Efficacy of Clopidogrel Reloading in Patients With Acute Coronary

Syndrome Undergoing Percutaneous Coronary Intervention During

Chronic Clopidogrel Therapy (from the Antiplatelet therapy
for Reduction of MYocardial Damage during Angioplasty
[ARMYDA-8 RELOAD-ACS] Trial)
Giuseppe Patti, MDa,*, Vincenzo Pasceri, MDb, Fabio Mangiacapra, MDa, Giuseppe Colonna, MDc,
Vincenzo Vizzi, MDa, Elisabetta Ricottini, MDa, Antonio Montinaro, MDc, Andrea D’Ambrosio, MDa,
William Wijns, MDd, Emanuele Barbato, MDd, and Germano Di Sciascio, MDa,
on behalf of the ARMYDA-8 RELOAD-ACS Investigators

Whether an additional clopidogrel load in patients receiving chronic clopidogrel therapy

and undergoing percutaneous coronary intervention (PCI) for acute coronary syndrome
(ACS) is associated with clinical benefit has not been well characterized. The aim of the
present study was to evaluate, in a randomized protocol, the safety and effectiveness of
clopidogrel reload for patients with ACS undergoing PCI in the background of chronic
clopidogrel therapy. A total of 242 patients with noneST-segment elevation ACS with
>10 days of clopidogrel therapy randomly received a 600-mg loading dose of clopidogrel
4 to 8 hours before PCI (n [ 122) or placebo (n [ 120). The primary end point was the
30-day incidence of major adverse cardiac events (death, myocardial infarction, target
vessel revascularization). The primary end point occurred in 4.1% of patients in the reload
arm versus 14.1% in the placebo arm (odds ratio 0.26, 95% confidence interval 0.10 to 0.73,
p [ 0.013). This benefit in the reload arm was mainly from the prevention of periproce-
dural myocardial infarction (4.1% vs 13%, p [ 0.02) and was paralleled by lower peri-
procedural platelet reactivity. The aggregometry data were consistent with the clinical
outcome. No difference was found in the bleeding outcomes between the 2 groups. In
conclusion, the results from the Antiplatelet therapy for Reduction of MYocardial Damage
during Angioplasty (ARMYDA-8 RELOAD-ACS) trial have shown a significant clinical
benefit from reloading patients with ACS receiving chronic clopidogrel therapy before PCI.
These data might be relevant in clinical practice, given the large number of patients with
ACS who are still currently treated with clopidogrel during PCI. Ó 2013 Elsevier Inc. All
rights reserved. (Am J Cardiol 2013;-:-e-)

The prevalence of patients undergoing percutaneous
coronary intervention (PCI) receiving chronic clopidogrel
therapy is relatively high, owing to previous drug-eluting
stent implantation, acute coronary syndrome (ACS) during
the preceding year, or staged PCI procedures. An interindi-
vidual variability in the clopidogrel response has been largely
demonstrated, and patients with low drug responsiveness
have a poorer outcome after PCI.1e3 Previous studies have
shown that an additional 600-mg clopidogrel loading dose in
patients receiving chronic therapy is associated with addi-
tional inhibition of residual platelet reactivity and a reduction
a
Department of Cardiovascular Sciences, Campus Bio-Medico
University of Rome, Rome, Italy; bInterventional Cardiology Unit, San
Filippo Neri Hospital, Rome, Italy; cInterventional Cardiology Unit, Vito
Fazzi Hospital, Lecce, Italy; and dCardiovascular Center, OLV Hospital,
Aalst, Belgium. Manuscript received December 21, 2012; revised manu-
script received and accepted March 6, 2013.
See page 6 for disclosure information.
*Corresponding author: Tel: (þ39) 06-22-541-1612; fax: 06-22-541-1638.
E-mail address: g.patti@unicampus.it (G. Patti).
of nonresponders.4 However, whether this pharmacodynamic
benefit translates into improvement in the clinical outcomes
has not been definitely characterized.5 A clinical benefit from
an additional loading dose with 600 mg clopidogrel in
patients with ACS undergoing PCI while receiving chronic
clopidogrel therapy was demonstrated in the prespecified
subgroup analysis of the randomized Antiplatelet therapy for
Reduction of MYocardial Damage during Angioplasty
(ARMYDA-4 RELOAD) trial,6 but this was not observed in
a more recent, nonrandomized, retrospective investigation.7
Thus, given those discrepancies, we designed a specific,
prospective, randomized trial to evaluate the effectiveness
and safety of a strategy of a 600-mg clopidogrel reload dose
in patients with ACS undergoing PCI while receiving chronic
clopidogrel therapy. The Clinicaltrials.gov number was
2011-005449-11.
Methods
The ARMYDA-8 RELOAD-ACS trial was a multicenter,
unfunded, randomized, double-blind, clinical trial per-
formed at 4 institutions (Campus Bio-Medico University of

