Author + information
- Received February 4, 2009
- Revision received May 26, 2009
- Accepted May 29, 2009
- Published online August 1, 2009.
- Roxana Mehran, MD⁎,⁎ (, )
- Eugenia Nikolsky, MD, PhD⁎,
- Alexandra J. Lansky, MD⁎,
- Ajay J. Kirtane, MD, SM⁎,
- Young-Hak Kim, MD⁎,
- Frederick Feit, MD†,
- Steven Manoukian, MD‡,
- Jeffrey W. Moses, MD⁎,
- Ramin Ebrahimi, MD§,
- E. Magnus Ohman, MD∥,
- Harvey D. White, MD¶,
- Stuart J. Pocock, PhD#,
- George D. Dangas, MD, PhD⁎ and
- Gregg W. Stone, MD⁎
- ↵⁎Reprint requests and correspondence:
Dr. Roxana Mehran, Columbia University Medical Center, 161 Fort Washington Avenue, 5th Floor, New York, New York 10032
Objectives In this substudy of the ACUITY (Acute Catheterization and Urgent Intervention Triage strategY) trial, we investigated the relationship between chronic kidney disease (CKD) and clinical outcomes, and compared the safety and efficacy of bivalirudin monotherapy versus heparin plus a glycoprotein IIb/IIIa inhibitor (GPI).
Background CKD is an important predictor of prognosis in the general population. The outcomes of patients with CKD and acute coronary syndromes (ACS) have not been well studied.
Methods In the ACUITY study, 13,819 patients with moderate- and high-risk ACS undergoing an early, invasive strategy were randomly assigned to 1 of 3 antithrombin regimens: a heparin plus a GPI, bivalirudin plus a GPI, or bivalirudin monotherapy. CKD (creatinine clearance <60 ml/min) was present in 2,469 (19.1%) of 12,939 randomized patients with baseline creatinine clearance data.
Results Patients with CKD had worse 30-day and 1-year clinical outcomes than those with normal renal function. There were no significant differences between bivalirudin monotherapy and heparin plus a GPI in rates of 30-day composite ischemia (11.1% vs. 9.4%, p = 0.27) and net clinical adverse outcomes (16.1% vs. 16.9%, p = 0.65). There was remarkably less major bleeding (6.2% vs. 9.8%, p = 0.008) at 30 days, but no significant difference in 1-year composite ischemia (22.0% vs. 18.9%, p = 0.10) or mortality (7.1% vs. 7.3%, p = 0.96).
Conclusions In patients with ACS, CKD is associated with higher 30-day and 1-year adverse event rates. Compared with heparin plus a GPI, the use of bivalirudin monotherapy in patients with CKD results in nonstatistically different ischemic outcomes, but significantly less 30-day major bleeding.
Chronic kidney disease (CKD) in patients with coronary artery disease is strongly associated with reduced survival and an elevated incidence of bleeding complications after percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) (1–9). Thus, considerable research has been conducted to investigate optimal adjunctive antithrombotic medications to suppress bleeding complications while maintaining anti-ischemic activity in these patients (3–5,7,10,11). Bivalirudin is a direct thrombin inhibitor whose clearance is less dependent on renal function than heparin, hirudin, or glycoprotein IIb/IIIa inhibitors (GPIs) (12). Furthermore, because thrombin activity is increased in patients with CKD, the pharmacologic properties of bivalirudin support the possibility of particular benefit in patients with renal insufficiency (13).
The ACUITY (Acute Catheterization and Urgent Intervention Triage strategY) study demonstrated that in patients with moderate- and high-risk acute coronary syndromes (ACS) undergoing an early invasive strategy, bivalirudin monotherapy with provisional use of a GPI was associated with a comparable rate of ischemic events at 30 days and 1 year, but with a significantly lower incidence of 30-day major bleeding than heparin (either unfractionated heparin [UFH] or enoxaparin) plus a GPI (14,15). In this substudy of the ACUITY trial, we investigated the relationship between CKD and clinical outcomes at 30 days and 1 year, with a focus on the safety and efficacy of contemporary antithrombotic regimens in patients with ACS and baseline CKD as measured by the clinical end points used in the original study.
