Continuous erythropoiesis receptor activator (CERA) for the anaemia of chronic kidney disease
Abstract
Background
Continuous erythropoiesis receptor activator (CERA) is a newer, longer acting ESA which might be preferred to other ESAs (epoetin or darbepoetin) based on its lower frequency of administration. Different dosing requirements and molecular characteristics of CERA compared with other ESAs may lead to different health outcomes (mortality, cardiovascular events, quality of life) in people with anaemia and chronic kidney disease (CKD).
Objectives
To assess benefits and harms of CERA compared with other epoetins (darbepoetin alfa and epoetin alfa or beta) or placebo/no treatment or CERA with differing strategy of administration for anaemia in individuals with CKD.
Search methods
We searched the Cochrane Kidney and Transplant Specialised Register to 13 June 2017 through contact with the Information Specialist using search terms relevant to this review. Studies contained in the Specialised Register are identified through search strategies specifically designed for CENTRAL, MEDLINE, and EMBASE; handsearching conference proceedings; and searching the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.
Selection criteria
We included randomised controlled trials (RCTs) of at least three months' duration, comparing CERA with a different ESA (darbepoetin alfa or epoetin alfa or beta) or placebo or standard care or versus CERA with different strategies for administration in people with any stage of CKD.
Data collection and analysis
Data were extracted by two independent investigators. We summarised patient‐centred outcomes (all‐cause and cardiovascular mortality, major adverse cardiovascular events, red cell blood transfusion, iron therapy, cancer, hypertension, seizures, dialysis vascular access thrombosis, drug injection‐related events, hyperkalaemia and health‐related quality of life and haemoglobin levels) using random effects meta‐analysis. Treatment estimates were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes and mean differences or standardized mean difference with 95% CI for continuous outcomes.
Main results
We included 27 studies involving 5410 adults with CKD. Seven studies (1273 participants) involved people not requiring dialysis, 19 studies (4209 participants) involved people treated with dialysis and one study (71 participants) evaluated treatment in recipients of a kidney transplant. Treatment was given for 24 weeks on average. No data were available for children with CKD. Studies were generally at high or unclear risk of bias from allocation concealment and blinding of outcomes. Only two studies masked participants and investigators to treatment allocation. One study compared CERA with placebo, nine studies CERA with epoetin alfa or beta, nine studies CERA with darbepoetin alfa, and two studies compared CERA with epoetin alfa or beta and darbepoetin alfa. Three studies assessed the effects of differing frequencies of CERA administration and five assessed differing CERA doses.
There was low certainty evidence that CERA had little or no effects on mortality (RR 1.07, 95% CI 0.73 to 1.57; RR 1.11, 95% CI 0.75 to 1.65), major adverse cardiovascular events (RR 5.09, 95% CI 0.25 to 105.23; RR 5.56, 95% CI 0.99 to 31.30), hypertension (RR 1.01, 95% CI 0.75 to 1.37; RR 1.00, 95% CI 0.79 to 1.28), need for blood transfusion (RR 1.02, 95% CI 0.72 to 1.46; RR 0.94, 95% CI 0.55 to 1.61), or additional iron therapy (RR 1.03, 95% CI 0.91 to 1.15; RR 0.99, 95% CI 0.95 to 1.03) compared to epoetin alfa/beta or darbepoetin alfa respectively. There was insufficient evidence to compare the effect of CERA to placebo on clinical outcomes. Only one low quality study reported that CERA compared to placebo might lead to little or no difference in the risk of major cardiovascular events (RR 2.97, 95% CI 0.31 to 28.18) and hypertension ((RR 0.73, 95% CI 0.35 to 1.52). There was low certainty evidence that different doses (higher versus lower) or frequency (twice versus once monthly) of CERA administration had little or no different effect on all‐cause mortality (RR 3.95, 95% CI 0.17 to 91.61; RR 0.97, 95% CI 0.56 to 1.66), hypertension (RR 0.45, 95% CI 0.08 to 2.52; RR 0.85, 95% CI 0.60 to 1.21), and blood cell transfusions (RR 4.16, 95% CI 0.89 to 19.53; RR 0.91, 95% CI 0.51 to 1.62). No studies reported comparative treatment effects of different ESAs on health‐related quality of life.
Authors' conclusions
There is low certainty evidence that CERA has little or no effects on patient‐centred outcomes compared with placebo, epoetin alfa or beta or darbepoetin alfa for adults with CKD. The effects of CERA among children who have CKD have not studied in RCTs.
PICOs
Plain language summary
CERA treatment for anaemia in people with chronic kidney disease
What is the issue?
Several treatments are available to treat anaemia in people who have kidney disease. These treatments boost the body's ability to produce red blood cells that take oxygen from the lungs and carry oxygen around the body. The kidney normally releases this hormone that prevents anaemia, but when the kidney function is low this hormone is insufficient to maintain an optimal level of red blood cells.
Several synthetic versions of this hormone (called erythropoietin) are used as drugs that can be given into the skin or the directly blood stream and can completely correct anaemia from kidney disease. Several different treatment versions of erythropoietin are available in some parts of the world ‐ these treatments generally differ by how often they need to be given to have an effect. The oldest versions of the drug (epoetin) need to be given several times per week, whereas newer drugs (darbepoetin and CERA) can be given much less often.
Unfortunately, when high doses of anaemia treatments are used to achieve high haemoglobin levels, they can increase the risks of complications like a heart attack or stroke. Because of this risk, people are advised to use the dose of anaemia treatment that gives relief from the problems of anaemia (tiredness, breathlessness) but to avoid higher doses that may cause problems. However, it is not certain whether the different versions of the anaemia drugs have different risks of complications.
What did we do?
This review looked at whether CERA has different complication rates and benefits from correcting anaemia (improved quality of life) than other anaemia treatments.
What did we find?
We found 27 studies involving over 5410 people with kidney disease that looked at the benefits and complications of different anaemia treatments, comparing the newer anaemia treatment (CERA) with the older treatments (darbepoetin and epoetin alfa or beta). We found that it was uncertain whether anaemia drugs had different effects on heart disease complications, life expectancy, or anaemia in the people receiving treatment to increase their blood count. There was no information about whether CERA led to better quality of life for people receiving this drug.
Conclusions
Based on the information in this Cochrane review, clinical decisions about the choice of different anaemia drugs can be based on drug cost and availability.
