CLINICAL RESEARCH: ACUTE CORONARY SYNDROME
Efficacy and Safety of Fondaparinux Versus Enoxaparin in Patients With Acute Coronary Syndromes Treated With Glycoprotein IIb/IIIa Inhibitors or ThienopyridinesResults From the OASIS 5 (Fifth Organization to Assess Strategies in Ischemic Syndromes) Trial
Sanjit S. Jolly, MD, MSc*,*,
David P. Faxon, MD ,
Keith A.A. Fox, MB, ChB ,
Rizwan Afzal, MSc*,
William E. Boden, MD ,
Petr Widimsky, MD||,
P. Gabriel Steg, MD¶,
Vicent Valentin, MD#,
Andrez Budaj, MD**,
Christopher B. Granger, MD,
Campbell D. Joyner, MD,
Susan Chrolavicius, BScN*,
Salim Yusuf, DPhil* and
Shamir R. Mehta, MD, MSc*
* Department of Medicine, Hamilton Health Sciences, Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
Royal Infirmary and University of Edinburgh, Edinburgh, Scotland
Department of Cardiology, University of Buffalo School of Medicine, Buffalo General Hospital, Buffalo, New York
|| Charles University, Hospital Kralovske Vinohrady, Prague, Czech Republic
¶ Département de Cardiologie, INSERM U-698, Université Paris 7, AP-HP, Paris, France
# Hospital Universitari Dr. Peset, Valencia, Spain
** Postgraduate Medical School, Department of Cardiology, Grochowski Hospital, Warsaw, Poland
Duke Clinical Research Institute, Duke University, Durham, North Carolina
Department of Medicine, Sunnybrook Health Sciences Center, University of Toronto, Toronto, Ontario, Canada
Manuscript received January 6, 2009;
revised manuscript received March 18, 2009,
accepted March 24, 2009.
* Reprint requests and correspondence: Dr. Sanjit S. Jolly, McMaster Clinic Room 630, Hamilton General Hospital, 237 Barton Street East, Hamilton, Ontario L8L 2X2, Canada (Email: jollyss{at}mcmaster.ca).
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Abstract
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Objectives: This study sought to evaluate the relative safety and efficacy of fondaparinux and enoxaparin in patients with acute coronary syndromes (ACS) treated with glycoprotein (GP) IIb/IIIa inhibitors or thienopyridines.
Background: The OASIS 5 (Fifth Organization to Assess Strategies in Ischemic Syndromes) trial showed that fondaparinux reduced major bleeding by 50% compared with enoxaparin while preserving similar efficacy. Whether this benefit is consistent in the presence or absence of concurrent antiplatelet therapy with clopidogrel and GP IIb/IIIa inhibitors is unknown.
Methods: Patients with ACS (n = 20,078) were randomized as a part of the OASIS 5 trial to receive either fondaparinux or enoxaparin. The use of GP IIb/IIIa inhibitors or thienopyridines was at the discretion of the treating physician. A Cox proportional hazard model was used to compare outcomes.
Results: Of the 20,078 patients randomized, 3,630 patients received GP IIb/IIIa and 13,531 received thienopyridines. There was a 40% reduction in major bleeding with fondaparinux compared with enoxaparin in those treated with GP IIb/IIIa (5.2% vs. 8.3%, hazard ratio [HR]: 0.61, p < 0.001). A similar reduction was found in those treated with thienopyridines (3.4% vs. 5.4%, HR: 0.62, p < 0.001). Ischemic events were similar between the groups, resulting in a superior net clinical outcome (death, myocardial infarction, refractory ischemia, or major bleeding) favoring fondaparinux (GP IIb/IIIa subgroup 14.8% vs. 18.9%, HR: 0.77, p = 0.001 and thienopyridines subgroup 11.0% vs. 13.2%, HR: 0.82, p < 0.001).
Conclusions: In patients receiving GP IIb/IIIa inhibitors or thienopyridines, fondaparinux reduces major bleeding and improves net clinical outcome compared with enoxaparin.
