Health Services and Outcomes Research

Initial Aspirin Dose and Outcome Among ST-Elevation

Myocardial Infarction Patients Treated
With Fibrinolytic Therapy
Jeffrey S. Berger, MD, MS; Amanda Stebbins, MS; Christopher B. Granger, MD;
Eric M. Ohman, MD; Paul W. Armstrong, MD; Frans Van de Werf, MD, PhD; Harvey D. White, DSc;
R. John Simes, MD; Robert A. Harrington, MD; Robert M. Califf, MD; Eric D. Peterson, MD, MPH

Background—Although treatment with immediate aspirin reduces morbidity and mortality in ST-elevation myocardial
infarction, the optimal dose is unclear. We therefore compared the acute mortality and bleeding risks associated with
the initial use of 162 versus 325 mg aspirin in fibrinolytic-treated ST-elevation myocardial infarction patients.
Methods and Results—Using combined data from the Global Utilization of Streptokinase and Tissue Plasminogen Activator
for Occluded Coronary Arteries (GUSTO I) and Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO III)
trials (n⫽48 422 ST-elevation myocardial infarction patients), we compared the association between initial aspirin dose of 162
versus 325 mg and 24-hour and 7-day mortality, as well as rates of in-hospital moderate/severe bleeding. Results were
adjusted for previously identified mortality and bleeding risk factors. Overall, 24.4% of patients (n⫽11 828) received an initial
aspirin dose of 325 mg, and 75.6% (n⫽36 594) received 162 mg. The 24-hour mortality rates were 2.9% versus 2.8%
(P⫽0.894) for those receiving an initial aspirin dose of 325 versus 162 mg. Mortality rates at 7 and 30 days were 5.2% versus
4.9% (P⫽0.118) and 7.1% versus 6.5% (P⫽0.017) among patients receiving the 325 versus 162 mg aspirin. After adjustment,
aspirin dose was not associated with 24-hour (odds ratio [OR], 1.01; 95% CI, 0.82 to 1.25), 7-day (OR, 1.00; 95% CI, 0.87
to 1.17), or 30-day (OR, 0.99; 95% CI, 0.87 to 1.12) mortality rates. No significant difference was noted for myocardial
infarction or the composite of death or myocardial infarction between groups. In-hospital moderate/severe bleeding occurred
in 9.3% of those treated with 325 mg versus 12.2% among those receiving 162 mg (P⬍0.001). After adjustment, 325 mg was
associated with a significant increase in moderate/severe bleeding (OR, 1.14; 95% CI, 1.05 to 1.24; P⫽0.003).
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Conclusion—These data suggest that an initial dose of 162 mg aspirin may be as effective as and perhaps safer than 325
mg for the acute treatment of ST-elevation myocardial infarction. (Circulation. 2008;117:192-199.)
Key Words: aspirin 䡲 death 䡲 hemorrhage 䡲 myocardial infarction 䡲 prognosis

A spirin therapy is a cornerstone in the immediate treat-

ment of ST-elevation myocardial infarction (STEMI).1–3
Much of the data supporting aspirin for STEMI are from the
Second International Study of Infarct Survival (ISIS-2),4
which demonstrated that 162.5 mg aspirin given immediately
with or without fibrinolytic therapy for STEMI reduced
5-week vascular mortality by 23% (P⬍0.0001). In addition,
aspirin significantly reduced nonfatal reinfarction and nonfa-
tal stroke and was not associated with any significant increase
in cerebral hemorrhage or in bleeds requiring transfusion.4 On
the basis of these data, the American College of Cardiology,
American Heart Association, and European Society of Car-
diology gave a class I level of evidence A to immediate use
of 162 mg aspirin.5,6 In contrast, there is a paucity of trial
evidence for an initial dose of 325 mg of aspirin, which led to
a class I level of evidence C recommendation in the American
College of Cardiology/American Heart Association guidelines.5
Despite these current recommendations, the most common
initial dose of aspirin in the United States has been 325 mg.7
Clinical Perspective p 199
The optimal aspirin dose for the prevention of vascular
events has been the subject of much debate.1–3,8 Experimen-
tally, a single oral 100-mg dose of aspirin is sufficient to
completely block the synthesis of thromboxane A2,9,10 the
predominant pathway by which aspirin inhibits platelet ag-
gregation.3 Studies comparing the dose effect of aspirin noted
increased bleeding complications with higher doses while
observing no differences in efficacy.1–3,8 The comparative
efficacy and safety of initial aspirin dose in the setting of

Received July 31, 2007; accepted October 19, 2007.