Authors' conclusions
Summary of findings
| CERA for the anaemia of CKD | |||||||
| Patient or population: CKD patients (any stage) treated for anaemia Intervention: CERA Comparison: epoetin alfa or beta, darbepoetin alfa, differing strategies for administration (higher versus lower doses; longer versus shorter dosing intervals) | |||||||
| Intervention | Comparison | Illustrative comparative risks* (95% CI) per 100 patients treated for 12 months | Relative effect | No. of participants | Quality of the evidence | Comments# | |
| Assumed risk | Corresponding risk | ||||||
| All‐cause mortality | |||||||
| CERA | Epoetin | 8 | 1 more (2 fewer to 5 more) | 1.07 (0.73 to 1.57) | 1846 (5) | ⊕⊕⊝⊝ | Study limitation ⊝ Imprecision ⊝ |
| CERA | Darbepoetin | 7 | 1 more (2 fewer to 5 more) | 1.11 (0.75 to 1.65) | 1657 (5) | ⊕⊕⊝⊝ | Study limitation ⊝ Imprecision ⊝ |
| CERA Q2W | CERA Q4W | 7 | 0 more (3 fewer to 5 more) | 0.97 (0.56 to 1.66) | 822 (2) | ⊕⊕⊝⊝ | Study limitation ⊝ Imprecision ⊝ |
| CERA lower dose | CERA higher dose | 0 | Not estimable | 3.95 (0.17 to 91.61) | 42 (1) | ⊕⊕⊝⊝ | Study limitation ⊝ Imprecision ⊝ |
| One or more red cell transfusions | |||||||
| CERA | Epoetin | 11 | 0 | 1.02 (0.72 to 1.46) | 1824 (5) | ⊕⊕⊝⊝ | Study limitation ⊝ Imprecision ⊝ |
| CERA | Darbepoetin | 11 | 2 fewer | 0.94 (0.55 to 1.61) | 1728 (6) | ⊕⊝⊝⊝ | Study limitation ⊝ Imprecision ⊝ Inconsistency ⊝ |
| CERA Q2W | CERA Q4W | 11 | 1 fewer | 0.91 (0.51 to 1.62) | 872 (3) | ⊕⊕⊝⊝ | Study limitation ⊝ Imprecision ⊝ |
| CERA lower dose | CERA higher dose | 28 | 88 more | 4.16 (0.89 to 19.53) | 125 (2) | ⊕⊝⊝⊝ | Study limitation ⊝ Imprecision ⊝ Inconsistency ⊝ |
| Vascular access thrombosis | |||||||
| CERA | Epoetin | 11 | 1 more (6 fewer to 15 more) | 1.09 (0.49 to 2.40) | 1419 (3) | ⊕⊝⊝⊝ | Study limitation ⊝ Imprecision ⊝ Inconsistency ⊝ |
| CERA | Darbepoetin | ‐ | ‐ | ‐ | ‐ | ‐ | ‐ |
| CERA Q2W | CERA Q4W | 9 | 1 fewer (4 fewer to 4 more) | 0.93 (0.61 to 1.41) | 822 (2) | ⊕⊕⊝⊝ | Study limitation ⊝ Imprecision ⊝ |
| CERA lower dose | CERA higher dose | ‐ | ‐ | ‐ | ‐ | ‐ | ‐ |
| Hypertension | |||||||
| CERA | Epoetin | 18 | 0 more (5 fewer to 7 more) | 1.01 (0.75 to 1.37) | 1821 (5) | ⊕⊕⊝⊝ | Study limitation ⊝ Imprecision ⊝ |
| CERA | Darbepoetin | 18 | 0 more (4 fewer to 5 more) | 1.00 (0.79 to 1.28) | 1752 (6) | ⊕⊕⊝⊝ | Study limitation ⊝ Imprecision ⊝ |
| CERA Q2W | CERA Q4W | 13 | 2 fewer (5 fewer to 3 more) | 0.85 (0.60 to 1.21) | 822 (2) | ⊕⊕⊝⊝ | Study limitation ⊝ Imprecision ⊝ |
| CERA lower dose | CERA higher dose | 54 | 30 fewer (50 fewer to 82 more) | 0.45 (0.08 to 2.52) | 89 (2) | ⊕⊕⊝⊝ | Study limitation ⊝ Imprecision ⊝ |
| CERA | PLACEBO | 7 | 2 fewer (4 fewer to 4 more) | 0.74 (0.37 to 1.50) | 235 (1) | ⊕⊕⊝⊝ | Study limitation ⊝ Imprecision ⊝ |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||||
| #We did not downgrade for reason of publication bias as insufficient studies contributed to treatment estimates to draw meaningful conclusions GRADE Working Group grades of evidence GRADE Working Group grades of evidence | |||||||
| CERA ‐ continuous erythropoiesis receptor activator | |||||||
Background
Description of the condition
Anaemia is a common occurrence in people with chronic kidney disease (CKD) (Hsu 2002). Because erythropoietin is synthesised predominantly by the normal kidney, CKD leads to insufficient erythropoietin release that impairs red blood cell production. Before recombinant human epoetins were introduced, people with end‐stage kidney disease (ESKD) frequently experienced profound anaemia and were dependent on iron replacement therapy and repeated red blood cell transfusions. In observational studies, lower haemoglobin levels have been consistently associated with cardiac abnormalities, mortality and cardiovascular events in people with ESKD (Foley 1996; Lacson 2009; Roberts 2006; Robinson 2005) and the risk of ESKD in those not yet requiring dialysis (Kovesdy 2006). However in subsequent randomised controlled trials (RCTs), human recombinant epoetins (erythropoietin or darbepoetin) corrected anaemia and reduced red cell transfusions in people with CKD, but targeting higher haemoglobin levels with these drugs increased mortality and cardiovascular events, without clinical improvements in quality of life (Besarab 1998; Drueke 2006; Singh 2006; TREAT Study 2009). The mechanisms by which epoetins increase cardiovascular events remains unclear; it is possible that the epoetin dose or action rather than targeted haemoglobin level may account for the adverse effects associated with these drugs. Patients who have lower responsiveness to epoetin treatment and require higher treatment doses have increased rates of mortality (Kilpatrick 2008; Solomon 2010). Novel treatment strategies for the anaemia of CKD are now needed to minimise transfusion dependence and improve quality of life and survival without incurring epoetin‐related harms.
Description of the intervention
Human recombinant epoetins were first used to treat anaemia in CKD over 30 years ago (Winearls 1986). This class of drug includes erythropoietin (alfa and beta), darbepoetin alfa, and methoxy ethylene‐glycol erythropoietin beta (also known as continuous erythropoietin receptor activator, CERA). Recombinant human erythropoietin alfa and beta are almost identical to endogenous erythropoietin hormone in the sequence of amino acids, but each differs in their glycosylation pattern (the attachment of carbohydrates to the erythropoietin protein). Erythropoietin alfa and beta have short circulating half‐lives (6 to 24 hours after intravenous (IV) or subcutaneous (SC) injection respectively) and are administered two or three times weekly to maintain haemoglobin levels (Halstenson 1991; Salmonson 1990). Darbepoetin alfa, a more recently developed epoetin, is more highly glycosylated and has a longer half‐life (24 to 72 hours after IV or SC injection respectively), allowing a dosing interval of once a week to once every other week (Macdougall 2007; Padhi 2006). CERA is a pegylated epoetin with a comparable half‐life of about 130 hours when administered either IV or SC extending dosing intervals further to once every two to four weeks (Macdougall 2006). Glycosylation and pegylation account for the longer half‐life of these molecules and also a lower affinity for the erythropoietin receptors, both factors resulting in a prolonged stimulation of the receptors and allowing a longer dosing interval administration (Egrie 2001; Jarsch 2006; Sinclair 2013).
How the intervention might work
Extending dosing intervals using CERA in place of erythropoietin and darbepoetin has the potential to provide more convenient treatment, lower costs of care, and more stable haemoglobin levels within a narrow target range. Different dosing requirements and molecular characteristics of CERA may also lead to different health outcomes (mortality, cardiovascular events, quality of life) compared with erythropoietin and darbepoetin in people with anaemia and CKD, independent of achieved haemoglobin levels.
Why it is important to do this review
Anaemia is common among people with CKD and is associated with worse outcomes. Considerable debate and controversy surround the optimal management of the anaemia of CKD. So far, and against early predictions, erythropoietin and darbepoetin alfa used targeting higher haemoglobin levels, increased cardiovascular events in this population. RCTs of CERA are now available and require systematic evaluation to determine the evidence for efficacy and safety of CERA in CKD.
Objectives
This review aimed to look at the benefits and harms of CERA compared with other epoetins (darbepoetin alfa and erythropoietin alfa or beta) or placebo/no treatment or CERA with differing strategy of administration for anaemia in individuals with CKD.
Methods
Criteria for considering studies for this review
Types of studies
All RCTs and quasi‐RCTs (RCTs in which allocation to treatment was obtained by alternation, use of alternate medical records, date of birth or other predictable methods) looking at CERA alone or in combination with other non‐randomised co‐interventions (such as iron supplementation or red cell transfusion) in people with CKD (any stage) and anaemia were included. The first period of randomised cross‐over studies was also considered. Studies were considered without language restriction. Studies of at least three months' follow‐up duration were included.
Types of participants
Inclusion criteria
Studies included people with CKD (as defined by the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF/KDOQI) guidelines (KDOQI 2002). People with stage 3 CKD (estimated glomerular filtration rate (eGFR) 30 to 59 mL/min/1.73 m2), Stage 4 CKD (eGFR 15 to 29 mL/min/1.73 m2) and stage 5 CKD (< 15 mL/min/1.73 m2) were included. Patients who required any form of long‐term dialysis were included. We also included people who have a functioning kidney transplant, regardless of their kidney function.
Exclusion criteria
Study populations with acute kidney injury were excluded.
Types of interventions
Studies of CERA (also known as methoxy poly ethylene‐glycol epoetin beta) by any route (IV or SC), any site of injection, and any dose, compared with epoetin alfa or beta, darbepoetin alfa, placebo, or no treatment, were included. The following comparisons were considered for inclusion.
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CERA versus placebo or no treatment
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CERA versus darbepoetin alfa
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CERA versus epoetin alfa or beta
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CERA versus CERA with differing strategies for administration (for example: higher versus lower doses; IV versus SC administration; longer versus shorter dosing intervals; higher versus lower target haemoglobin levels).
We excluded studies that compared CERA with another active treatment for anaemia, including blood transfusion or iron supplementation.
