Drug Evaluation
Clopidogrel for the secondary
1. Introduction
2. Clopidogrel: pharmacology
3. Clinical efficacy
4. Safety and tolerability
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by The University of Manchester on 12/01/14
5. Expert opinion and conclusion
For personal use only.
For reprint orders, please
contact:
reprints@ashley-pub.com
Ashley Publications
www.ashley-pub.com
10.1517/14656566.6.5.755 2005 Ashley Publications Ltd ISSN 1465-6566
prevention of stroke
Hans-Christoph Diener, Peter A Ringleb & Pierre Savi
Department of Neurology, University Essen, Germany
Patients suffering a transient ischaemic attack (TIA) or ischaemic stroke (IS)
have a high risk of recurrence. The inhibition of platelet function is effective
in the reduction of secondary vascular events in patients with TIA or stroke.
This is true for acetylsalicylic acid (ASA), clopidogrel, ticlopidine and the com-
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
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
Expert Opin. Pharmacother. (2005) 6(5):755-764
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).
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
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
755
 Clopidogrel
each account for 20% of all strokes, while the aetiology is
undetermined in 15% and the remaining 5% are due to other
defined causes [1]. Large-vessel disease is a predominant aetiol-
ogy in middle-aged men (45 70 years of age). Besides a
higher risk of recurrent cerebral events, stroke patients are also
at high risk of developing cardiac events [2].
1.3 Secondary prevention of stroke with antiplatelet
drugs
Recurrence risk after TIA or IS ranges from 5 to 20% per year
[1,3,4]. The risk is highest immediately after the first event
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by The University of Manchester on 12/01/14
[5,6,7]. Numerous trials and meta-analyses have left little doubt
that antiplatelet therapy effectively reduces stroke risk in
patients with prior IS or TIA [8-11]. The latest publication
from the Antithrombotic Trialists Collaboration [8] involves
the meta-analysis of 287 trials with 135,000 patients in com-
parisons of antiplatelet therapy versus controls, and 77,000 in
comparisons of different antiplatelet regimens. The main
results were summarised as a reduction of serious vascular
events (which include non-fatal MI, non-fatal stroke, or vas-
cular death) by 25% (relative percentage). In absolute
terms, the events prevented include 3.6% treated for 2 years
among those with previous IS or TIA, the absolute benefits
substantially outweigh the absolute risks of major extracranial
For personal use only.
bleeding. Nevertheless, controversies exist. Foremost among
them is the debate over the optimal antiplatelet regimen. The
majority of research in secondary stroke prevention supports
the clinical value of acetylsalicylic acid (ASA). Several key
questions, however, remain unanswered. Is the routine use of
antiplatelet therapy justified for all eligible patients? Should
ASA be used alone or in combination with another antiplate-
let agents such as clopidogrel with a different mode of action?
Will administration of low-dose ASA reduce the incidence of
side effects? Are the new antiplatelet drugs such as clopidogrel
superior to ASA? This chapter summarises the results of
recent clinical trials performed with clopidogrel in the context
of evolving strategies for stroke prevention.
2. Clopidogrel: pharmacology
Clopidogrel belongs to the thienopyridine family of ADP-recep-
tor antagonists. By contrast with ticlopidine, another thienopy-
ridine, the clopidogrel molecule contains an asymmetric carbon
atom. Clopidogrel is the S-enantiomer, and, when tested in ani-
mals, the corresponding R-enantiomer was devoid of antiaggre-
gant antithrombotic activity, indicating that this position is
critical for the pharmacological activity of the drug [12].
Clopidogrel is not directly active and needs to be metabo-
lised to achieve its antiaggregating activity. This metabolic con-
version is mainly hepatic. Experiments in rats showed that
clopidogrel lost its activity when the blood flow was diverted
from the liver and that antiaggregant activity could be obtained
in an isolated perfused liver model [13]. Further, the metabolic
transformation of clopidogrel was demonstrated to be depend-
ant on several cytochrome P450 isoenzymes [14]. Finally, an
756 Expert Opin. Pharmacother. (2005) 6(5)
active metabolite was identified and isolated [15]. This com-
pound results from a two-step enzymatic reaction that leads to
the opening of the thiophene ring, so generating a free thiol
function capable of covalent modification of P2Y12 ADP recep-
tors (Figure 1). In vitro, the active metabolite of clopidogrel
reproduces the effects observed ex vivo in platelets from clopi-
dogrel-treated subjects [16]. This includes inhibition of binding
of 2-methylthio-ADP, ADP-induced adenylyl cyclase downreg-
ulation, and ADP-induced platelet aggregation. Moreover,
ADP-induced platelet shape change and aggregation triggered
by adrenaline are not affected, as with clopidogrel in vivo. The
fact that no antiaggregating activity was detected in the plasma
from subjects treated with clopidogrel suggests that the active
metabolite has a short biological half-life.
The molecular target of clopidogrel has been extensively
investigated. The ADP-dependant platelet activation pathway
was identified very early as the main function affected by
clopidogrel. Platelet aggregation is inhibited when activated
by ADP or in conditions where ADP is required, such as with
low doses of collagen and thrombin. This is due to a dramatic
decrease in the number of ADP-binding sites on the platelet
surface after clopidogrel treatment, as demonstrated in diverse
studies in men and animals [17,18].
Two different ADP receptors on the platelet surface act
synergistically to initiate platelet aggregation. P2Y1 triggers
shape change and external calcium entry [19], whereas P2Y12 is
linked to the inhibition of adenylyl cyclase and the activation
of phosphatidylinositol trisphosphate kinase (PI3K) [20]. Acti-
vation of both receptors is required for sustained activation of
the GP IIb/IIIa receptor and fibrinogen binding [21]. In trans-
genic mice, deletion of either ADP receptor gene results in a
strong antiaggregant activity, a potent antithrombotic activity
and a prohaemorrhagic tendency [22,23].
Clopidogrel does not modify P2Y1, nor interfere with the
events included in its activation pathway [24]. However, P2Y12
has been demonstrated to be the target of the active metabo-
lite of clopidogrel [25] that is closely correlated with all the
effects of clopidogrel reported on platelets. This inhibition is
irreversible and lasts for the lifetime of modified platelets [26].
The major consequence of the inhibition of platelet aggre-
gation is a strong and long-lasting protection against throm-
bosis. The antithrombotic activity of thienopyridines has been
demonstrated in several animal species and models of throm-
bosis, part of them being insensitive to ASA [27]. In various
arterial-type models of thrombosis, clopidogrel exhibited a
potent, dose-dependent antithrombotic activity, being 50
times more potent than ticlopidine and 100-fold more
active than ASA [28-33].
In experiments aimed at determining the role of platelets in
experimental venous thrombosis, we showed that ADP-medi-
ated platelet activation played a major role in the development
of venous thrombosis under low thrombogenic conditions
[34]. This suggests that clopidogrel may be of therapeutic inter-
est in pathologies involving venous thrombosis, based on an
inhibition of thrombin generation in platelet-rich plasma [35].