From Duke Clinical Research Institute, Durham, NC (J.S.B., A.S., C.B.G., E.M.O., R.A.H., R.M.C., E.D.P.); University of Alberta, Edmonton, Alberta,
Canada (P.W.A.); Gasthuisberg University Hospital, Leuven, Belgium (F.V.d.W.); Auckland City Hospital, Auckland, New Zealand (H.D.W.); and
University of Sydney, Sydney, Australia (R.J.S.).
Guest Editor for this article was James T. Willerson, MD.
Correspondence to Jeffrey S. Berger, MD, MS, Department of Cardiovascular Medicine, Duke University Medical Center, PO Box 31007, Durham,
NC 27710. E-mail berge026@mc.duke.edu
© 2008 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.107.729558

192
 Berger et al Aspirin Dose in ST-Elevation Myocardial Infarction
STEMI remain unknown. To date, there has been only a
single randomized trial11 that compared initial aspirin doses
among those receiving fibrinolytic therapy, but unfortunately,
the trial stopped early after enrolling only 162 patients.
Given this paucity of information, we undertook a retrospec-
tive analysis of 2 large STEMI fibrinolytic trials, the Global
Utilization of Streptokinase and Tissue Plasminogen Activator
for Occluded Coronary Arteries (GUSTO I) and Global Use of
Strategies to Open Occluded Coronary Arteries (GUSTO III)
clinical trials, with a combined database of 56 080 STEMI
patients, to assess immediate aspirin dose (162 versus 325 mg)
and short-term outcomes after STEMI. We hypothesized that
aspirin dose (162 versus 325 mg) would be associated with less
bleeding, not with cardiovascular events.
Methods
Patient Population
The GUSTO I and GUSTO III studies were international fibrinolytic
trials that enrolled 56 080 patients with STEMI ⬍6 hours after
symptom onset from 1990 through 1993 and 1995 through 1997,
respectively. Gusto I enrolled 41 021 patients; Gusto III enrolled
15 059. Entry criteria and treatment protocols for these studies,
nearly identical, have been described.12,13
In GUSTO I, 35 529 patients received immediate chewable aspirin,
of whom 31 575 (88.9%) received 160 mg and 3954 (11.1%) received
325 mg. In GUSTO III, 12 893 patients received immediate aspirin:
5019 (38.9%) received 126 to 162 mg and 7874 (61.1%) received 163
to 325 mg. For purposes of the present analysis, patients administered
126- to 162-mg doses are identified as having received 162 mg, and
patients administered 163 to 330 mg are identified as having received
325 mg. We excluded 7658 patients (13.7%) because of missing or
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unknown data on immediate aspirin dose, 5492 (13.4%) from GUSTO
I and 2166 (14.4%) from GUSTO III. This provided a final cohort of
48 422 patients for the present study. Aspirin dose was left to the
discretion of the treating physician.
Outcomes
Efficacy outcomes of interest were all-cause mortality, reinfarction,
any stroke (both hemorrhagic and nonhemorrhagic), and the com-
posite end points of death or reinfarction and death, reinfarction, or
stroke. Safety outcomes of interest were GUSTO-defined bleeding
(moderate, severe, or moderate/severe intensity) and requirement for
blood transfusions. Events occurring within 24 hours, 7 days, and 30
days after randomization were evaluated, along with any bleeding
events that occurred during initial hospitalization.
Statistical Analysis
Baseline characteristics are reported as percentiles for discrete
variables and as medians (25th and 75th percentiles) for continuous
factors. The distribution of key baseline characteristics, in-hospital
medications, and procedures was compared for the 2 dose groups
through the use of a ␹2 test for categorical and a Wilcoxon sign-rank
test for continuous variables. Hochberg’s procedure for multiple tests
of significance was performed on the baseline characteristics.14 After
adjustment for multiple comparisons, only those factors with values
of P⬍0.001 are statistically significant. Models had been previously
developed, validated, and published for moderate to severe bleed-
ing,15 in-hospital death or myocardial infarction,16 stroke,17,18 and