Types of outcome measures
Primary outcomes
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Clinical outcomes
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One or more major adverse cardiovascular events (myocardial infarction; stroke; heart failure; need for any revascularisation including coronary, carotid or peripheral vascular)
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One or more hospital admissions (all‐cause, cardiovascular, vascular access)
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Vascular access thrombosis (≥ 1 events)
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Cardiovascular mortality
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All‐cause mortality
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Cancer (onset of new documented cancer, or as defined by the investigators).
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Quality of life
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End of treatment scores according to any measurement tool. If studies report heterogeneous outcomes, we tabulated the results when meta‐analysis was not possible.
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Adverse events
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Seizures (≥1 event)
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Hyperkalaemia (≥1 event)
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Hypertension (as defined by investigators; one or more events requiring additional antihypertensive medication) (≥ 1 event)
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Injection‐related events (e.g. infection, lipodystrophy, pain).
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Secondary outcomes
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Achieving and maintaining haemoglobin levels/iron status
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Number of participants achieving target haemoglobin levels (as defined by study investigators)
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Time to achieve target haemoglobin levels (days)
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Mean change in haemoglobin (in g/L) or haematocrit levels (%) at end of treatment
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Number of participants requiring one or more red cell transfusions during follow‐up
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Number of individuals requiring iron supplementation during follow‐up
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Number of patients with haemoglobin levels falling outside the haemoglobin target range (as defined by investigators) on one or more occasions during follow‐up
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Number of participants requiring one or more increases in dose during follow‐up
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Number of participants requiring one or more decreases in dose during follow‐up
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Dose of epoetin at end of follow‐up
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Change in dose of epoetin at end of follow‐up
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Serum ferritin (µg/L) at end of follow‐up
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Percent transferrin saturation (%) at end of follow‐up.
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Progression of CKD in participants with CKD not yet requiring RRT (dialysis or kidney transplantation)
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End of treatment eGFR (mL/min/1.73 m2)
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Change in GFR at end of follow‐up
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Number of participants who experienced doubling of SCr or who develop ESKD (eGFR < 15 mL/min/1.73 m2) or requiring RRT.
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Other
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End of treatment left ventricular mass (described using any diagnostic tool including magnetic resonance imaging or echocardiography (g or g/m2))
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C‐reactive protein (mg/L) at end of follow‐up.
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We tabulated any other adverse events identified in the available studies.
Search methods for identification of studies
Electronic searches
We searched the Cochrane Kidney and Transplant Specialised Register to 13 June 2017 through contact with the Information Specialist using search terms relevant to this review. The Cochrane Kidney and Transplant Specialised Register contains studies identified from the following sources.
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Monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL)
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Weekly searches of MEDLINE OVID SP
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Handsearching of kidney‐related journals and the proceedings of major kidney conferences
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Searching of the current year of EMBASE OVID SP
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Weekly current awareness alerts for selected kidney and transplant journals
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Searches of the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.
Studies contained in the Specialised Register are identified through search strategies for CENTRAL, MEDLINE, and EMBASE based on the scope of Cochrane Kidney and Transplant. Details of these strategies, as well as a list of handsearched journals, conference proceedings and current awareness alerts, are available in the Specialised Register section of information about Cochrane Kidney and Transplant.
See Appendix 1 for search terms used in strategies for this review.
Searching other resources
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Reference lists of review articles, relevant studies and clinical practice guidelines.
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Letters seeking information about unpublished or incomplete studies to investigators known to be involved in previous studies.
Data collection and analysis
Selection of studies
The search strategy described was used to obtain titles and abstracts of studies that may be relevant to the review. The titles and abstracts were screened independently by two authors who discarded studies that are not applicable; however, studies and reviews that might include relevant data or information on studies were retained initially. Two authors independently assessed retrieved abstracts, and if necessary the full text of these studies, to determine which satisfied the inclusion criteria.
Studies reported in non‐English language journals were translated before assessment.
Data extraction and management
Data extraction was carried out independently by two authors using standard data extraction forms. Studies reported in non‐English language journals were translated before assessment. Where more than one publication of one study existed, reports were grouped together and the publication with the most complete data was used in the analyses. Where relevant outcomes are only published in earlier versions these data were used. Any discrepancy between published versions was to be highlighted. Any further information required from the original author was requested by written correspondence and any relevant information obtained in this manner was included in the review. Disagreements were resolved by consultation among all authors.
Two authors independently used standardised data forms to extract the following data.
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Study design (parallel or cross‐over, risks of bias, duration, sample size, non‐randomised co‐interventions, location, number of study centres)
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Participants (source, stage of CKD or time on dialysis, type of dialysis, age, gender)
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Interventions (generic name, dose, dose interval, mode of administration, epoetin‐naive or previous epoetin use, mean or median dose (and range), target haemoglobin level)
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Outcomes as described (Types of outcome measures)
Assessment of risk of bias in included studies
The following items were assessed using the risk of bias assessment tool (Higgins 2011) (seeAppendix 2).
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Was there adequate sequence generation (selection bias)?
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Was allocation adequately concealed (selection bias)?
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Was knowledge of the allocated interventions adequately prevented during the study?
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Participants and personnel (performance bias)
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Outcome assessors (detection bias)
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Were incomplete outcome data adequately addressed (attrition bias)?
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Are reports of the study free of suggestion of selective outcome reporting (reporting bias)?
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Was the study apparently free of other problems that could put it at a risk of bias?
We made explicit judgements regarding whether studies were at high risk of bias according to the criteria provided in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
Measures of treatment effect
For dichotomous outcomes (mortality, cardiovascular events, hospitalisation, vascular access thrombosis, adverse events) results were expressed as risk ratio (RR) with 95% confidence intervals (CI). Where continuous scales of measurement were used to assess the effects of treatment (quality of life, haemoglobin and biochemical variables), the mean difference (MD) was used, or the standardised mean difference (SMD) if different scales had been used.
Meta‐analysis of change scores
We combined change‐from‐baseline and final value scores (haemoglobin levels) in a meta‐analysis using the MD method in RevMan. We placed end‐of‐treatment values and change‐from‐baseline scores in subgroups for clarity and summarised these treatment effects using random‐effects meta‐analysis.
Imputing standard deviation
We imputed a change‐from‐baseline standard deviation using an imputed correlation coefficient when sufficient data are available. We conducted sensitivity analyses when possible to evaluate the effect of imputing missing standard deviation data in our meta‐analysis.
Unit of analysis issues
We included only data from the first period of treatment in cross‐over studies (Higgins 2011). Data in different metrics were analysed by converting reported values to International System of Units (SI) units. The final results were presented in SI units with conventional units in parentheses.
Dealing with missing data
If possible, data for each specified outcome was evaluated regardless of whether the analysis was based on intention‐to‐treat or completeness to follow‐up. In particular, dropout rates were investigated and reported in detail such as drop out due to excessive haemoglobin levels, treatment failure, death, transplantation, withdrawal of consent, or loss to follow‐up. When data were unavailable or not reported in an extractable format, we contacted the original investigators to request the missing data. We assessed all studies for risks of bias due to incomplete reporting of results.
Assessment of heterogeneity
Heterogeneity was analysed using a Chi2 test on N‐1 degrees of freedom, with an alpha of 0.05 used for statistical significance and with the I2 test (Higgins 2003). I2 values of 25%, 50% and 75% were considered to correspond to low, medium and high levels of heterogeneity.
Assessment of reporting biases
We interrogated for asymmetries in the inverted funnel plots (that is, for systematic differences in the effect sizes between more precise and less precise studies using the original and modified Egger tests (Harbord 2006) and the Begg and Mazumdar correlation test (Begg 1994). There are many potential explanations for why an inverted funnel plot may be asymmetric, including chance, heterogeneity, publication and reporting bias (Terrin 2005). We refrained from judging funnel plot asymmetries based on visual inspection because this has been shown to be misleading in empirical research (Lau 2006). Publication bias was also evaluated by testing the robustness of the results according to publications, namely publication as a full manuscript in a peer reviewed journal versus studies published as abstracts/text/letters/editorials.
Data synthesis
Treatment effects were summarised using the random‐effects model but the fixed‐effect model was also used to ensure robustness of the model chosen and susceptibility to outliers. We qualitatively summarised data where insufficient data are available for meta‐analysis. Qualitative review was conducted for adverse events and quality of life outcomes. We determined the applicability of the results to individual patients (risk groups) using the baseline risk of the outcomes obtained from observational studies within an equivalent population together with the RR and 95% CI to calculate absolute risks for specific patient populations, where possible.
