Review Article
Clopidogrel withdrawal: Is there a “rebound” phenomenon?
Nalyaka Sambu1; Timothy Warner2; Nick Curzen1,3
1Wessex Cardiothoracic Unit, Southampton University Hospital, UK; 2The William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, London UK;
3Southampton University Medical School, UK
Summary
Dual antiplatelet therapy with aspirin and clopidogrel is routinely indi-
cated in patients with acute coronary syndromes and following percut-
aneous coronary intervention to reduce the risk of cardiovascular mor-
tality and ischaemic events. Although clinical guidelines recommend
aspirin lifelong and clopidogrel for between one and 12 months, de-
pending upon the indication, the optimal duration of clopidogrel ther-
apy actually remains contentious. Premature cessation of clopidogrel in
patients receiving drug-eluting stents is a clear risk factor for stent
thrombosis, but recent clinical studies have also demonstrated a link
between “appropriate” cessation of clopidogrel and clustering of ad-
verse clinical events. It has been suggested that this may be due to a
“rebound” prothrombotic and/ or proinflammatory response associ-
ated with clopidogrel withdrawal. This review will examine the defini-
Correspondence to:
Dr. N. Curzen, PhD FRCP
Consultant Cardiologist and Honorary Senior Lecturer
Cardiac Department, Level E, North Wing
Southampton General Hospital
Southampton SO16 6YD, UK
Tel.: +44 2380794972, Fax: +44 2380794772
E-mail: nick.curzen@suht.swest.nhs.uk
Introduction
In routine clinical cardiological practice the leading indications for
dual antiplatelet therapy with aspirin and clopidogrel include
acute coronary syndromes (ACS) and coronary stent placement. In
both cases (which of course are not mutually exclusive) a strategy is
employed that involves life-long aspirin together with clopidogrel
for between one and 12 months, depending upon the indication,
after which the clopidogrel is stopped. The evidence base indicat-
ing outcome benefit for clopidogrel in addition to aspirin is robust
both as a medical treatment for acute coronary syndromes (1–3)
and also for those patients receiving coronary stents in elective (4)
and acute (5) settings.
Conventionally, it is considered that the clinical benefit of clopi-
dogrel is due largely to its antithrombotic and antiplatelet activity.
Indeed this assumption is largely supported by some of the most
important beneficial effects of the drug such as (a) the reduction in
the incidence of stent thrombosis (ST) in patients who have receiv-
ed coronary stents (5, 6) and (b) a reduction in peri-procedural
myocardial infarction (MI) in patients undergoing percutaneous
coronary intervention (PCI) (4, 7–9). However, it is apparent that
clopidogrel also has the ability to modify vascular inflammatory
responses which are, as yet, poorly characterised (10–12).
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© Schattauer 2011 211
tion and concept of a “rebound” phenomenon associated with clopido-
grel cessation as well as the likely mechanisms behind this effect. With-
in the context of clinical event clustering after clopidogrel cessation, we
will also discuss (i) the clinical importance of clopidogrel and the in-
creasing uncertainty surrounding optimal duration of therapy, (ii) the
antiplatelet and anti-inflammatory properties of clopidogrel and, in
particular, its influence on arachidonic acid pathways traditionally
thought to be mediated predominantly by aspirin and (iii) the role of
newer, more potent antiplatelet agents and potential changes to anti-
platelet therapy prescribing guidelines in the future.
Keywords
Clopidogrel cessation, rebound, platelet aggregation, stent thrombosis,
inflammation
Received: August 27, 2010
Accepted after minor revision: October 20, 2010
Prepublished online: November 23, 2010
doi:10.1160/TH10-08-0554
Thromb Haemost 2011; 105: 211–220
There is increasing uncertainty about the precise mechanisms
by which clopidogrel achieves its anti-platelet effects. It is clear that
this primarily involves occupation of the P2Y12 receptor, hence
blocking ADP-induced platelet stimulation. Increasingly, however,
there is evidence that clopidogrel also interferes with arachidonic
acid (AA)-mediated platelet stimulation (13–16). There are there-
fore some important uncertainties about the intraplatelet ma-
chinery that mediate clopidogrel effects and the nature of its po-
tential interactions with aspirin (17).
