Prognostic Value of Red Blood Cell Distribution Width for Patients with Heart Failure: A Systematic Review and Meta-Analysis of Cohort Studies

Aims Multiple studies have investigated the prognostic role of red blood cell distribution width (RDW) for patients with heart failure (HF), but the results have been inconsistent. The aim of the present study was to estimate the impact of RDW on the prognosis of HF by performing a systematic review and meta-analysis. Methods and Results The Embase, PubMed, and Web of Science databases were searched up to November 16, 2013 to identify eligible cohort studies. The quality of each study was assessed using the Newcastle-Ottawa Scale (NOS). The association between RDW, either on admission or at discharge, and HF outcomes (all-cause mortality [ACM], heart transplantation, cardiovascular mortality, and rehospitalization, etc.) were reviewed. The overall hazard ratio (HR) for the effect of RDW on ACM was pooled using a random-effects model, and the publication bias was evaluated using funnel plots and Eggers' tests. Seventeen studies, with a total of 18288 HF patients, were included for systematic review. All eligible studies indicated that RDW on admission and RDW at discharge, as well as its change during treatment, were of prognostic significance for HF patients. The HR for the effect of a 1% increase in baseline RDW on ACM was 1.10 (95% confidence interval: 1.07–1.13), based on pooling of nine studies that provided related data. However, publication bias was observed among these studies. Conclusions HF patients with higher RDW may have poorer prognosis than those with lower RDW. Further studies are needed to explore the potential mechanisms underlying this association.


Introduction
Heart failure (HF) has been recognized as one of the most severe cardiovascular syndromes worldwide, with a high incidence, prevalence, mortality and morbidity [1]. Accurate risk stratification for the early identification of patients who are at higher risk for poor outcome is critical for the management of HF patients [2,3]. Laboratory tests, imaging examinations, and clinical signs are three categories of tools widely used in HF prognosis estimation [4,5]. Among these, laboratory tests are of great interest because the results are objective [6,7]. By contrast, clinical signs and imaging examinations are subjective in nature, and the accuracy of these measures is greatly affected by the experience of the clinicians.
Red blood cell distribution width (RDW) is a routine parameter of hematologic tests that is used to measure the variation in circulating erythrocyte volume [8]. For a long time, RDW has been regarded as a useful index to differentiate the etiology of anemia, such as thalassemia and megaloblastic anemia, as well as iron deficiency-related anemia [9]. Recently, the clinical significance of RDW in non-hematologic disorders, such as liver diseases [10,11], autoimmune diseases [12,13], respiratory diseases [14,15], stroke [16,17], critical illness [18,19], and cardiovascular diseases [20], has been extensively investigated. To date, many studies have explored the prognostic value of RDW for HF, but the results have been inconsistent. Meta-analysis, a statistical method to integrate the findings of available studies, has recently been recognized as an effective strategy to draw a robust and reliable conclusion on a certain topic. Therefore, we performed a systematic review and meta-analysis to estimate the prognostic value of RDW for patients with HF.

Literature searching
Two authors (ZD Hu and YL Huang) independently searched the PubMed, Embase, and Web of Science databases to identify eligible studies published up to November 16, 2013. The search terms for the Pubmed search were: ''heart failure'' OR ''cardiac failure'' AND ''RDW'' OR ''red cell distribution width'' OR ''erythrocyte indices''. A similar search strategy was used for searching Embase. Manual searches were also performed by reviewing the references of the eligible studies and reviews on this topic.

Inclusion criteria
Studies that fulfilled the following inclusion criteria were included: 1) cohort studies that evaluated the prognostic value of RDW for patients with HF, either acute or chronic HF; 2) studies with a follow-up duration of more than 1 year; 3) studies that reported at least one of the following outcomes: all-cause hospitalization, HF-related hospitalization, cardiovascular death, all-cause mortality (ACM), and heart transplantation. Studies that met any of the following exclusion criteria were excluded: 1) animal or cell line studies; 2) duplicated publications; 3) conference abstracts; and 4) manuscripts published in languages other than English. Two authors (ZD Hu and YL Huang) independently reviewed the abstracts and titles of the retrieved studies to identify potentially eligible studies. If necessary, review of the complete text was performed. Disagreements were resolved by discussion and consensus.

