CONGENITAL HEART DISEASE
Anemia in Adults With Congenital Heart Disease Relates to Adverse Outcome
Konstantinos Dimopoulos, MD, MSc, PhD*, ,*,
Gerhard-Paul Diller, MD, PhD*,,
Georgios Giannakoulas, MD, PhD*,
Ricardo Petraco, MD*,
Aikaterini Chamaidi, MD*,
Evaggelia Karaoli, MD*,
Michael Mullen, MD*,
Lorna Swan, MD, PhD*,
Massimo F. Piepoli, MD, PhD,
Philip A. Poole-Wilson, MD,
Darrel P. Francis, MA and
Michael A. Gatzoulis, MD, PhD*
* Adult Congenital Heart Centre and Centre for Pulmonary Hypertension, Royal Brompton Hospital, London, United Kingdom
Department of Clinical Cardiology, National Heart and Lung Institute, Imperial College School of Medicine, London, United Kingdom
International Centre for Cardiocirculatory Health, St. Mary's Hospital, London, United Kingdom
Manuscript received February 20, 2009;
revised manuscript received May 28, 2009,
accepted June 28, 2009.
* Reprint requests and correspondence: Dr. Konstantinos Dimopoulos, Adult Congenital Heart Centre and Centre for Pulmonary Hypertension, Royal Brompton Hospital, Sydney Street, London SW3 6NP, United Kingdom (Email: k.dimopoulos02{at}ic.ac.uk).
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Abstract
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Objectives: To assess the relation of anemia in noncyanotic adults with congenital heart disease (ACHD) to functional capacity and mortality.
Background: Anemia is common in acquired heart failure and affects prognosis. The presence of anemia and its relation to outcome in ACHD remain unknown.
Methods: Data were collected on consecutive noncyanotic ACHD patients attending our tertiary center between 2001 and 2006 in whom hemoglobin concentration was measured. Anemia was defined as hemoglobin concentration <13 g/dl in males and <12 g/dl in females. Cyanotic patients were excluded to avoid confounding from secondary erythrocytosis.
Results: Overall, 830 noncyanotic ACHD patients (age 36.5 ± 15.0 years, 49.6% male) fulfilled the inclusion criteria. The prevalence of anemia was 13.1% and was highest in patients with congenitally corrected transposition of great arteries and Ebstein anomaly of the tricuspid valve. Anemic patients were more likely to be receiving diuretics (p < 0.0001) and have a lower mean corpuscular volume (p = 0.0001), with a trend toward a higher New York Heart Association functional class (p = 0.06). During a median follow-up of 47 months, 55 patients died. Anemic patients had a 3-fold higher mortality risk compared with nonanemic patients, even after propensity score adjustment for clinical variables such as systemic ventricular function, renal impairment, and diuretic therapy (adjusted hazard ratio: 3.00; 95% confidence interval: 1.46 to 6.13).
Conclusions: Anemia is not uncommon in ACHD patients attending tertiary services and is associated with a 3-fold increased risk of death. Screening for anemia should be part of the routine assessment of ACHD patients for risk stratification and treatment when correctable causes are identified.
Key Words: congenital heart defects • anemia • prognosis
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Abbreviations and Acronyms
| | ACHD = adults with congenital heart disease | | ccTGA = congenitally corrected transposition of great arteries | | MCV = mean corpuscular volume | | NYHA = New York Heart Association |
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Anemia is common in acquired heart failure, relates to functional capacity, and, even when mild, is a strong prognostic marker for survival (1–9). The pathogenesis of anemia in this setting is multifactorial; its prevalence increases with age, chronic kidney disease, and clinical signs of congestive heart failure (10,11). Anemia has also been reported in mildly symptomatic or even asymptomatic patients, however, suggesting that its pathogenesis relates to other factors than just cardiac dysfunction (12). Impaired erythropoietic secretion and neurohormonal activation, for example, seem to be important additional contributors to the development of anemia in heart failure (13).