0002-9149/13/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. www.ajconline.org
http://dx.doi.org/10.1016/j.amjcard.2013.03.008
2 The American Journal of Cardiology (www.ajconline.org)

ARMYDA-8 RELOAD-ACS: Study design

Figure 1. Design of ARMYDA-8 RELOAD-ACS trial. MI ¼ myocardial infarction; NSTE ¼ noneST-segment elevation; TVR ¼ target vessel
revascularization.

Rome, Rome, Italy; Vito Fazzi Hospital, Lecce, Italy; San
Filippo Neri Hospital, Rome, Italy; and OLV Hospital,
Aalst, Belgium).
By protocol, patients were eligible if they were receiving
chronic (>10 days) therapy with clopidogrel (75 mg/day) and
had noneST-segment elevation ACS. NoneST-segment
elevation ACS was defined as symptoms of coronary
ischemia <24 hours before hospital admission and 1 of
the following findings: troponin or creatine kinase-MB
(CK-MB) values greater than the upper limit of normal, or
new ST-segment depression >0.1 mV, or transient ST-
segment elevation (<30 minutes) >0.1 mV in 2 contiguous
leads. Excluded were the patients undergoing primary PCI for
ST-segment elevation acute myocardial infarction, with
a platelet count <70  109/L, coronary bypass grafting in the
previous 3 months, chronic warfarin therapy, bleeding
diathesis, or major bleeding for <4 weeks. The design of the
study is illustrated in Figure 1. A total of 271 patients ful-
filling the enrollment criteria were randomized 4 to 8 hours
before diagnostic angiography to receive an additional
600-mg clopidogrel loading dose (n ¼ 136) or placebo
(n ¼ 135). The eligible patients were assigned to the alloca-
tion arm using an electronic spreadsheet indicating the group
assignment by random number. Randomization blocks were
created and distributed to all centers; in each center, the
investigators involved in the process of the randomization
assignment were not involved in performing PCI or
the follow-up evaluations. After coronary angiography,
29 patients (14 in the reload arm and 15 in the placebo arm)
without an indication for PCI were excluded from the present
study (19 were treated medically and 10 underwent bypass
surgery). Thus, a total of 242 patients receiving “ad hoc” PCI
immediately after coronary angiography were enrolled and
represent the study population. Of these 242 patients, 122
were randomized to the 600-mg clopidogrel reloading dose
and 120 to placebo. The physicians performing PCI were not
aware of the randomization allocation.
All interventions were performed using a standard tech-
nique. Glycoprotein IIb/IIIa inhibitors were used at the
operator’s discretion in both arms. All patients were taking
aspirin at PCI. After the procedure, they received aspirin
(100 mg/day) indefinitely. Clopidogrel was continued
(75 mg/day) for 12 months, irrespective of the randomiza-
tion assignment.
Blood samples were drawn before intervention and 6 and
24 hours after PCI to measure the CK-MB and troponin I
 Coronary Artery Disease/Clopidogrel Reloading in Patients With ACS 3

