Brief Rapid Communications
Atorvastatin Does Not Affect the Antiplatelet Potency of
Clopidogrel When It Is Administered Concomitantly for 5
Weeks in Patients With Acute Coronary Syndromes
John V. Mitsios, MSc; Athanasios I. Papathanasiou, MD; Foteini I. Rodis, BSc; Moses Elisaf, MD;
John A. Goudevenos, MD; Alexandros D. Tselepis, MD, PhD
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
Background—The antiplatelet effect of clopidogrel may be attenuated by short-term coadministration of lipophilic statins.
We investigated whether the coadministration of atorvastatin for 5 weeks in patients with acute coronary syndromes
(ACS) could affect the antiplatelet potency of clopidogrel.
Methods and Results—Forty-five hypercholesterolemic patients with the first episode of an ACS were included in the
study. Patients were randomized to receive daily either 10 mg of atorvastatin (n⫽21) or 40 mg of pravastatin (n⫽24).
Thirty patients who underwent percutaneous coronary intervention (PCI) received a loading dose of 375 mg of
clopidogrel, followed by 75 mg/d for at least 3 months. In the remaining 15 patients who refused to undergo PCI,
clopidogrel therapy was not administered. Eight normolipidemic patients with the first episode of an ACS were also
included and received only clopidogrel. The serum levels of soluble CD40L and the adenosine 5⬘-diphosphate– or
thrombin receptor activating peptide-14 –induced platelet aggregation, as well as P-selectin and CD40L surface
expression, were studied at baseline (within 30 minutes after admission) and 5 weeks later. Neither atorvastatin nor
pravastatin significantly influenced the clopidogrel-induced inhibition of platelet activation, nor did clopidogrel
influence the therapeutic efficacy of atorvastatin.
Conclusions—Atorvastatin does not affect the antiplatelet potency of clopidogrel when coadministered for 5 weeks in ACS
patients. (Circulation. 2004;109:1335-1338.)
Key Words: acute coronary syndromes 䡲 clopidogrel 䡲 platelets 䡲 drugs
C
lopidogrel is an orally administered inactive thienopyridine prodrug that is metabolized primarily in the liver
and converted into an active metabolite that selectively and
irreversibly inhibits adenosine 5⬘-diphosphate (ADP)–
induced platelet aggregation.1 Recently, it was shown that
cytochrome P-450, isoform 3A4 (CYP3A4), is primarily
responsible for the metabolism and activation of clopidogrel
in vivo.2 Several studies have shown that clopidogrel decreases the incidence of coronary artery stent thrombosis and
is approved for reduction of myocardial infarction, stroke,
and vascular death in patients with atherosclerotic vascular
disease.3
Patients with symptomatic coronary artery disease and
hypercholesterolemia are frequently given clopidogrel in
conjunction with the HMG-CoA inhibitors (statins). Some of
the statins (atorvastatin, lovastatin, simvastatin, etc) are
metabolized in vivo predominantly by CYP3A4, whereas
others are either not metabolized through cytochrome P-450
(pravastatin) or are metabolized through the isoform 2C9 of
cytochrome P-450 (fluvastatin).4 The possible interference of
statins, metabolized through CYP3A4, with the antiplatelet
efficacy of clopidogrel in vivo during the first days of their
coadministration was recently addressed in patients undergoing elective coronary artery stent implantation. These studies
provided controversial results suggesting that these statins
either attenuate5 or do not influence6 the antiplatelet effect of
clopidogrel.
In the present study, we investigated the consequences of
concomitant use of atorvastatin and clopidogrel for 5 weeks
in patients with the first episode of acute coronary syndrome
(ACS) on the antiplatelet efficacy of clopidogrel. We show
for the first time that the therapeutic efficacy of clopidogrel is
not significantly affected by atorvastatin when both drugs are
coadministered for 5 weeks in patients with ACS.
