Liver function abnormalities and outcome in patients with chronic heart failure: data from the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) program
1 Division of Cardiology, University of Colorado Denver, Aurora, CO, USA
2 Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, USA
3 London School of Hygiene and Tropical Medicine, London, UK
4 University of Glasgow, Glasgow, UK
5 Brigham and Women's Hospital, Boston, MA, USA
6 Department of Medicine, Sahlgrenska University Hospital/Östra, Göteburg, Sweden
7 McMaster University, Hamilton, Ontario, Canada
8 AstraZeneca LP, Wilmington, DE, USA
* Corresponding author. Tel: +1 919 668 8919, Fax: +1 919 668 7063, Email: michael.felker{at}duke.edu
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Abstract |
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Aims: The prevalence and importance of liver function test (LFT) abnormalities in a large contemporary cohort of heart failure patients have not been systematically evaluated.
Methods and results: We characterized the LFTs of 2679 patients with symptomatic chronic heart failure from the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity program (CHARM). We used multivariable modelling to assess the relationships between baseline LFT values and long-term outcomes. Liver function test abnormalities were common in patients with chronic heart failure, ranging from alanine aminotransferase elevation in 3.1% of patients to low albumin in 18.3% of patients; total bilirubin was elevated in 13.0% of patients. In multivariable analysis, elevated total bilirubin was the strongest LFT predictor of adverse outcome for both the composite outcome of cardiovascular death or heart failure hospitalization (HR 1.21 per 1 SD increase, P < 0.0001) and all-cause mortality (HR 1.19 per 1 SD increase, P < 0.0001). Even after adjustment for other variables, elevated total bilirubin was one of the strongest independent predictors of poor prognosis (by global chi-square).
Conclusion: Bilirubin is independently associated with morbidity and mortality. Changes in total bilirubin may offer insight into the underlying pathophysiology of chronic heart failure.
Key Words: Heart failure • Bilirubin • Liver function tests • Hepatic congestion • Prognosis • Death • Laboratory tests
Received March 27, 2008; Revised September 26, 2008; Accepted November 17, 2008
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Introduction |
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Chronic heart failure is a systemic clinical syndrome with a variety of potential effects on other organ systems. Recently, the interactions between heart failure and the kidney and bone marrow have been the subject of significant interest and investigation,1–3 but the interactions between heart failure and other organ systems have not been carefully studied. A variety of liver abnormalities and ‘cardio-hepatic syndromes’ have been previously described in patients with heart failure.4,5 Passive hepatic congestion due to increased central venous pressure is believed to cause elevations of both direct and indirect serum bilirubin (‘congestive hepatopathy’), with nutmeg liver on pathology. Impaired perfusion from decreased cardiac output is associated with acute hepatocellular necrosis (‘hepatic ischaemia’) with elevations primarily in serum aminotransferases.6 Cardiogenic ischaemic hepatitis (‘shock liver’) may ensue following an episode of profound hypotension. Bridging fibrosis (‘cardiac cirrhosis’) can result from prolonged haemodynamic abnormalities, resulting in an impaired hepatic function with impaired coagulation and decreased albumin synthesis.4
Although a variety of ‘cardio-hepatic’ syndromes are recognized by heart failure clinicians, systematic characterization of liver function abnormalities in a well characterized, contemporary cohort of patients with heart failure has not been performed. Prior studies on hepatic abnormalities in heart failure have reported various patterns in small, selected populations, ranging from predominantly hepatocellular7 to predominantly cholestatic8,9 to mixed.5,10 The prognostic importance of observed abnormalities in biochemical markers of hepatic function [liver function tests (LFTs)] has varied widely between published studies.
The purpose of this study was to prospectively characterize LFTs in a large, representative, well-treated cohort of patients with chronic heart failure (with both preserved and impaired left ventricular systolic function), as well as explore the prognostic information such markers provide. Specifically, we evaluated the association between LFTs and outcome in the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) program.
