The impact of generic clopidogrel bisulfate on platelet inhibition in patients with coronary artery stents: results of the ACCEL-GENERIC study.

Abstract

In patients with coronary artery stents, the cost of clopidogrel has been cited as a factor in the premature discontinuation of therapy. Thus, the introduction of lower-cost generic clopidogrel may increase patient compliance. However, platelet inhibition by generic clopidogrel has not been compared to the original clopidogrel formulation in patients with coronary artery stents.
We prospectively enrolled 20 patients receiving chronic therapy with the original clopidogrel bisulfate (Plavix). After assessing patient compliance with Plavix, maintenance therapy was switched to generic clopidogrel bisulfate (Plavitor). Platelet reactivity was assessed at baseline and 30-day after the switch using conventional aggregometry and the VerifyNow P2Y12 assay.
All patients completed maintenance therapy with Plavitor. Before and after switching therapy maximal (36.5 +/- 7.9% vs. 39.8 +/- 16.2%, p = 0.280) and late platelet aggregation (23.5 +/- 10.9% vs. 29.1 +/- 18.3%, p = 0.156) with 5 micromol/L adenosine diphosphate (ADP) stimulus did not differ. Likewise, 20 micromol/L ADP-induced platelet aggregation and P2Y12 reaction unit in patients on Plavitor therapy was comparable to that in patients on Plavix therapy. However, Bland-Altman analysis showed wide limits of agreement between measured platelet reactivity on Plavix vs. Plavitor therapies.
Among patients on Plavix maintenance therapy with coronary stents, replacement with Plavitor shows a comparable inhibition of ADP-induced platelet aggregation. However, due to poor inter-therapy agreement, between two regimens, physicians may be cautious when introducing generic clopidogrel bisulfate.

Full text

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The Impact of Generic Clopidogrel Bisulfate on Platelet
Inhibition in Patients with Coronary Artery Stents: Results
of the ACCEL-GENERIC Study
Young-Hoon Jeong1, Jin-Sin Koh1, Min-Kyung Kang1, Yeon-Jeong Ahn1, In-Suk Kim2, Yongwhi Park1,
Seok-Jae Hwang1, Choong Hwan Kwak1, and Jin-Yong Hwang1
Departments of 1Internal Medicine and 2Laboratory Medicine, Gyeongsang National University Hospital, Jinju, Korea
DOI: 10.3904/kjim.2010.25.2.154
ORIGINAL ARTICLE
Background/Aims: In patients with coronary artery stents, the cost of clopidogrel has been cited as a factor in
the premature discontinuation of therapy. Thus, the introduction of lower-cost generic clopidogrel may increase
patient compliance. However, platelet inhibition by generic clopidogrel has not been compared to the original
clopidogrel formulation in patients with coronary artery stents.
Methods: We prospectively enrolled 20 patients receiving chronic therapy with the original clopidogrel bisulfate
(Plavix®). After assessing patient compliance with Plavix®, maintenance therapy was switched to generic
clopidogrel bisulfate (Plavitor®). Platelet reactivity was assessed at baseline and 30-day after the switch using
conventional aggregometry and the VerifyNow P2Y12 assay.
Results: All patients completed maintenance therapy with Plavitor®. Before and after switching therapy maximal
(36.5 ± 7.9% vs. 39.8 ± 16.2%, p = 0.280) and late platelet aggregation (23.5 ± 10.9% vs. 29.1 ± 18.3%, p =
0.156) with 5 µmol/L adenosine diphosphate (ADP) stimulus did not differ. Likewise, 20 µmol/L ADP-induced
platelet aggregation and P2Y12 reaction unit in patients on Plavitor®therapy was comparable to that in patients
on Plavix®therapy. However, Bland-Altman analysis showed wide limits of agreement between measured
platelet reactivity on Plavix®vs. Plavitor®therapies.
Conclusions: Among patients on Plavix®maintenance therapy with coronary stents, replacement with Plavitor®
shows a comparable inhibition of ADP-induced platelet aggregation. However, due to poor inter-therapy
agreement, between two regimens, physicians may be cautious when introducing generic clopidogrel bisulfate.
