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Clinical Investigation and Reports
Effects of Aspirin Dose When Used Alone or in
Combination With Clopidogrel in Patients With Acute
Coronary Syndromes
Observations From the Clopidogrel in Unstable angina to prevent
Recurrent Events (CURE) Study
Ron J.G. Peters, MD; Shamir R. Mehta, MD; Keith A.A. Fox, MD; Feng Zhao, MSc;
Basil S. Lewis, MD; Steven L. Kopecky, MD; Rafael Diaz, MD; Patrick J. Commerford, MD;
Vicent Valentin, MD; Salim Yusuf, DPhil; for the Clopidogrel in Unstable angina to prevent Recurrent
Events (CURE) Trial Investigators
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Background—We studied the benefits and risks of adding clopidogrel to different doses of aspirin in the treatment of
patients with acute coronary syndrome (ACS).
Methods and Results—In the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial, 12 562 patients
with ACS using aspirin, 75 to 325 mg daily, were randomized to clopidogrel or placebo for up to 1 year. In this analysis,
patients were divided into the following 3 aspirin dose groups: ⱕ100 mg, 101 through 199 mg, and ⱖ200 mg. The
combined incidence of cardiovascular death, myocardial infarction, or stroke was reduced by clopidogrel regardless of
aspirin dose, as follows: ⱕ100 mg, 10.5% versus 8.6% (relative risk [RR], 0.81 [95% CI, 0.68 to 0.97]); 101 to 199 mg,
9.8% versus 9.5% (RR, 0.97 [95% CI 0.77 to 1.22]); and ⱖ200 mg, 13.6% versus 9.8% (RR, 0.71 [95% CI, 0.59 to
0.85]). The incidence of major bleeding increased with increasing aspirin dose both in the placebo group (1.9%, 2.8%,
and 3.7%, respectively; P⫽0.0001) and the clopidogrel group (3.0%, 3.4%, and 4.9%, respectively; P⫽0.0009); thus,
the excess risk with clopidogrel was 1.1%, 1.2%, and 1.2%, respectively. The adjusted hazard ratio for major bleeding
for the highest versus the lowest dose of aspirin was 1.9 (95% CI 1.29 to 2.72) in the placebo group, 1.6 (95% CI 1.19
to 2.23) in the clopidogrel group, and 1.7 (95% CI 1.36 to 2.20) in the combined group.
Conclusions—In patients with ACS, adding clopidogrel to aspirin is beneficial regardless of aspirin dose. Bleeding risks
increase with increasing aspirin dose, with or without clopidogrel, without any increase in efficacy. Our findings suggest
that the optimal daily dose of aspirin may be between 75 and 100 mg, with or without clopidogrel. (Circulation. 2003;
108:1682-1687.)
Key Words: aspirin 䡲 coronary disease 䡲 angina 䡲 platelets 䡲 thrombosis
A
ntiplatelet therapy is effective in preventing serious
vascular events both during short-term and long-term
treatment in patients with atherosclerotic arterial disease.1
Aspirin is the most widely studied antiplatelet drug, with
⬎60 000 patients included in randomized trials against placebo. However, there is no uniformity in the doses used in
clinical practice.2 Experimentally, a single oral 100-mg dose
of aspirin is sufficient to completely block the synthesis of
thromboxane A2 in healthy individuals, the predominant
pathway by which aspirin inhibits platelet aggregation. Lower
doses may require several days to reach complete blockade of
thromboxane A2 production or fail to do so.3 At higher doses,
the synthesis of prostacyclin is also inhibited, mainly in the
endothelium. This could paradoxically lead to thrombosis and
vasoconstriction. In addition, the incidence of other adverse
effects increases, particularly the risk of gastrointestinal
bleeding.3 Thus, careful selection of dose is important to
balance efficacy against safety.
Received November 22, 2002; de novo received March 6, 2003; revision received July 11, 2003; accepted July 11, 2003.
