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Drug Evaluation

Clopidogrel for the secondary

prevention of stroke
Hans-Christoph Diener, Peter A Ringleb & Pierre Savi
Department of Neurology, University Essen, Germany
1. Introduction
Patients suffering a transient ischaemic attack (TIA) or ischaemic stroke (IS)
2. Clopidogrel: pharmacology
have a high risk of recurrence. The inhibition of platelet function is effective
3. Clinical efficacy in the reduction of secondary vascular events in patients with TIA or stroke.
4. Safety and tolerability This is true for acetylsalicylic acid (ASA), clopidogrel, ticlopidine and the com-
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5. Expert opinion and conclusion bination of ASA plus slow-release dipyridamole. This overview analyses the
results of recent trials and presents ongoing or future trials with clopidogrel
as well as the combination of clopidogrel plus ASA. Clopidogrel is superior to
ASA in the prevention of vascular events in patients with IS, myocardial inf-
arction (MI) or peripheral arterial disease (PAD). The difference is highest for
high-risk patients such as diabetics, patients who underwent coronary bypass
surgery and patients with a remote prior history of ischaemic events. A pre-
diction model is presented which allows the identification of patients in
whom clopidogrel is superior to ASA for the secondary prevention of stroke.
The combination of clopidogrel and ASA is better than ASA alone in patients
undergoing coronary stent implantations and patients with unstable angina
or non-Q-wave MI. In high-risk patients with TIA or stroke, the addition of
For personal use only.

ASA to clopidogrel is not superior to ASA monotherapy but results in a

higher rate of bleeding complications. The long-term combination therapy is
currently investigated in several large trials in > 30,000 patients, with a large
number of stroke patients.

Keywords: acetylsalicylic acid, bleeding complications, clopidogrel, combination therapy,

secondary prevention, stroke

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1. Introduction

1.1 Patients at risk of ischaemic events

Atherosclerosis is a chronic, disseminated process that causes structural changes in
the intima and media of large and medium-sized arteries, initially resulting in
endothelial abnormalities and eventually producing atherosclerotic plaques. Throm-
bosis, as the main complication of atherosclerosis, is mainly caused by platelet acti-
vation and aggregation arising from disruption of an atherosclerotic plaque.
Atherothrombosis leads to local occlusion or distal embolism, the three common
clinical manifestations being coronary heart disease [myocardial infarction (MI) and
angina pectoris], peripheral arterial disease (PAD) and cerebrovascular events such as
transient ischaemic attacks (TIAs) and ischaemic stroke (IS).
For reprint orders, please
contact: 1.2 Stroke
Acute stroke is increasingly recognised as one of the leading factors of morbidity and
mortality worldwide. Its economic burden is among the highest of all diseases. Over
the past decades, acute stroke has increasingly being recognised as a medical emer-
gency. Acute, postacute, and rehabilitation care of stroke patients in specialised wards,
as well as revascularising therapies have been shown to be effective in acute IS. IS
Ashley Publications accounts for 85% of all strokes, while the remaining 15% are due to cerebral haem-
orrhage. Large-vessel atherothrombosis, cardiac embolism and small-vessel occlusion

10.1517/14656566.6.5.755 2005 Ashley Publications Ltd ISSN 1465-6566 755


each account for 20% of all strokes, while the aetiology is active metabolite was identified and isolated [15]. This com-
undetermined in 15% and the remaining 5% are due to other pound results from a two-step enzymatic reaction that leads to
defined causes [1]. Large-vessel disease is a predominant aetiol- the opening of the thiophene ring, so generating a free thiol
ogy in middle-aged men (45 70 years of age). Besides a function capable of covalent modification of P2Y12 ADP recep-
higher risk of recurrent cerebral events, stroke patients are also tors (Figure 1). In vitro, the active metabolite of clopidogrel
at high risk of developing cardiac events [2]. reproduces the effects observed ex vivo in platelets from clopi-
dogrel-treated subjects [16]. This includes inhibition of binding
1.3 Secondary prevention of stroke with antiplatelet of 2-methylthio-ADP, ADP-induced adenylyl cyclase downreg-
drugs ulation, and ADP-induced platelet aggregation. Moreover,
Recurrence risk after TIA or IS ranges from 5 to 20% per year ADP-induced platelet shape change and aggregation triggered
[1,3,4]. The risk is highest immediately after the first event by adrenaline are not affected, as with clopidogrel in vivo. The
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[5,6,7]. Numerous trials and meta-analyses have left little doubt fact that no antiaggregating activity was detected in the plasma
that antiplatelet therapy effectively reduces stroke risk in from subjects treated with clopidogrel suggests that the active
patients with prior IS or TIA [8-11]. The latest publication metabolite has a short biological half-life.
from the Antithrombotic Trialists Collaboration [8] involves The molecular target of clopidogrel has been extensively
the meta-analysis of 287 trials with 135,000 patients in com- investigated. The ADP-dependant platelet activation pathway
parisons of antiplatelet therapy versus controls, and 77,000 in was identified very early as the main function affected by
comparisons of different antiplatelet regimens. The main clopidogrel. Platelet aggregation is inhibited when activated
results were summarised as a reduction of serious vascular by ADP or in conditions where ADP is required, such as with
events (which include non-fatal MI, non-fatal stroke, or vas- low doses of collagen and thrombin. This is due to a dramatic
cular death) by 25% (relative percentage). In absolute decrease in the number of ADP-binding sites on the platelet
terms, the events prevented include 3.6% treated for 2 years surface after clopidogrel treatment, as demonstrated in diverse
among those with previous IS or TIA, the absolute benefits studies in men and animals [17,18].
substantially outweigh the absolute risks of major extracranial Two different ADP receptors on the platelet surface act
For personal use only.