H COOCH3
N N
S Cl
Clopidogrel
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by The University of Manchester on 12/01/14
O H
COOCH3
N N
HO
SS Cl
ADP receptor
Figure 1. Structure of clopidogrel and key metabolites.
For personal use only.
Moreover, recent studies have provided evidence that antago-
nism of the P2Y12 ADP receptor with clopidogrel reduces mark-
ers of vascular inflammation in addition to inhibiting platelet
activation and aggregation [36]. In healthy volunteers, clopidog-
rel, but not ASA alone, was shown to inhibit the ADP-induced
expression of platelet CD40 ligand, a pro-inflammatory media-
tor [37]. Additional effects of clopidogrel demonstrated in
healthy volunteers include a reduction in platelet-dependent
mitogenic signalling [38], inhibition of P-selectin expression and
plateletleukocyte formation [39,40], and a reduction in
cytokine-triggered priming of endothelial cells for enhanced
neutrophil transmigration [41]. Notably, in the latter study, the
effect on neutrophil migration was reversed after discontinua-
tion of clopidogrel treatment. In patients undergoing percuta-
neous coronary intervention, clopidogrel pretreatment reduced
platelet inflammatory markers expression (CD40 ligand and
CD62 P-selectin) and also attenuated the increased 30-day risk
of death or MI associated with elevated baseline levels of CRP
and attenuated the periprocedural rise of CRP [42-44].
Clopidogrel has also been found to reduce platelet-depend-
ant tissue factor expression in human leukocytes and vascular
cells [45]. This effect is known to be specifically dependent on
the platelet P2Y12 receptor [46].
3. Clinical efficacy
3.1 Clopidogrel for the prevention of vascular events
in patients with IS, MI or PAD (CAPRIE)
The CAPRIE (Clopidogrel versus Aspirin in Patients at Risk
of Ischemic Events) study was the largest study to date that
Expert Opin. Pharmacother. (2005) 6(5)
Diener, Ringleb & Savi
H COOCH3
O
S Cl
2-oxo clopidogrel
O
H COOCH3
HO
HS Cl
Active metabolite
has tested clopidogrel in the setting of stroke patients [47]. It
was a randomised, double-blind study, which compared the
effects of clopidogrel 75 mg/day with ASA 325 mg. The aim
was to reduce a composite end point, which consisted of
either IS, MI, or vascular death. A total of 19,185 patients
with a previous MI or IS, or established PAD were ran-
domised. TIA patients were not included into the CAPRIE
trial. After a mean follow-up period of 1.9 years there was a
significant absolute risk reduction of 0.5% and a relative risk
reduction of 8.7% in favour of clopidogrel. Thus, clopidogrel
is slightly more effective than ASA in preventing a composite
end point of vascular events. It is the agent of choice in
patients with contraindications to, or adverse effects on, ASA.
For the subgroup of patients in the CAPRIE trial with IS
(n = 6431) as the qualifying event, the relative risk reduction
was 7.3% and not statistically significant (95% Confidence
Interval [CI] -5.7 18.7). However, the CAPRIE study was not
designed or powered to specifically address this subgroup of
patients. In several posthoc analyses of the CAPRIE trial, the
benefit of clopidogrel was demonstrated to be amplified among
high-risk subgroups, including patients with a history of previ-
ous IS or MI [48], patients with diabetes [49], those with prior
cardiac surgery [50], and those receiving lipid-lowering therapy
[51]. In the 4496 patients with a history of previous IS or MI
before their qualifying event, clopidogrel produced a relative
risk reduction of 14.9% versus ASA for the primary CAPRIE
end point (p = 0.045) [48]. This risk reduction translates into a
number of patients needed to treat (NNT) of 71/year with
clopidogrel instead of ASA to prevent further vascular events.
For comparison, the NNT is 200 patients/ year for the overall
757
 Clopidogrel
20
16
Cumulative event rate (%)
12
8
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by The University of Manchester on 12/01/14
0
0 3
Patients at risk
ASA + clopidogrel 3797
Placebo + clopidogrel 3902
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
were 1480 patients with a history of cardiac surgery. The event
rate/year for MI, stroke, vascular death or rehospitalisation was
22.3% in the ASA group and 15.9% in the clopidogrel group
(p < 0.001) [50].
Data such as these remain to be verified in well powered
studies. The number of events prevented by treating 1,000
patients for 1 year with clopidogrel, rather than ASA, has
been shown to rise from 11 (all patients in the trial) to 28
(patients with any history of ischaemia) and to 34 (patients
with a prior major acute event [MI or IS]) [52].
3.2 MATCH
The MATCH (Management of ATherothrombosis with
Clopidogrel in High-risk patients with recent TIA or IS) trial
was a randomised, double-blind, placebo-controlled trial that
compared ASA (75 mg/day) versus placebo in 7599 high-risk
patients with recent TIA or IS and at least one additional vas-
cular risk factor in patients receiving clopidogrel 75 mg/day
[53,54]. Additional vascular risk factors were defined as previous
IS, previous MI, angina pectoris, diabetes mellitus, or symp-
tomatic PAD within the previous 3 years. The duration of
treatment and follow-up was 18 months. The primary end
point was a composite of IS, MI, vascular death, or rehospital-
isation for acute ischaemia (including rehospitalisation for
TIA, angina pectoris, or worsening of PAD). In the group
receiving ASA plus clopidogrel, 596 (15.7%) patients reached
the primary end point compared with 636 (16.7%) patients
758
Placebo + clopidogrel
ASA + clopidogrel
RRR = 6.4%
p = 0.244
6 9 12 15 18
Time since randomisation (months)
3576 3440 3321 3229 3130 2441
3576 3432 3326 3200 3119 2446
in the clopidogrel alone group (relative risk reduction 6.4%,
95% CI 4.6, 16.3; absolute risk reduction 1%, 95% CI -0.6,
2.7; Figure 2). Life-threatening bleedings were significantly
higher in the group receiving ASA plus clopidogrel (96
[2.6%] versus clopidogrel alone 49 [1.3%]; absolute risk
increase 1.3% [95% CI 0.6, 1.9]). Major bleedings were also
increased in the group receiving ASA in addition to clopidog-
rel but there was no difference in mortality. Adding ASA to
clopidogrel in high-risk patients with recent IS or TIA is asso-
ciated with a non-significant difference in terms of major vas-
cular events. However, the risk of life-threatening and major
bleeding is increased by the addition of ASA. Predefined sub-
group analyses were unable to identify a group of patients
where the benefit of combination therapy would outweigh the
bleeding risk. The benefit of the combination therapy was
highest in patients randomised early after the qualifying
event, whereas the differences in bleeding complications
emerged only after 3 months. Theoretically, this would indi-
cate that there is a window of opportunity for short-term use
of the combination. This, however, has to be investigated in a
separate trial (FASTER, see below).
3.3 Risk model to identify patients at high risk for
stroke recurrence
Based on a subgroup analysis of the CAPRIE trial [48] and the
risk factors identified by logistic regression analysis, the authors
developed a predictive model. As shown in Table 1 points were
assigned to certain baseline variables and risk factors, where the
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-
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by The University of Manchester on 12/01/14