Methods
Patient Selection
Forty-five patients (mean age, 60.9⫾11.2 years; range, 49 to 72
years; 41 men, 4 women; body mass index, 28.2⫾3.5 kg/m2) with the
first episode of an ACS (chest pain plus ECG changes and/or
Received December 19, 2003; revision received January 28, 2004; accepted January 29, 2004.
From the Laboratory of Biochemistry, Department of Chemistry, and Departments of Cardiology (A.I.P., J.A.G.) and Internal Medicine (M.E.), Medical
School, University of Ioannina, Ioannina, Greece.
Correspondence to Dr Alexandros D. Tselepis, MD, PhD, Laboratory of Biochemistry, Department of Chemistry, University of Ioannina, 45110
Ioannina, Greece. E-mail [email protected]
© 2004 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
DOI: 10.1161/01.CIR.0000124581.18191.15
1335
1336
Circulation
March 23, 2004
TABLE 1.
Platelet Activation Parameters in ACS Patients Treated With Clopidogrel and Statins
Clopidogrel ⫹ Atorvastatin
(n⫽13)
Clopidogrel
(n⫽8)
Baseline
After
Treatment
ADP, 2 ␮mol/L
31⫾9
ADP, 5 ␮mol/L
50⫾8
ADP, 10 ␮mol/L
TRAP-14, 10 ␮mol/L
Parameter
Change, %
Baseline
After
Treatment
16⫾7*
⫺52.1⫾5.9
29⫾10
26⫾10*
⫺51.3⫾10.5
54⫾14
68⫾14
41⫾15†
⫺42.5⫾11.7
53⫾12
51⫾14
Clopidogrel ⫹ Pravastatin
(n⫽17)
Change, %
Baseline
After
Treatment
Change, %
13⫾7*
⫺69.9⫾11.6
33⫾12
17⫾11*
⫺66.5⫾14.3
30⫾13*
⫺60.5⫾14.4
55⫾13
32⫾12*
⫺55.6⫾9.9
63⫾18
37.3⫾18.6†
⫺59.3⫾16.2
68⫾15
42⫾13†
⫺46.4⫾16.2
⫺4.9⫾0.7
48⫾18
44.9⫾17.5
⫺6.9⫾0.9
50⫾20
47⫾25
⫺6.4⫾1.2
Maximum aggregation, %
P-selectin expression, MFI
ADP, 50 ␮mol/L
26.2⫾9.6
13.6⫾6.5‡
⫺47.9⫾10.0
33.3⫾13.0
16.6⫾9.5‡
⫺50.5⫾12.8
27.3⫾6.3
14.8⫾5.7‡
⫺45.6⫾13.0
TRAP-14, 50 ␮mol/L
58.0⫾16.4
52.5⫾18.0
⫺9.3⫾3.4
65.2⫾25.9
59.2⫾12.9
⫺9.1⫾2.5
66.6⫾22.8
60.9⫾21.9
⫺8.4⫾1.7
CD40L expression, MFI
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
ADP, 50 ␮mol/L
0.96⫾0.33
0.54⫾0.28§
⫺44.1⫾14.1
0.88⫾0.37
0.48⫾0.29§
⫺45.1⫾15.1
0.91⫾0.32
0.54⫾0.22§
⫺40.8⫾12.7
TRAP-14, 50 ␮mol/L
1.68⫾0.49
1.55⫾0.56
⫺7.4⫾3.2
1.74⫾0.39
1.63⫾0.56
⫺6.5⫾1.8
1.89⫾0.51
1.79⫾0.43
⫺5.6⫾1.5
8.51⫾3.22
7.98⫾2.65
⫺6.2⫾1.1
8.24⫾2.67
7.70⫾1.54
⫺6.6⫾2.0
7.92⫾3.12
7.46⫾2.39
⫺5.8⫾1.4
sCD40L, ng/mL
MFI indicates mean fluorescence intensity.
