European Journal of Pharmacology 725 (2014) 18–22

Contents lists available at ScienceDirect

European Journal of Pharmacology

journal homepage: www.elsevier.com/locate/ejphar

Cardiovascular pharmacology

Pharmacodynamic effects of atorvastatin versus rosuvastatin in

coronary artery disease patients with normal platelet reactivity while
on dual antiplatelet therapy—The PEARL randomized cross-over study
Francesco Pelliccia a,n, Giuseppe Rosano b, Giuseppe Marazzi b, Cristiana Vitale b,c,
Ilaria Spoletini b, Ferdinando Franzoni d, Giuseppe Speziale e, Marina Polacco a,
Cesare Greco a, Carlo Gaudio a,f
a
Department “Attilio Reale”, Sapienza University, Rome, Italy
b
Medical Science Departement, IRCCS San Raffaele Pisana, Rome, Italy
c
Laboratory of Vascular Physiology, IRCCS San Raffaele, London, UK
d
Department of Internal Medicine, University of Pisa, Pisa, Italy
e
Anthea Hospital, GVM Care & Research, ES Health Science Foundation, Bari, Italy
f
Eleonora Lorillard Spencer Cenci Foundation, Rome, Italy

art ic l e i nf o a b s t r a c t

Article history: High platelet reactivity during co-administration of clopidogrel and a CYP3A4-metabolized statin (i.e.
Received 16 August 2013 atorvastatin) can be lowered by switching to a non-CYP3A4-metabolized statin (i.e rosuvastatin). Aim of
Received in revised form this study was to verify if atorvastatin and rosuvastatin have different pharmacodynamic effects also
23 December 2013
when platelet reactivity while on dual antiplatelet therapy (DAPT) is normal at baseline. A total of 122
Accepted 8 January 2014
Available online 17 January 2014
stable coronary artery disease patients receiving DAPT (clopidogrel 75 mg plus aspirin 100 mg) who had
evidence of normal platelet reactivity after a 1-week statin wash-out entered the trial. Patients were
Keywords: randomly assigned to atorvastatin (40 mg day, n ¼61) or rosuvastatin (20 mg day, n ¼61) for 30 days.
Clopidogrel After another 1-week wash-out to avoid any carryover effect, cross-over was performed, and patients
Coronary artery disease
were switched to the other drug which was continued for 30 days. Platelet reactivity (expressed as P2Y
Percutaneous coronary intervention
(12) reaction units (PRU) by the VerifyNow assay [Accumetrics, San Diego, California]) was measured
Platelet reactivity
after 1-week statin wash-out and at the end of each treatment period. High platelet reactivity was
defined as a PRU value 4235. After 30-day atorvastatin, platelet reactivity did not significantly change as
compared with pre-treatment evaluation (119 766 vs. 1367 59 PRU, NS), with 2 patients only showing a
PRU 4235. Similarly, after 30-day rosuvastatin, platelet reactivity was unchanged vs. baseline (135746
vs. 1287 62 PRU, NS), with PRU 4235 occurring in 3 patients. Atorvastatin does not negatively affect
DAPT as compared with rosuvastatin when is given to stable coronary artery disease patients with
normal platelet reactivity while in statin wash-out (ClinicalTrials.gov Identifier: NCT01567774).
& 2014 Elsevier B.V. All rights reserved.

1. Introduction The variability in the response to clopidogrel has been linked to

Dual antiplatelet therapy (DAPT) based on the combination
of clopidogrel and aspirin is widely used to achieve sustained
platelet inhibition in high-risk patients with coronary artery
disease (Levine et al., 2011). The pharmacodynamic effect of
clopidogrel, however, varies substantially among patients and
constitutes an important clinical problem as high on-treatment
platelet reactivity is associated with an increased risk of major
adverse cardiac events (Brar et al., 2011).
n
Corresponding author. Tel.: þ 39 348 3392006; fax: þ 39 06 330 62516.
E-mail address: f.pelliccia@mclink.it (F. Pelliccia).
drug–drug interactions, particularly with statins, that influence the
function of cytochrome P450 isoenzymes (Bates et al., 2011). Some
lipophilic statins, i.e. simvastatin and atorvastatin, may inhibit the
CYP3A4 enzyme, and therefore decrease the formation of the active
metabolite of clopidogrel (Clarke and Waskell, 2003). On the con-
trary, the cytochrome P450 mediated metabolism of rosuvastatin is
principally mediated by the 2C9 isoenzyme with little involvement of
CYP3A4 (Angiolillo and Alfonso, 2007), and therefore the drug has a
low potential for pharmacologic interactions. It remains undefined,
however, if atorvastatin and rosuvastatin have different pharmaco-
dynamic effects also when they are given to coronary artery disease
patients with normal platelet reactivity while on DAPT.
To address this issue, we designed the PEARL (Pharmacody-
namic Effects of Atorvastatin vs. Rosuvastatin in coronary artery