bleeding. Nevertheless, controversies exist. Foremost among synergistically to initiate platelet aggregation. P2Y1 triggers
them is the debate over the optimal antiplatelet regimen. The shape change and external calcium entry [19], whereas P2Y12 is
majority of research in secondary stroke prevention supports linked to the inhibition of adenylyl cyclase and the activation
the clinical value of acetylsalicylic acid (ASA). Several key of phosphatidylinositol trisphosphate kinase (PI3K) [20]. Acti-
questions, however, remain unanswered. Is the routine use of vation of both receptors is required for sustained activation of
antiplatelet therapy justified for all eligible patients? Should the GP IIb/IIIa receptor and fibrinogen binding [21]. In trans-
ASA be used alone or in combination with another antiplate- genic mice, deletion of either ADP receptor gene results in a
let agents such as clopidogrel with a different mode of action? strong antiaggregant activity, a potent antithrombotic activity
Will administration of low-dose ASA reduce the incidence of and a prohaemorrhagic tendency [22,23].
side effects? Are the new antiplatelet drugs such as clopidogrel Clopidogrel does not modify P2Y1, nor interfere with the
superior to ASA? This chapter summarises the results of events included in its activation pathway [24]. However, P2Y12
recent clinical trials performed with clopidogrel in the context has been demonstrated to be the target of the active metabo-
of evolving strategies for stroke prevention. lite of clopidogrel [25] that is closely correlated with all the
effects of clopidogrel reported on platelets. This inhibition is
2. Clopidogrel: pharmacology irreversible and lasts for the lifetime of modified platelets [26].
The major consequence of the inhibition of platelet aggre-
Clopidogrel belongs to the thienopyridine family of ADP-recep- gation is a strong and long-lasting protection against throm-
tor antagonists. By contrast with ticlopidine, another thienopy- bosis. The antithrombotic activity of thienopyridines has been
ridine, the clopidogrel molecule contains an asymmetric carbon demonstrated in several animal species and models of throm-
atom. Clopidogrel is the S-enantiomer, and, when tested in ani- bosis, part of them being insensitive to ASA [27]. In various
mals, the corresponding R-enantiomer was devoid of antiaggre- arterial-type models of thrombosis, clopidogrel exhibited a
gant antithrombotic activity, indicating that this position is potent, dose-dependent antithrombotic activity, being 50
critical for the pharmacological activity of the drug [12]. times more potent than ticlopidine and 100-fold more
Clopidogrel is not directly active and needs to be metabo- active than ASA [28-33].
lised to achieve its antiaggregating activity. This metabolic con- In experiments aimed at determining the role of platelets in
version is mainly hepatic. Experiments in rats showed that experimental venous thrombosis, we showed that ADP-medi-
clopidogrel lost its activity when the blood flow was diverted ated platelet activation played a major role in the development
from the liver and that antiaggregant activity could be obtained of venous thrombosis under low thrombogenic conditions
in an isolated perfused liver model [13]. Further, the metabolic [34]. This suggests that clopidogrel may be of therapeutic inter-
transformation of clopidogrel was demonstrated to be depend- est in pathologies involving venous thrombosis, based on an
ant on several cytochrome P450 isoenzymes [14]. Finally, an inhibition of thrombin generation in platelet-rich plasma [35].

756 Expert Opin. Pharmacother. (2005) 6(5)

Diener, Ringleb & Savi



S Cl S Cl

2-oxo clopidogrel
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Active metabolite
ADP receptor

Figure 1. Structure of clopidogrel and key metabolites.

For personal use only.

Moreover, recent studies have provided evidence that antago- has tested clopidogrel in the setting of stroke patients [47]. It
nism of the P2Y12 ADP receptor with clopidogrel reduces mark- was a randomised, double-blind study, which compared the
ers of vascular inflammation in addition to inhibiting platelet effects of clopidogrel 75 mg/day with ASA 325 mg. The aim
activation and aggregation [36]. In healthy volunteers, clopidog- was to reduce a composite end point, which consisted of
rel, but not ASA alone, was shown to inhibit the ADP-induced either IS, MI, or vascular death. A total of 19,185 patients
expression of platelet CD40 ligand, a pro-inflammatory media- with a previous MI or IS, or established PAD were ran-
tor [37]. Additional effects of clopidogrel demonstrated in domised. TIA patients were not included into the CAPRIE
healthy volunteers include a reduction in platelet-dependent trial. After a mean follow-up period of 1.9 years there was a
mitogenic signalling [38], inhibition of P-selectin expression and significant absolute risk reduction of 0.5% and a relative risk
plateletleukocyte formation [39,40], and a reduction in reduction of 8.7% in favour of clopidogrel. Thus, clopidogrel
cytokine-triggered priming of endothelial cells for enhanced is slightly more effective than ASA in preventing a composite
neutrophil transmigration [41]. Notably, in the latter study, the end point of vascular events. It is the agent of choice in
effect on neutrophil migration was reversed after discontinua- patients with contraindications to, or adverse effects on, ASA.
tion of clopidogrel treatment. In patients undergoing percuta- For the subgroup of patients in the CAPRIE trial with IS
neous coronary intervention, clopidogrel pretreatment reduced (n = 6431) as the qualifying event, the relative risk reduction
platelet inflammatory markers expression (CD40 ligand and was 7.3% and not statistically significant (95% Confidence
CD62 P-selectin) and also attenuated the increased 30-day risk Interval [CI] -5.7 18.7). However, the CAPRIE study was not
of death or MI associated with elevated baseline levels of CRP designed or powered to specifically address this subgroup of
and attenuated the periprocedural rise of CRP [42-44]. patients. In several posthoc analyses of the CAPRIE trial, the
Clopidogrel has also been found to reduce platelet-depend- benefit of clopidogrel was demonstrated to be amplified among
ant tissue factor expression in human leukocytes and vascular high-risk subgroups, including patients with a history of previ-
cells [45]. This effect is known to be specifically dependent on ous IS or MI [48], patients with diabetes [49], those with prior
the platelet P2Y12 receptor [46]. cardiac surgery [50], and those receiving lipid-lowering therapy
[51]. In the 4496 patients with a history of previous IS or MI
3. Clinical efficacy before their qualifying event, clopidogrel produced a relative
risk reduction of 14.9% versus ASA for the primary CAPRIE
3.1 Clopidogrel for the prevention of vascular events end point (p = 0.045) [48]. This risk reduction translates into a
in patients with IS, MI or PAD (CAPRIE) number of patients needed to treat (NNT) of 71/year with
The CAPRIE (Clopidogrel versus Aspirin in Patients at Risk clopidogrel instead of ASA to prevent further vascular events.
of Ischemic Events) study was the largest study to date that For comparison, the NNT is 200 patients/ year for the overall