Data extraction
Data extraction and quality assessment were performed independently by two authors (ZD Hu and YL Huang). The following data were extracted from eligible studies: names of the first authors, publication year, sources of participants, sample sizes, participants' characteristics, follow-up durations, event rates, endpoints with their corresponding hazard ratios (HRs) and 95% confidence intervals (CIs), and the confounding factors adjusted for. The corresponding authors of the eligible studies were not contacted for detailed information if the necessary data were not reported in the full-text of the papers.
The Newcastle-Ottawa Scale (NOS) [21], with minor modifications, was used to assess the quality of the included studies. This quality assessment tool consists of three domains, including selection of the exposed and unexposed cohort (maximum: four stars), comparability of the two cohorts (maximum: two stars), and outcome assessment (maximum: three stars). Two authors (ZD Hu and YL Huang) independently performed quality assessment, and any disagreements were resolved by discussion with a third author (SJ Liu, AM Deng, or RQ Zhong) who was blinded to the previous results.

Statistical analysis
This meta-analysis was performed and reported in accordance with the PRISMA guidelines for systematic reviews and metaanalyses (Checklist S1) [22]. The most fully-adjusted HR reported in the original articles was extracted. For example, in a study in which the unadjusted and multivariable adjusted HRs (95% CIs) were 2 (1.8-2.3) and 1.5 (1.3-1.8), the latter HR was extracted. Given that the endpoints, as well as the value assignment strategy for RDW across eligible studies, were variable, and it was not reasonable to pool HRs derived from different endpoints, only the studies that provided an HR for an increment of 1% unit RDW for ACM in HF patients were included in the meta-analysis. Cochrane's Q test (significance level of P,0.10), as well as the I 2 statistics, were used to assess the heterogeneity among the included studies. If I 2 .25% or P,0.10, we pooled the reported HRs using a random-effects model; otherwise, the HRs were pooled using a fixed-effects model. To explore the possible source of heterogeneity, subgroup analysis was performed according to the origins of participants (USA or Europe), follow-up duration (median or mean follow-up time .2 years or #2 years), study design (prospective, post-hoc, or retrospective), and whether natriuretic peptides (B-type natriuretic peptide [BNP] or N-terminal B-type natriuretic peptide [NT-proBNP]) were adjusted for in calculating the adjusted HRs. Sensitivity analysis was conducted to determine whether the exclusion of any single study would result in a significant change in the final results. Funnel plots and the Egger's test were applied to evaluate the potential publication bias [23]. All analyses were performed using STATA 12.0 (Stata Corp LP, College Station, TX).

RDW and HF outcomes
Nine studies reported the adjusted HRs for a 1% increase in RDW on admission for ACM [24][25][26][27][28]31,36,37,39] in HF patients, and therefore, it was reasonable to include these studies in the meta-analysis. The pooled HR, based on the HRs from the abovementioned nine studies, showed that for patients with HF, each 1% increase in RDW on admission was associated with a 10% higher risk of future mortality events (adjusted HR per 1% RDW: 1.10, 95% CI: 1.06-1.14, Figure 2). The I 2 was 68.9% (P,0.01), suggesting that considerable heterogeneity existed among the eligible studies.

Subgroup analysis and sensitivity analysis
To explore possible sources of heterogeneity among the eligible studies, subgroup analysis was performed. As shown in Table 3, study design, study location, and whether natriuretic peptide was adjusted for seemed to have no apparent effect on pooled HRs, because the heterogeneity remained in the subgroups according to the above characteristics. However, we found that the follow-up duration in the included studies had a significant impact on the pooled HR, and the pooled HR was higher for studies with a follow-up duration exceeding 2 years. More importantly, heterogeneity was resolved in subgroup analysis, indicating that the duration of follow-up was one of the sources of heterogeneity among the included studies.
The results of a sensitivity analysis showed that omission of each study individually did not significantly influence the overall results ( Figure 3), indicating that the results of the present meta-analysis are stable. Figure 4 shows a funnel plot for the nine studies that were included in the meta-analysis, and obvious asymmetry was observed. The results of Egger's test gave a co-efficient of bias of 2.78 (P = 0.002), also indicating that potential publication bias existed across the eligible studies.

