Author + information
- Received April 29, 2011
- Revision received June 8, 2011
- Accepted June 23, 2011
- Published online September 1, 2011.
- Adam J. Saltzman, MD⁎,
- Gregg W. Stone, MD⁎,
- Bimmer E. Claessen, MD⁎,
- Amar Narula, MD⁎,
- Selene Leon-Reyes, PhD⁎,
- Giora Weisz, MD⁎,
- Bruce Brodie, MD‡,
- Bernhard Witzenbichler, MD§,
- Giulio Guagliumi, MD∥,
- Ran Kornowski, MD¶,
- Dariusz Dudek, MD#,
- D. Christopher Metzger, MD⁎⁎,
- Alexandra J. Lansky, MD⁎,
- Eugenia Nikolsky, MD, PhD⁎,
- George D. Dangas, MD, PhD† and
- Roxana Mehran, MD⁎,†,⁎ ()
- ↵⁎Reprint requests and correspondence:
Dr. Roxana Mehran, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, New York 10029
Objectives This study sought to investigate the impact of chronic kidney disease (CKD) in patients undergoing percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI) with different antithrombotic strategies.
Background CKD is associated with increased risk of adverse ischemic and hemorrhagic events after primary PCI for STEMI.
Methods HORIZONS-AMI (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction) trial was a multicenter, international, randomized trial comparing bivalirudin monotherapy or heparin plus a glycoprotein IIb/IIIa inhibitor (GPI) during primary PCI in STEMI. CKD, defined as creatinine clearance <60 ml/min, was present at baseline in 554 of 3,397 patients (16.3%). Patients were followed for 3 years. Net adverse cardiac event (NACE) was defined as the composite of death, reinfarction, ischemia-driven target vessel revascularization (TVR), stroke or non–coronary artery bypass grafting (CABG)-related major bleeding.
Results Patients with CKD compared with patients without had higher rates of NACE (41.4% vs. 23.8%, p < 0.0001), death (18.7% vs. 4.4%, p < 0.0001), and major bleeding (19.3% vs. 6.7%, p < 0.0001). Multivariable analysis identified baseline creatinine as an independent predictor of death at 3 years (hazard ratio: 1.51, 95% confidence interval: 1.21 to 1.87, p < 0.001). Patients with CKD randomized to bivalirudin monotherapy versus heparin plus GPI had no significant difference in major bleeding (19.0% vs. 19.6%, p = 0.72) or death (19.0% vs. 18.4%, p = 0.88) at 3 years. In patients with CKD, there was no difference in the rates of TVR in bare-metal stents (BMS) versus drug-eluting stents (DES) at 3 years (14.1% vs. 15.1%, p = 0.8).
Conclusions STEMI patients with CKD have significantly higher rates of death and major bleeding compared with those without CKD. In patients with CKD, there appears to be no benefit of bivalirudin compared with heparin + GPI, or DES versus BMS during primary PCI in improving clinical outcomes.
Chronic kidney disease (CKD) is associated with reduced survival and increased bleeding in patients undergoing percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) for a variety of indications, including ST-segment elevation myocardial infarction (STEMI) (1–13). Substantial research has focused on identifying optimal antithrombotic agents in this patient population to maximize clinical benefit while minimizing bleeding complications (14). Previous work has suggested that patients with CKD have increased levels of oxidative stress, accelerated atherosclerosis, increased levels of thrombin, and suboptimal use of guideline-recommended therapies (15). Earlier data have demonstrated that bivalirudin, a direct thrombin inhibitor, may be associated with better outcomes in patients with CKD (8,16–18). In a previous analysis of CKD patients with non–ST-segment elevation acute coronary syndromes, treatment with bivalirudin was demonstrated to have similar ischemic outcomes, but significantly less 30-day major bleeding than unfractionated heparin (UFH) or enoxaparin plus glycoprotein IIb/IIIa inhibitors (GPIs) (13).