Even though chronic renal dysfunction and neurohormonal activation are commonly encountered in adults with congenital heart disease (ACHD) (14–18), limited data on the prevalence of anemia across the spectrum of ACHD are available at present (19). We hypothesized that anemia would be relatively common in ACHD and relate to functional class and survival.
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Methods
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Data were collected on all consecutive clinically stable noncyanotic ACHD patients who had hemoglobin concentration measured in our tertiary center between May 2001 and June 2006. Cyanotic patients (including those with Eisenmenger syndrome, where by definition, there is right-to-left shunting) were excluded to avoid bias deriving from the stimulant effect of chronic hypoxia on hemopoiesis. Anemia was defined as hemoglobin concentration <13 g/dl in males and <12 g/dl in females, according to the World Health Organization criteria (20). Mean corpuscular volume (MCV) and serum creatinine concentration were also recorded, when available, on the same date. Repeated measurements, other than the first, were excluded from analysis. Measurements made after emergency admissions or within 6 months after surgery, catheter intervention, and/or major bleeding were also excluded from the analysis. Clinical data were acquired from patient records; specific congenital heart disease diagnoses were previously verified by echocardiography, cardiovascular magnetic resonance, and/or cardiac catheterization. Patients were classified into diagnostic groups according to the underlying cardiac anatomy (21). Patients with more than 1 defect were classified according to the prevalent lesion from a clinical and/or hemodynamic point of view. Systemic ventricular function from transthoracic echocardiograms within a year of blood sampling was recorded as a 3-level categorical variable: normal, mildly impaired, and moderately/severely impaired (14).
Survival status and time to death were obtained from the National Health Service computer system, linked to the national database held by the Office of National Statistics. Approval by the local ethical committee of the Royal Brompton Hospital was obtained.
Statistical analysis.
Numerical values are presented as mean ± SD, categorical variables as percentage of total. Comparisons between groups were performed using the Wilcoxon rank sum and the Kruskal-Wallis tests for continuous variables and the Fisher exact test for categorical variables. Univariate logistic regression analysis was used to assess the relation between anemia and clinical and demographic parameters, followed by multivariate analysis including all parameters that were significant (2-sided p < 0.05) on univariate analysis, to the multivariate model. Cox regression analysis was used to assess the relation between anemia and death. To account for differences between anemic and nonanemic patients, propensity score matching was used. Propensity scores were computed using logistic regression, with anemia as the dependent variable and baseline demographic and clinical variables as independent variables: age, sex, functional class, previous palliative or reparative surgery/sternotomy, systemic ventricular function, serum creatinine levels, MCV, and medication (diuretics, beta-blockers, digoxin, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, warfarin, and aspirin) (18). Propensity scores were used to perform 5:1 nearest neighbor matching (4 nonanemic to 1 anemic patient) within a caliper of 0.05 SDs of the propensity score (R version 2.8.1, package "matchit") (22). Balance was verified by assessing standardized differences between groups for all variables in the matched cohort. A target of <10% standardized difference for all variables was set and obtained. Univariable Cox regression was then used to compare mortality between anemic and nonanemic patients in the matched cohort, thus accounting for baseline differences between groups while avoiding an over-fit of the Cox model. As a sensitivity analysis, regression adjustment using propensity score quartiles was also performed. Missing values were <10% for all variables (mean 1%, range 0% to 9%). As propensity score matching requires complete datasets, missing data were imputed using multiple imputation (R version 2.8.1, package "Amelia," which uses a bootstrapping-based expectation-maximization algorithm) (22). Ten values for each missing cell in the data were imputed to create 10 different "complete" datasets; models were then estimated for each dataset (23). Cox analysis was then performed after propensity score matching and propensity score regression adjustment using each of the 10 databases. Estimates were averaged, and the hazard ratio (HR) of anemic versus nonanemic patients was computed. The variance of the estimated log(HR) was calculated as the average of the estimated variances from each dataset plus the sample variance in point estimates across datasets (18). Moreover, Kaplan-Meier survival curves were plotted, and the log-rank test was used for comparison between groups. All p values were 2-sided, and p < 0.05 was considered to indicate statistical significance. Analyses were performed using R version 2.8.1. (22).