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

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

 Clopidogrel

12
Clopidogrel
ASA
10

Annual event rate (%) 8

2
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by The University of Manchester on 12/01/14

0
0 1 2 3 4 5 6 7 8

Score age > 50, > 60, > 70 years, prior MI, prior IS/TIA,
Score:
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

For personal use only.

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
MMSE 22
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
investigate the role of clopidogrel in both primary and second-
ary prevention [60]. The target study population is one at high
risk of atherothrombotic events subjects have documented
cerebrovascular, cardiovascular or PAD. However, subjects with
760
vascular risk factors without an actual event will also be enrolled
(primary prevention). CHARISMA will compare the combina-
tion of clopidogrel plus ASA with ASA plus placebo. MATCH
and CHARISMA together will provide data on whether the
combination is superior to ASA alone or clopidogrel alone.
Expert Opin. Pharmacother. (2005) 6(5)
 Diener, Ringleb & Savi

The recent CARESS trial, in which the combined use of
clopidogrel and ASA was significantly more effective than
ASA alone in reducing cerebral microemboli in patients with
recently symptomatic moderate-to-severe carotid stenosis,
identified a subgroup of patients in whom combination ther-
apy might be superior to monotherapy with ASA. The
number of patients, 110, was too small to reach a significant
reduction in clinical end points. However, the number of
strokes was smaller in the combination group (0 versus 4) [61].
The ongoing PRoFESS (Secondary Prevention of Small
Subcortical Strokes) trial will recruit 15,500 patients with IS
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by The University of Manchester on 12/01/14
However, in a review of ticlopidine-treated patients following
coronary stenting, the incidence of TTP was calculated to be
1 case/4,814 patients treated, which represents a higher inci-
dence in comparison with clopidogrel [66].
Experimental studies showed that other drugs metabolised
by cytochrome P450 may interfere with clopidogrel metabo-
lism. Some statins are also metabolised by cytochrome P450,
and it has been suggested that the HMG-CoA reductase
inhibitor atorvastatin may diminish the antiplatelet activity of
clopidogrel [58]. However, more recent clinical trials have
shown that the antiplatelet effect of clopidogrel was not

and compare 75 mg clopidogrel with the combination of low-
dose ASA with extended-release dipyridamole. This trial is
supposed to identify subgroups of patients who might benefit
more from one treatment regimen than the other based on
risk factors and concomitant diseases.
diminished by atorvastatin or simvastatin in cardiac patients
[67,68], and these results are reinforced by clinical-end point
data from CAPRIE [51], CREDO [69] and the MITRA PLUS
(maximal individual therapy of acute myocardial infarction
PLUS) registry [70].