0014-2999/$ - see front matter & 2014 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.ejphar.2014.01.006
 F. Pelliccia et al. / European Journal of Pharmacology 725 (2014) 18–22
disease patients with normal platelet reactivity while on duaL
antiplatelet therapy) trial, a prospective, randomized, cross-over
trial aimed at comparing the pharmacodynamic effects of the co-
treatment with the CYP3A4-metabolized atorvastatin or the non-
CYP3A4-metabolized rosuvastatin on the efficacy of clopidogrel
maintenance treatment in coronary artery disease patients show-
ing normal platelet reactivity while on DAPT.
2. Materials and methods
2.1. Study population
All stable patients with angiographically documented coronary
artery disease who underwent percutaneous coronary interven-
tion with 1 or more drug-eluting stents between January 2011 and
December 2012 were screened for the PEARL trial. By protocol,
only patients on chronic ( 410 days) therapy with clopidogrel
(75 mg/day) were considered for the study. Patients were not
deemed eligible if they had contraindications to statin treatment,
platelet function disorder or platelet count o150,000/ml, hemo-
globin o10 g/dl, need for warfarin treatment, active liver disease
or liver cirrhosis, unexplained transaminase increase Z 2 times
the upper limit of normal, peripheral muscle disease or creatine
kinase Z2.5 times the upper limit of normal, current treatment
with proton-pump inhibitors and/or omega-3, acute renal failure
or end-stage renal failure requiring dialysis, active bleeding
or recent (o1 month) bleeding diathesis, previous hemorrhagic
stroke, malignancy, and refusal of consent. The study was con-
ducted in accordance with the Declaration of Helsinki, and was
approved by the Institutional Board Review Committee. All eligible
patients signed informed, written consent. The PEARL trial is
registered at ClinicalTrials.gov (Identifier: NCT01567774).
2.2. Study design
The PEARL trial was a prospective, randomized, 2-period,
crossover trial. The study design is illustrated in Fig. 1. Patients
deemed to be eligible for the PEARL trial were offered to partici-
pate to the trial at time of 1-month post-angioplasty follow-up
visit. A total of 205 patients agreed to be included in the study and
therefore entered a wash-out period from any concomitant statin
therapy. All patients had VerifyNow P2Y12 platelet function test
(Accumetrics, San Diego, California) 1 week later in order to detect
the assess platelet function. High platelet reactivity was defined
as P2Y12 reaction units (PRU) Z235, a cut-off value proposed
by multiple previous studies (Price et al., 2008; Patti et al., 2008;
Marcucci et al., 2009; Bonello et al., 2010). Of these, 83 had a
Fig. 1. Study design and subject disposition.
19
PRUZ 235 and thus a total of 122 patients were included in the
study. Enrolled patients were then randomly assigned in a 1:1
fashion to a regimen of atorvastatin (40 mg day, n ¼ 61) or
rosuvastatin (20 mg day, n¼ 61) for 30 days. After another
1-week wash-out period to avoid any carryover effect, cross-over
was performed, and patients were switched to the other drug
which was continued for 30 days (Fig. 1). Platelet reactivity was
measured after the initial 1-week statin wash-out period and at
the end of each 30-day treatment period. Compliance and adverse
events were assessed by principal investigator (FP) based on
interview, pill counting, and a questionnaire. The primary end-
point of the trial was the PRU after each 30 day treatment period.
2.3. Platelet reactivity
Blood samples for platelet function testing were collected 2 h
after the ingestion of the last clopidogrel dose (6:00 AM) and 10 h
after the ingestion of the last statin dose (10:00 PM). Platelet
reactivity was evaluated by means of VerifyNow P2Y12 assay,
which is a whole blood, point-of-care turbidimetric assay that
measures the responsiveness to P2Y12 antagonists (Malinin et al.,
2006). The test measures ADP-induced platelet agglutination as an
increase in light transmittance and utilizes a proprietary algorithm
to report values in PRU, which measures platelet aggregation in
separate channels in response to ADP. Also, the device estimates
the maximal platelet function independent of P2Y12 receptor
blockade (BASE), which represents total platelet function in
response to thrombin receptor activating peptide. The instrument
provides the percent platelet P2Y12 inhibition (IPA), calculated by
comparing the PRU from the ADP channel to the PRU from the
thrombin receptor activating peptide channel. Genotyping of the
CYP2C19n2 loss-of-function polymorphism was performed with a
commercially available validated drug metabolism genotyping
assay (TaqMan Validated SNP assays) with the 7900HT sequence
Detection System (Applied Biosystems, Foster City, California)
(Saracini et al., 2012).
2.4. Coronary angiography and intervention
All interventions were performed according to standard tech-
niques. Analysis of coronary angiograms obtained before and after
angioplasty was independently performed by the core laboratory
ROMA (Ricerche Orientate alla Malattia Aterosclerotica). Percuta-
neous coronary intervention was performed according to current
standard guidelines, with the type of stent implanted left to the
discretion of the operator.
2.5. Adjunct drugs
According to our Institutional protocol, all stable patients
scheduled to undergo elective angiography are prescribed with
aspirin (100 mg/day) and clopidogrel (300 mg loading dose
followed by a maintenance dose of 75 mg/day) for at least 7 days.
During angioplasty, patients received procedural anticoagulation
with weight adjusted doses (100 U/kg) of unfractionated heparin.
Additional doses of unfractionated heparin were given to achieve
and maintain activated clotting time values 4300 s. After angio-
plasty, the protocol-mandated antiplatelet therapy consisted
of aspirin 100 mg/day indefinitely and clopidogrel 75 mg/day for
12 months. Other medications such as beta-blockers, angiotensin-
converting enzyme inhibitors, and angiotensin receptor blockers
were given as appropriate. Other lipid-lowering treatment or
medications that affect CYP3A4 mediated drug metabolism were
not permitted during the study. These included erythromycin,
antimycotic agents, and cyclosporine. Any change in other medi-
cations was not permitted during the study period.
20 F. Pelliccia et al. / European Journal of Pharmacology 725 (2014) 18–22