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Results
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Patient population.
Overall, 830 noncyanotic ACHD patients (mean age 36.5 ± 15.0 years, 49.6% male) (Table 1) attending our tertiary center fulfilled inclusion criteria. Patients from all major ACHD diagnostic groups were included; 72% had undergone previous surgical repair. The majority of patients (72.2%) were asymptomatic at the time of the study.
Hemoglobin concentration, hematocrit, and anemia.
Mean hemoglobin concentration in noncyanotic ACHD patients was 14.1 ± 1.7 g/dl (Table 2); 13.1% of patients were anemic (Table 3). As expected, hemoglobin concentration was higher in men compared with women (14.8 ± 1.6 g/dl vs. 13.4 ± 1.5 g/dl; p < 0.0001) (Fig. 1). No sex difference, however, was found in the prevalence of anemia (12.1% in men vs. 14.1% in women, p = 0.41). Mean hemoglobin concentration was within normal range for all ACHD diagnostic groups and was lowest in patients with congenitally corrected transposition of great arteries (ccTGA) (13.3 ± 2.1 g/dl). Patients with ccTGA had the highest prevalence of anemia (27.3%), followed by patients with Ebstein anomaly of the tricuspid valve (20.0%) (Fig. 2).
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Figure 2 Prevalence of Anemia
The prevalence of anemia in various adults with congenital heart disease diagnostic groups. ccTGA = congenitally corrected transposition of great arteries.
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Predictors of Anemia
Univariate predictors of anemia were a lower MCV (odds ratio [OR]: 1.89 per 10-fl decrease; 95% confidence interval [CI]: 1.37 to 2.61; p = 0.0001), treatment with diuretics (OR: 2.66; 95% CI: 1.74 to 4.03; p < 0.0001), and treatment with warfarin (OR: 1.59; 95% CI: 1.01 to 2.50; p = 0.046). In addition, a strong trend for anemia among patients in New York Heart Association (NYHA) functional class III or IV (OR: 1.86; 95% CI: 0.94 to 3.48; p = 0.06) and in those with higher creatinine concentration (OR: 1.50; 95% CI: 0.98 to 2.31; p = 0.06) was also observed. MCV (adjusted OR: 1.98 per 10-fl decrease; 95% CI: 1.43 to 2.75; p < 0.0001) and treatment with diuretics (adjusted OR: 2.86; 95% CI: 1.85 to 4.39; p < 0.0001) were the only multivariate predictors of anemia. Despite the clear association between MCV levels and anemia, only 25.7% of anemic patients were microcytic (MCV <84 fl).
To further investigate the relation between a low MCV, an indirect marker of bleeding, and anemia, we performed a subanalysis in patients on warfarin therapy. Microcytosis was found in 29.0% of anemic compared with 9.1% of nonanemic patients undergoing warfarin therapy. However, 22 of the 31 (71%) anemic patients on warfarin had no microcytosis.
Hemoglobin concentration and anemia as a predictor of outcome.
During a median follow-up of 47.3 months, 55 patients died. Overall mortality was 1.7% per year (95% CI: 1.3% to 2.2%). The highest mortality was observed in the ccTGA group (10.0% per year; 95% CI: 4.0% to 20.7%), followed by the Fontan population (5.3% per year; 95% CI: 2.1% to 11.0%). Median time to death was 48.6 months, and median age at death was 36.3 years.
Anemic patients were at significantly higher risk of death compared with patients without anemia (5-year mortality of 17.7% vs. 6.0% in nonanemic patients; log-rank p < 0.0001) (Fig. 3). On univariate Cox analysis, anemia was a strong predictor of mortality (HR: 3.13; 95% CI: 1.77 to 5.55; p < 0.0001) (Fig. 4). Other univariate predictors of death were a higher NYHA functional class; treatment with diuretics, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, beta-blockers, digoxin, or warfarin; a higher creatinine concentration; and moderate-severe systemic ventricular dysfunction. On multivariable analysis including all univariable predictors, anemia remained a predictor of outcome (adjusted HR: 2.26; 95% CI: 1.12 to 4.52). After propensity-score analysis, anemia remained a strong predictor of outcome (HR: 3.00; 95% CI: 1.46 to 6.13 by matching and HR: 2.83; 95% CI: 1.57 to 5.10 by regression adjustment).
