Published online before print December 17, 2007, doi: 10.1161/CIRCULATIONAHA.107.729558
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(Circulation. 2008;117:192-199.)
© 2008 American Heart Association, Inc.
Health Services and Outcomes Research |
Initial Aspirin Dose and Outcome Among ST-Elevation Myocardial Infarction Patients Treated With Fibrinolytic Therapy
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.).
Correspondence to Jeffrey S. Berger, MD, MS, Department of Cardiovascular Medicine, Duke University Medical Center, PO Box 31007, Durham, NC 27710. E-mail berge026{at}mc.duke.edu
Received July 31, 2007; accepted October 19, 2007.
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Abstract |
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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).
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.
Key Words: aspirin • death • hemorrhage • myocardial infarction • prognosis
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Introduction |
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Aspirin therapy is a cornerstone in the immediate treatment 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 nonfatal 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 Cardiology 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 Experimentally, 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 aggregation.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 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 retrospective 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.
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Methods |
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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 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 composite 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 bleeding,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 assessed 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.
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Results |
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Information on immediate aspirin dose and short-term outcomes was available for 48 422 patients (86%). An immediate 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).
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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 association 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 association 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.
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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 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.
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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 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 moderate 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.
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Discussion |
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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 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 is synthesized and released by platelets and acts as a platelet aggregator and vasoconstrictor.22 By preventing TXA2 formation, 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.
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 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 randomized 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 endarterectomy 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 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 decreased 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 cyclooxygenase-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 anisoylated 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 underpowered 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, reinfarction, 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
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 receiving 30 mg. Observational data from the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) investigators40 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 vascular 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 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. Nevertheless, 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 differences 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 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 importance of finding the lowest effective aspirin dose as an important goal in each clinical setting.
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Acknowledgments |
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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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Guest Editor for this article was James T. Willerson, MD.
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