Subgroup analysis and investigation of heterogeneity
We planned subgroup analysis to explore possible sources of heterogeneity (such as participants, interventions and study quality), however insufficient data observations were available to conduct these analyses.
Sensitivity analysis
Sensitivity analyses were planned to explore the robustness of findings to key decisions in the review process; however there were insufficient data observations to allow such analyses to be undertaken.
'Summary of findings' tables
We presented the main results of the review in 'Summary of findings' tables. These tables present key information concerning the quality of the evidence, the magnitude of the effects of the interventions examined, and the sum of the available data for the main outcomes (Schünemann 2011a). The 'Summary of findings' tables also include an overall grading of the evidence related to each of the main outcomes using the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) approach (GRADE 2008). The GRADE approach defines the quality of a body of evidence as the extent to which one can be confident that an estimate of effect or association is close to the true quantity of specific interest. The quality of a body of evidence involves consideration of within‐trial risk of bias (methodological quality), directness of evidence, heterogeneity, precision of effect estimates and risk of publication bias (Schünemann 2011b). We presented the following outcomes in the 'Summary of findings' tables:
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All‐cause mortality
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One or more red cell transfusions
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Vascular access thrombosis
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Hypertension
Results
Description of studies
See Characteristics of included studies; Characteristics of excluded studiesCharacteristics of ongoing studies.
Results of the search
Our search retrieved 123 reports of studies. After title and abstract review we excluded 13 records and we assessed the full text of the remaining 110 articles. We identified 27 studies (103 records; 5410 participants) that met our inclusion criteria (Figure 1). Three ongoing studies (NCT00773513; UMIN000008073; UMIN000009472) and one study awaiting classification (N0107151969) will be assessed in a future update of this review.
Study flow diagram.
Included studies
Of the 27 included studies, 26 were parallel designed studies (Al‐Ali 2015, AMICUS Study 2007; ARCTOS Study 2008; BA16260 Study 2006; BA16285 Study 2007; BA16286 Study 2007; Chen 2012e; CORDATUS Study 2011; Furukawa 2015; Kakimoto‐Shino 2014; Kinugasa 2011; MAXIMA Study 2007; Meier 2008; NCT00442702; NCT00717821; Oh 2014; Otsuka 2015; PATRONUS Study 2010; PRIMAVERA Study 2011; PROTOS Study 2007; Provenzano 2007; RUBRA Study 2008; STRIATA Study 2008; TIVOLI Study 2013; Toida 2014; Tsubakihara 2011), and one was a cross‐over study (Forni 2013).
No formal sample size calculation was undertaken in nine studies (33%) (BA16260 Study 2006; BA16285 Study 2007; BA16286 Study 2007; Forni 2013; Furukawa 2015; Kakimoto‐Shino 2014; Otsuka 2015; Provenzano 2007;Toida 2014).
Seven studies enrolled 1273 participants in earlier stages of CKD (ARCTOS Study 2008; CORDATUS Study 2011; Furukawa 2015; NCT00442702; PRIMAVERA Study 2011; Provenzano 2007; Tsubakihara 2011); 19 studies included 4209 patients on dialysis (Al‐Ali 2015; AMICUS Study 2007; BA16260 Study 2006; BA16285 Study 2007; BA16286 Study 2007; Chen 2012e; Forni 2013; Kakimoto‐Shino 2014; Kinugasa 2011; MAXIMA Study 2007; Meier 2008; NCT00717821; Oh 2014; Otsuka 2015; PATRONUS Study 2010; PROTOS Study 2007; RUBRA Study 2008; STRIATA Study 2008; Toida 2014) and one study provided data for 71 kidney transplant recipients (TIVOLI Study 2013). No data were available for children.
Twenty‐two of 27 studies (Al‐Ali 2015; AMICUS Study 2007; ARCTOS Study 2008; BA16260 Study 2006; BA16285 Study 2007; BA16286 Study 2007; Chen 2012e; CORDATUS Study 2011; Furukawa 2015; Kakimoto‐Shino 2014; MAXIMA Study 2007; NCT00442702; Oh 2014; PATRONUS Study 2010; PRIMAVERA Study 2011; PROTOS Study 2007; Provenzano 2007; RUBRA Study 2008; STRIATA Study 2008; TIVOLI Study 2013; Toida 2014; Tsubakihara 2011) provided data that could be included in our meta‐analyses.
Median follow‐up was 24 weeks, ranging from 8 to 96 weeks. The average age of participants ranged from 53.4 to 73.4 years.
CERA versus epoetin alfa or beta
Nine studies compared CERA with epoetin alfa or beta in 2339 participants (range 34 to 623 participants) (AMICUS Study 2007; Chen 2012e; Kakimoto‐Shino 2014; Meier 2008; Oh 2014; PROTOS Study 2007; RUBRA Study 2008; Tsubakihara 2011). Two of these studies were published in abstract‐form only (Meier 2008; Tsubakihara 2011). Eight studies enrolled participants receiving dialysis (AMICUS Study 2007; Chen 2012e; Kakimoto‐Shino 2014; MAXIMA Study 2007; Meier 2008; Oh 2014; PROTOS Study 2007; RUBRA Study 2008), and one included patients not requiring dialysis (Tsubakihara 2011). No data were available for kidney transplant recipients.
The mean age of participants ranged from 53.4 to 68.1 years. Treatment duration ranged between 16 and 52 weeks. Haemoglobin levels targeted by treatment ranged between 10 and 13.5 g/dL.
CERA versus darbepoetin alfa
Nine study compared CERA with darbepoetin alfa in 4143 participants (range 20 to 490 participants) (ARCTOS Study 2008; CORDATUS Study 2011; Forni 2013; Furukawa 2015; NCT00442702; Otsuka 2015; PATRONUS Study 2010; STRIATA Study 2008; TIVOLI Study 2013). Four studies included patients not requiring dialysis (ARCTOS Study 2008; CORDATUS Study 2011; Furukawa 2015; NCT00442702), four studies enrolled patients on dialysis (Forni 2013; Otsuka 2015; PATRONUS Study 2010; STRIATA Study 2008) and one study enrolled kidney transplant recipients (TIVOLI Study 2013).
The mean age of participants varied from 55.5 to 73.4 years. Treatment duration ranged between 8 and 52 weeks. Haemoglobin levels targeted by treatment ranged between 10 and 13.5 g/dL.
CERA versus epoetin alfa or beta or versus darbepoetin alfa
Two studies compared CERA with epoetin alfa or beta and with darbepoetin alfa in 748 participants receiving dialysis (Al‐Ali 2015; NCT00717821). Treatment duration ranged between 24 and 40 weeks. Haemoglobin levels target was 11 to 12 g/dL in one of the two studies (Al‐Ali 2015).
Frequency of CERA administration
Three studies compared once with twice monthly CERA administration in 878 participants on dialysis (MAXIMA Study 2007; PROTOS Study 2007; Toida 2014).
The mean age of participants ranged from 59 and 66 years. Treatment duration ranged between 8 and 52 weeks. Haemoglobin levels targeted by treatment ranged between 10 and 13.5 g/dL.
Different CERA doses
Five studies compared higher with lower CERA doses in 424 participants (BA16260 Study 2006; BA16285 Study 2007; BA16286 Study 2007; Kinugasa 2011; Provenzano 2007). Of these, four studies were conducted in dialysis patients (BA16260 Study 2006; BA16285 Study 2007; BA16286 Study 2007; Kinugasa 2011), and one in patients not receiving dialysis (Provenzano 2007).
None of these studies reported the mean age of participants. Treatment duration ranged from 12 to 28 weeks.
CERA versus placebo
One study compared CERA with placebo (PRIMAVERA Study 2011) in 241 stage 3 CKD patients with a mean age of 63 years. Treatment duration was 24 months.
Excluded studies
We excluded one study which was of short duration (Macdougall 2006).
Risk of bias in included studies
Figure 2 and Figure 3 summarise the risk of bias assessment for the included studies.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Allocation
Random sequence generation
Four studies (15%) were judged to be at low risk of selection bias due to appropriate random sequence generation: one compared CERA with epoetin (MAXIMA Study 2007), two CERA with darbepoetin (Forni 2013; PATRONUS Study 2010), and one CERA with placebo (PRIMAVERA Study 2011). The risk of bias was high in three studies (11%) comparing different doses of CERA (BA16260 Study 2006; BA16286 Study 2007; Provenzano 2007) while the remaining 20 studies (74%) did not provide sufficient information to assess risk (unclear risk).
