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cular inflammation following clopidogrel withdrawal, to a level drawal of clopidogrel following PCI is associated with a substan-
that exceeds what it was at baseline prior to the initiation of clopido- tially increased risk of adverse events and is a strong independent
grel therapy. True “rebound” is thus more difficult to ascertain in predictor of ST particularly after DES implantation (6, 19, 21,
clinical practice due to the lack of availability of comparative base- 33–35). In fact, early discontinuation of treatment is apparently
line (pre-treatment) levels. more common than expected. For example, among 500 patients
An improved assessment and appreciation of the way clopido- who received DES after MI, 13.6% stopped their thienopyridine
grel works, and specifically of its anti-inflammatory and AA path- therapy within 30 days (20). These patients were older with more
way activities, is likely to facilitate our understanding of the poten- co-morbidities, were of lower socioeconomic status and were less
tial mechanisms of the “rebound” effect, which is an iatrogenic en- likely to have received discharge advice about their medication or
tity, and hence allow for its modification. 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.
Clinical indications for clopidogrel !Table 1 summarises data on patients undergoing PCI who sub-
sequently present with ST. In general over 30% of these patients
ST is a significant and potentially life threatening complication of were not on clopidogrel at the time of their presentation and the
PCI with an associated mortality of at least 30%. Early clinical median time from clopidogrel cessation to ST varied between 5–90
trials using aspirin monotherapy or a combination of aspirin and days in most studies.
warfarin to reduce the risk of thrombotic complications associated The data in relation to the optimal duration of clopidogrel is,
with stent implantation reported a high incidence of acute ST with however, discrepant. For example, some smaller studies and obser-
rates of up to 20% in the aspirin monotherapy group. The evol- vational data on patients undergoing PCI have shown that the
ution to dual antiplatelet therapy with aspirin and a thienopyri- mortality benefit of clopidogrel extends beyond one year in pa-
dine resulted in a significant reduction in the risk of ST to approxi- tients with DES (34, 36, 37). By contrast, the combined analysis of
mately 1%, with a lower risk of bleeding compared to anticoagu- data from two recent randomised multicentre trials (REAL-LATE
lant regimes (24–26). Although these early studies used ticlopi- and ZEST-LATE) (38), found no significant difference in the com-
dine, it has since been replaced by clopidogrel which is a safer and bined risk of MI and cardiac death in patients with DES who re-
better tolerated agent with no requirement for routine haemato- ceived 12 versus 24 months of clopidogrel therapy (1.2% vs. 1.8%;
logical monitoring. Clopidogrel has been proven to be at least as ef- p=0.17; 95% confidence interval [CI] 0.8 to 3.36). Some clarity on
fective as ticlopidine in reducing thrombotic and ischaemic com- this controversial issue may be provided from the large, prospec-
plications after stent implantation (27, 28). tive, randomised controlled DAPT study (39), which will assess the
The randomised controlled CREDO trial established the safety and effectiveness of 12 versus 30 months of dual antiplatelet
beneficial effect of clopidogrel loading followed by maintenance therapy in 20,000 patients following PCI.
