
a reduction in the incidence of bleeding complications, without
Minor bleedings 7 (29%) 2 (8.3%) 0.064
affecting the efficacy profile of ticagrelor. If confirmed in future
Hospitalizations 0 2 <0.001 studies using clinical end points, this novel therapeutic schema
Interruption/modification of DAPT 0 0 … would improve patient safety while maintaining the significant
DAPT indicates dual antiplatelet therapy; and MI, myocardial infarction. efficacy of ticagrelor for reduction of cardiovascular events.
 112  Circ Cardiovasc Interv  February 2014
Limitations
This study was based on laboratory end points, and therefore,
it was not powered to assess clinical efficacy, including clini-
cally relevant bleeding events. However, although no serious
adverse events were registered in our study (ie, no major
bleeding events occurred within the 30-days follow-up), larger
trials are required to confirm this finding, which should be
adequately sized to evaluate appropriate clinical end points.
The LTA and MEA results in our study were not well corre-
lated, even though a certain degree of concordance was pres-
ent. This result is likely related to the higher methodological
variability of LTA. In fact, LTA requires skilled personnel
and lacks standardization among laboratories, making it dif-
ficult to use as a diagnostic method and causing inconsistent
results. Not surprisingly, agreement between different platelet
aggregation assays is low.17 In contrast, MEA does not require
time-consuming centrifugation steps, and it does not require
large sample volumes and lengthy processing time, which also
account for the high variability of LTA.18 For these reasons,
we selected MEA for our primary analysis because it strongly
reduces many potential disadvantages of LTA; LTA was only
performed at baseline, as well as 2 and 24 hours after the ther-
apeutic switch as a methodological control.
Because the present study was based on an instrumental
end point, namely the platelet aggregation test, we excluded
clopidogrel-­resistant patients. The main aim of this study was
to verify that no adjunctive loading dose is necessary to main-
tain an adequate level of platelet inhibition. Of course, the
exclusion of clopidogrel-resistant patients from the study rep-
Downloaded from http://ahajournals.org by on July 17, 2021
resents a potential limitation for the clinical application of our
findings because few centers systematically test their patients
for resistance to clopidogrel.
Acknowledgments
We thank Dr Augustin Kelava from the Eberhard Karls Universität
Tübingen for expert statistical advice.
Sources of Funding
This study was partly supported by a grant of the Italian Ministry
of Education, University and Research (MIUR): PON 01_02833
Cardiotech.
Disclosures
Dr Caiazzo received speaker’s honoraria from Astra Zeneca. Dr
Indolfi received research and educational grants from Astra Zeneca.
The other authors report no conflicts.
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