Understanding Clopidogrel Resistance and Its Implications

Thrombosis Research (2007) 120, 311–321

intl.elsevierhealth.com/journals/thre

REVIEW ARTICLE

Clopidogrel resistance?
Paul A. Gurbel ⁎, Udaya S. Tantry

Sinai Center for Thrombosis Research, Baltimore, Maryland, USA

Received 5 July 2006; received in revised form 31 July 2006; accepted 10 August 2006
Available online 14 November 2006

KEYWORDS Abstract Clopidogrel is an effective inhibitor of platelet activation and aggregation
Clopidogrel; due to its selective and irreversible blockade of the P2Y12 receptor. Combination
Responsiveness; antiplatelet therapy with clopidogrel and aspirin is an important strategy for patients
Resistance; with acute coronary syndromes and those undergoing percutaneous interventions.
Platelet aggregation; Despite significant benefits demonstrated with combination antiplatelet treatment
P2Y12 receptor in large clinical trials, the occurrence of adverse ischemic events, including stent
thrombosis, remains a serious clinical problem. Recent studies have demonstrated
distinct response variability and nonresponsiveness to clopidogrel therapy based on
ex vivo platelet function measurements. Small scale investigations have suggested
that nonresponsiveness may be associated with a heightened risk for adverse clinical
events. The above findings have stimulated a close examination of clopidogrel
metabolism.
© 2006 Elsevier Ltd. All rights reserved.

Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312
Mechanism of action. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313
Clopidogrel resistance — definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313
Laboratory evaluation of clopidogrel responsiveness. . . . . . . . . . . . . . . . . . . . . . . . . . . . 313
Clopidogrel responsiveness and time of treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 314
Clopidogrel responsiveness and effect of dose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315
Relation of clopidogrel nonresponsiveness to adverse clinical events . . . . . . . . . . . . . . . . . 315
Mechanism of clopidogrel resistance. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316
Management of clopidogrel resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318
Higher doses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318
New P2Y12 receptor antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318

⁎ Corresponding author. Sinai Center for Thrombosis Research, Hoffberger Building, Suite 56, 2401 W. Belvedere Ave, Baltimore, MD
21215, Maryland, USA. Tel.: +1 410 601 9600; fax: +1 410 601 9601.
E-mail address: PGURBEL@LIFEBRIDGEHEALTH.ORG (P.A. Gurbel).

0049-3848/$ - see front matter © 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.thromres.2006.08.012

312 P.A. Gurbel, U.S. Tantry

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319

Introduction antiplatelet treatment in large clinical trials, the
occurrence of adverse ischemic events, including
Clopidogrel effectively inhibits ADP-induced plate- stent thrombosis, remains a serious clinical prob-
let activation and aggregation by selectively and lem. Moreover, in the recent CHARISMA trial, the
irreversibly blocking the P2Y12 receptor [1]. The addition of clopidogrel to aspirin as a long term
CAPRIE study demonstrated the significant benefit treatment strategy was found to be beneficial only
of clopidogrel treatment in selected patients as in high risk patients with clinically evident athero-
compared to aspirin therapy alone [2]. Since thrombosis. In CHARISMA the effect of clopidogrel as
clopidogrel and aspirin inhibit platelet aggregation a primary prevention strategy in addition to aspirin
through different pathways, combined antiplatelet was associated with an increased risk of bleeding
therapy provides complementary and additive with no extra clinical benefits over aspirin therapy
benefits compared to either agent alone. Clopido- alone [7]. The recent ACTIVE W trial indicated that
grel treatment along with aspirin is considered the oral anticoagulation therapy was clearly superior to
“gold standard” for attenuation of platelet activa- dual antiplatelet therapy with clopidogrel and
tion and aggregation during acute coronary syn- aspirin for the prevention of vascular events in
dromes and in patients undergoing stenting [3–5]. In patients with atrial fibrillation at high risk of stroke
the United States, between 1998 and 2004, clopi- [8]. The latter trials highlight the importance of
dogrel use has increased seven times whereas use of understanding the pathophysiology of the disease
clopidogrel with aspirin has increased 16 times [6]. state and targeting dual antiplatelet therapy to
Despite significant benefits reported with combined patients at high risk for arterial thrombotic events.