Furthermore, there remain unanswered questions about clopi-
dogrel therapy. The duration of treatment after coronary drug-
eluting stent (DES) deployment, for example, remains uncertain
and contentious (18). Observation unequivocally demonstrates
that stopping clopidogrel “too early” is a powerful risk factor for ST
(19–21). By contrast, it is also well described that there is a cluster-
ing of adverse clinical events in the 90 days after cessation of long-
term clopidogrel in populations of ACS patients treated with stent-
ing and medical therapy (22, 23). The latter observation raises the
possibility that cessation of clopidogrel may be associated with a
“rebound” effect that is pro-thrombotic or pro-inflammatory or
both and is directly responsible for adverse clinical events. As de-
scribed in detail below, the more scientifically accurate meaning of
the term “rebound” is an increase in platelet reactivity and/or vas-
Thrombosis and Haemostasis 105.2/2011
212 Sambu et al. Clopidogrel withdrawal rebound phenomenon
cular inflammation following clopidogrel withdrawal, to a level
that exceeds what it was at baseline prior to the initiation of clopido-
grel therapy. True “rebound” is thus more difficult to ascertain in
clinical practice due to the lack of availability of comparative base-
line (pre-treatment) levels.
An improved assessment and appreciation of the way clopido-
grel works, and specifically of its anti-inflammatory and AA path-
way activities, is likely to facilitate our understanding of the poten-
tial mechanisms of the “rebound” effect, which is an iatrogenic en-
tity, and hence allow for its modification.
Clinical indications for clopidogrel
ST is a significant and potentially life threatening complication of
PCI with an associated mortality of at least 30%. Early clinical
trials using aspirin monotherapy or a combination of aspirin and
warfarin to reduce the risk of thrombotic complications associated
with stent implantation reported a high incidence of acute ST with
rates of up to 20% in the aspirin monotherapy group. The evol-
ution to dual antiplatelet therapy with aspirin and a thienopyri-
dine resulted in a significant reduction in the risk of ST to approxi-
mately 1%, with a lower risk of bleeding compared to anticoagu-
lant regimes (24–26). Although these early studies used ticlopi-
dine, it has since been replaced by clopidogrel which is a safer and
better tolerated agent with no requirement for routine haemato-
logical monitoring. Clopidogrel has been proven to be at least as ef-
fective as ticlopidine in reducing thrombotic and ischaemic com-
plications after stent implantation (27, 28).
The randomised controlled CREDO trial established the
beneficial effect of clopidogrel loading followed by maintenance
therapy in addition to aspirin in patients undergoing elective PCI
(4). Pre-treatment with clopidogrel 300 mg at least 6 hours (h)
prior to PCI was associated with a reduction in peri-procedural
major adverse cardiac events, and subsequent maintenance ther-
apy for 12 months compared to treatment for only four weeks re-
sulted in a significant reduction in the combined endpoint of
death, MI and stroke (26.9% relative risk reduction; p=0.02). Simi-
lar findings have been reported in patients undergoing PCI in the
acute setting, where maintenance dose clopidogrel was continued
for up to one year (5).
The beneficial effect of clopidogrel also extends to ACS patients
not undergoing PCI. Thus, large randomised studies of clopidogrel
therapy in addition to aspirin in patients with and without ST seg-
ment elevation managed medically, have demonstrated a signifi-
cant reduction in cardiovascular mortality and ischaemic events
(1–3).
Although all these early studies clearly demonstrate the import-
ance of clopidogrel pre-loading and treatment long term, the opti-
mal duration of therapy remains uncertain. Currently, 12 months
of clopidogrel 75 mg is recommended for all ACS patients with or
without ST segment elevation whether or not PCI is undertaken
(29, 30), as well as in elective patients undergoing PCI with DES
(31, 32). There is robust evidence to suggest that premature with-
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drawal of clopidogrel following PCI is associated with a substan-
tially increased risk of adverse events and is a strong independent
predictor of ST particularly after DES implantation (6, 19, 21,
33–35). In fact, early discontinuation of treatment is apparently
more common than expected. For example, among 500 patients
who received DES after MI, 13.6% stopped their thienopyridine
therapy within 30 days (20). These patients were older with more
co-morbidities, were of lower socioeconomic status and were less
likely to have received discharge advice about their medication or
referral to the cardiac rehabilitation services. At 11-month follow
up there was a highly significant increase in death (7.5% vs. 0.7%
p<0.0001) and cardiac rehospitalisation (23% vs. 14% p=0.08) in
those patients who discontinued their treatment prematurely.