*P⬍0.01, †P⬍0.02, ‡P⬍0.03, and §P⬍0.04 vs baseline values.
increased biochemical markers) and LDL cholesterol levels ⬎100
mg/dL (measured within 24 hours from the onset of symptoms) were
included in the study. No patient had a previous history of cardiovascular disease, and none were taking medication before the
coronary event. On admission, all patients received regular aspirin
therapy (100 mg/d). Patients were randomized to receive daily either
atorvastatin 10 mg (n⫽21) or pravastatin 40 mg (n⫽24) within 24
hours of admission. In 30 patients who underwent percutaneous
coronary intervention (PCI) with stent implantation, clopidogrel
therapy was initiated with a loading dose of 375 mg 6 to 12 hours
before PCI, followed by 75 mg/d. In 15 patients who were treated
with either atorvastatin (n⫽8) or pravastatin (n⫽7) and refused to
undergo PCI, clopidogrel therapy was not administered. Eight
normolipidemic patients (LDL cholesterol levels measured within 24
hours from the onset of symptoms ⬍100 mg/dL) with the first
episode of an ACS were also included in the study. They underwent
PCI with stent implantation and received clopidogrel but no statin
therapy (clopidogrel group). Compliance with treatment and with
diet was assessed as previously described.7 There was no significant
change in patients’ body weight or smoking habits during the study
period. The Ethics Committee of the University Hospital of Ioannina
approved the study, and written informed consent was obtained from
each patient.
Laboratory Determinations
Venous blood samples for platelet and lipid analysis were drawn at
baseline (within 30 minutes after admission) and 5 weeks later.
Platelet aggregation to ADP (2, 5, and 10 ␮mol/L) or to thrombin
receptor activating peptide-14 (TRAP-14; 10 ␮mol/L) was determined in platelet-rich plasma as previously described.8 The degree of
platelet activation was also evaluated by FACScan flow cytometry
(Becton-Dickinson), determining the surface expression of P-selectin
(CD62p) and CD40L induced by ADP or TRAP-14 (50 ␮mol/L for
either agonist) by use of the monoclonal antibodies CD62p and
CD154, respectively. Flow cytometry results are presented as the
mean fluorescence intensity of the activated sample minus the mean
fluorescence intensity of the unactivated sample as previously
described.9 Platelet activation in vivo was also studied by measuring
the plasma levels of soluble CD40L (sCD40L) with a commercially
available ELISA kit (Bender Medsystems). Serum lipid levels and
biochemical markers of liver and muscle function were determined
with an automatic analyzer (Olympus AU560).
Statistics
All values are expressed as mean⫾SD. ANOVA was assessed for
comparison of baseline parameters among the study groups. Changes
in the measured parameters after drug therapy were evaluated with
the Wilcoxon signed rank test. Differences in the changes observed
among studied groups were compared by ANCOVA, taking into
account the baseline values as a covariate. Categorical variables were
compared by Fisher’s exact ␹2 test. A value of Pⱕ0.05 was
considered significant.
Results
There were no differences in age, sex, body mass index, or
cardiovascular risk factors (current smoking, hypertension,
diabetes mellitus) among patient groups (data not shown). No
patient was under treatment with other medications that might
influence cytochrome P-450 metabolism or might have interfered with platelet function. As shown in Table 1, the baseline
values of all platelet activation parameters were not different
among all studied groups. Clopidogrel administration for 5
weeks significantly attenuated the platelet aggregatory response to 3 different concentrations of ADP ex vivo. Similarly, clopidogrel inhibited ADP-induced expression of
P-selectin and CD40L. Coadministration of clopidogrel with
either atorvastatin or pravastatin inhibited ADP-induced
platelet activation to the same extent as that observed for
clopidogrel alone (Table 1). The posttreatment values of all
the above platelet activation markers were lower but not
significantly different compared with the baseline values in
patients receiving atorvastatin or pravastatin (data not
shown).
Clopidogrel did not influence the platelet-aggregatory response to TRAP-14 or the TRAP-14 –induced surface expression of P-selectin and CD40L, although the posttreatment
values were lower than the baseline values (Table 1). Similar
results were obtained in patients treated with clopidogrel and
atorvastatin or pravastatin and in those treated only with
statin. Finally, the posttreatment plasma levels of sCD40L,
used as a marker of platelet activation in vivo, were lower but
Mitsios et al
TABLE 2.