(Korean J Intern Med 2010;25:154-161)
Keywords: Clopidogrel; Drugs, generic; Blood platelets; Purinoceptor P2Y12
Received: March 30, 2009
Accepted: July 22, 2009
Correspondence to Young-Hoon Jeong, M.D.
Department of Internal Medicine, Gyeongsang National University Hospital, Chiram-dong, Jinju 660-702, Korea
Tel: 82-55-758-9122, Fax: 82-55-750-8873, E-mail: goodoctor@naver.com
INTRODUCTION
Antiplatelert therapy that combines thienopyridine and
aspirin has reduced the incidence of ischemic cardiovascular
events in patients with percutaneous coronary intervention
(PCI) or acute coronary syndrome (ACS) [1-5]. Because
the introduction of drug-eluting stents (DES) has signifi-
cantly decreased neointimal hyperplasia and the need for
repeated procedures due to restenosis compared to bare-
metal stents. DESs are now used in high-risk lesions [6-8].
However, DES have been associated with delayed endothe-
lialization [9,10], localized hypersensitivity reactions [11],
endothelial dysfunction [12], and late stent thrombosis
(ST) [13-15].
Premature discontinuation of thienopyridine therapy
has been associated with a marked increase in the risk of
ST [16-19]. The Ameican Heart Association, American
College of Cardiology, Society for Cardiovascular Argiography

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Jeong YH, et al. Generic clopidogrel bisulfate on platelet inhibition 155
for Interventions, American College of Surgeors, and
American Dental Association Science Advisory has
stressed the importance of at least 12 months of dual
antiplatelet therapy after DES implantation, along with
educating the patient and healthcare providers about the
hazards of premature discontinuation [20]. Because the
cost of clopidogrel has been cited as a factor in the discon-
tinuation of therapy [21], the introduction of lower-cost
generic clopidogrel may significantly increase patient
compliance. Because, clopidogrel hyporesponsiveness or
high post-clopidogrel platelet reactivity (HPPR) has been
associated with untoward clinical events [22-25], adenosine
diphosphate (ADP) P2Y12 blockade by generic clopidogrel
must be as effective as that of original clopidogrel. However
this has not been demonstrated in patients with coronary
artery stents. We thus addressed this concern by performing
a prospective study comparing the degree of platelet
inhibition by original (Plavix®, Sanofi-Aventis, Paris,
France) versus generic (Plavitor®, Dong-A Pharmaceutical,
Seoul, Korea) clopidogrel bisulfate in patients receiving
dual antiplatelet therapy PCI-treated.
METHODS
Patient selection
Patients were eligible for enrollment if they were ≥ 18
years of age, previously treated with DES implantation for
documented coronary artery disease, and were receiving
clopidogrel bisulfate treatment at a steady state dose of
75 mg/day for at least 6 months. We enrolled patients
from cohorts admitted for follow-up coronary angiography.
Major exclusion criteria included repeated PCI after
follow-up coronary angiography; coronary stenting due to
a high-risk complex lesion; active bleeding and bleeding
diatheses; oral anticoagulation therapy with warfarin;
left ventricular ejection fraction < 30%; leukocyte count
< 3,000 /mm3; platelet count < 100,000 /mm3; aspartate
aminotransferase or alanine amino-transferase level ≥ 3
times upper normal; stroke within 3 months; non-cardiac
disease with a life expectancy < 1 year; and inability to
follow the protocol. The study protocol was approved by
the Institutional Review Board, and the patients provided
written informed consent for participation.