Patient population, randomization, and study protocol
The design and results of the ACUITY trial have been previously published (14–17). Briefly, 13,819 patients with moderate- and high-risk ACS undergoing an early, invasive management strategy were randomly assigned 1 × 1 × 1 in an open-label fashion to 1 of 3 antithrombin regimens starting immediately after randomization: a heparin (UFH or enoxaparin) plus a GPI (the control group), bivalirudin plus a GPI, or bivalirudin monotherapy with the provisional (bail-out) use of GPIs permitted only for limited pre-specified indications. Patients with baseline creatinine clearance (CrCl) <30 ml/min were excluded from enrollment.
UFH was administered as an intravenous bolus of 60 IU/kg plus an infusion of 12 IU/kg/h to achieve an activated partial thromboplastin time of 50 to 75 s before angiography and an activated clotting time of 200 to 250 s for patients undergoing PCI. Enoxaparin 1 mg/kg subcutaneously was administered at randomization and every 12 h thereafter until angiography. An additional intravenous bolus of 0.3 mg/kg or 0.75 mg/kg was administered before PCI if the most recent subcutaneous dose had been given >8 h or >16 h earlier, respectively. Bivalirudin was first administered upon presentation to the hospital with an intravenous bolus of 0.1 mg/kg and an infusion of 0.25 mg/kg/h. Before PCI, an additional intravenous bolus of 0.5 mg/kg was administered, and the infusion was increased to 1.75 mg/kg/h. Antithrombin agents were discontinued per protocol at the end of the procedure.
Patients assigned to a GPI arm were randomized again in a 2 × 2 factorial design to either upstream GPI initiation in all patients immediately after randomization or to deferred GPI initiation for selective use in PCI patients only starting in the catheterization laboratory. As per Food and Drug Administration-approved labeling, either eptifibatide or tirofiban was permitted for upstream use and either eptifibatide or abciximab was permitted for deferred selective use. Per study protocol, dosages of all GPIs were as per the package insert and were adjusted for calculated glomerular filtration rate.
Coronary angiography was required within 72 h of randomization, with subsequent triage to PCI, CABG, or medical management as per standard of care. Aspirin (300 to 325 mg orally or 250 to 500 mg intravenously) was administered before angiography. Clopidogrel dosing and timing were left to the discretion of the investigators, but in patients undergoing PCI, 300 mg of clopidogrel was required in all cases no later than 2 h after PCI. Clopidogrel 75 mg daily was recommended for 1 year in all patients after PCI and 75 to 325 mg of aspirin daily was recommended indefinitely. The study was approved by the institutional review board or ethics committee at each participating center, and all patients signed written, informed consent. The authors had full access to the data and take responsibility for its integrity. All authors have read and agreed to the manuscript as written.
End points and statistical methods
The ACUITY trial was powered for 3 primary 30-day end points: 1) composite ischemia, defined as death from any cause, myocardial infarction, or unplanned revascularization for ischemia; 2) major bleeding (non-CABG related), defined as intracranial, retroperitoneal, or intraocular bleeding, access site hemorrhage requiring intervention, hematoma ≥5 cm in diameter, reduction in hemoglobin of ≥4 g/dl without or ≥3 g/dl with an overt bleeding source, reoperation for bleeding, or blood product transfusion; and 3) net clinical outcome (composite ischemia or major bleeding) (16). Composite ischemia and mortality were assessed out to 1 year. A clinical events committee blinded to treatment assignment adjudicated all 30-day and 1-year primary end point events using original source documents.
CKD was defined as a calculated CrCl of <60 ml/min using the Cockcroft-Gault equation based on admission laboratory analysis (before any contrast media exposure). The present analysis examined baseline features and 30-day and 1-year outcomes: 1) of patients with versus those without CKD (CrCl ≥60 ml/min); and 2) by randomized group comparing each of the bivalirudin arms against the heparin plus GPI reference arm within the CKD cohort. In addition, a separate analysis was conducted in order to assess the impact of potential excess dose of study medication in CKD patients. Excess-dose patients were defined as those with: 1) CrCl <50 ml/min treated with more than the recommended dose of eptifibatide (>99 mμ/kg initial bolus or >1.1 mμ/kg/min initial infusion); and 2) CrCl <30 ml/min and receiving more than the recommended dose of enoxaparin (>0.55 mg/kg subcutaneously every 12 h or >0.165 mg/kg intravenously every 12 h). Although CrCl <30 ml/min was an exclusion criterion, a few such patients were enrolled. Only the first dose of enoxaparin after randomization was considered.