2.6. Statistical analysis
Data are presented as mean7standard deviation (S.D.) for con-
tinuous variables or frequency percentages for categorical variables.
Kolmogorov–Smirnov testing was applied to assess normality of
distribution for continuous variables. Chi-square test, or Fisher0 s exact
tests, when appropriate, were used to compare differences between
categorical variables, respectively. Non-normally distributed continu-
ous variables were compared by Kruskal–Wallis test and Mann–
Whitney U test. The repeated-measure analysis of variance was used
to evaluate platelet reactivity changes over time. The sample size
calculation (Campbell et al., 1995) was made by assuming baseline
mean7standard deviation of the PRU under clopidogrel treatment of
120750. The null hypothesis was that there was no difference in
clopidogrel effect during the atorvastatin and rosuvastatin treatments,
and the study was powered to reject this hypothesis. We calculated
that we needed to include a minimum of 116 patients to be able to
detect a 15% difference in means of PRU values with a power of 95%
and a 2-sided alpha value of 0.05. All analyses were performed with
the S-Plus statistical package (Mathsoft Inc, Seattle, Washington).
A two-sided P value o0.05 was considered statistically significant.
3. Results
3.1. Patients characteristics
Study patients demographics and baseline characteristics
are shown in Table 1. The mean age for the entire study cohort
was 62 715 years. Twenty-one percent of patients had diabetes
mellitus, and 48% multivessel coronary disease.
protocol. Withdrawal from the study drug occurred in 1 patient
during the 30-day atorvastatin treatment and in 1 patient during
rosuvastatin treatment. As regards side effects, 2 patients, 1 during
atorvastatin and 1 during rosuvastatin treatment, presented a
transaminase increase 42 the upper limit of normal.
3.3. Platelet reactivity
Results of platelet reactivity at each time point for both groups
are presented in Table 2. By definition, platelet reactivity was
normal in all patients at baseline (119 766). After the 30-day
treatment with atorvastatin, platelet reactivity (136 759 PRU) was
not significantly different than pre-treatment evaluation, with
2 patients only showing a PRU 4235. Similarly, after 30-day
treatment with rosuvastatin, platelet reactivity was unchanged as
compared with baseline (128762 PRU), with PRU 4235 occur-
ring in 3 patients. Similarly, BASE values did not significantly
change as compared with pre-treatment evaluation either after
the 30-day treatment with atorvastatin or after 30-day treatment
with rosuvastatin (Table 2). Based on the results of PRU and BASE,
the mean IPA did not significantly change as compared with pre-
treatment evaluation either after 1 month treatment with ator-
vastatin or after 1 month treatment with rosuvastatin (Fig. 2).
A subset of 44 patients had genotyping of the CYP2C19n2 loss-of-
function polymorphism. No significant differences in PRU with
atorvastatin and rosuvastatin were observed in patients stratified
for CYP2C19n2 loss-of function allele frequencies (n1n1: 126 748
vs. 132 742, NS; n1n2: 146 739 vs. 132 732, NS; n2n2: 139 739 vs.
1337 52, NS).
3.4. Lipid levels