!Table 1 summarises data on patients undergoing PCI who sub-
sequently present with ST. In general over 30% of these patients
were not on clopidogrel at the time of their presentation and the
median time from clopidogrel cessation to ST varied between 5–90
days in most studies.
The data in relation to the optimal duration of clopidogrel is,
however, discrepant. For example, some smaller studies and obser-
vational data on patients undergoing PCI have shown that the
mortality benefit of clopidogrel extends beyond one year in pa-
tients with DES (34, 36, 37). By contrast, the combined analysis of
data from two recent randomised multicentre trials (REAL-LATE
and ZEST-LATE) (38), found no significant difference in the com-
bined risk of MI and cardiac death in patients with DES who re-
ceived 12 versus 24 months of clopidogrel therapy (1.2% vs. 1.8%;
p=0.17; 95% confidence interval [CI] 0.8 to 3.36). Some clarity on
this controversial issue may be provided from the large, prospec-
tive, randomised controlled DAPT study (39), which will assess the
safety and effectiveness of 12 versus 30 months of dual antiplatelet
therapy in 20,000 patients following PCI.
The optimal maintenance dosage of clopidogrel therapy is also
the subject of debate (40). The recent CURRENT-OASIS 7 rando-
mised study undertaken in 25,086 ACS patients, compared 600 mg
loading dose clopidogrel followed by 150 mg maintenance therapy
for seven days versus 300 mg loading dose followed by the usual 75
mg maintenance therapy (41). In the sub-group of patients under-
going PCI (n=17,263), double-dose clopidogrel was associated
with a significant reduction in definite ST (0.7% vs. 1.3%, hazard
ratio [HR] 0.54, 95% CI 0.39 to 0.74, p=0.0001) and cardiovascu-
lar events (3.9% vs. 4.5%, HR 0.86, 95% CI 0.74 to 0.99, p=0.039)
compared to the standard dose group (42). However, more data are
needed to clarify the long-term risk reduction benefit associated
with high-dose clopidogrel and this would need to be weighed
against the increased risk of bleeding complications. Furthermore,
with the advent of newer more potent antiplatelet agents, such as
prasugrel and ticagrelor, and the robust data emerging supporting
their use as an alternative to clopidogrel in ACS (43–46), the focus
of antiplatelet therapy prescribing is likely to shift towards select-
ing the most appropriate, safe and effective agent for each individ-
ual patient.
© Schattauer 2011
 Sambu et al. Clopidogrel withdrawal rebound phenomenon 213

Table 1: Summary of data on patients undergoing PCI who subsequently present with stent thrombosis (ST).

Source No. of Study design Follow-up No. of ST % of patients off clopi- Median time from clopi-
patients cases n (%) dogrel at time of ST dogrel cessation to ST
n (%) (days)
vanWerkum (2009) (19) 21009 Registry data Median f/u 437 (2.1) 134 (30.7) 5 days (>24 hours – 30 days
DES + BMS 30.9 months post PCI)
13 days (>30 days – 1 year
post PCI)
Airoldi (2007) (21) 3021 Cohort study 18 months 58 (1.9) 17 (29.3) 13.5 days (≤6 months post
DES PCI)
90 days (6–18 months post
PCI)
Artang (2007) (93) 36 Published case - 36 (100) 34 (94.4) 7 days (≥30 days post PCI)
reports
DES
Pfisterer (2006) (94) 746 Cohort study 18 months 16 (2.1) 16 (100) 116 day (7–18 months post
DES + BMS PCI)
Kachulakanti (2006) (33) 2974 Cohort study 12 months 38 (1.27) 14 (36) 6.2 ± 4.9 days (≥24 hours to
DES 30 days post PCI)‡
55.5 ± 34.5 days (>30 days
post PCI)‡
Jeremias (2004) (95) 652 Cohort study Median f/u 7 (1.1) 4 (57.1) 4 days (<30 days post PCI)†
DES 100 days
†Dataunavailable on one patient. ‡Only mean times published. f/u, follow-up; ST, stent thrombosis; DES, drug-eluting stents; BMS, bare metal stents; PCI, percut-
aneous coronary intervention.