therapy in addition to aspirin in patients undergoing elective PCI The optimal maintenance dosage of clopidogrel therapy is also
(4). Pre-treatment with clopidogrel 300 mg at least 6 hours (h) the subject of debate (40). The recent CURRENT-OASIS 7 rando-
prior to PCI was associated with a reduction in peri-procedural mised study undertaken in 25,086 ACS patients, compared 600 mg
major adverse cardiac events, and subsequent maintenance ther- loading dose clopidogrel followed by 150 mg maintenance therapy
apy for 12 months compared to treatment for only four weeks re- for seven days versus 300 mg loading dose followed by the usual 75
sulted in a significant reduction in the combined endpoint of mg maintenance therapy (41). In the sub-group of patients under-
death, MI and stroke (26.9% relative risk reduction; p=0.02). Simi- going PCI (n=17,263), double-dose clopidogrel was associated
lar findings have been reported in patients undergoing PCI in the with a significant reduction in definite ST (0.7% vs. 1.3%, hazard
acute setting, where maintenance dose clopidogrel was continued ratio [HR] 0.54, 95% CI 0.39 to 0.74, p=0.0001) and cardiovascu-
for up to one year (5). lar events (3.9% vs. 4.5%, HR 0.86, 95% CI 0.74 to 0.99, p=0.039)
The beneficial effect of clopidogrel also extends to ACS patients compared to the standard dose group (42). However, more data are
not undergoing PCI. Thus, large randomised studies of clopidogrel needed to clarify the long-term risk reduction benefit associated
therapy in addition to aspirin in patients with and without ST seg- with high-dose clopidogrel and this would need to be weighed
ment elevation managed medically, have demonstrated a signifi- against the increased risk of bleeding complications. Furthermore,
cant reduction in cardiovascular mortality and ischaemic events with the advent of newer more potent antiplatelet agents, such as
(1–3). prasugrel and ticagrelor, and the robust data emerging supporting
Although all these early studies clearly demonstrate the import- their use as an alternative to clopidogrel in ACS (43–46), the focus
ance of clopidogrel pre-loading and treatment long term, the opti- of antiplatelet therapy prescribing is likely to shift towards select-
mal duration of therapy remains uncertain. Currently, 12 months ing the most appropriate, safe and effective agent for each individ-
of clopidogrel 75 mg is recommended for all ACS patients with or ual patient.
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-
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 treatment (55, 56). Furthermore, clinical studies have shown that
individuals with increased platelet aggregation profiles have a
clopidogrel greater proportion of immature platelets (57–61). These immature
Clopidogrel is an inactive pro-drug that is oxidised to its active reticulated platelets have a higher thrombotic potential which may,
metabolite via the hepatic cytochrome P450 system. The active in part, explain the prothrombotic events that occur soon after dis-
metabolite irreversibly binds to platelet P2Y12 adenosine diphos- continuation of clopidogrel therapy.
phate (ADP) receptors, thereby inhibiting both ADP-induced pla- In addition to its anti-platelet effect, clopidogrel has also been
telet aggregation as well as transformation of the glycoprotein (GP) shown to have anti-inflammatory properties. CD40 ligand (L) and
IIb/IIIa receptor to a form that allows binding of fibrinogen CD-62 P-selectin (P) are potent stimulators of vascular inflam-
(47–49) (!Fig. 1). Previous clinical studies have shown that stimu- mation expressed on activated platelet membranes and on many
lation of P2Y12 ADP receptors may enhance Von Willebrand factor cells of the immune and vascular systems. They play an important
(VWF)-mediated platelet activation. VWF binds to GPIbα recep- role in the pathogenesis and progression of atherosclerosis
tors at sites exposed to high shear arterial blood flow leading to pla- (62–64). Clopidogrel inhibits the expression of these inflamma-
telet adhesion, activation and thrombosis (50–52). The well de- tory mediators, both acutely and in patients on long term mainten-
scribed role of clopidogrel active metabolite on P2Y12 ADP receptor ance therapy (10–12).
blockade and therefore its potential effect in inhibiting VWF-me- CD40L also exists in its soluble form, almost all of which is pro-
diated pathways of platelet activation may, in part, explain the pro- duced and released from activated platelets. Soluble CD40L is a
thrombotic effect observed following clopidogrel cessation. prothrombotic and proinflammatory molecule that plays an im-
Clopidogrel only partially blocks ADP receptors with a high de- portant role in the pathophysiology of ACS. In fact, an elevated
gree of inter-individual variability. A maintenance dose of 75mg level is a prognostic marker and predictive of subsequent cardiac
requires at least five days to achieve approximately 50% steady state events (65, 66). Studies have shown that clopidogrel pre-treatment
of inhibition of ADP-induced platelet aggregation (53, 54). Al- in patients undergoing PCI attenuates the inflammatory response
though the half-life of clopidogrel is 4 h, its irreversible platelet in- as evidenced by a reduction in serum levels of soluble CD40L at 24
hibitory effect means that once treatment is discontinued platelet h (67, 68). This may be one of the mechanisms behind the reduced
function is only completely normalised after the 7–10 day period incidence of peri-procedural ischaemic events seen in patients
required for platelet regeneration. However, a significant decline in undergoing PCI who have received clopidogrel pre-treatment.