3.2. Study treatment Patients showed a significant reduction in total cholesterol and
low-density lipoprotein cholesterol levels at 30 days, either with
All patients enrolled in the study underwent platelet reactivity atorvastatin or with rosuvastatin. Therapies with atorvastatin and
testing as scheduled, and all were 100% compliant with the study rosuvastatin did not significantly affect high-density lipoprotein
cholesterol levels and triglycerides (Table 3).
Table 1
Baseline clinical and angiographic characteristics of the study patients. Values are
given as number of patients (%) or mean 7 S.D.
4. Discussion
Overall study population
(N ¼ 122) The principal findings from this crossover, randomized trial
is that atorvastatin co-treatment is not associated with a higher
Age (years) 627 15 platelet reactivity as compared with rosuvastatin when is given to
Male sex 86 (74%)
patients with baseline normal platelet reactivity while on dual
Medical history anti-platelet treatment.
Current smoking 68 (56%)
Hypertension 59 (48%)
Total cholesterol 4200 mg/dl 77 (63%) Table 2
Diabetes mellitus 26 (21%) Distribution of platelet function parameters over study time course. Values are
History of angina 34 (28%) given as number of patients (%) or mean 7S.D.
Previous myocardial infarction 38 (31%)
Previous percutaneous coronary 21 (17%) Baseline (1 week Atorvastatin Rosuvastatin
intervention statin wash-out) 30-day 30-day
Previous coronary artery by-pass grafting 10 (8%)
P2Y12 reaction units
Laboratory data Baseline 1197 66 1367 59 128 7 62
Angiographic features Absolute difference þ 177 9 þ9 7 8
1-vessel 63 (52%) from baseline
2- or 3-vessels 59 (48%) Relative difference from þ 147 10 þ8 7 7
Left ventricular ejection fraction (%) 60 7 11 baseline (%)
Blood creatinine (mg/dL) 1.25 7 0.35
P2Y12 receptor blockade
Baseline 205 7 69 1917 55 216 7 73
Concomitant medications Absolute difference  147 10 þ 11 7 9
Beta-blockers 89 (73%) from baseline
Calcium-channel blockers 28 (23%) Relative difference from  77 6 þ5 7 5
ACE-inhibitors 70 (57%) baseline (%)
Angiotensin receptor blockers 24 (20%) P2Y12 receptor 427 29 287 21 41 7 24
Nitrates 36 (30%) blockade (%)
 F. Pelliccia et al. / European Journal of Pharmacology 725 (2014) 18–22
Fig. 2. P2Y12 reaction units (left panel) and percent inhibition (right panel) at the end of the 30-day atorvastatin vs. rosuvastatin therapy.
Table 3
Change in total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density
lipoprotein (HDL) cholesterol, and triglycerides at the end of the 30-day period of
treatment with atorvastatin and rosuvastatin.
Baseline (1 week Atorvastatin Rosuvastatin
statin wash-out) 30-day 30-day
Total cholesterol (mg/dl) 205 749 1567 38a,b 1447 34a,b
LDL cholesterol (mg/dl) 128 723 847 36a,b 787 27a,b
HDL cholesterol (mg/dl) 47 715 457 12 467 16
Triglycerides (mg/dl) 121 762 1157 43a,b 1187 54
Values are given as number of patients (%) or mean 7S.D.
a
Indicates a significant difference with baseline condition (P o0.01).
b
Indicates a significant difference within group (Po 0.01).
The results of the PEARL trial further contribute to the debate
about possible drug-to-drug interference in patients receiving
clopidogrel. Clopidogrel is bioactivated by CYP3A4 mediated liver
metabolism that forms an active metabolite which irreversibly
binds to and inhibits the adenosine diphosphate P2Y12 receptor
(Gachet, 2001). As a result, CYP3A4-metabolized statins such as
atorvastatin might reduce the platelet inhibiting effects of clopi-
dogrel treatment due to interference with the CYP3A4-mediated
bioactivation of clopidogrel, though the clinical importance of this
putative drug–drug interaction is still to be defined (Steinhubl and
Akers, 2006).