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Source population
Details of the study design and primary findings of the CHARM program have been published elsewhere.11–14 Briefly, patients were eligible who were aged 18 years or older and had symptomatic chronic heart failure of at least 4 weeks duration. The major exclusion criteria were serum creatinine 265 µmol/L or more, serum potassium of 5.5 mmol/L or more, myocardial infarction (MI) or stroke in the prior 4 weeks, or non-cardiac disease (e.g. cancer) judged to limit 2-year survival; there were no exclusion criteria specifically related to liver function or LFTs. The program consisted of three separate trials that shared these inclusion and exclusion criteria, endpoint definitions, and follow-up methods. Patients were enrolled (i) with left ventricular ejection fraction >40% (CHARM-Preserved), (ii) with angiotensin converting enzyme inhibitor intolerance and left ventricular ejection fraction
40% (CHARM-Alternative), and (iii) on angiotensin converting enzyme inhibitor with left ventricular ejection fraction 40% (CHARM-Added). Patients were enrolled at 618 sites in 26 countries between March 1999 and March 2001, and patients were followed until March 2003 for a median follow-up of 38 months. The primary combined endpoint of each constituent trial was time to cardiovascular death or hospitalization for the management of worsening heart failure (adjudicated by a clinical events committee) and the primary endpoint of the overall program was all-cause mortality. Data from routine laboratory testing at a central core laboratory were collected on all patients enrolled in the CHARM program in the USA and Canada (n = 2679), who served as the population for this analysis. This included patients from all three component trials (n = 1085 from CHARM-Preserved, n = 931 from CHARM-Added, n = 663 from CHARM-Alternative; median follow-up 34 months). Baseline laboratory measurements were obtained at the time of randomization. For the purposes of this analysis, we separately analysed both the primary endpoint of the constituent trials (composite of cardiovascular death or hospitalization for worsening heart failure, 952 events) and the primary endpoint of the overall CHARM program (all-cause mortality, 625 events).
Statistical methods
Baseline variables were described using medians and interquartile ranges for continuous variables and percentages for categorical variables. A Cox proportional hazards model was used to evaluate the relationship between potential predictor variables of interest (specifically LFTs) and the primary study endpoint (time to cardiovascular death or heart failure hospitalization). The multivariable modelling approach used in the CHARM program has been described elsewhere.15 Briefly, a ‘best clinical model’ (excluding laboratory data) was created from the overall trial dataset (n = 7599) using standard modelling techniques. Models were built using a forward stepwise variable selection procedure. P < 0.01 was set as level of significance for including variables in the model due to the large number of candidate variables being considered. Randomization to candesartan or placebo was included as a variable in all models. The variables selected for this model were then used to estimate a final model for the study sub-cohort for whom laboratory data were available (n = 2679). Subsequently, laboratory variables were added to this model one at a time in a forward stepwise fashion to generate a final model that combined both clinical and laboratory variables. Adjusted hazard ratios (HRs) for continuous variables were described using standardized HRs, the HR associated with one standard deviation change in the variable. The statistical contribution of each variable to the prediction of outcome was assessed by the chi-square (
2) statistic with one degree of freedom (the larger the 2, the stronger the statistical association with outcome).
To evaluate the potential effects of non-normal distribution of laboratory values on our findings, we repeated the modelling with log transformation on all laboratory variables that had skew distributions. Additionally, we evaluated the possibility of non-linear relationships between variables and outcome by repeating the models with a quadratic term included for each laboratory variable.
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Results |
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Baseline clinical characteristics for patients enrolled in the CHARM program in North America (n = 2679), including LFTs, are shown in Table 1. In general, LFTs (serum values) were within the normal range for most patients in the study cohort. The most common LFT abnormalities were low albumin (below lower limit of normal in 18.3% of patients), elevated alkaline phosphatase (above upper limit of normal in 14.0% of patients), and elevated total bilirubin (above upper limit of normal in 13.0% of patients). Less commonly abnormal were alanine aminotransferase (above upper limit of normal in 3.1% of patients), aspartate aminotransferase (above upper limit of normal in 4.1% of patients), and direct bilirubin (above upper limit of normal in 3.7% of patients).
