Continuous Erythropoietin Receptor Activator for the Treatment of Chronic Dialysis Patients with Renal Anemia in Daily Clinical Practice in Poland: A Non-Interventional, Multi-Center, Pragmatic NAVIGO Trial Open Access

Renal anemia is an early and common complication of chronic kidney disease (CKD) and its prevalence rises as glomerular filtration rate decreases [1]. The problem is growing and affects up to 90% of patients along with the decrease of glomerular filtration rate below 30 mL/min [2, 3]. Renal anemia, typically normocytic normochromic, is caused by inadequate secretion of endogenous erythropoietin, which results in decreased production of erythrocytes in the bone marrow. A deficiency of iron, folic acid, vitamin B12, blood loss, chronic inflammation, reduced survival time of red blood cells, or increased resistance of bone marrow to erythropoietin may also contribute to the development of renal anemia. Untreated renal anemia leads to increased risk of cardiovascular disease due to hyperkinetic blood circulation and left ventricular dysfunction, as well as to cognitive impairment and fatigue [3, 4].

According to the European Renal Best Practice position statement [5] on the Kidney Disease: Improving Global Outcomes guidelines for anemia in CDK [6], renal anemia in patients with CKD can be diagnosed when the hemoglobin (Hb) concentration drops below 12.0 g/dL in adult women of all ages, 13.5 g/dL in adult men, and 13.2 g/dL in men older than 70 years of age [5]. The recommended treatment includes iron preparations, erythropoiesis-stimulating agents (ESAs), or blood transfusion [5]. Implementation of an appropriate ESA treatment strategy may improve survival and quality of life [7, 8]; however, high doses of ESAs were demonstrated to increase mortality in patients with CKD [9]. Moreover, a rapid increase in Hb concentration is associated with an increased risk of hypertension, arteriovenous fistula thrombosis, thrombotic events (including mesenteric ischemia and necrosis), and cardiovascular events and contributes to the progression of CKD [10]. According to the European Renal Best Practice position statement [5], the decision whether and when to start the administration of ESAs in dialysis CKD patients should be individualized on the basis of the following factors: ESA therapy-related risks, presence of anemia-attributable symptoms, and the risk of needing a transfusion. Routinely, Hb values should not fall below 10 g/dL in dialysis CKD patients. In high-risk patients (including patients with asymptomatic ischemic heart disease), ESA treatment should be started at Hb values of 9–10 g/dL. The target Hb value for high-risk patients should be approximately 10 g/dL through maintenance therapy. ESA treatment should be considered at higher Hb values (but not exceeding 12 g/dL) in the following patients: low-risk patients, patients with ischemic heart disease with exacerbation of ischemic symptoms associated with anemia, and patients in whom a benefit on quality of life can be foreseen [5]. Initially, low doses are recommended to prevent an increase in Hb concentration that is too rapid [10]. Currently, it is assumed that the target Hb concentration is determined individually, considering the possible comorbidities, and should be in the range of 10–12 g/dL [5, 11]. Lower target values in the suggested range should be planned for patients with specific risk factors, especially those with diabetes or those hyporesponsive to ESA treatment. There is no need for the existing dialysis schedule to be altered during therapy with ESAs [5].

Methoxy polyethylene glycol-epoetin beta (Mircera^®), the molecule formerly known as continuous erythropoietin receptor activator (C.E.R.A.), was registered in the EU for the treatment of symptomatic anemia associated with CKD in adults in 2007 [12]. This drug is distinguished from other ESAs by the pharmacological features of a long half-life – approximately 130 h after both intravenous and transdermal administration – and a lower receptor affinity alongside increased intrinsic activity [13, 14]. As a result of these properties, C.E.R.A. can be administered less frequently than other ESAs: specifically, once every 2 weeks for the treatment of anemia, and once a month to maintain the therapy in dialysis patients. The slower activity of the drug, which makes the clinical effect visible after the 43rd day of treatment, and the reduced rate at which Hb concentration increases (0.2 g/dL/week) allows for a stable Hb level to be obtained and controlled, preventing the target concentration from being exceeded [12]. C.E.R.A. is also characterized by high effectiveness in the treatment of renal anemia in dialysis patients, and non-inferiority to other ESAs [15].

Treatment of renal anemia with C.E.R.A. was previously evaluated in three phase III clinical trials (AMICUS, ARCTOS, CORDATUS) [16‒18]; however, only the first included dialysis patients. As daily clinical practice often differs from the recommended guidelines and from the results obtained in interventional trials, it is necessary to determine the effectiveness of C.E.R.A. for the treatment of renal anemia in an observational study. The aims of the NAVIGO study presented herein were to (a) evaluate the efficacy of C.E.R.A. in the treatment of renal anemia and (b) to determine the stability of the Hb concentration during the first 12 months of C.E.R.A. treatment of anemia in daily dialysis practice in Poland.