While CKD was a pre-specified subgroup for analysis, the ACUITY trial was not powered for formal superiority or noninferiority testing of this or any other subgroup. All analyses are by intention to treat. Chi-square tests were used for categorical variables. Continuous variables were tested using Wilcoxon rank sum test. Medians and interquartile ranges are presented for continuous variables. Follow-up analysis was performed using time-to-event data (for which patients were censored at the time of withdrawal from the study or at last follow-up) and were compared with the log-rank test.
Multivariable logistic regression analysis was performed to determine the predictors of composite ischemia and major bleeding. Potential predictors were selected using stepwise, forward, and backward procedures. Covariates were entered into the model with a p value ≤0.15 and retained with a p value ≤0.10. The final model includes all predictors that were selected by at least 1 of the 3 selection procedures. The p values, odds ratios (ORs), and corresponding 2-sided 95% confidence interval (CI) for predictors are presented. All statistical analyses were performed by SAS V8.2 (SAS Institute Inc., Cary, North Carolina).
CKD was present in 2,469 (19.1%) of 12,939 randomized patients with baseline CrCl data (Fig. 1). Baseline CrCl data were missing for 880 patients (6.8%). Baseline characteristics and treatment strategies by renal function are detailed in Table 1. Compared with patients without CKD, patients with CKD were more likely to be older, women, anemic, to have a history of hypertension or hyperlipidemia, to have had a previous myocardial infarction, to have undergone prior CABG surgery to be classified as high risk upon enrollment (defined as elevated creatine kinase-MB or troponin levels and/or ST-segment deviation), and to have ST-segment deviation. Patients without CKD were more likely to be smokers, to have higher body weight, and to have a family history of coronary artery disease. Patients without CKD were more likely to undergo PCI whereas those with CKD were more often medically managed. Proportion of patients who received enoxaparin did not differ significantly between groups with and without CKD (22.5% vs. 23.5%, p = 0.16), though patients who received enoxaparin <8 h before PCI were slightly more common in the CKD group (69.9% vs. 65.9%, p = 0.06) while patients who received enoxaparin ≥16 h before PCI were less common in the CKD group (25.0% vs. 29.2%, p = 0.04).
Renal function and outcome
Table 2 presents 30-day and 1-year clinical outcome data in patients with versus without CKD. Patients with CKD compared with those without had significantly higher rates of composite ischemia (10.8% vs. 7.0%, p < 0.0001) and major bleeding (9.2% vs. 3.6%, p < 0.0001) with a resultant increase in net clinical outcomes (17.5% vs. 9.9%, p < 0.0001). With respect to the components of the composite ischemic end point, patients with CKD had significantly increased rates of death, myocardial infarction, and unplanned revascularization. Non-CABG minor bleeding, Thrombolysis In Myocardial Infarction (TIMI) major and minor bleeding, and thrombocytopenia also occurred significantly more frequently in patients with versus without CKD. Patients with CKD were significantly more likely to experience retroperitoneal bleeding, access site hemorrhage, hematoma ≥5 cm in diameter, a hemoglobin drop of ≥4 g/dl without overt bleeding, or ≥3 g/dl with overt bleeding, and to require blood product transfusions. At 1 year, rates of composite ischemia (21.6% vs. 14.4%) and mortality (7.9% vs. 2.8%) were significantly higher (both p < 0.001) in patients with CKD compared with those without CKD (Table 2).
As seen in Table 3, bleeding and adverse ischemic events occurred more frequently with decreasing renal function. Patients with CrCl <30 or 30 to 59 ml/min had significantly higher rates of major bleeding and ischemic events at 30 days and 1 year compared with those patients with CrCl 60 to 89 or >90 ml/min.