Allocation concealment
Four studies (15%) reported adequate methods for allocation concealment, they were all comparing CERA with darbepoetin (ARCTOS Study 2008; PATRONUS Study 2010; PROTOS Study 2007; STRIATA Study 2008). The risk of bias was high in three studies (11%) (BA16260 Study 2006; BA16286 Study 2007; Provenzano 2007) all comparing different doses of CERA. The remaining 20 studies (74%) did not provide enough information (unclear risk).
Blinding
Performance bias
Two studies (7%) were judged to be low risk of performance bias (Kinugasa 2011; PRIMAVERA Study 2011). Twenty‐three studies (85%) were open‐label and therefore at high risk of bias due to absence of blinding of study personnel and patients. The remaining two studies did not provide enough information (unclear risk) (Otsuka 2015; Toida 2014).
Detection bias
There was insufficient information to assess detection bias in all of the included studies (unclear risk).
Incomplete outcome data
In seven studies (26%), data to identify loss to follow‐up were not provided (Forni 2013; Furukawa 2015; Kinugasa 2011; Meier 2008; NCT00717821; Otsuka 2015; Tsubakihara 2011). Four studies (15%) were judged to meet the criteria for low risk of attrition bias (below 10% of randomised patients not available for inclusion in analyses) (AMICUS Study 2007; ARCTOS Study 2008; BA16286 Study 2007; TIVOLI Study 2013). The remaining 16 studies were at high risk of attrition bias.
In each treatment comparison, two of the nine studies comparing CERA with darbepoetin (ARCTOS Study 2008; TIVOLI Study 2013), one of the nine studies comparing CERA with epoetin (AMICUS Study 2007), one of the six studies comparing differing doses (BA16285 Study 2007) and none of the studies comparing differing frequencies were at low risk of bias.
Selective reporting
Outcome of interest (mortality, haemoglobin level, mean dose, blood cell transfusions, vascular access thrombosis, hypertension) were reported in eight studies (30%) (low risk of bias) (CORDATUS Study 2011; MAXIMA Study 2007; NCT00442702; PATRONUS Study 2010; PROTOS Study 2007; RUBRA Study 2008; STRIATA Study 2008; TIVOLI Study 2013).
Seventeen studies (63%) were considered at high risk of bias (Al‐Ali 2015; AMICUS Study 2007; ARCTOS Study 2008; BA16260 Study 2006; BA16285 Study 2007; BA16286 Study 2007; Chen 2012e; Forni 2013; Furukawa 2015; Kinugasa 2011; Meier 2008; NCT00717821; Oh 2014; Otsuka 2015; PRIMAVERA Study 2011; Toida 2014; Tsubakihara 2011); the remaining tow studies did not report sufficient information for judgment (Kakimoto‐Shino 2014;; Provenzano 2007).
Results were only published in clinicaltrial.gov for NCT00442702 and only as part of a pooled analysis of 13, phase III studies for NCT00717821.
Three studies were only reported as conference proceedings (Meier 2008; Oh 2014; Tsubakihara 2011).
Other potential sources of bias
Other potential sources of bias included the following.
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Unequal baseline characteristics (3 studies, 11%) (AMICUS Study 2007; Provenzano 2007; STRIATA Study 2008)
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Industry sponsor involved in authorship/design/analysis (17 studies, 63%) (AMICUS Study 2007; ARCTOS Study 2008; BA16260 Study 2006; BA16285 Study 2007; BA16286 Study 2007; CORDATUS Study 2011; NCT00442702; NCT00717821; Oh 2014; MAXIMA Study 2007; PATRONUS Study 2010; PRIMAVERA Study 2011; PROTOS Study 2007; Provenzano 2007; RUBRA Study 2008; STRIATA Study 2008; TIVOLI Study 2013).
Effects of interventions
CERA versus epoetin alfa or beta
Overall there was low certainty evidence that CERA compared with epoetin alfa or beta had little or no effect on risk of all‐cause mortality (Analysis 1.1 (5 studies, 1846 participants): RR 1.07, 95% CI 0.73 to 1.57; I2 = 0%), major cardiovascular events (Analysis 1.2 (1 study, 333 participants): RR 5.09, 95% CI 0.25 to 105.23), cancer (Analysis 1.4 (2 studies, 903 participants): RR 0.82, 95% CI 0.18 to 3.67; I2 = 0%); hypertension (Analysis 1.5 (5 studies, 1821 participants): RR 1.01, 95% CI 0.75 to 1.37; I2 = 34%); blood cell transfusions (Analysis 1.7 (5 studies, 1824 participants): RR 1.02, 95% CI 0.72 to 1.46; I2 = 14%); or one or more hospital admissions (Analysis 1.14 (1 study, 94 participants): RR 0.56, 95% CI 0.20 to 1.53).
There was low certainty evidence that CERA compared with epoetin alfa or beta, might have little or no effect on risk of vascular access thrombosis (Analysis 1.3 (3 studies, 1419 participants): RR 1.09, 95% CI 0.49 to 2.40; I2 = 71%) and need for iron therapy (Analysis 1.8 (2 studies, 437 participants): RR 1.03, 95% CI 0.91 to 1.15; I2 = 73%) with substantial heterogeneity in the analyses.
There was low certainty evidence that CERA compared with epoetin might lead to little or no difference in haemoglobin levels achieved at the end of treatment (Analysis 1.9 (6 studies, 1626 participants): MD ‐0.12 g/dL, 95% CI ‐0.34 to 0.10; I2 = 68%) and mean change in haemoglobin levels at the end of treatment (Analysis 1.10 (4 studies, 1510 participants): MD 0.08 g/dL, 95% CI ‐0.04 to 0.19; I2 = 0%). It was uncertain if the percentage of patients achieving the haemoglobin target (10 to 13.5 g/dL) was increased by CERA treatment compared with epoetin alfa or beta (Analysis 1.11 (5 studies, 1133 participants): RR 1.03, 95% CI 0.94 to 1.12; very low certainty evidence; I2 = 48%) with moderate heterogeneity in the analysis. There was insufficient evidence on whether CERA compared with epoetin decreased the percentage of patients exceeding the haemoglobin target (Analysis 1.12 (1 study at high risk of bias, 69 participants): RR 0.65, 95% CI 0.33 to 1.29). The mean dose of CERA at the end of treatment appeared lower than the mean dose of epoetin but the certainty of evidence was low and there was high heterogeneity in the analysis (Analysis 1.13 (2 studies, 194 participants): SMD ‐2.11, 95% CI ‐3.60 to ‐0.62; I2 = 93%).
Two studies reported health‐related quality of life measured using the Short Form 36 tool and its Korean version respectively, during 25 weeks of treatment (AMICUS Study 2007; Oh 2014) but did not provide analyses of treatment effects comparing CERA with epoetin (Table 1).
| Study | Stage of CKD | Tool | Findings |
| CERA versus epoetin | |||
| Dialysis (HD, PD) | Short‐form 36 | Clinically meaningful changes from baseline (≥ 5 points) to week 13 and week 25 were noted in patients treated with CERA (score changes were reported in figure) Comparative effects for CERA versus epoetin on HRQOL were not reported | |
| Dialysis (HD, PD) | Korean version of Short‐form 36 | At week 13, a meaningful decrease (≥ 5 points) was observed on physical functioning for CERA group. At week 25, mean scores increased on all sub‐scales except role‐emotional for CERA group and clinically meaningful improvements was observed in vitality for CERA group (score changes were reported in figure) Comparative effects for CERA versus darbepoetin alfa on HRQOL were not reported | |
| CERA versus darbepoetin | |||
| Not on dialysis | Short‐form 36 | Relative to baseline, mean scores increased on each of the eight sub scales and summary scores in both treatment groups, representing an improvement in each parameter (score changes were reported in figure). Clinically meaningful improvements from baseline to weeks 13 and 29 (≥ 5 points) were observed for CERA once every 2 week in general health, vitality, role emotional, role physical (week 13 only), and social functioning and for darbepoetin alfa in vitality, role emotional, and role physical Comparative effects for CERA versus darbepoetin alfa on HRQOL were not reported | |
CERA ‐ continuous erythropoiesis receptor activator; CKD ‐ chronic kidney disease; HD ‐ haemodialysis; HRQOL ‐ Health‐related quality of life; PD peritoneal dialysis
Overall a similar incidence of adverse events between groups was reported; these were judged mild to moderate in intensity and mainly not treatment‐related (Table 2).
