Published online before print March 30, 2009, doi: 10.1161/CIRCULATIONAHA.108.821843
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(Circulation. 2009;119:1899-1907.)
© 2009 American Heart Association, Inc.
Health Services and Outcomes Research |
Elevated Admission Glucose and Mortality in Elderly Patients Hospitalized With Heart Failure
From the Mid America Heart Institute of Saint Luke’s Hospital, Kansas City, Mo (M.K., J.A.S.); University of Missouri, Kansas City (M.K., J.A.S.); Yale University (S.E.I., Y.W., H.M.K.) and Yale–New Haven Hospital, New Haven, Conn (S.E.I., H.M.K.); and Denver Health Medical Center and University of Colorado at Denver and Health Sciences Center, Denver (F.A.M., E.P.H.).
Correspondence to Mikhail Kosiborod, MD, Mid America Heart Institute of Saint Luke’s Hospital, 4401 Wornall Rd, Kansas City, MO 64111. E-mail mkosiborod{at}cc-pc.com
Received June 2, 2008; accepted February 9, 2009.
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Abstract |
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Background— Although some professional societies recommend target-driven glucose control for all hospitalized patients, the association between elevated glucose and adverse outcomes has not been well established in patients hospitalized with heart failure.
Methods and Results— We evaluated a nationally representative cohort of 50 532 elderly patients hospitalized with heart failure in the United States between April 1998 and June 2001. The association between admission glucose and all-cause mortality at 30 days and 1 year was analyzed with multivariable Cox regression models, both in the entire cohort and in patients with and without diabetes mellitus. After multivariable adjustment, no significant relationship was found between glucose and 30-day mortality (for glucose groups of >110 to 140, >140 to 170, >170 to 200, and >200 mg/dL; hazard ratios for 30-day mortality were 1.09 (95% confidence interval, 0.98 to 1.22), 1.27 (95% confidence interval, 1.11 to 1.45), 1.16 (95% confidence interval, 0.98 to 1.37), and 1.00 (95% confidence interval, 0.87 to 1.15), respectively, versus glucose 
110 mg/dL; P for linear trend=0.53). Results were similar for 1-year mortality and did not differ between patients with and without known diabetes mellitus (for diabetesxglucose interaction, P=0.11 and 0.55 for 30-day and 1-year mortality, respectively).
Conclusions— We found no significant association between admission glucose levels and mortality in a large cohort of patients hospitalized with heart failure. Our findings suggest that the relationship between hyperglycemia and adverse outcomes seen in acute myocardial infarction cannot be automatically extended to patients hospitalized with other cardiovascular conditions.
Key Words: diabetes mellitus • glucose • heart failure • prognosis
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Introduction |
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Elevated glucose is common and a well-recognized risk factor for higher mortality in various patient populations, including critically ill patients,1 patients hospitalized on general medical and surgical wards,2,3 and those admitted with an acute myocardial infarction (AMI).4–8 Although the value of intensive glucose lowering in these patient populations remains controversial, some preliminary data suggest that there may be a survival benefit associated with improving glucose control.9–11 Accordingly, current American College of Cardiology/American Heart Association guidelines advise strict glucose control in patients hospitalized with AMI.12,13 The Joint Commission on Accreditation of Healthcare Organization includes postoperative glucose control for cardiac surgery patients as a core quality-of-care measure for all US hospitals that participate in the Medicare program.14 Moreover, the American Diabetes Association15 and the American College of Endocrinology currently recommend target-driven glucose control in all hospitalized patients, regardless of the diagnosis.16
Clinical Perspective p 1907
Despite these broad recommendations, it remains unclear whether the association between elevated glucose and increased mortality extends across the entire spectrum of various cardiovascular conditions. Physiological mechanisms that may mediate adverse outcomes associated with hyperglycemia in AMI (such as microvascular dysfunction and proinflammatory and prothrombotic states)17 may not be as critically important in the absence of acute ischemic process such as in chronic heart failure (HF). Although HF accounts for a large proportion of acute care hospitalizations and is associated with high mortality rates,18 the prevalence and prognostic significance of elevated glucose in this patient group remain largely unknown. Establishing an association between elevated glucose and higher mortality in hospitalized HF patients could be the first step in identifying a potential modifiable risk factor in this patient population. The absence of such an association, however, would argue against implementing resource-intensive interventions designed to intensify glucose monitoring and management in this large patient group.
