Anemia is associated with poor prognosis in patients hospitalized with acute decompensated heart failure (ADHF). Whether the impact of anemia differs by heart failure with preserved ejection fraction (HFpEF) or heart failure with reduced ejection fraction (HFrEF) is uncertain. We examined hospital surveillance data captured by the Atherosclerosis Risk in Communities Study from January 1, 2005, to December 31, 2010. Diagnoses of ADHF were validated by standardized physician review of the medical record. Anemia was classified using the World Health Organization criteria (<12 g/dl for women and <13 g/dl for men), and HF type was determined by the ejection fraction (<40% for HFrEF and ≥40% for HFpEF). Hospital length of stay and 1-year mortality outcomes were analyzed by multivariable regression, weighted to account for the sampling design, and adjusted for demographics and clinical covariates. Over 6 years, 15,461 (weighted) hospitalized events for ADHF (59% HFrEF) occurred in the catchment of the Atherosclerosis Risk in Communities, based on 3,309 sampled events. Anemia was associated with a mortality hazard ratio of 2.1 (95% confidence interval [CI] 1.6 to 2.7) in patients classified with HFpEF and 1.4 (95% CI 1.1 to 1.7) in those with HFrEF; p for interaction = 0.05. The mean increase in length of hospital stay associated with anemia was 3.5 days (95% CI 3.4 to 3.6) for patients with HFpEF, compared with 1.8 days (95% CI 1.7 to 1.9) for those with HFrEF; p for interaction <0.0001. In conclusion, the incremental risks of death and lengthened hospital stay associated with anemia are more pronounced in ADHF patients classified with HFpEF than HFrEF.
Anemia is a common co-morbidity of heart failure (HF) and has been associated with poor functional status, longer hospitalizations, rehospitalizations, and death. In clinical trials, the benefit of anemia treatment to HF patients has been questionable. However, most research has focused on HF with reduced ejection fraction (HFrEF), and there is some evidence to suggest that the impact of anemia may differ by HF type. Although this trend has not been consistently reported, few studies have examined outcomes in patients hospitalized with acute decompensated heart failure (ADHF). We investigated whether the mortality risk and length of hospital stay (LOS) associated with anemia would differ by HF type, by analyzing a population-based sample of ADHF hospitalizations captured by the Atherosclerosis Risk in Communities (ARIC) study.
Methods
Since 2005, the ARIC study has conducted population-based retrospective surveillance of hospitalized events in Forsyth County, North Carolina; Washington County, Maryland; Jackson, Mississippi; and 8 northwest suburbs of Minneapolis, Minnesota. Surveillance eligibility is restricted to residents ≥55 years, with a hospitalization spanning at least 1 day and, for the purposes of our analysis, a discharge date between January 1, 2005, and December 31, 2010. Hospitalizations with any discharge codes for congestive HF, rheumatic heart disease, hypertensive heart disease, acute cor pulmonale, chronic pulmonary heart disease, cardiomyopathies, acute edema of lung, or dyspnea were randomly sampled, using prespecified sampling fractions within strata of ARIC communities, International Classification of Diseases, Ninth Revision , code (428.x or all other eligible codes), age (55 to 74, 75 to 84, or ≥85), sex, and race (black or white).
Hospitalized medical records indicating signs or symptoms of HF were fully abstracted and reviewed by ARIC physicians, as previously described. Using standardized criteria, hospitalizations were classified as definite ADHF, probable ADHF, stable chronic HF, not HF, or unclassifiable based on diagnostic reports from the hospital record, physician notes, and discharge summaries. ADHF was differentiated from stable chronic HF by evidence of new onset or worsening signs or symptoms.
Hemoglobin and serum creatinine were abstracted from the medical record, by recording the lowest and last values over the course of the hospitalization. To minimize potential confounding by hemodilution, the last values were used to determine anemia and glomerular filtration rate. For the purposes of our analysis, anemia was defined by the World Health Organization criteria (hemoglobin <12 g/dl for women and <13 g/dl for men). Polycythemia was considered a hemoglobin value ≥17 g/dl. Glomerular filtration rate was estimated by the Chronic Kidney Disease Epidemiology Collaboration formula.