| Study | Stage of CKD | Findings |
| CERA versus epoetin | ||
| Dialysis (HD) | Overall adverse events during the study were mild to moderate, among which thrombosed arteriovenous shunt was considered as the most specific complication to the given medications, nevertheless incidence remained low | |
| Dialysis (HD, PD) | The incidence of adverse events did not differ between groups (P > 0.05) | |
| Dialysis (HD, PD) | The incidence of adverse events did not differ between groups (P = 0.12).The most common serious adverse events were sepsis, pneumonia and arteriovenous graft thrombosis. Only 6 patients had serious adverse events that were judged to be treatment‐related (three and two with CERA every 2 and 4 weeks, respectively, and one with epoetin; P = 0.40) | |
| Dialysis (HD) | Overall and frequently reported adverse events during the correction phase were comparable between the two study arms. Serious adverse events were reported 14 events in 10 patients (26.3%) in CERA and 7 events in 6 patients (15.4%) in epoetin beta group. None of them was judged to be related with study drugs | |
| Dialysis (HD, PD) | The most commonly reported adverse events were hypertension, procedural hypotension (induced by dialysis), nasopharyngitis, headache, and diarrhoea. Most events were mild or moderate in intensity and distributed evenly across groups. The incidence of treatment‐related adverse events was low in all groups (once monthly CERA 6%; twice monthly CERA 4%; epoetin 2%) | |
| Dialysis (PD) | The overall incidence of adverse events was similar between the two treatment groups; at least one adverse event was experienced by 94.5% and 94.6% of patients in the CERA and epoetin groups, respectively. Most events were mild to moderate in intensity | |
| CERA versus darbepoetin | ||
| Dialysis (HD) | Overall adverse events during the study were mild to moderate, among which thrombosed arteriovenous shunt was considered as the most specific complication to the given medications, nevertheless incidence remained low | |
| Not on dialysis | The number of patients who experienced one or more adverse events was similar between groups and typical of this patient population. The most commonly reported adverse events included hypertension, peripheral oedema, diarrhoea, and nasopharyngitis. Most events were mild or moderate and very few were considered treatment related (CERA 7.5%; darbepoetin alfa 5.6%) | |
| Not on dialysis | Most adverse events experienced by patients in each study arm were reported to be mild to moderate intensity, and rates were comparable between the two groups. The most frequently reported adverse events were hypertension, renal impairment, hyperkalaemia, upper respiratory tract infection and constipation. Numerically more patients in the darbepoetin alfa arm experienced resinous adverse events compared with patients in the CERA arm (12% versus 6% respectively). No patient had a serious adverse event that was judged to be treatment related | |
| Dialysis (HD) | The incidence of adverse events did not differ between groups (P = 0.55). Six were judged to be related to treatment (four with CERA and two with darbepoetin alfa, respectively). Serious adverse events were comparable in the two groups (P = 0.71). The most common serious adverse events were arteriovenous fistula site complication, arteriovenous fistula thrombosis and sepsis. No patient had serious adverse events that was judged to be treatment related | |
| Dialysis (HD) | The overall incidences of adverse and serious adverse events were similar between the two treatment groups and typical of the patient population. The most commonly reported adverse events were diarrhoea, nasopharyngitis and influenza. Serious adverse events were considered to be related to study treatment in one patient in the CERA group (arteriovenous graft thrombosis) and three patients in the darbepoetin group (arteriovenous graft thrombosis, arteriovenous fistula site haemorrhage and cerebral infarction) | |
| CERA lower versus higher doses | ||
| Dialysis (HD) | The most commonly reported adverse events were gastrointestinal disorders, infections, nervous system and vascular disorders. Most events were mild or moderate in intensity | |
| Dialysis (HD) | The adverse events manifested were similar among the dose groups investigated | |
| Not on dialysis | The most commonly reported adverse events were hypertension, urinary tract infection and kidney failure. The majority of events were mild or moderate in intensity | |
| CERA versus placebo | ||
| Not on dialysis | Adverse events with a suspected relation to the study drug occurred in 22% and 16% of patients randomised to CERA and placebo, respectively | |
CERA ‐ continuous erythropoiesis receptor activator; CKD ‐ chronic kidney diease; HD ‐ haemodialysis; PD ‐ peritoneal dialysis
CERA versus darbepoetin alfa
Overall there was low certainty evidence that CERA compared to darbepoetin alfa had little or no effect on risk of all‐cause mortality (Analysis 2.1 (5 studies, 1657 participants): RR 1.11, 95% CI 0.75 to 1.65; I2 = 0%), cardiovascular mortality (Analysis 2.2 (2 studies, 633 participants): RR 1.68, 95% CI 0.74 to 3.78; I2 = 0%), major cardiovascular events (Analysis 2.3 (2 studies, 551 participants): RR 5.56, 95% CI 0.99 to 31.30; I2 = 0%), hypertension (Analysis 2.4 (6 studies, 1725 participants): RR 1.00, 95% CI 0.79 to 1.28; I2 = 8%), hyperkalaemia (Analysis 2.5 (3 studies, 854 participants): RR 1.23, 95% CI 0.63 to 2.39; I2 = 4%), and need for iron therapy (Analysis 2.15 (2 studies, 798 participants): RR 0.99, 95% CI 0.95 to 1.03; I2 = 0%).
There was low certainty evidence that CERA compared with darbepoetin had little or no effect on the risk of blood cell transfusions (Analysis 2.14 (6 studies, 1728 participants): RR 0.94, 95% CI 0.55 to 1.61; I2 = 52%) with substantial heterogeneity in the analysis.
There was low certainty evidence that CERA might lead to a little or no effect on the mean change in haemoglobin levels (Analysis 2.8 (2 studies, 261 participants): MD 0.18 g/dL, 95% CI ‐0.07 to 0.42; I2 = 0%) and the haemoglobin levels at the end of treatment (Analysis 2.7 (4 studies, 750 participants): MD 0.03, 95% CI ‐0.13 to 0.18; I2 = 0%) compared to darbepoetin. The percentage of patients achieving the haemoglobin target (10 to 13 g/dL) (Analysis 2.6 (5 studies, 1251 participants; RR 1.10, 95% CI 0.93 to 1.29; low certainty evidence; I2 = 84%) and the mean treatment dose at the end of the follow‐up (Analysis 2.9 (4 studies, 632 participants): SMD 0.24, 95% CI ‐0.30 to 0.77; low certainty evidence; I2 = 85%) seemed to be similar for CERA and darbepoetin alfa with substantial heterogeneity in the analysis of achieving haemoglobin target.
One study at moderate risk of bias reported that once monthly CERA treatment compared to twice monthly darbepoetin alfa probably reduced the need for a dose decrease (Analysis 2.13 (430 participants): RR 3.84, 95% CI 1.96 to 7.52) and probably avoid a dose increase (Analysis 2.12 (430 participants): RR 0.55, 95% CI 0.44 to 0.69) in order to achieve the haemoglobin target (11 to 13 g/dL) over a follow‐up period of 12 months. One study at moderate‐high risk of bias reported that CERA compared with darbepoetin probably reduced the risk of exceeding the haemoglobin target (11 to 13 g/dL) (Analysis 2.10 (324 participants): RR 0.84, 95% CI 0.74 to 0.96). There was insufficient evidence to compare CERA to darbepoetin on the time to achieve the haemoglobin target (10 to 12 g/dL) (Analysis 2.11 (one study, 71 participants): MD 6.50 days, 95% CI ‐6.38 to 19.38).
One study reported health‐related quality of life measured using the Short Form 36 tool during 25 weeks of treatment (ARCTOS Study 2008) but did not provide analyses of treatment effects comparing CERA with darbepoetin alfa (Table 1).
Overall a similar incidence of adverse events between groups was reported; most of these were judged to be not treatment‐related (Table 2).
