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Is there a role to erythropoiesis-stimulating proteins in the treatment of anemic chronic heart failure patients: a meta-analysis of randomized controlled trials

Bárbara Vieira, [email protected]; Diana Pires, [email protected]; Iolanda Vieira, [email protected]; João Novo, joã[email protected]; José Machado, [email protected]; Lia Rodrigues, [email protected]; Maria Lume, [email protected]; Mário Sousa, [email protected]; Mónica Pereira, [email protected]; Patrícia Gouveia, [email protected]; Pedro Vieira [email protected]

Dra. Filipa Almeida, turma 6

ABSTRACT: Problem: The study aim is to define if treatment of anemia with erythropoietin stimulating proteins influences and improves survival, prognosis and quality of life of severe heart failure patients. Summary of background: Anaemia is frequently observed in patients with chronic heart failure (CHF). Erythropoietin (EPO) is a glycoprotein hormone that acts on erythroid stem cells of the bone marrow to stimulate proliferation and differentiation. It has been successfully used in the treatment of many types of anaemia. Methods: We performed a systematic review and meta-analysis of randomized controlled trials reporting outcomes of heart failure patients with anaemia treated with erythropoietin stimulating proteins (ESP) versus placebo or iron therapy. Our systematic review compares ESP therapy with standard care in severe CHF patients published in Medline, IsiWeb of Knowledge and Scopus. Data were analyzed using the software SPSS 16® and the meta-analysis software in Review Manager 5®. Results: The electronic search retrieved 1187 eligible articles. 1174 were rejected initially and the other 13 were detailed evaluated and 5 of them were rejected. 8 studies were included in the meta- analysis. The outcomes selected to the meta-analysis were exercise duration (p< 0.00001)), six- minute walk distance (p= 0.03), left ventricular ejection fraction (LVEF) (p=0.02) and the peak Vo2 (p=0.03), New York Heart Association classification (p=0.01), serum ferritin (p=0.92), haemoglobin concentration(p<0.00001) and mortality (p=0.48). Conclusion: The advantages of erythropoietin administration in patients with HF and anaemia are significant, this treatment should, therefore, be considered a serious therapeutic option.

KEY WORDS: Anaemia, Chronic heart failure, Erythropoietin INTRODUCTION: Heart failure (HF) is a condition in which the heart is unable to pump out sufficient blood to meet the metabolic need of the body. Chronic HF refers to a persistent symptomatic HF and is the most common form of HF leading to hospital admission, accounting for 80% of cases [1]. The prevalence of HF is between 2 and 3% and rises sharply at 75 years old, so the prevalence in 70 to 80-year-old people is between 10 and 20% [2]. Anaemia is frequently observed in patients with chronic heart failure (CHF). Prevalence of anaemia depends both on the severity of CHF and diagnostic criteria used to define it. Using the most commonly employed definition of the World Health Organization (Haemoglobin [Hb] <12g/dL in women and <13g/dL in men), anaemia is present in one-third of the CHF patients [3, 4]. Its pathogenesis in CHF is complex and renal dysfunction, inflammation; changes in plasma volume, hematinic deficiencies, and drug treatment are common causes [5]. Anaemia in patients with HF is frequently associated with a substantially decreased aerobic capacity, a subjective experience of fatigue and reduced functional status and poor quality of life. Anaemia in CHF is independently associated with increased morbidity and mortality, and is considered as a useful prognostic marker [3], suggesting that treatment for anaemia should benefit patients . The recognition of the high prevalence and the independent prognostic role of anaemia in HF have contributed to intensification of research for an effective treatment. Erythropoietin (EPO) is a glycoprotein hormone that acts on erythroid stem cells of the bone marrow to stimulate proliferation and differentiation. It has been successfully used in the treatment of many types of anaemia such as anaemia due to kidney failure [6] and anaemia associated with cancer [7]. A central role of erythropoietin in cardiorenal anaemia syndrome has been proposed. Treatment of anaemia with erythropoiesis-stimulating proteins in patients with CHF would thus seem attractive and has been explored in several studies [3, 8-12]. Several randomized controlled trials (RCT) have demonstrated the safety and efficacy of erythropoietin-stimulating proteins (ESP) in correcting anaemia in patients with HF. However, as some studies have failed to show benefit, the role of this novel therapy in the treatment of HF is not defined. The aim of this study is to define if treatment of anemia with erythropoietin stimulating proteins influences and improves survival, prognosis and quality of life of severe heart failure patients.

