Anemia and chronic kidney disease are common in patients with heart failure (HF) and are associated with adverse outcomes. We analyzed the effect of cardiorenal anemia (CRA) syndrome, defined as anemia (hemoglobin <130 g/L for men, <120 g/L for women) and stage 3 or greater chronic kidney disease (estimated glomerular filtration rate <60 ml/min/1.73 m 2 ), in outpatients with HF. Consecutive patients with HF were prospectively enrolled from 2000 to 2005 (n = 748). The baseline clinical characteristics, pathology test results, and medication use were compared between those with and without CRA syndrome. The primary end point was all-cause mortality. The mean follow-up was 2.5 ± 1.6 years, with a left ventricular ejection fraction <45% present in 70% of patients. Angiotensin-converting enzyme inhibitors, β blockers, and spironolactone were used in 87%, 67%, and 37%, respectively. CRA syndrome was present in 224 patients (30%). These patients had greater all-cause mortality (51% vs 26%, p <0.001), older age (mean 77 ± 8 vs 67 ± 14 years, p <0.001), and greater rates of diabetes mellitus (35% vs 23%, p <0.001) and ischemic heart disease (50% vs 35%, p <0.001). The independent predictors of mortality were CRA syndrome (hazard ratio 2.0, 95% confidence interval 1.4 to 2.8, p <0.001), left ventricular systolic dysfunction per grade (hazard ratio 1.5, 95% confidence interval 1.3 to 1.8, p <0.001), the absence of a β blocker (hazard ratio 1.6, 95% confidence interval 1.1 to 2.2, p = 0.005), New York Heart Association class per class (hazard ratio 1.5, 95% confidence interval 1.2 to 1.9, p <0.01), and age per decade (hazard ratio 1.6, 95% confidence interval 1.4 to 2.0, p <0.001). In conclusion, CRA syndrome was common in patients with HF and was an independent predictor of all-cause mortality. Consideration should be given to identifying CRA syndrome and modifying reversible factors.
Anemia and chronic kidney disease (CKD) are frequently observed in patients with heart failure (HF). The reported prevalence of anemia in multicenter HF studies has ranged from 4% to 60%. Similarly, ≤50% of patients with HF have stage 3 or greater CKD (estimated glomerular filtration rate <60 ml/min/1.73 m 2 ). The presence of HF, stage 3 or greater CKD, and anemia have been associated with an accelerated adverse prognosis. More recently, Silverberg et al and others have labeled this unfavorable triad, the cardiorenal anemia (CRA) syndrome. However, the exact pathophysiologic mechanisms of this association remain uncertain. Limited contemporary Australian data assessing the clinical effect of the CRA syndrome on patients with HF are available. We investigated and compared the prevalence and predictors of the clinical outcomes in outpatients with and without CRA syndrome who were enrolled from a multidisciplinary HF clinic in a tertiary teaching hospital during medium-term follow-up.
Methods
The HF clinic at Austin Health is a service coordinated by the medicine and cardiology departments and consists of a team of HF cardiologists, general physicians, pharmacists, and HF nurse specialists with dedicated rehabilitation and outreach services. Consecutive patients reviewed in the HF clinic with a clinical diagnosis of HF using the Framingham criteria were prospectively enrolled in the present study from 2000 to 2005. The data collected included demographic data, HF etiology, co-morbid conditions such as diabetes mellitus, atrial fibrillation, New York Heart Association functional class, medication use (angiotensin-converting enzyme [ACE] inhibitors, angiotensin receptor antagonists, β blockers, and spironolactone), and pathology results (hemoglobin, serum potassium, sodium, and creatinine). The baseline left ventricular systolic function at clinical review was determined using echocardiography or radionucleotide ventriculography. For the present analysis, we used a left ventricular ejection fraction (LVEF) cutoff of 45% to differentiate those with HF-preserved or HF-reduced LVEF, as reported in previous clinical studies. Furthermore, within the HF-reduced LVEF group, the LVEF was subdivided into grades. Mild left ventricular dysfunction was defined as LVEF 40% to 45%, moderate as LVEF 30% to 39%, and severe left ventricular systolic dysfunction as LVEF <30%.
Anemia was defined according to the World Health Organization definitions: hemoglobin <120 g/L for women and hemoglobin <130 g/L for men.
For CKD, we used the initial creatinine to derive the estimated glomerular filtration rate using the Modification of Diet in Renal Disease study formula. CKD was defined as stage 1, estimated glomerular filtration rate >90 ml/min/1.73 m 2 ; stage 2, 60 to 89 ml/min/1.73 m 2 ; stage 3, 30 to 59 ml/min/1.73 m 2 ; and stages 4 and 5, <30 ml/min/1.73 m 2 . CRA syndrome was considered present if HF and both anemia and stage 3 or greater CKD were present.
The patients were censored at disenrollment or at the end of the follow-up period on January 31, 2007. Disenrollment was defined as the final HF clinic review or death. The primary outcome was all-cause mortality. Deaths were identified from the hospital database and chart review, with cross-reference to the National Death Index from the Australian Institute of Health and Welfare. The local human research and ethics review board approved the present study.
Statistical analyses were performed with the SPSS statistical computer package, version 17 (SPSS, Chicago, Illinois). Descriptive analyses were used for demographic characteristics and the study population was divided according to the absence or presence of the CRA syndrome, and the groups were compared using the analysis of variance test. Cox proportional hazards regression analyses were performed to determine the independent predictors of all-cause mortality. The first model incorporated CRA syndrome, and the second model included anemia and stages of CKD in place of the CRA syndrome. Kaplan-Meier survival curves were created for all-cause mortality. The log-rank test was used to assess the significance on Kaplan-Meier analyses. Multiple logistic regression analysis was performed to find independent associations of CRA syndrome. Two-tailed p values <0.05 were taken as denoting statistical significance.
Results
The baseline patient characteristics, stratified by the presence of the CRA syndrome, are listed Table 1 . A total of 748 patients participated, with a mean follow-up of 2.5 ± 1.6 years. The mean age was 70 ± 14 years, and 66% were men. The mean LVEF was 37 ± 14%, and HF-reduced LVEF was present in 70% of the patients. New York Heart Association class III and IV was reported in 18%. The etiology of HF was ischemia in 56%, and atrial fibrillation was present in 24% and diabetes mellitus in 27%. Anemia was present in 43%. CKD stage 1, 2, 3, and ≥4 was present in 14%, 37%, 33%, and 16%, respectively. The use of guideline-recommended therapy, including ACE inhibitor or angiotensin receptor antagonists, β blockers, and spironolactone, was 87%, 67%, and 37%, respectively.