Known pharmacological activity of
clopidogrel
Clopidogrel is an inactive pro-drug that is oxidised to its active
metabolite via the hepatic cytochrome P450 system. The active
metabolite irreversibly binds to platelet P2Y12 adenosine diphos-
phate (ADP) receptors, thereby inhibiting both ADP-induced pla-
telet aggregation as well as transformation of the glycoprotein (GP)
IIb/IIIa receptor to a form that allows binding of fibrinogen
(47–49) (!Fig. 1). Previous clinical studies have shown that stimu-
lation of P2Y12 ADP receptors may enhance Von Willebrand factor
(VWF)-mediated platelet activation. VWF binds to GPIbα recep-
tors at sites exposed to high shear arterial blood flow leading to pla-
telet adhesion, activation and thrombosis (50–52). The well de-
scribed role of clopidogrel active metabolite on P2Y12 ADP receptor
blockade and therefore its potential effect in inhibiting VWF-me-
diated pathways of platelet activation may, in part, explain the pro-
thrombotic effect observed following clopidogrel cessation.
Clopidogrel only partially blocks ADP receptors with a high de-
gree of inter-individual variability. A maintenance dose of 75mg
requires at least five days to achieve approximately 50% steady state
of inhibition of ADP-induced platelet aggregation (53, 54). Al-
though the half-life of clopidogrel is 4 h, its irreversible platelet in-
hibitory effect means that once treatment is discontinued platelet
function is only completely normalised after the 7–10 day period
required for platelet regeneration. However, a significant decline in
the platelet inhibitory effects of clopidogrel has been observed
much earlier, at approximately 3–5 days after discontinuation of
treatment (55, 56). Furthermore, clinical studies have shown that
individuals with increased platelet aggregation profiles have a
greater proportion of immature platelets (57–61). These immature
reticulated platelets have a higher thrombotic potential which may,
in part, explain the prothrombotic events that occur soon after dis-
continuation of clopidogrel therapy.
In addition to its anti-platelet effect, clopidogrel has also been
shown to have anti-inflammatory properties. CD40 ligand (L) and
CD-62 P-selectin (P) are potent stimulators of vascular inflam-
mation expressed on activated platelet membranes and on many
cells of the immune and vascular systems. They play an important
role in the pathogenesis and progression of atherosclerosis
(62–64). Clopidogrel inhibits the expression of these inflamma-
tory mediators, both acutely and in patients on long term mainten-
ance therapy (10–12).
CD40L also exists in its soluble form, almost all of which is pro-
duced and released from activated platelets. Soluble CD40L is a
prothrombotic and proinflammatory molecule that plays an im-
portant role in the pathophysiology of ACS. In fact, an elevated
level is a prognostic marker and predictive of subsequent cardiac
events (65, 66). Studies have shown that clopidogrel pre-treatment
in patients undergoing PCI attenuates the inflammatory response
as evidenced by a reduction in serum levels of soluble CD40L at 24
h (67, 68). This may be one of the mechanisms behind the reduced
incidence of peri-procedural ischaemic events seen in patients
undergoing PCI who have received clopidogrel pre-treatment.
High sensitivity C-reactive protein (hsCRP) is another impor-
tant inflammatory marker that is elevated in patients presenting

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214 Sambu et al. Clopidogrel withdrawal rebound phenomenon
with ACS and is an independent predictor of adverse outcomes
(69). A significant reduction in hsCRP levels following PCI has
been reported in patients receiving clopidogrel pre-treatment (70)
as well as in medically managed ACS patients. Specifically, those
treated with a combination of clopidogrel and aspirin have been
shown to have a more significant reduction in serum hsCRP levels
compared with aspirin alone (71) which may in part explain the
well documented beneficial effects of dual antiplatelet therapy in
reducing ischaemic events and cardiovascular mortality in ACS
patients compared with aspirin monotherapy.