To address this issue, we analyzed data from the National Heart Care (NHC) Project, a large, nationally representative sample of patients in the United States hospitalized with HF from April 1, 1998, to June 30, 2001. Detailed clinical information about these patients, including the presence and severity of comorbid conditions, provided an ideal opportunity to establish whether blood glucose on admission is an independent predictor of prognosis in this patient population. We specifically focused on the association between glucose levels on admission and the risk of death at 30 days and 1 year.
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Methods |
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Data Source
The patient cohort was selected from the NHC sample. The NHC Project was a Centers for Medicare and Medicaid Services (CMS) initiative designed to assess and improve the quality of care for Medicare beneficiaries hospitalized with HF.19 Medicare fee-for-service beneficiaries hospitalized with a principal discharge diagnosis of HF (International Classification of Diseases, ninth revision, clinical modification code 402.01, 402.11, 402.91, 404.01, 404.91, or 428) between April 1998 and March 1999 or July 2000 and June 2001, inclusive, were identified. In each sampling period, discharges were grouped by state and sorted by age, sex, race, and treating hospital, and up to 800 discharges were randomly selected from each state. All records were included if <800 hospitalizations occurred in a state during a sampling period (Alaska, Hawaii, Idaho, Utah, Vermont, and Wyoming in both samples). Medical records were obtained from the treating hospital and underwent detailed review by trained data abstractors in central data abstraction centers. Data quality was ensured through the use of trained reviewers, medical record abstraction software, and random record reabstraction. Patients with invalid social security numbers were excluded. The NHC sample thus consisted of 78 882 records, of which 39 477 were from 1998 to 1999 and 39 405 were from 2000 to 2001.
Study Cohort
To ensure examination of a representative cohort of older patients admitted with HF, we subsequently excluded patients <65 years of age (n=6558); those without documented HF on admission (n=5003); those transferred from another hospital (n=2419); those receiving long-term hemodialysis (n=549); those with a history of severe aortic (n=5498) or mitral stenosis (n=243); those with chronic liver disease/cirrhosis, immunologic suppression, HIV infection, or malignancy (n=6216); and those with missing or extreme (<70 or >600 mg/dL) admission glucose values (n=4318). For patients with multiple admissions, only the first admission was included; thus, 3732 readmission records were excluded. Because we were interested in evaluating the association between admission glucose and mortality, patients with missing or unknown vital status (n=48) also were excluded. In total, 28 350 patients met 
1 of the above exclusion criteria, leaving a final cohort of 50 532 patients for the analysis.
Independent Variables
Admission glucose, defined as the blood glucose value closest to the patient arrival time, was obtained within 1 day of the admission date and classified into the following categories: 110, >110 to 140, >140 to 170, >170 to 200, and >200 mg/dL, similar to previously published thresholds.5,6 Patients were classified as having recognized diabetes mellitus if their medical record contained documentation of a previous history of diabetes mellitus, diagnosis of diabetes mellitus on admission, or the use of an oral antihyperglycemic agent or insulin at the time of hospital admission.
Professional abstractors collected information about demographic variables, noncardiac and cardiac comorbidities, and admission characteristics, including medications, vital signs, physical examination, laboratory values, and diagnostic imaging data from medical records. Left ventricular ejection fraction (LVEF) was defined as either normal or mildly, moderately, or severely abnormal on the basis of either quantitative or qualitative assessment. In cases when patients had >1 assessment of LVEF, an evaluation performed during the index hospitalization was given precedence. In cases when patients had both quantitative and qualitative assessment of LVEF, the quantitative assessment was considered before the qualitative assessment.
Outcomes
The main outcomes were time to death from all causes within 30 days and 1 year of admission.
Statistical Analysis
Baseline demographic and clinical characteristics were compared among patients in different admission glucose groups through the use of the Pearson 
2 test for categorical variables and the F test for continuous variables. The unadjusted association between higher glucose and mortality was tested with Cox regression models.