The HORIZONS-AMI (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction) trial demonstrated that in patients with STEMI, bivalirudin compared with UFH plus a GPI was associated with lower rates of major bleeding, cardiac mortality, and all-cause mortality at 30 days and 1 year (19,20). In this substudy of HORIZONS-AMI, we examined the relationship between CKD and clinical outcomes with follow-up through 3 years. Moreover, we investigated the relative safety and efficacy of an antithrombotic regimen consisting of bivalirudin monotherapy compared with UFH plus a GPI in patients with and without CKD.
Patient population, randomization, and study protocol
The design, inclusion and exclusion criteria, and results of the HORIZONS-AMI trial have been previously published (19–21). Briefly, HORIZONS-AMI was a prospective, open-label, multicenter trial involving patients with STEMI who were undergoing primary PCI as a management strategy. A total of 3,602 patients with STEMI presenting within 12 h of symptom onset were prospectively randomized to UFH plus the routine use of a GPI versus bivalirudin plus provisional use of a GPI reserved for predefined refractory thrombotic complications. Immediate coronary angiography with left ventriculography was performed after randomization, followed by PCI, CABG, or medical management at the discretion of the physician. In a second randomization, 3,006 eligible patients were randomly assigned to either a Taxus Express paclitaxel-eluting stent (Boston Scientific, Natick, Massachusetts) or to an otherwise identical Express bare-metal stent (BMS) (Boston Scientific).
UFH was administered as an intravenous bolus of 60 IU/kg, and then continued boluses were administered to reach a target activated clotting time of 200 to 250 s. GPIs were administered before PCI in all patients in the control group; either abciximab (a bolus of 0.25 mg/kg followed by an infusion of 0.125 μg/kg/min; maximum dose, 10 μg/min) or double-bolus eptifibatide (a bolus of 180 μg/kg followed by an infusion of 2.0 μg/kg/min, with a second bolus given 10 min after the first) was permitted at the discretion of the investigator and was continued for 12 h (abciximab) or 12 to 18 h (eptifibatide). In patients with a creatinine clearance (CrCl) <50 ml/min, the infusion dose of eptifibatide was reduced to 1.0 μg/kg/min. Bivalirudin was administered as an intravenous bolus of 0.75 mg/kg, followed by an infusion of 1.75 mg/kg/h. For patients with a CrCl <30 ml/min, the infusion rate was decreased to 1 mg/kg/h. For those patients on hemodialysis, the infusion rate was decreased to 0.25 mg/kg/h. Both heparin and bivalirudin were discontinued at the completion of angiography or PCI unless clinically indicated thereafter.
Aspirin (324 mg given orally or 500 mg administered intravenously) was given in the emergency room, after which 300 to 325 mg was given orally every day during the hospitalization and 75 to 81 mg every day thereafter indefinitely. A loading dose of clopidogrel (either 300 mg or 600 mg, at the discretion of the investigator), or ticlopidine (500 mg), in case of allergy to clopidogrel, was administered before catheterization, followed by 75 mg orally every day for at least 6 months (1 year or longer recommended).
The study was approved by the institutional review board or ethics committee at each participating center, and all patients signed written, informed consent.
Study endpoints and definitions
The HORIZONS-AMI trial was powered for two 30-day endpoints: major bleeding (not related to CABG) and combined net adverse clinical events (NACE, consisting of non–CABG-related major bleeding or a composite of major adverse cardiovascular events (MACE), including death, reinfarction, target vessel revascularization for ischemia, or stroke). Non–CABG-related major bleeding was defined as intracranial or intraocular hemorrhage, a 5-cm or greater hematoma at the access site, or bleeding requiring intervention, a decrease in the hemoglobin level ≥4 g/dl without an overt bleeding source or ≥3 g/dl with an overt bleeding source, reoperation for bleeding, or blood transfusion. Outcomes for the primary endpoints were assessed out to 3 years. All events were adjudicated by an independent clinical events committee blinded to treatment assignment.
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) (22). Anemia was defined using the World Health Organization criteria (hemoglobin ≤13 g/dl for men and ≤12 g/dl for women) (23). The present analysis examined the baseline features and 30-day, 1-year, and 3-year outcomes in patients with CKD (CrCl ≤60 ml/min) and severe CKD (CrCl ≤30 ml/min) versus those without, and patients randomized to bivalirudin versus UFH plus a GPI according to the presence or absence of CKD.