Table 1 Table 2
Main clinical features Procedural features
Variable Clopidogrel Placebo p Value Variable Clopidogrel Placebo p
Reload (n ¼ 122) (n ¼ 120) Reload (n ¼ 120) Value
(n ¼ 122)
Age (yrs) 66  11 66  12 1
Men 94 (77) 84 (70) 0.2 Femoral access 122 (100) 120 (100) 1
Diabetes mellitus 33 (27) 37 (31) 0.6 Coronary vessel treated 131 (100) 144 (100) e
Systemic hypertension* 86 (70) 95 (79) 0.1 Left main 1 (0.5) 2 (1.5) 1
Hypercholesterolemia† 82 (67) 76 (63) 0.6 Left descending artery 56 (43) 66 (46) 0.6
Current smoker 31 (25) 32 (27) 0.9 Left circumflex 34 (26) 35 (24) 0.8
BMI (kg/m2) 24.1  4.2 24.8  4.3 0.2 Right 39 (30) 38 (26) 0.6
Previous MI 23 (19) 36 (30) 0.052 Saphenous vein graft 1 (0.5) 2 (1.5) 1
Previous PCI 29 (24) 44 (37) 0.036 Left internal mammary graft 0 1 (1) 1
Previous coronary bypass 6 (5) 9 (7) 0.4 Restenotic lesion 10 (8) 13 (11) 0.5
Unstable angina pectoris 44 (36) 48 (40) 0.6 Lesion type B2/C 82 (67) 76 (63) 0.6
NSTEMI 78 (64) 72 (60) 0.6 Chronic total occlusion (>3 mo) 3 (2) 3 (2) 1
LVEF (%) 57  9 56  9 0.4 Multivessel coronary intervention 17 (14) 22 (18) 0.4
Multivessel coronary artery 53 (43) 55 (46) 0.8 Type of intervention
disease Balloon only 6 (5) 6 (5) 1
Blood creatinine (mg/dl) 0.94  0.23 0.99  0.3 0.15 Stent 116 (95) 114 (95) 1
Therapy Bifurcation with kissing balloon 7 (6) 5 (4) 0.8
Aspirin 122 (100) 120 (100) 1 Stents per patient (n) 1.3  0.8 1.3  0.9 1
Statins 110 (90) 102 (85) 0.2 Stent diameter (mm) 2.9  0.9 2.9  0.9 1
PPIs 67 (55) 77 (64) 0.18 Total stent length (mm) 16.5  6 16  6 0.5
b Blockers 59 (48) 63 (52) 0.5 Use of drug-eluting stent 57 (47) 52 (43) 0.6
ACE inhibitors 79 (65) 69 (57) 0.3 Direct stenting 49 (40) 42 (35) 0.4
Predilation (n) 1.3  1.7 1.5  2 0.4
Data are presented as n (%) or mean  SD. Stent deployment pressure (atm) 12  4 12  4 1
ACE ¼ angiotensin-converting enzyme; BMI ¼ body mass index; Duration of stent deployment (s) 21  8 21  9 1
LVEF ¼ left ventricular ejection fraction; MI ¼ myocardial infarction; Total myocardial ischemia >120 s 23 (19) 25 (21) 0.7
NSTEMI ¼ noneST-segment elevation myocardial infarction; PPI ¼ proton Use of postdilation 3 (2) 4 (3) 0.7
pump inhibitor. Antithrombin regimen during
* Arterial pressure >160/90 mmHg. intervention
†
Total cholesterol >200 mg/dl. Bivalirudin 13 (11) 7 (6) 0.2
Unfractionated heparin 109 (89) 113 (94) 0.3
Use of GPIIb/IIIa inhibitors 14 (11) 19 (16) 0.3
(mass) values. Additional determinations were performed, if (provisional)
clinically indicated. The measurements of CK-MB were Data are presented as n (%) or mean  SD.
obtained using the Access 2 Immunochemiluminometric GP ¼ glycoprotein.
assay (Beckman Coulter, Fullerton, California). The normal
limits were 3.6 ng/ml for CK-MB and 0.06 ng/ml for
troponin I. Patients treated at Campus Bio-Medico Univer- The primary end point of the ARMYDA-8 RELOAD-
sity received platelet reactivity evaluation at baseline (4 to ACS trial was the 30-day incidence of major adverse cardiac
8 hours before intervention), in the catheterization labora- events (MACE; death, myocardial infarction, target vessel
tory immediately before PCI and 6 and 24 hours after PCI revascularization). Periprocedural myocardial infarction was
using the VerifyNow P2Y12 assay (Accumetrics, San defined according to the pre-PCI clinical presentation. For
Diego, California). VerifyNow P2Y12 is a rapid, cartridge- patients with normal baseline CK-MB levels (i.e., under-
based assay specifically measuring the direct effects of going angioplasty for unstable angina), it was defined as
clopidogrel on the platelet P2Y12 receptor.8,9 The postintervention increases in CK-MB >3  99th percentile
measurement results are expressed as P2Y12 reaction units of the upper limit of normal.10 In patients with noneST-
(PRU); the lower the PRU value, the greater the degree of segment elevation myocardial infarction (i.e., elevated
P2Y12 receptor inhibition by clopidogrel, and vice versa. baseline CK-MB levels), a subsequent elevation of 50% of
Patients treated with glycoprotein IIb/IIIa inhibitors were the baseline CK-MB value was applied to detect peri-
excluded from the VerifyNow analysis, because these drugs procedural myocardial infarction.11 Target vessel revascu-
interfere with the PRU measurements.9,10 larization included bypass surgery and repeat PCI of the
Clinical follow-up data were obtained at 30 days by target vessels.
office visits for all study patients. The physicians evaluating The secondary end points were as follows: (1) the
the patients during these follow-up visits were not aware of occurrence of vascular or bleeding complications, including
the randomization assignment. Each patient gave informed major bleeding (intracranial bleeding or clinically overt
consent for participation in the study. The institutional bleeding associated with a decrease in hemoglobin >5 g/dl,
review board of the Campus Bio-Medico University according to the Thrombolysis In Myocardial infarction
approved the study. The trial was not supported by any criteria12), minor bleeding (clinically overt hemorrhage
external source of funding. associated with a decrease in hemoglobin of 5 g/dl), and
4 The American Journal of Cardiology (www.ajconline.org)