Study design
The ACCEL-GENERIC (platelet inhibition After Change
of ClopidogrEL bisulfate with GENERIC tablet) study is a
prospective, controlled, platelet function study of patients
with coronary artery stents. A diagram of the study
protocol is illustrated in Fig. 1. All patients were treated
with DES, followed by 75 mg/day Plavix®for at least 6
months. We evaluated patient compliance by interview
and tablet counting and enrolled patients showing
complete compliance for at least 1 month. Immediately
after insertion of the radial sheath for follow-up coronary
angiography, blood samples for residual platelet reactivity
analyses were obtained. Coronary angiography was
performed according to standard techniques. If patients
met the enrolled criteria and gave permission, Plavix®
was replaced with 75 mg/day of Plavitor®. At the 30-day
follow-up visit, patient compliance to antiplatelet therapy
was assessed by interview and tablet counting. Blood
samples for platelet function testing were obtained at 30
days after Plavitor®replacement, 2 to 4 hours after the
last intake of the study medication. Peripheral venous
blood samples were drawn from an antecubital vein using
a 21-gauge needle.
Platelet function measurements
Blood samples were collected using the double-syringe
technique, in which the first 2 to 4 mL blood is discarded
to avoid spontaneous platelet activation. Platelet function
was measured by light transmittance aggregometry (LTA)
and the VerifyNow P2Y12 assay (Accumetrics, San Diego,
CA, USA).
Platelet aggregation was assessed by LTA according to a
standard protocol [26]. Briefly, blood samples were drawn
into Vacutainer tubes containing 0.5 mL sodium citrate
Figure 1. Diagram of the ACCEL-GENERIC study.

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156 The Korean Journal of Internal Medicine Vol. 25, No. 2, June 2010
3.2% (Becton-Dickinson, San Jose, CA, USA) and processed
within 60 minutes. Platelet-rich plasma (PRP) was
obtained as a supernatant fluid after centrifuging blood at
120 g for 10 minutes. The remaining blood was further
centrifuged at 1,200 g for 10 minutes to prepare platelet-
poor plasma (PPP). PRP was adjusted to platelet counts of
250,000/µL by adding PPP as needed. Platelet aggregation
was assessed at 37˚C using an AggRAM aggregometer
(Helena Laboratories Corp., Beaumont, TX, USA). Light
transmission was adjusted to 0% with PRP and to 100%
with PPP for each measurement. Platelet functions were
measured after adding 5 and 20 µmol/L ADP, and curves
were recorded for 10 minutes. Platelet aggregation was
measured at peak (Aggmax) and at 5 minutes (Agglate) by
laboratory personnel blinded to group assignment. Aggmax
is considered to reflect the activity of both P2Y1 and P2Y12
receptors, whereas Agglateis indicative of P2Y12 receptor
activity. The percentage of platelet disaggregation between
Aggmaxand Agglatewas defined as follows: disaggregation
(%) = [(Aggmax- Agglate) / (Aggmax)] × 100 [26].
The VerifyNow P2Y12 assay is a whole-blood, point-of-
care (POC) system, which was developed to assess respon-
siveness to clopidogrel and other P2Y12 antagonists [26].
Blood was drawn into a Greiner Bio-One 3.2% citrate
Vacuette tube (Greiner Bio-One, KremsmÜnster, Austria).
The assay device consists of whole-blood assay channels.
One contains fibrinogencoated polystyrene beads and 20
µmol/L ADP. This channel also contains 22 nmol/L PGE1
to reduce the nonspecific contribution of P2Y1 receptors.
Results are reported in P2Y12 reaction units (PRU). We
have previously correlated the two methods in our
laboratory [27].
End point definition
The primary end point was ADP-induced Aggmax at
baseline and 30-day after the switch to Plavitor®. The
secondary end points were ADP-induced Agglate, per-
centages of platelet disaggregation, and PRU at baseline
and 30-day after the switch.
