CLINICAL RESEARCH: HEART FAILURE
Anemia and Mortality in Heart Failure PatientsA Systematic Review and Meta-Analysis
Hessel F. Groenveld, MD*,
James L. Januzzi, MD, FACC ,
Kevin Damman, MD*,
Jan van Wijngaarden, MD, PhD ,
Hans L. Hillege, MD, PhD*,
Dirk J. van Veldhuisen, MD, PhD, FACC* and
Peter van der Meer, MD, PhD,*
* Department of Cardiology, University Medical Center Groningen, Groningen, the Netherlands
Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
Department of Cardiology, Deventer Hospital, Deventer, the Netherlands
Manuscript received February 19, 2008;
revised manuscript received April 23, 2008,
accepted April 28, 2008.
* Reprint requests and correspondence: Dr. Peter van der Meer, Cardiovascular Research Center, Massachusetts General Hospital, Charles River Plaza, 185 Cambridge Street, Boston, Massachusetts 02114 (Email: pvandermeer{at}partners.org).
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Abstract
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Objectives: The aim of this study was to assess the effect of anemia on mortality in chronic heart failure (CHF).
Background: Anemia is frequently observed in patients with CHF, and evidence suggests that anemia might be associated with an increased mortality.
Methods: A systematic literature search in MEDLINE (through November 2007) for English language articles was performed. In addition, a manual search was performed. We included cohort studies and retrospective secondary analyses of randomized controlled trials whose primary objective was to analyze the association between anemia and mortality in CHF. Of a total of 1,327 initial studies, we included 34 studies, comprising 153,180 patients. Information on study design, patient characteristics, outcome, and potential confounders were extracted.
Results: Anemia was defined by criteria used in the original articles. Of the 153,180 CHF patients, 37.2% were anemic. After a minimal follow-up of 6 months, 46.8% of anemic patients died compared with 29.5% of nonanemic patients. Crude mortality risk of anemia was odds ratio 1.96 (95% confidence interval: 1.74 to 2.21, p < 0.001). Lower baseline hemoglobin values were associated with increased crude mortality rates (r = –0.396, p = 0.025). Adjusted hazard ratios showed an increased adjusted risk for anemia (hazard ratio 1.46 [95% confidence interval: 1.26 to 1.69, p < 0.001]). Subgroup analysis showed no significant difference between mortality risk of anemia in diastolic or systolic CHF.
Conclusions: Anemia is associated with an increased risk of mortality in both systolic and diastolic CHF. Anemia should, therefore, be considered as a useful prognosticator, and therapeutic strategies aimed to increase hemoglobin levels in CHF should be investigated.
Key Words: heart failure • anemia • prognosis
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Abbreviations and Acronyms
| | CHF = chronic heart failure | | CI = confidence interval | | EPO = erythropoietin | | ESP = erythropoiesis-stimulating protein | | Hb = hemoglobin | | HR = hazard ratio | | Ht = hematocrit | | OR = odds ratio | | WHO = World Health Organization |
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Anemia is frequently observed in patients with chronic heart failure (CHF) (1–5). Prevalence of anemia depends both on the severity of CHF and diagnostic criteria used to define it, but may be as high as 50% in selected patient cohorts (3,6). Of note, anemia is not only prevalent in the CHF population, but several studies in different patient populations found an association with anemia, impaired cardiac function, more health care utilization, and morbidity (1,7–11). In addition, numerous studies have assessed associations between anemia and mortality in CHF. Although most studies have documented higher mortality rates in anemic CHF patients (1,3,12–17), some studies report the absence of an adverse effect of anemia on mortality in CHF (4,18–20). Therefore, better understanding of the risk associated with the presence of anemia is necessary. Elucidating the contribution of anemia to mortality may lead to a more accurate risk profiling in CHF patients, especially since several treatment options for anemia exist including erythropoietin (EPO) and iron therapy (21,22). Ultimately, this may lead to more effective therapeutic strategies from a risk-benefit perspective in heart failure patients.
We, therefore, performed a rigorous systematic review and meta-analysis of published literature to more comprehensively assess the effect of anemia on mortality in CHF. In addition, we explored whether subgroups of anemic patients were at particularly high mortality risk.
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Methods
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Search strategy.
We adhered to the MOOSE (Meta-analysis Of Observational Studies in Epidemiology) study guidelines as previously published (23). To identify all relevant studies, we performed a literature search in MEDLINE accessed by PubMed (1966 through November 2007). Two of the authors (H.G. and P.v.d.M.) developed a search strategy. To identify heart failure patients and anemia, we used both the Medical Subject Heading term (MeSH) and text word search (Table 1). In addition, we identified potentially relevant studies using a manual search of references lists from all eligible studies and review articles. We consulted experts in the field and searched the Institute for Scientific Information Web of Sciences for publications that cited key publications.