4. Safety and tolerability 5. Expert opinion and conclusion

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

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

Bibliography 4. WEIMAR C, KRAYWINKEL K, RODL J 7. LOVETT J, COULL A, ROTHWELL P:

1. GRAU AJ, WEIMAR C, BUGGLE F et al.:
Risk factors, outcome, and treatment in
subtypes of ischemic stroke: the German
stroke data bank. Stroke (2001)
32:2559-2566.
2. HANKEY GJ: Stroke. How large a public
health problem, and how can the
neurologist help? Arch. Neurol. (1999)
56:748-754.
3. WILTERDINK JL, EASTON JD: Vascular
event rates in patients with atherosclerotic
cerebrovascular disease. Arch. Neurol.
(1992) 49:857-863.
et al.: Etiology, duration, and prognosis of
transient ischemic attacks: an analysis from
the German Stroke Data Bank.
Arch. Neurol. (2002) 59:1584-1588.
5. JOHNSTON SC, GRESS DR,
BROWNER WS, SIDNEY S: Short-term
prognosis after emergency department
diagnosis of TIA. JAMA (2000)
284:2901-2906.
6. WEIMAR C, ROTH MP, ZILLESSEN G
et al.: Complications following acute
ischemic stroke. Eur. Neurol. (2002)
48:133-140.
Early risk of recurrence by subtype of
ischemic stroke in population-based
incidence studies. Neurology (2004)
62:569-573.
8. ANTITHROMBOTIC TRIALISTS
COLLABORATION: Collaborative meta-
analysis of randomised trials of antiplatelet
therapy for prevention of death, myocardial
infarction, and stroke in high risk patients.
Br. Med. J. (2002) 524:71-86.
9. ANTIPLATELET TRIALISTS
COLLABORATION: Collaborative
overview of randomised trials of antiplatelet