Multivariable Cox regression models were subsequently constructed to test whether higher glucose levels were independently associated with 30-day and 1-year mortality. Covariates included sociodemographic factors (age, sex, race, and nursing home residence), noncardiac comorbidities (mobility, urinary incontinence, dementia, stroke, chronic obstructive pulmonary disease, creatinine and blood urea nitrogen levels, and diabetes mellitus), cardiac comorbidities (coronary artery disease, hypertension, severity of left ventricular systolic dysfunction, left bundle-branch block, and atrial fibrillation), HF severity indicators (peripheral edema, pulmonary edema, hyponatremia, and history of HF), vital signs on admission (systolic and diastolic blood pressures, heart rate, and respiratory rate), other laboratory values on admission (albumin, potassium, hematocrit, and white blood cell count), and admission medications (angiotensin-converting enzyme [ACE] inhibitors, angiotensin receptor blockers, β-blockers, diuretics, digoxin, calcium channel blockers, insulin, and oral antihyperglycemic agents), which were identified in bivariate analyses or previous studies as or were clinically considered important predictors of mortality. Analyses were repeated with glucose modeled in successive 10-mg/dL increments to examine the nature of association between glucose levels and mortality. In addition, interaction terms were introduced into the models to examine whether the nature of the association between admission glucose and mortality over 30 days and 1 year differed according to the presence of known diabetes mellitus, according to age, and according to left ventricular systolic function. To further ensure that the nature of the relationship between glucose and mortality was uniform across various patient characteristics, models were then repeated within subgroups of patients with and without known diabetes mellitus, as well as within subgroups of age, left ventricular systolic function, renal dysfunction, and preexisting coronary artery disease. To better understand the impact of various potential confounders on the association between glucose and mortality, models were also repeated (modeling glucose in 10-mg/dL increments and analyzing the outcome of 30-day mortality) using sequential incremental adjustments for different categories of covariates. Finally, models were repeated after incorporating discharge antihyperglycemic medications as covariates (given the previously demonstrated association between discharge antihyperglycemic medications and mortality).20
Continuous variables, for which <5% of data were missing, had the missing values replaced with the cohort’s median values. Those continuous variables for which between 5% and 10% of data were missing were assigned the cohort’s median values and a dummy binary variable denoting the missing value. A similar procedure was followed for binary (yes or no) variables, with missing data imputed as no. All continuous and binary variables in our analyses, except for albumin level, had <10% missing data. For categorical variables with missing values, multiple dichotomous variables (dummy variables) were created corresponding to each of the categories (including unknown) and then incorporated into the models, with one of the categories being a reference group. All categorical variables in the models had <10% missing data except LVEF, immobility, and urinary incontinence; these variables were retained in the model given their importance as predictors of outcome. In a sensitivity analysis, a multiple imputations technique was used to impute values for the continuous variables with missing data.
All analyses incorporated probability weights based on the inverse sampling fraction of state in the study cohort, and all models were adjusted for clustering by hospital. Analyses were conducted with SAS 9.1 (SAS Institute, Inc, Cary, NC) and STATA version 10.0 (Stata Corp, College Station, Tex). The use of the CMS NHC database was approved by the Yale University School of Medicine Human Investigation Committee.
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
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Results |
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Baseline Characteristics
The distribution of glucose values is shown in Figure 1. Median admission glucose was 130 mg/dL (interquartile range, 100 to 170 mg/dL); 43.7% of patients were hyperglycemic (glucose >140 mg/dL); and 41.8% of patients had recognized diabetes mellitus. Among those patients who were hyperglycemic on admission (glucose >140 mg/dL),17 35.0% did not have recognized diabetes mellitus. Among patients with severe hyperglycemia on presentation (glucose >200 mg/dL), 20.6% did not have recognized diabetes mellitus. Of nearly 2000 patients who had severe hyperglycemia and did not have recognized diabetes mellitus on admission, only 138 (7.0%) received a new diagnosis of diabetes mellitus on discharge.
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Compared with patients who had lower admission glucose, a greater proportion of those with higher glucose had known diabetes mellitus, hypertension, and stroke, as well as coronary artery disease, HF, pulmonary edema on presentation, and left ventricular systolic dysfunction. Patients with higher glucose also had higher systolic blood pressure, higher creatinine and blood urea nitrogen, and lower sodium, and they were more likely to be treated with ACE inhibitors, diuretics, calcium channel and β-blockers, oral antihyperglycemic agents, and insulin (Table 1
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Unadjusted Association Between Admission Glucose and Mortality
In the unadjusted analysis, no significant association was found between admission glucose and 30-day mortality (mortality for admission glucose groups of 110, >110 to 140, >140 to 170, >170 to 200, and >200 mg/dL was 8.1%, 9.5%, 10.5%, 9.9%, and 8.2% respectively; P for linear trend=0.49; Table 2). Also, no significant association was found between admission glucose and 1-year mortality (mortality for the corresponding admission glucose groups of 110, >110 to 140, >140 to 170, >170 to 200, and >200 mg/dL was 35.8%, 36.5%, 36.9%, 36.7%, and 34.5% respectively; P for linear trend=0.25; Table 2).
