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J Am Coll Cardiol, 2007; 49:1362-1368, doi:10.1016/j.jacc.2007.02.027 (Published online 8 March 2007).
© 2007 by the American College of Cardiology Foundation
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EXPEDITED REVIEW

Impact of Major Bleeding on 30-Day Mortality and Clinical Outcomes in Patients With Acute Coronary Syndromes

An Analysis From the ACUITY Trial

Steven V. Manoukian, MD, FACC*,*, Frederick Feit, MD, FACC{dagger}, Roxana Mehran, MD, FACC{ddagger}, Michele D. Voeltz, MD*, Ramin Ebrahimi, MD, FACC§, Martial Hamon, MD||, George D. Dangas, MD, PhD, FACC{ddagger}, A. Michael Lincoff, MD, FACC, Harvey D. White, DSc, FACC#, Jeffrey W. Moses, MD, FACC{ddagger}, Spencer B. King, III, MD, MACC**, E. Magnus Ohman, MD, FACC{dagger}{dagger} and Gregg W. Stone, MD, FACC{ddagger}

* Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
** Fuqua Heart Center, Atlanta, Georgia
{dagger} Department of Medicine, New York University School of Medicine, New York, New York
{ddagger} Department of Medicine, Columbia University Medical Center and the Cardiovascular Research Foundation, New York, New York
§ Department of Medicine, University of California Los Angeles, Los Angeles, California
|| Service des Maladies du Coeur et des Vaisseaux, Centre Hospitalier Universitaire de Caen, Caen, France
Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, Ohio
# Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, New Zealand
{dagger}{dagger} Department of Medicine, Duke University School of Medicine, Durham, North Carolina.

Manuscript received February 10, 2007; revised manuscript received February 26, 2007, accepted February 26, 2007.

* Reprint requests and correspondence: Dr. Steven V. Manoukian, Emory University School of Medicine, Emory Crawford Long Hospital, 550 Peachtree Street, MOT, 6th Floor, Cardiology, Atlanta, Georgia 30308. (Email: steven.manoukian{at}emory.edu).


   Abstract
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Methods
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 Discussion
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 References
 
Objectives: The purpose of this study was to determine the predictors of major bleeding and the impact of major bleeding on outcomes, including mortality, in acute coronary syndromes (ACS).

Background: Whether major bleeding independently predicts mortality in patients with ACS undergoing an early invasive strategy is undefined.

Methods: Patients (n = 13,819) with moderate- and high-risk ACS were randomized to heparin (unfractionated or enoxaparin) plus glycoprotein IIb/IIIa inhibition (GPI), bivalirudin plus GPI, or bivalirudin monotherapy (plus provisional GPI). Logistic regression was used to determine predictors of 30-day major bleeding and mortality.

Results: Major bleeding rates in patients treated with heparin plus GPI were higher versus bivalirudin monotherapy (5.7% vs. 3.0%, p < 0.001) and similar versus bivalirudin plus GPI (5.7% vs. 5.3%, p = 0.38). Independent predictors of major bleeding were advanced age, female gender, diabetes, hypertension, renal insufficiency, anemia, no prior percutaneous coronary intervention, cardiac biomarker elevation, ST-segment deviation ≥1 mm, and treatment with heparin plus GPI versus bivalirudin monotherapy. Patients with major bleeding had higher 30-day rates of mortality (7.3% vs. 1.2%, p < 0.0001), composite ischemia (23.1% vs. 6.8%, p < 0.0001), and stent thrombosis (3.4% vs. 0.6%, p < 0.0001) versus those without major bleeding. Major bleeding was an independent predictor of 30-day mortality (odds ratio 7.55, 95% confidence interval 4.68 to 12.18, p < 0.0001).

Conclusions: Major bleeding is a powerful independent predictor of 30-day mortality in patients with ACS managed invasively. Several factors independently predict major bleeding, including treatment with heparin plus GPI compared with bivalirudin monotherapy. Knowledge of these findings might be useful to reduce bleeding risk and improve outcomes in ACS.