Atorvastatin and Clopidogrel in Platelet Function
1337
Lipidemic Profile and Serum Levels of Liver and Muscle Enzymes in ACS Patients Treated With Clopidogrel and Statins
Clopidogrel ⫹ Atorvastatin
(n⫽13)
Clopidogrel ⫹ Pravastatin
(n⫽17)
Atorvastatin
(n⫽8)
Pravastatin
(n⫽7)
Lipid
Parameter
Baseline
After
Treatment
Change,
%
Baseline
After
Treatment
Change,
%
Baseline
After
Treatment
Change,
%
Baseline
After
Treatment
Change,
%
TC, mg/dL
223⫾56
163⫾55*
⫺26.5⫾4.4
241⫾30
172⫾49*
⫺28.8⫾5.1
245⫾53
188⫾31*
⫺23.6⫾6.5
249⫾46
192⫾47*
⫺22.6⫾7.4
LDL-C, mg/dL
144⫾63
91⫾41†
⫺37.0⫾9.1
154⫾42
98⫾41†
⫺36.1⫾7.6
162⫾48
113⫾35†
⫺30.4⫾7.8
155⫾47
110⫾62†
⫺28.8⫾9.7
TG, mg/dL
154⫾68
139⫾57
⫺9.5⫾1.1
165⫾31
148⫾34
⫺10.5⫾0.8
176⫾34
167⫾59
⫺4.8⫾0.7
167⫾91
159⫾65
⫺5.0⫾1.0
HDL-C, mg/dL
48.0⫾9.2
49.6⫾7.1
3.1⫾0.6
44.3⫾5.6
45.6⫾13.0
3.2⫾0.6
47.8⫾8.9
48.7⫾5.6
2.1⫾0.3
41.7⫾7.5
42.2⫾4.0
1.4⫾0.4
ALT, IU/L
䡠䡠䡠
31⫾11
䡠䡠䡠
䡠䡠䡠
30⫾10
䡠䡠䡠
䡠䡠䡠
36⫾8
䡠䡠䡠
䡠䡠䡠
35⫾7
AST, IU/L
䡠䡠䡠
22⫾5
䡠䡠䡠
䡠䡠䡠
24⫾5
䡠䡠䡠
䡠䡠䡠
20⫾4
䡠䡠䡠
䡠䡠䡠
22⫾3
LDH, IU/L
䡠䡠䡠
334⫾34
䡠䡠䡠
䡠䡠䡠
307⫾33
䡠䡠䡠
䡠䡠䡠
316⫾38
䡠䡠䡠
䡠䡠䡠
326⫾42
CK, IU/L
䡠䡠䡠
70⫾20
䡠䡠䡠
䡠䡠䡠
75⫾19
䡠䡠䡠
䡠䡠䡠
83⫾24
䡠䡠䡠
䡠䡠䡠
85⫾26
TC indicates total cholesterol; LDL-C, LDL cholesterol; TG, triglycerides; HDL-C, HDL cholesterol; ALT, alanine aminotransferase; AST, aspartate aminotransferase;
LDH, lactic dehydrogenase; and CK, creatine phosphokinase.
*P⬍0.005, †P⬍0.01 vs baseline values.
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
not significantly different compared with the baseline values
in all patient groups (Table 1).
The present study also demonstrates that the coadministration of clopidogrel with atorvastatin for 5 weeks did not
influence the hypolipidemic effect of atorvastatin, and the
same results were obtained in patients treated with clopidogrel and pravastatin (Table 2). Importantly, none of our
patients exhibited increased serum levels of liver or muscle
enzymes (more than 3 times the upper normal limits) (Table
2) or myositis during the study period. As expected, no
difference between baseline and posttreatment values in all
lipid parameters studied was observed in normolipidemic
patients treated with clopidogrel alone (data not shown).