mortality19,20 using the GUSTO I and III databases. All factors found
to be predictive in the death or MI model were included in a logistic
model for covariate adjustment for the end point of in-hospital
reinfarction alone. For the composite end point of death, reinfarction,
or stroke, all factors found in the published models for death, death
or reinfarction, or stroke were included as potential confounders. The
aspirin dose (325 versus 162 mg) was included in each of these
models to assess the association between dose and outcome after
adjustment for differences in baseline risk. This association was as-
193
sessed at 24 and 168 hours (7 days) after randomization for all outcomes
of interest. In addition, the association between aspirin dose and
mortality was evaluated out to 30 days after randomization. Logistic
modeling techniques were used for all of the adjusted and unadjusted
modeling. The effect of trial was evaluated 2 ways: by including trial as
a covariate and by stratifying on trial.
A value of P⬍0.05 was used to declare statistical significance,
bearing in mind the hypothesis-generating nature of this study. SAS
version 8.2 (SAS Institute Inc, Cary, NC) was used for all statistical
analyses.
All authors had access to the data and the statistical analysis
report. Each author approved the final manuscript and attests to the
validity of the results.
Results
Information on immediate aspirin dose and short-term out-
comes was available for 48 422 patients (86%). An immedi-
ate aspirin dose of 162 mg was given to 36 594 patients
(75.6%). Patients from GUSTO I were more likely to receive
162 mg, whereas patients from GUSTO III were more likely
to receive 325 mg. Baseline characteristics according to
aspirin dose are presented in Table 1. It is evident that there
were some imbalances between the groups. Patients receiving
162 mg were more frequently enrolled from North America,
more likely to be current smokers and diabetic, less likely to
have a family history of cardiac disease or history of MI, and
more likely to have an inferior MI than those receiving 325
mg. Treatment and procedural characteristics are depicted in
Table 2. Patients who received 162 mg were more likely to
receive streptokinase; were less likely to receive tenectaplase
and reteplase; had significantly higher measured activated
partial thromboplastin times at 6, 12, and 24 hours; and were
more likely to undergo invasive procedures. In-hospital
medications also were significantly different between the
groups (Table 2).
At 24 hours, there were 1370 deaths (2.8%): 2.9% among
the 325-mg and 2.8% among the 162-mg (P⫽0.894) groups.
After adjustment for baseline imbalances, there was no
significant association of aspirin 325 versus 162 mg on
24-hour mortality (odds ratio [OR], 1.01; 95% CI, 0.82 to
1.25). When stratified by clinical trial, no significant associ-
ation was noted for aspirin dose and 24-hour mortality for
GUSTO I (OR, 0.88; 95% CI, 0.66 to 1.17) and GUSTO III
(OR, 1.29; 95% CI, 0.88, 1.72). MI and stroke occurred more
frequently in patients receiving 325 mg (Table 3). However,
after multivariable adjustment, there was no significant asso-
ciation between aspirin dose and risk of MI (OR, 1.22; 95%
CI, 0.89 to 1.67) or stroke (OR, 1.16; 95% CI, 0.87 to 1.53).
In addition, there was no association between aspirin dose
and the composite of death, MI, or stroke at 24 hours.
At 7 days, there were 2393 deaths (4.9%): 5.2% among the
325-mg and 4.9% among the 162-mg (P⫽0.118) groups.
After adjustment for baseline imbalances (Figure), there was
no significant association of aspirin 325 versus 162 mg on
7-day mortality (OR, 1.00; 95% CI, 0.87 to 1.17). When
stratified by clinical trial, no association was noted for aspirin
dose and 7-day mortality in GUSTO I (OR, 0.97; 95% CI,
0.79 to 1.19) or GUSTO III (OR, 1.07; 95% CI, 0.84 to 1.36).
The individual frequency of MI was similar in the 2 groups;
however, stroke was more frequent in patients receiving 325
mg (Table 4). After multivariable adjustment, there was no
 194 Circulation January 15, 2008