This non-interventional, prospective, multicenter, real-world, pragmatic study was conducted between July 2011 and June 2015. The target population was patients treated with repeated hemodialysis or peritoneal dialysis (automated peritoneal dialysis or continuous ambulatory peritoneal dialysis), with CKD-associated anemia, who were never previously treated with ESA, had Hb concentration levels below 10 g/dL, and were qualified for treatment with C.E.R.A. Two hundred and forty-seven patients from 26 centers in Poland were enrolled after meeting the following inclusion criteria: symptomatic CKD-associated anemia, balanced iron stores in the opinion of the investigator, investigator’s decision to start treatment with C.E.R.A., aged older than 18 years, and informed written consent to participate in the study. Exclusion criteria included: other causes of anemia; pregnancy and breast-feeding; contraindications included in the Summary of Product Characteristics (uncontrolled hypertension, hypersensitivity to drug ingredients); and lack of qualifications for treatment (e.g., due to comorbidities such as active bleeding, infections, cancer, or blood transfusion).

Observations were carried out for 12 months over 12 visits for hemodialysis patients (once a month) and over 8 visits for peritoneal dialysis patients (every 6 weeks). During the initial visit, basic demographic data (age, sex, height, weight, age) as well as history of CKD (cause, duration, pre-dialysis period), comorbidities, and medications were collected and entered into the electronic clinical observation form (eCRF). At each subsequent visit, the results of routine laboratory tests (Hb, blood count: HCT, WBC, PLT, RET, ESR, CRP level, PTH concentration, iron stores – the degree of transferrin saturation, ferritin concentration); information regarding the dose, route of administration, and dosing scheme of C.E.R.A.; the assessment of dialysis adequacy; anemia treatment (e.g., iron, vitamin B6, B12, C); and blood transfusions were collected. In addition, during these visits, data regarding adverse events (AEs), serious AEs, and AEs of special interest (predefined in the study protocol) were collected. Special interest AEs included among others: antibody-mediated pure red cell aplasia, pure red cell aplasia, measurement or presence of anti-erythropoietin antibodies, ESA treatment-resistant anemia, hematologic disorders, cardiovascular disorders, gastrointestinal or cerebral bleeding, thrombocytopenia, pulmonary embolism, hemodialysis fistula thrombosis, infections, new onset or progression of a malignant neoplasm, inappropriate drug response (inadequate response or no response to ESA treatment, unexplained loss of ESA treatment effect), skin hypersensitivity at C.E.R.A. injection site, red blood cell transfusion, and death. The primary endpoints were (a) the proportion of patients who achieved a Hb concentration of 10 g/dL, or an increase in Hb concentration of at least 0.8 g/dL/month between months 3 and 6 after the start of treatment, and (b) the percentage of patients with a Hb concentration of ≥12 g/dL in the subsequent months of the study. Secondary endpoints included: the average rate of increase of Hb (g/dL/month), between months 1 and 6 of the study; the average time that elapsed from the beginning of treatment with C.E.R.A. to when Hb concentration exceeded 10 g/dL; the number and percentage of patients with Hb levels maintained within 10–12 g/dL in the subsequent months; as well as the average time for which Hb levels remained within 10–12 g/dL over the 12 months.

The results were analyzed using descriptive statistics according to the intention to treat principle. Patient data were excluded if they not met any of the inclusion or exclusion criteria, or derogated from study protocol. For categorical variables, occurrences and percentages were reported. Continuous variables were first analyzed using a Shapiro-Wilk test; then, for normally distributed variables, mean and standard deviation were given, and for variables with distribution varying from normal distribution, the median and interquartile range (25%: Q1; 75%: Q3) were reported. Statistical analysis was performed using R^® version 3.1.2 (R Core Team, 2014, Vienna, Austria).

A total number of 248 patients from 26 centers in Poland entered screening and met all study inclusion criteria and none of the study exclusion criteria. One patient, who did not receive treatment because of investigator’s decision (suspicion of cancer and planned diagnostics), was excluded from the analysis. Of the remaining 247 patients that were enrolled into the study, 219 (88.7%) received chronic hemodialysis, and 28 (11.3%) received peritoneal dialysis (Table 1). Five patients changed from hemodialysis to peritoneal dialysis during the observation period, thus changing their group affiliation (primary group allocations: 224 in the hemodialysis group, 23 in the peritoneal dialysis group; changed allocations: 219 in the hemodialysis group, 28 in the peritoneal dialysis group). Women accounted for 42.9% of the study population. The median age was 61.5 [50.3–71.3] years. The main causes of CKD were glomerular diseases (23.1%) and diabetic nephropathy (21.1%). Multiple comorbidities were diagnosed, including arterial hypertension (93.5%), hyperparathyroidism (53.4%), coronary heart disease (43.0%), and dyslipidemia (39.3%). Approximately half (48.6%) of all subjects were under predialysis care by a nephrologist (Table 1).