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The proportion of patients with impaired left ventricular systolic function (ejection fraction
0.40, n = 1594) who had elevations in total bilirubin (15.8%) was almost double that of patients with preserved left ventricular systolic function (ejection fraction >0.40, n = 1085; elevated total bilirubin in 9.4%; P < 0.001 for the comparison). Other LFTs were not markedly different in patients with impaired vs. preserved left ventricular systolic function. Total bilirubin was modestly higher (mean 11.2 µmol/L) in patients who had significant evidence of volume overload on physical examination (S3 gallop, pulmonary crackles, and/or venous congestion) compared to those without these three signs (total bilirubin mean = 10.5 µmol/L, P = 0.015).
Association of liver function tests with outcomes
Baseline abnormalities in bilirubin, alkaline phosphatase, and albumin were more common in patients who died or were hospitalized in follow-up (Figure 1). Because patients are typically first evaluated in clinical practice based on their clinical characteristics, a best clinical model was initially constructed using clinical characteristics alone (without laboratory values). In this clinical model, the most powerful predictors of outcome were diabetes mellitus, hospitalization for heart failure within the previous 6 months, age, and left ventricular ejection fraction.15 The 36 candidate laboratory variables, including LFTs, were then evaluated to identify associations between each individual biochemical variable and outcome. In univariate analysis of laboratory predictors (adjusted for the variables in the final clinical model but not for other laboratory variables), total bilirubin (HR 1.17 per 1 SD increase, P < 0.0001), direct bilirubin (HR 1.15 per 1 SD increase, P < 0.0001), alkaline phosphatase (HR 1.08 per 1 SD increase, P = 0.003), and albumin (HR 0.91 per 1 SD increase, P = 0.003) were significant predictors of outcome (Table 2). In order to evaluate these laboratory variables in the context of all available clinical information, a final multivariable model was generated that included all significant laboratory and clinical predictors (Table 3). In this final model, total bilirubin (adjusted HR 1.14 per 1 SD increase, P < 0.0001) was among the most highly significant overall predictors of adverse cardiovascular outcome, showing greater association with outcome (based on global 2 with one degree of freedom) than many traditional measures of risk, including New York Heart Association functional class, left ventricular ejection fraction, serum creatinine, and diabetes mellitus. Of clinical variables tested, only age, cardiomegaly, hospitalization for heart failure in the previous 6 months, and red cell distribution width showed a greater independent association with outcome than total bilirubin. Adjusted HRs by quintiles of total bilirubin are shown in Figure 2A.
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Total bili, total bilirubin above upper limit of normal; 
Albumin, albumin below lower limit of normal; *primary study outcome was CV death or HF hospitalization at a mean follow up of 3.1 years.
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To further evaluate the association between bilirubin and clinical outcomes, we repeated this modelling procedure using the endpoint of all-cause mortality (625 events) rather than the composite of cardiovascular death or heart failure hospitalization. In this mortality analysis, total bilirubin remained a highly significant independent predictor of outcome (adjusted HR 1.19 per 1 SD increase, 95% confidence interval 1.11–1.27, P < 0.0001) after adjustment for other clinical and laboratory measures (Figure 2B). The global
2 for total bilirubin was the second highest among laboratory predictors and the fourth highest among all predictors of all-cause mortality, behind age, left ventricular ejection fraction, and serum chloride. None of the LFT values were normally distributed in the study population, so we repeated the modelling procedure using log transformation of individual LFT variables prior to insertion in the model. This did not result in any substantive change in our findings, with total bilirubin remaining a powerful predictor of adverse outcome (HR 1.44 per 1 SD increase, P < 0.0001) using the model with log-transformed variables. Inclusion of a quadratic term in the multivariable model (total bilirubin squared) did not change the statistical significance of the relationship, suggesting that there was no statistical evidence of a non-linear or j-shaped relationship between bilirubin and outcomes.
Although HRs for continuous predictors expressed as per SD increase provide standardization and maximize predictive power, such information may be difficult to use in routine clinical practice. To simplify interpretation, total bilirubin was dichotomized into normal (17 µmol/L) and abnormal (>17 µmol/L). After adjustment, the HR for an abnormal total bilirubin was 1.55 (CI 1.30–1.84, P < 0.001) for cardiovascular death or heart failure hospitalization, and 1.60 (CI 1.30–1.97, P < 0.001) for all cause mortality.