Abbreviations and Acronyms
  ACS = acute coronary syndromes
  CABG = coronary artery bypass graft surgery
  GRACE = Global Registry of Acute Coronary Events
  GPI = glycoprotein IIb/IIIa inhibitor/inhibition
  MI = myocardial infarction
  PCI = percutaneous coronary intervention

Antithrombotic therapy is an important component of the management of patients with acute coronary syndromes (ACS) (unstable angina or non–ST-segment elevation myocardial infarction) (1). Although advances in antithrombotic therapy have reduced rates of ischemic events, they typically have increased the risk of bleeding complications (2,3), and data suggest an adverse relationship between bleeding and outcomes (4,5).

Bivalirudin has demonstrated anti-ischemic efficacy and favorable bleeding complication rates in percutaneous coronary intervention (PCI) and ACS (6,7). In the REPLACE (Randomized Evaluation of PCI Linking Angiomax to Reduced Clinical Events)-2 trial, bivalirudin (plus provisional glycoprotein IIb/IIIa inhibition [GPI]) was noninferior to unfractionated heparin plus planned GPI in suppressing ischemic events, while markedly reducing bleeding (6). In the ACUITY (Acute Catheterization and Urgent Intervention Triage strategY) trial, bivalirudin (plus provisional GPI) resulted in similar 30-day composite ischemic event rates, less bleeding, and superior net clinical outcomes, compared with heparin (unfractionated or enoxaparin) plus GPI in ACS (7).

This analysis examines the predictors of major bleeding and its impact on 30-day outcomes, including mortality, in the ACUITY trial.


   Methods
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Results
 Discussion
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Study design.   In the ACUITY trial (7), 13,819 patients with moderate- and high-risk ACS were randomly assigned in open-label fashion to heparin (unfractionated or enoxaparin) plus GPI, bivalirudin plus GPI, or bivalirudin monotherapy (plus provisional GPI). Unfractionated heparin was administered intravenously as a 60 IU/kg bolus plus 12 IU/kg/h infusion, to achieve an activated partial thromboplastin time of 50 to 75 s before angiography and an activated clotting time of 200 to 250 s during PCI. The median maximum activated clotting time among patients undergoing PCI with unfractionated heparin was 239 s (interquartile range 211 to 291 s) (7). Enoxaparin was administered 1 mg/kg subcutaneously twice a day, with a 0.3 mg/kg intravenous bolus immediately before PCI, if the last subcutaneous dose was >8 h earlier or 0.75 mg/kg if >16 h earlier. Bivalirudin was administered intravenously as a 0.1 mg/kg bolus plus 0.25 mg/kg/h infusion, with a bolus of 0.5 mg/kg and an increase in the infusion to 1.75 mg/kg/h before PCI. Antithrombotic monitoring was not performed for enoxaparin or bivalirudin. Antithrombins were routinely discontinued after angiography or after PCI. The GPI group patients were randomized again (2 x 2 factorial design) to either initiation upstream or deferred (before PCI). Provisional GPI was permitted in deferred GPI or bivalirudin monotherapy patients for severe breakthrough ischemia and during PCI in bivalirudin monotherapy patients for prespecified criteria. The GPI was administered per labeling and continued 12 to 18 h after PCI. Coronary angiography was required within ≤72 h, with triage to PCI, coronary artery bypass graft surgery (CABG), or medical management. Aspirin (300 to 325 mg orally or 250 to 500 mg intravenously) was administered daily during hospital stays. Thienopyridine dosing and timing were left to investigator discretion; however, the protocol required a clopidogrel loading dose of ≥300 mg ≤2 h after PCI, and 75 mg daily was recommended for 1 year in coronary artery disease patients. The institutional review or ethics board at each center approved the study, and patients signed written, informed consent.

End points and statistical methods.   The ACUITY study was powered for 3 primary 30-day end points: composite ischemia, major bleeding (not CABG-related), and net clinical outcomes. A blinded clinical events committee adjudicated all primary and secondary end points. Major bleeding (not CABG-related) was defined as: intracranial or intraocular; access site bleeding requiring intervention; ≥5-cm diameter hematoma; hemoglobin reduction of ≥4 g/dl without or ≥3 g/dl with an overt source; reoperation for bleeding; or blood product transfusion. All analyses are intention to treat. Chi-square test was used for categorical variables, unless the observation in any cell was <5, in which the Fisher exact test was used. Continuous variables were tested with the Wilcoxon rank sum test. Medians and interquartile ranges are presented for continuous variables. Time-to-event distributions are displayed according to the Kaplan-Meier method and compared with log-rank test. The p values are given for informational purposes and no multiplicity adjustment was done. Predictors of major bleeding and 30-day mortality were identified with logistic regression analyses. Potential predictors were selected with stepwise, forward, and backward procedures. For each procedure, a prediction factor entered into the model with p ≤ 0.20 and retained with p ≤ 0.10. The final model includes all predictors selected by at least 1 of the procedures. The p values, odds ratios (ORs), and corresponding 2-sided 95% confidence interval (CI) for predictors are presented. Statistical analyses were performed by SAS version 8.2 (SAS Institute Inc., Cary, North Carolina).