Expert Opin. Pharmacother. (2005) 6(5) 757


Placebo + clopidogrel
ASA + clopidogrel
RRR = 6.4%

Cumulative event rate (%)


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p = 0.244
0 3 6 9 12 15 18
Time since randomisation (months)
Patients at risk
ASA + clopidogrel 3797 3576 3440 3321 3229 3130 2441
Placebo + clopidogrel 3902 3576 3432 3326 3200 3119 2446

Figure 2. Patients remaining event-free over time for the primary end point (MI, IS, cardiovascular death, or
For personal use only.

rehospitalisation due to ischaemic event) in the MATCH trial; intention-to-treat population [51].
ASA: Acetylsalicylic acid; IS: Ischaemic attack; MI: Myocardial infarction; MATCH: Management of ATherothrombosis with Clopidogrel in High-risk patients with recent
TIA or IS; RRR: Relative risk reduction.

CAPRIE population. In the entire CAPRIE population, there in the clopidogrel alone group (relative risk reduction 6.4%,
were 1480 patients with a history of cardiac surgery. The event 95% CI 4.6, 16.3; absolute risk reduction 1%, 95% CI -0.6,
rate/year for MI, stroke, vascular death or rehospitalisation was 2.7; Figure 2). Life-threatening bleedings were significantly
22.3% in the ASA group and 15.9% in the clopidogrel group higher in the group receiving ASA plus clopidogrel (96
(p < 0.001) [50]. [2.6%] versus clopidogrel alone 49 [1.3%]; absolute risk
Data such as these remain to be verified in well powered increase 1.3% [95% CI 0.6, 1.9]). Major bleedings were also
studies. The number of events prevented by treating 1,000 increased in the group receiving ASA in addition to clopidog-
patients for 1 year with clopidogrel, rather than ASA, has rel but there was no difference in mortality. Adding ASA to
been shown to rise from 11 (all patients in the trial) to 28 clopidogrel in high-risk patients with recent IS or TIA is asso-
(patients with any history of ischaemia) and to 34 (patients ciated with a non-significant difference in terms of major vas-
with a prior major acute event [MI or IS]) [52]. cular events. However, the risk of life-threatening and major
bleeding is increased by the addition of ASA. Predefined sub-
3.2 MATCH group analyses were unable to identify a group of patients
The MATCH (Management of ATherothrombosis with where the benefit of combination therapy would outweigh the
Clopidogrel in High-risk patients with recent TIA or IS) trial bleeding risk. The benefit of the combination therapy was
was a randomised, double-blind, placebo-controlled trial that highest in patients randomised early after the qualifying
compared ASA (75 mg/day) versus placebo in 7599 high-risk event, whereas the differences in bleeding complications
patients with recent TIA or IS and at least one additional vas- emerged only after 3 months. Theoretically, this would indi-
cular risk factor in patients receiving clopidogrel 75 mg/day cate that there is a window of opportunity for short-term use
[53,54]. Additional vascular risk factors were defined as previous of the combination. This, however, has to be investigated in a
IS, previous MI, angina pectoris, diabetes mellitus, or symp- separate trial (FASTER, see below).
tomatic PAD within the previous 3 years. The duration of
treatment and follow-up was 18 months. The primary end 3.3 Risk model to identify patients at high risk for
point was a composite of IS, MI, vascular death, or rehospital- stroke recurrence
isation for acute ischaemia (including rehospitalisation for Based on a subgroup analysis of the CAPRIE trial [48] and the
TIA, angina pectoris, or worsening of PAD). In the group risk factors identified by logistic regression analysis, the authors
receiving ASA plus clopidogrel, 596 (15.7%) patients reached developed a predictive model. As shown in Table 1 points were
the primary end point compared with 636 (16.7%) patients assigned to certain baseline variables and risk factors, where the

758 Expert Opin. Pharmacother. (2005) 6(5)

Diener, Ringleb & Savi

reduction observed in the primary end point. Combined

Table 1. Stroke prediction model based on the stroke
ASA and clopidogrel resulted in a 38% higher rate of overall
subgroup in the CAPRIE trial.
major bleeding events and a statistically significant increase
Risk factors Points in minor bleeding. However, there was no significant
< 65 years 0
increase in the incidence of life-threatening major bleeding
complications between the two groups (2.2 versus 1.8%).
65 75 years 1
The CREDO (Clopidogrel for Reduction of Events During
> 75 years 2 Observation) trial was performed in 2116 patients undergo-
Hypertension yes 1 ing coronary stent placement [56]. In this trial, the use of a
Diabetes yes 1 clopidogrel 300 mg loading dose followed by long-term
Previous MI 1
(12 months) treatment with clopidogrel 75 mg/day in addi-
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tion to ASA was compared with the traditional 30 days of

Other cardiovascular disease (except MI 1
clopidogrel plus ASA followed by ASA plus placebo until the
and AF)
end of 12 month follow-up. At 12 months, long-term clopi-
PAD 1 dogrel treatment was associated with a relative risk reduction
Smoker yes 1 of 27% for the composite of death, MI or stroke (p = 0.02).
Additional TIA or ischaemic stroke in 1 As in CURE, there was a consistent benefit of extended
addition to qualifying event clopidogrel therapy for each component of the composite
AF: Atrial fibrillation; MI: Myocardial infarction; PAD: Peripheral artery disease; end point, with a 25.1% relative risk reduction for all-cause
CAPRIE: Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events; TIA: stroke.
Transient ischaemic attack.