Given the evidence that clopidogrel exerts anti-inflammatory
effects, it is plausible to hypothesise that cessation of clopidogrel
may result in a proinflammatory and atherothrombotic state due
to loss of its inhibitory effect on these vascular biomarkers of in-
flammation. Such a mechanism may not fulfil the true definition
Figure 1: Mechanism of action of clopidogrel. Clopidogrel is a pro-drug
that is metabolised by the cytochrome P450 system to generate the active
metabolite which irreversibly inhibits the adenosine diphosphate (ADP)
P2Y12 receptor. ADP binds to the P2Y1 and P2X1 receptors leading to a change
in platelet shape initiating a weak and transient phase of platelet aggre-
gation. The binding of ADP to its Gi-coupled P2Y12 receptor liberates the Gi
protein subunits αGi and βγ and this results in stabilisation of platelet aggre-
gation. The subunit αGi leads to inhibition of adenylyl cyclase (AC), which re-
duces cyclic adenosine monophosphate (cAMP) levels. This inhibits the
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of “rebound” but could nevertheless provide an explanation for the
clustering of clinical events described after cessation of clopidogrel
therapy.
The “rebound” phenomenon
How do we define “rebound”?
Although the expression “rebound” phenomenon is now relatively
widely used in the context of clopidogrel therapy, its definition is
unclear and is often the focus for confusion and/or misunder-
standing. The two most widely accepted interpretations of “re-
bound” are:
cAMP-mediated phosphorylation of vasodilator-stimulated phosphoprotein
(VASP) (VASP-P), which is known to be closely related to the inhibition of gly-
protein IIb/IIIa receptor activation. (Multiple arrows indicate that intermedi-
ate steps may be involved; dotted arrows = inhibition; solid arrows = acti-
vation. CYP450 = cytochrome P450; PGE1 = prostaglandin E1; PKA = protein
kinase activation; PLC = phospholipase C ). Reprinted with permission from
Elsevier from Nguyen et al. Resistance to clopidogrel: a review of the evi-
dence. JACC 2005; 45: 1158.
© Schattauer 2011

(i) simply that an adverse clinical event occurs shortly after, and
because of clopidogrel cessation,
(ii) that, as a result of clopidogrel cessation, one or more parame-
ters of either platelet reactivity or vascular inflammation
reaches a level that is higher than it was at baseline before clopi-
dogrel therapy was ever initiated.
The latter is the stricter and more scientifically accurate definition.
However, the weakness with this definition is that it demands a
pre-clopidogrel baseline assessment which is unlikely to be avail-
able in routine clinical practice outside the realms of carefully de-
signed research. The term “rebound” has been increasingly used in
clinical practice and publications to indicate any clinical event that
occurs after clopidogrel cessation. The term “rebound phenom-
enon” will encompass both definitions in this paper.
Studies have shown a clear link between cessation of long term
clopidogrel therapy after PCI and adverse events including ST (18,
23, 72–74). Specifically, a significant proportion of these events
occur within days or weeks after clopidogrel has been discontinu-
ed, hence fulfilling at least definition (i) of “rebound phenom-
enon”. This effect has not only been observed in patients with cor-
onary stents. Thus, Ho et al. (22) reported a clustering of adverse
clinical events in the initial 90 days after stopping clopidogrel in a
large retrospective study of ACS patients on dual antiplatelet ther-
apy treated either medically or with PCI and stents. In the medi-
cally treated group, death or MI occurred in 17.1% of patients with
60.8% of the events occurring 0–90 days after the cessation of
clopidogrel. Similarly, in PCI-treated patients death or MI oc-
curred in 7.9%, with 58.9% of these events taking place within the
initial 90 days after clopidogrel cessation. The findings from this
study potentially support the hypothesis of a prothrombotic and/
or proinflammatory state precipitated by clopidogrel withdrawal,
a theory that has no requirement for true “rebound”. In this study,
the relative increase in adverse events in the early 90-day period
after stopping clopidogrel was nearly two-fold higher than at later
time periods (i.e. 91 to 360 days). This is one of the few studies that
examined the pattern of events that occur with clopidogrel ces-
sation in medically managed ACS patients without the confound-
ing factor of previous coronary stenting.