All analyses are by intention to treat. Chi-square tests were used to compare categorical variables. Continuous variables are presented as medians with interquartile ranges, and were compared using the Wilcoxon rank sum test. 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), with the event rates estimated by Kaplan-Meier methods, and were compared with the log-rank test. Cox multivariable regression models were used to identify independent predictors of NACE, death, MACE, and major bleeding. The model included age, diabetes, recent smoking, hypertension, hyperlipidemia, prior myocardial infarction (MI), prior PCI, prior CABG, congestive heart failure (CHF), peripheral vessel disease, end-stage renal disease on current dialysis, major cardiac rhythm/rate disturbance, gender, Killip class 2 to 4 (vs. class 1), baseline Thrombolysis In Myocardial Infarction score 0 to 1 (vs. 2 to 3), creatinine level, left ventricular ejection fraction (10% decrease), platelet count (per 100,000 increase), current smoker, baseline hemoglobin (10-U decrease), mitral regurgitation 3 to 4+ (vs. 1 to 2), left anterior descending disease, and randomization arm (bivalirudin monotherapy vs. UFH plus a GPI). The final Cox models used were selected by the use of a stepwise selection algorithm, with an entry and exit level of significance of 0.10. Interaction tests were performed using multivariable Cox models with main effects of CKD and randomization arm plus the interaction only. All statistical analyses were performed by SAS version 9.2 (SAS Institute Inc., Cary, North Carolina).
Of the 3,602 randomized patients, 3,397 patients had available baseline creatinine clearance data, 554 of whom (16.3%) had CKD (Fig. 1). Compared with those without CKD, patients with CKD were more likely to be older, female, diabetic, anemic, or hypertensive, to have had prior MI, and to have undergone prior PCI or CABG (Table 1). Patients with CKD were more likely to have peripheral artery disease, and more often had Killip class >1 at the time of presentation compared with those without CKD. There was no difference in the primary management strategy (PCI, CABG, medical) or in the type of stent used between those with and without CKD. CKD patients were less likely to receive an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, statin, or beta-blocker at discharge. There were no significant differences in patients with and without CKD in the discharge rates of aspirin (96.9% vs. 97.7%, p = 0.28) or clopidogrel (91.2% vs. 91.6%, p = 0.73) use. Patients with (n = 3,337) compared with patients without (n = 265) available baseline creatinine data had no significant differences in NACE (26.7% vs. 25.0%, p = 0.6), death (6.8% vs. 7.6%, p = 0.6), or major bleeding (8.7% vs. 8.2%, p = 0.8).
Renal function and clinical outcomes
Patients with compared with those without CKD had increased rates of NACE at 30 days (21.3% vs. 9.0%, p < 0.0001), 1 year (30.3% vs. 14.4%, p < 0.0001), and 3 years (41.4% vs. 23.8%, p < 0.0001), with the hazard curves diverging over time (Fig. 2A). At 3 years, patients with compared with those without CKD had higher rates of death (18.7% vs. 4.4%, p < 0.0001) (Fig. 2B), major bleeding (non–CABG-related) (19.3% vs. 6.7%, p < 0.0001) (Fig. 2C), stroke (3.2% vs. 1.6%, p = 0.01), and MACE (16.0% vs. 11.1%, p = 0.003) (Fig. 2D). At 3 years, 52.9% of patients presenting with STEMI and more advanced CKD (CrCl <30 ml/min) were deceased (Table 2). Multivariate analysis confirmed admission creatinine as an independent predictor of risk for death (hazard ratio [HR]: 1.51, 95% confidence interval [CI]: 1.21 to 1.87, p < 0.001), NACE (HR: 1.39, 95% CI: 1.24 to 1.56, p < 0.0001), MACE (HR: 1.38, 95% CI: 1.20 to 1.59, p < 0.0001), and non-CABG major bleeding (HR: 1.43, 95% CI: 1.26 to 1.62, p < 0.0001) at 3 years (Table 3).