Key Words: anticoagulants • acute coronary syndromes • hemorrhage
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Abbreviations and Acronyms
| | ACS = acute coronary syndrome | | CI = confidence interval | | CK-MB = creatine kinase-myocardial band | | GP = glycoprotein | | HR = hazard ratio | | MI = myocardial infarction | | NSTE = non–ST-segment elevation | | OR = odds ratio | | PCI = percutaneous coronary intervention | | RR = relative risk |
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Antiplatelet therapy with either glycoprotein (GP) IIb/IIIa inhibitors or thienopyridines reduces ischemic events at the cost of an increase in bleeding in patients with acute coronary syndromes (1,2). The American College of Cardiology and American Heart Association as well as the European Society of Cardiology guidelines recommend early treatment with either clopidogrel or intravenous GP IIb/IIIa inhibitors (3,4). Major bleeding has been shown repeatedly in observational analyses to be associated with an increased risk of death (5–7). As a result, it is important to determine the risk of bleeding of novel antithrombotic agents when combined with these potent antiplatelet agents compared with standard therapies.
Fondaparinux is a synthetic factor Xa inhibitor (Arixtra, GlaxoSmithKline, Brentford, United Kingdom) that selectively binds antithrombin and potentiates neutralization of factor Xa. The OASIS 5 (Fifth Organization to Assess Strategies in Ischemic Syndromes) trial demonstrated that fondaparinux compared with enoxaparin reduced major bleeding by 50% and mortality by 17% in over 20,000 patients with non–ST-segment elevation (NSTE) (8).
The objective of this analysis was to determine the efficacy, safety, and net clinical outcome of fondaparinux versus enoxaparin in patients with NSTE-acute coronary syndrome (ACS) treated with: 1) a GP IIb/IIIa inhibitor; and 2) thienopyridines.
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Methods
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Patients.
The OASIS 5 trial briefly enrolled 20,078 patients with NSTE-ACS and randomized them to fondaparinux 2.5 mg subcutaneously once daily or enoxaparin 1 mg/kg of body weight subcutaneously twice daily in a double-blind fashion (8). Patients were eligible if they had had ischemic symptoms within 24 h and at least 2 of the 3 following criteria: an age of at least 60 years, an elevated level of troponin or creatine kinase-myocardial band (CK-MB) isoenzyme, or electrocardiographic changes indicative of ischemia. In the fondaparinux arm, patients were treated with fondaparinux for up to 8 days or until hospital discharge, whichever came first. In the enoxaparin arm, patients were treated with enoxaparin for 2 to 8 days until the patient was deemed clinically stable. The use of GP IIb/IIIa inhibitors or thienopyridines was left to the discretion of the treating physician.
Outcomes.
Efficacy was assessed by evaluating rates of the composite of death, myocardial infarction (MI), and refractory ischemia at 30 days. Safety was assessed by evaluating rates of major bleeding, and net clinical outcome was assessed evaluating rates of the composite of death, MI, refractory ischemia, or major bleeding at 30 days.
MI was defined as the following: in those without previous infarction within 7 days, as prolonged ischemic symptoms with cardiac enzyme elevation (troponin or CK-MB) of >2x upper limit of normal, electrocardiographic changes indicative of ischemia or Q waves or pathologic evidence of acute MI (9). In those who presented with an MI at baseline, a new MI within 24 h was defined as >20 min of ischemic symptoms with either new ST-segment elevation or depression. In those who presented with an MI at baseline, a new MI within 24 h to 7 days was defined as ischemic symptoms >20 min with 1 of the following: 1) typical rise and fall of cardiac biomarker levels (including troponin, CK-MB) to at least 2x upper limit of normal (if markers are already elevated, then >50% increase in enzymes required); 2) new ST-segment elevation or depression; or 3) new Q waves in 2 contiguous leads. Within 48 h of percutaneous coronary intervention (PCI), a new MI was defined as CK-MB >3x the upper limit of normal (50% increase required if elevated) or new ST-segment elevation or development of new Q waves. Similarly, within 48 h of coronary artery bypass surgery, a new MI was defined as a CK-MB 5x upper limit of normal or new Q waves in 2 contiguous leads.