One hundred and 32 (61.1%) hemodialysis patients and 19 (67.9%) peritoneal dialysis patients completed the study. The percentage of patients who did not attend visits was a maximum of 2.2% at visit 11 in hemodialysis patients, and maximum 12.5% at visit 7 in the peritoneal dialysis patients. The main reasons for absences and study interruptions were kidney transplantation, death of patients in the hemodialysis group, and change of ESA due to the limited market availability of C.E.R.A.

During treatment with C.E.R.A., the maximal mean concentration of Hb was 11.1 ± 1.2 g/dL in hemodialysis patients observed in months 9 and 10. In peritoneal dialysis patients, the maximal mean concentration of Hb was observed at the 2nd visit (11.3 ± 1.2 g/dL), as well as at the 4th and 8th visits (11.3 ± 1.6 g/dL) (Fig. 1). The highest percentage of patients meeting the criterion of Hb concentration of >10 g/dL was observed in 83.6% of hemodialysis patients at the 9^th visit and in 87.0% of peritoneal patients at the 2nd visit (Fig. 2). Between the 3rd and 6th month after beginning treatment with C.E.R.A., an increase in Hb concentration of at least 0.8 g/dL was observed in 30.4% of hemodialysis patients between the 3rd and 4th visits, in 18.1% between the 3rd and 5th visits, and in 13.1% between the 3rd and 6th visits; as well as in 26.1% of peritoneal dialysis patients between the 2nd and 3rd visits and in 13.0% between the 2nd and 4th visits. Thus, the combined primary endpoint was achieved in 97.1% of hemodialysis patients and 100% of peritoneal dialysis patients. After 7 months of treatment, a Hb concentration of ≥12 g/dL was observed in a maximum of 24.1% of hemodialysis patients and 31.8% of peritoneal dialysis patients.

The median time from the start of treatment with C.E.R.A. to Hb concentration exceeding 10 g/dL was 42.0 (21.0–79.0) days for the hemodialysis patients, 40.0 (20.0–66.5) days for the peritoneal dialysis patients, and 42.0 (21.0–78.2) days for the entire study population. The average rate at which the concentration of Hb increased between the 1st and 6th months of the study was 0.094 (95% confidence interval [CI]: 0.055–0.134) g/dL/month. At the initial visit, the proportion of patients with a Hb concentration of 10–12 g/dL was 7.8%. In the 2nd month, it reached 41.8% and gradually increased to 63.3% by month 12 (Fig. 3). The median time that Hb concentration was within 10–12 g/dL was 121.1 (44.6–195.2) days for hemodialysis patients, 99.4 (63.3–123.3) days for peritoneal dialysis patients, and 115.2 (49.1–188.7) days for the entire study population. The concentration of Hb was within 10–12 g/dL for a median of 39.9 (21.6–59.7) % of the time of patient participation in the study.

Treatment with C.E.R.A. was introduced at an average Hb concentration of 9.0 ± 0.8 g/dL in hemodialysis patients and 9.3 ± 0.7 g/dL in peritoneal dialysis patients. The median drug dosage was 50.0 (50.0–75.0) µg at the first visit in hemodialysis patients, which was increased to 75.0 (50.0–120.0) µg by the last month of the study. The initial dose was similar in peritoneal dialysis patients (median 50.0 [50.0–75.0] µg) and reached a maximum of 62.5 (30.0–75.0) µg during the 7th visit (Fig. 4). In hemodialysis patients, C.E.R.A. was primarily administered intravenously (69.3%), whereas peritoneal dialysis patients received the drug almost solely via subcutaneous injection (98.4%). Of the hemodialysis patients, 81.4% received iron supplementation, which was administered intravenously in nearly 94.6% of cases. Iron supplementation, usually via oral administration (52.2%), was necessary in 39.2% of patients in the peritoneal dialysis group. During the study, there were no clinically significant changes in other laboratory parameters.