Statistical analysis
Sample size was selected on the basis of practical con-
sideration, and the trial was designed to be a pilot study in
accordance with the paucity of platelet function tests
directly comparing Plavix®and Plavitor®. Continuous
variables are presented as mean ± standard deviation
(SD) and compared using Student paired t, Wilcoxon
signed-rank, or Mann-Whitney U tests. Categorical
Table 1. Baseline characteristics of the study
population (n = 20)
Characteristics Value
Age, yr
Male
BMI, kg/m2
Indication of coronary stenting
Stable angina
Unstable angina
NSTEMI
STEMI
Risk factors / past history
Diabetes mellitus
Hypertension
Hypercholesterolemia
Current smoking
Previous myocardial infarction
Previous CABG 0 (0)
Previous stroke
Concomitant medications
Statin
CYP 3A4 metabolized
Non-CYP 3A4 metabolized
Beta blocker
ACEI or ARB
Nitrate
Calcium channel blocker
Laboratory findings
Hemoglobin, g/dL
Platelet count, x103/mm3
HbA1C, %
Creatinine clearance, mL/min
Total cholesterol, mg/dL
LDL-cholesterol, mg/dL
HDL-cholesterol, mg/dL
Triglyceride, mg/dL
LV ejection fraction, %
Multivessel intervention
Used stent
Sirolimus-eluting
Paclitaxel-eluting
Zotarolimus-eluting
61 ± 9
16 (80.0)
25.0 ± 2.4
4 (20.0)
5 (25.0)
2 (10.0)
9 (45.0)
5 (25.0)
9 (45.0)
2 (10.0)
12 (60.0)
11 (55.0)
0 (0)
17 (85.0)
1 (5.0)
19 (95.0)
18 (90.0)
12 (60.0)
7 (35.0)
13.4 ± 1.8
260 ± 64
6.4 ± 1.4
82 ± 25
137 ± 38
73 ± 27
45 ± 18
134 ± 82
60 ± 6
7 (35.0)
8 (40.0)
8 (40.0)
4 (20.0)
Values are presented as number (%) or mean ± SD.
BMI, body mass index; NSTEMI, non-ST-segment elevation
myocardial infarction; STEMI, ST-segment elevation myocardial
infarction; CABG, coronary artery bypass grafting; CYP 3A4,
cytochrome P450 3A4 isoenzyme; ACEI, angiotensin-
converting enzyme inhibitor; ARB, angiotensin receptor blocker;
HbA1C, hemoglobin A1C; LDL, low-density lipoprotein; HDL,
high-density lipoprotein; LV, left ventricular.

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Jeong YH, et al. Generic clopidogrel bisulfate on platelet inhibition 157
variables are presented as numbers or percentages and
were compared using chi-square or Fisher exact tests (if
an expected frequency was < 5). Agreement of platelet
function measurements between baseline and 30-day
after switch to Plavitor®was assessed using the Bland-
Altman analysis. This analysis measures bias, which
shows the systematic error responsible for either under-
or overestimation of a value, and sets the limits of agreement
between the Plavix®and Plavitor®measurements. A
p value < 0.05 was considered statistically significant.
Statistical analyses were performed using SPSS version 13
(SPSS Inc., Chicago, IL, USA).
RESULTS
Patient characteristics and follow-up
Platelet function measurements in patients taking 75
mg/day of Plavix®were performed in a total of 20 patients
(Table 1). These patients received Plavix®for 271 ± 81
days. Because treatment with Plavitor®was well tolerated
and no subject discontinued the study drugs, platelet
function 30 days after replacing medications was assessed
in all patients. The number of remaining tablets demon-
strated complete compliance with the study protocol.
Figure 2. Comparison of maximal platelet aggregation on
Plavix®versus Plavitor®therapies. Bars indicate standard
deviations. ADP, adenosine diphosphate.
A
C
B
Figure 3. Comparison of late platelet aggregation (A) platelet
disaggregation (B) and P2Y12 reaction unit (C) on Plavix®versus
Plavitor®therapies. Bars indicate standard deviations. ADP,
adenosine diphosphate.

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158The Korean Journal of Internal Medicine Vol. 25, No. 2, June 2010
There were no cardiovascular events, and no major or
minor bleeding noted.
Primary end point
Aggmaxvalues after 30 days of Plavitor®therapy were
similar to those after chronic Plavix®administration (Fig.