From the Department of Cardiology (P.J.G.P.), Academic Medical Center, Amsterdam, the Netherlands; Canadian Cardiovascular Collaboration
Project Office (S.R.M., F.Z., S.Y.), McMaster University, Hamilton, Ontario, Canada; Royal Infirmary of Edinburgh (K.A.A.F.), Edinburgh, UK; Lady
Davis Carmel Medical Center (B.S.L.), Haifa, Israel; Division of Cardiovascular Diseases (S.L.K.), Mayo Clinic and Foundation, Rochester, Minn;
Estudios Cardiologicos Latinoamerica (R.D.), Instituto Cardiovascular de Rosario, Argentina; Department of Medicine (P.J.C.), University of Cape Town,
South Africa; and Unidad Coronaria (V.V.), Hospital Universitario Dr Peset, Valencia, Spain.
All authors, except Dr Zhao, have received honoraria and travel expenses for speaking at scientific meetings from Sanofi-Synthelabo and Bristol Myers
Squibb. All centers received a grant for the conduct of the CURE trial.
Correspondence to Salim Yusuf, Canadian Cardiovascular Collaboration Project Office, Population Health Research Institute, McMaster University,
Hamilton General Hospital, 237 Barton Street East, Hamilton, ON L8L 2X2, Canada. E-mail [email protected]
© 2003 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
DOI: 10.1161/01.CIR.0000091201.39590.CB
1682
Peters et al
Compared with the original trials of aspirin in acute
coronary syndrome (ACS), additional antithrombotic therapy
(such as heparin) or invasive strategies are now commonly
used. Furthermore, recent guidelines recommend the use of
clopidogrel4 and glycoprotein (GP) IIb/IIIa receptor inhibitors. When all these drugs and interventions are used together, the risk of a major bleeding complications increases
and optimal dosing of each drug, including aspirin, is even
more important.5 Therefore, we performed an analysis of the
Clopidogrel in Unstable angina to prevent Recurrent Events
(CURE) study to explore the relationship between the dose of
aspirin and risks of bleeding when used alone or in combination with clopidogrel in the context of current treatment
strategies.
Methods
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The CURE study compared aspirin alone with aspirin plus clopidogrel in 12 562 patients with ACS without ST-segment elevation.6
Doses in the range of 75 to 325 mg daily were recommended by the
study protocol. Almost all patients (99.8%) used aspirin. The dose of
aspirin was chosen by the patient’s physician and in general was the
same within a center. The design of the CURE study has been
published previously7 and is summarized briefly.
Patients
Patients were eligible for inclusion if they had had symptoms
indicative of ACS within the past 24 hours and if they did not have
ST-segment elevation ⬎1 mm on their ECG. Other electrocardiographic evidence of new ischemia or concentrations of cardiac
enzymes (including troponin) at least twice the upper limit of normal
was required. Patients were excluded if they had New York Heart
Association class IV heart failure, if they had undergone percutaneous coronary intervention (PCI) or coronary artery bypass grafting
(CABG) in the previous 3 months, if they had contraindications to
antithrombotic or antiplatelet therapy, if they had previous disabling
or hemorrhagic stroke or intracranial hemorrhage, if they had
clinically severe thrombocytopenia, if they used or required oral
anticoagulants or nonstudy antiplatelet agents, or if they had received
a GP IIb/IIIa inhibitor fewer than 3 days before randomization.
Study Treatments
Patients were randomly assigned clopidogrel or placebo. A loading
dose of clopidogrel 300 mg orally or matching placebo was given
immediately on a double-blind basis, followed by clopidogrel (75 mg
per day) or matching placebo for 3 to 12 months. Aspirin was started
or continued simultaneously with clopidogrel or placebo. The dose
was left to the discretion of the local investigator; the study protocol
recommended a dose of 75 to 325 mg. The dose and compliance with
aspirin therapy was recorded on the case report forms and at each
visit.
Outcomes
Efficacy
The first coprimary outcome of the study was the composite of
cardiovascular (CV) death, myocardial infarction (MI), or stroke.