The definition of major bleeding was any clinically overt bleeding that was either fatal, intracranial bleeding, retroperitoneal, intraocular leading to significant visual loss, requiring  2 U of blood transfused, or associated with a decrease of hemoglobin >3 g/dl (with each unit of transfused blood counting for 1.0 g/dl).
Statistical analysis.
Patients were stratified into subgroups that received GP IIb/IIIa inhibitors and the subgroup that did not. Patients were also stratified into subgroups that received thienopyridines in the hospital and those that did not. Baseline characteristics were compared using the chi-square test for proportions and Student t test for continuous variables.
A Cox proportional hazards model was used to compare efficacy (death, MI, or refractory ischemia) as well as major bleeding and net clinical outcome in the fondaparinux versus enoxaparin groups in: 1) those that received GP IIb/IIIa inhibitors; 2) those that received thienopyridines; and 3) those that received both agents. This analysis was repeated in the PCI subgroup in those that received GP IIb/IIIa inhibitors, those that received thienopyridines at least 6 h before PCI, and both. In the PCI subgroup, outcomes by type of GP IIb/IIIa inhibitor and loading dose of clopidogrel were compared between the fondaparinux and enoxaparin groups. Statistical significance was defined as a p < 0.05 and for interaction tests p < 0.10.
A propensity score was developed for the use of GP IIb/IIIa inhibitors and included variables that influenced the use of GP IIb/IIIa inhibitors such as age, sex, diabetes, ST-segment deviation, and elevated cardiac enzymes and other baseline variables. The propensity score was used to adjust the Cox proportional hazards model to compare outcomes in the fondaparinux versus enoxaparin groups by use of GP IIb/IIIa. A second propensity score for the use of thienopyridines was developed similarly to adjust the Cox proportional hazard model comparing the fondaparinux versus enoxaparin groups by use of thienopyridines.
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Results
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In the OASIS 5 trial, of the 20,078 patients with acute coronary syndromes that were enrolled, 3,630 patients (18%) received a GP IIb/IIIa inhibitor, 13,532 patients (67%) received a thienopyridine, and 13,916 patients (69%) received either a thienopyridine or GP IIb/IIIa inhibitor in the hospital.
GP IIb/IIIa inhibitors.
Baseline characteristics of patients who received a GP IIb/IIIa inhibitor are compared with those who did not receive one in Table 1. Patients treated with GP IIb/IIIa inhibitors were younger, were a higher proportion of male subjects, and had elevated cardiac enzymes. For geographic variation, the highest rate of GP IIb/IIIa use was in North America and Western Europe, and the lowest rates were in Asia and Eastern Europe (Table 1).
In those treated with GP IIb/IIIa inhibitors, fondaparinux had similar rates of death, MI, or refractory ischemia at 30 days as enoxaparin (11.8% vs. 13.2%, unadjusted hazard ratio [HR]: 0.89, 95% confidence interval [CI]: 0.74 to 1.07, p = 0.20, and adjusted HR: 0.87, 95% CI: 0.72 to 1.06, p = 0.16) (Table 2) (Fig. 1). In those not treated with GP IIb/IIIa inhibitors, there were similar rates of death, MI, or refractory ischemia between fondaparinux and enoxaparin, (7.1% and 7.7%, unadjusted HR: 0.93, 95% CI: 0.83 to 1.04, p = 0.23, and adjusted HR: 0.93, 95% CI: 0.82 to 1.04, p = 0.19, interaction p = 0.63).
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Table 2 Death, MI, Refractory Ischemia, Major Bleeding, and Net Clinical Outcome at 30 Days in Those Treated With a GP IIb/IIIa Inhibitor
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Figure 1 Safety and Efficacy of Fondaparinux Versus Enoxaparin in GP IIb/IIIa and Thienopyridine Subgroups
Fondaparinux reduced major bleeding and improved net clinical outcome compared with enoxaparin irrespective of glycoprotein (GP) IIb/IIIa or thienopyridine use. CI = confidence interval; MI = myocardial infarction.