2). Aggmaxwith 5 µmol/L ADP stimulus was 39.8 ± 16.2%
on Plavitor®therapy and 36.5 ± 7.9% on Plavix®therapy,
with a mean difference of 3.3% (95% confidence interval
[CI], - 2.9 to 9.4; p = 0.280). When Aggmaxwas assessed
after stimulation with 20 µmol/L ADP, Plavitor®therapy
achieved a similar platelet aggregation relative to Plavix®
therapy (54.1 ± 16.0% vs. 52.8 ± 9.8%), with a mean
difference of 1.3% (95% CI, - 4.9 to 7.5; p= 0.667).
A
C
E
B
D
Figure 4. Bland-Altman agreement analysis in assessing
residual platelet reactivity on Plavix®versus Plavitor®
therapies. 5 and 20 µmol/L ADP-induced maximal plateler
aggregation (A and B), P2Y12 reaction unit and 5 and 20 µmol/L
ADP-irduced late plateler aggregation (B and E). Solid line
represents bias, dotted lines represent 95% confidence interval of
bias, and dashed lines represent limits of agreement. ADP,
adenosine diphosphate; Aggmax, maximal platelet aggregation;
Agglate, late platelet aggregation.

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Jeong YH, et al. Generic clopidogrel bisulfate on platelet inhibition 159
Secondary end points
Significant changes in Agglateafter 30-day of Plavitor®
therapy were not observed compared to Plavix®therapy
(Fig. 3A). Agglatewith 5 µmol/L ADP stimulation was 29.1
± 18.3% on Plavitor®therapy and 23.5 ± 10.9% on Plavix®
therapy, with a mean difference of 5.6% (95% CI, - 2.3 to
13.5; p= 0.156). When Agglatewas assessed after stimulation
with 20 µmol/L ADP, platelet reactivity in patients on
Plavitor®therapy was similar to that in patients on
Plavix®therapy (42.7 ± 21.7% vs. 40.1 ± 15.9%), with a
mean difference of 2.6% (95% CI, - 5.5 to 10.6; p= 0.518).
A significant change in platelet disaggregation after 30-
day of Plavitor®therapy was not identified compared to
Plavix®therapy (Fig. 3B). Platelet disaggregations in
patients on Plavitor®therapy were similar to those in
patients on Plavix®therapy after stimulation with 5
µmol/L ADP (33.1 ± 22.2% vs. 38.5 ± 21.3%; 95% CI, -
15.5 to 4.9; p = 0.288) and 20 µmol/L ADP (26.6 ± 23.6%
vs. 27.1 ± 21.4%; 95% CI, - 7.5 to 6.5; p= 0.882).
Using the VerifyNow P2Y12 assay, PRU values in
samples from patients who had received the two therapies
were comparable (Fig. 3C):Plavitor®therapy of 218.4 ±
75.2 so Plavix®therapy of 229.2 ± 57.7 (95% CI, - 12.7 to
34.3; p= 0.348).
Agreement of platelet reactivity between Plavix®
and Plavitor® therapy
We conducted a Bland-Altman analysis to evaluate the
agreement between platelet function measurements after
Plavix®or Plavitor®therapy. We first compared Aggmax
values after stimulation with 5 and 20 µmol/L ADP. Inter-
therapy analysis of 5 µmol/L ADP-induced Aggmaxvalues
showed a bias of - 3.3%, with a lesser Aggmaxon Plavix®
therapy (Fig. 4A). However, the limits of agreement varied
from - 29.0 to 22.5%, indicating that the two therapies
may significantly disagree in certain individuals.
Furthermore, 20 µmol/L ADP-induced Aggmaxvalues on
Plavix®and Plavitor®therapies indicated poor accord
with a slight bias of - 1.3% and wide limits of agreement
ranging from - 27.4 to 24.8% (Fig. 4B). Compared to PRU
on Plavitor®therapy, that on Plavix®therapy showed a
bias of 10.8% and wide limits of agreement ranging from -
87.5 to 109.1 (Fig. 4C). Agglatevalues after stimuli with 5
and 20 µmol/L ADP also showed poor accord between
Plavix®and Plavitor®therapies (Fig. 4D and 4E).