the platelet inhibitory effects of clopidogrel has been observed High sensitivity C-reactive protein (hsCRP) is another impor-
much earlier, at approximately 3–5 days after discontinuation of tant inflammatory marker that is elevated in patients presenting
with ACS and is an independent predictor of adverse outcomes of “rebound” but could nevertheless provide an explanation for the
(69). A significant reduction in hsCRP levels following PCI has clustering of clinical events described after cessation of clopidogrel
been reported in patients receiving clopidogrel pre-treatment (70) therapy.
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 The “rebound” phenomenon
well documented beneficial effects of dual antiplatelet therapy in
reducing ischaemic events and cardiovascular mortality in ACS How do we define “rebound”?
patients compared with aspirin monotherapy.
Given the evidence that clopidogrel exerts anti-inflammatory Although the expression “rebound” phenomenon is now relatively
effects, it is plausible to hypothesise that cessation of clopidogrel widely used in the context of clopidogrel therapy, its definition is
may result in a proinflammatory and atherothrombotic state due unclear and is often the focus for confusion and/or misunder-
to loss of its inhibitory effect on these vascular biomarkers of in- standing. The two most widely accepted interpretations of “re-
flammation. Such a mechanism may not fulfil the true definition bound” are:
Figure 1: Mechanism of action of clopidogrel. Clopidogrel is a pro-drug cAMP-mediated phosphorylation of vasodilator-stimulated phosphoprotein
that is metabolised by the cytochrome P450 system to generate the active (VASP) (VASP-P), which is known to be closely related to the inhibition of gly-
metabolite which irreversibly inhibits the adenosine diphosphate (ADP) protein IIb/IIIa receptor activation. (Multiple arrows indicate that intermedi-
P2Y12 receptor. ADP binds to the P2Y1 and P2X1 receptors leading to a change ate steps may be involved; dotted arrows = inhibition; solid arrows = acti-
in platelet shape initiating a weak and transient phase of platelet aggre- vation. CYP450 = cytochrome P450; PGE1 = prostaglandin E1; PKA = protein
gation. The binding of ADP to its Gi-coupled P2Y12 receptor liberates the Gi kinase activation; PLC = phospholipase C ). Reprinted with permission from
protein subunits αGi and βγ and this results in stabilisation of platelet aggre- Elsevier from Nguyen et al. Resistance to clopidogrel: a review of the evi-
gation. The subunit αGi leads to inhibition of adenylyl cyclase (AC), which re- dence. JACC 2005; 45: 1158.
duces cyclic adenosine monophosphate (cAMP) levels. This inhibits the
(i) simply that an adverse clinical event occurs shortly after, and cessation levels. The PACT trial (75) is an ongoing randomised
because of clopidogrel cessation, controlled study that will investigate this effect by measuring pla-
(ii) that, as a result of clopidogrel cessation, one or more parame- telet reactivity before, during and at various time intervals after
ters of either platelet reactivity or vascular inflammation discontinuation of clopidogrel in healthy subjects on aspirin.
reaches a level that is higher than it was at baseline before clopi- However, extrapolation of the results to a co-morbid patient group
dogrel therapy was ever initiated. with cardiovascular disease or diabetes may not be justified.
Further data are clearly needed.