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Discussion |
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The principal findings of our analysis are that mild abnormalities of LFTs are relatively common in patients with chronic heart failure, with a predominately cholestatic pattern of greater elevation in bilirubin than transaminases. Additionally, total bilirubin is a strong, independent predictor of adverse prognosis, even after adjustment for a wide variety of demographic, clinical, and biochemical variables. These data provide a comprehensive evaluation of the prevalence and prognostic importance of LFT abnormalities in chronic heart failure with both preserved and impaired left ventricular systolic function.
Prior studies investigating biochemical abnormalities of liver function have been relatively small and evaluated highly selected populations. Kubo et al.8 analysed biochemical profiles and intracardiac haemodynamics in 133 patients with stable chronic congestive heart failure due to systolic dysfunction, and reported that changes in LFTs were common but typically of small magnitude, particularly in those patients with a cardiac index of >1.5 L/min/m2. Mild elevations in alkaline phosphatase and total bilirubin, as well as mild decreases in albumin, were frequent in this population regardless of haemodynamics. With more significant decreases in cardiac output and associated increases in cardiac filling pressures, elevations in transaminases, lactate dehydrogenase, and total bilirubin were seen, but did not correlate with clinically apparent hepatic disease. A retrospective study of 110 patients hospitalized with heart failure with both impaired and preserved left ventricular function confirmed the predominantly cholestatic pattern and showed that increases in LFTs were most strongly correlated with severity of tricuspid regurgitation.9 A longitudinal prospective study of 552 chronic heart failure patients found that all abnormal LFTs were significantly related to mortality, but that aspartate transaminase (2 17.36, P < 0.001) accounted for the greatest variance followed by total bilirubin (2 14.35, P < 0.001).10 Variability between published studies may relate to differences in the population studied (acute vs. chronic heart failure) or to greater use of contemporary medical therapy (such as β-blockers) in the CHARM program. CHARM excluded patients with acute decompensated heart failure, symptomatic hypotension, recent MI, or serum creatinine >3.0 mg/dL at the time of enrolment, and only 2.6% of subjects had New York Heart Association functional class IV heart failure.11 Thus, as was confirmed in our results, hypotension-related elevations in transaminases would have been unexpected at the time of enrolment in an ambulatory population of heart failure patients.
Clinically, the validation of elevated bilirubin as a strong independent predictor of outcome has potentially important value for risk stratification of chronic heart failure patients. Unlike the only other published study of LFT association with outcome,10 our study had sufficient numbers of events to investigate a wide range of prognostically important clinical and laboratory variables. In final analysis, total bilirubin was among the most powerful contributors to the prognostic model for both the composite of cardiovascular death or worsening heart failure (fifth most powerful overall predictor) and for all-cause mortality (fourth most powerful overall predictor). Total bilirubin is a widely available, low-cost, non-invasive test, which is often measured in the course of routine inpatient care. Our results suggest that bilirubin in combination with automated blood count, basic metabolic panel, and some straightforward clinical characteristics (age, recent hospitalization, New York Heart Association functional class) may provide a powerful estimation of overall risk of morbidity and mortality in patients with symptomatic chronic heart failure.
Mechanisms
Our results are consistent with existing knowledge of hepatic pathophysiology. Compared to other organs such as the kidney, the liver's complex dual blood supply makes it relatively resistant to hepatocyte necrosis from haemodynamic perturbations. Thus, significant transaminase elevations are expected only in cases of marked hypotension or hypoperfusion. Previous haemodynamic data suggest that the elevated right atrial pressure may contribute to cholestatic abnormalities of liver function in patients with heart failure.8 Elevated central venous pressure is transmitted directly to the hepatic veins, leading to impairment of hepatocyte function.4 Additionally, the extent of biochemical liver abnormalities may be related to the severity of tricuspid regurgitation.9 Right ventricular dysfunction, typically the cause of elevated venous pressure and tricuspid regurgitation, has been shown to be a significant marker for adverse outcomes in heart failure patients.16 In our study, total bilirubin was significantly higher in patients who had evidence of volume overload on physical examination compared to patients who did not. It seems likely that the prognostic importance of total bilirubin in our study at least in part reflects greater elevations in central venous pressure (whether due to right ventricular dysfunction or tricuspid regurgitation) and therefore more severe haemodynamic perturbation. Other signs of elevated central venous pressure, such as elevated jugular venous pressure, have also been shown to be associated with adverse prognosis in chronic heart failure.17 Even though signs of congestion were similar for patients with preserved and impaired left ventricular systolic function, those with impaired left ventricular systolic function had significantly higher total bilirubin, arguing that the low output may also contribute to the cholestatic abnormalities seen in these heart failure patients. Alternatively, this lack of difference in signs of volume overload between patients with preserved and impaired systolic function may reflect the relatively poor reproducibility of the physical examination.
