European Heart Journal Supplements (2007) 9 (Supplement D), D3–D9
doi:10.1093/eurheartj/sum016
Dual antiplatelet therapy in high-risk patients
Frans Van de Werf
Department of Cardiology, University Hospitals, Leuven, Belgium
KEYWORDS
Antiplatelet therapy;
Aspirin;
Stroke;
Acute coronary syndromes
The use of antiplatelet monotherapy as part of treatment regimens for high-risk
patients with thrombotic disease results in significant reductions in ischaemic outcomes. Numerous studies have highlighted the benefits of antiplatelet monotherapy,
including the 2002 meta-analysis by the Antiplatelet Trialists’ Collaboration. Aspirin
was the most commonly studied agent in this analysis and, while it remains the mainstay of antiplatelet therapy for reducing the risk of cardiovascular events, it is associated with significant residual cardiovascular risk. There is, however, a growing body of
evidence demonstrating that combining aspirin with other antiplatelet agents with
different mechanisms of action further improves long-term clinical outcomes both
in stroke patients and in patients with acute coronary syndromes.
Despite the evidence from clinical trials and guidelines supporting the use of
additional antiplatelet therapies in high-risk patients, several large-scale studies
(GRACE, Euroheart survey, REACH) have shown that antiplatelet therapies remain significantly underused. Improved physician education and the availability of new antiplatelet treatment options that potentially overcome some of the limitations of
existing agents may increase the implementation of antiplatelet guidelines and the
use of combination antiplatelet therapy.
Introduction
Globally, atherothrombosis is the leading cause of cardiovascular morbidity and mortality.1 Currently, cardiovascular disease accounts for 16.7 million deaths worldwide
each year and, with this number increasing, strategies for
improving prevention and management of thrombotic
conditions are required.2,3 There are two main groups
of antithrombotic therapy: anticoagulants, which
prevent fibrin-based clotting, and antiplatelet drugs,
which inhibit platelet aggregation. Arterial thrombi,
which commonly lead to ischaemic damage or infarction,
are predominantly formed by platelet aggregation at
sites of atherosclerotic vascular injury or disturbed
blood flow. Thus, agents that target platelets constitute
a core component of treatment.4 The benefits of antiplatelet therapy have been established through numerous
studies over the past few decades, the majority of
which have utilized aspirin, a cycloxygenase (COX)
Corresponding author. Tel: þ32 16 344254; fax: þ32 16 343467.
E-mail address: [email protected]
inhibitor, which is currently the mainstay of antiplatelet
treatment.4,5
The 2002 meta-analysis by the Antiplatelet Trialists’
Collaboration involved 195 randomized trials and compared 135 000 high-risk patients predominantly receiving
aspirin, but in some cases other antiplatelet agents such
as dipyridamole, the irreversible thienopyridine ADP
P2Y12 receptor antagonists clopidogrel and ticlopidine,
and glycoprotein (GP) IIb/IIIa antagonists were used.6
Patients were defined as being at high risk of a vascular
event (over 3% per year) if they had evidence of preexisting vascular disease, or another predisposing
condition such as atrial fibrillation or diabetes mellitus.6
Antiplatelet therapy reduced the risk of serious
vascular events by 25% and overall mortality by 17%
(P , 0.0001 vs. control).6 The adjusted incidence of vascular events in those receiving antiplatelet therapy and
in control subjects is shown in Figure 1.
Despite the proven benefit and widespread use of
aspirin, patients using aspirin retain a significant risk
for vascular events, with 10–20% suffering a recurrence
within 5 years.5,6 The REduction of Atherothrombosis
& The European Society of Cardiology 2007. All rights reserved. For Permissions, please e-mail: [email protected]
D4
F. Van de Werf
for Continued Health (REACH) Registry illustrates the rate
of adverse cardiovascular events in patients with existing
coronary artery disease, peripheral artery disease, or significant risk factors.7 Data collected from this large registry, which included approximately 68 000 patients
from 44 countries, has shown that in individuals with
established disease, cardiovascular death, myocardial
infarction (MI), or stroke occurred in 3.9% of the population per year, whereas these major events occurred in
just 1.7% of patients with only risk factors for disease
(Table 1; REACH trial, personal communication).
The question therefore arises, does the addition
of an antiplatelet agent which modifies non-COX-1/
thromboxane-dependent platelet activation offer additional protection for high-risk patients? There is substantial evidence to indicate that combining aspirin with
another antiplatelet agent with a different mechanism
of action further improves long-term clinical outcome.
This article examines results from key studies that
demonstrate the advantages of a dual antiplatelet treatment approach.