3.5 Ongoing trials (Table 2)

maximal possible score was 9. Rates for recurrent strokes were Ongoing cardiology trials with clopidogrel include COM-
calculated for the ASA and clopidogrel groups for each risk-fac- MIT (Clopidogrel Metoprolol Myocardial Infarction Trial),
For personal use only.

tor score. Overall, the patient population can be separated at an a study of clopidogrel versus placebo in acute ST-elevation
annual stroke risk of smaller or greater than 4% into low- and MI patients with a sample size of 45,000 patients [58].
high-risk groups. As can be seen from Figure 3, in the high-risk CLARITY-TIMI 28 (CLopidogrel as Adjunctive Reper-
group (3 6 points), there is an amplified benefit of clopidog- fusIon TherapY - Thrombolysis In Myocardial Infarction
rel over ASA. The very high-risk group (> 6 points) contains Study 28) is a trial of 3500 patients with acute MI in which
few patients and the results have wide confidence intervals. clopidogrel is compared with placebo in addition to throm-
Although this model requires further validation, these bolytic therapy [59]. The ACTIVE (Atrial fibrillation Clopi-
results clearly favour a strategy in which the stroke recurrence dogrel Trial with Irbesartan for the prevention of Vascular
risk guides the decision to use either ASA or clopidogrel for Events) trial will enrol 14,000 patients with atrial fibrilla-
secondary stroke prevention. A prospective validation of the tion and is a two-armed treatment comparison of ASA and
risk model is necessary and has recently been initiated. clopidogrel versus oral anticoagulation and combined
ASA/clopidogrel versus ASA.
3.4 CURE FASTER (Fast Assessment of Stroke and TIA to prevent
Although not a trial of patients with stroke, CURE (Clopi- Early Recurrence trial) will focus on clopidogrel and ASA in the
dogrel in Unstable Angina to Prevent Recurrent Events) setting of TIA. In this trial, a loading dose of clopidogrel
compared clopidogrel 75 mg with placebo; patients also 300 mg is used. A secondary consideration is whether simvasta-
received open-label ASA 75 325 mg/day [55]. Thus, it pro- tin is superior to placebo. The primary end point is the 90-day
vides relevant data on the use of clopidogrel plus ASA, com- risk of stroke. The inclusion time (12 h after a TIA) is short.
pared with ASA alone. Patients, who totalled > 12,500, had Therefore, FASTER will focus on early secondary prevention.
unstable angina or non-Q wave MI, and were followed for a The SPS3 (Secondary Prevention of Small Subcortical
median of 9 months. Results showed a 20% relative risk Strokes) trial investigates not only whether recurrent stroke can
reduction (p = 0.00009) in the likelihood of a recurrent be avoided but also whether dementia a high risk in this pop-
ischaemic event in favour of the combination therapy. Eval- ulation can be prevented. Around 2500 patients with small
uation of single end points demonstrated a statistically sig- subcortical strokes will be included; those with cardioembolic,
nificant improvement in event rates for MI (p < 0.001) with cortical or haemorrhagic stroke are excluded. The trial has two
the combination. For stroke, event rates were low and simi- treatment arms. In the antiplatelet study, patients will be ran-
lar for the treatments (ASA and placebo 1.4% versus ASA domised to clopidogrel or placebo, with all patients receiving
and clopidogrel 1.2%, p = non-significant). ASA. The other treatment arm investigates moderate versus
The absolute clinical benefit demonstrated by CURE was aggressive blood pressure control.
2.1% treating 1000 patients for a mean of 9 months The CHARISMA (Clopidogrel for High Atherothrombotic
would avoid 11 events. There was a price to pay for the 20% Risk and Ischemic Stabilization, Management and Avoidance)

Expert Opin. Pharmacother. (2005) 6(5) 759



Annual event rate (%) 8

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0 1 2 3 4 5 6 7 8

Score age > 50, > 60, > 70 years, prior MI, prior IS/TIA,
CHF, diabetes, PAD, CAD, smoking

Figure 3. Annual event rate for ischaemic stroke (%) in the CAPRIE trial gained from the ischaemic stroke population
according to the risk score (see Table 1). Please note that the risk scores of 7 and 8 are based on small patient numbers and have wide
confidence intervals. A risk score of 9 was achieved by very few patients and is omitted from the figure.
ASA: Acetylsalicylic acid; CAD: Coronary artery disease; CAPRIE: Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events; CHF: Congestive heart failure;
IS: Ischaemic stroke; MI: Myocardial infarction; PAD: Peripheral arterial disease; TIA: Transient ischaemic attack.

Table 2. Ongoing and planned clinical trials of antiplatelet therapy in stroke prevention [57,101].

Trial Patients Onset Interventions Primary end point Sample size

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ARCH TIA or IS and aortic arch 0 6 months Clop. 75 mg + ASA 75 325 mg IS, MI, vascular death or 1500
plaque (> 4 mm) versus warfarin emboli
ACTIVE Atrial fibrillation (high Clop. + ASA versus warfarin IS, MI, vascular death (+ 14,000
risk) Clop. + ASA versus ASA emboli for the comparisons
Irbesartan versus placebo between clop. + ASA versus
ASA and between clop. + ASA
versus warfarin)
CHARISMA High-risk 0 5 years Clop. 75 mg versus placebo; IS, MI or vascular death 15,000
atherothrombotic event low-dose ASA for all patients
or symptomatic
cerebrovascular disease,
coronary heart disease or
PAD or 2 major, 1 major
and 2 minor, or 3 minor
risk factors
FASTER TIA or minor IS, 0 12 h Clop. 300 mg loading dose, Stroke at 90 days, combined 7500
treatment within 12 h 75 mg/day versus placebo out-come of MI, stroke, or
after symptom onset ASA for all patients; simvastatin vascular death at 90 days,
40 mg versus placebo stroke severity
PRoFESS IS 0 90 days Clop. versus dipyridamole + First recurrent stroke 15,500
ASA; telmisartan versus placebo
SPS3 Small subcortical stroke 0 3 months Clop. versus placebo Stroke 2500
(MRI) ASA for all patients
ACTIVE: Atrial fibrillation Clopidogrel Trial with Irbesartan for the prevention of Vascular Events; ASA: acetylsalicylic acid; CHARISMA: Clopidogrel for High
Atherothrombotic Risk and Ischemic Stabilization, Management; Clop.: Clopidogrel; IS: Ischaemic stroke; MI: Myocardial infarction; FASTER: Fast Assessment of Stroke
and TIA to prevent Early Recurrence trial; SPS3: Secondary Prevention of Small Subcortical Strokes.