The second coprimary outcome was the composite of the first
coprimary outcome or refractory ischemia. Detailed definitions of
study outcomes have been previously published.6
Safety
Major bleeding was defined as being significantly disabling, intraocular bleeding leading to significant loss of vision, or bleeding
requiring transfusion of 2 or 3 units of red blood cells or equivalent
whole blood. Major bleeding was subclassified as life-threatening or
other major bleeding. Life-threatening bleeding complications were
defined as fatal or leading to a drop in hemoglobin of ⱖ5 g/dL or
significant hypotension with the need for inotropes, requiring sur-
Aspirin Dose and Clopidogrel in Unstable Angina
1683
gery (other than vascular site repair) or symptomatic intracranial
hemorrhage, or requiring transfusion of 4 or more units of red blood
cells or equivalent whole blood. Minor bleeding was defined as any
other bleeding requiring modification of the drug regimen.
Analyses
Patients were divided into the following 3 groups based on daily
aspirin dose at the time of randomization: ⱕ100 mg, 101 through
199 mg, or ⱖ200 mg. An intention-to-treat analysis approach was
used. The difference in proportions was tested by ␹2 test, and for the
difference in means, the Student t test was used. The CochranArmitage trend test was used to test the trend in rates in aspirin dose
groups.
All hazard ratios (HRs) and 95% CIs for primary and secondary
outcomes comparing the clopidogrel and placebo groups were
derived by use of the Cox proportional hazards model. Efficacy HRs
were adjusted for gender, weight, hypertension, components of the
TIMI risk score, and rates of angiography, PCI, and CABG.
For bleeding outcomes, a logistic regression model was used. HRs
for bleeding events were adjusted for gender, weight, hypertension,
components of the TIMI risk score, rates of angiography, PCI, and
CABG, and the use of nonsteroidal anti-inflammatory drugs, heparin, GPIIb/IIIa inhibitors, oral anticoagulants, open-label ticlopidine,
or clopidogrel at any time during the study period. In addition, a
stratified analysis of the risk of bleeding at various doses of aspirin
was performed in selected subgroups of patients. Tests for heterogeneity among various subgroups were also carried out.
Results
The main findings of the CURE study have been published
previously.4 The first coprimary outcome of CV death, MI, or
stroke occurred in 9.3% of the patients in the clopidogrel
group and in 11.4% of the patients in the placebo group
(relative risk [RR], 0.80; 95% CI, 0.72 to 0.90; P⬍0.001).
The second coprimary outcome occurred in 16.5% of the
patients in the clopidogrel group and 18.8% of the patients in
the placebo group (RR, 0.86; 95% CI, 0.79 to 0.94;
P⬍0.001). The overall risk of major bleeding was 3.7% in the
clopidogrel group compared with 2.7% in the placebo group
(RR 1.4; 95% CI, 1.1 to 1.7; P⫽0.001). Life-threatening
bleeding occurred in 2.2% compared with 1.8%, respectively
(RR 1.2; 95% CI, 1.0 to 1.6; P⫽0.13).
The baseline characteristics of the patients in the 3 groups
based on aspirin dose are presented in Table 1. There were
5320 patients receiving low-dose (ⱕ100 mg), 3109 receiving
medium-dose (101 to 199 mg), and 4110 receiving high-dose
(ⱖ200 mg) aspirin. Aspirin dosing varied among regions
(Table 1). The use of the highest dose was most common in
North and South America, the medium dose was common in
Australia and New Zealand, and the lowest dose was common
in Eastern and Western Europe. The median dose of aspirin
used in the study was 150 mg. Within each center, the
variation in aspirin dose was small; an average of 89% of all
patients per center used a dose of aspirin within 50 mg of the
most frequently used dose. Aspirin dose per patient varied
little during the course of the study. Only 14% of patients
used a dose that differed at least 50 mg from the initial dose
for ⬎50% of the duration of follow-up. In general, the
high-dose group included a greater proportion of men and
patients with a prior history of diabetes, PCI, and CABG
surgery.