Study selection.
We included cohort studies and retrospective secondary analyses of randomized controlled trials whose primary objective was to analyze the association between anemia and mortality in CHF. Titles and abstracts of all articles were evaluated and rejected on initial screen if they: 1) included subjects other than CHF patients; 2) had no evaluation of hemoglobin (Hb) or hematocrit (Ht) levels; 3) did not include all-cause mortality as outcome; 4) were published only in abstract form; 5) included patients  18 years old; 6) had follow-up of <6 months; or 7) were published in another language than English.
After obtaining full reports of candidate studies, the same reviewers independently assessed eligibility. Differences in data between the 2 reviewers were solved by rereviewing corresponding articles, and the final set was agreed on by consensus. For studies in which not all data were published, or data was insufficient, authors were addressed and asked for additional information (3,4,12,19,24–26).
Quality assessment and data abstraction.
Each study was evaluated on quality according to the guidelines provided by the United States Preventive Task Force (27) and published recommendations (28). The following characteristics were assessed: 1) duration of follow-up >12 months; 2) reporting loss of follow-up; 3) adjustment of possible confounders in multivariate analysis; 4) definition of anemia; 5) full specification of outcome; 6) study sample representative for mentioned population; 7) full specification of clinical and demographic variables; 8) explanation of sample selection; 9) temporality (Hb measured at baseline, not at time of outcomes assessment); and 10) clear inclusion and exclusion criteria. Studies were graded as poor quality if they met <5 criterion, fair if they met 5 to 7 criteria, and good if they met  8 criteria.
Statistical analysis.
Random effects meta-analysis was conducted to estimate the magnitude of risk associated with anemia and all-cause mortality, as measured by crude mortality risks and unadjusted odds ratios (ORs). Where available, adjusted hazard ratios (HRs) were extracted from Cox regression analysis. Adjusted risk estimates included those components as published in final multivariate models for each study including confounding sociodemographic and clinical covariates. We performed tests of heterogeneity between studies using a standard chi-square test and I2 statistic. When heterogeneity was found to be significant, pooled estimates based on random effects models were reported. To examine sources of heterogeneity, we conducted meta-regression analysis. Bias in published studies was assessed using a funnel plot of study results against study precision. We tested symmetry of the funnel plot by the Egger's test. Subgroup analysis was pre-defined for systolic versus diastolic CHF. Statistical significance was set at p < 0.05, and all statistical analyses were performed using Stata 9.0 (Stata Corp., College Station, Texas).
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Results
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Description of included studies.
The electronic search retrieved 1,327 eligible studies. Nonelectrical search identified 4 additional studies. On initial screening, 1,142 were rejected, based on title. Of the 185 screened abstracts, 56 studies were retrieved for detailed evaluation. Eventually 34 studies were included in this meta-analysis (Fig. 1). Secondary analysis of the Val-HeFT (Valsartan Heart Failure Trial) study was described in 2 separate manuscripts: Anand et al. (29) and Maggioni et al. (5). Crude mortality data were not published by Anand et al. (29), and for this reason this study was excluded and the data of Maggioni et al. (5) was used. In addition, 1 article described the effect of anemia from 2 different studies (5). Both studies in this published report were analyzed separately for the meta-analysis. The 34 included studies described a total of 153,180 patients (1,3–20,24–26,30–41). Characteristics of the included studies are listed in Table 2, characteristics of study populations are listed in Online Tables 1 and 2. Ten different definitions of anemia were used in the included studies. The World Health Organization (WHO) definition (Hb <13.0 g/dl for males and Hb <12.0 g/dl for females) was used in the majority of the studies. Table 3
displays the different definitions of anemia in the included studies. Anemia, as defined in the original articles, was present in 37.2% of the CHF patients. Mean Hb from the studies ranged from 12.2 to 14.0 g/dl. Mean Ht values ranged from 36.6% to 42.7%.
Meta-analysis findings.