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Adjusted Association Between Admission Glucose and Mortality
After multivariable adjustment, there remained no significant relationship between admission glucose and either 30-day or 1-year mortality. Adjusted 30-day mortality was slightly higher in patients with admission glucose of >140 to 170 mg/dL (hazard ratio, 1.27; 95% confidence interval, 1.11 to 1.45) but similar in patients with admission glucose >110 to 140, >170 to 200, and >200 compared with the reference glucose group of 110 mg/dL (Table 3). Overall, no relationship was found between higher admission glucose and higher risk of 30-day mortality (adjusted P for linear trend=0.53). Adjusted 1-year mortality also was similar across all admission glucose groups (adjusted P for linear trend=0.78; Table 3). A lack of significant association between admission glucose and mortality over 30 days and 1 year also was observed when glucose was analyzed in 10-mg/dL increments (Figure 2A and 2B, respectively).
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The interaction terms between admission glucose and known diabetes mellitus in models for 30-day and 1-year mortality were not significant (P=0.11 and 0.55, respectively), suggesting that the absence of a relationship between higher glucose and increased mortality was consistent across the subgroups of patients both with and without diabetes mellitus. The interaction terms between admission glucose and age (P=0.86 and 0.50 for 30-day and 1-year mortality, respectively), as well as admission glucose and left ventricular systolic function (P=0.66 and 0.48, respectively) also were not significant. The effect of glucose on 30-day mortality across various patient subgroups (Table 4) was uniformly nonsignificant; the results were similar to the outcome of 1-year mortality.
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Table 5 demonstrates the results of sequential adjustments for categories of potential confounders (modeling glucose in 10-mg/dL increments and using the outcome of 30-day mortality). Although some evidence was found of competing confounding (patients with higher glucose were on average younger and had lower burden of some comorbidities such as immobility but greater severity of HF), none of the adjustments made a marked impact on the lack of meaningful relationship between admission glucose and mortality. Incorporating discharge antihyperglycemic medications into the models as covariates did not produce any significant change in the results; using a multiple imputations technique for the continuous variables with missing values also did not change the study findings (data not shown).
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Discussion |
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In this large, nationally representative cohort of elderly patients hospitalized with HF, we demonstrate that hyperglycemia on admission occurs in nearly half of patients hospitalized with HF. However, we found no significant graded association between glucose values on admission and short- and long-term mortality. Of note, this lack of increase in risk with higher glucose levels, even in unadjusted analyses, was observed despite the greater severity of HF on presentation observed in hyperglycemic HF patients. Our findings contrast distinctly with those observed in other hospitalized patient populations.
The relationship between hyperglycemia and adverse outcomes in a setting of acute illness has been well documented in many inpatient populations, including those with a variety of cardiovascular diseases such as AMI4–8 and stroke21 and after cardiothoracic surgery,2 as well as other patient populations (critically ill patients1 and those hospitalized with COPD and pneumonia).22,23 On the basis of a few preliminary studies that suggested lower mortality and morbidity with intensive glucose lowering across different disease states,9–11 several professional societies now recommend strict glucose control in their clinical guidelines.12,13,15,16 In fact, the American College of Endocrinology makes this recommendation for all hospital inpatients regardless of diagnosis.16 Similar but less stringent recommendations come from the American Diabetes Association.15 Yet, an association between hyperglycemia and adverse outcomes in patients hospitalized with HF, one of the most common reasons for acute care hospitalizations,18 has not been well explored until now.
Several prior and smaller studies evaluated the association between admission glucose and mortality in hospitalized patients with HF24–26 but had important limitations. The largest of these observational studies analyzed the medical record data from 1122 patients hospitalized with HF and did not identify a significant relationship between admission glucose and longer-term (6-month and 1-year) mortality, consistent with our findings.24 The authors found an association between higher admission glucose and increased risk of in-hospital and 60-day mortality24; this divergence in short-term outcome results between this study and ours is likely due to significant differences in patient cohorts. Specifically, the prior study had a higher incidence of prior AMI and excluded patients with diabetes mellitus or admission glucose 200 mg/dL. It is possible that exclusion of patients with glucose >200 mg/dL could have prevented the authors from documenting a lack of graded relationship between blood glucose levels and short-term mortality. Two additional studies also suggested a possible association between admission glucose and mortality in hospitalized patients with HF; however, these studies analyzed younger patient cohorts with fewer coexisting illnesses25,26 and were limited by small patient samples25,26 and single-center experience.25
Several explanations are possible for our findings. First, it is possible that although elevated glucose may mediate adverse events in a setting of acute myocardial ischemia (through vascular inflammation,27–29 prothrombotic effects,30–36 microvascular37,38 and endothelial dysfunction,39 impaired myocardial glucose use, enhanced fatty acid oxidation,40,41 etc), these mechanisms do not play as significant a role in patients with decompensated HF. Second, the renal diuretic effects of hyperglycemia could conceivably offset any deleterious effects on endothelial function, inflammation, and myocardial metabolism. Third, it is possible that patients with higher admission glucose were more likely to receive insulin during hospitalization, which could lower their average postadmission glucose levels and possibly improve their outcomes; however, given the low rate of insulin use on admission and discharge (even among patients with severe hyperglycemia on admission), this is unlikely. Finally, hyperglycemia in this population may be a surrogate for intact adrenocortical status. "Relative adrenal insufficiency" has been associated with increased mortality in sepsis patients,42 and a similar relationship could conceivably be playing a role in acutely decompensated HF patients.