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-
Potential mechanisms of clustering of events after
able in routine clinical practice outside the realms of carefully de-
clopidogrel cessation with or without true “rebound”
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- The mechanisms and pathophysiology of the observed phenom-
enon” will encompass both definitions in this paper. enon of a clustering of clinical events are currently matters for
Studies have shown a clear link between cessation of long term speculation (!Fig. 2). Postulated mechanisms include:
clopidogrel therapy after PCI and adverse events including ST (18, (a) increased platelet activation resulting in a pro-thrombotic ten-
23, 72–74). Specifically, a significant proportion of these events dency due to the direct loss of the effect of clopidogrel on the
occur within days or weeks after clopidogrel has been discontinu- inhibition of ADP-induced platelet aggregation,
ed, hence fulfilling at least definition (i) of “rebound phenom- (b) increase in biomarkers of inflammation resulting in a pro-in-
enon”. This effect has not only been observed in patients with cor- flammatory state and increased local vascular inflammation
onary stents. Thus, Ho et al. (22) reported a clustering of adverse which could be prothrombotic,
clinical events in the initial 90 days after stopping clopidogrel in a (c) loss of the synergistic effect of clopidogrel on the inhibition of
large retrospective study of ACS patients on dual antiplatelet ther- AA-induced platelet aggregation which is predominantly af-
apy treated either medically or with PCI and stents. In the medi- fected by aspirin,
cally treated group, death or MI occurred in 17.1% of patients with (d) a combination of more than one of the above.
60.8% of the events occurring 0–90 days after the cessation of
clopidogrel. Similarly, in PCI-treated patients death or MI oc- In (a), (b) and (c) it is possible, but there are as yet no data to sup-
curred in 7.9%, with 58.9% of these events taking place within the port it, that these processes involve genuine type (ii) definition of
initial 90 days after clopidogrel cessation. The findings from this rebound.
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, 1. Loss of anti-thrombotic and anti-inflammatory effects
the relative increase in adverse events in the early 90-day period It has been well established that clopidogrel exhibits both anti-
after stopping clopidogrel was nearly two-fold higher than at later thrombotic and anti-inflammatory properties. The former is me-
time periods (i.e. 91 to 360 days). This is one of the few studies that diated via irreversible binding to platelet P2Y12 ADP receptors
examined the pattern of events that occur with clopidogrel ces- thereby inhibiting ADP-induced platelet aggregation and the latter
sation in medically managed ACS patients without the confound- is achieved via inhibition of vascular inflammatory biomarker ex-
ing factor of previous coronary stenting. pression. The adverse clinical events that have been reported not
Ho et al. have recently confirmed and expanded their findings long after clopidogrel is discontinued may be simply due to a pro-
in a retrospective cohort study in 1,656 ACS patients receiving thrombotic and/or proinflammatory effect that occurs as the level
clopidogrel therapy (23). They observed a similar two-fold in- of active clopidogrel metabolite diminishes.
crease in the risk of death or MI in the 0–90 day interval after clopi- Angiolillo et al. (76) investigated the effect of clopidogrel with-
dogrel cessation compared with later time intervals. These findings drawal on platelet reactivity and inflammatory biomarkers in 54
were consistent across all patient subgroups evaluated, specifically, diabetic patients on long-term dual antiplatelet therapy following
males versus females, medically managed versus PCI treated pa- PCI. Blood samples were taken at 12 months post-PCI on dual
tients, DES versus BMS and with clopidogrel therapy duration of antiplatelet therapy and one month after clopidogrel cessation.
≥6 versus <6 months. Furthermore, they established that the clus- Platelet reactivity was measured using light transmission aggrego-
tering of events was specific to clopidogrel discontinuation as this metry (LTA). As predicted, a significant increase in ADP-induced
was not observed among patients stopping angiotensin converting platelet aggregation, hsCRP and surface P-selectin expression at
enzyme (ACE) inhibitors. Additional studies are clearly needed to one month was observed. Without pre-clopidogrel baseline data it
explore the mechanisms behind this consistently observed effect. is not possible to determine whether this observation is consistent
With regards to definition (ii) above, there is no published data with a possible rebound effect associated with clopidogrel with-
so far specifically comparing baseline pre-treatment platelet reac- drawal. However, this is a small study and the results cannot be
tivity and/or inflammatory biomarker levels with post-clopidogrel extrapolated to the non-diabetic population. It is widely accepted
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.