Figure 1 Mechanism of action of clopidogrel and laboratory evaluation of clopidogrel nonresponsiveness. Abbreviations; ADP —
adenosine diphosphate, CYP3A4; hepatic cytochrome 3A4, TxA2 — thromboxane A2, LS-MS/MS — liquid chromatography-mass
spectrometry, LTA — light transmittance aggregometry, PRP — platelet rich plasma, TEG — thrombelastography, VASP-P — vasodilator-
stimulated phosphoprotein-phosphorylated, PLA — platelet–leukocyte aggregation, PFA-100 — platelet function analyzer.

Clopidogrel resistance? 313

B:1 Box 1 egy directed against a specific receptor cannot
overcome all thrombotic complications. With this in
mind, it is our opinion that the optimal definition of
resistance or nonresponsiveness to an antiplatelet
agent is the failure of the antiplatelet agent to
inhibit the target of its action. The identification of
resistance would therefore utilize a laboratory
technique that detects residual activity of the
target. Therefore, clopidogrel resistance is best
demonstrated by evidence of residual post-treat-
ment P2Y12 activity by measuring ADP-induced
platelet aggregation before and after treatment.
Since thrombosis involves multiple signaling path-
ways, treatment failure is not synonymous with drug
In addition, the previous clinical trials focussed on resistance (BOX-1).
the reduction of clinical events following antiplate-
let therapy without laboratory evaluation of plate- Laboratory evaluation of clopidogrel
let function. However, subsequent demonstrations responsiveness
of distinct response variability and nonresponsive-
ness to clopidogrel therapy, based on the laboratory A standardized laboratory method that simulates
evaluation of platelet response and the association the in vivo platelet response to antiplatelet therapy
of nonresponsiveness to adverse clinical events, is still lacking. Since clopidogrel specifically inhibits
demand a closer look at the effectiveness of one of two ADP receptors, ex-vivo measurement of
clopidogrel treatment [9–12]. ADP-induced maximum platelet aggregation by light
transmittance aggregometry (LTA) has been the
Mechanism of action most commonly used laboratory method to evaluate
clopidogrel responsiveness and is considered the
Clopidogrel inhibits ADP-induced platelet aggrega- gold standard [9]. Recently, it was suggested that
tion. Clopidogrel also inhibits collagen-, and throm- since antiplatelet drugs (especially clopidogrel),
bin-induced aggregation; however, the inhibitory induce platelet disaggregation, the response to
effect on collagen- and thrombin-induced aggrega- clopidogrel would be better demonstrated by
tion can be overcome by increased concentrations measuring late platelet aggregation at 6 min after
of these agonists. These findings suggest that stimulation with ADP rather than maximum aggre-
clopidogrel indirectly inhibits the effect of these gation [20]. However, unpublished data from our
agonists via the attenuation of ADP-mediated laboratory, based on the evaluation of both maxi-
amplification of the platelet response [13]. mum and final aggregation from 100 consecutive
Clopidogrel is rapidly absorbed from the intestine patients undergoing stenting and treated with
and extensively converted by hepatic cytochrome clopidogrel, indicated that both measurements
P450 isoenzymes (CYP3A4, CYP3A5, 2C19) to an were equivalent in determining the prevalence of
active thiol metabolite [14,15]. This short lived clopidogrel nonresponsiveness. Flow cytometric
active metabolite binds to the P2Y12 receptor via a measurements of the expression of activated GP
disulfide bridge between the reactive thiol group IIb/IIIa receptor and p-selectin expression after ADP
and two cysteine residues (cys17 and cys270) stimulation can also identify clopidogrel nonrespon-
present in the extracellular domains of the P2Y12 siveness and correlated with measurements of
receptor. Thus, the binding of ADP to the P2Y12 maximum aggregation stimulated by ADP [9,21]. In
receptor is permanently inhibited [1](Fig. 1). addition, measurements of ADP-induced platelet-
Clopidogrel has also been reported to attenuate fibrin clot strength by whole blood thrombelasto-
platelet–leukocyte aggregate formation, and the graphy and the VerifyNow P2Y12 receptor assay using
levels of CRP, p-selectin and CD 40L; and the rate of ADP as the agonist can also be used to measure
thrombin formation [16–20]. clopidogrel responsiveness as point-of-care assays
[22,23]. The PFA-100 method using collagen-ADP
Clopidogrel resistance — definition based cartridges and whole blood aggregometry are
associated with inconsistent estimates of platelet
No single receptor signaling pathway mediating reactivity to ADP. The phosphorylation state of
platelet activation is responsible for all thrombotic vasodilator-stimulated phosphoprotein is a specific
complications. Therefore, a single treatment strat- intracellular marker of residual P2Y12 receptor


