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Complete correction of anemia with Recormon[R] (erythropoietin [beta]) in patients on chronic hemodialysis/Kompletna korekcija anemije Rekormonom[R] (eritropoetin [beta]) kod bolesnika na hronicnom programu hemodijalize.

Introduction

Anemia is a common finding in patients with chronic kidney disease (CKD). The moment when anemia occurs during the progression of CKD is individual and depends on various factors, but it is usually present when creatinine clearance is decreased under 30 ml/min/1.73 [m.sup.2] [1]. Although anemia has multifactorial etiology, it is usually a consequence of erythropoietin deficiency and decreased synthesis by the impaired kidneys. Therefore, the main strategy of renal anemia treatment is administration of erythropoiesis-stimulating agents (ESA) [2, 3].

It has been shown that anemia and its suboptimal correction are associated with the increased prevalence of cardiovascular diseases which is in correlation with the increased morbidity and mortality in pre-dialysis patients, as well as in those who are on renal replacement therapy [4-7]. Statistical analyses show that 50-60% of deaths among the patients on dialysis are related to cardiovascular complications [8, 9]. Anemia is associated with left ventricular hypertrophy (LVH) and coronary artery disease (CAD) [10, 11]. Thus, if the left ventricular mass exceeds 165 g/[m.sup.2], the risk of death is 3.7 times higher than in case of the normal left ventricle morphology [9]. Higher heart rate and higher stroke volume due to anemia increase the minute volume which is a significant stimulus for LVH development [12, 13].

Literature data show that treatment of anemia with ESA has resulted in decreased LVH [14, 15]. Besides, correction of anemia has increased ischemic tolerance and coronary reserve [16]. These results suggest the importance of early detection of anemia during the progression of renal disease as well as of the administration of appropriate therapy [9].

In Serbia, ESA therapy has been applied in more than 50% of patients who are on renal replacement therapy. Due to the current National Heath Fund restriction, therapy of renal anemia is suboptimal. Therefore, the aim of this study was to compare the effect of optimal and suboptimal correction of anemia in patients on hemodialysis having left ventricular hyperthrophy.

Material and Methods

The aim of this open, comparative, multicenter phase IV study was the complete correction of anemia with RECORMON[R] (erythropoietin [beta]) in patients on hemodialysis already receiving suboptimal doses of ESA and who had suboptimal correction of hemoglobin. Another inclusion criterion was the presence of LVH.

The study sample consisted of 50 patients, 32 males and 18 females, their mean age being 49 [+ or -] 11 years (median 52 years) from five dialysis centers (Clinical Hospital Center /CHC/ Zvezdara, Belgrade, Clinical Center (CC) Novi Sad, hospitals in Krusevac, Pirot and Zrenjanin). Forty six patients ended the study: one patient was excluded due to the deterioration of hypertension, one patient was diagnosed to have hepatic tumor and sudden cardiac death was registered in 2 patients. The most common renal disease was chronic glomerulonephritis (30% of patients) and nephroangiosclerosis (14%). The main inclusion criteria were:

* 18-75 years of age

* Hemodialysis treatment over 6 months

* Previous therapy with erythropoietin [beta] 3 months prior the inclusion in the study

* Steady hemoglobin level with values [less than or equal to] 10.5 g/ dl during the last 3 months

* Left ventricle mass index (LVMI) above 160 g/[m.sup.2]

* Hemodialysis adequacy: Kt/V [greater than or equal to] 1.2

* No contraindications for anemia correction up to the target values defined in the study

The major exclusion criteria were: pregnancy (diagnosed by detection of human chorionic gonadotropine levels), patients with hypersensitivity to erythropoietin [beta], administration of other ESA, hemoglobin (Hb) levels above 10.5 g/dl, unregulated hyperparathyroidism (intact parathormone (iPTH) >300 pg/ml), hypertension not regulated with the administered therapy ([greater than or equal to]160/100 mmHg), history of myocardial infarction, unstable angina, thromboembolic disease and cerebrovascular insult during the last six months.

The target levels of HE were 12-13 g/dl. Erythropoietin [beta] was administered several times a week until target Hb levels were achieved, followed by the reduction in dosing interval (once a week or once in two weeks) if the investigator assed that the target level of Hb would not be compromised by this dosing schedule.

The major efficacy endpoints were a decrease in LVMI (the primary efficacy endpoint) and maintenance of Hb levels within the targeted range (the secondary efficacy endpoint). The safety profile of drug was closely monitored, and all adverse events were reported, including changes of diastolic and systolic blood pressure. This study went on for 12 months, and the patients had 6 visits in total - at the beginning, after one, three, six, nine and twelve months. All patients signed the informed consent to participate in the study having been given detailed information about the protocol. The study was approved by the local Ethics Committees and the National Regulatory Authority.