METHODS Study objectives and design: We performed a systematic review and metanalysis of randomized controlled trials reporting outcomes of heart failure patients with anaemia treated with erythropoietin stimulating proteins versus placebo or iron therapy. The primary endpoints evaluated were effects of the therapy in mortality rates, prognosis defined as readmission rates, NYHA functional class, exercise capacity and quality of life, evaluated with validated questionnaires. The second endpoint was evaluation of complication rates and safety of erythropoietin stimulating proteins treatment. The outcomes of interest were mortality, readmission rates, left ventricle ejection fraction, NYHA functional class, exercise capacity defined by oxygen consumption in the exercise test and 6 min walking test and vascular complications. Search Strategy: We preformed a Systematic review of randomized controlled trials that compare ESP therapy with standard care in severe CHF patients published in Medline, IsiWeb of Knowledge and Scopus, since 1985 (year when ESP were first described and synthesised) until February 2009. In the search criteria defined the Mesh Terms: heart failure; anemia; erythropoietin recombinant and the text words: heart failure; congestive heart failure; chronic heart failure; heart insuficiency; systolic dysfunction; symptomatic heart failure; anemia; epoetin delta; erythropoiesis stimulating protein, human; darbepoetin alfa; recombinant erythropoietin; erythropoietin; erythropoietin recombinant, were used. The final query used to select the articles was: ("Heart Failure“ [Mesh] OR "heart failure“ [All Fields] OR "congestive heart failure“ [All Fields] OR "chronic heart failure“ [All Fields] OR "systolic dysfunction“ [All Fields] OR "symptomatic heart failure“ [All Fields]) AND ("Anaemia“ [Mesh] OR "anaemia“ [All Fields] OR "anaemia“ [All Fields]) AND ("Erythropoietin, Recombinant“ [Mesh] OR "epoetin delta“ [Substance Name] OR "erythropoiesis stimulating protein, human“ [Substance Name] OR "darbepoetin alfa“ [Substance Name] OR "recombinant erythropoietin“ [All Fields] OR "erythropoietin“ [All Fields] OR "erythropoietin“ [MeSH Terms] OR "erythropoietin recombinant“ [All Fields]) Study Selection: We included randomized controlled trials whose primary objective was to compare ESP treatment in CHF patients with placebo or iron therapy. Titles and abstracts of all articles were evaluated independently by two reviewers and rejected on initial screen if they: 1) included subjects other than CHF patients or evaluated erythropoietin therapy in other diseases; 2) had no evaluation of hemoglobin (Hb) or hematocrit (Ht) levels; 3) were not randomized controlled trials; 4) were published only in abstract form; 5) were published in another language than English or Portuguese. After obtaining full texts of the selected studies, the same reviewers independently assessed eligibility according to the following criteria: 1) studies that compared Erythropoietin group or erythropoietin + iron therapy vs placebo group or iron therapy; 2) studies where treatment of heart failure other than ESP is optimize in the 2 groups; 3) Articles that evaluate prognosis, mortality and quality of life; 4) articles addressing animal experiments and not phase III or IV RCT. Differences in data between the 2 reviewers were solved by rereviewing corresponding articles, and the final set was agreed on by consensus. Data extraction: Two reviewers extracted independently pre-specified data elements from each study, and data was organized in five different categories: study sample, effect of ESP treatment on anaemia, effect of ESP on mortality and prognosis, effect on quality of life and complication events. Charts were used to compile the data of each category. The following variables we created according to the four categories: (1) study sample variables: total patients in each group, age and heart failure treatment; (2) effect of ESP treatment on anaemia variables: hemoglobin level and serum ferritin for each group before and after treatment; (3) effect of ESP on mortality and prognosis variables: NYHA, left ventricle ejection fraction, peak of oxygen volume, distance in the 6 min walking test, in each group before and after treatment and mortality in the two groups; (4) quality of life variables: type of questionnaire used, global score before and after intervention in the 2 groups; (5) complication events variables: which complication event and incidence per group. Statistical analysis: Data were analyzed using the software SPSS 16® on an intention to treat basis. Where appropriate, data from all trials were combined using the meta-analysis software in Review Manager 5®. Random effects meta-analysis was conducted to determine a summary estimate of the relative risk and the 95% confidence interval and estimate the magnitude of the effect of ESP treatment in anemic heart failure patients and the primary endpoints determined. We performed tests of heterogeneity between studies using a standard chi-square test and I2 statistic. Statistical significance was set at p < 0.05.