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In those treated with GP IIb/IIIa inhibitors, there was a 40% reduction in major bleeding with fondaparinux versus enoxaparin at 30 days (5.2% vs. 8.3% respectively, unadjusted HR: 0.61, 95% CI: 0.47 to 0.79, p < 0.001, and adjusted HR: 0.60, 95% CI: 0.46 to 0.78, p < 0.001) (Fig. 2). In those not treated with GP IIb/IIIa inhibitors, there was also a 40% reduction in major bleeding with fondaparinux compared with enoxaparin (2.7% vs. 4.3%, respectively, unadjusted HR: 0.62, 95% CI: 0.53 to 0.74, p < 0.001, and adjusted HR: 0.62, 95% CI: 0.52 to 0.73, p < 0.001, interaction p = 0.86). In terms of net clinical outcome (composite of death, MI, refractory ischemia, or major bleeding) at 30 days, there was a consistent benefit for fondaparinux for those treated with GP IIb/IIIa inhibitors (14.9% vs. 18.9%, unadjusted HR: 0.77, 95% CI: 0.66 to 0.90, p < 0.001, and adjusted HR: 0.76, 95% CI: 0.65 to 0.90, p = 0.001) as well those not treated with GP IIb/IIIa (9.1% vs. 11.0%, unadjusted HR: 0.83, 95% CI: 0.75 to 0.91, p < 0.001, and adjusted HR: 0.81, 95% CI: 0.65 to 0.90, p < 0.001, interaction p = 0.42).
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Figure 2 Kaplan-Meier Event Curves for Major Bleeding and Net Clinical Outcome for GP IIb/IIIa and Thienopyridine Subgroups
Net clinical outcome (death, myocardial infarction, refractory ischemia, or major bleeding). GP = glycoprotein; HR = hazard ratio.
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For the PCI subgroup, there were similar rates of death, MI, and refractory ischemia in both the fondaparinux and the enoxaparin groups, regardless of GP IIb/IIIa use (Fig. 3). There were consistent benefits in terms of major bleeding of fondaparinux compared with enoxaparin in the PCI population in both those treated and not treated with GP IIb/IIIa inhibitors (Fig. 3). In terms of net clinical outcome, there was trend for a reduction in events in the PCI populations in those treated with GP IIb/IIIa with fondaparinux versus enoxaparin (p = 0.05) (Fig. 3). The outcomes by type of GP IIb/IIIa inhibitor during PCI are shown in Table 3.
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Figure 3 In Those Undergoing PCI, the Efficacy and Safety of Fondaparinux Versus Enoxaparin in Those Treated With GP IIb/IIIa Inhibitors or Pre-Treated (6 h) With Thienopyridines or Both
In the PCI population, fondaparinux reduced major bleeding compared with enoxaparin regardless of GP IIb/IIIa or thienopyridine pre-treatment. PCI = percutaneous coronary intervention; other abbreviations as in Figure 1.
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Table 3 Death, MI, or Refractory Ischemia or Major Bleeding in Patients Undergoing PCI by Loading Dose of Clopidogrel or Type of GP IIb/IIIa Inhibitor
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Up-front GP IIb/IIIa inhibitors for patients undergoing PCI (excludes bailout treatment after PCI started) did not seem to be protective against catheter thrombus in both the fondaparinux (0.7% [15 of 2,028] not receiving up-front GP IIb/IIIa vs. 1.3% [14 of 1,077] receiving up-front GP IIb/IIIa, p = 0.12) and enoxaparin groups (0.3% [5 of 1,987] not receiving up-front GP IIb/IIIa vs. 0.3% [3 of 1,085] receiving up-front GP IIb/IIIa, p = 0.90).
Thienopyridines.
As shown in Table 4, 13,532 patients (67%) received thienopyridines versus 6,546 (33%) patients not treated with thienopyridines in the hospital. Patients treated with thienopyridines were slightly younger and more likely to be male and to have elevated cardiac enzyme levels. Patients treated with thienopyridines were more likely to have been treated with statins, unfractionated heparin, and PCI in the hospital (Table 4). The highest rate of thienopyridine use was in Asia and North America, and the lowest rate was in Eastern Europe (Table 4).