After 2 years of treatment, the relative risk reduction
for stroke was 37% with dual antiplatelet therapy
(P , 0.001 vs. placebo), compared with 18.1% with
aspirin alone (P ¼ 0.013) and 16.3% with dipyridamole
alone (P ¼ 0.039).8 This investigation clearly showed
that the two treatments together were more effective
than either agent individually, perhaps due to their
different mechanisms of action.
Further evidence for dual therapy with aspirin and
dipyridamole vs. either agent alone comes from the
recently published European/Australasian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT).9 The study
compared aspirin alone with aspirin plus dipyridamole
in 2739 patients following ischaemic stroke or TIA.9
ESPRIT demonstrated a reduction in the primary
outcome events in patients assigned to dual therapy;
death from vascular causes, non-fatal stroke, or MI, or
major bleeding occurred in 13% of patients vs. 16% in
those assigned to monotherapy.9 However, there was a
higher rate of patients discontinuing their medication
with the combined regimen (34% compared with 13%
with aspirin alone), reportedly citing headache as the
main reason for stopping treatment.9
Dual antiplatelet therapy in ischaemic
stroke or transient ischaemic attack
Dual antiplatelet therapy in patients with
NSTEMI or undergoing PCI
The European Stroke Prevention Study-2 (ESPS-2) was one
of the first studies to investigate dual antiplatelet
therapy.8 ESPS-2 followed 6602 patients with a history
of stroke or transient ischaemic attack (TIA) randomized
to four treatment options: aspirin alone, dipyridamole
alone, aspirin and dipyridamole, and matched placebo.8
The advantages of a dual antiplatelet approach, which have
been established in stroke, have also been demonstrated
in non-ST-elevation MI (NSTEMI) and percutaneous coronary
intervention (PCI). One of the most important studies in
this regard is the widely cited Clopidogrel in Unstable
angina to prevent Recurrent Events (CURE) trial. In CURE,
patients admitted to hospital within 24 h of symptom
onset without ST-segment elevation were randomized to
receive either clopidogrel or placebo, plus aspirin, with
a mean follow-up of 9 months.10 The primary outcome
(cardiovascular death, non-fatal stroke, or MI) occurred
in 9.3% of patients receiving clopidogrel plus aspirin and
11.4% receiving aspirin alone (P , 0.001).10 The overall
20% relative risk reduction achieved with dual therapy
was sustained throughout the study period (Figure 2).10
The CURE trial also investigated 2658 patients who
underwent PCI (CURE-PCI), a population at very high
risk of vascular events.11 After PCI, clopidogrel plus
aspirin significantly reduced the primary outcome (cardiovascular death, MI, or urgent revascularization) compared with placebo plus aspirin [59 patients (4.5%) in
Figure 1 Effect of antiplatelet therapy on the incidence of vascular
events in high-risk patients.6 Reproduced with permission from
Antithrombotic Trialists’ Collaboration. BMJ 2002;324:71–86. TIA, transient ischaemic attack.
Table 1 Major adverse cardiovascular event rates at 1 year: results from the REACH trial (personal communication)
Event
Total (n ¼ 63 129)
Symptomatic (n ¼ 51 685)
Multiple RF only (n ¼ 11 444)
CV death (%)
Non-fatal MI (%)
Non-fatal stroke (%)
CV death/MI/stroke (%)
1.5
1.1
1.6
3.5
1.7
1.2
1.8
3.9
0.6
0.8
0.8
1.7
RF, risk factors; CV, cardiovascular; MI, myocardial infarction.
Dual antiplatelet therapy in high-risk patients
Figure 2 Cumulative hazard rate for the primary outcome (cardiovascular death, non-fatal MI, or stroke) with clopidogrel and aspirin in NSTEMI
and unstable angina: results from the CURE trial.10 Reproduced with permission from The CURE Trial Investigators. N Engl J Med 2001;345:
494–502. NSTEMI, non-ST-elevation myocardial infarction; RRR, relative
risk reduction. Copyright & 2004 Massachusetts Medical Society.