HF type was determined by the abstracted ejection fraction, from either inpatient diagnostic tests or, when absent, preadmission imaging studies. Most abstracted ejection fractions (71%) were in-hospital, and of these, 96% were based on transthoracic echocardiograms. Consistent with previous analyses of hospitalized ADHF and anemia, heart failure with preserved (HfpEF) was classified by a normal or mildly decreased systolic function (ejection fraction ≥40%), whereas HFrEF was considered an ejection fraction <40%.
Length of stay (LOS) was calculated by subtracting the admission date from the discharge date, excluding transfers to and from another hospital. Mortality outcomes were ascertained for up to 1 year after admission, by linking hospital records with death files.
Over 6 years, 6,291 hospitalizations were sampled and abstracted. Of these, 4,271 were classified as definite or probable ADHF. We omitted hospitalizations with no abstracted hemoglobin values (n = 33) or ejection fraction (n = 576) and patients transferred to or from another hospital (n = 77). In addition, we excluded patients receiving dialysis (n = 337), as this represents a distinct subgroup of anemic HF, and patients identified with polycythemia (n = 19) because of the known U-shaped relation between hemoglobin and mortality risk. After exclusions, 3,309 unweighted events remained in analysis, corresponding to 15,461 weighted hospitalizations for definite (79%) or probable (21%) ADHF.
All analyses were performed using SAS 9.3 (SAS Institute, Cary, NC) and weighted by the inverse of the sampling probability. Proportions were compared using Rao-Scott chi-square tests, and means were compared using analysis of variance. Correlations of hemoglobin with ejection fraction, age, and glomerular filtration rate were assessed by Pearson regression. The crude incidence of death was examined by Kaplan-Meier regression. Adjusted mortality hazard ratios were examined using Cox regression, and associations with length of hospital stay were analyzed by linear regression. All multivariable regression models were adjusted for age, race, sex, and clinical covariates associated with anemia (glomerular filtration rate, smoking, systolic blood pressure, diastolic blood pressure, diabetes, coronary heart disease, β blockers, and diuretics). Interactions were analyzed by entering the cross product of anemia and HF type, or the cross product of hemoglobin and HF type, into the fully adjusted models. Significance of interactions was assessed by Wald chi-square tests, using a threshold of α = 0.10, because of the reduced power to detect interaction.
Results
All results are weighted to account for the sampling design, unless otherwise indicated. Of 15,461 hospitalizations with verified ADHF, 6,414 (41%) were classified as HFpEF and 9,047 (59%) as HFrEF. The mean age at discharge was 76 years; approximately half (52%) were women, and nearly 1/3 (29%) were black. The overall anemia prevalence was 70% and did not differ by HF type (p = 0.4). In unadjusted analyses, hemoglobin was positively correlated with glomerular filtration rate (r = 0.21; p <0.0001) and negatively correlated with age (r = −0.11; p <0.0001) and ejection fraction (r = −0.15; p <0.001).
Patients classified with HFpEF were more often women (61% vs 46%, p <0.0001), white (74% vs 69%, p = 0.003), and older (76 vs 75 years, p = 0.02) than those with HFrEF. Hypertension was more prevalent with HFpEF (86% vs 83%, p = 0.02); however, myocardial infarction was less common (20% vs 33%, p <0.0001). As listed in Table 1 , gender-specific mean hemoglobin levels were similar in patients with HFpEF and HFrEF. In univariate analyses, anemia was strongly associated with race, kidney function, blood pressure, smoking, and history of coronary heart disease for both HF types (p <0.05 for each). However, diabetes was associated with anemia only in HFpEF patients, whereas use of diuretics correlated with anemia only in those with HFrEF.