Impact of antithrombotic regimen in patients with CKD
Baseline demographic, clinical, and procedural characteristics among the 3 randomized groups were similar except for mean serum CrCl values, which were lowest in the bivalirudin monotherapy group (45.4 ± 12.3 ml/min) compared with patients in the heparin plus GPI group (47.3 ± 10.8 ml/min, p = 0.005) and patients in the bivalirudin plus GPI group (46.0 ± 11.5 ml/min, p = 0.67 and p = 0.01 as compared with bivalirudin alone and heparin plus GPI groups, respectively). At 30 days, patients with CKD treated with bivalirudin alone compared with those treated with heparin plus a GPI had a remarkably reduced rate of non-CABG major bleeding (6.2% vs. 9.8%, p = 0.008), though somewhat higher rates of composite ischemia (11.1% vs. 9.4%, p = 0.27) (Table 4). None of the individual end points of composite ischemia differed significantly between patients treated with bivalirudin monotherapy and those treated with heparin plus a GPI (Table 4). This was also true with regard to 30-day composite death or myocardial infarction. By formal interaction testing, there was no significant interaction between the presence or absence of CKD; antithrombin randomization; and the occurrence of composite ischemia, major bleeding, or net clinical outcomes (p values for interaction = 0.49, 0.25, and 0.42, respectively). Excluding access site hematoma still resulted in significant reduction of major bleeding rates in favor of bivalirudin compared with heparin plus a GPI (5.6% vs. 8.5%, p = 0.024). Non-CABG minor bleeding, TIMI major bleeding, TIMI minor bleeding, access site hemorrhage, hemoglobin decreases of ≥3 g/dl with overt bleeding, and blood transfusions all occurred significantly less frequently in the bivalirudin alone arm compared with the heparin plus GPI arm. At 1 year, rates of composite ischemia were slightly but nonsignificantly higher in the bivalirudin monotherapy arm versus the heparin plus GPI arm (22.0% vs. 18.9%, p = 0.10). However, rates of hard clinical end points including mortality (7.1% vs. 7.3%, p = 0.96), Q-wave myocardial infarction (9.9% vs. 8.5%, p = 0.29), and the composite of death or myocardial infarction (15.6% vs. 13.9%, p = 0.33) were not significantly different between the 2 arms (Fig. 2).
Assessment of dosing
We performed a separate analysis to identify and exclude any patients who may have received more than the recommended dose from the package insert in order to determine if the overall results persisted. A total of 428 patients (17%) with CKD and potential excess dosing as previously described were excluded from the analyses (204 patients in the heparin plus GPI group [25%], 208 patients in the bivalirudin plus GPI group [25%], and 16 patients in the bivalirudin monotherapy arm [2%]). In the subset of correctly dosed patients, at 30 days, bivalirudin monotherapy compared with heparin plus a GPI provided similar protection from composite ischemia (10.8% vs. 9.0%, p = 0.26) with significantly less major bleeding (6.1% vs. 9.0%, p = 0.04). One-year results were concordant with the overall findings, without any interaction between excess dosage and clinical outcome, and with no significant differences observed in composite ischemia (21.3% vs. 18.2%, p = 0.11) or mortality (7.0% vs. 6.4%, p = 0.61) among those treated with bivalirudin monotherapy versus heparin plus a GPI.
Factors associated with composite ischemia and major bleeding in patients with CKD
A multivariable logistic regression analysis was performed to evaluate the impact of baseline characteristics on composite ischemia and 30-day (non-CABG related) major bleeding in all patients with CrCl <60 ml/min. Factors associated with composite ischemia included presence of ST-segment deviation ≥1 mm (OR: 1.61 [95% CI: 1.23 to 2.11], p = 0.0005), prior cerebrovascular accident (stroke or transient ischemic attack) (OR: 1.79 [95% CI: 1.19 to 2.67], p = 0.005), positive cardiac markers (OR: 1.58 [95% CI: 1.18 to 2.12], p = 0.002), and baseline anemia (OR: 1.51 [95% CI: 1.14 to 1.99], p = 0.004), but did not include randomization to bivalirudin compared with heparin plus GPI (OR: 1.15 [95% CI: 0.83 to 1.60], p = 0.54). Factors associated with major bleeding included baseline anemia, prior cerebrovascular accident, diabetes mellitus, electrocardiogram changes, female gender, and treatment with heparin plus the routine use of a GPI rather than bivalirudin monotherapy (Fig. 3).
The main findings of this analysis of patients with moderate- and high-risk non–ST-segment elevation ACS undergoing an early invasive management strategy are as follows: 1) treatment with bivalirudin monotherapy resulted in significantly fewer 30-day bleeding complications with no significant difference in either composite ischemia or mortality at 30 days or 1 year compared with treatment with heparin plus a GPI; and 2) the results were consistent after patients who received excess dosages of either eptifibatide or enoxaparin were excluded from the analysis, providing evidence that the reduced rate of major bleeding observed with bivalirudin monotherapy among patients with CKD is not driven by excess dosing in the heparin plus GPI arm. Our findings are consistent with the overall results of the ACUITY study in terms of the effect of bivalirudin monotherapy on composite ischemia, major bleeding, and net clinical outcomes at 30 days and 1 year (14,15).