the clopidogrel group vs. 86 patients (6.4%) with placebo;
relative risk: 0.70; P ¼ 0.03].11 The beneficial effect of
dual therapy continued in the 8 months of follow-up,
with a total reduction in the risk of cardiovascular
death or MI by approximately one-third in the clopidogrel
plus aspirin group compared with placebo plus aspirin.11
Although the original CURE study reported dual therapy
to significantly increase major bleeding complications
(3.7 vs. 2.7%; relative risk: 1.38; P ¼ 0.001), the
CURE-PCI study reported no statistical significance
between the treatment groups (P ¼ 0.64).10,11
The Clopidogrel for the Reduction of Events During
Observation (CREDO) trial investigated clopidogrel and
aspirin dual antiplatelet therapy in a lower-risk population undergoing elective PCI.12 The investigators
reported a 26.9% risk reduction of death, MI, or stroke
after long-term dual therapy (1 year; P ¼ 0.02), and a
borderline-significant 38.6% (P ¼ 0.051) reduction with
clopidogrel administered 6–24 h prior to PCI.12 These
data support the CURE trial data, although the relatively
small sample size (n ¼ 2116) prevents wider conclusions
being drawn.12
Benefits of dual antiplatelet therapy in the
STEMI population
Dual therapy has thus been shown to reduce death and
ischaemic complications in patients with acute coronary
syndromes (ACS) without ST-segment elevation. However,
this benefit can also be applied to the higher-risk group
of patients who have ST-segment elevation MI (STEMI).
This population has been studied in three trials: the
CLopidogrel as Adjunctive ReperfusIon TherapY - Thrombolysis In Myocardial Infarction (CLARITY-TIMI 28) and
PCI-CLARITY trials, and the ClOpidogrel and Metoprolol
in Myocardial Infarction Trial (COMMIT).13–15
The CLARITY-TIMI 28 trial randomized 3491 patients not
older than 75 years to receive either clopidogrel or
placebo, in addition to aspirin, a fibrinolytic agent, and
heparin if appropriate.13 After 30 days of treatment,
the event rate for the composite endpoint of death
D5
from cardiovascular causes, recurrent MI, or recurrent
ischaemia leading to urgent revascularization was
reduced in the clopidogrel group by 20% (incidence 11.6
vs. 14.1% with placebo; P ¼ 0.03).13 Separating out the
individual endpoints, dual therapy reduced event rates
by 31% for MI (P ¼ 0.02), 24% for revascularization
(P ¼ 0.11), and 46% for stroke (P ¼ 0.052), but had no
effect on the rates of death from a cardiovascular
cause.13 Interestingly, angiography revealed improvements, such as larger luminal diameter of the
infarct-related artery and reduced intracoronary thrombus, in patients treated with dual antiplatelet therapy
compared with placebo.13 The rate of major bleeding
at 30 days was comparable between the two treatment
groups (1.9% clopidogrel, 1.7% placebo; P ¼ 0.80).13
The CLARITY-PCI study was carried out as a prespecified analysis on a subgroup of 1863 patients from
the CLARITY-TIMI trial, who underwent PCI during the
treatment period.14 Pre-treatment with clopidogrel, in
addition to the other standard treatments, significantly
reduced the odds of cardiovascular death, recurrent MI,
or stroke by 46% (odds ratio 0.54; P ¼ 0.008), again
with no increase in major bleeding.14
COMMIT was a large study (45 852 patients) that also
assessed dual aspirin and clopidogrel therapy in STEMI
patients.15 However, unlike the CLARITY trials where
all patients had STEMI alone, COMMIT recruited patients
(including elderly) with suspected acute MI and evident ST-segment elevation, left bundle branch block,
or ST-segment depression on electrocardiogram.13–15 As
in the CLARITY study, patients were randomized to
receive aspirin and clopidogrel (75 mg without a loading
dose), or aspirin and matched placebo, and, similarly,
the primary outcome was death, recurrent MI, or
stroke. Clopidogrel resulted in a 9% proportional risk
reduction in primary outcome (P ¼ 0.002), which, owing
to the large sample size, is highly significant.15 Again,
dual antiplatelet therapy was not associated with any
significant increase in bleeding (0.58 vs. 0.55% with
placebo; P ¼ 0.59).15
Together, these studies demonstrate a consistent
benefit of aspirin and clopidogrel dual therapy for reducing the rate of ischaemic complications in patients presenting with STEMI.
Use of dual antiplatelet therapy in
primary prevention?
The recently published Clopidogrel for High Atherothrombotic Risk and Ischaemic Stabilization, Management, and
Avoidance (CHARISMA) trial examined the use of dual
antiplatelet therapy in the prevention of thrombotic
events in a population with either documented evidence
of cardiovascular disease (coronary, cerebrovascular, or
peripheral) or with multiple risk factors, such as diabetes, diabetic nephropathy, hypertension, and hypercholesterolaemia.3 The aim was to test dual antiplatelet
therapy with clopidogrel and aspirin against aspirin
alone in a broader population, providing more information regarding safety and efficacy of dual treatment.