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

 Clopidogrel
therapy I: Prevention of death, myocardial
infarction, and stroke by prolonged
antiplatelet therapy in various categories of
patients. Br. Med. J. (1994) 308:81-106.
10. ANTIPLATELET TRIALISTS
COLLABORATION: Secondary
prevention of vascular disease by prolonged
antiplatelet treatment. Br. Med. J. (1988)
296:320-331.
11. PATRONO C, ROTH GJ: Aspirin in
ischemic cerebrovascular disease.
Stroke (1996) 27:756-760.
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by The University of Manchester on 12/01/14
12. HERBERT JM, FREHELD, BERNAT A
et al.: Clopidogrel hydrogensulfate.
Drugs Future (1993) 18:107-112.
13. SAVI P, HERBERT JM, PFLIEGER AM
et al.: Importance of hepatic metabolism in
the antiaggregating activity of the
thienopyridine clopidogrel. Biochem.
Pharmacol. (1992) 44:527-532.
14. SAVI P, COMBALBERT J, GAICH C
et al.: The antiaggregating activity of
clopidogrel is due to a metabolic activation
by the hepatic cytochrome P450 1A.
Thromb. Haemost. (1994) 72:313-317.
For personal use only.
15. PEREILLO JM, MAFTOUH M,
ANDRIEU A et al.: Structure and
stereochemistry of the active metabolite of
clopidogrel. Drug Metab. Dispos. (2002)
30:1288-1295.
16. SAVI P, PEREILLO JM, UZABIAGA MF
et al.: Identification and biological activity
of the active metabolite of clopidogrel.
Thromb. Haemost. (2000) 84:891-896.
17. MILLS DC, PURI R, HU CJ et al.:
Clopidogrel inhibits the binding of ADP
analogues to the receptor mediating
inhibition of platelet adenylate cyclase.
Arterioscler. Thromb. (1992) 12:430-436.
18. SAVI P, LAPLACE MC, MAFFRAND JP,
HERBERT JM: Binding of [3H]-2-
Methylthio-ADP to rat platelets Effect of
clopidogrel and ticlopidine. J. Pharmacol.
Exp. Ther. (1994) 269:772-777.
19. LEON C, VIAL C, CAZENAVE JP,
GACHET C: Cloning and sequencing of a
human cDNA encoding endothelial P2Y1
purinoceptor. Gene (1996) 171:295-297.
20. HOLLOPETER G, JANTZEN HM,
VINCENT D et al.: Identification of the
platelet ADP receptor targeted by
antithrombotic drugs. Nature (2001)
409:202-207.
21. JIN J, DANIEL JL, KUNAPULI SP:
Molecular basis for ADP-induced platelet
activation. II. The P2Y1 receptor mediates
762
ADP-induced intracellular calcium
mobilization and shape change in platelets.
J. Biol. Chem. (1998) 273:2030-2034.
22. FABRE JE, NGUYEN M, LATOUR A
et al.: Decreased platelet aggregation,
increased bleeding time and resistance to
thromboembolism in P2Y1-deficient mice.
Nat. Med. (1999) 5:1199-1202.
23. ANDRE P, DELANEY SM, LAROCCA T
et al.: P2Y12 regulates platelet
adhesion/activation, thrombus growth, and
thrombus stability in injured arteries.
J. Clin. Invest. (2003) 112:398-406.
24. SAVI P, BEAUVERGER P, LABOURET C
et al.: Role of P2Y1 purinoceptor in
ADP-induced platelet activation. FEBS Lett.
(1998) 422:291-295.
25. SAVI P, LABOURET C, DELESQUE N,
GUETTE F, LUPKER J, HERBERT JM:
P2y(12), a new platelet ADP receptor, target
of clopidogrel. Biochem. Biophys. Res.
Commun. (2001) 283:379-383.
26. WEBER AA, BRAUN M, HOHLFELD T,
SCHWIPPERT B, TSCHPE D,
SCHRR K: Recovery of platelet function
after discontinuation of clopidogrel