Our results have several potentially important implications for the field of metabolic control in the acute care setting. First, one of the critical questions in this field is whether elevated glucose is merely a marker of increased "stress" and disease severity or a direct mediator of adverse clinical outcomes. If elevated glucose were simply a marker of acute illness severity, one would expect the association between hyperglycemia and adverse outcomes to be relatively uniform across different disease states. In our study, although higher glucose was associated with greater severity of HF, this association did not predict worse survival (likely because of competing confounders). This nonuniformity of hyperglycemia as a risk factor for higher mortality across different cardiovascular conditions suggests (albeit indirectly) that elevated glucose may be more than just a simple marker of illness severity. Second, our results clearly demonstrate that the strong association between glucose values and increased mortality risk seen in patients hospitalized with AMI and several other cardiovascular and noncardiovascular conditions cannot simply be extended across all hospitalized patients regardless of the diagnosis. Although the impact of glucose lowering on the outcomes of patients hospitalized with HF cannot be determined from this study, our findings suggest that careful, disease-specific examination of the relationship between glucose control and patient outcomes may be warranted before resource-intensive glycemic management strategies are implemented in all hospitalized patients. Finally, a large proportion of patients with elevated glucose did not have preexisting history of diabetes mellitus, even among those with severe hyperglycemia on presentation. An almost negligible minority of these hyperglycemic patients were diagnosed with diabetes mellitus on discharge. Despite the lack of association between elevated glucose and mortality, better diabetes screening may be warranted in these patients to facilitate appropriate outpatient follow-up.
The results of our study need to be interpreted in the context of several potential limitations. Our analysis was limited to admission glucose values. Because we could not determine how many patients with elevated glucose on admission had persistent hyperglycemia during hospitalization, the relationship between persistently elevated glucose and outcomes in HF cannot be ascertained. We also could not assess the intensity of glucose-lowering therapy such as insulin or its potential effect on patient outcomes in our cohort; however, given the lack of association between glucose levels and outcomes, accounting for the intensity of glucose-lowering therapy would likely not influence our results. Although we analyzed a large, nationally representative cohort of Medicare beneficiaries hospitalized with HF, our results may not apply to certain selected HF patient populations such as those with HF in the setting of AMI. Furthermore, patients in our cohort were hospitalized during 1999 to 2001, a time period during which the use of ACE inhibitors and β-blockers was considerably lower than the current rates; however, differences in the use of these medications did not affect the relationship between glucose levels and mortality. Our study was performed in patients 65 years of age with heavy burden of comorbid conditions. Although older patients represent the vast majority of HF patients, the results of this investigation might not apply to younger HF patients with fewer comorbidities. Finally, it is possible that the lack of association between elevated glucose and mortality in our cohort is a false-negative finding; however, our large sample size makes this very unlikely.
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Conclusions |
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TopAbstractIntroductionMethodsResultsDiscussionConclusionsReferences |
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We found no significant association between admission glucose levels and mortality in a large cohort of patients hospitalized with HF. Our results demonstrate that the relationship between hyperglycemia and adverse outcomes seen in AMI cannot be automatically extrapolated to patients hospitalized with other cardiovascular conditions.
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Acknowledgments |
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Sources of Funding
CMS conducted the data collection for the NHC Project and approved this manuscript for publication. CMS had no involvement in study design, analysis, interpretation of data, or the writing or editing of the manuscript. Dr Kosiborod receives research grant support from the American Heart Association.
Disclosures
Dr Kosiborod has received honoraria from the Vascular Biology Working Group and DiaVed, Inc, and has served on the advisory board of Sanofi-Aventis (but did not receive personal financial compensation). Dr Spertus receives research grant support from Sanofi-Aventis and Lilly. Dr Inzucchi has received research grant support from Lilly. Dr Masoudi has been a member of the advisory board for Takeda Pharmaceuticals. The other authors report no conflicts.
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Guest Editor for this article was Douglas L. Mann, MD.
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