D6
Figure 3 Effect of aspirin plus clopidogrel on the clinical endpoint (MI,
stroke, or cardiovascular death) in patients with risk factors only, or
established disease. Results of the CHARISMA trial.3 CAD, coronary
artery disease; CVD, cerebrovascular disease; PAD, peripheral artery
disease.
The results indicated that dual antiplatelet therapy
reduced the risk of atherothrombotic events in patients
with established vascular disease (symptomatic), but in
individuals with multiple atherothrombotic risk factors
without documented cardiovascular disease (asymptomatic) such therapy was of no benefit. Among the symptomatic patients (n ¼ 12 153), dual therapy significantly
reduced the rate of MI, stroke, or cardiovascular death
compared with aspirin alone (6.9 vs. 7.9%; P ¼ 0.046;
Figure 3).3 However, among the asymptomatic patients
(n ¼ 3284), dual therapy was associated with a 20%
increase in the rate of these primary endpoints (6.6 vs.
5.5% with aspirin alone; P ¼ 0.20), and an increase in
the rate of death from all causes (5.4 vs. 3.8% with
aspirin alone; P ¼ 0.04) and from cardiovascular causes
(3.9 vs. 2.2%; P ¼ 0.01).3 Dual antiplatelet therapy also
produced increased rates of bleeding in the asymptomatic subgroup (2.0 vs. 1.2% with aspirin alone;
P ¼ 0.07), which, while not statistically significant,
were more marked than the rates of bleeding in the
symptomatic group (1.6% in the dual therapy group,
1.4% in the aspirin monotherapy group; P ¼ 0.39).3
Hence, in asymptomatic patients, the benefit-risk
profile was not in favour of dual antiplatelet therapy.
The Management of ATherothrombosis with Clopidogrel
in High-risk patients (MATCH) trial16 investigated the
beneficial effects of clopidogrel and aspirin dual
therapy and reported that, in patients with recent
ischaemic stroke or TIA and at least one additional
vascular risk factor, dual therapy modestly reduced the
rate of primary vascular events, compared with clopidogrel monotherapy (16 vs. 17%; absolute risk reduction:
1.0%; P ¼ 0.244).16 Of note, significantly higher bleeding
rates were reported in patients receiving dual therapy,
particularly for life-threatening bleeds, with 96 events
(2.6%) compared with 49 events (1.3%) among patients
receiving monotherapy (% difference: 1.26; 95% CI:
0.64–1.88).16
The data from CHARISMA and MATCH therefore suggest
that dual antiplatelet therapy may not be the best
approach for primary prevention. The CHARISMA
authors suggest that this may be linked to platelet
F. Van de Werf
activity. They hypothesize that, in established vascular
disease, agents that reduce platelet activity should be
of benefit due to platelet hyperactivity, while in stable,
asymptomatic patients with only risk factors for vascular
disease, platelet activity is not increased and inhibiting
platelets may increase the risk of bleeding complications,
including haemorrhage into an atherosclerotic plaque.3
This could potentially explain the greater benefits of
antiplatelet therapy reported in the first month of
treatment as shown in the Antiplatelet Trialists’
Collaboration, as platelets are the most active during
this acute phase.6
A further hypothesis relates to the genetics of disease
susceptibility. Patients symptomatic of vascular disease
demonstrate a predisposition to form thrombi and are
thus more likely to benefit from antiplatelet treatment.3
The interpatient variability in responsiveness to aspirin
and clopidogrel described in some studies may reflect
this susceptibility.17,18 The issue of aspirin and clopidogrel response variability is discussed further in this supplement in the article by Steen Husted.19
The MATCH investigators suggest that their finding of
dual antiplatelet therapy having no significant beneficial
effect for the prevention of vascular events may differ
from previous findings because most of their patients
had suffered lacunar infarcts due to microangiopathy,
which may have a different pathophysiology to major
vessel atherothrombosis.16 A key insight from these two
studies seems to be that not all patients are suitable candidates for dual antiplatelet therapy.
Maximizing available treatments: is it
beneficial to add a third agent?