that diabetes is associated with diffuse and accelerated progression platelet reactivity following clopidogrel withdrawal. Specifically,
of atherosclerosis which may be related to the prothrombotic and ADP-induced platelet aggregation was measured using both LTA
proinflammatory status observed in these patients (77). As a result, and multiple electrode aggregometry over various time points
diabetics may potentially be more vulnerable to adverse events fol- during treatment with clopidogrel and following cessation of ther-
lowing clopidogrel withdrawal. apy. They examined the effect of abrupt cessation of clopidogrel
The DECADES study (78) examined the effect of clopidogrel therapy versus tapered withdrawal on platelet aggregation and
cessation on markers of inflammation 12 months after implan- found no significant difference between the two groups and no sig-
tation of DES in a non-diabetic population. A significant increase nificant increase in platelet reactivity from 2–8 weeks following
in the inflammatory biomarkers sCD40L and P-selectin was ob- clopidogrel withdrawal (79). Several larger studies are ongoing
served between two and four weeks after clopidogrel withdrawal. that will specifically address and further clarify this issue. For
There was, however, an unexplained and apparently inconsistent example, the randomised controlled PACT trial will determine the
decrease in hsCRP levels by 21% (p=0.008) one week after ces- effect of clopidogrel withdrawal on platelet reactivity after 14 days
sation of clopidogrel. The questions that arose from this study are of treatment in healthy subjects on aspirin (75) and the retrospec-
whether the increase in these specific inflammatory biomarkers tive observational PRACTICE 1 study will examine whether
following clopidogrel withdrawal are due to a loss of the inhibitory abrupt discontinuation of clopidogrel at six and 12 months after
effect of clopidogrel on platelet reactivity or whether it is due to a PCI is associated with a rebound increase in platelet reactivity (80).
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 2. Does clopidogrel potentiate the effect of aspirin?
in this study. Thromboxane A2 (TXA2) is a potent vasoconstrictor and platelet
In contrast to these results, a recent small randomised study in agonist that is produced from activated platelets via the AA path-
64 patients undergoing PCI with DES did not demonstrate a rise in way. It is well established that aspirin exerts its anti-thrombotic ef-
fects by irreversibly blocking the enzyme cyclooxygenase-1 and thrombelastography (15) were converted to ‘normal re-
(COX1) which is required for the synthesis of the precursors of sponders’ as a result of increased inhibition of AA-induced platelet
TXA2. aggregation by the addition of clopidogrel. Further support of the
One of the possible mechanisms of a “rebound” effect of clopi- potentiation theory is demonstrated by Angiolillo et al. (76) who
dogrel has only recently come to light. It is based upon the simple, reported that, following clopidogrel withdrawal, 44% of patients
but still controversial, notion that clopidogrel exerts some of its exhibited a ‘poor response’ to aspirin determined using the platelet
antiplatelet activity via the AA-TXA2-COX pathway, as well as via function analyser (PFA)-100 system, but yet when these patients
the more established P2Y12 ADP mechanism. The obvious impli- were taking aspirin and clopidogrel concomitantly their AA-in-
cation of this would be that when clopidogrel stops, then both duced platelet aggregation profiles were consistent with an appar-
pathways would be affected and this would result in an increase in ent ‘normal’ response to aspirin.
both ADP- and AA-induced platelet aggregation. This would These data sponsor the hypothesis that clopidogrel may in-
manifest as an apparent (or perhaps genuine) reduction in the re- fluence AA-mediated platelet aggregation and its cessation could
sponse of an individual patient to aspirin when clopidogrel is therefore lead to loss of the aspirin-synergistic effect resulting in
stopped as assessed by AA-induced platelet reactivity. rebound attenuation of the antiplatelet effect of aspirin. If this
In fact, there is accumulating evidence to suggest that clopido- mechanistic theory were examined and proven in larger studies, it
grel influences AA-TXA2-COX pathways, thereby potentiating the would mean that patients who are relatively hyporesponsive to as-
effect of aspirin (13, 14, 81, 82). For example, two small studies pirin would be at particular risk of adverse events when clopido-
have shown that patients who were initially labelled as ‘non-re- grel is discontinued. It would follow that all patients requiring dual
sponders’ to aspirin as determined by optical aggregometry (16) antiplatelet therapy, either in the context of PCI or following an
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