RESULTS: Description of the included articles: The electronic search retrieved 1187 eligible articles. On initial screening, 1174 were rejected based on title and abstract and the other 13 were detailed evaluated. Of the 13 screened full text articles, 5 were rejected. Thus 8 studies were included in this meta- analysis (Fig.1). The characteristics of the included articles are listed Table 1. Data were analyzed using the software SPSS 16® on an intention to treat basis and data from all trials were combined using the meta-analysis software in Review Manager 5® .P-values up to 0,1 indicates homogeneity.

Figure 1 Flow Chart for articles selection Meta-analysis findings: According to the information available in the 8 articles, the outcomes selected to the meta-analysis were exercise duration, six-minute walk distance, left ventricular ejection fraction (LVEF) and the peak Vo2, serum ferritin, haemoglobin concentration, mortality (objective variables), and New York Heart Association classification (subjective variable). To evaluate the efficiency of the treatment with erythropoietin were also analysed the variation of haemoglobin concentration and serum ferritin. On the other hand duration of exercise data was available in 4 articles [14, 17, 21] and its analysis showed a statistically significant increase (p < 0.00001) of the distance walked (Fig.3). Relatively to the heterogeneity test, it was homogeneous (95% CI; p=0.59). Six-minute-walk distance improved with erythropoietin administration. Six-minute-walk distance data was available in 4 articles [15, 18, 20, 21] . Analysis revealed that there is a statistically significant improvement (p = 0.03) of this outcome in patients treated with erythropoietin compared with placebo group (Fig.2). The p-value of heterogeneity test (95% CI; p=0.01) indicates that exercise duration data is heterogeneous. Left ventricular ejection fraction, an efficiency marker, was measured in 4 studies. The mean LVEF increased significantly (p = 0.02) in patients treated with erythropoietin compared with placebo group (Fig.4) and its test was heterogeneous (95% CI; p=0.009).

Peak Vo2 was evaluated in 3 articles [14, 17, 21] and analysis shows that it significantly increased (p = 0,03) in treatment group compared with placebo (Fig.5) while the heterogeneity test p-value demonstrated that this variable is heterogeneous (95% CI; p=0.0002). Although the heterogeneity graph represents an homogeneous distribution. Changes in New York Heart Association classification were evaluated in 6 articles [15, 16, 17, 18, 19, 20]. Data analyse revealed a significant decrease (p = 0,01) in NYHA class in experimental group compared with placebo group (Fig.6) and meta-analysis showed that NYHA class has an heterogeneous distribution (95% CI; p<0.00001). Mortality was considerate in all 8 articles which promote a better analysis with efficient results. There is no significant difference (p = 0,48) between the groups (Fig.7) and its distribution is homogeneous according to the heterogeneity test (95% CI; p=0.33). Variation in Haemoglobin (Hb) concentration was monitored in 7 articles [14, 15, 16, 17, 18, 20, 21]. There was a significantly increase in Hb concentration (p < 0.00001) as result of the administration of erythropoietin (Fig.8). Hb concentration distribution is homogeneous according to the test of heterogeneity (95% CI; p=0.08). Although this heterogeneity is not too much significant as the p- value indicates because it is not to much lower than 0.1 and the heterogeneity graph representation also doesn’t show a bigger heterogeneity. Serum ferritin was measured in only 3 articles [15, 16, 18] and there is no significantly changes (p = 0,92) between the study groups (Fig.9). The heterogeneity test indicates an homogeneity in the distribution of serum ferritin data (95% CI; p=0.27).

Table 1 Description of the included articles

Article N N Age Title Authors Age (Study) Outcomes identifiation placebo study (Placebo)

Effect of darbepoetin alfa Piotr Ponikowski, MD, on exercise tolerance in PHD, Stefan D. Anker, Mortality, hemoglobin, 1 anemia patients with et al 22 19 72 ± 7 70 ± 7 exercise duration, peak symptomatic chronic heart VO2. failure Randomized, double- blind, placebo- controlled Dirk J. van Veldhuisen, Mortality, hemoglobin, study o evaluate the effect Kenneth Dickstein, NYHA class, 6-minute 2 of two dosing regimens of Alain Cohen-Solal, et 55 110 71 ± 9 71 ± 11 walk distance, left darbepoetin alfa in al ventricular ejection patients with heart failure fraction, serum ferritin. and anaemia

