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Clinical evaluation of clopidogrel across the whole spectrum of indications: primary and secondary prevention of coronary artery disease
Eduardo I. de Oliveira1,2 and
Deepak L. Bhatt2,*
1 Department of Cardiology, Hospital Santa Maria, Lisbon, Portugal
2 Department of Cardiology, F25, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA
* Corresponding author. Tel: +1 216 445 4042; fax: +1 216 445 8531.E-mail address: bhattd{at}ccf.org
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Abstract
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Clopidogrel has been evaluated across the spectrum of secondary
and primary prevention. Initially, the CAPRIE trial randomized
patients with recent myocardial infarction, ischemic stroke
or symptomatic peripheral arterial disease to either clopidogrel
or aspirin and followed them for up to three years. That study
found clopidogrel to be superior to aspirin, with subsequent
post hoc analyses finding the greatest benefit in higher risk
subgroups. Favorable data from multiple clinical trials of aspirin
plus clopidogrel in percutaneous coronary intervention and acute
coronary syndromes led to the CHARISMA study. This trial randomized
patients to clopidogrel plus aspirin versus placebo plus aspirin
for a median of 28 months. Patients with stable coronary artery
disease, cerebrovascular disease, or peripheral arterial disease
(meant to represent secondary prevention) or with multiple risk
factors (meant to represent primary prevention) were enrolled.
The trial did not find a significant reduction in cardiovascular
death, myocardial infarction, or stroke with dual antiplatelet
therapy in the overall population, though the subgroup of patients
with documented cardiovascular disease did appear to have some
benefit. Further analysis of the CHARISMA data set and future
trials should further refine which patients are most likely
to benefit from intensification of antithrombotic therapy beyond
aspirin alone.
Key Words: Aspirin • Clopidogrel • Myocardial infarction • Peripheral arterial disease • Stroke
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Introduction
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The humanitarian and economical impact of cardiovascular ischaemic
events has lead to extensive investigation in the field of atherothrombosis.
Antiplatelet therapy has been a very successful pharmacological
strategy and is still being evaluated in a wide range of indications
(different vascular territories, different population subgroups,
primary and secondary prevention, acute treatment, etc.). The
constant demand for better clinical efficacy beyond aspirin
monotherapy lead to the production of different molecules such
as the second generation thienopyridine clopidogrel. After a
decade of scientific evidence provided by randomized clinical
trials, clopidogrel has emerged as a major agent in the medical
armamentarium for the prevention and treatment of ischaemic
events.
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Clopidogrel in the prevention of coronary events: antiplatelet monotherapy
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The Clopidogrel versus Aspirin in Patients at Risk of Ischemic
Events (CAPRIE)
1 was the first randomized, blinded, international
trial to evaluate the efficacy and safety of clopidogrel in
the prevention of arterial ischaemic events (ischaemic stroke,
myocardial infarction, or vascular death). The population was
composed of individuals with a recent history of ischaemic stroke
(
1 week and
6 months) or myocardial infarction (
35 days) or
symptomatic peripheral arterial disease. The mean age was 62.5±11.1
years with 72% males, 95% Caucasians, 20% with diabetes, 52%
with hypertension, 41% with hypercholesterolaemia, 30% current
smokers, 49% former smokers, 17% with previous myocardial infarction,
22% with stable angina, and 9% with a history of unstable angina.
A total of 19 185 patients were randomized (1:1) to receive
clopidogrel 75 mg daily or medium dose aspirin (325 mg
daily). The mean follow-up time was 1.91 years (1–3 years).
Patients treated with clopidogrel had an annual 5.32% risk of
ischaemic stroke, myocardial infarction, or vascular death compared
with 5.83% with aspirin, reflecting a significant (
P=0.043)
relative risk reduction of 8.7% in favour of clopidogrel. Regarding
myocardial infarction (non-fatal and fatal), patients treated
with clopidogrel had an annual risk of 1.56% compared with 1.90%
with aspirin with a relative risk reduction of 17.9% in favour
of clopidogrel. Clopidogrel was an independent factor for protection
from myocardial infarction and was superior to aspirin despite
the number of risk factors.
2
There were no major differences regarding safety, namely intracranial haemorrhage (clopidogrel 0.33% vs. aspirin 0.47%) and gastrointestinal haemorrhage (clopidogrel 0.52% vs. aspirin 0.72%).
