Published online before print August 14, 2006, doi: 10.1161/CIRCULATIONAHA.106.612812
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(Circulation. 2006;114:774-782.)
© 2006 American Heart Association, Inc.
Coronary Heart Disease |
Adverse Impact of Bleeding on Prognosis in Patients With Acute Coronary Syndromes
From the Thrombosis Service (J.W.E.) and Population Health Research Institute (J.W.E., S.R.M., S.S.A., C.X., S.Y.), Hamilton Health Sciences, Hamilton, Canada; Department of Medicine, McMaster University, Hamilton, Ontario, Canada (J.W.E., S.R.M., S.S.A., S.Y.); and University and the Royal Infirmary of Edinburgh, Edinburgh, Scotland, UK (K.A.A.F.).
Correspondence to John Eikelboom, Thrombosis Service, Hamilton General Hospital, 237 Barton St East, Hamilton, Ontario L8L 2X2, Canada. E-mail eikelbj{at}mcmaster.ca
Received January 7, 2006; revision received June 21, 2006; accepted June 22, 2006.
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Abstract |
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Background— The use of multiple antithrombotic drugs and aggressive invasive strategies has increased the risk of major bleeding in acute coronary syndrome (ACS) patients. It is not known to what extent bleeding determines clinical outcome.
Methods and Results— Using Cox proportional-hazards modeling, we examined the association between bleeding and death or ischemic events in 34 146 patients with ACS enrolled in the Organization to Assess Ischemic Syndromes and the Clopidogrel in Unstable Angina to Prevent Recurrent Events studies. Patients with major bleeding were older, more often had diabetes or a history of stroke, had a lower blood pressure and higher serum creatinine, more often had ST-segment changes on the presenting ECG, and had a 5-fold-higher incidence of death during the first 30 days (12.8% versus 2.5%; P<0.0001) and a 1.5-fold-higher incidence of death between 30 days and 6 months (4.6% versus 2.9%; P=0.002). Major bleeding was independently associated with an increased hazard of death during the first 30 days (hazard ratio, 5.37; 95% CI, 3.97 to 7.26; P<0.0001), but the hazard was much weaker after 30 days (hazard ratio, 1.54; 95% CI, 1.01 to 2.36; P=0.047). The association was consistent across subgroups according to cointerventions during hospitalization, and there was an increasing risk of death with increasing severity of bleeding (minor less than major less than life-threatening; P for trend=0.0009). A similar association was evident between major bleeding and ischemic events, including myocardial infarction and stroke.
Conclusions— In ACS patients without persistent ST-segment elevation, there is a strong, consistent, temporal, and dose-related association between bleeding and death. These data should lead to greater awareness of the prognostic importance of bleeding in ACS and should prompt evaluation of strategies to reduce bleeding and thereby improve clinical outcomes.
Key Words: acute coronary syndrome • bleeding • death • prognosis
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Introduction |
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Antithrombotic drugs and revascularization procedures are effective for preventing recurrent ischemic events or death in patients with acute coronary syndromes.1–6 However, they also increase the risk of bleeding, especially among older patients, those treated with multiple antithrombotic drugs, and patients undergoing early revascularization.7–9 In some high-risk subgroups, the reported incidence of major bleeding during hospitalization is as high as 5%,10,11 approximating the incidence of refractory ischemia, myocardial infarction (MI), or death. Determining the appropriate balance between preventing ischemic events and causing bleeding in these patients presents a challenging problem for clinicians.
Clinical Perspective p 782
Reliable information on the incidence and prognosis of recurrent ischemic events is available from large international registries and randomized trials of patients with acute coronary syndromes.12–14 However, the prognosis of major bleeding is less certain because individual randomized trials generally lack the statistical power to clarify the association between major bleeding and death or ischemic events. Registry data and pooled data from randomized trials have suggested that bleeding and transfusion in patients with acute coronary syndromes are associated with worse clinical outcomes, but the data are conflicting.15–19 Clinicians meanwhile tend to favor the use of treatments that prevent ischemia, even if the treatments cause major bleeding, because recurrent ischemia increases the risk of death,12 whereas major bleeding is perceived as a reversible event that is not associated with permanent adverse sequelae and can readily be treated in most patients by stopping antithrombotic therapy and transfusing red cells as required.
To further explore the prognostic importance of major bleeding in patients presenting with acute coronary syndromes, we analyzed individual patient data from >30 000 patients enrolled in 3 large studies: the Organization to Assess Ischemic Syndromes (OASIS) Registry,20–22 OASIS-2,23 and the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE)2 randomized trials.