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Figure 4 Univariate Predictors of Mortality
Univariate predictors of death: hazard ratio and 95% confidence interval. ACEi/ARB = angiotensin-converting enzyme inhibitor/angiotensin receptor blockers; NYHA = New York Heart Association.
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Discussion
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Anemia was relatively common in this young population of noncyanotic ACHD patients. Low MCV and treatment with diuretics were significant predictors of anemia, suggesting a possible role of iron deficiency and of the heart failure syndrome in its pathogenesis. Anemic ACHD patients were at a 3-fold risk of death, even after adjustment for functional class, systemic ventricular function, and other established risk factors.
The prevalence of anemia in ACHD.
The prevalence of anemia in this ACHD population appears to be lower than that reported for acquired heart failure, even though reported estimates of the prevalence of anemia in acquired heart disease vary widely (ranging between 9% and 79%, according to the characteristics of the population studied) (1–4,6–8). ACHD patients in our study were much younger than the average cohort of patients with ischemic heart disease or heart failure and were, in their vast majority (72%), asymptomatic.
The pathogenesis of anemia in congenital heart disease.
The etiology of anemia in ACHD is likely to be multifactorial (12). Patients in the ccTGA diagnostic subgroup, who had the highest prevalence of anemia (27.3%), also had the highest prevalence of symptoms (70%) (Table 1) and the highest prevalence of systemic ventricular dysfunction, suggesting a possible role of ventricular dysfunction in pathogenesis. However, a high prevalence of anemia was also observed in patients with Ebstein anomaly of the tricuspid valve, a primarily right-sided lesion with resultant low systemic cardiac output. MCV and the use of diuretics were independent predictors of anemia in the noncyanotic population, suggesting that renal impairment, abnormal iron metabolism, and circulatory congestion contribute independently toward the occurrence of anemia in ACHD. Furthermore, anemia in ACHD patients can occur as the result of acute or chronic blood loss due to abnormal hemostasis, vascular bleeding (arteriovenous malformations or collateral vessels), use of anticoagulants and antiplatelets, hemolysis (prosthetic valves, intracardiac patches, or conduits), intervention, or surgery. The strong relation between anemia and MCV found in this study is in favor of iron deficiency being a predisposing factor for anemia. Although we have excluded patients who had recent catheter interventions or surgery to account for post-operative anemia (common), we cannot exclude that anemia is due to inadequate iron intake (dietary or due to malabsorption), although this, we speculate, is unlikely in the noncyanotic ACHD patients (24). Despite the strong correlation between MCV, treatment with warfarin, and anemia, only a minority of patients from the subgroup of patients undergoing warfarin therapy were microcytic, suggesting a multifactorial etiology of anemia in this population.
Reduced hemopoiesis is another potential mechanism of anemia in ACHD. Reduced erythropoietin production is associated with renal dysfunction, which we have recently shown to be common in ACHD (18). However, no significant relation was found between creatinine concentration and anemia in the present study. "Anemia of chronic disease" is another plausible cause of anemia in ACHD patients. Acute or chronic immune activation is the basis of anemia of chronic disease, as cytokines and the reticuloendothelial system affect iron homeostasis, erythropoietin production, and the life duration of erythrocytes (10,18,25–28). Immune activation increases hepcidin concentration, which interacts with intestinal iron transport proteins such as ferroportin, and inhibits iron absorption (29,30). Elevated cytokine levels such as tumor necrosis factor-alpha have been reported in ACHD patients, especially in the presence of cyanosis and peripheral edema (31–33). The strong relation between diuretic use and anemia underlines the importance of the heart failure syndrome in the pathophysiology of ACHD (34).
The relation between anemia and outcome of ACHD patients.