The effect of correction of mild anemia in severe, resistant congestive heart Donald S. Silverberg, Mortality, hemoglobin, failure using MD, Dov Wexler, MD, NYHA class, left 3 subcutaneous 16 16 72.2 ± 9.9 75.3 ± 14.6 David Sheps, et al ventricular ejection fraction erythropoietin and serum ferritin. intravenous iron: a randomized controlled study

Erythropoietin improves anemia exercise tolerance Alberto Palazzuoli, and renal function and MD, PhD,a Donald Mortality, hemoglobin, reduces B-type natriuretic 4 Silverberg, MD,b 18 20 75 ± 6 72 ± 5 exercise duration, NYHA peptide and Francesca Iovine, MD, class, peak VO2. hospitalization in patients et al with heart failure and anemia

Effects of darbepoetin α on right and left John T. Parissis, MD,a ventricular systolic and Kallirrhoe Kourea, Mortality, hemoglobin, diastolic function in MD,a Fotios Panou, et NYHA class, 6-minute 5 anemic patients with al 11 21 69 ± 4 72 ± 5 walk distance, left chronic heart failure ventricular ejection secondary to ischemic or fraction, serum ferritin. idiopathic dilated cardiomyopathy

Randomized double-blind Jalal K. Ghali, Inder S. trial of darbepoetin alfa in 6 Anand, William T. 157 162 69 ± 10 68 ± 12 Mortality, NYHA class. patients with symptomatic Abraham, et al heart failure and anemia

Effect of darbepoetin- alfa on plasma pro-inflamatory Kallirrhoe Kourea 1, Mortality, hemoglobin, cytokines, anti- John T. Parissis, NYHA class, 6-minute inflamatory cytokine Dimitrios Farmakis, et 7 20 21 68 ± 13 72 ± 5 walk distance, left interleukin- 10 and solube al ventricular ejection Faz/Faz ligand system in fraction. anemic patient with chronic heart failure

Effect of Erythropoietin on Donna M. Mancini, Mortality, hemoglobin, Exercise Capacity in Stuart D. Katz, Chim exercise duration, 6- 8 Patients With Moderate to 8 15 55 ± 7 60 ± 12 C. Lang, John minute walk distance, Severe Chronic Heart LaManca, et al peak VO2. Failure

Figure 2 Exercise duration Figure 3 Six-minute walk distance

Figure 4 Left ventricular ejection fraction (LVEF)

Figure 5 Peak Vo2

Erythropoietin Placebo Mean Difference Mean Difference Study or Subgroup Mean SD Total Mean SD Total Weight IV, Random, 95% CI IV, Random, 95% CI A.H. Journal 2006 (4) 2.2 0.7 20 3.9 0.3 18 16.5% -1.70 [-2.04, -1.36] A.H. Journal 2008 (5) 2.1 0.5 21 3.2 0.6 11 16.0% -1.10 [-1.51, -0.69] A.H. Journal 2008 (6) 2.43 0.32 162 2.52 0.36 157 17.5% -0.09 [-0.16, -0.02] ELSEVIER 2007 (7) 2.8 0.5 21 2.55 0.5 20 16.7% 0.25 [-0.06, 0.56] JACC 2001 (3) 2.2 0.7 16 3.9 0.3 16 16.3% -1.70 [-2.07, -1.33] JACC 2007 (2) 2.3 0.64 110 2.315 0.68 55 17.1% -0.02 [-0.23, 0.20]

Total (95% CI) 350 277 100.0% -0.71 [-1.28, -0.14] Heterogeneity: Tau² = 0.48; Chi² = 175.90, df = 5 (P < 0.00001); I² = 97% -2 -1 0 1 2 Test for overall effect: Z = 2.44 (P = 0.01) Favours experimental Favours control