DISCUSSION
This, ACCEL-GENERIC study compared residual
platelet reactivity measured by LTA and the POC
VerifyNow assay after therapy with original versus generic
clopidogrel bisulfate. There were no inter-therapy differences
in residual platelet reactivity in patients treated with
coronary stents. However, inter-therapy agreements were
poor when comparing platelet function measurements,
indicating that there might be a risk of clinical events in
some cases after switching to generic clopidogrel bisulfate.
In-vitro platelet function assays have revealed response
variability in platelet inhibition with the standard clopidogrel
dose [28]. Furthermore, high residual platelet reactivity
contributes to adverse clinical outcomes, including ST after
stenting or in ACS patients [22-25]. Adequate inhibition of
ADP-induced platelet aggregation by P2Y12 antagonists
may contribute to decreased rates of ischemic clinical
events.
Studies have investigated whether platelet reactivity
events accrue after a cut-off point of platelet reactivity in a
stepwise or linear manner, and recent data have shown
that a potential threshold of platelet reactivity, measured
by ADP-induced LTA or the POC VerifyNow assay, may
be associated with an increased risk of post-discharge
ischemic events after PCI [22-25,29-31]. This suggests
that in patients with platelet reactivity values below a
threshold point, the risk of adverse clinical events is minimal.
An definite threshold of HPPR has not been estab-
lished [32]. Bliden et al. [33] demonstrated that PCI-treaty
patients with a 5 µmol/L ADP-induced Aggmax≥ 50%
were at increased risk for recurrent ischemic events (odds
ratio, 34.6; 95% CI, 8.3 to 144.2; p < 0.001). Based on this
suggested value, our patients demonstrated an increased
risk of HPPR after switching from Plavix®to Plavitor®
(0% vs. 30%, p < 0.001). However, when we adopted
another suggested value of PRU ≥ 240 [29-31], switching
from Plavix®to Plavitor®produced a reduced risk of high
residual platelet reactivity (45% vs. 35%, p = 0.009).
Although there were some differences between the results
obtained with the two methods, poor inter-therapy
agreement suggests that switching medications may
increase the possibility of risk of adverse ischemic events
in some patient. Therefore, physicians should be cautious
when routinely switching to generic clopidogrel due to
cost, particularly during the early phase of coronary
stenting or ACS.
Recently, Kimura et al. [34] demonstrated that Japanese

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160The Korean Journal of Internal Medicine Vol. 25, No. 2, June 2010
patients with sirolimus-eluting stents showed a relatively
lower incidence of ST (0.2% per year), and discontinuation
of thienopyridine only in these patients was not associated
with any increased risk of ST beyond 6 months. Based on
these data, we may consider that switching to generic
clopidogrel may be possible in Asian patients be, and 6
months after coronary stenting. However, the decision to
introduce generic clopidogrel might be determined based
on analysis of platelet function, clinical risk factor, and
lesion complexity.
The short duration of the study period and the small
number of study subjects limits the conclusions that can
be drawn from our study. Other limitation includes
variability in LTA values with sample conditions and
processing, even though an expert performed the platelet
function tests and validation tests daily. However, while
the present study does not have the statistical power to
confirm the efficacy of Plavitor®over Plavix®, the pilot
data justify conducting a larger, more definitive study.
In conclusion, among patients on Plavix®maintenance
therapy after coronary stenting, a switch to Plavitor®
produces a similar inhibition of ADP-induced platelet
aggregation. However, inter-therapy agreement between
platelet function measurements is relatively poor. Thus,
physicians may be cautious when routinely introducing
generic clopidogrel bisulfate.
Conflict of interest
This study was partly supported by grants from the
Dong-A Pharmaceutical Corporation, Seoul, Korea.
No potential conflict of interest relevant to this article
was reported.
Acknowledgements
This study was partly supported by grants from the
Research Foundation of Gyeongsang National University
Hospital, Jinju, Korea.
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