Laboratory tests were conducted in the automatic analyzer at the baseline, after 3, 6, 9 and 12 months. Cardiac ultrasound (LVMI, left ventricular ejection fraction /LVEF/) was performed at the beginning of the study, after 6 months and at the end of the study. LVH was defined as interventricular septal diameter (IVSd) > 1.2 cm and/or left ventricular posterior wall diameter (LVPWd) > 1.1 cm. LVMI values higher or equal to 110 g/[m.sup.2] for the female patients and 131 g/[m.sup.2] for the male patients were considered as LVH according to Framingham trial criteria.

The doses of ESA were defined according to the current guidelines. Iron stores were monitored at 3 to 6 months intervals and iron supplementation was performed if concentration of serum ferritin was under 100 [micro]g/L.

The following descriptive statistical methods were used in this study: arithmetic mean with standard deviation, median with the interquartile range, minimal and maximal values as well as relative numbers for categorical variables. Differential statistical analysis methods were also used, such as: Student's T test, ANOVA for repeated measures, Friedman test, Chi square test, Fischer's exact test depending on numerical limitations, as well as McNemar's test. Pearson's coefficient of linear correlation was used for correlation analysis. Statistical analysis was performed in SPSS software (SPSS for Windows, release 17.0, SPSS, Chicago, IL).

Results

Correction of Anemia

At the baseline, the patients had suboptimal values of Hb (mean Hb 7.8 [+ or -] 3.8 g/dl) with suboptimal dose of erythropoietin [beta]. After increasing ESA doses, the Hb levels increased as compared to the baseline values, and a statistically significant difference was present after the third, sixth, ninth and twelfth month of therapy compared to the baseline values (8.4 [+ or -] 4.3 g/dl, 9.1 [+ or -] 4.6 g/dl, 9.1 [+ or -] 4.6 g/dl, 9.5 [+ or -] 4.8 g/dl, 11.7 [+ or -] 1.8 g/dl, p=0.000 vs. baseline values, Graph 1). Table 1 shows that during the study the number of patients with Hb levels of [greater than or equal to] 12 g/dl gradually increased, and the number of patients with Hb levels of [less than or equal to] 12 g/dl gradually decreased (p=0.0001). At the end of the study, the target Hb levels were achieved in 24 (52%) patients.

Dosing and Frequency of Administration

Mean erythropoietin [beta] doses were increased in the phase of correction (from the initial to the third visit), and then the doses were stabilized in the maintenance phase (from the third to the twelfth month). There was a statistically significant difference between a weekly dose of drug at the baseline and after one month. During this study, the frequency of drug dosing was variable. During the correction phase, the majority of patients had multiple doses during a week (90% of patients after one month and 82% patients after 3 months), while the patients received the drug mainly once a week or once in two weeks in the maintenance phase. Table 2 shows the mean weekly dose of erythropoietin p by visits. It is obvious that patients who did not decrease LVMI required the higher doses of erythropoietin [beta] for anemia correction than the patients who decreased LVMI at the end of the study.

Left Ventricle Mass Index

LVMI values are shown in Graph 2. During this study, LVMI decreased, and at the end of it there was a statistically significant difference between the value of LVMI compared to the baseline values (p=0.014). The baseline values of LVMI were not statistically different between the compared groups. Graph 3 shows that the patients who did not achieve the target Hb levels did not have a significant decrease of LVMI (207 [+ or -] 65 vs. 217 [+ or -] 38 g, p=ns) compared to the patients who achieved the target Hb levels (179 [+ or -] 32 g/[m.sup.2] vs. 197 [+ or -] 38 g/[m.sup.2], p=0.007). The LVEF values were not significantly different after 6 and 12 months compared to the baseline values.

Adverse Events

During the study all adverse events as well as blood pressure values were recorded. Neither systolic nor diastolic blood pressure was statistically different during the study. Four patients did not finish the study: deterioration of hypertension was recorded in one patient probably due to the drug used, sudden death was registered in two patients, and one patient was diagnosed to have hepatic tumor (neither event was considered to be associated with the study drug).