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Methods |
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We combined individual patient data from the OASIS Registry,20–22 OASIS-2,23 and CURE2 into a single database of 34 146 patients with acute coronary syndromes. Details of these studies have been published elsewhere. Each study was approved by the relevant local research ethics boards, and all patients provided informed consent. The OASIS-1 and -2 registries prospectively enrolled &11 500 patients with acute coronary syndrome without persistent ST-segment elevation from 12 countries in North America, South America, Europe, Asia, and Australasia. Baseline characteristics, interventions, and outcomes were recorded in hospital and at 6 months.20–22 OASIS-2 was an international, double-blind, randomized trial of 10 141 patients with acute coronary syndromes without ST elevation who were randomized within 12 hours of symptom onset to receive intravenous unfractionated heparin or hirudin.23 Patients with contraindications to unfractionated heparin or hirudin, with renal impairment (ie, creatinine >175 µmol/L or >2.0 mg/dL), or judged by the local investigator to be at high risk of bleeding complications or to have significant thrombocytopenia were excluded.23 CURE was an international, double-blind, randomized trial of 12 562 patients with acute coronary syndrome without persistent ST elevation who were randomized within 24 hours of symptom onset to receive clopidogrel 300 mg immediately, followed by 75 mg once daily (6259 patients) or placebo (6303 patients) in addition to aspirin for 3 to 12 months.2 Patients at high risk of bleeding, with a contraindication to anticoagulant or antiplatelet therapy, requiring long-term oral anticoagulation, or who underwent coronary revascularization within the previous 3 months were not eligible for inclusion.2
Definitions
Major bleeding was defined in the same way in each study as bleeding that was significantly disabling, bleeding requiring transfusion of 
2 units of packed cells, or bleeding that was life-threatening. Life-threatening bleeding was defined as bleeding that was fatal; bleeding that was intracranial; bleeding that led to a reduction in the hemoglobin level of at least 5 g/dL or led to substantial hypotension requiring the use of intravenous inotropic agents; bleeding that required surgical intervention; or bleeding that necessitated the transfusion of 4 units of blood. All other bleeding was defined as minor. Minor bleeding was not reported in the OASIS Registry20–22 and was reported only during the first 7 days in the OASIS-2 study.23 MI was defined in the OASIS Registry20–22 and OASIS-2 trial23 as recurrent typical symptoms with either new ECG or enzyme changes if occurring within 24 hours of randomization or at least 2 of the following: pain, ECG changes, or an increase in enzymes if occurring >24 hours after randomization. In the CURE trial,2 2 of the 3 criteria were required regardless of timing. Stroke was defined as a new focal neurological deficit of vascular origin lasting >24 hours and, when possible, was further classified on the basis of CT or MRI as ischemic, hemorrhagic, or of uncertain cause. We counted hemorrhagic strokes as life-threatening bleeds and did not include them in the stroke analyses.
Outcomes
Our primary outcome was death during the first 30 days. We also examined MI and stroke outcomes in patients with major bleeding. Outcomes were examined during the first 30 days and were examined separately beyond 30 days (between 30 days and 6 months) after the exclusion of outcomes that occurred during the first 30 days or within 30 days of major bleeding.
We examined the consistency of the association between major bleeding and outcomes among key subgroups according to those with a low (below the median) and high (equal to or above the median) propensity for major bleeding and in subgroups according to cointervention received (aspirin, clopidogrel, unfractionated heparin, low-molecular-weight heparin, hirudin, oral anticoagulants).
We explored the dose relation between bleeding and death by comparing the association with minor, major (excluding life-threatening), and life-threatening bleeding and death. This analysis was performed using outcomes that occurred during the first 30 days in the CURE trial because CURE was the only study included in our analyses that reported minor bleeding beyond day 7 and outcomes that occurred during the first 7 days in the combined OASIS-2 and CURE datasets.
Statistical Analysis
All analyses were performed with SAS software, version 9.1 (SAS Institute Inc, Cary, NC). Baseline characteristics among patients who developed a major bleed compared with those who did not develop a major bleed were compared by use of a 
2 test for categorical variables and a t test for continuous variables. A time-to-event analysis was used to illustrate survival among patients who did or did not develop major bleeding during the first 30 days and between 30 days and 6 months after exclusion of those who died during the first 30 days or within 30 days of major bleeding.