   Results
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Discussion
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Patient characteristics.   Of 13,819 patients, 644 (4.7%) experienced major bleeding. Patients with major bleeding were older, more likely female, and of lower body weight. They were more likely to have diabetes, hypertension, anemia, and renal insufficiency and less likely to have hyperlipidemia, smoke, or have prior PCI. Patients with major bleeding more often presented with cardiac biomarker elevation or ST-segment deviation of ≥1 mm. Compared with the group without major bleeding, the treatment strategy of patients in the major bleeding group was more commonly PCI and less commonly CABG or medical therapy (Table 1).


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  		Table 1 Characteristics of Patients With and Without Major Bleeding
 
Antithrombotic medications and major bleeding.   Major bleeding occurred less frequently in patients treated with bivalirudin monotherapy versus heparin plus GPI. However, major bleeding was similar in patients treated with bivalirudin plus GPI versus heparin plus GPI (Table 2). Patients with major bleeding more frequently received GPI before angiography. The timing of aspirin, thienopyridine, and antithrombin administration related to angiography did not influence major bleeding, nor did several other time intervals (Table 3).


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  		Table 2 Types of Major Bleeding by Treatment Group
 

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  		Table 3 Antithrombotic Medications in Patients With and Without Major Bleeding
 
Predictors of major bleeding.   Independent predictors of major bleeding were: age ≥75 years, female gender, anemia, renal insufficiency, diabetes, hypertension, no prior PCI, ST-segment deviation ≥1 mm, and cardiac biomarker elevation (Fig. 1). Treatment with heparin plus GPI versus bivalirudin monotherapy also independently predicted major bleeding.


Figure 1
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  		Figure 1 Independent Predictors of Major Bleeding

*Anemia was defined as baseline hemoglobin <13 g/dl in men and <12 g/dl in women. {dagger}Renal insufficiency was defined as a creatinine clearance <60 ml/min as calculated by the Cockcroft-Gault equation. {ddagger}Unfractionated heparin or enoxaparin. CI = confidence interval; GPI = glycoprotein IIb/IIIa inhibitor; OR = odds ratio; PCI = percutaneous coronary intervention.

 
Major bleeding and mortality.   Patients with versus without major bleeding had higher rates of 30-day mortality (7.3% vs. 1.2%, p < 0.0001) (Fig. 2). Major bleeding was an independent predictor of 30-day mortality (OR 7.55, 95% CI 4.68 to 12.18; p < 0.0001). Other independent predictors of 30-day mortality included: age ≥75 years, left ventricular ejection fraction ≤50%, prior stroke, ST-segment deviation ≥1 mm, cardiac biomarker elevation, treatment strategy of CABG (vs. PCI), and myocardial infarction (MI) (Fig. 3).


Figure 2
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  		Figure 2 Kaplan-Meier Curves for Mortality

 

Figure 3
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  		Figure 3 Independent Predictors of Mortality

CABG = coronary artery bypass surgery; other abbreviations as in Figure 1.

 
Major bleeding and other outcomes.   Patients with major bleeding had higher rates of 30-day composite ischemic events (death, MI, or unplanned revascularization for ischemia), MI, and unplanned revascularization for ischemia (Table 4). Stent thrombosis, thrombocytopenia, and length of hospital stay (6 vs. 3 days, p < 0.0001) were also higher in patients with versus without major bleeding.


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  		Table 4 Clinical Outcomes in Patients With and Without Major Bleeding
 

   Discussion
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 Abstract
 Methods
 Results
 Discussion
Conclusions
 References
 
Our analysis of 13,819 moderate- and high-risk patients with ACS from the ACUITY trial reveals the following: 1) major bleeding occurs in nearly 5% of patients; 2) several readily identifiable factors independently predict major bleeding; 3) major bleeding is associated with increased 30-day ischemic event rates; 4) major bleeding is an independent predictor of 30-day mortality; and 5) bivalirudin monotherapy is an independent predictor of lower rates of major bleeding compared with combination therapy with heparin plus GPI.