Discussion

The results of this multi-center study showed that hemoglobin was significantly increased by increasing the dose of erythropoietin [beta] during the study compared to the baseline values. This significant increase was recorded after the third month of therapy, and it continued up to the twelfth month. Although at the end of the study, 52% of patients achieved the target hemoglobin level, a higher percentage of patients (83%) achieved hemoglobin levels >11 g/dl, that being in accordance with the current guidelines (10-12 g/dl) [17], and much higher than the range defined by legislation in Serbia (10-11 g/dl).

Although erythropoietin therapy began in 1989, the optimal hemoglobin was often the subject of clinical studies. Normal Hematocrit trial, CHOIR trial and TREAT trial have shown that the range of normal Hb level for healthy population is not optimal for patients with CKD and patients on dialysis, and the majority of authors agree that hemoglobin values above 12 g/dl are not recommended due to potential adverse events, primarily cardiovascular ones. However, according to the current guidelines, the Hb levels of 12 g/dl can be recommended if it is assumed that the patient may have benefit, and if cardiovascular and cerebrovascular risk is low [17]. This criterion was taken into consideration when selecting the patients for this study.

The primary efficacy endpoint in this study was a decrease in LVMI values as a consequence of correction of anemia with erythropoietin [beta]. The results show that LVMI was significantly decreased compared to the baseline values after 12 months of therapy with erythropoietin [beta]. More importantly, a decrease in LVMI was recorded in the patients who achieved the target levels of hemoglobin ([greater than or equal to]12 g/dl). This finding indicates that the target hemoglobin level set in this study is the level that can lead to regression of identified changes in the cardiac muscle, unlike suboptimal correction of anemia.

It is well known that a coronary disease and left ventricle hypertrophy are the leading comorbidity in dialysis patients. Both are the risk factors for myocardial ischemia and heart failure, which is the strong predictor of death in these patients [21-23]. Several studies have shown that the long-term administration of ESA leads to LVH decrease primarily by normalizing diastolic left ventricular dimension [24-26]. Partial correction of anemia may reduce the load-mediated myocardial ischemia [16, 27]. Other authors agree that ESA therapy leads to regression of LVH, repairs morphology of left ventricle, ejection fraction and cardiovascular status [14, 28-30]. It is shown that Hb is an independent indicator of hospitalization rate as well as of the survival of patients on dialysis [30]. In addition, it is shown that the Hb levels of 12-13 g/dl were associated with a higher risk of death [31]. Since mortality in dialysis patients usually has cardiovascular causes [32], the results of this study are in accordance with other results where the Hb levels >12g/dl have beneficial effect on cardiac muscle leading to regression of LVH [33]. Our authors also showed that therapy with erythropoietin [beta] during 25 months led to partial LVH regression (17%) in 30 hemodialysis patients [34].

During this study, the dosing schedule was variable. As usual, the dose of the drug was significantly increased in the correction phase (first months of the study) and then gradually decreased until the end of the study. The frequency of dosing was changed in line with the increase in hemoglobin: 94% of patients were administered the drug several times a week at the beginning of correction phase, while 50% of patients were administered the drug once a week, or once in two weeks at the end of the study. According to the current guidelines, the drug dosage can be decreased either by absolute dose decrease or by increasing the dosing interval.

It is shown that average doses of erythropoietin [beta] were higher in the patients who did not decrease LVMI values. It is possible that in this group of patients, anemia had additional co-factors (chronic inflammation, hyperparathyroidism, or other) which disable optimal correction of hemoglobin and require an increase in erythropoietin dose. Finally, these patients may have another factor(s) besides anemia that led to LVH (hypertension, uncontrolled hypervolemia).

The left ventricular ejection fraction (LVEF) is a measure of left ventricle function, and the values < 50% with left ventricular fractional shortening of <25% and mid-wall fractional shortening (mwFS) <14% are a sign of systolic dysfunction [35]. Systolic dysfunction is present in approximately 15% of patients who start dialysis [36]. Anemia usually causes a hyperdynamic state in order to maintain an adequate oxygen supply to the peripheral tissues [37]. During this study, the LVEF values were not significantly changed, thus indicating the preserved left ventricular function after the correction of hyperdynamic state.

This study had certain limitations. Its design was predominantly focused on the correction of anemia as an important risk factor for the development of LVH, while other risk factors were not investigated (principal diagnosis including diabetes, previous cardiovascular diseases, hypertension and its duration, dialysis conditions and hydration status, inflammatory status, homocysteine, prescribed therapy, etc.). However, these factors were constant during the study, and did not change significantly which may indicate that the resulting effects in this study were mainly the consequence of the drug administration and correction of anemia.