Clopidogrel responsiveness and time of
treatment

Similar to other drugs, response variability and
nonresponsiveness to clopidogrel have been dem-
onstrated in patients following coronary stenting
[9,25]. In an early investigation from our center, 96
patients undergoing elective stenting were treated
with a 300 mg clopidogrel loading dose in the
catheterization laboratory followed by a 75 mg
Figure 2 Relationship between frequency of patients and
maintenance dose. ADP-induced platelet aggrega-
absolute change in aggregation (Δ Aggregation [%]) in
tion and activation dependent platelet surface
response to 5 uM ADP at 2 h (A), 24 h (B), days (C), and
30 days (D) after stenting. Δ Aggregation (%) is defined
marker expression (p-selectin and activated GPIIb/
baseline aggregation (%) minus post-treatment aggregation IIIa) were assessed at baseline and serially for
(%). Resistance, as defined therein, is Δ Aggregation ≤ 10%. 30 days following stenting. Response variability to
Resistance is present in those patients subtended by double- clopidogrel was demonstrated as measured by all
headed arrow. Curves represent normal distribution of data. markers and a certain percentage of patients were
(Adapted from, Gurbel et al. Circulation 2003;107:2908–13). found to have no demonstrable antiplatelet effect
[9]. In the latter patients, the difference between
pre- and post-treatment ADP-induced platelet
reactivity in patients treated with clopidogrel and aggregation was ≤10%. We defined these patients
can be measured by flow cytometry. This technique as clopidogrel “resistant” or “nonresponsive” to
is perhaps the most specific indicator of residual clopidogrel therapy. A subgroup of resistant patients
P2Y12 activity in patients treated with a P2Y12 exhibited platelet aggregation that was greater
inhibitor. However, the methodology is labor inten- after stent implantation than at baseline despite
sive and requires permeation of the platelet clopidogrel therapy. These patients were defined as
membrane and use of monoclonal antibodies spe- having heightened platelet reactivity to ADP.
cific for phosphorylated vasodilator-stimulated In the latter study, 53–63% of patients were
phosphoprotein [21,24] (Fig. 2). resistant to clopidogrel treatment at 2 h post-

Table 1 Clopidogrel resistance studies
Investigators n Patients Clopidogrel dose Definition of clopidogrel resistance Time Incidence
(mg, load/qd)
Gurbel et al [9] 92 PCI 300/75 5 and 20 uM ADP-induced aggregation 24 h 31–35%
b10% absolute change
Jaremo et al [27] 18 PCI 300/75 ADP-induced fibrinogen binding b40% of 24 h 28%
baseline
Muller et al [28] 119 PCI 600/75 5 and 50 uM ADP-induced aggregation 4h 5–11%
b10% relative change
Mobely et al [29] 50 PCI 300/75 1 uM ADP-induced aggregation, TEG and Pre and 30%
Ichor PW; b10% absolute inhibition post
Lepantalo et al [30] 50 PCI 300/75 2 or 5 uM AD-induced aggregation and 2.5 h 40%
PFA-100 10% inhibition and 170s
Angiolillo et al [31] 48 PCI 300/75 6 uM ADP-induced aggregation b40% 10 min, 4 44%
inhibition and 24 h
Matetzky et al [32] 60 STEMI 300/75 5 uM ADP-induced aggregation and CPA Daily for 25%
b10% inhibition 5 days
Dziewierz A et al 31 CAD 300 20 uM ADP-induced aggregation b 10% 24 h 23%
[33] absolute change
Lev EI et al [34] 150 PCI 300 5 uM ADP-induced aggregation b10% 20–24 h 24%
absolute change
Angiolillo et al [35] 52 Diabetics and 300 b10% relative inhibition 24 h 38% diabetics 8%
non-diabetics non-diabetics
Gurbel et al [25] 190 PCI 300 or 600/75 5 and 20 uM ADP-induced aggregation 24 h 28–32% with
b10% absolute inhibition 300 mg 8% with
600 mg
Abbreviations— PCI = percutaneous coronary interventions; ADP= adenosine diphosphate; CAD = Coronary artery disease TEG = throm-
belastography; PW= Plateletworks; PFA-100= Platelet function analyzer-100; CPA= Cone and platelet analyzer.