Considerable evidence supports the use of dual antiplatelet therapy with clopidogrel and aspirin in treating
patients with existing vascular disease who are at highrisk of vascular events. The question of whether the
addition of a third antiplatelet is of further benefit has
been investigated in recent trials. For example, in the
Intracoronary Stenting and Antithrombotic Regimen:
Rapid Early Action for Coronary Treatment (ISAR-REACT)
study, the GP IIb/IIIa inhibitor abciximab was used alongside clopidogrel and aspirin.20 Here, 2159 patients were
randomized to receive a bolus of abciximab or placebo
before undergoing planned PCI.20 All patients also
received heparin, aspirin, and clopidogrel. ISAR-REACT
revealed no clinical advantage in adding abciximab to
therapy for reducing ischaemic complications.20 Furthermore, although the incidence of bleeding in both study
groups was low, abciximab was associated with a higher
rate of thrombocytopenia (1% with triple antiplatelet
therapy vs. 0% with placebo; P ¼ 0.002) and an increased
need for blood transfusion (2 vs. 1% with placebo;
P ¼ 0.007).20
The more recent ISAR-REACT 2 trial extended the
concept of triple therapy to 2022 higher-risk patients
presenting with NSTEMI and undergoing early (within
48 h) PCI.21 Again, patients received abciximab or
placebo, along with standard heparin, aspirin, and
Dual antiplatelet therapy in high-risk patients
D7
clopidogrel, but this time a significant 25% risk reduction
was found in the triple antiplatelet therapy group
(P ¼ 0.03).21 The incidence of death or MI was 8.6% in
the triple antiplatelet therapy group and 11.5% in the
placebo group (P ¼ 0.03), and there was no difference
in rate of major bleeding complications.21
Another trial, published in 2006, also favoured triple
antiplatelet therapy with the addition of a GP IIb/IIIa
inhibitor to aspirin and clopidogrel. The smaller Early or
Late Intervention in unStable Angina (ELISA) 2 study
measured the effects of triple therapy on enzymatic
infarct size, angiography measurements, and rates of
death or MI in 328 patients with non-ST-segment elevation ACS.22 The results showed a small, non-significant
reduction in enzymatic infarct size, measured by
reduced concentrations of the cardiac enzymes lactate
dehydrogenase and creatinine kinase, and an improved
vessel flow rate as measured by the TIMI flow grade.22
There was also a reduced rate of death or MI in the
triple therapy group, with these events occurring in 74
individuals (46%) compared with 92 (57%) individuals
in the dual aspirin and clopidogrel treatment group
(P ¼ 0.05).22
Use of antiplatelet agents in the ‘real world’
Despite the extensive body of evidence from clinical
trials, antiplatelet therapies for the treatment of highrisk patients with thrombotic disease remain underutilized, even with the inclusion of antiplatelet therapies
in international and national clinical guidelines, e.g.
those issued by the American College of Cardiology/
American Heart Association (ACC/AHA) and the European
Society of Cardiology (ESC).23,24
The underutilization of antiplatelet agents in clinical
practice has been reported in several large-scale registries.1,24 In 2003, the Global Registry of Acute Coronary
Events (GRACE) highlighted the variability of antiplatelet
use across different geographical regions and patient
groups.25 The data from this multinational registry of
12 665 patients with ACS revealed that, while aspirin
was used in a consistently high number of cases (over
90%), other antiplatelet agents were prescribed less frequently.25 Thienopyridine uptake was 39% in the USA and
24% in Europe, while GP IIb/IIIa inhibitor use was 33% in
the USA and only 9% in Europe.25 Within patient groups
(patients from all geographical locations combined),
those who underwent PCI were much more likely to
receive additional antiplatelet agents, with the use
of thienopyridines occurring in 83.3% and GP IIb/IIIa
inhibitors in 46.6% of patients.25 In patients (from all
geographic locations) not undergoing PCI, use of thienopyridines was 8.8% and GP IIb/IIIa inhibitors only 4.9%.25
The REACH registry involved a greater number of
countries and patients than GRACE.7 However, consistent
with GRACE, a study by Bhatt et al.,1 based on data from
the REACH registry, demonstrated underutilization of
antiplatelet therapies, with only 78.6% of patients
taking at least one antiplatelet therapy. The percentage
of patients using two antiplatelet medications was low,
at 11% for western Europe and 14.3% for North America
(P , 0.001), again showing geographical inequality.1
A more encouraging report comes from the second
European Heart Survey on ACS (EHS-ACS 2), conducted
in 2004.26 This survey was an update of the 2000
EHS-ACS 1 and compared adherence to guidelines since
the first study.26 In EHS-ACS 2, use of all antiplatelet
therapies increased in both ST-elevation and non-STelevation ACS (Table 2).26 Of particular note is the
increase in use of clopidogrel, from 27.6% for nonST-elevation ACS patients in EHS-ACS 1 to double the
rate at 67.4% in EHS-ACS 2.26 Furthermore, the increased
use of these treatments was accompanied by reduced
in-hospital and 30-day mortality rates of 42% and 34%,
respectively, between EHS-ACS 1 and 2, which is at
least partly due to improved use of evidence-based
treatments.26
Improving use of antiplatelet agents and
awareness of treatment guidelines
As demonstrated above, antiplatelet therapies are
clearly not being used to their potential. This point was
reinforced in the ESC 2004 Expert Consensus Document
on the use of antiplatelet agents, which stated that
additional antiplatelet agents were advantageous in
high-risk patients, but that many patients who may
benefit were not receiving antiplatelet therapy, and
Table 2 In-hospital medical therapy in EHS-ACS 1 (2000) and EHS-ACS 2 (2004)26
In-hospital medications
Aspirin
Warfarin
Heparin/LMWH
Thienopyridine
GP IIb/IIIa antagonist
ST-elevation (%)
Non-ST-elevation (%)
ACS 1 (n ¼ 4431)
ACS 2 (n ¼ 3004)
ACS 1 (n ¼ 5367)
ACS 2 (n ¼ 3063)
93.0
5.3
81.5
36.1
19.6
96.8
13.1
77.2
69.8
30.7
88.5
5.7
79.1
27.6
10.0
94.5
17.1
67.4
67.4
20.8
LMWH, low-molecular-weight heparin; GP, glycoprotein.