CKD and coronary artery disease
In agreement with previous studies, the presence of CKD in this analysis was associated with a significantly increased incidence of bleeding complications at 30 days as well as an increased incidence of ischemic events and mortality at 30 days and 1 year (2,5–7,9,18). This may, in part, be attributable to the frequent presence of comorbid conditions and more advanced coronary artery disease in patients with CKD. High-risk characteristics such as older age, hypertension, anemia, hyperlipidemia, elevated levels of cardiac biomarkers, and ST-segment changes were more common in patients with CKD. Increased systemic inflammation, heightened coagulation, and greater atheromatous plaque burden may also contribute to a higher risk of acute adverse events (19–22). Furthermore, just as in the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the American College of Cardiology/American Heart Association Guidelines) registry (9), PCI in the ACUITY study was used less frequently in patients with CKD than in those without CKD. Whether this contributed to the worse prognosis in these patients is uncertain.
CKD and bleeding complications
In the present study, patients with CKD demonstrated a 3-fold increase in major bleeding complications. This excess bleeding risk may be attributed to functional abnormalities in platelets and coagulation in these patients (23). Therefore, when treating patients with CKD presenting with non–ST-segment elevation ACS, administration of the optimal antithrombotic regimen should minimize the risk of hemorrhagic complications while providing sufficient protection from adverse ischemic events. In previous studies, both GPIs and bivalirudin significantly decreased the risk of early ischemic or thrombotic events in patients with ACS compared with traditional heparin therapy (1,3,4,10,24,25), though an increased bleeding risk was noted with GPIs in patients with CKD (1,3,25). The results of the present study, demonstrating reduced major bleeding in patients with CKD randomized to bivalirudin monotherapy rather than heparin plus a GPI, confirms the results of an earlier meta-analysis (3). However, an important finding from this analysis is that bivalirudin was no more beneficial in patients with CKD when used in combination with a GPI. Moreover, in the bivalirudin plus GPI arm, there was a trend toward higher rates of 30-day composite ischemia (11.9% vs. 9.4%, p = 0.11), major bleeding (11.4% vs. 9.8%, p = 0.29), and net clinical outcome (19.5% vs. 16.9%, p = 0.17) compared with the heparin plus GPI arm. Thus, physicians should be aware that the combination of bivalirudin and a GPI in patients with CKD may increase bleeding and ischemic adverse events, and should be administered only in bail-out situations.
Higher, although not significantly so, rates of the composite ischemic end point of death/myocardial infarction/unplanned revascularization in the bivalirudin arm as opposed to the heparin plus GPI arm at 30-day and 1-year follow-up in this analysis deserves comment. Had more patients been enrolled, it is possible that the difference between the 2 groups in rates of the composite ischemic end point would have been more apparent. Yet, hard clinical end points of death, myocardial infarction, or composite death/myocardial infarction did not differ significantly between the 2 groups, and by multivariable analysis composite ischemia was not associated with randomization to bivalirudin. Finally, given the fact that bleeding represents a short- and long-term mortality risk for non–ST-segment elevation ACS patients that is at least equivalent to that of ischemic events (26–28), preventing both ischemic and bleeding complications is important for optimizing patient outcomes.
For patients undergoing elective or urgent PCI, the REPLACE-2 (Second Randomized Evaluation in PCI Linking Bivalirudin to Reduced Clinical Events) trial showed that, among 886 patients with CKD, bivalirudin monotherapy resulted in fewer major bleeding complications than heparin plus a GPI (3.2% vs. 7.1%, p = 0.009), with no significant differences in 30-day rates of composite ischemia (5.1% vs. 7.1%, p = 0.21) (10). And given the previous finding in the CRUSADE trial that patients with CKD are less likely to receive American College of Cardiology/American Heart Association guidelines-recommended therapies due to the fear of bleeding complications, the present study suggests that the use of bivalirudin plus bail-out GPI (with its reduction of bleeding risk) may permit more appropriate evidence-based use of PCI. This would potentially improve clinical outcomes in patients with NSTE-ACS and CKD.