There was no difference between those with versus without CKD in the type of stent received (Taxus drug-eluting stent [DES], 75.0% vs. 75.5%, p = 0.83; Express BMS 25.0% vs. 24.5%, p = 0.83). In patients without CKD, the rate of MACE at 3 years was significantly higher in those receiving BMS compared with DES (22.7% vs. 18.1%, p = 0.01) primarily driven by increased rates of target vessel revascularization (TVR) in the BMS group (18.2% vs. 13.2%, p = 0.003). However, in patients with CKD, there was no difference in the 3-year MACE rates in those receiving BMS versus DES (33.3% vs. 33.6%, p = 0.9), and there was no difference in rates of TVR in BMS versus DES at 3 years (14.1% vs. 15.1%, p = 0.8). The test for interaction of CKD and stent type used on 3-year outcomes showed no significance for death, MACE, NACE, stent thrombosis, or TVR (Table 4).
Impact of antithrombotic regimen in patients with CKD
Baseline demographic, clinical, and procedural characteristics were similar among patients with CKD in the 2 antithrombotic treatment groups. However, peak activated clotting time values were higher (381 s vs. 272 s, p < 0.0001), and rates of use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers at discharge were lower (69.3% vs. 78.9%, p = 0.0132) in the bivalirudin group compared with the UFH plus GPI group. Among patients with CKD treated with bivalirudin versus UFH + GPI, there were no significant differences in NACE and death at 30 days or 3 years (Table 5). In contrast, in patients without CKD, patients treated with bivalirudin had lower 30-day rates of NACE (7.3% vs. 10.7%, p = 0.002), driven by significantly reduced rates of mortality and major bleeding. In patients without CKD, the difference in NACE at 1 year (13.2% vs. 15.4%, p = 0.08) and 3 years was no longer significant. However, bivalirudin monotherapy resulted in significantly less non–CABG-related major bleeding at 3 years compared with heparin plus a GPI (5.0% vs. 8.5%, p = 0.0003), and reduced mortality (3.4% vs. 5.4%, p = 0.01). The interaction between CKD and antithrombotic strategy was significant for death at 30 days (p = 0.02), and approached statistical significance for death (p = 0.07) and major bleeding (p = 0.06) at 3 years (Table 5).
In the present analysis from the HORIZONS-AMI study, the presence of CKD in patients with STEMI undergoing PCI was a powerful predictor of adverse clinical events at 3 years. Patients with CKD had higher 3-year rates of death, stroke, non–CABG-related major bleeding, and the composite outcomes of MACE and NACE. High-risk patients with CKD did not experience lower rates of NACE with bivalirudin monotherapy compared with UFH and a GPI. In addition, the long-term benefit of DES on TVR appears to be diminished in patients with CKD.
In multivariable analysis, admission creatinine was an independent predictor for death, MACE, NACE, and major bleeding at 3 years. Indeed, CKD conferred greater risk for NACE then traditional STEMI risk factors such as a reduced ejection fraction, left anterior descending coronary artery culprit vessel, or a high Killip class. Interestingly, low-admission hemoglobin conferred the greatest risk (HR: 3.10, CI: 2.03 to 6.11, p < 0.0001) for NACE at 3 years. In addition, patients with the lowest CrCl (<30 ml/min) experienced a relative increase in clinical events compared with patients with moderate CrCl 30 to 60 ml/min reduction. The risk of dying within 3 years if one presents with a CrCl <30 ml/min and a STEMI exceeds most major cancers.
Consistent with previous reports, CKD was associated with higher rates of adverse clinical events in the current study (24,25). Compared with patients without CKD, patients with CKD have more cardiac risk factors and comorbid conditions. Moreover, patients with CKD received fewer evidence-based strategies to modify cardiovascular risk compared with patients without CKD (7,26). Notably, the predominant driver for the higher rates of NACE in CKD patients over 3 years were death, stroke, and major bleeding, not reinfarction or repeat revascularization. The 3-fold increase in bleeding in the current study is consistent with a previous report highlighting the impact of CKD on bleeding complications (13), and may be attributed to functional abnormalities in platelets and coagulation factors in patients with CKD (27,28).