Adapted with permission from Mandelzweig L, et al. Eur Heart J 2006;27:2285–2293.
D8
substantial efforts were required to redress this.24
So how can this be redressed? Ultimately, the underuse
of antiplatelet therapy, despite guidelines, suggests a
need for improved physician education. The US educational initiative, Can Rapid risk stratification of
Unstable angina patients Suppress ADverse outcomes
with Early implementation of the ACC/AHA guidelines
(CRUSADE), was launched in 2001 to try and improve
the use of evidence-based medicine for the management
of non-ST-segment elevation ACS.23 The 2005 fourthquarter results published by CRUSADE reported on the
use of antiplatelet agents in 403 sites across the USA,
revealing that, despite guidelines, antiplatelet prescribing was highly variable between centres.23 Aspirin was
prescribed as part of the discharge care for 94% of
patients in leading centres and 80% in lagging hospitals,
while clopidogrel was prescribed to 62% of patients in
leading centres and 38% in other centres.23
The conclusion of the CRUSADE committee was that
more quality initiative efforts are needed to improve
the adherence to guidelines and support evidence-based
care.23 The MAINTAIN CRUSADE initiative has been
launched as a longitudinal follow-up of CRUSADE, along
with a number of other educational programmes.27
MAINTAIN will provide information on the utilization of
antiplatelet agents in the outpatient setting, and the
long-term adherence to this therapy by both physicians
and patients.27 This information will be collected via
telephone interviews at 3 and 12 months from patient
discharge. The underuse of therapies found in the ESC
consensus document perhaps indicates that a similar
enterprise is necessary in Europe.24
The benefit of educational interventions in improving
patient care in ACS, including the use of antiplatelet
agents, was demonstrated in a 2004 study by Vikman
et al. (FINACS 2).28 This study was a follow-up to a 2001
study (FINACS 1) evaluating the treatment and clinical
outcome of 500 non-ST-segment elevation ACS patients
admitted to hospitals in Finland. FINACS 1 reported
that modern antiplatelet therapy was generally underused and adherence to clinical guidelines was poor, so
FINACS 2 arranged targeted educational initiatives in
the form of multidisciplinary teaching sessions and the
creation of critical care pathways, before repeating the
FINACS study, in the same hospitals.28 In the follow-up
study, the survival of high-risk patients was significantly
improved (89 vs. 78% in FINACS 1; P ¼ 0.05). Furthermore, while the use of aspirin was similar between the
two studies, the number of patients receiving clopidogrel
and GP IIb/IIIa inhibitors increased from 16 to 35% for clopidogrel and from 14 to 25% for GP IIb/IIIa inhibitors
(P , 0.001).28 Since there were no changes in public
health resources or the severity of disease between the
two studies, the improved patient outcome and guideline
implementation appeared to arise from the educational
programmes.28 Analogously, in the aforementioned
EHS-ACS 2, 34 centres (out of 190) that had participated
in the previous EHS-ACS 1 survey showed the greatest
improvement in prescribing evidence-based medicines,
including antiplatelets, implying that involvement with
research raises awareness.26
F. Van de Werf
Conclusions
Aspirin has been used as an effective antiplatelet agent
for many years. However, high-risk cardiovascular
patients treated with aspirin alone retain a significant
risk of atherothrombotic events. Other effective antiplatelet therapies are available, and numerous studies have
demonstrated that these agents are beneficial in further
lowering risk in unstable patients when used in
combination with aspirin. Despite strong evidence and
recommendations from guidelines, antiplatelet therapy
remains underused in clinical practice. The arrival of
new agents providing improved benefit-risk profiles and
reduced variability of response may encourage greater
use of dual antiplatelet therapy, but education is
required to make physicians aware of these developments and increase uptake of appropriate treatments.