treatment in healthy volunteers. Br. J. Clin.
Pharmacol. (2001) 52:333-336.
27. HERBERT JM, FREHEL D, VALLEE E
et al.: Clopidogrel, a novel antiplatelet and
antithrombotic agent. Cardiovasc. Drug Rev.
(1993) 11:180-198.
28. YAO SK, OBER JC, MCNATT J et al.:
ADP plays an important role in mediating
platelet aggregation and cyclic flow
variations in vivo in stenosed and
endothelium-injured canine coronary
arteries. Circ. Res. (1992) 70:39-48.
29. HERBERT JM, BERNAT A,
SAINTE-MARIE M, DOL F,
RINALDI M: Potentiating effect of
clopidogrel and SR 46349, a novel 5-HT2
antagonist, on streptokinase-induced
thrombolysis in the rabbit. Thromb.
Haemost. (1993) 69:268-271.
30. BERNAT A, DOL F, HERBERT JM,
SAINTE-MARIE M, MAFFRAND JP :
Potentiating effects of anticoagulants and
antiplatelet agents on streptokinase-induced
thrombolysis in the rabbit. Fibrinolysis
(1993) 7:23-30.
31. YAO SK, MCNATT J, ANDERSON HV
et al.: Concomitant administration of
clopidogrel with tissue type plasminogen
activator delays reocclusion after the lysis of
thrombi in canine coronary arteries.
Circulation (1990) 82:770.
Expert Opin. Pharmacother. (2005) 6(5)
32. ROSS R: The pathogenesis of
atherosclerosis. An update. N. Engl. J. Med.
(1986) 314: 488-492.
33. HERBERT JM, TISSINIER A,
DEFREYN G, MAFFRAND JP: Inhibitory
effect of clopidogrel on platelet adhesion
and intimal proliferation following arterial
injury. Arterioscler. Thromb. (1993)
13:1171-1179.
34. HERBERT JM, BERNAT A,
MAFFRAND JP: Importance of platelets in
experimental venous thrombosis in the rat.
Blood (1992) 80:2281-2286.
35. DOL F, GAICH C, BERNAT A,
MAURAN G, HERBERT JM: Effect of
clopidogrel on thrombin generation in the
rat. Thromb. Res. (1992) 65:S160.
36. HERBERT JM: Effects of ADP-receptor
antagonism beyond traditional inhibition of
platelet aggregation. Expert Opin. Investig.
Drugs (2004) 13:457-460.
37. HERMANN A, RAUCH BH, BRAUN M,
SCHRR K, WEBER AA: Platelet CD40
ligand (CD40L) subcellular localization,
regulation of expression, and inhibition by
clopidogrel. Platelets (2001) 12:74-82.
38. HERMANN A, WEBER AA, SCHRR K:
Clopidogrel inhibits platelet adhesion and
platelet-dependent mitogenesis in vascular
smooth muscle cells. Thromb. Res. (2002)
105:173-175.
39. KLINKHARDT U, GRAFF J,
HARDER S: Clopidogrel, but not
abciximab, reduces platelet leukocyte
conjugates and P-selectin expression in a
human ex vivo in vitro model. Clin.
Pharmacol. Ther. (2002) 71:176-185.
40. KLINKHARDT U, BAUERSACHS R,
ADAMS J, GRAFF J,
LINDHOFF-LAST E, HARDER S:
Clopidogrel but not aspirin reduces P-
selectin expression and formation of
plateletleukocyte aggregates in patients
with atherosclerotic vascular disease.
Clin. Pharmacol. Ther. (2003) 73:232-241.
41. DUNZENDORFER S, REINISCH CM,
KANEIDER NC, PECHLANER CH,
WIEDERMANN CHJ: Inhibition of
plasma-dependent monocyte chemokinesis
and cytokine-triggered endothelial
activation for neutrophil transmigration by
administration of clopidogrel in man.
Acta Med. Austriaca (2002) 29:100-106.
42. QUINN MJ, BHATT DL, ZIDAR F et al.:
Effect of clopidogrel pre-treatment on
inflammatory marker expression in patients
undergoing parcutaneous coronary