Discussion
The present systematic review and meta-analysis indicated that increased RDW, either at baseline or at discharge, as well as the change in RDW during treatment are associated with poor prognosis in patients with HF. The meta-analysis of the results of nine studies demonstrated that the pooled HR for a 1% increase in RDW for ACM was 1.10, suggesting that the risk of ACM increases by 10% with each 1% increase in the baseline RDW. Prognostic evaluation is especially important for HF management, because it will greatly affect clinical decisions. Our results indicate that RDW is an effective index for HF prognosis evaluation. This means RDW should be measured when comprehensively assessing the prognosis of HF patients, and more intensive treatment for HF may be needed for patients with a higher RDW.
The exact mechanisms underlying the association between RDW and poor prognosis for patients with HF remain unknown at this stage. One suggested hypothesis is that inflammation may bridge the relationship between higher RDW and poorer HF prognosis. It is well documented that the inflammatory response plays a critical role in the development and progression of HF [41,42]. Inflammatory biomarkers, as indicated by previous evidence, can provide important prognostic information for HF [43]. On the other hand, it is widely accepted that inflammation inhibits erythrocyte maturation and accelerates the migration of reticulocytes into the peripheral circulation, thereby increasing RDW [44][45][46]. Indeed, the positive relationships between RDW and inflammatory indices have also been documented [30,47,48]. Our previous studies also showed that glucocorticoid, a wellknown anti-inflammatory agent, could reduce the RDW in patients with systemic lupus erythematosus [13]. Together, these findings indicate that inflammation plays an important role in the  association between a relatively higher RDW and poor HF prognosis. Further studies are needed to explore the detailed mechanisms of the relationships between RDW and HF prognosis. Compared with traditional prognostic indices, such as BNP, NT-proBNP, midregional pro-atrial natriuretic peptide (MR-proANP), and troponins [6,7], RDW as a prognostic factor for patients with HF offers at least three advantages. First, it is an inexpensive index. Because blood cell count is a routine test for patients with HF and RDW is a regular hematologic parameter, no additional cost should be needed to introduce RDW into the estimation of HF prognosis. Second, RDW is an easily acquired index, which can be tested even in a community hospital. Third, the lifespan of red blood cells is approximately 130 days [49], which is much longer than that of natriuretic peptides [50,51]. Therefore, RDW may have less biological variation, and this characteristic may make its clinical interpretation much easier than the parameters evaluated in traditional HF laboratory tests.
The results of our subgroup analyses suggest that follow-up duration is an important source of heterogeneity among the included studies, and the association between a higher RDW and a higher risk for future ACM events seemed to be stronger in studies with longer follow-up durations (.2 years). More importantly, the heterogeneity was resolved in subgroup analysis according to follow-up duration. These results indicate that the prognostic value of RDW may be underestimated by studies with shorter follow-up durations. It should be noted that although adjustment for natriuretic peptides was not the source of heterogeneity, it had a moderate effect on pooled HRs. This result indicates that the prognostic value of RDW might be overestimated by studies with no adjustment for BNP or NT-proBNP. In addition, sensitivity analysis was performed to explore the impact of each individual study on the overall outcomes of the meta-analysis. The results showed that no individual study had an obvious effect on the pooled HR, suggesting that the results of the present meta-analysis are stable.
The present systematic review and meta-analysis has some limitations. First, only studies published in English were included; therefore, study selection bias could not be completely excluded. Second, only nine studies were included in the final meta-analysis, and publication bias was observed. Therefore, the prognostic value of RDW for HF may be overestimated. Third, the confounding factors adjusted in individual studies varied; some well-established indices, including natriuretic peptides, troponins, renal function, and history of cardiovascular events, were not fully adjusted for in some of the studies. Inadequate adjustment for confounders may lead to bias, either towards over-or under-estimation of the HR of RDW. Residual or unknown confounding factors cannot be excluded as possible interpretations for the observed findings, as well as heterogeneity across eligible studies. Further studies, with larger sample sizes, longer follow-up durations, various defined endpoints, and adequate adjustments for confounding factors, should be performed to rigorously confirm the prognostic value of RDW for patients with HF.
In conclusion, the results of the present systematic review and meta-analysis indicate that RDW, an easily and inexpensively acquired index, is of prognostic significance for patients with HF. Further studies are needed to uncover the potential mechanisms underlying the associations between a higher RDW and poor prognosis in HF patients. However, the potential prognostic value of RDW should be taken into consideration in the comprehensive management of patients with HF.