Figure 6 New York Heart Association classification Figure 7 Mortality

Figure 8 Haemoglobin concentration

Figure 9 Serum Ferritin

DISCUSSION: This is the first meta-analysis to evaluate survival and quality of life related aspects in patients with Heart Failure and anaemia treated with erythropoietin. We found statistically significant improvements in many aspects associated with quality of life in patients treated with erythropoietin, such as exercise duration, six-minute walk distance, left ventricular ejection fraction (LVEF) and peak Vo2. A significant decrease in NYHA classification in experimental group is a positive subjective consequence which seems to be associated to the treatment. Haemoglobin also improved with erythropoietin administration comparing with the placebo group. Therefore we can conclude that erythropoietin treatment benefices haemoglobin concentration in patients. The differences found in mortality frequency weren’t statistically significant. So, we conclude that the treatment with erythropoietin does not improve patient’s survival. Three of the studies included in meta-analysis [14, 15, 18] refer rates complication after the treatment and it let us conclude that exist an higher level of safety associated with the treatment. Another three articles [14, 15, 21] evaluate quality of life trough two type of questionnaire: Kansas City Cardiomyopathy Questionnaire (KCCQ) and Minnesota Living with Heart Failure Questionnaire (MLHFQ). The first one was used only in articles [14], where quality of life improved in experimental group and it was statistically significant, and [15] where the improve of quality of life was not statistically significant. The MLHFQ was mentioned in the three articles. The quality of life improved with erythropoietin administration in all of them but only in article [21] it was statistically significant. The advantages of erythropoietin administration in patients with HF and anaemia are significant, this treatment should, therefore, be considered a serious therapeutic option. After this analysis we may suggest that should not be done more randomized controlled clinical trial about erythropoietin administration in patients with Chronic Heart Failure because of ethical questions. Studies made until now are enough, so people should not be submitted to this type of treatment if it is not necessary. Study limitations. Limitation of meta-analysis basically included heterogeneity, absence of full article and differences in data presentation used in the selected articles which difficult data aggregation. The articles that weren’t available were excluded. In articles with same variables in different units we tried to convert them into the same unit. If it was not possible, the variable was excluded. Some relevant variables, as B-type Natriuretic Peptide (BNP), an important data to evaluate the efficiency of treatment, rate readmission and safety, were mentioned only in less than three articles, so it wasn’t possible include them into the meta-analysis. These limitations led to the impossibility of running a meta-analysis with a larger number of variables and analyzing more articles which titles and abstracts indicated them relevant for our study. During the meta-analysis using meta-analysis software in Review Manager 5® the heterogeneity test values were affected because of the restrict number of article values therefore, sometimes, the p- value allowed us to conclude heterogeneity that did not exist in the graphic interpretation.

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14. Piotr Ponikowski, Stefan D. Anker, Joanna Szachniewicz, Darlington Okonko, Mark Ledwidge, Robert Zymlinski, Enda Ryan, Scott M. Wasserman, Nigel Baker, Dylan Rosser, Stuart D.Rosen, Philip A. Poole-wilson, Waldemar Banasiak. Effect of Darbepoietin Alfa on Exercise Tolerance in Anemic Patients With Symptomatic Chronic Heart Failure. JACC 2007, Vol 49, No 7

15. Dirk J. Van Veldhusien, Kenneth Dickstein, Alain Cohen-Solal, Dirk J.A. Lok, Scott M. Wassermans, Nigel Baker, Dylan Rosser, John G.F. Cledand, Piotr Ponikowskis. Randomized, double-blind, placebo-controlled study to evaluate the effect os two dosing regimens of darbepoetin alfa in patients with heart failure and anemia. European Heart Journal (2007) 28, 2208–2216

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17. Alberto Palazzuoli, PhD Donald Silverberg, Francesca Iovine, Stefano Capobianco, Giovanna Giannoti, Anna Calabro, Maria stella Campagna, Ranuccio Nuti. Erythropoietin improves anemia exercise tolerance and renal function and reduces B-type natriuretic peptide and hospitalization in patients with heart failure and anemia. American Heart Journal, September 2006

18. John T. Parissis, Kallirrhoe Kourea, Fotios Panou, Dimitrios Farmakis, Ioannis Paraskevaidis, Ignatios Ikonomidis, Gerasimos Filippatos, Dimitrios Th Kremastinos. Effects of darbepoetin alfa on right and left ventricular systolic and diastolic function in anemic patients with chronic heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. American Heart Journal, April 2008

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20. Kallirrhoe Kourea, John T. Parissis, Dimitrios Farmakis, Fotios Panou, Ioannis Paraskevaidis, Koula Venetsanou, Gerasimos Filippatos, Dimitrios Th. Kremastinos. Effects of darbepoetin-alpha on plasma pro-inflammatory cytokines, anti-inflammatory cytokine interleukin-10 and soluble Fas/Fas ligand system in anemic patients with chronic heart failure. ELSEVIER, Atherosclerosis 199 (2008) 215–221

21. Donna M. Mancini, Stuart D. Katz, Chim C. Lang, John LaManca, Alhakam Hudaihed and Ana- Silvia Androne. Effect of Erythropoietin on Exercise Capacity in Patients With Moderate to Severe Chronic Heart Failure. Circulation 2003;107;294-299

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