During the study, 397 AEs were registered: 312 in hemodialysis patients and 85 in peritoneal dialysis patients (Table 2). Most AEs (n = 211) were serious. A list of serious adverse events is presented in online supplementary material 1, Table 1 (for all online suppl. material, see https://doi.org/10.1159/000534070). Twenty-four patients from the hemodialysis group died; no patients died from the peritoneal dialysis group (online suppl. material 1, Table 2). The investigators attributed none of the deaths to C.E.R.A. treatment. Frequent AEs, which occur in 1–10% of patients according to MedDRA [19] classification, accounted for 43.2% (n = 173) of all AEs (online suppl. material 1, Table 3). The others were rare or very rare. The observed AEs were mostly related to medical and surgical procedures (14.5%), the gastrointestinal tract (12.3%), or bacterial infections (9.4%). A total of 30 special interest AEs were reported during the study, most (n = 29) in hemodialysis patients (online suppl. material 1, Table 4). AEs associated with the use of the C.E.R.A. occurred only in hemodialysis patients (n = 4), and included anemia (n = 1), inappropriate response to the drug (n = 2), and dialysis fistula thrombosis (n = 1). Details can be found in online supplementary material 1, Table 5. One event related to the C.E.R.A. therapy (hemodialysis fistula thrombosis) was expected according to the Summary of Product Characteristics.

The study presented herein describes the treatment of renal anemia with C.E.R.A. in daily (“real-world”) clinical practice in Poland. The study results generally confirmed those of previous clinical trials (ARCTOS, CORDATUS) [17, 18], and similar results were obtained in a study evaluating the use of C.E.R.A. in renal anemia in patients receiving dialysis (AMICUS) [16]. In this study, C.E.R.A. preparation was demonstrated to be effective in >91.0% of patients, with a maximum rate of increase in Hb concentration observed during the 23rd week of treatment, and an average response time of 8 weeks. Although the results obtained in the observational NAVIGO study cannot be directly compared with the results of an open, interventional AMICUS trial, they provide evidence to support the effective treatment of anemia with C.E.R.A. in the majority of patients (>90.0%). The median of treatment response time was 42 days, which was similar to the AMICUS study.

Twenty-four deaths (9.7% of the study population) occurred during the observation period; however, the mortality of dialysis patients in Poland is >20.0%, and the mortality rate observed during the study was not higher than previously reported [20, 21]. Results of the clinical trials indicate that the safety profile of C.E.R.A. is comparable to other ESAs, including darbepoetin alfa, epoetin alfa, and epoetin beta [16, 17, 22]. The results of our study confirm an acceptable safety profile and tolerability of C.E.R.A., as well as its efficacy in the treatment of renal anemia in dialysis patients.

The work presented herein has some limitations. In some centers, a limited number of patients were included, which could affect the quality of care (online suppl. material 2). Randomization was performed twice due to the very slow recruitment of participants, which suggests the results may not be representative. There were also problems with market availability of C.E.R.A. during the study, which resulted in changes in pharmacotherapy for other drugs from the group of ESAs. Moreover, the group of patients receiving peritoneal dialysis was small. Analysis of differences between the groups, or at different time points, was not performed.

Despite these limitations, our analysis was one of the few to provide results from a pragmatic study of the treatment of anemia with the longest-acting ESA currently available for patients with CKD. We were able to demonstrate that under these real-world conditions, the C.E.R.A. corrects renal anemia in dialysis patients and maintains Hb levels within the recommended target range. The study also confirmed the drug’s good safety profile.

The authors would like to thank all NAVIGO Investigators for collecting the data used in this study. The authors thank Proper Medical Writing Sp. z o.o., Warsaw, Poland, for providing support in the form of writing and formatting, figure preparation, language editing, and proofreading.

Ethical approval was not required for this non-interventional, observational, real-world. Study due to Polish national law. The local Bioethics Committee of the Medical University of Łódź was therefore notified about the study and a summary of the study protocol was submitted to the Committee. The study protocol was compliant with the Declaration of Helsinki 1975, as revised in 2000. A written informed consent was obtained from participants to participate in the study. The study is registered at www.clinicaltrials.gov database as NCT01690455.

Michał Nowicki reports receiving investigator’s fee from Roche Poland, during the conduct of the study and investigator’s fees from Omeros Corp., J&J, Abbvie, outside the submitted work. Maciej Drożdż reports honorary from Roche, during the conduct of the study. Agnieszka Segiet-Święcicka reports honorary from Institute of Education I.E., Warsaw, Poland for performing statistical analysis for the study and co-edited the Clinical Study Report funded by Sponsor of the study – Roche Poland. Wiesław Klatko and Jarosław Wajda declare no other conflicts of interest.

The study was funded by Roche Poland and Polish Society for Research in Kidney Diseases (PTBChN). Services provided by Proper Medical Writing Sp. z o.o. were sponsored by Roche Poland.

Michał Nowicki, Wiesław Klatko, Jarosław Wajda, Maciej Drożdż, and Agnieszka Segiet-Święcicka substantially contributed to the conception or design or the acquisition, analysis, or interpretation of data, critically revised this manuscript and provided important intellectual contributions. The final version to be published was approved by the authors.

Study Identifier at ClinicalTrials.gov: NCT01690455.Study ID number: ML25701.

The data that support the findings of this study are available on request from Roche Poland and the corresponding author of this manuscript.