Among the 34 studies, mean follow-up ranged from a minimum of 6 months to a maximum of 5 years. Crude mortality data were available in 33 studies. In one study, only the adjusted HR was available, whereas the unpublished crude mortality data were lost after hurricane Katrina (25). Analysis of the crude mortality revealed that 26,687 (46.8%) anemic patients died compared with 28,274 (29.5%) nonanemic patients. This translated into an unadjusted mortality risk of OR 1.96 (95% confidence interval [CI]: 1.74 to 2.21, p < 0.001) in anemic CHF patients compared with that in nonanemic CHF patients (Fig. 2). When the 2 largest studies (Go et al. [3] and Kosiborod et al. [4]) were excluded, the mortality risk of anemia was identical (OR: 1.95, 95% CI: 1.78 to 2.14, p < 0.001). There was no evidence for publication bias. The funnel plot did not show asymmetry (Fig. 3), which was confirmed by the Egger's test (p = 0.93). We found a significant heterogeneity between included studies (I2 = 92.4%, p < 0.001). Meta-regression analysis was performed using sociodemographic variables, medical history, drug use, and laboratory data as parameters. In this sensitivity analysis, excluding studies not adhering to the WHO definition of anemia, no heterogeneity was observed (I2 = 36.5%, p = NS), yet the mortality risk remained (OR: 2.22, 95% CI: 2.04 to 2.42, p < 0.001). In addition, we found an inverse interstudy relationship between serum creatinine levels and the effect of anemia on mortality. The effect of anemia on mortality declined with higher serum creatinine levels. When assessing the gradual effect of baseline Hb values on mortality, we found a linear trend between baseline Hb measurements and mortality rates. Lower baseline Hb values were associated with increased annual mortality rates (r = –0.396, p = 0.025) (Fig. 4).
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Figure 4 Relationship Between Baseline Hemoglobin and Annual Mortality
The area of each circle is proportional to the sample size in each cohort. The center line shows the estimated mortality risk per year of lower baseline Hb values on a continuous scale. The dotted lines represent the 95% confidence intervals.
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Confouding factors.
In 127,437 patients (83.1% of the total included patients), reported mortality risks were adjusted for several sociodemographic and clinical covariates. Potential confounders that were adjusted for in the original reports are shown in Table 4. In all but one study, age and renal function were considered as potential confounders (this study included 178 patients) (33). When mortality risk, estimated by adjusted HR, was combined, anemia remained an independent predictor of mortality HR 1.46 (95% CI: 1.26 to 1.69, p < 0.001).
Subgroup analysis.
In the subgroup analysis, we assessed the difference between mortality risk of anemia in patients with systolic or diastolic CHF. Table 5
displays the definitions of systolic and diastolic CHF used in the original articles. Studies or substudies in patients with only diastolic CHF included 20,924 patients of which 5,957 (28.5%) patients died. In studies or substudies including only patients with systolic CHF, 40,025 patients were included, of which 12,423 (31.0%) died. The mortality risk associated with the presence of anemia was not significantly different between patients with systolic CHF (OR: 1.96, 95% CI: 1.70 to 2.25, p < 0.001) and diastolic CHF (OR: 2.09, 95% CI: 1.53 to 2.86, p < 0.001).
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Discussion
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This is the first meta-analysis to address the relationship between anemia and mortality in patients with CHF. In our analysis, which examined more than 150,000 subjects, anemia was frequently observed, found in over one-third of CHF patients. Presence of anemia in CHF patients is associated with an increased mortality risk in patients with systolic as well as diastolic heart failure. The adverse effect we found is substantial and significant. When assessing the mortality risk by using multivariate analyses, anemia remains an independent risk factor for mortality in CHF patients.
Prevalence.
In prior studies, it is observed that CHF is often accompanied by anemia. A wide range of anemia prevalence in CHF has been reported, ranging from 7% to over 50% (1–4,10,17,32,35). This range can be attributed to multiple factors, including the use of multiple definitions of anemia. The WHO criteria was used in the majority of studies. In addition, administrational codes or arbitrary boundary values to define anemia were also used. Studies defining anemia with administrative codes (such as International Classification of Diseases, 9th Revision, codes) have clear limitations. The use of this coding system solely relies on physicians to consider anemia as a possible diagnosis leading to an underestimation of the prevalence. Therefore, we excluded in this meta-analysis studies without measurements of actual Hb or Ht values. This resulted in the exclusion of only one study (2). Results of the current meta-analysis clearly indicate the need for standardized definitions of anemia in CHF patients. The definition of anemia appeared to be a major source of heterogeneity. However, despite different definitions of anemia in the present meta-analysis, the association with mortality was robust, using different analysis strategies.
Pathophysiology.
It is tempting to speculate about the mechanisms behind the increased mortality risk observed in anemic CHF patients. Anemia may lead to an increased work load, resulting from an increased heart rate and stroke volume (32,42,43). In response to the increased workload, the heart undergoes "remodeling," marked by left ventricular hypertrophy and dilation. This eventually may lead to CHF with an increased mortality risk. Also, renal failure, as a common comorbidity in CHF, might be implicated in the pathophysiology. CHF and renal failure are 2 entities that are often seen together with prevalences ranging from 20% to 40% (2,38,44–46). With meta-regression analysis, we found an inverse interstudy relationship between serum creatinine levels and the effect of anemia on mortality. However, this result does not suggest that the mortality risk declines with higher creatinine levels. It merely illustrates a statistical decreasing effect of anemia on mortality with increasing creatinine levels; the decline of the effect of anemia on mortality can be the result of an increased mortality risk caused by renal failure (47). From a pathophysiological standpoint, CHF can also cause renal failure due to a decreased cardiac output reducing renal perfusion (i.e., forward failure); subsequent renal failure may lead to decreased endogenous EPO levels and may ultimately induce anemia, leading to an increased cardiac workload completing the vicious circle. Recently this has been called the "cardio-renal-anemia syndrome" (48).