Conclusion

This national, multicenter study showed that correction of anemia with erythropoietin [beta] in the patients who were on hemodialysis and who had had suboptimal levels of hemoglobin led to the correction of left ventricle hypertrophy, with preserved the left ventricle ejection fraction and with the excellent safety profile of administered therapy. Our experience shows that reversion of left ventricular hypertrophy requires minimal hemoglobin values of 12 g/dl. It is necessary to conduct new clinical studies that will include a larger number of patients and assess whether the results obtained in this study are specific for erythropoietin [beta] or the same results can be obtained when administering other erythropoiesis-stimulating agents.

Abbreviations

CKD    --chronic kidney disease
ESA    --erythropoiesis-stimulating agents
LVH    --left ventricular hypertrophy
Hb     --hemoglobin
LVMI   --left ventricle mass index
LVEF   --left ventricular ejection fraction


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[36.] Sood MM, Pauly RP, Rigatto C, Komenda P. Left centricular dysfunction in the hemodialysis population. NDT Plus. 2008;1(4):199-205.

[37.] Pappas KD, Gouva CD, Katopodis KP, Nikolopoulos PM, Korantzopoulos PG, Michalis LK, et al. Correction of anemia with erythropoietin in chronic kidney disease (stage 3 or 4): effects on cardiac performance. Cardiovasc Drugs Ther. 2008;22(1):37-44.

Nada DIMKOVIC (1,2), Igor MITIC (3,4), Branislav ANDRIC (5), Branislav LILIC HAVIDZA (6), Rosa JELACIC (7) and Natasa MILIC (8)

University of Belgrade, Faculty of Medicine (1) Zvezdara University Medical Center, Clinical Department of Renal Diseases, Belgrade (2) University of Novi Sad, Faculty of Medicine (3) Clinical Center of Vojvodina Novi Sad, Clinic for Nephrology and Immunology (4) Medical Center Krusevac Medical Center Pirot (6) General Hospital "Djordje Joanovic", Zrenjanin (7) University of Belgrade, Faculty of Medicine, Institute for Medical Statistic and Informatics8

UDK 616.155.194:616.61-78]-08 i UDK 616.124-007.1:616.61-78

DOI: 10.2298/MPNS1510324D

Corresponding Author: Prof. Dr Nada Dimkovic, KBC Zvezdara, klinicko odeljenje za bubrezne boesti 11000 Beograd, Dimitrija Tucovica 161, E-mail: dim@eunet.rs

Table 1. Hemoglobin values during the study visits (number, %)

Tabela 1. Vrednosti hemoglobina po vizitama (broj, %)

                                      Hb [greater
                                      than or equal
                       Hb < 120 g/L    to] 120 g/L       P

Beginning/Start         50 (100%)        0 (0%)       <0,0001
n=50
1st month/1. mesec       44 (88%)        6 (12%)
n=50
3rd month/3. mesec       26 (53%)       23 (47%)
n=49
6th month/6. mesec       28 (58%)       20 (42%)
n=48
9. month/9. mesec        19 (40%)       28 (60%)
n=47
12th month/12. mesec     22 (48%)       24 (52%)

Hb--hemoglobin

Table 2. Mean doses of erythropoietin [beta] in the patients who
decreased their left ventricular mass index (LVMI) and in those who
did not decrease it

Tabela 2. Prosecne doze eritropoetina [beta] kod bolesnika kod kojih
je na kraju studije smanjen indeks mase leve komore (IMLK) i kod
kojih nije smanjen indeks mase leve komore

Mean weekly                                 LVMI/IMLK
erythropoietin [beta]
dose Prosecna nedeljna    Decreased (N = 24)   Not decreased (N = 22)
doza eritropoetina         Smanjen (N = 24)    Nije smanjen (N = 22)
[beta]

Month 1, IU/Mesec 1, IJ   6125 [+ or -] 2379     6166 [+ or -] 2758
Month 3, IU/Mesec 3, IJ   6156 [+ or -] 2515     8208 [+ or -] 3041
Month 6, IU/Mesec 6, IJ   5351 [+ or -] 2772     7500 [+ or -] 2576
Month 9, IU/Mesec 9, IJ   4587 [+ or -] 2387     6958 [+ or -] 3414
Month 12, IU/Mesec 12,    5397 [+ or -] 3155     7208 [+ or -] 3939
  IJ
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Title Annotation:Original study/Originalni naucni rad
Author:Dimkovic, Nada; Mitic, Igor; Andric, Branislav; Lilic Havidza, Branislav; Jelacic, Rosa; Milic, Nata
Publication:Medicinski Pregled
Article Type:Report
Geographic Code:1USA
Date:Sep 1, 2015
Words:4106
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