stenting; ∼ 30% were resistant at day 1 and day 5 pendent on dose. In the largest pharmacodynamic
post-stenting; and 13%–21% were resistant at day 30 study comparing 300 mg and 600 mg clopidogrel
post-stenting [9] (Fig. 2). Therefore, clopidogrel loading doses, treatment with a 600 mg loading dose
“resistance” in this study appeared to be time during elective PCI reduced clopidogrel nonrespon-
dependent. Based on the results we hypothesized siveness to 8% compared to 28–32% after a 300 mg
that the occurrence of clopidogrel resistance might loading dose (Fig. 3). Moreover, the study demon-
be related to the inadequacy of a 300 mg loading strated a narrower response profile following
dose to provide sufficient active metabolite gener- treatment with 600 mg compared to 300 mg
ation to arrest platelet reactivity in selected clopidogrel [25]. Muller et al also observed a time
patients, and that these resistant patients may be and dose dependent effect of clopidogrel in patients
at particular risk for thrombotic complications undergoing stenting [28]. A similar increased re-
including periprocedural infarction and stent sponsiveness was also observed in the ISAR-CHOICE
thrombosis [9,22,26]. study, where a ceiling effect of platelet inhibition
Since this initial description, multiple investiga- was observed with a 600 mg clopidogrel loading dose
tors have confirmed the phenomenon of clopidogrel whereas a nonsignificant increase in platelet inhi-
resistance [27–35]. The prevalence of clopidogrel bition was observed with a 900 mg loading dose [36].
nonresponsiveness has been reported at 5–44%. This
wide variation in prevalence is primarily due to Relation of clopidogrel nonresponsiveness to
dosing and is less related to various definitions, adverse clinical events
laboratory methods, and the time at which blood
samples were evaluated for responsiveness [27–35] Limited data are available to link clopidogrel
(Table 1). As demonstrated in Table 1, the data are nonresponsiveness to the occurrence of thrombotic
markedly concordant. The higher resistance esti- events. Matetzky et al studied clopidogrel respon-
mates are present following the 300 mg loading dose siveness in patients undergoing stenting for acute
and the lower estimates occur after the 600 mg ST-elevation myocardial infarction and found that
loading dose [25,28]. Diabetic patients who were on patients who exhibited the highest quartile of ADP-
long term dual antiplatelet therapy had a higher induced aggregation had a 40% probability for a
number of clopidogrel nonresponders compared to recurrent cardiovascular event within 6 months
nondiabetic patients in a recent study [35]. [32]. In the PREPARE POST-STENTING (Platelet
REactivity in Patients And Recurrent Events POST-
Clopidogrel responsiveness and effect of STENTING) Study, patients suffering a recurrent
dose ischemic event within 6 months of elective stenting
had high post-stent platelet reactivity to ADP
Subsequent investigations have unequivocally dem- compared to patients without ischemic events
onstrated that clopidogrel nonresponsiveness is de- despite dual antiplatelet therapy [22]. In the
CLEAR PLATELETS (Clopidogrel Loading with Eptifi-
batide to Arrest PLATELET reactivity) and CLEAR
PLATELETS Ib Studies, a 600 mg clopidogrel loading
dose used to treat patients undergoing elective
stenting was associated with superior early platelet
inhibition compared to a 300 mg loading dose and
this inhibition was accompanied by a decrease in
release of myocardial necrosis and inflammation
markers [37,38]. Cuisset et al demonstrated that
patients with high post-treatment platelet reactiv-
ity had an increased risk of cardiovascular events.
More importantly, these patients were resistant to
both clopidogrel and aspirin treatment [39]. Simi-
Figure 3 Distribution of the absolute change in 5 uM ADP- larly Lev et al demonstrated that occurrence of
induced aggregation (Δ aggregation) and incidence of clopido-
creatinine kinase-myocardial band after stenting
grel resistance in patients treated with 300 mg and 600 mg
was more frequent in patients exhibiting aspirin and
clopidogrel loading dose. All of the patients under double-
headed arrow meet the definition of clopidogrel resistance. clopidogrel resistance [34]. Finally, significantly
The distribution is shifted rightward and narrower in the higher recurrent ischemic events within 6 months
600 mg group indicating greater inhibition (responsiveness to of the procedure were observed in patients who
clopidogrel) and lower incidence of resistance. (Adapted from were on chronic clopidogrel therapy undergoing
Gurbel et al. J Am Coll Cardiol 2005;45:1392–1396). elective coronary stenting and had higher pre-