Modeling of Outcomes
The association between bleeding and outcome is potentially confounded by baseline patient characteristics and cointerventions, including the use of antithrombotic therapies and invasive procedures, which can affect bleeding outcomes, ischemic outcomes, and death. To control for these potential biases, we developed several statistical models. For each model, we prespecified baseline characteristics and cointerventions believed to be associated with the outcome of interest on the basis of biology, pharmacology, and clinical experience. We included only cointerventions that were used before major bleeding and outcomes that occurred after major bleeding. The first model examined independent baseline predictors of major bleeding using logistic regression, incorporating baseline characteristics as independent variables and major bleeding as the dependent variable. The second model examined independent predictors of death using logistic regression, incorporating baseline characteristics as independent variables and death as the dependent variable. The third model examined a patient’s propensity for major bleeding using logistic regression and incorporating both baseline characteristics and cointerventions known to be associated with major bleeding as independent variables and major bleeding as the dependent variable. The final model examined the association between major bleeding and death using Cox regression after formally testing the assumption of proportionality. Major bleeding was incorporated as a time-dependent covariate to account for survival bias and for the possibility that timing of major bleeding relative to an outcome may be important (eg, bleeding that occurs after a nonfatal outcome). The model was adjusted for the propensity for major bleeding and baseline variables. A similar model was used to examine the association between major bleeding and MI or stroke. A 2-sided value of P<0.05 was considered statistically significant.
The authors had full access to the data and take responsibility for their integrity. All authors have read and agree to the manuscript as written.
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Results |
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Our analysis included a total of 34 126 patients with acute coronary syndrome; 783 (2.3%) developed major bleeding during the respective study follow-up periods and 667 (2.0%) developed major bleeding during the first 6 months (Figure 1).
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Baseline Characteristics
The baseline characteristics of patients who developed major bleeding compared with those who did not develop major bleeding are presented in Table 1. Compared with those who did not develop major bleeding, patients who developed major bleeding were older, more often had diabetes or a history of stroke, had lower systolic and diastolic blood pressures and a higher serum creatinine, and more often had ST-segment changes on the presenting ECG.
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Cointerventions
Cointerventions used in patients who developed major bleeding compared with those who did not develop major bleeding are presented in Table 1. Compared with those who did not develop major bleeding, patients who developed major bleeding were more often treated during hospitalization with a glycoprotein IIb/IIIa inhibitor, unfractionated heparin, low-molecular-weight heparin, or fibrinolysis and more often underwent coronary angiography, coronary artery bypass graft surgery, or an intra-aortic balloon pump insertion. They also were more likely to be treated with oral anticoagulants during hospitalization or after discharge.
Independent Baseline Predictors of Major Bleeding and Death and Propensity for Major Bleeding
Independent baseline predictors of major bleeding and death are presented in Table 2, and variables included in the propensity model for major bleeding are presented in Table 3. The C statistic for the propensity model was 0.70.
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Outcomes
Figure 2 presents Kaplan-Meier curves for mortality during the first 30 days for patients who developed major bleeding and those who did not develop major bleeding. Figure 3 presents the curves for mortality between 30 days and 6 months after the exclusion of deaths that occurred within 30 days of entry into the study or within 30 days of major bleeding.
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The results of Cox regression analysis, unadjusted, adjusted for independent baseline predictors, and adjusted for both independent baseline predictors and propensity for major bleeding, are presented in Table 4. The incidence of death during the first 30 days was higher among those who developed major bleeding compared with those who did not (12.8% versus 2.5%; P<0.0001). Compared with during the first 30 days, death after major bleeding was much less common between 30 days and 6 months after the exclusion of deaths that occurred within 30 days of major bleeding (4.6% versus 2.9%; P=0.002). The hazard for death among those with major bleeding was significantly increased during the first 30 days (adjusted hazard ratio [HR], 5.37; 95% CI, 3.97 to 7.26; P<0.0001) but was much weaker between 30 days and 6 months after the exclusion of deaths that occurred during the first 30 days or within 30 days of bleeding (HR, 1.54; 95% CI, 1.01 to 2.36; P=0.047). A similar pattern was evident for MI and stroke (Table 4). Stratification of the analyses according to study did not meaningfully alter the results of our analyses (results not presented).
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Our results were consistent among a range of patient subgroups, including those with a high or low propensity for major bleeding, as well as among those patients treated with aspirin, clopidogrel, unfractionated heparin, low-molecular-weight heparin, hirudin, or oral anticoagulants (data not shown).
In analyses confined to 30-day outcomes in the CURE study dataset and separately for 7-day outcomes in the combined OASIS-2 and CURE datasets, there was evidence of a "dose relation" in the association between severity of bleeding and death, with increasing bleeding severity (minor less than major [excluding life-threatening] less than life-threatening) associated with increasing risk of death (Figure 4 and Table 5). The association between bleeding and death in the CURE dataset remained evident after adjustment for body mass index, biomarker positivity at baseline, and the occurrence of heart failure during hospitalization.