Finally, it must be noted that no significant difference
between baseline and posttreatment body mass index values
was observed in any patient group.
Discussion
The results of the present study demonstrate that the coadministration of atorvastatin with clopidogrel in patients with
the first episode of an ACS for 5 weeks does not significantly
influence the antiplatelet activity of clopidogrel. Recent
studies provided controversial results as to whether shortterm (1 to 8 days) therapy with clopidogrel in conjunction
with lipophilic statins could attenuate the antiplatelet efficacy
of clopidogrel.5,6 Data from a post hoc analysis of the
Clopidogrel for Reduction of Events During Observation
(CREDO) trial showed that there is no adverse effect on the
28-day or 1-year composite clinical end points with clopidogrel and statin coadministration.10 Similarly, the results of
the prospective Maximal Individual TheRapy of Acute myocardial infarction PLUS (MITRA PLUS) registry demonstrated that there was no significant difference between
atorvastatin therapy and other statin therapies over a
follow-up period of 14 months in the clinical outcomes
(mortality and stroke) of patients receiving clopidogrel therapy.11 In accordance with these studies, our results demonstrate for the first time that atorvastatin plus clopidogrel
therapy for 5 weeks is as effective at the level of platelet
function as that obtained with clopidogrel alone or the
combination of clopidogrel plus the hydrophilic pravastatin.
Overall, on the basis of the results of all recent studies,
including ours, we may suggest that although CYP3A4metabolized statins may influence the antiplatelet effect of
clopidogrel within the first days of coadministration, concomitant use of these drugs for a longer period of time (4 to 5
weeks or longer) does not have an adverse interaction in
platelet function and does not affect the clinical outcome.
It is known that the degree of competitive inhibition
between 2 substrates of CYP3A4 depends on their relative
concentrations as well as on their relative affinity for the
CYP3A4 binding site.12 Clopidogrel exhibits lower affinity
for CYP3A4 than atorvastatin or its lactone metabolite, and
on a daily basis, its plasma levels may be remarkably lower
than those of atorvastatin. However, we should not exclude
the possibility that clopidogrel could affect the CYP3A4catalyzed conversion of atorvastatin to its inactive lactone
form, thus influencing the effectiveness of this statin. Nevertheless, our results provide evidence that clopidogrel does not
influence the hypolipidemic effect of atorvastatin, and most
importantly, none of our patients exhibited an elevation of
liver and muscle enzymes that could be observed in cases of
competitive inhibition of atorvastatin metabolism, resulting in
high plasma concentrations of this statin.13
A limitation of the present study could be that the baseline
values of all platelet activation parameters may be elevated
because of the acute coronary event.14,15 However, according
to our results, the posttreatment values of platelet activation
to TRAP-14, the activity of which is not influenced by
clopidogrel, were lower but not significantly different compared with the baseline values. The same phenomenon was
observed in patients treated with statins alone. Furthermore,
the plasma levels of sCD40L (used as a marker of in vivo
platelet activation) were lower but not significantly different
compared with the baseline values in all patient groups. These
lower posttreatment values of platelet activation parameters
reflect the trend of these parameters to reach the normal
values, a phenomenon that is observed within 6 months after
the onset of the ACS.15 Consequently, the significant de-
1338
Circulation
March 23, 2004
crease in platelet activation observed in the present study
could be attributed exclusively to clopidogrel.
In conclusion, our study shows for the first time that the
therapeutic efficacy of clopidogrel in patients with ACS is not
significantly influenced by the concomitant administration of
atorvastatin for 5 weeks. Moreover, clopidogrel does not
affect the therapeutic efficacy of atorvastatin.
References
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
1. Savi P, Pereillo JM, Uzabiaga MF, et al. Identification and biological
activity of the active metabolite of clopidogrel. Thromb Haemost. 2000;
84:891– 896.
2. Sugidachi A, Asai F, Yoneda K, et al. Antiplatelet action of R-99224, an
active metabolite of a novel thienopyridine-type G(i)-linked P2T antagonist, CS-747. Br J Pharmacol. 2001;132:47–54.