study, which has recruited > 15,000 patients, is an attempt to vascular risk factors without an actual event will also be enrolled
investigate the role of clopidogrel in both primary and second- (primary prevention). CHARISMA will compare the combina-
ary prevention [60]. The target study population is one at high tion of clopidogrel plus ASA with ASA plus placebo. MATCH
risk of atherothrombotic events subjects have documented and CHARISMA together will provide data on whether the
cerebrovascular, cardiovascular or PAD. However, subjects with combination is superior to ASA alone or clopidogrel alone.
760 Expert Opin. Pharmacother. (2005) 6(5)
Diener, Ringleb & Savi

The recent CARESS trial, in which the combined use of However, in a review of ticlopidine-treated patients following
clopidogrel and ASA was significantly more effective than coronary stenting, the incidence of TTP was calculated to be
ASA alone in reducing cerebral microemboli in patients with 1 case/4,814 patients treated, which represents a higher inci-
recently symptomatic moderate-to-severe carotid stenosis, dence in comparison with clopidogrel [66].
identified a subgroup of patients in whom combination ther- Experimental studies showed that other drugs metabolised
apy might be superior to monotherapy with ASA. The by cytochrome P450 may interfere with clopidogrel metabo-
number of patients, 110, was too small to reach a significant lism. Some statins are also metabolised by cytochrome P450,
reduction in clinical end points. However, the number of and it has been suggested that the HMG-CoA reductase
strokes was smaller in the combination group (0 versus 4) [61]. inhibitor atorvastatin may diminish the antiplatelet activity of
The ongoing PRoFESS (Secondary Prevention of Small clopidogrel [58]. However, more recent clinical trials have
Subcortical Strokes) trial will recruit 15,500 patients with IS shown that the antiplatelet effect of clopidogrel was not
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and compare 75 mg clopidogrel with the combination of low- diminished by atorvastatin or simvastatin in cardiac patients
dose ASA with extended-release dipyridamole. This trial is [67,68], and these results are reinforced by clinical-end point
supposed to identify subgroups of patients who might benefit data from CAPRIE [51], CREDO [69] and the MITRA PLUS
more from one treatment regimen than the other based on (maximal individual therapy of acute myocardial infarction
risk factors and concomitant diseases. PLUS) registry [70].

4. Safety and tolerability 5. Expert opinion and conclusion

Based on the data of the CAPRIE trial, clopidogrel had better Clopidogrel is effective in the prevention of vascular events in
gastric tolerability and haemorrhagic safety profiles than ASA high-risk patients and, as shown in subgroup analyses of
[47]. Clopidogrel was associated with a significantly lower risk CAPRIE, this is especially true for people with PAD or diabe-
of gastrointestinal haemorrhage (25%), although it was asso- tes mellitus. A stroke recurrence prediction model offers guid-
ciated with a slight excess in the odds of skin rash and diar- ance on which patients should receive ASA or clopidogrel for
For personal use only.

rhoea. Clopidogrel was not associated with a risk for secondary stroke prevention. Clopidogrel has fewer gastroin-
neutropenia, a side effect well known from the other testinal side effects than ASA. However, it does not demon-
thienopyridine ticlopidine. An extensive discussion concerns strate difference from ASA in patients with IS overall.
the suggested causative relationship between clopidogrel and Presently the addition of ASA to clopidogrel can not be rec-
cases of thrombotic thrombocytopenic purpura (TTP). TTP ommended in high-risk patients with TIA or IS. In this
can occur after the initiation of clopidogrel therapy. If it group, the combination is not superior to clopidogrel mono-
occurs, it is most likely ( 90%) within the first 2 weeks of therapy but leads to more bleeding complications.
treatment [62]. In postmarketing follow-up, the pharmaceuti- In the future, trials may show that the combination of clopi-
cal companies have reported the estimate of TTP to be dogrel plus ASA is superior to ASA or clopidogrel alone in the
4 cases/1 million patients but no TTP cases were observed in secondary prevention of stroke, vascular events after TIA or lac-
the published clinical trials. Many drugs have been reported unar stroke, and vascular dementia. However, this higher effi-
as possibly inducing a TTP and clopidogrel, with 8% of any cacy may come at the price of a higher bleeding rate. The results
reported TTP cases possibly associated with its prescription, of the ongoing PRoFESS trial, comparing clopidogrel with
is the second most frequent after ticlopidine [63,64]. In a recent dipyridamole + ASA will complete the assessment of clopidogrel
publication, up to 24 cases were reported from the US [65]. risk/benefit ratio accurately.


1. GRAU AJ, WEIMAR C, BUGGLE F et al.: et al.: Etiology, duration, and prognosis of Early risk of recurrence by subtype of
Risk factors, outcome, and treatment in transient ischemic attacks: an analysis from ischemic stroke in population-based
subtypes of ischemic stroke: the German the German Stroke Data Bank. incidence studies. Neurology (2004)
stroke data bank. Stroke (2001) Arch. Neurol. (2002) 59:1584-1588. 62:569-573.
2. HANKEY GJ: Stroke. How large a public BROWNER WS, SIDNEY S: Short-term COLLABORATION: Collaborative meta-
health problem, and how can the prognosis after emergency department analysis of randomised trials of antiplatelet
neurologist help? Arch. Neurol. (1999) diagnosis of TIA. JAMA (2000) therapy for prevention of death, myocardial
56:748-754. 284:2901-2906. infarction, and stroke in high risk patients.
6. WEIMAR C, ROTH MP, ZILLESSEN G Br. Med. J. (2002) 524:71-86.
event rates in patients with atherosclerotic et al.: Complications following acute 9. ANTIPLATELET TRIALISTS
cerebrovascular disease. Arch. Neurol. ischemic stroke. Eur. Neurol. (2002) COLLABORATION: Collaborative
(1992) 49:857-863. 48:133-140. overview of randomised trials of antiplatelet