Acknowledgements
This work was supported by an unrestricted educational grant
from AstraZeneca. Editorial assistance was provided by MediTech
Media Ltd.
Conflict of interest: The author has received research grants
from Sanofi-Aventis, Schering Plough, and Eli Lilly, and speaker
honoraria from Sanofi-Aventis, AstraZeneca, Eli Lilly, and
Schering Plough. The author has also contributed to advisory
boards for AstraZeneca.
References
1. Bhatt DL, Steg PG, Ohman EM, Hirsch AT, Ikeda Y, Mas JL, Goto S,
Liau CS, Richard AJ, Rother J, Wilson PW. International prevalence,
recognition, and treatment of cardiovascular risk factors in outpatients with atherothrombosis. J Am Med Assoc 2006;295:180–189.
2. The World Health Organization. Global Strategy on Diet, Physical
Activity & Health. Chronic disease information sheets. Cardiovascular
disease: prevention and control. 2003.
3. Bhatt DL, Fox KA, Hacke W, Berger PB, Black HR, Boden WE, Cacoub P,
Cohen EA, Creager MA, Easton JD, Flather MD, Haffner SM, Hamm CW,
Hankey GJ, Johnston SC, Mak KH, Mas JL, Montalescot G, Pearson TA,
Steg PG, Steinhubl SR, Weber MA, Brennan DM, Fabry-Ribaudo L,
Booth J, Topol EJ. Clopidogrel and aspirin versus aspirin alone for
the prevention of atherothrombotic events. N Engl J Med
2006;354:1706–1717.
4. Schafer AI. Antiplatelet therapy. Am J Med 1996;101:100–209.
5. Michos ED, Ardehali R, Blumenthal RS, Lange RA, Ardehali H. Aspirin
and clopidogrel resistance. Mayo Clin Proc 2006;81:518–526.
6. 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;324:71–86.
7. REACH Registry. http://www.reachregistry.org/index.cfm?sect51&
subSect51 (May 2007).
8. Diener HC, Cunha L, Forbes C, Sivenius J, Smets P, Lowenthal
A. European Stroke Prevention Study 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci
1996;143:1–13.
9. Halkes PH, van Gijn J, Kappelle LJ, Koudstaal PJ, Algra A. Aspirin plus
dipyridamole versus aspirin alone after cerebral ischaemia of arterial
origin (ESPRIT): randomised controlled trial. Lancet 2006;367:
1665–1673.
10. The CURE Trial Investigators. 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.
Dual antiplatelet therapy in high-risk patients
11. Mehta SR, Yusuf S, Peters RJ, Bertrand ME, Lewis BS, Natarajan MK,
Malmberg K, Rupprecht H, Zhao F, Chrolavicius S, Copland I, Fox KA.
Effects of pretreatment with clopidogrel and aspirin followed by
long-term therapy in patients undergoing percutaneous coronary
intervention: the PCI-CURE study. Lancet 2001;358:527–533.
12. Steinhubl SR, Berger PB, Mann JT III, Fry ET, DeLago A, Wilmer C,
Topol EJ. Early and sustained dual oral antiplatelet therapy following
percutaneous coronary intervention: a randomized controlled trial.
J Am Med Assoc 2002;288:2411–2420.
13. Sabatine MS, Cannon CP, Gibson CM, Lopez-Sendon JL, Montalescot G,
Theroux P, Claeys MJ, Cools F, Hill KA, Skene AM, McCabe CH,
Braunwald MD. Addition of clopidogrel to aspirin and fibrinolytic
therapy for myocardial infarction with ST-segment elevation.
N Engl J Med 2005;352:1179–1189.
14. Sabatine MS, Cannon CP, Gibson CM, Lopez-Sendon JL, Montalescot G,
Theroux P, Lewis BS, Murphy SA, McCabe CH, Braunwald E. Effect of
clopidogrel pretreatment before percutaneous coronary intervention
in patients with ST-elevation myocardial infarction treated with
fibrinolytics: the PCI-CLARITY study. J Am Med Assoc 2005;294:
1224–1232.
15. COMMIT Trial Collaborative Group. Addition of clopidogrel to aspirin
in 45 852 patients with acute myocardial infarction: randomised
placebo-controlled trial. Lancet 2005;366:1607–1621.