1684
Circulation
October 7, 2003
TABLE 1. Regional Distribution and Baseline Characteristics by Aspirin
Dose Group
Aspirin Dose
ⱕ100 mg
101 to 199 mg
ⱖ200 mg
5320 (42.4)
3109 (24.8)
4110 (32.8)
Canada/United States, n (%)
232 (10.5)
78 (3.5)
1906 (86.0)
Latin America, n (%)
187 (13.8)
144 (10.7)
1019 (75.5)
Australia/New Zealand/South Africa, n (%)
209 (18.4)
832 (73.4)
93 (8.2)
Western Europe, n (%)
3096 (61.6)
954 (19.0)
979 (19.5)
Eastern Europe, n (%)
1596 (56.8)
1101 (39.2)
113 (4.0)
Weight, kg, mean
77.3
77.3
78.2
Male, %
58.8
61.1
65.4
Body mass index, mean
27.3
27.4
27.6
Current smokers, %
20.8
24.2
25.1
Previous MI, %
32.0
31.1
33.2
Diabetes, %
21.0
19.8
26.8
Hypertension, %
58.8
56.6
60.5
History of PCI, %
9.2
7.1
12.8
10.0
8.9
13.8
3.3
3.1
3.5
N, %
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History of CABG, %
TIMI risk score, mean
Additional Medication and
Revascularization Procedures
Table 2 presents the frequencies of the use of other antithrombotic medication and of revascularization procedures in the
various aspirin dose groups. These additional treatments,
except the use of nonsteroidal anti-inflammatory drugs and
oral anticoagulants, were significantly more frequent in the
highest aspirin dose group, reflecting practice patterns in the
regions where higher doses are routinely used.
Efficacy
The impact of clopidogrel in preventing CV death, MI, or
stroke was not significantly heterogeneous by aspirin dose
(high-dose group, 9.8% versus 13.6%; RR, 0.71; 95% CI,
0.59 to 0.85; medium-dose group, 9.5% versus 9.8%; RR,
0.97; 95% CI, 0.77 to 1.22; low-dose group, 8.6% versus
10.5%; RR, 0.81; 95% CI, 0.68 to 0.97) (Figure 1). Similar
results were observed with the composite of CV death, MI,
stroke, and refractory ischemia (Figure 2).
The results were not heterogeneous in patients receiving
aspirin alone when examined by dose (highest and medium
aspirin dose groups compared with the low-dose group:
adjusted OR, 1.0 (95% CI, 0.82 to 1.23) and 1.2 (95% CI,
1.08 to 1.51), respectively (Table 3). In the aspirin plus
clopidogrel group, event rates appeared to be similar across
various doses (adjusted OR, 1.2 [95% CI, 0.98 to 1.48] and
1.2 [95% CI, 0.95 to 1.40] for medium- and high-dose groups
compared with the low-dose group, respectively).
Bleeding
Clopidogrel increased the risk of bleeding at each dose of
aspirin. However, the incidence of major bleeding complications increased significantly with increasing aspirin dose both
TABLE 2. Additional Medications and Procedures During the
Entire Study Period
Aspirin Dose
ⱕ100
mg
N
5320
101 to
199 mg
ⱖ200
mg
3109
4110
P
Value
Heparin, %
89.7
93.6
95.1
䡠䡠䡠
⬍0.0001
NSAIDs, %
14.1
14.9
13.2
0.13
GP IIb/IIIa inhibitors, %
5.6
3.7
10.0
⬍0.0001
Other antiplatelet
agents* combined, %
19.0
17.5
25.4
⬍0.0001
Oral anticoagulants, %
5.0
5.1
5.2
0.95
PCI, %
19.9
17.3
25.9
⬍0.0001
CABG, %
15.6
16.5
17.7
0.02
*Open-label ticlopidine or clopidogrel.
NSAIDs indicates nonsteroid anti-inflammatory drugs.
Figure 1. Aspirin dose and incidence of first coprimary outcome
(CV death, nonfatal MI, and stroke).
Peters et al
Aspirin Dose and Clopidogrel in Unstable Angina
Figure 2. Aspirin dose and the incidence of the second coprimary outcome (CV death, nonfatal MI, stroke, and refractory
angina).
Figure 3. Aspirin dose and the incidence of major bleeding.