ARMYDA-8 RELOAD-ACS: Primary end-point

600 mg Clopidogrel reload

Placebo

18
18 P=0.012 14.1 15 13.3

% of patients
15
% of patients

12
12
9
9
4.1 6
6 4.1

3 3 0.8
0 0
Death MI TVR
Composite primary end-point
Individual components
30-day MACE
Figure 2. Incidence of the primary end point in the 2 arms. MI ¼ myocardial infarction; TVR ¼ target vessel revascularization.

ARMYDA-8 RELOAD-ACS study

0 1 3 6 9 12

OR (95% CI) P

0.10 (0.01-0.73) 0.024

6.9 (0.88-54.9) 0.06

4.4 (1.2-15.9) 0.025

2.5 (0.91-6.7) 0.07

0.26 (0.10-0.73) 0.013

Figure 3. Multivariate analysis. CAD ¼ coronary artery disease; PPI ¼ proton pump inhibitors.

entry-site complications (hematoma >10 cm, pseudoaneur-
ysm or arteriovenous fistula), and (2) the evaluation of
periprocedural platelet reactivity at different points in the
2 treatment arms using the VerifyNow assay.
In the ARMYDA-4 RELOAD study,6 subgroup analysis
using prespecified clinical subsets of patients with ACS,
showed a MACE incidence of 6.4% in the reload arm versus
16.3% in the placebo arm (odds ratio [OR] 0.34, multivar-
iate analysis). For the sample size calculation of the
ARMYDA-8 RELOAD-ACS, we hypothesized a similar
16% occurrence of MACE in the placebo group and a
similar 66% risk reduction in the clopidogrel reload arm.
Thus, a study population of 240 patients would be needed
to detect such a reduction with an a of 0.05 (2 tailed) and
a b of 0.08.
Categorical variables are expressed as percentages and
continuous variables as the mean  SD, unless otherwise
specified. Proportions were compared using Fisher’s exact test
when the expected frequency was <5, otherwise the chi-square
test (Yates’ corrected) was applied. Continuous variables
between the 2 arms were compared using the t test for normally
distributed values (as assessed by the Kolmogorov-Smirnov
test), otherwise, the Mann-Whitney U test was used. ORs and
95% confidence intervals assessing the risk of the primary end
point according to potential confounding variables were
assessed by logistic regression analysis. All variables listed in
Tables 1 and 2 were evaluated first in a univariate model, and,
for those with p <0.15, in a multivariate logistic regression
analysis. All calculations were performed using the Statistical
Package for Social Sciences, version 12.0, and p <0.05
(2 tailed) was considered significant.
Results
The clinical and procedural variables in the 2 arms are
listed in Tables 1 and 2, respectively. The timing of study
 Coronary Artery Disease/Clopidogrel Reloading in Patients With ACS
ARMYDA-8 RELOAD-ACS: Platelet aggregometry
P=0.011
Clopidogrel
600 mg
P=0.16
260 244±93
P=0.012
238±69
240 224±51 221±92
Clopidogrel
220 228±48
200
PRU
Placebo 199±86
180
185±90
160
172±83
140
120
Study drug PCI 6 hrs 24 hrs
Figure 4. Aggregometry data.
drug administration versus placebo before PCI (6  0.4 vs
6  0.5 hours, p ¼ 0.89) and the prevalence of diabetes
mellitus (27% vs 31%), noneST-segment elevation
myocardial infarction (64% vs 60%), and the use of drug-
eluting stents (47% vs 43%) were similar. The large
majority of patients were receiving statin therapy at PCI
(90% vs 85%). The mean duration of chronic clopidogrel
therapy was 5 months in both arms. In the overall study
population, the indication for chronic clopidogrel therapy
was mainly previous ACS or drug-eluting stent implanta-
tion, without differences in the prevalence of these indica-
tions between the 2 arms. Among the initial population of
patients meeting the enrollment criteria (n ¼ 271), after
coronary angiography, 19 patients (7%) were excluded
because they received medical therapy and 10 patients (4%)
because they were deemed to require surgical revasculari-
zation. Of the 10 patients treated with bypass surgery, 5
were randomized to the reload arm, but they had no excess
bleeding during the perioperative period. Among the 19
patients treated medically because of nonsignificant coro-
nary disease or disease not suitable for PCI, 10 were
randomized to the reload arm and 9 to the placebo arm; none
of the 19 patients had any additional events during the study