Ho et al. have recently confirmed and expanded their findings
in a retrospective cohort study in 1,656 ACS patients receiving
clopidogrel therapy (23). They observed a similar two-fold in-
crease in the risk of death or MI in the 0–90 day interval after clopi-
dogrel cessation compared with later time intervals. These findings
were consistent across all patient subgroups evaluated, specifically,
males versus females, medically managed versus PCI treated pa-
tients, DES versus BMS and with clopidogrel therapy duration of
≥6 versus <6 months. Furthermore, they established that the clus-
tering of events was specific to clopidogrel discontinuation as this
was not observed among patients stopping angiotensin converting
enzyme (ACE) inhibitors. Additional studies are clearly needed to
explore the mechanisms behind this consistently observed effect.
With regards to definition (ii) above, there is no published data
so far specifically comparing baseline pre-treatment platelet reac-
tivity and/or inflammatory biomarker levels with post-clopidogrel
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Sambu et al. Clopidogrel withdrawal rebound phenomenon 215
cessation levels. The PACT trial (75) is an ongoing randomised
controlled study that will investigate this effect by measuring pla-
telet reactivity before, during and at various time intervals after
discontinuation of clopidogrel in healthy subjects on aspirin.
However, extrapolation of the results to a co-morbid patient group
with cardiovascular disease or diabetes may not be justified.
Further data are clearly needed.
Potential mechanisms of clustering of events after
clopidogrel cessation with or without true “rebound”
The mechanisms and pathophysiology of the observed phenom-
enon of a clustering of clinical events are currently matters for
speculation (!Fig. 2). Postulated mechanisms include:
(a) increased platelet activation resulting in a pro-thrombotic ten-
dency due to the direct loss of the effect of clopidogrel on the
inhibition of ADP-induced platelet aggregation,
(b) increase in biomarkers of inflammation resulting in a pro-in-
flammatory state and increased local vascular inflammation
which could be prothrombotic,
(c) loss of the synergistic effect of clopidogrel on the inhibition of
AA-induced platelet aggregation which is predominantly af-
fected by aspirin,
(d) a combination of more than one of the above.
In (a), (b) and (c) it is possible, but there are as yet no data to sup-
port it, that these processes involve genuine type (ii) definition of
rebound.
1. Loss of anti-thrombotic and anti-inflammatory effects
It has been well established that clopidogrel exhibits both anti-
thrombotic and anti-inflammatory properties. The former is me-
diated via irreversible binding to platelet P2Y12 ADP receptors
thereby inhibiting ADP-induced platelet aggregation and the latter
is achieved via inhibition of vascular inflammatory biomarker ex-
pression. The adverse clinical events that have been reported not
long after clopidogrel is discontinued may be simply due to a pro-
thrombotic and/or proinflammatory effect that occurs as the level
of active clopidogrel metabolite diminishes.
Angiolillo et al. (76) investigated the effect of clopidogrel with-
drawal on platelet reactivity and inflammatory biomarkers in 54
diabetic patients on long-term dual antiplatelet therapy following
PCI. Blood samples were taken at 12 months post-PCI on dual
antiplatelet therapy and one month after clopidogrel cessation.
Platelet reactivity was measured using light transmission aggrego-
metry (LTA). As predicted, a significant increase in ADP-induced
platelet aggregation, hsCRP and surface P-selectin expression at
one month was observed. Without pre-clopidogrel baseline data it
is not possible to determine whether this observation is consistent
with a possible rebound effect associated with clopidogrel with-
drawal. However, this is a small study and the results cannot be
extrapolated to the non-diabetic population. It is widely accepted
Thrombosis and Haemostasis 105.2/2011
216 Sambu et al. Clopidogrel withdrawal rebound phenomenon
that diabetes is associated with diffuse and accelerated progression
of atherosclerosis which may be related to the prothrombotic and
proinflammatory status observed in these patients (77). As a result,
diabetics may potentially be more vulnerable to adverse events fol-
lowing clopidogrel withdrawal.
The DECADES study (78) examined the effect of clopidogrel
cessation on markers of inflammation 12 months after implan-
tation of DES in a non-diabetic population. A significant increase
in the inflammatory biomarkers sCD40L and P-selectin was ob-
served between two and four weeks after clopidogrel withdrawal.