Findings from intervention studies.
Considering the increased mortality risk caused by anemia, in heart failure as well as renal failure, trials have been designed in which patients receive erythropoiesis-stimulating proteins (ESPs) to increase Hb levels. The first intervention study to address the efficacy of EPO in CHF patients was performed by Silverberg et al. (49) in 32 patients. Correction of anemia with EPO and intravenous iron led to a significant increase in left ventricular ejection fraction and decrease in New York Heart Association functional class, which was reflected by almost 90% reduction in the number of hospitalizations. A similar study showed that EPO treatment significantly increased peak oxygen consumption and exercise duration in patients with moderate-to-severe CHF (50). Recently, 2 substantially larger multicenter phase II studies evaluated the effects of darbepoetin (a long-acting ESP) on surrogate cardiovascular end points (51,52). Treatment with darbepoetin was safe and effectively raised Hb. Moreover, it significantly improved clinical status; however, no significant improvement in exercise tolerance could be observed.
However, recently several studies showed a potentially harmful effect of ESP treatment in patients with kidney disease and malignancies. A meta-analysis in patients with cancer-associated anemia showed an increased risk in venous thromboembolism and mortality associated with recombinant EPO and darbepoetin administration (53). Furthermore, concerns about the cardiovascular safety of ESP in patients with kidney disease have been raised. Two separate studies showed that patients targeted to a higher Hb level had an increased incidence of cardiovascular events (54,55). However, in these studies, no placebo groups were included. These studies were all performed in patients with severe renal failure, and only a minority of patients suffered from heart failure. Consequently, the results of the studies mentioned in the preceding text cannot be extrapolated to the CHF population.
Larger randomized studies are clearly needed to determine the impact on morbidity and mortality in CHF. Currently, a large phase III morbidity and mortality trial, the RED-HF (Reduction of Events with Darbepoetin alfa in Heart Failure) trial (56), is being conducted to answer the question whether the use of ESPs in anemic heart failure patients is beneficial. Besides ESP, intravenous iron treatment is another intervention modality in anemic CHF patients. Recently, 2 trials appeared showing that intravenous iron without ESPs increased Hb levels in patients with CHF. Moreover, they showed an improved exercise capacity and decreased NT-proBNP levels (57,58). Further research is needed to study the effect of intravenous iron on morbidity and mortality in anemic CHF patients.
Study limitations.
Limitations of meta-analyses include differences in designs and populations used in included trials, quality of studies, and heterogeneity (59). However, the quality of all studies was graded according to published guidelines and all met at least 7 of 12 criteria.
Evaluation of anemia was only at baseline in all included studies. Tang et al. (60) recently reported a study with serial hemoglobin measurements and showed that persistent anemia has a larger effect on mortality than transient anemia. No evaluation of Hb was performed during the studies; thus, it remains unknown whether anemia in the included studies was persistent or transient. Furthermore, heterogeneity in our study is substantial and can be attributed to differences in duration of follow-up, type of patients included, study design, and definition of anemia. Definition of anemia was a major cause of heterogeneity. When mortality risk was assessed using studies that defined anemia by WHO criteria, heterogeneity was no longer significant, while the increased mortality risk caused by anemia remained. Furthermore, our meta-analysis could not exclude residual confounding from studies in the adjusted analyses, although most studies adjusted for many known major confounders. However, this limitation emphasizes the inability of our analysis to prove causality.
Previously, it has been argued that a larger meta-analysis (e.g., >1,000 events) is clinically more meaningful (59); our study, which includes over 50,000 events, is therefore of particular note. Besides the overall size, the individual studies in the present analysis were of considerable size, with 14 including more than 1,000 patients. These strengths make our findings all the more firm.
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Conclusions
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Anemia is present in one-third of the CHF population and is an independent risk prognosticator for mortality in subjects so affected, irrespective of a systolic versus diastolic etiology of CHF. Further research is needed to assess the effect of correcting anemia in CHF patients.
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Appendix
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For the Acknowledgments and supplementary Tables 1 and 2, please see the online version of this article.
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Footnotes
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Dr. Damman is supported by the Netherlands Heart Foundation (grant 2006B157). Dr. van Veldhuisen is a Clinical Established Investigator of the Netherlands Heart Foundation (D97-017). Dr. van der Meer is supported by the Dutch Scientific Organization (Rubicon grant: 825-07-011).
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