Expert Opin. Pharmacother. (2005) 6(5) 761


therapy I: Prevention of death, myocardial ADP-induced intracellular calcium 32. ROSS R: The pathogenesis of
infarction, and stroke by prolonged mobilization and shape change in platelets. atherosclerosis. An update. N. Engl. J. Med.
antiplatelet therapy in various categories of J. Biol. Chem. (1998) 273:2030-2034. (1986) 314: 488-492.
patients. Br. Med. J. (1994) 308:81-106. 22. FABRE JE, NGUYEN M, LATOUR A 33. HERBERT JM, TISSINIER A,
10. ANTIPLATELET TRIALISTS et al.: Decreased platelet aggregation, DEFREYN G, MAFFRAND JP: Inhibitory
COLLABORATION: Secondary increased bleeding time and resistance to effect of clopidogrel on platelet adhesion
prevention of vascular disease by prolonged thromboembolism in P2Y1-deficient mice. and intimal proliferation following arterial
antiplatelet treatment. Br. Med. J. (1988) Nat. Med. (1999) 5:1199-1202. injury. Arterioscler. Thromb. (1993)
296:320-331. 23. ANDRE P, DELANEY SM, LAROCCA T 13:1171-1179.
11. PATRONO C, ROTH GJ: Aspirin in et al.: P2Y12 regulates platelet 34. HERBERT JM, BERNAT A,
ischemic cerebrovascular disease. adhesion/activation, thrombus growth, and MAFFRAND JP: Importance of platelets in
Stroke (1996) 27:756-760. thrombus stability in injured arteries. experimental venous thrombosis in the rat.
Expert Opin. Pharmacother. Downloaded from by The University of Manchester on 12/01/14

12. HERBERT JM, FREHELD, BERNAT A J. Clin. Invest. (2003) 112:398-406. Blood (1992) 80:2281-2286.
et al.: Clopidogrel hydrogensulfate. 24. SAVI P, BEAUVERGER P, LABOURET C 35. DOL F, GAICH C, BERNAT A,
Drugs Future (1993) 18:107-112. et al.: Role of P2Y1 purinoceptor in MAURAN G, HERBERT JM: Effect of
13. SAVI P, HERBERT JM, PFLIEGER AM ADP-induced platelet activation. FEBS Lett. clopidogrel on thrombin generation in the
et al.: Importance of hepatic metabolism in (1998) 422:291-295. rat. Thromb. Res. (1992) 65:S160.
the antiaggregating activity of the 25. SAVI P, LABOURET C, DELESQUE N, 36. HERBERT JM: Effects of ADP-receptor
thienopyridine clopidogrel. Biochem. GUETTE F, LUPKER J, HERBERT JM: antagonism beyond traditional inhibition of
Pharmacol. (1992) 44:527-532. P2y(12), a new platelet ADP receptor, target platelet aggregation. Expert Opin. Investig.
14. SAVI P, COMBALBERT J, GAICH C of clopidogrel. Biochem. Biophys. Res. Drugs (2004) 13:457-460.
et al.: The antiaggregating activity of Commun. (2001) 283:379-383. 37. HERMANN A, RAUCH BH, BRAUN M,
clopidogrel is due to a metabolic activation 26. WEBER AA, BRAUN M, HOHLFELD T, SCHRR K, WEBER AA: Platelet CD40
by the hepatic cytochrome P450 1A. SCHWIPPERT B, TSCHPE D, ligand (CD40L) subcellular localization,
Thromb. Haemost. (1994) 72:313-317. SCHRR K: Recovery of platelet function regulation of expression, and inhibition by
For personal use only.

15. PEREILLO JM, MAFTOUH M, after discontinuation of clopidogrel clopidogrel. Platelets (2001) 12:74-82.
ANDRIEU A et al.: Structure and treatment in healthy volunteers. Br. J. Clin. 38. HERMANN A, WEBER AA, SCHRR K:
stereochemistry of the active metabolite of Pharmacol. (2001) 52:333-336. Clopidogrel inhibits platelet adhesion and
clopidogrel. Drug Metab. Dispos. (2002) 27. HERBERT JM, FREHEL D, VALLEE E platelet-dependent mitogenesis in vascular
30:1288-1295. et al.: Clopidogrel, a novel antiplatelet and smooth muscle cells. Thromb. Res. (2002)
16. SAVI P, PEREILLO JM, UZABIAGA MF antithrombotic agent. Cardiovasc. Drug Rev. 105:173-175.
et al.: Identification and biological activity (1993) 11:180-198. 39. KLINKHARDT U, GRAFF J,
of the active metabolite of clopidogrel. 28. YAO SK, OBER JC, MCNATT J et al.: HARDER S: Clopidogrel, but not
Thromb. Haemost. (2000) 84:891-896. ADP plays an important role in mediating abciximab, reduces platelet leukocyte
17. MILLS DC, PURI R, HU CJ et al.: platelet aggregation and cyclic flow conjugates and P-selectin expression in a
Clopidogrel inhibits the binding of ADP variations in vivo in stenosed and human ex vivo in vitro model. Clin.
analogues to the receptor mediating endothelium-injured canine coronary Pharmacol. Ther. (2002) 71:176-185.
inhibition of platelet adenylate cyclase. arteries. Circ. Res. (1992) 70:39-48. 40. KLINKHARDT U, BAUERSACHS R,
Arterioscler. Thromb. (1992) 12:430-436. 29. HERBERT JM, BERNAT A, ADAMS J, GRAFF J,
HERBERT JM: Binding of [3H]-2- RINALDI M: Potentiating effect of Clopidogrel but not aspirin reduces P-
Methylthio-ADP to rat platelets Effect of clopidogrel and SR 46349, a novel 5-HT2 selectin expression and formation of
clopidogrel and ticlopidine. J. Pharmacol. antagonist, on streptokinase-induced plateletleukocyte aggregates in patients
Exp. Ther. (1994) 269:772-777. thrombolysis in the rabbit. Thromb. with atherosclerotic vascular disease.
Haemost. (1993) 69:268-271. Clin. Pharmacol. Ther. (2003) 73:232-241.
GACHET C: Cloning and sequencing of a 30. BERNAT A, DOL F, HERBERT JM, 41. DUNZENDORFER S, REINISCH CM,
purinoceptor. Gene (1996) 171:295-297. Potentiating effects of anticoagulants and WIEDERMANN CHJ: Inhibition of
antiplatelet agents on streptokinase-induced plasma-dependent monocyte chemokinesis
thrombolysis in the rabbit. Fibrinolysis and cytokine-triggered endothelial
VINCENT D et al.: Identification of the
(1993) 7:23-30. activation for neutrophil transmigration by
platelet ADP receptor targeted by
31. YAO SK, MCNATT J, ANDERSON HV administration of clopidogrel in man.
antithrombotic drugs. Nature (2001)
et al.: Concomitant administration of Acta Med. Austriaca (2002) 29:100-106.
clopidogrel with tissue type plasminogen 42. QUINN MJ, BHATT DL, ZIDAR F et al.:
activator delays reocclusion after the lysis of Effect of clopidogrel pre-treatment on
Molecular basis for ADP-induced platelet
thrombi in canine coronary arteries. inflammatory marker expression in patients
activation. II. The P2Y1 receptor mediates
Circulation (1990) 82:770. undergoing parcutaneous coronary