CERA once versus twice monthly administration
Overall there was low certainty evidence that CERA administered twice versus once/month had little or no effect on all‐cause mortality (Analysis 3.1 (2 studies, 822 participants): RR 0.97, 95% CI 0.56 to 1.66; I2 =24%), vascular access thrombosis (Analysis 3.2 (2 studies, 822 participants): RR 0.93, 95% CI 0.61 to 1.41; I2 = 0%), hypertension (Analysis 3.3 (2 studies, 822 participants): RR 0.85, 95% CI 0.60 to 1.21; I2 = 0%), hyperkalaemia (Analysis 3.4 (1 study, 380 participants): RR 0.50, 95% CI 0.05 to 5.47), haemoglobin levels at the end of treatment (Analysis 3.5 (2 studies, 653 participants): MD 0.15 g/dL, 95% CI 0.00 to 0.31; I2 = 0%), blood cell transfusions (Analysis 3.9 (3 studies, 872 participants): RR 0.91, 95% CI 0.51 to 1.62; I2 =25%), and cancer (Analysis 3.8 (1 study, 380 participants): RR 7.0, 95% CI 0.36 to 134.60).
It was uncertain whether CERA administered twice versus once monthly might lead to little or no difference in the mean change of haemoglobin levels at the end of treatment (Analysis 3.6 (2 studies, 701 participants): MD 0.03 g/dL, 95% CI ‐0.12 to 0.18; I2 = 1%; low certainty evidence), the percentage of patients achieving the haemoglobin target (11 to 13 g/dL) (Analysis 3.7 (1 study at high risk of bias, 381 participants): RR 0.96, 95% CI 0.90 to 1.03), and mean dose at the end of treatment (Analysis 3.10 (1 study at unclear risk of bias, 42 participants); MD ‐11.20 µg, 95% CI ‐35.52 to 13.12).
CERA higher versus lower doses
There was insufficient evidence to compare lower doses versus higher doses of CERA on the risk of all‐cause mortality (Analysis 4.1 (1 study, 42 participants): RR 3.95, 95% CI 0.17 to 91.61), hypertension (Analysis 4.2 (2 studies, 89 participants): RR 0.45, 95% CI 0.08 to 2.52; I2 = 24%), and blood cell transfusions (Analysis 4.3 (2 studies, 125 participants): RR 4.16, 95% CI 0.89 to 19.53; I2 = 67%).
There was very low certainty evidence that lower compared to higher doses of CERA might lead to less mean change in haemoglobin levels (Analysis 4.4 (4 studies, 250 participants): MD ‐1.26 g/dL, 95% CI ‐1.77 to ‐0.74; I2 = 73%) with substantial heterogeneity in the analysis. It was unclear whether different doses of CERA had different effect on the probability to achieve the haemoglobin target (Analysis 4.7 (1 study at high risk of bias, 47 participants): RR 0.74, 95% CI 0.52 to 1.05) and the need for a dose increase (Analysis 4.6 (2 studies, 125 participants); RR 4.16, 95% CI 0.89 to 19.53; very low certainty evidence; I2 = 69%) or decrease (Analysis 4.5 (1 study at high risk of bias, 42 participants): RR 1.00, 95% CI 0.25 to 3.92) to achieve the target.
Three studies reported information on adverse events but without comparing their incidence between groups (Table 2).
CERA versus placebo
There was insufficient evidence to compare CERA and placebo on clinical outcomes. One study (235 participants not requiring dialysis) at moderate‐high risk of bias reported that CERA treatment compared with placebo had little or no effect on the risk of major cardiovascular events (Analysis 5.1: RR 2.97, 95% CI 0.31 to 28.18), cancer (Analysis 5.2: RR 0.99, 95% CI 0.06 to 15.67), hypertension (Analysis 5.3: RR 0.73, 95% CI 0.35 to 1.52), hyperkalaemia (Analysis 5.4: RR 4.96, 95% CI 0.24 to 102.17), and end of treatment eGFR (Analysis 5.5 (210 participants): MD ‐0.70 mL/min/1.73 m2, 95% CI ‐3.71 to 2.31).
Subgroup and sensitivity analyses
While there was evidence of statistical heterogeneity in some meta‐analysis, there were insufficient observations to perform subgroup and/or sensitivity analyses to explore potential sources of heterogeneity.
Discussion
Summary of main results
We found that there was low certainty evidence that CERA compared to epoetin or darbepoetin had little or no effect on patient‐centred outcomes (all‐cause and cause‐specific mortality, major cardiovascular adverse events, cancer, high blood pressure, seizures, dialysis vascular access thrombosis or treatment injection‐related events, blood cell transfusions) among adults with CKD.
There was low certainty evidence whether participants receiving CERA experienced different haemoglobin levels on treatment compared to other ESAs.
In one study at moderate risk of bias adults receiving once monthly CERA treatment seemed to be more likely to require a dose decrease and less likely to require a dose increase in order to achieve the specified haemoglobin target (11 to 13 g/dL) than participants receiving twice monthly darbepoetin alfa treatment (PATRONUS Study 2010); and in one study, at moderate‐high risk of bias, those treated with CERA seemed to be less likely to exceed the haemoglobin target (11 to 13 g/dL) during treatment (ARCTOS Study 2008).
No evidence was available for the comparative effects of different ESAs on health‐related quality of life.
Lower doses of CERA compared to higher doses resulted in a lower haemoglobin change at the end of treatment in five studies but there was substantial heterogeneity in the analysis and the certainty of evidence was very low.
There was insufficient evidence to compare CERA and placebo on clinical outcomes. One study of stage 3 CKD patients reported uncertain effect of CERA compared with placebo on risk of major cardiovascular adverse events, cancer, hypertension, hyperkalaemia and change in GFR levels at the end of treatment between groups. We found no studies conducted in children, one study in 71 kidney transplant recipients, and six in earlier stages of CKD (one of which in abstract publication only and two reporting results only on clinicaltrial.gov), making assessments of treatment efficacy and safety in these clinical situations difficult.
Overall completeness and applicability of evidence
We aimed to assess the safety and efficacy of longer‐acting ESAs for treatment of anaemia in people with CKD. This review included only a small number of studies of short duration, lasting approximately six months on average. The short duration of the included studies resulted in inconclusive effects on major cardiovascular outcomes including mortality as well as other side‐effects due to the lack of sufficient power in the available studies, both individually and collectively. This limitation is important as previous analyses have shown increased mortality and cardiovascular endpoints among patients treated with ESAs to a higher haemoglobin target, (Phrommintikul 2007) although it remains uncertain whether this increased complication rate is due to the ESA dose or the haemoglobin levels achieved. Future completion of an ongoing large RCT assessing the comparative effect of CERA and other ESAs on all‐cause mortality and cardiovascular morbidity may add new and more conclusive evidence to the topic.
Exploration of any different effects of CERA by severity of CKD, type of dialysis, duration of treatment or haemoglobin level was limited due to the small number of included studies. Evidence of the effectiveness of differing frequency of administration and dose was restricted to adults with CKD stage 5 with largely inconclusive results. Notably, information about quality of life was limited to three studies and comparative analyses comparing CERA with other ESAs were not provided. Therefore, confident conclusions about effects of CERA on health‐related quality of life cannot be drawn. In a previous systematic review of the impact of haemoglobin target levels on health‐related quality of life, only a small and not clinically meaningful improvement in quality of life was observed with a haemoglobin level above 12 g/dL, although reporting of quality of life was frequently incomplete (Clement 2009).
Quality of the evidence
There was considerable under‐reporting of study design and conduct which led to lower confidence in the results due to potential or unclear risks of bias in the included studies. Data comparing CERA with epoetin alfa or beta were generally at high or unclear risk of bias while data comparing CERA with darbepoetin alfa were at lower risk of bias. Information about the effects of differing frequency of administration and dose were limited by studies commonly using inadequate methods for allocation concealment, and selectively reporting of outcomes. Any inconsistency in treatment effects between studies (principally seen for outcomes related to haemoglobin levels or concomitant iron or blood transfusion use) were likely to relate to differing clinical approaches to anaemia management but the sources could not be explored statistically due to lack of a sufficient number of studies.
Potential biases in the review process
This review was carried out using standard Cochrane methods to minimise bias inherent in the review process. We screened for eligible studies and assessed for risks of bias by two authors working independently. The key limitations in this review relate to the number of studies available, the treatment duration, and the risks of bias due to individual study limitations. First, relatively few data were available for most treatment comparisons resulting in inconclusive evidence for many outcomes including mortality and cardiovascular events. Second, the studies differed in management of anaemia including co‐interventions leading to potential heterogeneity in treatment effects, which could not be further explored. Finally, data for patient outcomes including mortality and health‐related quality of life were often reported ad hoc and reduced our confidence in the reliability of these treatment effects. This was particularly the case for quality of life assessments.