procedure ADP-induced platelet aggregation [40] grel-induced P2Y12 receptor inhibition, nonrespon-
(Table 2). All these findings strongly suggest that a siveness to clopidogrel treatment has been
high platelet reactivity despite currently recom- suggested as a risk factor for the occurrence of
mended antiplatelet therapy is a risk factor for stent thrombosis [21,41]. In the recent CREST
ischemia in patients undergoing PCI. (Clopidogrel effect on platelet REactivity in
Based on the analysis of flow cytometric mea- patients with Stent Thrombosis) Study, elevated
surements of intracellular VASP phosphorylation levels of ADP-induced platelet aggregation, ADP-
levels, a specific intracellular marker of clopido- stimulated expression of active GPIIb/IIIa expres-
sion and the P2Y12 reactivity ratio measured by VASP
phosphorylation were observed in patients with
stent thrombosis compared to patients without
Table 2 Clinical relevance of clopidogrel
stent thrombosis, indicating inadequate inhibition
nonresponsiveness
of P2Y12 receptor [21]. Other investigators have
Study n Results Clinical reported that high ex vivo shear-induced platelet
relevance aggregation despite dual antiplatelet therapy may
Post-stent ischemic events and periprocedural infarction be a risk factor for stent thrombosis [42] (Table 2).
1. Matetzky et al. [32] 60 ↑ ADP-induced Recurrent
platelet cardiac
aggregation events
Mechanism of clopidogrel resistance
(4th quartile)
2. Gurbel et al. [22] 192 ↑ Periprocedural Post-PCI The mechanisms responsible for clopidogrel re-
(PREPARE Post- platelet ischemic sponse variability and resistance are incompletely
Stenting Study) aggregation events defined. Differences in intestinal absorption, he-
(6 months)
patic conversion to the active metabolite through
3. Gurbel et al. 120 ↑ Periprocedural Myonecrosis
[37,38] (CLEAR platelet and cytochrome 3A4 (CYP3A4) activity, and platelet
PLATELETS and aggregation inflammation receptor polymorphisms have been suggested
CLEAR PLATELETS marker [14,43–46].
Ib) release Only up to 30–50% inhibition of ex vivo ADP-
4. Bliden et al. [40] 100 ↑ Periprocedural Post-PCI
induced platelet aggregation was demonstrated
platelet ischemic
aggregation in events following a repeated daily dose of 75 mg in normal
patients on (6 months) volunteers or loading doses of 300 or 600 mg in
chronic patients undergoing PCI [13,37,38]. This level of
clopidogrel inhibition indicated an incomplete P2Y12 receptor
5. Cuisset et al. [39] 106 ↑ Platelet Recurrent
blockade and suboptimal inhibition of ADP-induced
aggregation events
6. Lev et al. [34] 120 ↑ Clopidogrel/ Post-PCI platelet aggregation. The repeated demonstrations
aspirin resistant myonecrosis that a high loading dose of 600 mg clopidogrel is
patients associated with increased inhibition of ex vivo ADP-
induced platelet aggregation in patients undergoing
Stent thrombosis
PCI and a decreased prevalence of nonresponders
7. Barragen et al. [41] 36 ↑ P2Y12 reactivity Stent
ratio (VASP-levels) thrombosis support insufficient active metabolite generation as
8. Gurbel et al. [21] 120 ↑ P2Y12 reactivity Stent a major factor in clopidogrel resistance [25,28,36,
(CREST Study) ratio thrombosis 43,47].
↑ platelet Recent studies involving the measurement of
aggregation
hepatic cytochrome (CYP) P450 activity suggest that
↑ stimulated
GPIIb/IIIa individual variations in the activity of this enzyme
expression play a major role [14,48–50]. In a landmark
9. Ajzenberg et al. [42] 49 ↑ Shear-induced Stent investigation, Lau et al demonstrated that pharma-
platelet thrombosis cologic stimulation of CYP3A4 activity by rifampin
aggregation
enhances the inhibitory effect of clopidogrel,
ADP=adenosine diphosphate; CLEAR PLATELETS Study =clopido- whereas agents that compete with clopidogrel for
grel loading with eptifibatide to arrest the reactivity of platelets:
CYP 3A4 activity (e.g. erythromycin) attenuate the
results of the Clopidogrel Loading With Eptifibatide to Arrest the
Reactivity of Platelets study; CREST Study=clopidogrel effect on antiplatelet effect of clopidogrel [14,48]. Addition-
platelet reactivity in patients with stent thrombosis; GP=glyco- al information supporting the pivotal role of CYP
protein; PCI=percutaneous coronary intervention; PREPARE P450 in generating the active metabolite of clopi-
POST-Stenting Study=platelet reactivity in patients and recur- dogrel was demonstrated in a small study involving
rent events post-stenting study; VASP=vasodilator-stimulated
human volunteers where the effects of the CYP3A4
phosphoprotein.
inhibitor, ketoconazole, on the pharmacokinetics