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in the placebo (1.9%, 2.8%, 3.7%; P⫽0.0001) and the
clopidogrel (3.0%, 3.4%, 4.9%; P⫽0.0009) groups (Figure
3). The risk of bleeding at the highest dose of aspirin given
with placebo was higher than the risk of bleeding with the
combination of clopidogrel and aspirin in the lowest-dose
group (Figure 3). HRs for major bleeding for the 2 higherdose groups compared with the lowest-dose group are presented in Table 4. The risk of bleeding is lower at the lowest
dose of aspirin. A similar pattern is observed in the subgroup
of major bleeding complications defined as life-threatening
(Table 4). Table 5 presents the results of a stratified analysis
of the risk of major bleeding in selected subgroups of
patients. In support of the multivariate analysis, a trend of a
higher risk of bleeding with increasing doses of aspirin is
observed consistently in patients undergoing PCI, CABG, or
no revascularization. In patients who were not treated with
heparin, no such trend is apparent. However, these numbers
are small. In patients who were treated with GP IIb/IIIa
inhibitors, no trend is observed. Again, the numbers are small
and the use of these agents may increase the risk of bleeding
to a rate where the impact of aspirin dose is masked.
Regarding the site of bleeding, the rates of surgical, gastrointestinal, and puncture site bleeding increased significantly
with increasing aspirin dose both in the placebo and the
clopidogrel groups (data not shown). Minor bleeding compliTABLE 3.
cations were not clearly related to aspirin dose (data not
shown).
Discussion
Our study demonstrates 3 important observations. First, the
benefits of clopidogrel, when added to aspirin, in reducing
major ischemic events do not vary significantly by the aspirin
dose used. Second, higher doses of aspirin are not associated
with lower clinical event rates and may in fact be associated
with higher event rates. Third, with increasing doses of
aspirin, the risk of major bleeding increases, irrespective of
whether it is used alone or in combination with clopidogrel.
The ideal dose of aspirin for the prevention of vascular
events has been the subject of much debate.3 This is best
evaluated by comparing patients randomized to different
doses; however, observational data may also be useful. Trials
in patients with a cerebral transient ischemic attack have
demonstrated increased bleeding complications with higher
doses while observing no differences in efficacy.8,9 Other
observations suggest that a low dose may be associated with
a lower risk of vascular complications compared with higher
doses.10,11
The latest report of the AntiThrombotic Triallists Collaboration (ATTC) identifies 10 trials that have directly compared 2 doses of aspirin across a variety of indications; 7
compared 500 to 1500 mg with 75 to 325 mg daily. Overall,
there was no difference in the rates of vascular events (high-
Incidence of the First Coprimary End Point by Various Doses of Aspirin
Aspirin Alone
ASA ⱕ100 mg
ASA 101–199 mg
ASA ⱖ200 mg
P value for trend
1685
Aspirin⫹Clopidogrel
All Patients
HR Aspirin Plus
Clopidogrel vs
Aspirin Alone*
95% CI
10.5%
8.6%
9.6%
0.81
0.68–0.97
9.8%
9.5%
9.7%
0.97
0.77–1.22
13.6%
9.8%
11.7%
0.71
0.59–0.85
0.0016
0.17
0.0011
䡠䡠䡠
䡠䡠䡠
Adjusted† HR for 101 to 199 vs ⱕ100
1.0 (0.82–1.23)
1.2 (0.98–1.48)
1.09 (0.95–1.26)
䡠䡠䡠
䡠䡠䡠
Adjusted† HR for ⱖ200 vs ⱕ100
1.3 (1.08–1.52)
1.2 (0.95–1.40)
1.23 (1.08–1.39)
䡠䡠䡠
䡠䡠䡠
*Test for heterogeneity, P⫽NS.
†Adjustment for gender, weight, hypertension, components of the TIMI risk score, and rates of angiography, PCI, and CABG.
1686
Circulation
October 7, 2003
TABLE 4.