Table 1. Baseline Characteristics

All Patients Aspirin 126 –162 mg Aspirin 163–330 mg
(n⫽48 422) (n⫽36 594) (n⫽11 828) P
Trial ⬍0.001
GUSTO I 73.4 86.3 33.4
GUSTO III 26.6 13.7 66.6
Demographics
Mean age, y 62 (52, 70) 62 (52, 70) 62 (53, 71) ⬍0.001
Female, % 25.7 25.5 26.6 0.010
White, % 91.5 91.2 92.6 ⬍0.001
Weight, kg 78 (70–89) 78 (70–89) 78 (70–88) 0.015
Region, % ⬍0.001
Canada and America 62.1 67.2 46.2
Western Europe 20.3 16.6 31.8
Eastern Europe 2.5 1.6 5.3
Latin America 0.2 0.0 0.9
Australia 8.8 6.9 14.8
Other* 6.1 7.7 1.1
Clinical history, %
Current smoker 42.8 43.0 42.1 0.099
Hypertension 38.5 38.3 39.1 0.121
Diabetes 15.0 15.2 14.4 0.041
Hyperlipidemia 34.1 34.0 34.5 0.309
Family history of CHD 43.1 42.7 46.5 ⬍0.001
Recent chest pain 37.3 36.7 39.2 ⬍0.001
Previous CVD 2.1 2.1 2.4 0.010
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Previous CHF 2.1 2.0 2.3 0.022

Previous MI 16.7 16.4 17.5 0.004
Previous cardiac surgery 4.2 4.2 4.3 0.741
Previous PCI 4.3 4.2 4.4 0.409
Clinical presentation, %
Systolic BP 130 (114–146) 130 (113–145) 131 (117–150) ⬍0.001
Diastolic BP 80 (70–90) 80 (70–90) 80 (70–90) ⬍0.001
Entry heart rate 73 (62–86) 73 (62–86) 73 (62–86) 0.853
Killip class at entry ⬍0.001
I 86.1 86.4 84.9
II 12.1 11.8 13.1
III 1.2 1.2 1.5
IV 0.6 0.6 0.6
MI location by ECG ⬍0.001
Anterior 41.2 40.0 45.2
Inferior 55.6 56.9 51.5
Other 3.2 3.2 3.3
Symptom to treatment 2.8 (2.0–3.9) 2.8 (2.0–3.8) 2.8 (2.0–4.0) ⬍0.001
CHD indicates coronary heart disease; CVD, cardiovascular disease; CHF, congestive heart failure; PCI,
percutaneous coronary intervention; and BP, blood pressure. Values in parentheses are 95% CI.
*Other includes Israel and South Africa.

significant association between aspirin dose and the risk of
MI (OR, 1.00; 95% CI, 0.87 to 1.15) or stroke (OR, 1.14;
95% CI, 0.91 to 1.41). In addition, there was no association
between aspirin dose and the composite of death, MI, or
stroke at 7 days. At 30 days, mortality rates were higher in the
325-mg group compared with the 162-mg group (7.1 versus
6.5%; P⫽0.017). However, after adjustment for baseline
imbalances, there was no significant association between
aspirin dose and 30-day mortality.
Moderate or severe bleeding occurred in 11.5% of the
population (Table 4). In unadjusted analysis, there were fewer
moderate/severe bleeding episodes and blood transfusions in
 Berger et al Aspirin Dose in ST-Elevation Myocardial Infarction 195

Table 2. Procedural Characteristics

All Patients Aspirin 126 –162 mg Aspirin 163–330 mg
(n⫽48 422) (n⫽36 594) (n⫽11 828) P
Study drug administration, %
tPA 27.1 26.2 30.0 ⬍0.001
STK⫹IV heparin 18.6 21.9 8.6
STK⫹tPA 18.6 21.9 8.5
STK⫹SQ heparin 17.6 20.8 7.6
rPA 18.1 9.3 45.2
APTT
6h 97 (59–135) 100 (59–139) 90 (58–127) ⬍0.001
12 h 67 (47–100) 70 (48–106) 61 (46–89) ⬍0.001
24 h 56 (42–78) 58 (43–82) 51 (41–66) ⬍0.001
In-hospital medications, %
Aspirin subsequent dose
126–162 mg 37.9 39.0 34.4 ⬍0.001
163–330 mg 62.1 61.0 65.6 ⬍0.001
␤-Blocker 77.2 77.0 77.7 0.167
Lidocaine 39.5 44.2 25.0 ⬍0.001
Calcium channel blocker 28.2 29.6 23.5 ⬍0.001
ACE inhibitor 28.1 24.5 39.5 ⬍0.001
Digitalis 12.6 13.1 11.1 ⬍0.001
Procedures
Pacemaker, % 6.0 6.7 4.0 ⬍0.001
Swan Ganz catheter, % 10.4 11.5 7.1 ⬍0.001
Ventilator, % 9.7 10.5 7.2 ⬍0.001
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CABG, % 8.5 8.9 7.1 ⬍0.001