16. Diener HC, Bogousslavsky J, Brass LM, Cimminiello C, Csiba L, Kaste M,
Leys D, Matias-Guiu J, Rupprecht H. Aspirin and clopidogrel compared
with clopidogrel alone after recent ischaemic stroke or transient
ischaemic attack in high-risk patients (MATCH): randomised, doubleblind, placebo-controlled trial. Lancet 2004;364:331–337.
17. Serebruany VL, Steinhubl SR, Berger PB, Malinin AI, Bhatt DL,
Topol EJ. Variability in platelet responsiveness to clopidogrel among
544 individuals. J Am Coll Cardiol 2005;45:246–251.
18. Gum PA, Kottke-Marchant K, Welsh PA, White J, Topol EJ. A prospective, blinded determination of the natural history of aspirin resistance among stable patients with cardiovascular disease. J Am Coll
Cardiol 2003;41:961–965.
19. Husted S. New developments in oral antiplatelet therapy. Eur Heart J
2007;9(Suppl. D):D20–D27.
20. Kastrati A, Mehilli J, Schuhlen H, Dirschinger J, Dotzer F, ten Berg JM,
Neumann FJ, Bollwein H, Volmer C, Gawaz M, Berger PB, Schomig A.
A clinical trial of abciximab in elective percutaneous coronary intervention after pretreatment with clopidogrel. N Engl J Med
2004;350:232–238.
21. Kastrati A, Mehilli J, Neumann FJ, Dotzer F, ten Berg J, Bollwein H,
Graf I, Ibrahim M, Pache J, Seyfarth M, Schuhlen H, Dirschinger J,
D9
22.
23.
24.
25.
26.
27.
28.
Berger PB, Schomig A. Abciximab in patients with acute coronary
syndromes undergoing percutaneous coronary intervention after
clopidogrel pretreatment: the ISAR-REACT 2 randomized trial. J Am
Med Assoc 2006;295:1531–1538.
Rasoul S, Ottervanger JP, de Boer MJ, Miedema K, Hoorntje JC,
Gosselink M, Zijlstra F, Suryapranata H, Dambrink JH, van’t Hof AW.
A comparison of dual vs. triple antiplatelet therapy in patients with
non-ST-segment elevation acute coronary syndrome: results of the
ELISA-2 trial. Eur Heart J 2006;27:1401–1407.
CRUSADE Executive Committee. 2005 CRUSADE 4th quarter results.
http://www.crusadeqi.com (April 2007).
Patrono C, Bachmann F, Baigent C, Bode C, De Caterina R,
Charbonnier B, Fitzgerald D, Hirsh J, Husted S, Kvasnicka J,
Montalescot G, Garcia Rodriguez LA, Verheugt F, Vermylen J,
Wallentin L, Priori SG, Alonso Garcia MA, Blanc JJ, Budaj A, Cowie M,
Dean V, Deckers J, Fernandez BE, Lekakis J, Lindahl B, Mazzotta G,
Morais J, Oto A, Smiseth OA, Morais J, Deckers J, Ferreira R,
Mazzotta G, Steg PG, Teixeira F, Wilcox R. Expert consensus document on the use of antiplatelet agents. The task force on the use
of antiplatelet agents in patients with atherosclerotic cardiovascular
disease of the European society of cardiology. Eur Heart J 2004;
25:166–181.
Budaj A, Brieger D, Steg PG, Goodman SG, Dabbous OH, Fox KA,
Avezum A, Cannon CP, Mazurek T, Flather MD, Van de Werf F. Global
patterns of use of antithrombotic and antiplatelet therapies in
patients with acute coronary syndromes: insights from the Global
Registry of Acute Coronary Events (GRACE). Am Heart J 2003;146:
999–1006.
Mandelzweig L, Battler A, Boyko V, Bueno H, Danchin N, Filippatos G,
Gitt A, Hasdai D, Hasin Y, Marrugat J, Van de Werf F, Wallentin L,
Behar S. The second Euro Heart Survey on acute coronary syndromes:
characteristics, treatment, and outcome of patients with ACS in
Europe and the Mediterranean Basin in 2004. Eur Heart J 2006;27:
2285–2293.
CRUSADE Executive Committee. MAINTAIN CRUSADE: Medication
applied and sustained over time. http://www.crusadeqi.com/Main/
Ecab/Slides/MAINTAINSlidesOctober2005.ppt (April 2007).
Vikman S, Airaksinen KE, Tierala I, Peuhkurinen K, Majamaa-Voltti K,
Niemela M, Tuunanen H, Nieminen MS, Niemela K. Improved
adherence to practice guidelines yields better outcome in highrisk patients with acute coronary syndrome without ST elevation:
findings from nationwide FINACS studies. J Intern Med 2004;
256:316–323.