Major and Life-Threatening Bleeding by Various Doses of Aspirin
Aspirin Alone
Aspirin⫹Clopidogrel
All Patients
Major bleeding complications
ASA ⱕ100 mg, %
1.86
2.97
2.41
ASA 101–199 mg, %
2.82
3.41
3.12
ASA ⱖ200 mg, %
3.67
4.86
4.26
P value for trend
⬍0.0001
⬍0.001
⬍0.0001
Adjusted* OR for 101–199 vs ⱕ100
1.52 (1.00–2.31)
1.20 (0.84–1.73)
1.33 (1.01–1.74)
Adjusted* OR for ⱖ200 vs ⱕ100
1.7 (1.22–2.59)
1.63 (1.19–2.23)
1.70 (1.33–2.16)
ASA ⱕ100 mg, %
1.26
1.75
1.50
ASA 101–199 mg, %
1.90
1.39
1.64
ASA ⱖ200 mg, %
2.37
3.29
P value for trend
0.004
0.0006
Life-threatening bleeding complications
2.82
⬍0.0001
Adjusted* OR for 101–199 vs ⱕ100
1.48 (0.89–2.46)
0.79 (0.47–1.32)
1.06 (0.74–1.52)
Adjusted* OR for ⱖ200 vs ⱕ100
1.64 (1.04–2.59)
1.82 (1.22–2.71)
1.72 (1.27–2.32)
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*Adjusted for gender, weight, hypertension, components of the TIMI risk score, rates of angiography, PCI and CABG,
and the use of NSAIDs, heparin, GP2B3A inhibitors, oral anticoagulants, open-label ticlopidine, or clopidogrel at any
time during the study period.
versus low-dose RR, 1.03; SE⫽10, P⫽NS).1 Three trials
compared doses ⬍75 mg daily with 75 mg or more daily.
Again, there was no difference in event rates (high versus low
RR, 0.92; SE⫽10).1 Taken together, these 10 trials demonstrated no significant difference in efficacy between different
doses ranging from 75 to 1500 mg/d. Recently, a randomeffects model was used to analyze the same data. After
adjustment for temporal trends, higher doses of aspirin were
associated with less benefit.12
Indirect comparisons between the results of trials comparing different doses of aspirin versus placebo are also available. The ATTC report divided the trials into 4 subgroups
based on daily aspirin dose, as follows: ⬍75, 75 to 150, 160
to 325, and ⬎500 mg, each compared with placebo. The odds
reductions were 13%, 32%, 26%, and 19%, respectively.
Thus, consistent with our findings, there is no evidence that
the benefit of aspirin increases at dose ⬎75 mg/d. Furthermore, 4 studies have compared aspirin with placebo in
patients with unstable angina using doses of 75,13 325,14
650,15 and 1300 mg.16 All studies showed a similar degree of
risk reduction, consistent with our findings.
In the pooled analysis by the ATTC in trials comparing
aspirin with control, the proportional increase in the risk of a
major extracranial bleed was similar with all daily aspirin
doses ⬍325 mg. However, their analysis included smaller
TABLE 5.
patient numbers and patients at a lower overall risk of
bleeding. Two trials that compared 75 to 325 mg aspirin daily
with ⬍75 mg daily found a nonsignificant trend toward an
increase in major extracranial bleeds at the higher dose of
aspirin (39 of 1576 [2.5%] with 75 to 325 mg versus 28 of
1555 [1.8%] with ⬍75 mg).
The mechanism underlying the differences in bleeding
rates is not clear. Consistent with the literature,17 higher doses
of aspirin were associated with higher rates of gastrointestinal
bleeding, particularly in the placebo group, although the rates
were low in the CURE study. This dose-response relationship
may reflect at least 2 cyclo-oxygenase (COX)-1– dependent
mechanisms, dose-dependent inhibition of COX-1 in the
gastric mucosa and (relatively) dose-independent inhibition
of COX-1 in platelets.18 Whereas platelet thromboxane synthesis is blocked completely at a daily dose of 100 mg, higher
(or repeated) doses would be expected to inhibit COX-2–
dependent thromboxane synthesis in vascular endothelium,
monocytes, and macrophages. This could contribute to the
impairment of hemostasis in patients using higher doses of
aspirin.