IABP, % 3.6 3.7 3.2 0.0114
Catheterization, % 53.2 55.4 46.4 ⬍0.001
Time to first catheterization, d 3.7 (1.8–5.9) 3.8 (1.8–5.9) 3.3 (1.6–5.7) ⬍0.001
IRA, % 0.0103
LAD 36.3 36.2 36.5
LCx 11.6 11.7 10.8
RCA 45.6 45.6 45.3
LM 0.4 0.4 0.3
Graft 1.7 1.6 2.6
Unknown 4.4 4.4 4.3
PCI, % 22.2 22.6 20.9 ⬍0.001
Time to first PCI, d 3.9 (1.8–6.3) 4.0 (1.9–6.3) 3.3 (1.2–6.0) ⬍0.001
tPA indicates tissue plasminogen activator; STK, streptokinase; SQ, subcutaneous; rPA, RNA protection assay;
APTT, activated partial thromboplastin time; ACE, angiotensin-converting enzyme; CABG, coronary artery bypass graft;
IABP, intraaortic balloon pump; IRA, infarct-related artery; LAD, left anterior descending artery; LCx, left circumflex
artery; RCA, right coronary artery; LM, left main artery; and PCI, percutaneous coronary intervention. Values in
parentheses are 95% CI.

the 325-mg group. However, using the previously validated
GUSTO I moderate- or severe-bleeding prediction model,15
325 mg was associated with an independent increase in the
risk of moderate or severe bleeding (OR, 1.14; 95% CI, 1.05
to 1.24) compared with 162 mg (Figure). When stratified by
clinical trial, the association between aspirin dose and mod-
erate or severe bleeding remained significant for both
GUSTO I (OR, 1.14; 95% CI, 1.02 to 1.27) and GUSTO III
(OR, 1.24; 95% CI, 1.06 to 1.44). In addition, increased risk
of moderate or severe bleeding in those receiving 325 mg
aspirin was similar between patients who did (OR, 1.11; 95%
CI, 0.99 to 1.24) and did not (OR, 1.12; 95% CI, 0.95 to 1.33)
undergo cardiac catheterization.
Discussion
There are 2 major findings of the current analyses. First, in the
acute setting of STEMI, there is no significant association
between initial aspirin dose (162 versus 325 mg) and risk of
 196 Circulation January 15, 2008

Table 3. Twenty-Four–Hour Adverse Events

All Patients 162 mg 325 mg Unadjusted OR Adjusted OR
Clinical Events (n⫽48 422) (n⫽36 594) (n⫽11 828) P (95% CI) (95% CI)
Death 2.8 2.8 2.9 0.894 1.01 (0.89–1.14) 1.01 (0.82–1.25)
MI 0.6 0.5 0.7 0.057 1.28 (0.99–1.66) 1.22 (0.89–1.67)
Stroke 0.7 0.7 0.9 0.017 1.33 (1.05–1.67) 1.16 (0.87–1.53)
Hemorrhagic 0.5 0.5 0.6 0.067 1.30 (0.98–1.72) 1.04 (0.75–1.45)
Nonhemorrhagic 0.2 0.1 0.2 0.034 1.68 (1.03–2.74) 1.68 (0.94–2.99)
Death/MI/stroke 4.0 3.9 4.2 0.111 1.09 (0.98–1.21) 1.05 (0.91–1.21)
Death or MI 3.5 3.4 3.6 0.362 1.05 (0.94–1.18) 1.04 (0.89–1.21)