interventions. Am. J. Cardiol. (2004)
93:679-684.
43. CHEW DP, BHATT DL, ROBINS MA
et al.: Am. J. Cardiol. 2001 88:672-674.
44. VIVEKANANTHAN DP, BHATT DL,
CHEW DP et al.: Effect of clopidogrel pre-
treatment on periprocedural rise in
C-reactive protein after percutaneous
coronary intervention. Am. J. Cardiol.
(2004) 94:358-360.
45. LEON C, ALEX M, KLOCKE A et al.:
Platelet ADP receptors contribute to the
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by The University of Manchester on 12/01/14
initiation of intravascular coagulation.
Blood (2004) 103:594-600.
46. LEON C, RAVANAT C, FREUND M,
CAZENAVE JP, GACHET G: Differential
involvement of the P2Y1 and P2Y12
receptors in platelet procoagulant activity.
Arterioscler. Thromb. Vasc. Biol. (2003)
23:1941-1947.
47. CAPRIE STEERING COMMITTEE: A
randomised, blinded, trial of clopidogrel
versus aspirin in patients at risk of ischaemic
events (CAPRIE). Lancet (1996)
348:1329-1339.
For personal use only.
48. RINGLEB P, BHATT D, HIRSCH A
et al.: Benefit of clopidogrel over aspirin is
amplified in patients with a history of
ischemic events. Stroke (2004) 35:528-532.
49. BHATT DL, MARSO SP, HIRSCH AT
et al.: Amplified benefit of clopidogrel
versus aspirin in patients with diabetes
mellitus. Am. J. Cardiol. (2002)
90:625-628.
50. BHATT D, CHEW D, HIRSCH A et al.:
Superiority of clopidogrel versus aspirin in
patients with prior cardiac surgery.
Circulation (2001) 103:363-368.
51. BHATT D, FOODY J, HIRSCH A et al.:
Complementary, additive benefit of
clopidogrel and lipid-lowering therapy in
patients with atherothrombosis. J. Am. Coll.
Cardiol. (2000) 35(Suppl. A):326.
52. JARVIS B, SIMPSON K: Clopidogrel: a
review of its use in the prevention of
atherothrombosis. Drugs (2000)
60:347-377.
53. DIENER HC, BOGOUSSLAVSKY J,
BRASS LM et al.: Management of
atherothrombosis with clopidogrel in high-
risk patients with recent transient ischaemic
attack or ischaemic stroke (MATCH):
Study design and baseline data. Cerebrovasc.
Dis. (2004) 17:253-261.
54. DIENER HC, BOGOUSSLAVSKY J,
BRASS LM et al.: Aspirin and clopidogrel
compared with clopidogrel alone after
recent ischaemic stroke or transient
ischaemic attack in high-risk patients
(MATCH): randomised, double-blind,
placebo-controlled trial. Lancet (2004)
364:331-337.
55. YUSUF S, ZHAO F, MEHTA SR et al.:
Effects of clopidogrel in addition to aspirin
in patients with acute coronary syndromes
without ST-segment elevation. N. Engl. J.
Med. (2001) 345:494-502.
56. STEINHUBL SR, BERGER PB,
MANN JTR et al.: Early and sustained dual
oral antiplatelet therapy following
percutaneous coronary intervention: a
randomized controlled trial. JAMA (2002)
288:2411-2420.
57. HANKEY GJ: Ongoing and planned trials
of antiplatelet therapy in the acute and
long-term management of patients with
ischaemic brain syndromes: Setting a new
standard of care. Cerebrovasc. Dis. (2004)
17(Suppl. 3):11-16.
58. BHATT DL, TOPOL EJ: Clopidogrel
added to aspirin versus aspirin alone in
secondary prevention and high-risk primary
prevention: rationale and design of the
clopidogrel for high atherothrombotic risk
and ischemic stabilization, management,
and avoidance (CHARISMA) trial.
Am. Heart J. (2004) 148:263-268.
59. LIU LS, COLLINS R, CHEN ZM et al.:
Rationale, design and organization of the
second Chinese cardiac study (CCS-2): a
randomized trial of clopidogrel plus aspirin,