A post hoc analysis of the CAPRIE trial3 revealed a statistically significant decrease in rehospitalizations for ischaemic or bleeding causes in the clopidogrel arm (relative risk reduction of 9.1%, P=0.018). The results were consistent when ischaemic (any cause, angina, transient ischaemic attack, limb ischemia) or bleeding (any cause, intracranial, gastrointestinal) indications for hospitalization were analysed separately. Rehospitalization rates provide useful information to establish risk and economical burden related to therapeutic strategies. Other post hoc analyses of CAPRIE demonstrated a greater degree of benefit with clopidogrel vs. aspirin in higher risk subgroups such as those with prior ischaemic events,4 coronary artery bypass surgery,5 or diabetes.6
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Clopidogrel in the prevention of coronary events: dual antiplatelet therapy
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Trials such as The Clopidogrel Aspirin Stent Intervention Cooperative
Study (CLASSICS),
7 Clopidogrel in Unstable Angina to Prevent
Recurrent Events (CURE)
8,9 and Clopidogrel for the Reduction
of Events During Observation (CREDO)
10 introduced the concept
of aspirin and clopidogrel as dual antiplatelet therapy in the
secondary prevention of cardiovascular events. Dual platelet
inhibition demonstrated a reduction of cardiovascular events
from 28 days
7 to up to 1 year
8–10 in patients undergoing
elective
7,10 or urgent
9,11 percutaneous coronary intervention
or post-myocardial infarction with
11 or without
8,9 ST-elevation.
Whether even longer term protection with dual platelet therapy
was beneficial in a broader population of stable patients was
an issue that had to be addressed by clinical trials. The Clopidogrel
for High Atherothrombotic Risk and Ischemic Stabilization, Management,
and Avoidance (CHARISMA) trial
12,13 was designed to address
this issue in primary and secondary prevention in high-risk
patients. CHARISMA was a randomized, double blinded, event-driven,
international trial that included 15 603 high cardiovascular
risk patients
45 years old who were randomized to one of two
arms (clopidogrel 75 mg/day plus aspirin 75–162 mg/day
vs. placebo 1 tablet/day plus aspirin 75–162 mg/day).
For inclusion, the patients had to have at least one of the
following criteria: (i) documented coronary disease (previous
myocardial infarction, previous multivessel percutaneous intervention,
previous multivessel bypass surgery, or stable angina with documented
multivessel disease); (ii) documented cerebrovascular disease
(ischaemic stroke or transient ischaemic attack in the last
5 years); (iii) documented symptomatic peripheral arterial disease
(intermittent claudication with ankle-brachial index
0.85 or
previous related interventions); (iv) high cardiovascular risk
profile without documented prior events. The high risk profile
was defined as having (i) two major risk factors or (ii) one
major and two minor risk factors or (iii) three minor risk factors.
The major risk factors were treated diabetes, diabetic nephropathy,
ankle-brachial index
0.85, asymptomatic carotid stenosis
70%,
and the presence of at least one carotid plaque. The minor risk
factors were systolic blood pressure
150 mmHg, despite
therapy, primary hypercholesterolaemia, smoking, male
65 years,
or female
70 years. The exclusion criteria were requirement
for clopidogrel (e.g. recent stenting or acute coronary syndrome
without ST-segment elevation), chronic therapy with high-dose
aspirin (>162 mg/day) or non-steroidal anti-inflammatory
drugs (except COX-2 inhibitors), other oral anti-thrombotic
medications (e.g. warfarin), or planned revascularization procedure.
The primary efficacy endpoint was the first occurrence of (i)
myocardial infarction (fatal or non-fatal), (ii) stroke (any
cause, fatal, or non-fatal), and (iii) cardiovascular death
(including haemorrhagic death). The secondary efficacy endpoint
was the first occurrence of (i) any of the primary endpoint
events and (ii) hospitalization for unstable angina or transient
ischaemic attack or revascularization. The primary safety endpoint
was severe bleeding according to the GUSTO
14 criteria, including
fatal bleeding or intracranial haemorrhage. The population had
a median age of 64 years and consisted of 70% males, 80% Caucasians,
20% current smokers, 49% former smokers, with documented cardiovascular
disease in 78% and multiple risk factors in 21%. The median
follow-up was 28 months. The primary efficacy endpoint rate
(
Figure 1A) was 7.3% in the placebo group vs. 6.8% in the
clopidogrel group (relative risk reduction of 7.1% in dual antiplatelet
therapy) which was not significantly different (
P=0.22). The
secondary efficacy endpoint (
Figure 1B), which included
hospitalization for ischaemic events, was significantly higher
in the placebo group (17.9 vs. 16.7%), with a relative risk
reduction of 7.7% in favour of dual antiplaletet therapy (
P=0.04).