period.
In the overall population, procedural success, defined as
residual coronary stenosis <30%, was achieved in 239 of
242 patients (120 of 122 in the reload arm [98.4%] and 119
of 120 [99.2%] in the placebo arm, p ¼ 0.99). An unsuc-
cessful procedure resulted from an inability to cross a total
occlusion in all cases. No-reflow phenomenon occurred in 4
patients (1 in the reload and 3 in the placebo arm), who
successfully received intracoronary nitrates, adenosine, and
glycoprotein IIb/IIIa inhibitors. No evident vessel or side
branch (2 mm) closure occurred when bifurcating lesions
were treated.
The incidence of the composite primary end point of
death, myocardial infarction, and target vessel revasculari-
zation at 1 month was 4.1% (5 of 122 patients) in the reload
arm versus 14.1% (17 of 120) in the placebo arm (p ¼
0.012; Figure 2). The occurrence of 30-day MACE was
essentially owing to periprocedural myocardial infarction in
both arms: 5 of 122 patients (4.1%) versus 16 of 120 (13%;
p ¼ 0.02). The rates of large periprocedural myocardial
infarction, defined as post-PCI CK-MB elevation 5 times the
5
upper limit of normal, were also lower in the reload arm
(0.8% vs 7.5%; p ¼ 0.022). One patient in the placebo
group experienced sudden cardiac death 7 days after the
index procedure. No patient required emergency coronary
artery bypass surgery or repeat PCI within 30 days. Multi-
variate logistic regression analysis showed that clopidogrel
reload reload was an independent predictor of a decreased risk of
MACE at 1 month (OR 0.26, 95% confidence interval 0.10
Placebo
to 0.73, p ¼ 0.013; Figure 3). The risk of events was also
lower in male patients (OR 0.10, 95% confidence interval
0.01 to 0.73, p ¼ 0.024) and was greater in patients
receiving proton pump inhibitors (OR 4.4, 95% confidence
interval 1.2 to 15.9, p ¼ 0.025).
No patient in the present study had major bleeding or
required transfusions. Minor bleeding occurred in 2.5% of
patients (3 of 122) in the reload arm versus 3.3% (4 of 120)
of those in the placebo arm (p ¼ 0.98). Minor bleeding
included 3 urethral bleeding events, 1 conjunctival bleeding
event, and 3 gum bleeding events. The incidence of hema-
tomas >10 cm was 4% (5 of 122) versus 5% (6 of 120) in
the reload and placebo group, respectively (p ¼ 0.98). In
contrast, postintervention femoral arteriovenous fistulas
were observed in 1.6% (2 of 122) and 1.7% (2 of 120) of
patients (p ¼ 0.63).
A total of 85 patients underwent a complete platelet
reactivity evaluation, 44 in the reload group and 41 in the
placebo group (Figure 4). In the placebo arm, the PRU
values at PCI remained essentially unchanged compared
with baseline (224  51 vs 228  48, p ¼ 0.52), increased
at 6 hours (244  93, p ¼ 0.05, vs baseline), and decreased
at 24 hours to levels similar to those at baseline (221  92,
p ¼ 0.67). After clopidogrel reload, the platelet reactivity at
PCI was significantly attenuated compared with at baseline
(199  86 vs 238  69 PRU, p ¼ 0.02), with an additional
progressive decrease of PRU levels at 6 hours (185  90
PRU, p ¼ 0.003, vs baseline) and 24 hours (172  83 PRU,
p <0.0001). As a result, patients randomized to the clopi-
dogrel reload arm had lower PRU levels (i.e., greater platelet
inhibition) than the placebo arm at PCI and at both post-PCI
determinations (Figure 4).
Discussion
The ARMYDA-8 RELOAD-ACS trial investigated the
issue of whether an additional 600-mg clopidogrel loading
dose in the background of chronic clopidogrel therapy
would provide a significant clinical benefit in patients with
noneST-segment elevation ACS undergoing early PCI. Our
results have indicated that in this setting a reloading strategy
reduces the cumulative incidence of adverse events at 30
days.
Previous studies have demonstrated that 600 mg clopi-
dogrel in patients with coronary artery disease receiving the
chronic 75 mg/day dose was associated with 68% additional
inhibition of adenosine diphosphate (5 mmol/L)-induced
platelet aggregation at 6 hours4 and with a reduction of
interindividual variability in the response to the drug.13 This