In their pivotal study, Lau et al. (2003) used a novel point-of-
care method to study platelet microaggregation and found that
atorvastatin but not pravastatin treatment was associated with
a dose-dependent reduction of the antiplatelet activity of clopido-
grel 6–8 days after clopidogrel initiation. In support of the hypo-
thesis, strong CYP3A4 inhibition by erythromycin co-treatment
also reduced the efficacy of clopidogrel treatment. However, only 9
pravastatin-treated and 19 atorvastatin-treated patients were
studied, and statin co-treatment was not randomized (Lau et al.,
2003). Similarly, Piorkowski et al. (2004) assessed platelet reactiv-
ity in healthy individuals, 17 pretreated with atorvastatin and 17
without pretreatment, and in 15 patients with stable coronary
artery disease, and found that atorvastatin reduces platelet reac-
tivity before administration of clopidogrel. At variance with these
preliminary results, our findings yield no support to the hypoth-
esis that statin co-therapy would interfere with the efficacy of
clopidogrel maintenance therapy to any extent that might be
clinically important. We suggest that the most likely explanation
for the difference in results lies in the study designs, as our trial
was prospective and randomized, a design that minimizes possible
confounding factors, and not observational in nature.
The recent ACCEL-Study showed that in clopidogrel-treated
patients with high platelet reactivity during chronic co-adminis-
tration of atorvastatin, switching to a non-CYP3A4-metabolized
21
statin resulted in a significant decrease in platelet reactivity (Park
et al., 2012). The investigators concluded that their study supports
the beneficial effect of replacing atorvastatin therapy with a non-
CYP3A-metabolized statin with regard to reducing platelet reac-
tivity in clopidogrel-treated patients with high platelet reactivity.
Based on the results of our trial, however, the strategy proposed by
Park et al. should not be taken into consideration in those patients
with baseline normal platelet reactivity while on DAPT.
Our findings are in agreement with original findings from
Malmstrom et al. who investigated interactions between clopido-
grel and atorvastatin, simvastatin or rosuvastatin (a ‘non-CYP3A4’
metabolized statin) in a randomized, prospective study using
ex vivo platelet function tests (Malmström et al., 2009). Patients
were studied before and after 2 weeks treatment with clopidogrel
after completed atorvastatin and rosuvastatin dose titration,
and no dose-dependent effects of atorvastatin or rosuvastatin
co-treatment on clopidogrel efficacy were observed. They con-
cluded that treatment with CYP3A4 metabolized statins, atorvas-
tatin or simvastatin, did not attenuate the platelet inhibitory effect
of clopidogrel maintenance treatment compared with the non-
CYP3A4 metabolized, rosuvastatin. Similarly, Vinholt et al. (2009)
reported that the antiplatelet effect of clopidogrel is not attenu-
ated by concomitant treatment with a CYP3A4 metabolized statin.
They evaluated how CYP3A4 metabolized statins and non-CYP3A4
metabolized statins influence platelet aggregation when given
concomitantly with clopidogrel, but no difference was observed
between patients treated with a CYP3A4 metabolized statin –
simvastatin or atorvastatin – and patients receiving a non-CYP3A4
metabolized statin – pravastatin.
Our study suffers from some limitations. Only the VerifyNow
P2Y12 assay was used to evaluate platelet function. Also, we could
assess the CYP2C19 polymorphism in a subgroup of patients only.
One should consider, however, that recent findings suggests that
carriage of loss of function n2 allele of CYP2C19 gene only accounts
for 5% of the variability of the pharmacodynamic response to