| Characteristic | HFpEF | HFrEF | ||
|---|---|---|---|---|
| Anemia (n=4,566) | No Anemia (n=1,848) | Anemia (n=6,289) | No Anemia (n=2,758) | |
| No. (%) or Mean ± SEM | No. (%) or Mean ± SEM | |||
| Female ∗ | 2,675 (59%) | 1,253 (68%) | 2,844 (45%) | 1,341 (49%) |
| Black ∗ † | 1,297 (28%) | 356 (19%) | 1,826 (29%) | 944 (34%) |
| Age (years) † | 77 ± 0.3 | 76 ± 0.4 | 76 ± 0.2 | 73 ± 0.3 |
| Hemoglobin (g/dL) | ||||
| Women | 10.3 ± 0.05 | 13.1 ± 0.06 | 10.4 ± 0.04 | 13.2 ± 0.06 |
| Men | 10.6 ± 0.08 | 14.2 ± 0.07 | 10.9 ± 0.05 | 14.1 ± 0.05 |
| Creatinine (mg/dL) ∗ † | 1.6 ± 0.03 | 1.2 ± 0.02 | 1.6 ± 0.02 | 1.3 ± 0.02 |
| GFR (mL/min/1.73 m 2 ) ∗ † | 48 ± 0.8 | 58 ± 0.9 | 48 ± 0.6 | 57 ± 0.8 |
| BMI (kg/m 2 ) | 31 ± 0.3 | 31 ± 0.7 | 28 ± 0.2 | 29 ± 0.3 |
| Systolic BP (mm Hg) ∗ † | 146 ± 1.1 | 148 ± 1.4 | 135 ± 0.9 | 142 ± 1.2 |
| Diastolic BP (mm Hg) ∗ † | 75 ± 0.7 | 80 ± 0.8 | 75 ± 0.6 | 83 ± 0.8 |
| Ejection Fraction (%) † | 54 ± 0.3 | 55 ± 0.4 | 34 ± 0.4 | 29 ± 0.5 |
| Coronary Heart Disease ∗ † | 2,078 (46%) | 690 (37%) | 3,189 (51%) | 1,272 (46%) |
| Myocardial Infarction | 975 (21%) | 337 (18%) | 2,109 (34%) | 878 (32%) |
| Hypertension ∗ | 4,414 (88%) | 1,525 (83%) | 5,240 (83%) | 2,260 (82%) |
| Current Smoker ∗ † | 487 (11%) | 317 (17%) | 799 (13%) | 540 (20%) |
| COPD | 1,406 (31%) | 636 (34%) | 2,215 (35%) | 890 (32%) |
| Diabetes ∗ | 2,350 (51%) | 561 (30%) | 2,953 (47%) | 1,183 (43%) |
| ACE Inhibitors | 1,727 (38%) | 667 (36%) | 2,555 (41%) | 1,235 (45%) |
| Beta blockers ∗ | 2,914 (64%) | 1,050 (57%) | 4,362 (69%) | 1,790 (65%) |
| ARB | 648 (14%) | 333 (18%) | 851 (14%) | 360 (13%) |
| Diuretics † | 3,142 (68%) | 1,208 (65%) | 4,820 (77%) | 1,991 (72%) |
| Statins | 1,964 (43%) | 745 (40%) | 3,023 (48%) | 1,187 (43%) |
| Mean stay (days) ∗ † | 8.9 ± 0.3 | 5.6 ± 0.2 | 7.5 ± 0.2 | 5.7 ± 0.2 |
| In-hospital Mortality ∗ † | 348 (8%) | 50 (3%) | 517 (8%) | 83 (3%) |
| 28 day Mortality ∗ † | 563 (12%) | 122 (7%) | 824 (13%) | 250 (9%) |
| 365 day Mortality ∗ † | 1,652 (36%) | 379 (21%) | 2,724 (43%) | 800 (29%) |
∗ Significantly associated with anemia in patients with HFpEF (p<0.05).
† Significantly associated with anemia in patients with HFrEF (p<0.05).
Overall, HFrEF was associated with greater mortality. In both types of HF, anemia was related to a higher incidence of death, and those with HFrEF and anemia fared worst ( Figure 1 ). However, in relative analyses comparing outcomes of anemic with nonanemic HFpEF patients, and anemic with nonanemic HFrEF patients, the incremental risk of death was higher with HFpEF. After adjustments, anemia was associated with more than twice the risk of death in patients with HFpEF (HR 2.1, 95% confidence interval [CI] 1.6 to 2.7), but only a 40% higher risk in those with HFrEF (HR 1.4, 95% CI 1.1 to 1.7); p for interaction = 0.05. As listed in Table 2 , a slightly higher relative risk (RR) of death was also observed for HFpEF (HR 1.2, 95% CI 1.1 to 1.3) compared with HFrEF (HR 1.1, 95% CI 1.0 to 1.2), when examining mortality risk per 1 g/dl decrement of hemoglobin.