There was, however, an unexplained and apparently inconsistent
decrease in hsCRP levels by 21% (p=0.008) one week after ces-
sation of clopidogrel. The questions that arose from this study are
whether the increase in these specific inflammatory biomarkers
following clopidogrel withdrawal are due to a loss of the inhibitory
effect of clopidogrel on platelet reactivity or whether it is due to a
genuine rebound pro-inflammatory state. The latter suggestion is
apparently inconsistent with the observed decline in hsCRP levels.
Unfortunately, no data were obtained regarding platelet reactivity
in this study.
In contrast to these results, a recent small randomised study in
64 patients undergoing PCI with DES did not demonstrate a rise in
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Figure 2: Potential
pathophysiological
mechanisms respon-
sible for the rebound
clustering of adverse
clinical events follow-
ing clopidogrel with-
drawal. *Mechanistic
theories suggested from
previous clinical studies
but demand further in-
vestigation. ADP, adeno-
sine diphosphate; AA,
arachidonic acid; COX,
cyclo-oxygenase; GP,
glycoprotein; VWF, von
Willebrand factor.
platelet reactivity following clopidogrel withdrawal. Specifically,
ADP-induced platelet aggregation was measured using both LTA
and multiple electrode aggregometry over various time points
during treatment with clopidogrel and following cessation of ther-
apy. They examined the effect of abrupt cessation of clopidogrel
therapy versus tapered withdrawal on platelet aggregation and
found no significant difference between the two groups and no sig-
nificant increase in platelet reactivity from 2–8 weeks following
clopidogrel withdrawal (79). Several larger studies are ongoing
that will specifically address and further clarify this issue. For
example, the randomised controlled PACT trial will determine the
effect of clopidogrel withdrawal on platelet reactivity after 14 days
of treatment in healthy subjects on aspirin (75) and the retrospec-
tive observational PRACTICE 1 study will examine whether
abrupt discontinuation of clopidogrel at six and 12 months after
PCI is associated with a rebound increase in platelet reactivity (80).
2. Does clopidogrel potentiate the effect of aspirin?
Thromboxane A2 (TXA2) is a potent vasoconstrictor and platelet
agonist that is produced from activated platelets via the AA path-
way. It is well established that aspirin exerts its anti-thrombotic ef-
© Schattauer 2011

Figure 3: Potential ap-
proaches to manage-
ment of the rebound
clustering of clinical
events following clopi-
dogrel cessation.
fects by irreversibly blocking the enzyme cyclooxygenase-1
(COX1) which is required for the synthesis of the precursors of
TXA2.
One of the possible mechanisms of a “rebound” effect of clopi-
dogrel has only recently come to light. It is based upon the simple,
but still controversial, notion that clopidogrel exerts some of its
antiplatelet activity via the AA-TXA2-COX pathway, as well as via
the more established P2Y12 ADP mechanism. The obvious impli-
cation of this would be that when clopidogrel stops, then both
pathways would be affected and this would result in an increase in
both ADP- and AA-induced platelet aggregation. This would
manifest as an apparent (or perhaps genuine) reduction in the re-
sponse of an individual patient to aspirin when clopidogrel is
stopped as assessed by AA-induced platelet reactivity.
In fact, there is accumulating evidence to suggest that clopido-
grel influences AA-TXA2-COX pathways, thereby potentiating the
effect of aspirin (13, 14, 81, 82). For example, two small studies
have shown that patients who were initially labelled as ‘non-re-
sponders’ to aspirin as determined by optical aggregometry (16)
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Sambu et al. Clopidogrel withdrawal rebound phenomenon 217
and thrombelastography (15) were converted to ‘normal re-
sponders’ as a result of increased inhibition of AA-induced platelet
aggregation by the addition of clopidogrel. Further support of the
potentiation theory is demonstrated by Angiolillo et al. (76) who
reported that, following clopidogrel withdrawal, 44% of patients
exhibited a ‘poor response’ to aspirin determined using the platelet
function analyser (PFA)-100 system, but yet when these patients
were taking aspirin and clopidogrel concomitantly their AA-in-
duced platelet aggregation profiles were consistent with an appar-
ent ‘normal’ response to aspirin.