762 Expert Opin. Pharmacother. (2005) 6(5)

Diener, Ringleb & Savi

interventions. Am. J. Cardiol. (2004) 54. DIENER HC, BOGOUSSLAVSKY J, 63. GORDON LI, KWAAN HC: Cancer- and
93:679-684. BRASS LM et al.: Aspirin and clopidogrel drug-associated thrombotic
43. CHEW DP, BHATT DL, ROBINS MA compared with clopidogrel alone after thrombocytopenic purpura and hemolytic
et al.: Am. J. Cardiol. 2001 88:672-674. recent ischaemic stroke or transient uremic syndrome. Sem in. Hematol. (1997)
ischaemic attack in high-risk patients 34:140-147.
(MATCH): randomised, double-blind, 64. MAJHAIL NS, LICHTIN AE: Clopidogrel
CHEW DP et al.: Effect of clopidogrel pre-
placebo-controlled trial. Lancet (2004) and thrombotic thrombocytopenic purpura:
treatment on periprocedural rise in
364:331-337. no clear case for causality. Cleve. Clin. J.
C-reactive protein after percutaneous
coronary intervention. Am. J. Cardiol. 55. YUSUF S, ZHAO F, MEHTA SR et al.: Med. (2003) 70:466-470.
(2004) 94:358-360. Effects of clopidogrel in addition to aspirin 65. ZAKARIJA A, BANDARENKO N,
in patients with acute coronary syndromes PANDEY DK et al.: Clopidogrel-associated
45. LEON C, ALEX M, KLOCKE A et al.:
without ST-segment elevation. N. Engl. J. TTP. An update of pharmacovigilance
Platelet ADP receptors contribute to the
Expert Opin. Pharmacother. Downloaded from by The University of Manchester on 12/01/14

Med. (2001) 345:494-502. efforts conducted by independent

initiation of intravascular coagulation.
Blood (2004) 103:594-600. 56. STEINHUBL SR, BERGER PB, researchers, pharmaceutical suppliers, and
MANN JTR et al.: Early and sustained dual the food and drug administration.
oral antiplatelet therapy following Stroke (2004) 35(2):533-537.
percutaneous coronary intervention: a 66. STEINHUBL S et al.: Incidence and
involvement of the P2Y1 and P2Y12
randomized controlled trial. JAMA (2002) clinical course of thrombotic
receptors in platelet procoagulant activity.
288:2411-2420. thrombocytopenic purpura due to
Arterioscler. Thromb. Vasc. Biol. (2003)
23:1941-1947. 57. HANKEY GJ: Ongoing and planned trials ticlopidine following coronary stenting.
of antiplatelet therapy in the acute and J. Am. Med. Assoc. (1999) 281:806-810.
long-term management of patients with 67. CLARKE TA, WASKELL LA: The
randomised, blinded, trial of clopidogrel
ischaemic brain syndromes: Setting a new metabolism of clopidogrel is catalyzed by
versus aspirin in patients at risk of ischaemic
standard of care. Cerebrovasc. Dis. (2004) human cytochrome P450 3A and is
events (CAPRIE). Lancet (1996)
17(Suppl. 3):11-16. inhibited by atorvastatin. Drug. Metab.
For personal use only.

58. BHATT DL, TOPOL EJ: Clopidogrel Dispos. (2003) 31(1):53-59.

added to aspirin versus aspirin alone in 68. SEREBRUANY VL, MIDEI MG,
et al.: Benefit of clopidogrel over aspirin is
secondary prevention and high-risk primary MALININ AI et al.: Absence of interaction
amplified in patients with a history of
prevention: rationale and design of the between atorvastatin or other statins and
ischemic events. Stroke (2004) 35:528-532.
clopidogrel for high atherothrombotic risk clopidogrel: results from the interaction
49. BHATT DL, MARSO SP, HIRSCH AT and ischemic stabilization, management, study. Arch. Intern. Med. (2004)
et al.: Amplified benefit of clopidogrel and avoidance (CHARISMA) trial. 164:2051-2057.
versus aspirin in patients with diabetes Am. Heart J. (2004) 148:263-268.
mellitus. Am. J. Cardiol. (2002) 69. GORCHAKOVA O,
Rationale, design and organization of the Antiplatelet effects of a 600 mg loading dose
50. BHATT D, CHEW D, HIRSCH A et al.: second Chinese cardiac study (CCS-2): a of clopidogrel are not attenuated in patients
Superiority of clopidogrel versus aspirin in randomized trial of clopidogrel plus aspirin, receiving atorvastatin or simvastatin for at least
patients with prior cardiac surgery. and of metoprolol, among patients with 4 weeks prior to coronary artery stenting. Eur.
Circulation (2001) 103:363-368. suspected acute myocardial infarction. Heart J. (2004) 25:1898-1902.
51. BHATT D, FOODY J, HIRSCH A et al.: J. Cardiovasc. Risk (2000) 7:435-441.
Complementary, additive benefit of 60. SABATINE MS, McCABE C, GIBSON C, et al.: Lack of adverse
clopidogrel and lipid-lowering therapy in CANNON CP: Design and rationale of clopidogrelatorvastatin clinical interaction
patients with atherothrombosis. J. Am. Coll. clopidogrel as adjunctive reperfusion from secondary analysis of a randomized,
Cardiol. (2000) 35(Suppl. A):326. therapy -thrombolysis in myoacrdial placebo-controlled clopidogrel trial.
52. JARVIS B, SIMPSON K: Clopidogrel: a infarction (CLARITY-TIMI 28) trial. Circulation (2003) 108:921-924.
review of its use in the prevention of Am. Heart J. 149:227-233.
atherothrombosis. Drugs (2000) 61. MARKUS H, DROSTE D, KAPS M et al.: SCHIELE R et al.: Comparison of clinical
60:347-377. Dual antiplatelet therapy with clopidogrel benefits of clopidogrel therapy in patients
53. DIENER HC, BOGOUSSLAVSKY J, and aspirin in symptomatic carotid stenosis with acute coronary syndromes taking
BRASS LM et al.: Management of evaluated using Doppler embolic signal atorvastatin versus other statin therapies.
atherothrombosis with clopidogrel in high- detection; the multicenter CARESS study. Am. J. Cardiol. (2003) 92:285-288.
risk patients with recent transient ischaemic Circulation (2005) In Press.
attack or ischaemic stroke (MATCH): 62. BENNETT CL, CONNORS JM, Website
Study design and baseline data. Cerebrovasc. CARWILE JM et al.: Thrombotic
Dis. (2004) 17:253-261. thrombocytopenic purpura associated with 101. Stroke trials directory. Available at URL:
clopidogrel. N. Engl. J. Med. (2000) Accessed 14
342:1773-1777. January 2005.