Despite the important benefits of clopidogrel in preventing
major ischemic events in the CURE trial, there was an excess
in (mostly reversible) major bleeding. However, our present
analysis clearly demonstrates that the increase in bleeding
Risk of Major Bleeding by Aspirin Dose in Various Patient Subgroups
ⱕ100 mg, % (n)
101 to 199 mg, % (n)
ⱖ200 mg, % (n)
PCI alone
1.9 (997)
2.4 (508)
3.9 (1000)
11.1 (728)
P Value for Trend
0.0068
CABG
6.9 (829)
7.6 (514)
No revascularization
1.5 (3494)
2.2 (2087)
2.3 (2382)
0.0030
0.019
Heparin
2.6 (4774)
3.2 (2909)
4.4 (3910)
⬍0.0001
No heparin
0.9 (546)
2.0 (200)
1.5 (200)
0.39
GP IIb/IIIa
5.4 (298)
1.7 (115)
5.1 (410)
0.96
No GP IIb/IIIa
2.2 (5022)
3.2 (2994)
4.2 (3700)
⬍0.0001
Peters et al
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was largely dependent on the dose of aspirin used. By
lowering the dose of aspirin, the risk of major bleeding may
be substantially attenuated without loss of efficacy. Indeed,
the major bleeding rates for combined use of low-dose aspirin
plus clopidogrel are lower than for using aspirin alone at
higher doses. Similarly, the risk of surgical bleeding with the
combination of aspirin and clopidogrel seems also to be
dependent on the dose of aspirin used. Consequently, surgical
bleeding risks may also be reduced by using lower aspirin
doses than presently used in several regions of the world,
including North and South America.
Balancing risk and benefit is particularly important when
patients are at increased risk of bleeding, based on the
presence of multiple risk factors such as age, weight, and
female sex.18,19 Furthermore, combinations of antithrombotic
medications are used in high-risk patients, which are likely to
increase the risk of bleeding (clopidogrel, heparin, aspirin,
and GP IIb/IIIA inhibitors). In addition, the risk of bleeding
increases additionally when interventions, especially coronary bypass surgery, are performed in the presence of these
drugs. Therefore, approaches to maintaining the benefits of
the various treatments while reducing the risk of bleeding
would be useful. Because the use of clopidogrel in patients
with unstable coronary syndromes is now recommended
(class IA recommendation in the United States guidelines), it
is important that clinicians consider the dose of aspirin that is
to be used in ACS. Based on our findings and on the
observations in the ATTC, a dose between 75 and 100 mg
may be optimal, either alone or in combination with
clopidogrel.
Limitations
Our findings are based on a post hoc observational analysis
and should be considered exploratory. The dose of aspirin
was not prescribed by the study protocol, nor was it randomized. However, the data with respect to both efficacy and
bleeding are internally consistent in both the placebo and the
clopidogrel groups and externally consistent with data from
the ATTC meta-analysis. Second, the main determinant of the
dose used in patients in CURE was the routine approach of
centers and specific countries (Table 1). This argues against
the possibility that the selection of dose may be related to the
risk profile of patients, thus confounding the differences in
efficacy or safety between dose groups. Third, regional
differences in patient populations and practice patterns are
reflected by significant differences in the baseline characteristics of the patients (Table 1) and in additional treatments.
However, after adjustment for these differences, including the
use of other antithrombotics, a dose response between aspirin
and bleeding complications is still observed.
Conclusions
Our findings demonstrate that clopidogrel, when added to
aspirin and other standard therapies, is beneficial in patients
with ACS irrespective of the dose of aspirin used. Compared
with a daily dose of 75 to 100 mg with or without concomitant use of clopidogrel, higher doses of aspirin lead to higher
Aspirin Dose and Clopidogrel in Unstable Angina
1687
rates of bleeding complications without increasing efficacy.
The available data suggest that in patients treated for unstable
coronary syndromes, a daily dose of aspirin in the range of 75
to 100 mg may be optimal.
Acknowledgments
The CURE study was funded by Sanofi-Synthelabo and Bristol
Meyers Squibb. However, the study was conducted independently
under the supervision of the CURE Steering Committee and coordinated by the Population Health Research Institute at McMaster
University and Hamilton Health Sciences. Dr Yusuf is a Senior
Scientist of the Canadian Institutes of Health Research and holds a
Heart and Stroke Foundation of Ontario Research Chair.