could be critical, because recent data have shown that the
degree of platelet reactivity with clopidogrel therapy
correlates with the clinical outcome after PCI, with an
increased risk of cardiac events, including stent thrombosis,
6 The American Journal of Cardiology (www.ajconline.org)
in patients with high on-treatment platelet reactivity.3 The
randomized ARMYDA-4 RELOAD trial included patients
receiving chronic clopidogrel therapy receiving PCI for
a variety of clinical syndromes and suggested that in the
subgroup of patients with ACS, a reloading strategy was
associated with a 66% relative risk reduction of 30-day
MACE.6 This was a negative study in the overall compar-
ison, and it was possibly underpowered for subgroup anal-
ysis. A more recent investigation demonstrated no clinical
benefit for clopidogrel reloading in patients receiving long-
term clopidogrel therapy and undergoing coronary stenting
for ACS.7 However, this was a retrospective, single-center
study, and the results were not adjusted for possible
confounders. Given these results, we specifically designed
a prospective, multicenter, randomized protocol to clarify
this issue.
The results of the ARMYDA-8 RELOAD-ACS trial have
indicated that an additional 600 mg clopidogrel load given 6
hours before PCI is associated with a lower incidence of
MACE at 1 month in patients receiving chronic clopidogrel
therapy admitted for ACS. In particular, the risk reduction of
events was 74% on multivariate analysis, and this clinical
benefit on the composite end point was mainly driven by the
prevention of periprocedural myocardial infarction. The
clinical value of periprocedural myocardial infarction as
detected by cardiac marker elevation, without symptoms or
electrocardiographic or echocardiographic changes, is not
well established. However, even small cardiac marker
releases are an expression of true infarction, as assessed by
contrast-enhanced magnetic resonance imaging, and might
negatively affect the prognosis during follow-up.14,15 In the
reload arm, the occurrence of periprocedural myocardial
infarction was lower, also considering the more specific
definition of larger infarction (post-PCI CK-MB elevation 5
times the upper limit of normal). Patients with ACS present
with enhanced baseline platelet activity and an impaired
response to standard doses of clopidogrel, with an increased
prevalence of high on-treatment platelet reactivity.16,17
Thus, an additional antiplatelet effect beyond that achieved
with the currently recommended maintenance dose of clo-
pidogrel might be indicated before PCI for such patients to
achieve a significant clinical benefit. Patients who develop
ACS during dual antiplatelet therapy are potentially at even
greater risk of early ischemic events and might derive the
greatest benefit from “more aggressive” antiplatelet strate-
gies (i.e., more liberal use of glycoprotein IIb/IIIa inhibitors,
a switch to ticagrelor, or a reload dose with clopidogrel, if
ticagrelor is contraindicated because of high bleeding risk).
In the ARMYDA-8 RELOAD-ACS trial, the prevention of
periprocedural ischemic events using a clopidogrel reload-
ing dose was associated with attenuation of platelet reac-
tivity at PCI that continued in the first hours after the
procedure. In contrast, as expected, in the placebo group,
procedural platelet activation occurred, with a peak at 6
hours, that was not observed in the active treatment arm.
Our aggregometry data indicated that the periprocedural
degree of platelet inhibition in response to clopidogrel can
influence the early outcome, with lower ischemic events
paralleled by lower residual platelet reactivity in the reload
arm. Importantly, our study showed no increased bleeding
risk with the reload approach. These findings are reassuring,
considering the strong negative prognostic effect of peri-
procedural hemorrhage.18 The administration of glycopro-
tein IIb/IIIa inhibitors was limited in the ARMYDA-8
RELOAD-ACS trial; therefore, the study did not draw
conclusions about the bleeding risk if both reloading and