For the composite of death, MI, or refractory ischemia, fondaparinux had similar efficacy compared with enoxaparin in both those treated with thienopyridines (8.6% vs. 9.1%, respectively, unadjusted HR: 0.94, 95% CI: 0.84 to 1.05, p = 0.20, and adjusted HR: 0.94, 95% CI: 0.84 to 1.06, p = 0.29) and those not (6.7% vs. 7.5%, respectively, unadjusted HR: 0.89, 95% CI: 0.74 to 1.07, p = 0.21, and adjusted HR: 0.87, 95% CI: 0.72 to 1.05, interaction p = 0.61) (Table 5) (Fig. 1).
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Table 5 Death, MI, Refractory Ischemia, Major Bleeding, and Net Clinical Outcome at 30 Days in Those Treated With Thienopyridines
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In terms of safety, fondaparinux was associated with a 40% reduction in major bleeding at 30 days in both the subgroup treated with thienopyridines (3.4% vs. 5.4%, respectively, unadjusted HR: 0.62, 95% CI: 0.53 to 0.73, p < 0.001, and adjusted HR: 0.62, 95% CI: 0.52 to 0.73, p < 0.001) and the subgroup not treated with thienopyridines (2.6% vs. 4.2%, unadjusted HR: 0.63, 95% CI: 0.48 to 0.83, p < 0.001, and adjusted HR: 0.62, 95% CI: 0.47 to 0.83, p = 0.001, interaction p = 0.92) (Fig. 2) (Table 5).
With regard to net clinical outcome at 30 days (death, MI, refractory ischemia, or major bleeding), fondaparinux was associated with a 20% reduction in both the subgroup treated with thienopyridines (11.0% vs. 13.2%, unadjusted HR: 0.82, 95% CI: 0.75 to 0.91, p < 0.001, and adjusted HR: 0.82, 95% CI: 0.74 to 0.90, p < 0.001) and those not treated with thienopyridines (8.5% vs. 10.6%, unadjusted HR: 0.80, 95% CI: 0.68 to 0.93, p < 0.001, and adjusted HR: 0.78, 95% CI: 0.66 to 0.92, p = 0.003, interaction p = 0.78) (Table 5).
For those patients undergoing PCI during the initial hospitalization, there were similar rates of death, MI, and refractory ischemia in both the fondaparinux and enoxaparin groups at 30 days, regardless of whether thienopyridines were given at least 6 h before PCI (Fig. 3). There were consistent benefits in terms of major bleeding of fondaparinux compared with enoxaparin in the PCI population in both those pre-treated (minimum 6 h) and not pre-treated with thienopyridines (Fig. 3). The outcomes by loading dose of clopidogrel in PCI population are shown in Table 3, which shows that the vast majority of patients received a 300-mg loading dose of clopidogrel.
GP IIb/IIIa inhibitors and thienopyridine use.
For patients treated with both GP IIb/IIIa inhibitors and thienopyridines, there were similar rates of death, MI, and refractory ischemia in both the fondaparinux and the enoxaparin groups (Fig. 1). There was a significant reduction in the rates of major bleeding and net clinical outcome with fondaparinux compared with enoxaparin in those treated with both agents during initial hospitalization (Fig. 1). In those undergoing PCI during the initial hospitalization, there was a significant reduction in major bleeding with fondaparinux regardless of whether patients received combined therapy with both GP IIb/IIIa inhibitors and thienopyridine pre-treatment (at least 6 h pre-PCI) (Fig. 3).
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Discussion
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Our analysis shows that fondaparinux is associated with a 40% reduction in major bleeding compared with enoxaparin when used on top of background therapy with GP IIb/IIIa inhibitors or thienopyridines. Ischemic outcomes were similar between the 2 groups, but fondaparinux was associated with superior net clinical outcomes. These data provide support for the efficacy and safety of fondaparinux use in patients treated concurrently with GP IIb/IIIa inhibitors and thienopyridines.
Thienopyridines have been shown to reduce the composite of death, MI, or stroke in patients with acute coronary syndromes in the CURE (Clopidogrel in Unstable angina to prevent Recurrent Events) trial by 20% (relative risk [RR]: 0.80, 95% CI: 0.72 to 0.90) but at the expense of an increased risk of bleeding (RR: 1.38, 95% CI: 1.13 to 1.67) (1). Similarly, GP IIb/IIIa inhibitors have been shown to have a modest benefit with regard to death or MI in all patients with acute coronary syndromes from a meta-analysis (odds ratio [OR]: 0.91, 95% CI: 0.85 to 0.99) but at the expense of a 60% increase in the odds of bleeding (OR: 1.62, 95% CI: 1.36 to 1.94) (2).