References
1. Antithrombotic Triallists Collaboration. BMJ. 2002;324:71– 86.
2. Patrono C, Coller B, Dalen JE, et al. Platelet-active drugs: the relationships among dose, effectiveness, and side effects. Chest. 2001;119:
39S– 63S.
3. Awtry EH, Loscalzo J. Aspirin. Circulation. 2000;101:1206 –1218.
4. Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA Guideline
Update for the Management of Patients With Unstable Angina and
Non–ST-Segment Elevation Myocardial Infarction, 2002: Summary
Article. A Report of the American College of Cardiology/American Heart
Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina). Circulation. 2002;106:
1893–1900.
5. Gilchrist IC, Berkowitz SD, Thompson TD, et al. Heparin dosing and
outcome in acute coronary syndromes: the GUSTO-IIb experience. Am
Heart J. 2002;144:73– 80.
6. The Clopidogrel in Unstable Angina to Prevent Recurrent Events 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.
7. CURE study investigators. The Clopidogrel in Unstable Angina to
Prevent Recurrent Events (CURE) Trial programme: rationale, design and
baseline characteristics including a meta-analysis of the effects of thyenopyridines in vascular disease. Eur Heart J. 2000;21:2033–2041.
8. UK-TIA Study Group. United Kingdom Transient Ischaemic Attack
(UK-TIA) aspirin trial: interim results. BMJ. 1988;296:316 –320.
9. The Dutch TIA Trial Study Group. A comparison of two doses of aspirin
(30 mg vs 283 mg a day) in patients after a transient ischemic attack or
minor stroke. N Engl J Med. 1991;325:1261–1266.
10. Taylor DW, Barnett HJM, Haynes RB, et al. Low-dose and high-dose
acetylsalicylic acid for patients undergoing carotid endarterectomy: a
randomised controlled trial. Lancet. 1999;353:2179 –2184.
11. van Gijn J. Low doses of aspirin in stroke prevention. Lancet. 1999;353:
2172–2173.
12. Kong DF, Hasselblad V, Kandzari DE, et al. Seeking the optimal aspirin
dose in acute coronary syndromes. Am J Cardiol. 2002;90:622– 625.
13. The RISC Group. Risk of myocardial infarction and death during
treatment with low dose aspirin and intravenous heparin in men with
unstable coronary artery disease. Lancet. 1990;336, 827– 830.
14. Lewis HD, Davis JW, Archibald DG, et al. Protective effects of aspirin
against acute myocardial infarction and death in men with unstable
angina: results of a Veterans Administration cooperative study. N Engl
J Med. 1983;309:396 – 403.
15. Theroux P, Ouimet H, McCans J, et al. Aspirin, heparin, or both to treat
acute unstable angina. N Engl J Med. 1988;319:1105–1111.
16. Cairns JA, Gent M, Singer J, et al. Aspirin, sulfinpyrazone, or both in
unstable angina. N Engl J Med. 1985;313:1369 –1375.
17. Roderick PJ, Wilkes HC, Meade TW. The gastrointestinal toxicity of
aspirin: an overview of randomized controlled trials. Br J Clin
Pharmacol. 1993;35:219 –226.
18. Blankenship JC. Bleeding complication of glycoprotein IIb-IIIa receptor
inhibitors. Am Heart J. 1999;138:S87–S296.
19. Aguirre FV, Topol EJ, Ferguson JJ, et al for the EPIC investigators.
Bleeding complications with the chimeric antibody to platelet glycoprotein IIb/IIIa integrin in patients undergoing percutaneous coronary intervention. Circulation. 1995;91:2882–2890.
Effects of Aspirin Dose When Used Alone or in Combination With Clopidogrel in Patients
With Acute Coronary Syndromes: Observations From the Clopidogrel in Unstable angina
to prevent Recurrent Events (CURE) Study
Ron J.G. Peters, Shamir R. Mehta, Keith A.A. Fox, Feng Zhao, Basil S. Lewis, Steven L.
Kopecky, Rafael Diaz, Patrick J. Commerford, Vicent Valentin and Salim Yusuf
for the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) Trial Investigators
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Circulation. 2003;108:1682-1687; originally published online September 22, 2003;
doi: 10.1161/01.CIR.0000091201.39590.CB
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