Agents such as enoxaparin and eptifibatide are supposed to be dose-adjusted for patients with CKD per current package inserts. However, at the time the ACUITY trial was enrolling, the package insert for enoxaparin did not specify dose adjustments. Clinical trials and large registries have raised concerns that, even with package-insert recommended adjusted dosing, some patients were still potentially at risk of receiving an excess dose of either enoxaparin, eptifibatide, or both. This is an important consideration because excess dosing may result in increased bleeding complications (29,30). For example, an analysis of the large CRUSADE registry (31) demonstrated that an excess dose of enoxaparin—compared with a recommended dose—was significantly associated with major bleeding (OR: 1.43; 95% CI: 1.18 to 1.75) and death (OR: 1.35; 95% CI: 1.03 to 1.77). In the ACUITY trial, not only was bivalirudin less frequently associated with excess dosing (perhaps due to greater adherence to the dosage chart of the investigational agent), but it was also associated with similar overall results after exclusion of patients with excess dosing.
Several limitations of the present analysis must be addressed. First, while CKD was a pre-specified subgroup for analysis, the ACUITY trial was not powered for formal superiority or noninferiority testing of this or any other subgroup, so these results should be considered exploratory (32). Nonetheless, this is the largest cohort of patients with CKD enrolled in a prospective randomized trial of patients with non–ST-segment elevation ACS. Second, the precise mechanism of the association between CKD and a high rate of complications was not elucidated by this analysis. Third, approximately 9% of patients in the ACUITY study who did not have baseline CrCl data were not included in this analysis. Finally, the ACUITY trial did not enroll patients with severe CKD (CrCl <30 ml/min or those requiring dialysis). Further study is required to determine the optimal anticoagulant regimen in patients with that degree of renal impairment.
In summary, we found that in patients presenting with moderate- and high-risk non–ST-segment elevation ACS undergoing an early invasive strategy, CKD was associated with an increased incidence of ischemic and bleeding complications and reduced 30-day and 1-year survival. In these patients, treatment with bivalirudin monotherapy resulted in a significant reduction in major bleeding complications at 30 days, and no significant difference in either ischemic complications or mortality at 30 days and 1 year compared with heparin plus the routine use of GPIs. These findings indicate that bivalirudin monotherapy is an acceptable alternative to heparin plus a GPI in patients with CKD.
The ACUITY trial was sponsored by The Medicines Company. Dr. Mehran has received research grants from The Medicines Company. Dr. Dangas is a consultant for Lilly and Daichi-Sankyo and is a member of the Speakers' Bureaus of Sanofi-Aventis, Astra Zeneca, and the Medicines Company. Dr. Kirtane is a member of the Speakers' Bureau of The Medicines Company. Dr. Feit is a consultant for the Medicines Company and a shareholder of Millennium Pharmaceuticals, Johnson & Johnson, and The Medicines Company. Dr. Manoukian is a consultant, member of the Speakers' Bureau, and has received honoraria from The Medicines Company. Dr. Ebrahimi is a consultant and member of the Speakers' Bureau of The Medicines Company. Dr. Ohman is a consultant for The Medicines Company, Inovise, Savacor, Liposcience, Response Biomedical, Datascope, and Abioed; is in receipt of research grants from Sanofi-Aventis, Bristol-Myers Squibb, Eli Lilly, Berlex, and Millennium Pharmaceuticals; is on the Speakers' Bureau of Schering Plough and CV Therapeutics; and is a shareholder of Inovise, Savacor, and Medtronic. Dr. White is in receipt of research grants from Sanofi-Aventis, Eli Lilly, Merck Sharpe & Dohme, The Medicines Company, Neuren Pharmaceuticals, NIH, GlaxoSmithKline, Pfizer, Roche, Fournier Laboratories, Johnson & Johnson, Schering Plough, and Janssen-Cilag; is a consultant for Medicure, The Medicines Company, Neuren Pharmaceuticals, GlaxoSmithKline, Bayer, and Sanofi-Aventis; and has received honoraria from Sanofi-Aventis and The Medicines Company. Dr. Pocock is in receipt of honoraria from The Medicines Company. Dr. Stone is a consultant for The Medicines Company and has received research grants from The Medicines Company.
- Abbreviations and Acronyms
- acute coronary syndromes
- coronary artery bypass grafting
- confidence interval
- chronic kidney disease
- creatinine clearance
- glycoprotein IIb/IIIa inhibitor
- odds ratio
- percutaneous coronary intervention
- unfractionated heparin
- Received February 4, 2009.
- Revision received May 26, 2009.
- Accepted May 29, 2009.
- American College of Cardiology Foundation
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