Comparing single efficacy endpoints, significant differences
were found in non-fatal stroke (placebo 2.4% vs. clopidogrel
1.9%,
P=0.03) and hospitalization (placebo 12.3% vs. clopidogrel
11.1%,
P=0.02) rates.
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Figure 1 Cumulative incidence of the primary and secondary endpoints in the CHARISMA trial. (A) Composite of myocardial infarction, stroke, or death from cardiovascular causes. (B) Secondary endpoint including hospitalization for ischemia. Reprinted with permission from New England Journal of Medicine.6
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In terms of the overall population primary safety endpoints,
the results were not significantly different between treatments,
despite a trend to more frequent GUSTO severe bleeding in the
clopidogrel plus aspirin arm (clopidogrel 1.7% vs. placebo 1.3%,
P=0.09). Fatal bleeding and primary intracranial bleeding, analysed
separately, were not different between groups. GUSTO moderate
bleeding, the secondary safety endpoint, was significantly higher
in the clopidogrel arm (2.1 vs. 1.3%,
P<0.001).
Analysing separately the primary (
20%) from the secondary prevention subgroups (80%), it was found that the primary efficacy endpoint was significantly lower with dual antiplatelet therapy in patients enrolled with documented previous cardiovascular disease (regardless of the arterial territory). The multiple risk factor subgroup showed no benefit. The overall outcome appeared to be influenced by these divergent findings in this pre-specified analysis (Figure 2). The divergence of results between the primary and secondary prevention subgroups was also noted in GUSTO severe bleeding, with rates higher with dual therapy in the multiple risk factor subgroup but not in the documented cardiovascular disease subgroup. Other safety endpoints showed rates similar to the overall population. In summary, in the CHARISMA trial, dual antiplatelet therapy was not beneficial in the subgroup of patients with multiple risk factors without documented arterial disease. This subgroup also had increased severe bleeding. In secondary prevention patients, (documented coronary, cerebral, or peripheral arterial disease) long-term dual antiplatelet therapy provided a 12.5% relative and 1% absolute risk reduction in the composite of myocardial infarction/stroke/cardiovascular death (6.9 vs. 7.9%, P=0.046) with no significant increase in GUSTO severe bleeding (1.6 vs. 1.4%, P=0.39).
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Figure 2 Hazard ratio for the primary endpoint in various subgroups examined in the CHARISMA trial. Reprinted with permission from New England Journal of Medicine.6 CABG, coronary artery bypass grafting; PCI, percutaneous coronary intervention.
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Conclusions
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Clopidogrel has been proved to be beneficial in several clinical
settings. However, as with other antiplatelet and antithrombotic
strategies, the overall benefit depends on a delicate balance
between baseline ischaemic and bleeding risk and potential antithrombotic
benefit. Patients should be stratified according to data provided
by clinical trials in order to select the appropriate antiplatelet
therapy. The Women's Health Study
15 and the CHARISMA
13 trial
provide clear examples that not all populations benefit from
the same strategy, especially at the lower end of the risk spectrum.
Clopidogrel as antiplatelet monotherapy is beneficial in the secondary prevention of cardiovascular events in patients with documented atherothrombotic disease, with incremental benefit in high-risk patients. Clopidogrel combined with aspirin provides a safer way to offer dual antiplatelet therapy3 when compared with ticlopidine plus aspirin. It is widely used in secondary prevention after percutaneous interventions and acute coronary syndromes. The CHARISMA trial suggested a modest benefit of clopidogrel plus aspirin with long-term use (median 28 months) over monotherapy with aspirin for secondary prevention in patients with documented arterial disease. It prevented approximately nine events (cardiovascular death, myocardial infarction, or stroke) per 1000 patients treated, potentially balanced by two severe GUSTO bleeds; it reinforced the place of clopidogrel as an antiplatelet agent in secondary prevention. Regarding primary prevention, even in high-risk patients, the combination was not beneficial and is therefore not recommended. Further analysis of the CHARISMA data set and future trials will further refine just which patients most greatly benefit from intensification of antithrombotic therapy beyond aspirin.
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Acknowledgements
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Dr. de Oliveira is funded by the Luso-American Foundation &
Portuguese Society of Cardiology.
Conflict of interest: Dr Bhatt has received honoraria from Astra Zeneca, Bristol Myers Squibb, Eli Lilly, Millennium, Sanofi Aventis, Schering Plough, and The Medicines Company.
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References
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Abstract
Introduction