Figure 4 Clopidogrel metabolism and factors affecting clopidogrel responsiveness.

and the ex vivo platelet inhibitory effects of CYP3A4 gene may be an important contributor to
prasugrel and clopidogrel were investigated. Prasu- clopidogrel response variability [53] (Fig. 4).
grel is also a thienopyridine that requires conversion Suboptimal platelet response to clopidogrel may
to an active metabolite by a hepatic cytochrome. In be due to an increased number of platelet P2Y12
this study, ketoconazole co-administration did not receptors, or polymorphism of platelet receptors.
have any effect on prasugrel active metabolite Genetic polymorphisms of platelet GPIIb/IIIa, GPIa/
generation or prasugrel-induced platelet inhibition, IIa, or P2Y12 receptors have been reported to affect
whereas clopidogrel-induced platelet inhibition was platelet function and may influence clopidogrel
reduced following a loading dose as well as after a response variability [54–56]. Recently, it was
maintenance dose [49]. The latter effect on reported that an increased percentage of patients
clopidogrel-induced platelet inhibition was accom- with peripheral arterial disease have the P2Y12
panied by lesser active metabolite generation. receptor H2 haplotype [55]. However, in another
Similarly, in another study, prasugrel treatment study, the relation of this haplotype to clopidogrel
was associated with superior active metabolite responsiveness could not be demonstrated [56]. Since
generation and platelet inhibition together with a the relation of genetic polymorphisms to clopidogrel
lower incidence of nonresponsiveness compared to responsiveness is inconclusive, further studies are
clopidogrel treatment [50]. required to establish a correlation between receptor
In recent studies, the influence of CYP3A5 and polymorphisms and clopidogrel nonresponsiveness.
CYP2C19 isoenzymes on clopidogrel metabolic It has been shown that patients with diabetes
activation and responsiveness has been demonstrat- exhibit platelet activation and increased reactivity
ed [51,52]. Suh J et al demonstrated higher to agonists. The heightened platelet reactivity may
clopidogrel responsiveness among subjects with be related to the increased prevalence of nonre-
the CYP3A5 expressor genotype than subjects with sponders and occurrence of ischemic events
the non-expressor genotype. Moreover, worse out- reported in patients with diabetes [57,58]. It has
comes were seen in patients undergoing stent also been reported that patients with a high body
implantation with the non-expressor genotype mass index (BMI) exhibited a suboptimal platelet
following treatment with clopidogrel than in response with the standard 300 mg loading dose
patients with the CYP3A5 expressor genotype [51]. [59].
Similarly, Hulto J et al and Brandt et al indepen- All of the above data strongly support the
dently demonstrated the influence of the CYP2C19 importance phenomenon of insufficient metabolite
genotype on clopidogrel responsiveness in healthy generation secondary to limitations in the intestinal
volunteers [52]. Finally, Angiolillo DJ et al demon- absorption, drug–drug interaction at CYP 3A4 or
strated that the IVS10 + 12G N A polymorphism of the genetic polymorphisms of CYP isoenzymes as the


primary explanations for resistance rather than data to support the cutpoint of 50% inhibition [21,37].
genetic polymorphisms of platelet receptors or In the CLEAR PLATELETS Study we observed peripro-
intracellular signaling mechanisms. The latter cedural myocardial infarction only in those patients
mechanisms may be relevant in those patients who with 5 μM ADP-induced aggregation N 50% [37]. In the
remain resistant and with high platelet reactivity to CREST Study the cutpoint for stent thrombosis was
ADP even after high dosing strategies. 20 μM ADP-induced aggregation N40% [21].