death, MI, or stroke. Second, the initial dose of 325 mg is
associated with a significant increase in the risk of moderate or
severe bleeding compared with 162 mg in the initial treatment of
STEMI. Our data are consistent with prior aspirin studies that
have shown similar efficacy and increased bleeding risk with a
higher aspirin dose.8 The present study extends these findings
and demonstrates that even the initial dose of aspirin may have
clinical implications and therefore should not be overlooked.
Our study raises the hypothesis that lowering the initial dose of
aspirin from 325 to 162 mg may substantially lower the risk of
bleeding without loss of efficacy.
Aspirin Dose: Mechanism of Action
Aspirin irreversibly inhibits platelet cyclooxygenase-1, thereby
preventing the conversion of arachidonic acid to prostaglandin
H2, which, under normal circumstances, is then converted to
thromboxane (TX) A2 and other bioactive prostanoids.21 TXA2
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A wide range of aspirin doses have been evaluated to
determine the best way to achieve maximal antiplatelet activity
in the acute setting.24 –26 In a study that evaluated the acute effect
of 40-, 100-, 300-, and 500-mg doses of aspirin, the 100-, 300-,
and 500-mg doses were found to inhibit platelet aggregation at 2
hours, with no difference observed between the 100- and
300-mg doses.24 Serum TXB2 was significantly reduced 2 hours
after administration in each group, yet only 300 and 500 mg
exerted ⬎99% inhibition of TXB2 synthesis.24 In another study
comparing 81, 162, and 324 mg aspirin, maximal platelet
inhibition after 15 minutes was greatest in the 162- and 324-mg
groups.26 No significant difference in production of TXB2 was
noted between the 162- and 324-mg groups.26 Moreover, such a
dose-response relationship is substantially identical in healthy
subjects9 and in patients with atherosclerosis.10 For complete
inhibition of thromboxane synthesis, Patrono et al23 suggested a

is synthesized and released by platelets and acts as a platelet
aggregator and vasoconstrictor.22 By preventing TXA2 forma-
tion, aspirin irreversibly blocks platelet function. At higher
doses, aspirin suppresses vascular endothelial cell production of
prostacyclin,23 which, if unopposed, results in inhibition of
platelet aggregation and induces vasodilation.
loading dose of at least 120 mg.
Aspirin Dose and Efficacy
The ideal dose of aspirin for the prevention of vascular events
has been the subject of much debate.1–3,8 Direct comparison of
aspirin dose has been evaluated in a small number of random-

1.4
Adjuated Odds Ratio

1.2

0.8

0.6
Death MI Stroke Death/ M I/ Stroke M oderate/ Blood Transfusion
Severe Bleeding
Figure. Adjusted OR for 7-day events of those who received 325 mg (versus 162 mg) aspirin for the initial treatment of STEMI. Bleed-
ing and blood transfusion are recorded as in-hospital results.
 Berger et al Aspirin Dose in ST-Elevation Myocardial Infarction 197

Table 4. In-Hospital, 7-Day, and 30-Day Adverse Events

All Patients Aspirin 162 mg Aspirin 325 mg Unadjusted OR Adjusted OR
(n⫽48 422) (n⫽36 594) (n⫽11 828) P (95% CI) (95% CI)
At 7 d
Death 5.0 4.9 5.2 0.118 1.08 (0.98–1.18) 1.00 (0.86–1.17)
MI 3.1 3.1 3.2 0.650 1.03 (0.91–1.16) 1.0 (0.87–1.15)
Stroke 1.2 1.2 1.4 0.0528 1.20 (1.0–1.43) 1.14 (0.91–1.41)
Hemorrhagic 0.67 0.65 0.76 0.1807 1.18 (0.93–1.51) 0.96 (0.72–1.29)
Nonhemorrhagic 0.41 0.38 0.51 0.0663 1.32 (0.98–1.80) 1.54 (1.08–2.20)
Death/MI/stroke 8.4 8.4 8.6 0.403 1.03 (0.96–1.11) 1.0 (0.91–1.10)
Death or MI 7.7 7.7 7.8 0.570 1.02 (0.95–1.11) 0.99 (0.90–1.10)
In hospital
Severe bleeding 1.2 1.2 1.1 0.328 0.91 (0.74–1.10) 1.08 (0.85–1.38)
Moderate bleeding 10.3 11.0 8.3 ⬍0.001 0.73 (0.68–0.79) 1.15 (1.05–1.26)
Moderate/severe bleeding 11.5 12.2 9.3 ⬍0.001 0.74 (0.69–0.79) 1.14 (1.05–1.24)
Blood transfusion 9.4 10.0 7.5 ⬍0.001 0.74 (0.68–0.79) 1.09 (0.99–1.20)
At 30 days
Death 6.7 6.5 7.1 0.017 1.10 (1.02–1.20) 0.99 (0.87–1.12)