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Discussion |
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Our results indicate that major bleeding in patients with acute coronary syndromes is associated with a 5-fold increase in risk of death. Approximately 1 in 10 patients who develop major bleeding during the first 30 days after hospitalization/randomization is dead at 30 days compared with 1 in 40 of those who do not develop major bleeding during the first 30 days.
The increase in hazard of death among patients who develop major bleeding remains evident after adjustment for baseline characteristics, timing of death in relation to the bleed, and propensity to develop major bleeding; is greatest during the first 30 days; and is markedly reduced if patients survive at least 30 days after a major bleed. Furthermore, there is a dose relation between severity of bleeding and death, with increasing severity of bleeding associated with an increasing risk of death (minor less than major [excluding life-threatening] less than life-threatening bleeding). The association between bleeding and death also is evident across a broad range of patient subgroups, regardless of their propensity for major bleeding or cointerventions. Thus, the association between major bleeding and death appears to be strong, consistent, temporal, and dose related (higher risk of death in those with more severe degrees of bleeding). Taken together, this is consistent with the conclusion that bleeding independently predicts death.
Major bleeding also is associated with an increased risk of recurrent ischemic events, including MI and stroke, and this association remains evident after adjustment for baseline differences and major bleeding propensity. Approximately 1 in 5 patients who develop major bleeding during the first 30 days experiences death, MI, or stroke by 30 days compared with 1 in 20 of those who do not develop major bleeding during the first 30 days. Like death, the association between major bleeding and both MI and stroke is strong and consistent, but the association is no longer evident between 30 days and 6 months after the exclusion of events that occur during the first 30 days or within 30 days of bleeding, indicating a temporal relation.
The association between major bleeding and death, MI, or stroke is biologically plausible. Major bleeding is likely to lead clinicians to discontinue effective antithrombotic drugs such as aspirin, clopidogrel, heparin, low-molecular-weight heparin, and warfarin, which in turn could increase the risk of MI, stroke, and cardiovascular death. This is consistent with our findings that &1 in 3 patients who died after major bleeding experienced MI before death. Bleeding also may reduce oxygen delivery to the myocardium as a result of hypoperfusion or reduced oxygen carrying capacity as a result of lower blood hemoglobin levels24; in addition, bleeding may result in platelet activation, which is associated with an increased risk of recurrent ischemic events.
It is possible that the relation between bleeding and death or ischemic events observed in our study is mediated, at least in part, by an adverse effect of transfusion.25 Stored red cells are depleted of intracellular 2,3 diphosphoglycerate, thereby increasing the affinity of hemoglobin for oxygen and pulling oxygen out of tissues and away from normal red blood cells.26 Stored red cells also are depleted in nitric oxide and therefore may act as a nitric oxide sink, resulting in vasoconstriction and reduced oxygen carriage of the blood.27 The hypothesis that transfusion causes adverse outcomes is consistent with the findings of Rao and colleagues,17 who demonstrated a significant association between transfusion and hazard of death at 30 days (HR, 3.94; 95% CI, 3.26 to 4.75) among 24 112 patients with acute coronary syndrome without persistent ST elevation. However, the decision to transfuse also is determined by the availability of blood, patient and physician preferences, arbitrary transfusion triggers that may differ across institutions, and the presence of other comorbidities (eg, cardiac failure, chronic respiratory disease). Wu and colleagues18 reported that blood transfusion was associated with a lower mortality rate in elderly patients with MI if the admission hematocrit was 
30%; others have suggested that blood transfusion at best is neutral with respect to survival and at worst is associated with decreased survival.28–31
The strengths of our study are that we analyzed individual patient data from a large dataset involving >30 000 patients, of whom >700 developed major bleeding. A uniform definition of major bleeding was used in all the studies, and the association between major bleeding and death or ischemic events was robust, remaining evident after adjustment for baseline characteristics, propensity for bleeding, and inclusion of major bleeding as a time-dependent variable.