clopidogrel (Bouman et al., 2011). In line with these observations,
we found no difference in PRU with atorvastatin and rosuvastatin
in the subset of our study patients that underwent genotyping and
were stratified according to CYP2C19n2 loss-of function allele
frequencies. Given its pilot nature, this study was not designed
to evaluate clinical outcomes, which would require larger popula-
tions. We did not measure clopidogrel and its active metabolite,
similarly to most other studies. The levels of clopidogrel and its
active metabolite are, however, likely to be similar either on
atorvastatin or rosuvastatin as the platelet inhibitory effects
were similar. In addition, one should take into account the possi-
bility that our results might have been affected in part by
the evolving pattern over time of on-clopidogrel platelet reactivity
(Campo et al., 2011). Finally, confounders could interfere with
alternative metabolic pathways of rosuvastatin, but possible effects
of differences in ongoing medications (nitrates and angiotensin
22 F. Pelliccia et al. / European Journal of Pharmacology 725 (2014) 18–22
inhibiting drugs) on clopidogrel efficacy are unlikely, as medications
were kept constant during the study.
5. Conclusion
In conclusion, the results of this crossover, randomized trial
yields no support to the possibility that statin co-therapy would
interfere with the efficacy of clopidogrel maintenance therapy to
any extent in those patients who show normal platelet reactivity
while on DAPT in statin wash-out. In this important subgroup of
patients, our results do not support the idea that co-treatment
with CYP3A4 metabolized statins attenuate the bioactivation of
clopidogrel to any extent that might be clinically important.
References
Angiolillo, D.J., Alfonso, F., 2007. Clopidogrel–statin interaction: myth or reality? J.
Am. Coll. Cardiol. 50, 296–298.
Bates, E.R., Lau, W.C., Angiolillo, D.J., 2011. Clopidogrel-drug interactions. J. Am. Coll.
Cardiol. 57, 1251–1263.
Bonello, L., Tantry, U.S., Marcucci, R., Blindt, R., Angiolillo, D.J., Becker, R., Bhatt, D.L.,
Cattaneo, M., Collet, J.P., Cuisset, T., Gachet, C., Montalescot, G., Jennings, L.K.,
Kereiakes, D., Sibbing, D., Trenk, D., Van Werkum, J.W., Paganelli, F., Price, M.J.,
Waksman, R., Gurbel, P.A., 2010. Consensus and future directions on the
definition of high on-treatment platelet reactivity to adenosine diphosphate.
J. Am. Coll. Cardiol. 56, 919–933.
Bouman, H.J., Bouman, H.J., Harmsze, A.M., van Werkum, J.W., Breet, N.J., Bergmei-
jer, T.O., Ten Cate, H., Hackeng, C.M., Deneer, V.H., Ten Berg, J.M., 2011.
Variability in on-treatment platelet reactivity explained by CYP2C19*2 geno-
type is modest in clopidogrel pretreated patients undergoing coronary stenting.
Heart 97, 1239–1244.
Brar, S.S., ten Berg, J., Marcucci, R., Price, M.J., Valgimigli, M., Kim, H.S., Patti, G.,
Breet, N.J., DiSciascio, G., Cuisset, T., Dangas, G., 2011. Impact of platelet
reactivity on clinical outcomes after percutaneous coronary intervention: a
collaborative meta-analysis of individual participant data. J. Am. Coll. Cardiol.
58, 1945–1954.
Campbell, M.J., Julious, S.A., Altman, D.G., 1995. Estimating sample sizes for binary,
ordered categorical, and continuous outcomes in two group comparisons. B.M.J.
311, 1145–1148.
Campo, G., Parrinello, G., Ferraresi, P., 2011. Prospective evaluation of on-
clopidogrel platelet reactivity over time in patients treated with percutaneous
coronary intervention: relationship gene polymorphisms clinical outcomes. J.
Am. Coll. Cardiol. 57, 2474–2483.
Clarke, T.A., Waskell, A.L., 2003. The metabolism of clopidogrel is catalyzed by
human cytochrome P450 3A and is inhibited by atorvastatin. Drug Metab.
Dispos. 31, 53–59.