These data sponsor the hypothesis that clopidogrel may in-
fluence AA-mediated platelet aggregation and its cessation could
therefore lead to loss of the aspirin-synergistic effect resulting in
rebound attenuation of the antiplatelet effect of aspirin. If this
mechanistic theory were examined and proven in larger studies, it
would mean that patients who are relatively hyporesponsive to as-
pirin would be at particular risk of adverse events when clopido-
grel is discontinued. It would follow that all patients requiring dual
antiplatelet therapy, either in the context of PCI or following an
Thrombosis and Haemostasis 105.2/2011
218 Sambu et al. Clopidogrel withdrawal rebound phenomenon
● CURE: Clopidogrel in Unstable Angina to Prevent Recurrent Events
trial
● CLARITY: Clopidogrel as Adjunctive Reperfusion Therapy trial
● COMMIT: Clopidogrel and Metoprolol in Myocardial Infarction trial
● CREDO: Clopidogrel for the Reduction of Events During Observa-
tion trial
● CURRENT OASIS 7: Clopidogrel Optimal Loading Dose Usage to
Reduce Recurrent EveNTs/Optimal Antiplatelet Strategy for Inter-
ventionS trial
● DAPT: Dual AntiPlatelet Therapy Study
● DECADES: Discontinuation Effect of Clopidogrel After Drug Eluting
Stent trial
● PACT: Platelet Activity After Clopidogrel Termination trial
● PRACTICE 1: Platelet Reactivity After Cessation of Clopidogrel in
the Setting of coronary Stent Implantation 1 study
● REAL-LATE: Correlation of Clopidogrel Therapy Discontinuation in
Real-World Patients Treated with Drug-Eluting Stent Implantation
and Late Coronary Arterial Thrombotic Events trial
● ZEST-LATE: Evaluation of the Long-Term Safety after Zotarolimus-
Eluting Stent, Sirolimus-Eluting Stent, or Paclitaxel-Eluting Stent
Implantation for Coronary Lesions – Late Coronary Arterial Throm-
botic Events trial
acute coronary event, would need to undergo an individualised as-
sessment of their response to aspirin and clopidogrel with a view to
tailoring treatment according to their level of response (83–88).
Conclusion
There is sufficient evidence to suggest that a pro-thrombotic phe-
nomenon following clopidogrel withdrawal is real and may be re-
sponsible for a clustering of clinical events. Further robust data is
needed from large scale randomised studies to (i) further elicit the
mechanisms and pathophysiology behind the rebound effect, (ii)
specifically assess platelet reactivity and vascular inflammation
both pre-treatment as well as post clopidogrel cessation, (iii) deter-
mine precisely how clopidogrel achieves its effects including the
extent to which it influences aspirin-specific pathways of platelet
aggregation, and (iv) determine whether the rebound phenom-
enon is also exhibited in the newer, more potent third generation
thienopyridines. A priority must be to provide a strict definition
for the term “rebound” and exclude its use outside that context.
There are a few such trials underway, the results of which should
help identify strategies to attenuate the effect of the rebound phe-
nomenon and therefore reduce the incidence of adverse clinical
events (!Fig. 3). Specifically, this could potentially involve impor-
tant changes in antiplatelet therapy prescribing guidelines such as
extending the duration of clopidogrel therapy (39), tapered rather
than abrupt interruption of chronic clopidogrel therapy (89) or
indeed tailoring antiplatelet therapy regimes to the individual pa-
tient (90), particularly those who are found to be aspirin hypore-
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For personal or educational use only. No other uses without permission. All rights reserved.
sponsive. In order to adopt the latter approach in every day clinical
practice, we would need a widely available, point-of-care test of in-
dividual patient response to antiplatelet therapy.
Clopidogrel may eventually be replaced by the more potent
P2Y12 receptor blockers, prasugrel or ticagrelor (43, 44). Recent
data have shown no difference in inflammatory biomarker levels in
ACS patients receiving clopidogrel or ticagrelor (91). Although
prasugrel is currently only recommended as an alternative to clopi-
dogrel in patients presenting with stent thrombosis during clopi-
dogrel treatment and in primary PCI for ST-segment elevation
myocardial infarction (92), the use of these agents is likely to ex-
tend to other patient groups in the future. The theoretical basis for
the pro-inflammatory “rebound” and aspirin potentiation phe-
nomena are likely to also be relevant to the newer and more potent
P2Y12 inhibitors.
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