Both thienopyridines and GP IIb/IIIa inhibitors were tested on top of either enoxaparin or unfractionated heparin in this analysis of the OASIS 5 study. Our study suggests that fondaparinux instead of enoxaparin can potentially offset the increased bleeding risk associated with thienopyridines and GP IIb/IIIa inhibitors, both agents recommended as options in the current European and American guidelines (3,4). In the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial, bivalirudin alone reduced major bleeding compared with unfractionated heparin plus GP IIb/IIIa inhibitors (10). However, in this trial, bivalirudin plus GP IIb/IIIa had similar rates of major bleeding compared with heparin plus GP IIb/IIIa. These results suggested that the increased risk of bleeding with GP IIb/IIIa inhibitors was so significant that it seemed to overwhelm the effect of different antithrombins in terms of bleeding. On the other hand, our analysis shows that in the setting of GP IIb/IIIa use, the choice of antithrombin agent is important and fondaparinux can reduce bleeding events compared with enoxaparin in this setting.
A number of studies (5–7) have shown a marked increased risk in death associated with major bleeding. In an analysis of over 34,000 patients with acute coronary syndromes, major bleeding was associated with not only a 5-fold increase in mortality but also a 4-fold increase in MI after adjusting for covariates (5). With increased use of thienopyridines and GP IIb/IIIa inhibitors, the bleeding risk associated with combining these agents with different antithrombotic medications is an important issue in the therapy of NSTE-ACS.
The safety and efficacy of enoxaparin compared with unfractionated heparin with frequent use of GP IIb/IIIa inhibitors use was assessed in the SYNERGY (Superior Yield of the New strategy of Enoxaparin, Revascularization, and GlYcoprotein inhibitors) trial (11). In over 10,000 patients with NSTE-ACS, enoxaparin was associated with a 20% increase in risk of major bleeding compared with unfractionated heparin (11). The finding of an increased risk of bleeding with enoxaparin in the setting of potent antiplatelet therapy is consistent with our findings.
Study limitations.
The main limitation of this study is that it is based on a post-randomization subgroup and the results may have been influenced by potential confounding variables. To partially offset this, we extensively adjusted both the efficacy and the safety results with a propensity analysis. In addition, these subgroup results are consistent with the results of the overall trial.
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Conclusions
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Fondaparinux had a superior net efficacy to safety balance compared with enoxaparin in those treated with either GP IIb/IIIa inhibitors or thienopyridines. In the setting of GP IIb/IIIa inhibitors, fondaparinux is the only agent compared with enoxaparin that has been shown to have a superior net efficacy to safety balance.
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Footnotes
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The OASIS 5 trial was supported by Sanofi-Aventis, Organon, and GlaxoSmithKline.
Dr. Jolly has received honoraria from GlaxoSmithKline. Dr. Faxon is on the advisory board of Johnson & Johnson and has received a research grant from Boston Scientific. Dr. Fox has received grants and honoraria from Sanofi-Aventis, Bristol-Myers Squibb, and GlaxoSmithKline. Dr. Steg has received a research grant from Sanofi-Aventis. Dr. Budaj is on the advisory boards of Sanofi-Aventis and GlaxoSmithKline, and has received research grants or honoraria for lectures from Sanofi-Aventis, GlaxoSmithKline, AstraZeneca, and Boehringer Ingelheim. Dr. Granger has received grant funding from GlaxoSmithKline. Dr. Yusuf has received honoraria, consulting fees, and research grants from GlaxoSmithKline and Sanofi-Aventis. Dr. Mehta has received grant support from GlaxoSmithKline and Sanofi-Aventis, and has received honoraria or consulting fees from GlaxoSmithKline, Sanofi-Aventis, Bristol-Myers Squibb, AstraZeneca, Eli Lilly, and Astellas.
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References
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Abstract
Methods