and of metoprolol, among patients with
suspected acute myocardial infarction.
J. Cardiovasc. Risk (2000) 7:435-441.
60. SABATINE MS, McCABE C, GIBSON C,
CANNON CP: Design and rationale of
clopidogrel as adjunctive reperfusion
therapy -thrombolysis in myoacrdial
infarction (CLARITY-TIMI 28) trial.
Am. Heart J. 149:227-233.
61. MARKUS H, DROSTE D, KAPS M et al.:
Dual antiplatelet therapy with clopidogrel
and aspirin in symptomatic carotid stenosis
evaluated using Doppler embolic signal
detection; the multicenter CARESS study.
Circulation (2005) In Press.
62. BENNETT CL, CONNORS JM,
CARWILE JM et al.: Thrombotic
thrombocytopenic purpura associated with
clopidogrel. N. Engl. J. Med. (2000)
342:1773-1777.
Expert Opin. Pharmacother. (2005) 6(5)
Diener, Ringleb & Savi
63. GORDON LI, KWAAN HC: Cancer- and
drug-associated thrombotic
thrombocytopenic purpura and hemolytic
uremic syndrome. Sem in. Hematol. (1997)
34:140-147.
64. MAJHAIL NS, LICHTIN AE: Clopidogrel
and thrombotic thrombocytopenic purpura:
no clear case for causality. Cleve. Clin. J.
Med. (2003) 70:466-470.
65. ZAKARIJA A, BANDARENKO N,
PANDEY DK et al.: Clopidogrel-associated
TTP. An update of pharmacovigilance
efforts conducted by independent
researchers, pharmaceutical suppliers, and
the food and drug administration.
Stroke (2004) 35(2):533-537.
66. STEINHUBL S et al.: Incidence and
clinical course of thrombotic
thrombocytopenic purpura due to
ticlopidine following coronary stenting.
J. Am. Med. Assoc. (1999) 281:806-810.
67. CLARKE TA, WASKELL LA: The
metabolism of clopidogrel is catalyzed by
human cytochrome P450 3A and is
inhibited by atorvastatin. Drug. Metab.
Dispos. (2003) 31(1):53-59.
68. SEREBRUANY VL, MIDEI MG,
MALININ AI et al.: Absence of interaction
between atorvastatin or other statins and
clopidogrel: results from the interaction
study. Arch. Intern. Med. (2004)
164:2051-2057.
69. GORCHAKOVA O,
VON BECKERATH N, GAWAZ M et al.:
Antiplatelet effects of a 600 mg loading dose
of clopidogrel are not attenuated in patients
receiving atorvastatin or simvastatin for at least
4 weeks prior to coronary artery stenting. Eur.
Heart J. (2004) 25:1898-1902.
70. SAW J, STEINHUBL SR, BERGER PB
et al.: Lack of adverse
clopidogrelatorvastatin clinical interaction
from secondary analysis of a randomized,
placebo-controlled clopidogrel trial.
Circulation (2003) 108:921-924.
71. WIENBERGEN H, GITT AK,
SCHIELE R et al.: Comparison of clinical
benefits of clopidogrel therapy in patients
with acute coronary syndromes taking
atorvastatin versus other statin therapies.
Am. J. Cardiol. (2003) 92:285-288.
Website
101. Stroke trials directory. Available at URL:
www.strokecenter.org/trials. Accessed 14
January 2005.
763
 Clopidogrel

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

1Department of Neurology, University Essen,

Germany
2Department of Neurology, University

Heidelberg, Germany
3Sanofi-Aventis Research, Cardiovascular

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

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

 Errata

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 informahealthcare.com 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)
(AMX, CLR or CFU)
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)
(AMXCLA)
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.
*Cure.

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