Expert Opin. Pharmacother. (2005) 6(5) 763


Hans-Christoph Diener1, Peter A Ringleb2 &
Pierre Savi3
Author for correspondence

1Department of Neurology, University Essen,

2Department of Neurology, University

Heidelberg, Germany
3Sanofi-Aventis Research, Cardiovascular

Research Department,
Toulouse, France
Expert Opin. Pharmacother. Downloaded from by The University of Manchester on 12/01/14
For personal use only.

764 Expert Opin. Pharmacother. (2005) 6(5)


In the Drug Evaluation Clopidogrel for the secondary prevention of stroke, published in the May 2005 issue of Expert Opinion
on Pharmacotherapy (Expert Opin. Pharmacother. (2005) 6(5):755-764), in the Abstract the sentence In high-risk patients with
TIA or stroke, the addition of ASA to clopidogrel is not superior to ASA monotherapy but results in a significant higher rate of
bleeding complications. should have read In high-risk patients with TIA or stroke, the addition of ASA to clopidogrel is not
superior to clopidogrel monotherapy but results in a significant higher rate of bleeding complications.

In the Drug Evaluation Moxifloxacin in respiratory tract infections, published in the February 2005 issue of Expert Opinion on
Pharmacotherapy (Expert Opin. Pharmacother. (2005) 6(2):283-293), Table 3 should have read:
Expert Opin. Pharmacother. Downloaded from by The University of Manchester on 12/01/14

Table 3. A summary of clinical trials with moxifloxacin 400 mg/day in acute exacerbations of chronic bronchitis and
exacerbations of chronic obstructive pulmonary disease.

Outcomes by treatment group

Study Design Patients Test of cure Treatment group Clinical Bacteriological

response rate (%) response rate (%)
Chodosh Randomised, E-CB (n = 926) 0 6 days 5-day MOX (n = 312) 89 94
(2000) [67] double-blind post-treatment 10-day MOX (n = 302) 91 95
10-day CLR (n = 312) 91 91
Wilson (1999) Randomised, E-CB Type I/II, 7 days 5-day MOX (n = 322) 89 77
[23] double-blind (n = 649) post-treatment 7-day CLR (n = 327) 88 62
DeAbate Randomised, E-CB (n = 567) 14 21 days 5-day MOX (n = 283) 88 95
For personal use only.

(2000) [68] double-blind post-treatment 5-day AZM (n = 284) 88 94

Wilson (2004) Randomised, E-CB Type I, 7 10 days 5-day MOX (n = 354) 71* 92
[42] double-blind (n = 730) post-treatment 7-day comparator 63* 81
(n = 376)
Kreis (2000) Randomised, E-CB (n = 124) 14 21 days 5-day MOX (n = 62) 85 NA
[43] open-label post-treatment 5-day AZM (n = 62) 88 NA
Miravitlles Observational, E-COPD 30 days 5-day MOX (111 66* NA
(2003) [48] open-label post-treatment Events)
Relapse-free 7-day comparator 65*
period (503 Events)
Grassi (2002) Randomised, E-CB (n = 423) 10 days 5-day MOX 91 92
[69] open-label post-treatment 7-day CRO 89 91
Schaberg Randomised, E-CB (n = 512) 14 days 5-day MOX (n = 261) 96 88
(2001) [70] open-label post-treatment 7-day AMX (n = 251) 92 90
Landen (2001) Observational, CA-RTIs 3 10 days 5- to 10-day MOX 97 NA
[45] open-label E-CB post-treatment
(n = 7944)
Lorenz (2001) Open-label E-CB Type I, 12 days from 5-day MOX 91 NA
[46] (n = 328) treatment onset
Miravitlles Observational, E-CB Types I 10 days from 5-day MOX 97 NA
(2004) [49] open-label and II treatment onset 7-day CLR 94
7-day AMXCLA 93
Miravitlles Observational, E-CB 7 days 5- to 10-day MOX 93 NA
(2001) [40] open-label (n = 5737) post-treatment
AMX: Amoxicillin; AMXCLA: Amoxicillin-clavulanate; AZM: Azithromycin; CA-RTIs: Community-acquired respiratory tract infections; CFU: Cefuroxime-axetil; CLR:
Clarithromycin;CRO: Ceftriaxone; E: Exacerbation; E-CB: Exacerbation of chronic bronchitis; E-COPD: Exacerbation of chronic obstructive pulmonary disease; NA: Not
available; MOX: Moxifloxacin.

10.1517/14656566.6.4.1045 2005 Ashley Publications Ltd ISSN 1465-6566 1045