glycoprotein IIb/IIIa inhibitors were used. Moreover, the
drug-eluting stent penetration was low (44%), reflecting the
practice patterns in Europe and centers involved in the
present study.
The recent guidelines of the European Society of
Cardiology on noneST-segment elevation ACS assigned
a level of recommendation of 1B for prasugrel and tica-
grelor, with clopidogrel recommended for patients who
cannot receive prasugrel or ticagrerlor.19 Nevertheless, we
do not believe that the use of clopidogrel has been outdated
because of concerns related to major bleeding and cost.
Disclosures
The authors have no conflicts of interest to disclose.
Appendix
The following investigators participated in the ARMYDA-
8 RELOAD-ACS trial:
Chairman: Germano Di Sciascio, MD, Campus Bio-
Medico University, Rome
Principal investigator: Giuseppe Patti, MD, Campus
Bio-Medico University, Rome
Investigators:
Campus Bio-Medico University, Rome: Andrea
D’Ambrosio, MD, Fabio Mangiacapra, MD,
Vincenzo Vizzi, MD, Elisabetta Ricottini, MD,
Annunziata Nusca, MD, Rosetta Melfi, MD, Marco
Miglionico, MD, Rocco Contuzzi, MD, Paolo
Gallo, MD.
San Filippo Neri Hospital, Rome: Vincenzo Pasceri,
MD, Giulio Speciale, MD, Christian Pristipino, MD,
Massimo Santini, MD, Francesco Pelliccia, MD.
Vito Fazzi Hospital, Lecce: Giuseppe Colonna, MD,
Antonio Montinaro, MD, Luigi Cavallo, Luisella
Serafino, Dorella Pelagalli, Anita Stanga, Patrizia
Petrachi, Pietro Montuori, Ramona Chiriatti,
Patrizia Cascione, Maria Grazia Perrone, Anna
Protopapa, Lucia Martella, Emanuela Mele,
Caterina Carlino.
Cardiovascular Center, OLV Hospital of Aalst: William
Wijns, MD, Emanuele Barbato, MD, Bernard De
Bruyne, MD, Jozef Bartunek, MD, Marc Vander-
heyden, MD, Carlos Van Mieghem, MD, Aaron J
Peace, MD.
1. Gurbel PA, Bliden KP, Hiatt BL, O’Connor CM. Clopidogrel for
coronary stenting: response variability, drug resistance, and the effect
of pretreatment platelet reactivity. Circulation 2003;107:2908e2913.
2. Serebruany VL, Steinhubl SR, Berger PB, Malinin AI, Bhatt DL, Topol
EJ. Variability in platelet responsiveness to clopidogrel among 544
individuals. J Am Coll Cardiol 2005;45:246e251.
3. Brar SS, ten Berg J, Marcucci R, Price MJ, Valgimigli M, Kim HS,
Patti G, Breet NJ, DiSciascio G, Cuisset T, Dangas G. Impact of
platelet reactivity on clinical outcomes after percutaneous coronary
 Coronary Artery Disease/Clopidogrel Reloading in Patients With ACS
intervention: a collaborative meta-analysis of individual participant
data. J Am Coll Cardiol 2011;58:1945e1954.
4. Kastrati A, von Beckerath N, Joost A, Pogatsa-Murray G, Gorchakova O,
Schömig A. Loading with 600 mg clopidogrel in patients with coronary
artery disease with and without chronic clopidogrel therapy. Circulation
2004;110:1916e1919.
5. Williams DO, Abbott JD. What to do with patients receiving long-term
clopidogrel: reload or relax? Circulation 2008;118:1219e1222.
6. Di Sciascio G, Patti G, Pasceri V, Colonna G, Mangiacapra F,
Montinaro A; ARMYDA-4 RELOAD Investigators. Clopidogrel
reloading in patients undergoing percutaneous coronary intervention on
chronic clopidogrel therapy: results of the ARMYDA-4 RELOAD
(Antiplatelet therapy for Reduction of MYocardial Damage during
Angioplasty) randomized trial. Eur Heart J 2010;31:1337e1343.
7. Mahmoudi M, Syed AI, Ben-Dor I, Gonzalez M, Maluenda G,
Gaglia MA Jr, Sardi G, Wakabayashi K, Torguson R, Xue Z, Satler LF,
Suddath WO, Pichard AD, Waksman R. Safety and efficacy of clopi-
dogrel reloading in patients on chronic clopidogrel therapy who present
with an acute coronary syndrome and undergo percutaneous coronary
intervention. Am J Cardiol 2011;107:1779e1782.
8. Malinin A, Pokov A, Swaim L, Kotob M, Serebruany V. Validation of
a VerifyNow-P2Y12 cartridge for monitoring platelet inhibition with
clopidogrel. Methods Find Exp Clin Pharmacol 2006;28:315e322.
9. Malinin A, Pokov A, Spergling M, Defranco A, Schwartz K, Schwartz
D, Mahmud E, Atar D, Serebruany V. Monitoring platelet inhibition
after clopidogrel with the VerifyNow-P2Y12(R) rapid analyzer: the