Bleeding complications continue to occur frequently in ACS, although rates of bleeding in clinical trials might vary widely. The current analysis is consistent with the GRACE (Global Registry of Acute Coronary Events) (8), which reported major bleeding in 3.9% of 24,045 patients, and the meta-analysis by Eikelboom et al. (5), which reported major bleeding in 2.3% of 34,146 patients.

We identified several independent predictors of major bleeding, including advanced age, female gender, diabetes, hypertension, renal insufficiency, anemia, cardiac biomarker elevation, and ST-segment deviation. These readily identifiable factors are useful in assessing bleeding risk on presentation, before initiating antithrombotic therapy. Our findings are consistent with the GRACE registry, which reported that factors including advanced age, renal insufficiency, history of bleeding, GPI, and PCI independently predicted major bleeding in unstable angina. Furthermore, GRACE found higher rates of major bleeding in non–ST-segment elevation MI (4.7%) compared with unstable angina (2.3%) (8). Our analysis confirmed these findings by revealing that baseline cardiac biomarker elevation and ST-segment deviation were independent predictors of both major bleeding and mortality, suggesting that patients with increased ischemic risk might also have increased bleeding risk.

Mortality at 30 days was >6-fold higher among patients with major bleeding. Major bleeding was the strongest independent predictor of mortality, even more so than MI. This underscores the adverse impact of major bleeding on early mortality and extends the findings from Eikelboom et al. (5), who reported that major bleeding was independently associated with early mortality in patients predominantly treated with a conservative strategy (hazard ratio 5.37, 95% CI 3.97 to 7.27, p < 0.0001). In addition, our analysis revealed that 30-day ischemic event rates were >3-fold higher with major bleeding, occurring in nearly 25% of patients. Rates of MI, unplanned revascularization for ischemia, and notably, stent thrombosis were all significantly higher with major bleeding.

Several hypotheses might underlie the association between bleeding and mortality. First, bleeding often necessitates the discontinuation and/or reversal of antithrombotic therapy, which might result in ischemia, hemodynamic decompensation, arrhythmias, stent thrombosis, MI, unplanned revascularization, or death (9). Supporting this possibility is our finding of a nearly 6-fold higher rate of stent thrombosis in patients with major bleeding. Second, bleeding with hypovolemia, anemia, and impaired oxygen carrying capacity might precipitate tachycardia, hypotension, and congestive heart failure. Third, blood product transfusions have been associated with adverse outcomes. In a meta-analysis of 24,112 patients by Rao et al. (10), transfusion was associated with an increased hazard for 30-day death (adjusted hazard ratio 3.94, 95% CI 3.26 to 4.75, p < 0.001). Next, anemia also independently predicted major bleeding in our analysis, and the mechanisms for this increase in adverse outcomes might include transfusion and associated risks, the bleeding complication, and the etiology of the anemia (11). Lastly, patients with bleeding complications have a more prolonged, complex, and costly hospital stay and might require invasive monitoring, intra-aortic balloon counterpulsation, intubation, endoscopy, anesthesia, and surgical procedures, all of which might increase the likelihood of adverse outcomes, including death.

In the ACUITY trial, bivalirudin monotherapy (with 9.1% provisional GPI use) was associated with significantly lower rates of major bleeding and similar rates of ischemic events (7) compared with combination therapy with heparin plus GPI. These results mirror the REPLACE-2 PCI trial (6). Collectively, these 2 trials of nearly 20,000 patients confirm that the use of bivalirudin, compared with heparin plus GPI, is associated with a significant reduction in the risk of bleeding complications, while maintaining efficacy in reducing ischemic events. Importantly, in the ACUITY trial, major bleeding, as defined by the study protocol, was strongly and independently predictive of subsequent mortality, validating this definition as clinically relevant.

Limitations of the ACUITY trial have been described (7). The current analysis was not prespecified in the original trial. In addition, multivariable analysis might not adequately account for all relevant factors. This analysis reports 30-day results, and 1-year data might provide additional information. However, given the consistency of these results with previous data and the large size of the population, these data add significantly to the understanding of the adverse association between bleeding and outcomes.