ized trials.11,27–31 After a transient ischemic attack or stroke, no
difference in efficacy was noted between 300 and 1200 mg28 or
between 30 and 283 mg.27 The Acetylsalicylic Acid and Carotid
Endarterectomy (ACE) trial reported that the risk of stroke, MI,
or death within 3 months of undergoing a carotid endarterecto-
my is significantly lower for patients receiving 81 or 325 mg
aspirin daily than for those receiving 650 or 1300 mg.31 In the
largest investigation to date, which compiled data from ⬎250
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Aspirin Dose and Safety
The major risk of aspirin therapy is the risk of bleeding, and
there is considerable evidence that the side effects of aspirin
are dose dependent.3,8,38,39 A UK study group found that
patients with higher aspirin dose were more likely to have
both gastrointestinal tract symptoms and gastrointestinal
hemorrhage.28 In the Dutch TIA trial,27 risk of bleeding was

higher in patients receiving 283 mg compared with those

antiplatelet trials, the Antiplatelet Trialists’ Collaboration (ATC)
demonstrated that when aspirin use was divided into dosage
categories of 75 to 150, 160 to 325, and ⬎500 mg, the reduction
in vascular events was 32%, 26%, and 19%, respectively.1,2
Although not significant, the protective effect of aspirin de-
creased with higher doses. A more recent examination of the
ATC data in patients with acute coronary syndrome showed a
greater benefit at lower doses compared with higher doses32 in a
nonrandomized comparison. This potential inverse relationship
between aspirin dose and cardiovascular efficacy may reflect the
progressive inhibition of prostacyclin, similar to cyclooxygen-
ase-2 inhibitors, thereby inducing platelet aggregation and
vasoconstriction.23,33
There has been only 1 single randomized study11 that directly
compared aspirin dose in STEMI. The Duke University Clinical
Cardiology Group Study-II (DUCCS-II) compared the efficacy
of 81- and 325-mg aspirin doses in 162 patients with STEMI
treated with front-loaded tissue plasminogen activator or anisoy-
lated plasminogen streptokinase activator complex.11 No effect
of aspirin dose on clinical outcomes was noted; however,
because of its early termination, the study was severely under-
powered to do so. The majority of data supporting the use of
aspirin in the acute setting of a myocardial are from ISIS-2.4 In
this study, 162.5 mg aspirin reduced vascular mortality, reinfarc-
tion, and stroke without substantially increasing the risk of major
bleeding.4 Other studies of aspirin in the acute setting of
myocardial infarction have been severely underpowered to
address the clinical efficacy and safety profile of aspirin in this
setting.34 –37
receiving 30 mg. Observational data from the Clopidogrel in
Unstable Angina to Prevent Recurrent Events (CURE) inves-
tigators40 noted increased bleeding risks with increasing
aspirin dose (⬍100 mg, 1.9%; 101 to 199 mg, 2.8%; ⬎200
mg, 3.7%; P⫽0.0001). In a recent analysis of 31 randomized
controlled trials, major, minor, gastrointestinal, and fatal
bleeding all increased with increased aspirin dose.41
Our analysis extends the importance of aspirin dose and
risk of bleeding to the initial dose. The reason for this
increased risk after a single dose is not entirely clear. Aspirin
is rapidly absorbed in the upper gastrointestinal tract and
results in a measurable inhibition of platelet function within
60 minutes.42 This antiplatelet effect occurs even before
acetylsalicylic acid is detectable in the peripheral blood
owing to the exposure of platelets to aspirin in the portal
circulation.42 The plasma half-life of aspirin is only 20
minutes; however, because platelets cannot generate new
cyclooxygenase, the effects of aspirin last for the duration of
the life of the platelet (⬇10 days).3 Whereas platelet
thromboxane synthesis is blocked completely with a single
dose of 100 mg, higher doses would be expected to inhibit
cyclooxygenase-2– dependent thromboxane synthesis in vas-
cular endothelium, monocytes, and macrophages.3,42 This
could contribute to the impairment of hemostasis in patients
using higher doses of aspirin. Another explanation for the
increase in bleeding is the aspirin-dose–induced loss of the
cytoprotective effects of prostaglandin E2 on the gastric