VERIfy Thrombosis risk ASsessment (VERITAS) study. Thromb Res
2007;119:277e284.
10. Lim CC, van Gaal WJ, Testa L, Cuculi F, Arnold JR, Karamitsos T,
Francis JM, Petersen SE, Digby JE, Westaby S, Antoniades C, Khar-
banda RK, Burrell LM, Neubauer S, Banning AP. With the “universal
definition,” measurement of creatine kinase-myocardial band rather
than troponin allows more accurate diagnosis of periprocedural
necrosis and infarction after coronary intervention. J Am Coll Cardiol
2011;57:653e661.
11. Prasad A, Gersh BJ, Bertrand ME, Lincoff AM, Moses JW, Ohman
EM, White HD, Pocock SJ, McLaurin BT, Cox DA, Lansky AJ,
Mehran R, Stone GW. Prognostic significance of periprocedural versus
spontaneously occurring myocardial infarction after percutaneous
coronary intervention in patients with acute coronary syndromes: an
analysis from the ACUITY (Acute Catheterization and Urgent Inter-
vention Triage Strategy) trial. J Am Coll Cardiol 2009;54:477e486.
12. Rao AK, Pratt C, Berke A, Jaffe A, Ockene I, Schreiber TL, Bell WR,
Knatterud G, Robertson TL, Terrin ML. Thrombolysis In Myocardial
Infarction (TIMI) trial—phase I: hemorrhagic manifestations and
changes in plasma fibrinogen and the fibrinolytic system in patients
7
treated with recombinant tissue plasminogen activator and streptoki-
nase. J Am Coll Cardiol 1988;11:1e11.
13. Collet JP, Silvain J, Landivier A, Tanguy ML, Cayla G, Bellemain A,
Vignolles N, Gallier S, Beygui F, Pena A, Montalescot G. Dose effect
of clopidogrel reloading in patients already on 75-mg maintenance
dose: the Reload with Clopidogrel Before Coronary Angioplasty in
Subjects Treated Long Term with Dual Antiplatelet Therapy
(RELOAD) study. Circulation 2008;118:1225e1233.
14. Ricciardi MJ, Wu E, Davidson CJ, Choi KM, Klocke FJ, Bonow RO,
Judd RM, Kim RJ. Visualization of discrete microinfarction after
percutaneous coronary intervention associated with mild creatine
kinase-MB elevation. Circulation 2001;103:2780e2783.
15. Ioannidis JPA, Karvouni E, Katritis DG. Mortality risk conferred by
small elevations of creatine-kinase MB isoenzyme after percutaneous
intervention. J Am Coll Cardiol 2003;42:1406e1411.
16. Geisler T, Kapp M, Göhring-Frischholz K, Daub K, Dösch C, Bigalke
B, Langer H, Herdeg C, Gawaz M. Residual platelet activity is
increased in clopidogrel- and ASA-treated patients with coronary
stenting for acute coronary syndromes compared with stable coronary
artery disease. Heart 2008;94:743e747.
17. Ault KA, Cannon CP, Mitchell J, McCahan J, Tracy RP, Novotny WF,
Reimann JD, Braunwald E. Platelet activation in patients after an acute
coronary syndrome: results from the TIMI-12 trial. Thrombolysis in
Myocardial Infarction. J Am Coll Cardiol 1999;33:634e639.
18. Rao SV, O’Grady K, Pieper KS, Granger CB, Newby LK, Van de Werf
F, Mahaffey KW, Califf RM, Harrington RA. Impact of bleeding
severity on clinical outcomes among patients with acute coronary
syndromes. Am J Cardiol 2005;96:1200e1206.
19. Hamm CW, Bassand JP, Agewall S, Bax J, Boersma E, Bueno H, Caso
P, Dudek D, Gielen S, Huber K, Ohman M, Petrie MC, Sonntag F, Uva
MS, Storey RF, Wijns W, Zahger D, ESC Committee for Practice
Guidelines, Bax JJ, Auricchio A, Baumgartner H, Ceconi C, Dean V,
Deaton C, Fagard R, Funck-Brentano C, Hasdai D, Hoes A, Knuuti J,
Kolh P, McDonagh T, Moulin C, Poldermans D, Popescu BA, Reiner Z,
Sechtem U, Sirnes PA, Torbicki A, Vahanian A, Windecker S, Docu-
ment Reviewers, Windecker S, Achenbach S, Badimon L, Bertrand M,
Bøtker HE, Collet JP, Crea F, Danchin N, Falk E, Goudevenos J, Gulba
D, Hambrecht R, Herrmann J, Kastrati A, Kjeldsen K, Kristensen SD,
Lancellotti P, Mehilli J, Merkely B, Montalescot G, Neumann FJ,
Neyses L, Perk J, Roffi M, Romeo F, Ruda M, Swahn E, Valgimigli M,
Vrints CJ, Widimsky P. The task force for the management of acute
coronary syndromes in patients presenting without persistent ST-
segment elevation of the European Society of Cardiology (ESC). ESC
Guidelines for the management of acute coronary syndromes in patients
presenting without persistent ST-segment elevation. Eur Heart J
2011;32:2999e3054.