Abnormalities of the haematologic system in advanced heart failure provide a potential, but less likely, mechanism for elevations of bilirubin. Anaemia is a well-known predictor of adverse outcome in heart failure patients,1 and haemolysis increases indirect bilirubin. In our study, total and indirect bilirubin were better predictors of outcome than direct bilirubin. However, total bilirubin was not significantly correlated with haemoglobin or red cell distribution width (Pearson correlation coefficients 0.18 and 0.20, respectively).
Of note, bilirubin has recently been shown to be inversely associated with the risk of MI in a cohort from the Framingham Offspring study.18 Bilirubin may act as an anti-oxidant and free radical scavenger, and has been hypothesized to decrease rates of incidence MI through anti-atherosclerotic properties. In contrast to patients enrolled in the Framingham Offspring study, the patients enrolled in CHARM already had significant heart failure at the time of study entry, with high rates of concomitant pre-existing coronary disease (67% with ischaemic cardiomyopathy). Thus, it is likely that any potential benefits related to the anti-oxidant effects of bilirubin are outweighed by elevated bilirubin's reflection of elevated right-sided filling pressures in patients with greater degrees of heart failure.
Limitations and generalizability
Other than the baseline LFTs, we do not have additional information on liver pathology, such as serial LFTs, hepatitis serologies, liver imaging, haemodynamic measures, or histologic tissue. Eligibility criteria excluding patients with ‘non-cardiac disease judged to limit 2 year survival’ should have limited the potential impact cancer and cirrhosis might have had on our findings; in follow-up, there were only 45 deaths due to cancer. Patients enrolled in the CHARM program were symptomatic but stable outpatients at the time of enrolment. Consequently, our findings do not reflect either the clinical characteristics or the LFT profiles of patients hospitalized with acute decompensated heart failure. As in other randomized clinical trials, the very elderly and patients with severe comorbid conditions were less likely to be enrolled in the CHARM program. Because the hyperbilirubinaemia of Gilbert's does not carry with it the same negative predictive value as the hyperbilirubinaemia of advancing heart failure, the potential for spurious prognostication exists in the application of these findings to heart failure patients who also have Gilbert's. Given the independent predictive value of hyponatraemia seen in other survival models of chronic heart failure,19,20 it was surprising that the sodium was not retained in the final CHARM risk model. We speculate that colinearity between the sodium and other predictor variables may in part explain its absence from the final multivariable model. This study is a retrospective review of a clinical trial dataset, and as such is subject to the limitations of this type of analysis. Importantly, however, the CHARM cohort is generally representative of the epidemiology and treatment milieu of contemporary heart failure, with a high proportion of patients with preserved systolic function and widespread use of contemporary medical therapy. Additionally, the large number of events in our cohort (952 for the composite endpoint and 625 events for all-cause mortality) greatly strengthened our ability to make conclusions about the relative prognostic information contained in a variety of clinical and laboratory variables.
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Conclusions |
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Bilirubin is frequently elevated in patients with symptomatic chronic heart failure and is strongly associated with morbidity and mortality after adjusting for a wide array of other clinical and laboratory predictors. Further research into the complex relationship between cardiac and hepatic function in heart failure may improve both understanding of pathophysiology and the clinical care of heart failure patients.
Conflict of interest: none declared.
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Funding |
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The CHARM program was funded by AstraZeneca. Drs M.A.P., K.S., J.J.V.M., S.Y., C.B.G., and S.P. have served as consultants to or received research grants and honoraria from AstraZeneca. Dr E.L.M. is an employee of AstraZeneca.
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