Management of clopidogrel resistance New P2Y12 receptor antagonists

Higher doses New P2Y12 receptor antagonists are currently under-
going investigation. AZD 6140 (Astra-Zeneca) and
In recent clinical studies of patients undergoing cangrelor (Medicines Company) are reversible, direct
stenting, a 600 mg clopidogrel loading dose was and potent inhibitors of the P2Y12 receptor [64,65].
associated with a higher level of platelet inhibition, AZD 6140 is an oral inhibitor whereas cangrelor is
lower mean post-treatment reactivity to ADP, and a administered parenterally. Both of these agents
lower incidence of nonresponsiveness when com- exhibit more consistent and greater platelet inhibition
pared to a 300 mg dose [25,28,37,60]. Moreover, a compared to clopidogrel. The short onset and offset of
600 mg clopidogrel loading dose was associated with action make these agents appealing adjunctive anti-
a narrower response profile [25]. Kastrati et al found platelet agents during PCI when maximum and rapid
that patients achieved additional platelet inhibition platelet inhibition of ADP-induced aggregation is
when a 75 mg/day clopidogrel maintenance dose desired [64,65]. Prasugrel is an irreversible inhibitor
was followed by an additional 600 mg loading dose of P2Y12 and, similar to clopidogrel, is a prodrug that
[61]. In the CLEAR PLATELETS Study a 600 mg loading requires metabolic activation. In the JUMBO-TIMI-26
dose was associated with a superior pharmacody- trial, prasugrel treatment was associated with a
namic antiplatelet profile compared to a 300 mg similar primary endpoint of significant bleeding
clopidogrel loading dose [37,38]. In the recent ISAR- compared to standard clopidogrel regimen (1.7 vs.
CHOICE (Intracoronary Stenting and Antithrombotic 1.2) and the bleeding events were the same for all
Regimen: Choice Between 3 High Oral doses for doses of prasugrel [66]. The pharmacodynamic profile
Immediate Clopidogrel Effect) Study, there was a of prasugrel is superior to clopidogrel and is associated
ceiling effect in unchanged clopidogrel and clopido- with lesser incidences of nonresponsiveness [67]. All
grel metabolite levels and platelet inhibition with three of the above agents will undergo study in phase 3
the 600 mg loading dose, and no significant clinical trials. Prasugrel is currently being compared to
additional effect was seen with the 900 mg loading clopidogrel in an ACS trial in patients undergoing PCI.
dose. Based on the pharmacokinetic profile of the
free drug and metabolites the investigators con- Conclusion
cluded that intestinal absorption was the major
factor explaining response variability [62]. Clopidogrel use has increased over the last few
Thus, higher loading doses may be considered for years following its effectiveness together with
selected patients exhibiting high platelet reactivity to aspirin in significantly reducing adverse events in
ADP However, the superiority of a high dose regimen
. large-scale clinical trials. At the same time, based
in reducing ischemic events and the associated risk on the laboratory evaluation of platelet response,
profile compared to a standard dose has yet to be wide response variability and nonresponsiveness in
established in large scale clinical trials. Despite these selected patients are also present. In the recent
limitations, the current ACC/AHA guidelines for PCI small studies, heightened platelet reactivity or
provide a Class IIa recommendation that “a regimen clopidogrel nonresponsiveness in patients who
of greater than 300 mg is reasonable to achieve higher were on clopidogrel treatment was associated
levels of antiplatelet activity more rapidly”. Finally, with adverse thrombotic events including stent
the ACC/AHA Guidelines provide a Class IIb recom- thrombosis. The primary reason has been attributed
mendation that “in patients in whom subacute to the suboptimal generation of active metabolite
thrombosis may be catastrophic or lethal… platelet secondary to potential limitation in intestinal
aggregation studies may be considered and the dose absorption, drug–drug interaction at CYP3A4 and
of clopidogrel increased to 150 mg per day if less than genetic polymorphism of hepatic cytochrome P450
50% inhibition of platelet aggregation is demonstrat- isoenzymes. Use of higher loading or maintenance
ed” [63]. The latter guidelines however, do not doses of clopidogrel or new and more potent P2Y12
specify the methodology that should be used to assess receptor blockers is a potential alternative strategy.
inhibition. Moreover, there are very limited clinical In addition, treatment with combined antiplatelet