Gachet, C., 2001. ADP receptors of platelets and their inhibition. Thromb. Haemost.
86, 222–232.
Lau, W.C., Waskell, L.A., Watkins, P.B., Neer, C.J., Horowitz, K., Hopp, A.S., Tait, A.R.,
Carville, D.G., Guyer, K.E., Bates, E.R., 2003. Atorvastatin reduces the ability of
clopidogrel to inhibit platelet aggregation: a new drug–drug interaction.
Circulation 107, 32–37.
Levine, G.N., Bates, E.R., Blankenship, J.C., Bailey, S.R., Bittl, J.A., Cercek, B., Chambers,
C.E., Ellis, S.G., Guyton, R.A., Hollenberg, S.M., Khot, U.N., Lange, R.A., Mauri, L.,
Mehran, R., Moussa, I.D., Mukherjee, D., Nallamothu, B.K., Ting, H.H., ACCF,
AHA, SCAI, 2011. 2011 ACCF/AHA/SCAI guideline for percutaneous coronary
intervention: a report of the American College of Cardiology Foundation/
American Heart Association Task Force on Practice Guidelines and the, Society
for Cardiovascular Angiography and Interventions. J. Am. Coll. Cardiol. 58,
e44–e122.
Malinin, A., Pokov, A., Swaim, L., Kotob, M., Serebruany, V., 2006. Validation of
VerifyNow-P2Y12 cartridge for monitoring platelet inhibition with clopidogrel.
Methods Find. Exp. Clin. Pharmacol. 28, 315–322.
Malmström, R.E., Ostergren, J., Jørgensen, L., Hjemdahl, P., 2009. CASTOR investi-
gators, 2009. Influence of statin treatment on platelet inhibition by clopidogrel
– a randomized comparison of rosuvastatin, atorvastatin and simvastatin co-
treatment. J. Intern. Med. 266, 457–466.
Marcucci, R., Gori, A.M., Paniccia, R., Giusti, B., Valente, S., Giglioli, C., Buonamici, P.,
Antoniucci, D., Abbate, R., Gensini, G.F., 2009. Cardiovascular death and nonfatal
myocardial infarction in acute coronary syndrome patients receiving coronary
stenting are predicted by residual platelet reactivity to ADP detected by a point-
of-care assay: a 12-month follow-up. Circulation 119, 237–242.
Park, Y., Jeong, Y.H., Tantry, U.S., Ahn, J.H., Kwon, T.J., Park, J.R., Hwang, S.J., Gho, E.H.,
Bliden, K.P., Kwak, C.H., Hwang, J.Y., Kim, S., Gurbel, P.A., 2012. Accelerated
platelet inhibition by switching from atorvastatin to a non-CYP3A4-
metabolized statin in patients with high platelet reactivity (ACCEL-STATIN)
study. Eur. Heart J. 33, 2151–2162.
Patti, G., Nusca, A., Mangiacapra, F., Gatto, L., D0 Ambrosio, A., Di Sciascio, G., 2008.
Point-of-care measurement of clopidogrel responsiveness predicts clinical
outcome in patients undergoing percutaneous coronary intervention: results
of the ARMYDA-PRO (Antiplatelet therapy for Reduction of Myocardial Damage
during Angioplasty–Platelet Reactivity Predicts Outcome) study. J. Am. Coll.
Cardiol. 52, 1128–1133.
Piorkowski, M., Weikert, U., Schwimmbeck, P.L., Martus, P., Schultheiss, H.P., Rauch, U.,
2004. ADP induced platelet degranulation in healthy individuals is reduced by
clopidogrel after pretreatment with atorvastatin. Thromb. Haemost. 92, 614–620.
Price, M.J., Endemann, S., Gollapudi, R.R., Valencia, R., Stinis, C.T., Levisay, J.P.,
Ernst, A., Sawhney, N.S., Schatz, R.A., Teirstein, P.S., 2008. Prognostic signifi-
cance of post-clopidogrel platelet reactivity assessed by a point-of-care assay
on thrombotic events after drug-eluting stent implantation. Eur. Heart J. 29,
992–1000.
Saracini, C., Vestrini, A., Galora, S., Armillis, A., Abbate, R., Giusti, B., 2012.
Pharmacogenetics of clopidogrel: comparison between a standard and a rapid
genetic testing. Genet. Test. Mol. Biomark. 16, 500–503.
Steinhubl, S.R., Akers, W.S., 2006. Clopidogrel-statin interaction: a mountain or a
mole hill? Am. Heart J. 152, 200–203.
Vinholt, P., Poulsen, T.S., Korsholm, L., Kristensen, S.R., Hallas, J., Damkier, P.,
Mickley, H., 2009. The antiplatelet effect of clopidogrel is not attenuated by
statin treatment in stable patients with ischemic heart disease. J. Intern. Med.
266, 457–466.