3. The CURE Trial Investigators. Effects of clopidogrel in addition to
aspirin in patients with acute coronary syndromes without ST-elevation.
[Published correction appears in N Engl J Med. 2001;345:1506, 1716].
N Engl J Med. 2001;345:494 –502.
4. Christians U, Jacobsen W, Floren LC. Metabolism and drug interactions
of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors in
transplant patients: are the statins mechanistically similar? Pharmacol
Ther. 1998;80:1–34.
5. Lau WC, Waskell LA, Watkins PB, et al. Atorvastatin reduces the ability
of clopidogrel to inhibit platelet aggregation: a new drug-drug interaction.
Circulation. 2003;107:32–37.
6. Müller I, Besta F, Schulz C, et al. Effects of statins on platelet inhibition
by a high loading dose of clopidogrel. Circulation. 2003;108:2195–2197.
7. Tsimihodimos V, Karabina SA, Tambaki AP, et al. Atorvastatin preferentially reduces LDL-associated platelet-activating factor acetylhydrolase
activity in dyslipidemias of type IIA and type IIB. Arterioscler Thromb
Vasc Biol. 2002;22:306 –311.
8. Goudevenos J, Tselepis AD, Tsoukatos D, et al. Platelet aggregability to
platelet activating factor at rest and after exercise in patients with coronary artery disease. Eur Heart J. 1995;16:1036 –1043.
9. Biris N, Abatzis M, Mitsios JV, et al. Mapping the binding domains of the
␣IIb subunit: a study performed on the activated form of the platelet
integrin ␣IIb␤3. Eur J Biochem. 2003;270:3760 –3767.
10. Saw J, Steinhubl SR, Berger PB, et al. Clopidogrel for the Reduction of
Events During Observation Investigators. Lack of adverse clopidogrelatorvastatin clinical interaction from secondary analysis of a randomized,
placebo-controlled clopidogrel trial. Circulation. 2003;108:921–924.
11. Wienbergen H, Gitt AK, Schiele R, et al. Comparison of clinical benefits
of clopidogrel therapy in patients with acute coronary syndromes taking
atorvastatin versus other statin therapies. Am J Cardiol. 2003;92:
285–288.
12. Thummel KE, Wilkinson GR. In vitro and in vivo drug interactions
involving human CYP3A. Annu Rev Pharmacol Toxicol. 1998;38:
389 – 430.
13. Horsmans Y. Differential metabolism of statins: importance in drug-drug
interactions. Eur Heart J Supplement. 1999;(suppl T):T7–T12.
14. Heeschen C, Dimmeler S, Hamm CW, et al. Soluble CD40 ligand in acute
coronary syndromes. N Engl J Med. 2003;348:1104 –1111.
15. Garlichs CD, Eskafi S, Raaz D, et al. Patients with acute coronary
syndromes express enhanced CD40 ligand/CD154 on platelets. Heart.
2001;86:649 – 655.
Atorvastatin Does Not Affect the Antiplatelet Potency of Clopidogrel When It Is
Administered Concomitantly for 5 Weeks in Patients With Acute Coronary Syndromes
John V. Mitsios, Athanasios I. Papathanasiou, Foteini I. Rodis, Moses Elisaf, John A.
Goudevenos and Alexandros D. Tselepis
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
Circulation. 2004;109:1335-1338; originally published online March 15, 2004;
doi: 10.1161/01.CIR.0000124581.18191.15
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2004 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://circ.ahajournals.org/content/109/11/1335
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published
in Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial
Office. Once the online version of the published article for which permission is being requested is located,
click Request Permissions in the middle column of the Web page under Services. Further information about
this process is available in the Permissions and Rights Question and Answer document.
Reprints: Information about reprints can be found online at:
http://www.lww.com/reprints
Subscriptions: Information about subscribing to Circulation is online at:
http://circ.ahajournals.org//subscriptions/