The prognostic power of anemia may derive from its relation to disease severity and exercise capacity (4,6,11). The oxygen-carrying capacity of the blood is, in fact, an essential component of the cardiorespiratory chain responsible for providing peripheral tissues with oxygen adequate for their metabolic needs. Anemia results in reduced oxygen-carrying capacity and a premature shift to anaerobic metabolism during exertion. Anemia may also precipitate heart failure and cause deterioration in exercise capacity by increasing venous return and reducing oxygen delivery to the myocardium. However, there was only a trend toward higher prevalence of anemia in more impaired patients. This may reflect the poor ability of subjective assessment of functional status in predicting true functional capacity, rather than a lack of relation between anemia and exercise capacity. It has, in fact, been shown that subjective measures of functional status such as the NYHA functional classification tend to underestimate the degree of impairment in ACHD patients (21,34–36).
The prognostic power of anemia could also derive from its established relation to renal dysfunction. Decreased renal function and anemia are risk factors for all-cause mortality in patients with left ventricular dysfunction, especially when both are present, and renal dysfunction is a strong predictor of outcome in ACHD (1,2,6,8,11,18,37). However, anemia was a strong predictor of death even after adjustment for systemic ventricular function, functional class, and renal impairment. The established relation between neurohormonal and cytokine activation and anemia in acquired heart failure may also explain the prognostic power of anemia in ACHD.
Clinical implications.
In this population, anemia was a strong and independent prognostic marker. Screening for anemia should become part of the routine assessment of ACHD patients as a measure of risk stratification. Correctable causes of anemia, such as bleeding, should always be sought and treated. Trials of administration of recombinant erythropoietin in anemic patients with acquired heart failure have been promising (38–40). Erythropoietin and iron administration have resulted in reduction of symptoms, improvement of exercise tolerance, and reduced need for diuretics. Whether or not chronic treatment of anemia with iron supplementation and erythropoietin leads to an improvement in outcome in ACHD patients needs to be established.
Study limitations.
Cyanotic ACHD patients (including those with Eisenmenger syndrome) were excluded from this study to avoid confounding from secondary erythrocytosis and the inherent difficulty of defining anemia in this population. Increased hemoglobin levels in cyanotic patients represent an appropriate physiological adaptation to chronically low oxygen saturations. Iron deficiency "relative anemia" is frequent in cyanotic patients, but occurs at hemoglobin levels much higher than those of noncyanotic individuals, and its diagnosis requires information in addition to mere hemoglobin concentration (e.g., transferrin saturation and ferritin levels) (24,41–44). Thus, a uniform definition of anemia across the entire ACHD spectrum is not feasible.
Although not every single patient seen in our center during the study period underwent blood testing, this was more likely due to patient preference rather than physician choice. Our tertiary ACHD center manages patients from England and Wales, and many of them opt to have their blood tests locally. Thus, a selection bias cannot be excluded. Furthermore, the case mix of ACHD diagnostic subgroups in our study, excluding the cyanotic patients, is very representative of ACHD tertiary work. Future, larger prospective studies with longer follow-up and including patients who are not under tertiary care may provide additional information on anemia mechanisms as well as its prognostic value in ACHD patients in general and specific ACHD diagnostic subgroups in particular.
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Conclusions
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Anemia is not uncommon in ACHD patients attending tertiary centers. Anemic ACHD patients have a 3-fold increased mortality risk in the medium term. Screening for anemia should be part of the routine assessment of ACHD patients for risk stratification, and for treatment, when correctable causes are identified.
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Footnotes
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Dr. Dimopoulos has been supported by the European Society of Cardiology. Dr. Giannakoulas is supported by the Hellenic Heart Foundation, the DG Education & Culture—LLP Programme—Leonardo Da Vinci Mobility, and the Hellenic Cardiological Society. Dr. Karaoli was supported by the European Union (DaVinci programme). Dr. Francis is supported by the British Heart Foundation. The Royal Brompton Adult Congenital Heart Programme and the Department of Clinical Cardiology have received support from the British Heart Foundation and the Clinical Research Committee, Royal Brompton Hospital, London.
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