The limitations of our study must be considered. First, although randomization represents the strongest level of evidence for association, it is not possible to explore the association between bleeding and outcome in a randomized trial because patients cannot be randomly assigned to experience major bleeding. However, this also means that the next most reliable source of evidence concerning the association between major bleeding and clinical outcomes derives from observational analyses, as performed here. Second, it is possible that some of the deaths that occurred in patients with major bleeding were a direct consequence of bleeding and thus are evidence of "association by definition." However, the independent and graded association between bleeding and death observed in our study remained evident after the exclusion of life-threatening bleeding and deaths that occurred within 3 days or within 7 days of major bleeding; an association also was evident between minor bleeding and death. We also demonstrated that approximately one third of the patients who died after major bleeding experienced MI in the time period between bleeding and death and that major bleeding was independently associated with ischemic events, including MI and stroke. These data provide clear evidence that association by definition cannot account for our findings. Third, we were unable to examine the effect of the direct consequences of bleeding (eg, hypotension) or discontinuation of antithrombotic therapy after bleeding on outcome because these data were not reported. Fourth, more than one half of the patients included in our analysis were participating in a clinical trial in which patients were intentionally excluded if they were at increased risk of bleeding. In everyday clinical practice, patients may be at greater risk of major bleeding and ischemic events. However, the incidence of ischemic events and death was similar among the studies included in our analyses, and stratification by study did not meaningfully alter the results. Finally, although our data yield robust estimates of relative risk, extrapolating these data to individual patients who present with an acute coronary syndrome remains challenging because most patients do not develop major bleeding and the absolute risk of death attributable to major bleeding is very low (<1% in most patients). Nevertheless, given that overall 30-day mortality is only 4% or 5% in acute coronary syndromes, a 1% rate of death after a bleed (especially if this is potentially reversible or avoidable) represents a substantial risk.
The immediate implications of our results for clinical practice are that bleeding should be considered a marker for increased risk of death and ischemic events even when the severity of the bleed does not indicate that it is life-threatening. Strategies must be developed to minimize the risk of bleeding, eg, by avoiding excessive doses of antithrombotic therapies in patients with acute coronary syndromes, particularly those at increased risk of bleeding.8 Early resumption of effective antithrombotic therapies that were discontinued at the time of bleeding also may help to reduce the risk of subsequent ischemic events and death. However, this may be difficult in patients with recent major bleeding, and there are no data to guide clinicians as to the best approach in this setting.
Our results also have important research implications. Commonly used definitions for bleeding classify only the most serious bleeds as major or life-threatening and may underestimate the true impact of major bleeding on outcome.32 Future trial design should adopt definitions of bleeding that include all bleeding events associated with clinically important outcomes. Furthermore, the timing of primary outcomes should include the time period during which adverse events possibly attributable to major bleeding may occur. Tools must be developed to stratify individual patients according to their risk of bleeding so that harm is reduced and optimal use is made of the large number of effective antithrombotic strategies currently available. Finally, the potential adverse effect of transfusion must be further explored and treatment strategies must be developed to limit the risk of death and ischemic events after major bleeding.
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Acknowledgments |
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Sources of Funding
Dr Eikelboom holds a Tier II Canada Research Chair in Cardiovascular Medicine from the Canadian Institutes of Health Research. Dr Mehta holds a New Investigator Award from the Canadian Institutes of Health Research. Dr Anand holds a Canadian Institutes of Health Research Clinician–Scientist Phase-2 award. Professor Yusuf holds a Heart and Stroke Foundation of Ontario Research Chair. The OASIS registries were supported by Behringwerke (Germany) and DuPont Pharmaceuticals (United States). The OASIS-2 study was funded by Hoechst Marion Roussel (Germany) with additional support from DuPont Pharmaceuticals and the Medical Research Council of Canada. The CURE study was funded by Sanofi-Synthelabo and Bristol-Myers Squibb. No funding was received for the preparation of this manuscript.
Disclosures
None.
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CLINICAL PERSPECTIVE
Antithrombotic drugs and revascularization procedures are effective for preventing recurrent ischemic events or death in patients with acute coronary syndromes, but they increase the risk of bleeding. In the past, clinicians have discounted bleeding complications in patients with acute coronary syndromes, reasoning that ischemic events cause irreversible complications, whereas even severe bleeding is rarely associated with permanent morbidity. Using Cox proportional-hazards modeling, we explored the association between bleeding and death or ischemic events in 34 146 patients with acute coronary syndromes enrolled in the Organization to Assess Ischemic Syndromes and the Clopidogrel in Unstable Angina to Prevent Recurrent Events studies. Patients with major bleeding were older, more often had diabetes or a history of stroke, had a lower blood pressure and higher serum creatinine, more often had ST-segment changes on the presenting ECG, and had >5-fold-higher incidence of death during the first 30 days. The association between bleeding and death was independent of baseline characteristics and cointerventions, and there was an increasing risk of death with increasing severity of bleeding. Bleeding also was independently associated with an increased risk of ischemic events, including myocardial infarction and stroke. Our data should lead to greater awareness of the prognostic importance of bleeding in acute coronary syndromes and should prompt evaluation of strategies to reduce bleeding and thereby improve clinical outcomes.
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