mucosa.3 Consistent with this, it is imperative to examine the
absolute thrombotic versus hemorrhagic risk of the individual
 198 Circulation January 15, 2008
patient and to determine the lowest effective dose of aspirin
in each clinical setting.
Study Limitations
There are several limitations to our study. First, our study was
a post hoc analysis of prospectively collected data within the
context of 2 clinical trials. As such, the dose of aspirin was
not prescribed by the study protocol, nor was it randomized.
In general, treatment effects cannot be reliably estimated by
observational studies, even when good adjustment models are
available. However, the data with respect to both efficacy and
safety are mechanistically consistent. Second, we could not
explore the indications for a specific aspirin dose. Neverthe-
less, the main determinant of the dose used in patients in
GUSTO I and GUSTO III 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, trial differ-
ences and 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 fibrinolytics and other
antithrombotics, and stratification by clinical trial and region,
a dose response between aspirin and bleeding complications
is still observed. Fourth, it was unknown whether the patient
was on aspirin before the infarction. Finally, GUSTO I and III
were performed 10 to 15 years ago, before clopidogrel and
Downloaded from http://ahajournals.org by on June 14, 2022
glycoprotein IIb/IIIa use, which may limit the generalizability
of the results. Nevertheless, with the current use of dual and
triple antiplatelet therapy in STEMI, great focus remains on
minimizing bleeding risk.
Conclusions
This analysis of ⬇50 000 patients with STEMI receiving
fibrinolytic therapy from GUSTO I and III demonstrated that
the initial dose of aspirin is significantly (and independently)
associated with patient outcome. Specifically, a single initial
dose of 325 mg was associated with a significant increase in
the risk of moderate or severe in-hospital bleeding compared
with 162 mg. Aspirin dose, however, was not significantly
associated with a difference in the incidence of death, MI, or
stroke. Although these data are nonrandomized, they suggest
that for the first dose of aspirin, 162 mg may be as effective
as and safer than 325 mg for the acute treatment of STEMI.
This higher associated bleeding risk reinforces the impor-
tance of finding the lowest effective aspirin dose as an
important goal in each clinical setting.
Source of Funding
This was an investigator-initiated unfunded study. Dr Berger is
funded by an American Heart Association Fellow to Faculty Award
(0775074N).
Disclosures
None.
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CLINICAL PERSPECTIVE
The International Study of Infarct Survival (ISIS-2) trial demonstrated that treatment with 162.5 mg aspirin reduces
morbidity and mortality in ST-elevation myocardial infarction (STEMI). On the basis of these data, the American College
of Cardiology, American Heart Association, and European Society of Cardiology gave a class I level of evidence A to
immediate use of 162 mg of aspirin. Nevertheless, the most common initial dose of aspirin in the immediate setting of
STEMI is 325 mg (class I level of evidence C). Given the uncertainty of immediate aspirin dose, we performed a
retrospective analysis of 2 large STEMI fibrinolytic trials (Global Utilization of Streptokinase and Tissue Plasminogen
Activator for Occluded Coronary Arteries [GUSTO I] and Global Use of Strategies to Open Occluded Coronary Arteries
[GUSTO III]) to assess the relationship between aspirin dose (162 versus 325 mg) and short-term outcomes after STEMI.
We demonstrated no significant association between initial aspirin dose (162 versus 325 mg) and risk of death, myocardial
infarction, or stroke. However, the initial dose of 325 mg was associated with a significant increase in the risk of moderate
or severe bleeding compared with 162 mg. Although these data are nonrandomized, they suggest that for the first dose of
aspirin, 162 mg may be as effective as and safer than 325 mg for the acute treatment of STEMI. Until future randomized
data are provided to support the use of 325 mg in the setting of STEMI, it may be worthwhile to use 162 mg, a dose
previously established to lessen cardiovascular morbidity and mortality in this setting.