In the HORIZONS-AMI trial, among 3,602 patients with STEMI undergoing primary PCI randomized to bivalirudin monotherapy versus heparin + GPI, bivalirudin resulted in reduced rates of major bleeding, cardiac mortality, and all-cause mortality. Somewhat surprisingly, these benefits were restricted largely to patients without CKD. In contrast, a meta-analysis of 3 randomized trials comparing bivalirudin with UFH during PCI showed a significant reduction in bleeding events with bivalirudin in patients with an estimated glomerular filtration rate of 30 to 59 ml/min (8). Moreover, a subgroup analysis of 886 patients with CKD in the REPLACE-2 (Second Randomized Evaluation in PCI Linking Bivalirudin to Reduced Clinical Events) trial reported fewer major bleeding complications (3.2% vs. 7.1%, p < 0.01) and no significant difference in 30-day rates of a composite ischemic endpoint (5.1% vs. 7.1%, p = 0.21) with bivalirudin compared with UFH plus a GPI (16). Finally, a recent analysis from the ACUITY (Acute Catheterization and Urgent Intervention Triage strategY) trial reported significantly lower rates of 30-day major bleeding with bivalirudin monotherapy compared with UFH plus a GPI in 2,469 patients with non–ST-segment elevation acute coronary syndromes and CKD (13). The interaction p values in the present study are of borderline significance, and with only 554 STEMI patients with CKD, we cannot exclude the possibility that chance may explain the differences between the present and prior bivalirudin trials in patients with CKD (20,29,30).
Although CKD was a pre-specified subgroup for analysis, the HORIZONS-AMI trial was not powered for formal superiority or noninferiority testing of this subgroup, and the results should be considered hypothesis generating. Furthermore, 7.4% of patients randomized in the HORIZONS-AMI trial did not have baseline creatinine values and were excluded from the present analysis.
In STEMI patients treated with primary PCI, CKD was associated with increased long-term rates of NACE, bleeding, and death. There appears to be no benefit of bivalirudin compared with heparin + GPI during PCI in reducing major bleeding and mortality in patients with CKD. In addition, there appears to be no benefit for DES on future TVR in patients with CKD. Further investigation is warranted to identify novel therapeutic strategies to improve the untoward prognosis of patients with CKD and STEMI.
Dr. Stone is a consultant for Boston Scientific, Abbott Vascular, Medtronic, and The Medicines Co. Dr. Witzenbichler has received lecture fees (modest) from The Medicines Company and Boston Scientific. Dr. Guagliumi has received grant/research support from Boston Scientific, Medtronic Vascular, LightLab Imaging, and Labcoat; and is a consultant for Boston Scientific, Cordis, and Volcano. Dr. Dudek has received research grants or served as consultant/advisory board member for Abbott, Adamed, AstraZeneca, Biotronik, Balton, Bayer, BBraun, BioMatrix, Boston Scientific, Boehringer Ingelheim, Bristol-Myers Squibb, Cordis, Cook, Eli Lilly, EuroCor, Glaxo, Invatec, Medtronic, The Medicines Co., MSD, Nycomed, Orbus-Neich, Pfizer, Possis, Promed, Sanofi-Aventis, Siemens, Solvay, Terumo, and Tyco. Dr. Metzger is a consultant for Abbott, Cordis, and IDEV. Dr. Dangas is a consultant for AstraZeneca; has received research grants from BMS/Sanofi-Aventis and The Medicines Co.; and whose spouse is on the advisory board for Abbott Vascular, Ortho McNeil, and Regado BioSciences. Dr. Mehran is on the advisory board of Abbott Vascular, Ortho McNeil, and Regado Biosciences; has received research support from BMS/Sanofi-Aventis; and whose spouse is a consultant for AstraZeneca and has received research grant support from The Medicines Co. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- bare-metal stent(s)
- coronary artery bypass grafting
- confidence interval
- chronic kidney disease
- creatinine clearance
- drug-eluting stent(s)
- glycoprotein IIb/IIIa inhibitor
- hazard ratio
- major adverse cardiovascular event(s)
- net adverse cardiac event(s)
- percutaneous coronary intervention
- ST-segment elevation myocardial infarction
- target vessel revascularization
- unfractionated heparin
- Received April 29, 2011.
- Revision received June 8, 2011.
- Accepted June 23, 2011.
- American College of Cardiology Foundation
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