therapies may be confined to the pharmacologic [7] Bhatt DL, Fox KA, Hacke W, Berger PB, Black HR, Boden WE,
management of patients at high risk for arterial et al. CHARISMA Investigators. Clopidogrel and aspirin versus
aspirin alone for the prevention of atherothrombotic events.
thrombotic events but not as a primary prevention N Engl J Med 2006;354:1706–17.
strategy or as an alternative to anticoagulants. [8] ACTIVE Writing Group on behalf of the ACTIVE Investiga-
tors, Connolly S, Pogue J, Hart R, Pfeffer M, Hohnloser S,
Acknowledgements et al. Clopidogrel plus aspirin versus oral anticoagulation
for atrial fibrillation in the Atrial fibrillation Clopidogrel
Trial with Irbesartan for prevention of Vascular Events
Dr. Gurbel has a research grant from Schering and (ACTIVE W): a randomised controlled trial. Lancet 2006;
Millenium in the last 2 years studying antiplatelet 367:1903–12.
effects of clopidogrel and eptifibatide in elective [9] Gurbel PA, Bliden KP, Hiatt BL, O'Connor CM. Clopidogrel for
stenting. Dr. Gurbel has a research grant from Astra coronary stenting: response variability, drug resistance, and
the effect of pretreatment platelet reactivity. Circulation
Zeneca in the last 2 years studying antiplatelet 2003;107:2908–13.
effects of clopidogrel in relation to stent thrombosis. [10] Cattaneo M. Aspirin and clopidogrel: efficacy, safety, and
Dr. Gurbel has a research grant from Bayer in the last the issue of drug resistance. Arterioscler Thromb Vasc Biol
2 years studying antiplatelet effects of aspirin in 2004;24:1980–7.
outpatients. Dr. Gurbel has a research grant from [11] Rocca B, Patrono C. Determinants of the interindividual
variability in response to antiplatelet drugs. J Thromb
Astra Zeneca in the last 2 years studying antiplatelet
Haemost 2005;3:1597–602.
effects of AZD6140 in elective stenting. Dr. Gurbel has [12] Tantry US, Bliden KP, Gurbel PA. Resistance to antiplatelet
a research grant from Haemoscope and NIH in the last drugs: current status and future research. Expert Opin
2 years studying physical properties of clot formation Pharmacother 2005;6:2027–45 [Review].
and recurrent ischemic events post-elective stenting. [13] Patrono C, Coller B, FitzGerald GA, Hirsh J, Roth G.
Platelet-active drugs: the relationships among dose, ef-
Dr. Gurbel has been a co-investigator in the last 2 years
fectiveness, and side effects: the Seventh ACCP Confe-
for Medtronic and Boston Scientific studying new drug- rence on Antithrombotic and Thrombolytic Therapy. Chest
eluting stents in elective stenting. Dr. Gurbel was a 2004;126(3 Suppl):234S–64S.
scientific officer for a start-up company — Throm- [14] Lau WC, Gurbel PA, Watkins PB, Neer CJ, Hopp AS, Carville
boscience that is no longer in existence. Dr. Gurbel DG, et al. Contribution of hepatic cytochrome P450 3A4
metabolic activity to the phenomenon of clopidogrel
serves as consultant for Astra Zeneca, Lilly, Sanofi,
resistance. Circulation 2004;109:166–71.
Bayer, and the Medicines Company. There is no con- [15] Savi P, Combalbert J, Gaich C, Rouchon MC, Maffrand JP,
flict of interest for other authors. Berger Y, et al. The antiaggregating activity of clopidogrel is
due to a metabolic activation by the hepatic cytochrome
P450-1A. Thromb Haemost 1994;72:313–7.
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