   Conclusions
Top
 Abstract
 Methods
 Results
 Discussion
 Conclusions
References
 
In summary, in the large-scale ACUITY trial, major bleeding complications had a significant, independent, adverse impact on 30-day outcomes, including mortality, in patients with ACS undergoing early invasive management. Several readily identifiable factors independently predicted major bleeding. In addition, treatment with bivalirudin rather than heparin plus GPI was an independent predictor of freedom from major bleeding. Knowledge of these findings and a baseline assessment of hemorrhagic risk might facilitate the choice of an antithrombotic regimen with a favorable safety and efficacy profile, resulting in improved outcomes for patients with ACS.


   Acknowledgments
 
The authors greatly appreciate the statistical support of Junyuan Wang, PhD, in the preparation of this article.


   Footnotes
 
The trial was funded by The Medicines Company, Parsippany, New Jersey, and Nycomed, Roskilde, Denmark. Drs. Manoukian, Mehran, Dangas, White, and Stone have received lecture fees from The Medicines Company. Drs. Manoukian and Stone have received lecture fees from Nycomed. Dr. Feit holds equity interests in The Medicines Company, Johnson & Johnson, and Millennium Pharmaceuticals. Drs. Feit, Ohman, White, and Stone have received consulting fees from The Medicines Company. Dr. Lincoff has received research support from The Medicines Company. Dr. White has received consulting fees and lecture fees from Sanofi-Aventis and grant support from The Medicines Company, Sanofi-Aventis, Proctor and Gamble, Schering Plough, and Eli Lilly. Dr. Moses has received consulting fees from Johnson & Johnson and is on the speaker’s bureau for Astra Zeneca. Dr. Ohman has received consulting fees from Sanofi-Aventis, Liposcience, Inovise Medical, Response Biomedical, and Savacor; holds equity interests in Medtronic and Savacor; received lecture fees from Schering Plough, Bristol Myers Squibb, and Datascope; and has received grant support from Schering Plough, Bristol Myers Squibb, and Berlex.


   References
Top
 Abstract
 Methods
 Results
 Discussion
 Conclusions
 References
 

  1. 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.[Free Full Text]
  2. The PRISM-PLUS Study Investigators Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non-Q-wave myocardial infarctionPlatelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) Study Investigators. N Engl J Med 1998;338:1488-1497.[Abstract/Free Full Text]
  3. The PURSUIT Trial Investigators Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromesThe PURSUIT Trial Investigators. Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy. N Engl J Med 1998;339:436-443.[Abstract/Free Full Text]
  4. Rao SV, O’Grady K, Pieper KS, et al. A comparison of the clinical impact of bleeding measured by two different classifications among patients with acute coronary syndromes J Am Coll Cardiol 2006;47:809-816.[Abstract/Free Full Text]
  5. Eikelboom JW, Mehta SR, Anand SS, Xie C, Fox KAA, Yusuf S. Adverse impact of bleeding on prognosis in patients with acute coronary syndromes Circulation 2006;114:774-782.[Abstract/Free Full Text]
  6. Lincoff AM, Bittl JA, Harrington RA, et al. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention JAMA 2003;289:853-863.[Abstract/Free Full Text]
  7. Stone GW, McLaurin BT, Cox DA, et al. ACUITY Investigators Bivalirudin for patients with acute coronary syndromes N Engl J Med 2006;355:2203-2216.[Abstract/Free Full Text]
  8. Moscucci M, Fox KAA, Cannon CP, et al. Predictors of major bleeding in acute coronary syndromes: the Global Registry of Acute Coronary Events (GRACE) Eur Heart J 2003;24:1815-1823.[Abstract/Free Full Text]
  9. Iakovou I, Schmidt T, Bonizzoni E, et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents JAMA 2005;293:2126-2130.[Abstract/Free Full Text]
  10. Rao SV, Jollis JG, Harrington RA, et al. Relationship of blood transfusion and clinical outcomes in patients with acute coronary syndromes JAMA 2004;292:1555-1562.[Abstract/Free Full Text]
  11. Voeltz MD, Feit F, Stone GW, Manoukian SV. Anemia and outcomes in ACS Acute Coronary Syndromes 2005;7:47-55.



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