Agreements and disagreements with other studies or reviews
The finding that different ESAs have uncertain effects on patient‐level outcomes compared with each other is similar to the conclusions of a recent Cochrane network meta‐analysis of all ESA drugs in the setting of kidney disease (Palmer 2014), which also observed a lack of difference among ESA types. The similar in findings between this review and the previous network meta‐analysis, despite different methodologies, strengthens confidence in the findings of both studies. In a previous systematic review directly comparing darbepoetin alfa with epoetins, there were few studies and aggregated data were insufficient to identify any treatment effects on mortality (Wilhelm‐Leen 2015), a finding that was similar to a longer‐term analysis in USA dialysis facilities (Winkelmayer 2015). Similarly, a recent systematic review of CERA versus darbepoetin alfa in people with non‐dialysis dependent CKD reported similar serious adverse events in each treatment group (Alsalimy 2014).
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Comparison 1 CERA versus epoetin alfa or beta, Outcome 1 All‐cause mortality.
Comparison 1 CERA versus epoetin alfa or beta, Outcome 2 Major adverse cardiovascular event.
Comparison 1 CERA versus epoetin alfa or beta, Outcome 3 Vascular access thrombosis.
Comparison 1 CERA versus epoetin alfa or beta, Outcome 4 Cancer.
Comparison 1 CERA versus epoetin alfa or beta, Outcome 5 Hypertension.
Comparison 1 CERA versus epoetin alfa or beta, Outcome 6 Hyperkalaemia.
Comparison 1 CERA versus epoetin alfa or beta, Outcome 7 Blood transfusion.
Comparison 1 CERA versus epoetin alfa or beta, Outcome 8 Iron supplementation.
Comparison 1 CERA versus epoetin alfa or beta, Outcome 9 Haemoglobin (end of treatment).
Comparison 1 CERA versus epoetin alfa or beta, Outcome 10 Haemoglobin (change during treatment).
Comparison 1 CERA versus epoetin alfa or beta, Outcome 11 Achieved haemoglobin level target.
Comparison 1 CERA versus epoetin alfa or beta, Outcome 12 Exceeding haemoglobin level target.
Comparison 1 CERA versus epoetin alfa or beta, Outcome 13 Epoetin dose (end of treatment).
Comparison 1 CERA versus epoetin alfa or beta, Outcome 14 One or more hospital admissions.
Comparison 1 CERA versus epoetin alfa or beta, Outcome 15 Serum ferritin at end of follow‐up.
Comparison 1 CERA versus epoetin alfa or beta, Outcome 16 Transferrin saturation at end of follow‐up.
Comparison 2 CERA versus darbepoetin alfa, Outcome 1 All‐cause mortality.
Comparison 2 CERA versus darbepoetin alfa, Outcome 2 Cardiovascular mortality.
Comparison 2 CERA versus darbepoetin alfa, Outcome 3 Major adverse cardiovascular event.
Comparison 2 CERA versus darbepoetin alfa, Outcome 4 Hypertension.
Comparison 2 CERA versus darbepoetin alfa, Outcome 5 Hyperkalaemia.
Comparison 2 CERA versus darbepoetin alfa, Outcome 6 Achieved haemoglobin level target.
Comparison 2 CERA versus darbepoetin alfa, Outcome 7 Haemoglobin (end of treatment).
Comparison 2 CERA versus darbepoetin alfa, Outcome 8 Haemoglobin (change during treatment).
Comparison 2 CERA versus darbepoetin alfa, Outcome 9 Epoetin dose (end of treatment).
Comparison 2 CERA versus darbepoetin alfa, Outcome 10 Exceeding haemoglobin level target.
Comparison 2 CERA versus darbepoetin alfa, Outcome 11 Time within the target haemoglobin range.
Comparison 2 CERA versus darbepoetin alfa, Outcome 12 Need for one or more dose increase.
Comparison 2 CERA versus darbepoetin alfa, Outcome 13 Need for one or more dose decrease.
Comparison 2 CERA versus darbepoetin alfa, Outcome 14 Blood transfusion.
Comparison 2 CERA versus darbepoetin alfa, Outcome 15 Iron supplementation.
Comparison 2 CERA versus darbepoetin alfa, Outcome 16 Serum ferritin at the end of follow‐up.
Comparison 2 CERA versus darbepoetin alfa, Outcome 17 Transferrin saturation at end of follow‐up.
Comparison 3 CERA: once every 2 weeks (Q2W) versus once every 4 weeks (Q4W), Outcome 1 All‐cause mortality.
Comparison 3 CERA: once every 2 weeks (Q2W) versus once every 4 weeks (Q4W), Outcome 2 Vascular access thrombosis.
Comparison 3 CERA: once every 2 weeks (Q2W) versus once every 4 weeks (Q4W), Outcome 3 Hypertension.
Comparison 3 CERA: once every 2 weeks (Q2W) versus once every 4 weeks (Q4W), Outcome 4 Hyperkalaemia.
Comparison 3 CERA: once every 2 weeks (Q2W) versus once every 4 weeks (Q4W), Outcome 5 Haemoglobin (end of treatment).
Comparison 3 CERA: once every 2 weeks (Q2W) versus once every 4 weeks (Q4W), Outcome 6 Haemoglobin (change during treatment).
Comparison 3 CERA: once every 2 weeks (Q2W) versus once every 4 weeks (Q4W), Outcome 7 Achieved haemoglobin level target.
Comparison 3 CERA: once every 2 weeks (Q2W) versus once every 4 weeks (Q4W), Outcome 8 Cancer.
Comparison 3 CERA: once every 2 weeks (Q2W) versus once every 4 weeks (Q4W), Outcome 9 Blood transfusion.
Comparison 3 CERA: once every 2 weeks (Q2W) versus once every 4 weeks (Q4W), Outcome 10 Epoetin dose (end of treatment).
Comparison 4 CERA lower versus higher doses, Outcome 1 All‐cause mortality.
Comparison 4 CERA lower versus higher doses, Outcome 2 Hypertension.
Comparison 4 CERA lower versus higher doses, Outcome 3 Blood transfusion.
Comparison 4 CERA lower versus higher doses, Outcome 4 Haemoglobin (change during treatment).
Comparison 4 CERA lower versus higher doses, Outcome 5 Need for one or more dose decrease.
Comparison 4 CERA lower versus higher doses, Outcome 6 Need for one or more dose increase.
Comparison 4 CERA lower versus higher doses, Outcome 7 Achieved haemoglobin level target.
Comparison 5 CERA versus placebo, Outcome 1 Major adverse cardiovascular event.
Comparison 5 CERA versus placebo, Outcome 2 Cancer.
Comparison 5 CERA versus placebo, Outcome 3 Hypertension.
Comparison 5 CERA versus placebo, Outcome 4 Hyperkalaemia.
![Comparison 5 CERA versus placebo, Outcome 5 End of treatment eGFR [mL/min/1.73 m²].](/cdsr/doi/10.1002/14651858.CD009904.pub2/media/CDSR/CD009904/image_n/nCD009904-CMP-005-05.png)
Comparison 5 CERA versus placebo, Outcome 5 End of treatment eGFR [mL/min/1.73 m²].
| CERA for the anaemia of CKD | |||||||
| Patient or population: CKD patients (any stage) treated for anaemia Intervention: CERA Comparison: epoetin alfa or beta, darbepoetin alfa, differing strategies for administration (higher versus lower doses; longer versus shorter dosing intervals) | |||||||
| Intervention | Comparison | Illustrative comparative risks* (95% CI) per 100 patients treated for 12 months | Relative effect | No. of participants | Quality of the evidence | Comments# | |
| Assumed risk | Corresponding risk | ||||||
| All‐cause mortality | |||||||
| CERA | Epoetin | 8 | 1 more (2 fewer to 5 more) | 1.07 (0.73 to 1.57) | 1846 (5) | ⊕⊕⊝⊝ | Study limitation ⊝ Imprecision ⊝ |
| CERA | Darbepoetin | 7 | 1 more (2 fewer to 5 more) | 1.11 (0.75 to 1.65) | 1657 (5) | ⊕⊕⊝⊝ | Study limitation ⊝ Imprecision ⊝ |
| CERA Q2W | CERA Q4W | 7 | 0 more (3 fewer to 5 more) | 0.97 (0.56 to 1.66) | 822 (2) | ⊕⊕⊝⊝ | Study limitation ⊝ Imprecision ⊝ |
| CERA lower dose | CERA higher dose | 0 | Not estimable | 3.95 (0.17 to 91.61) | 42 (1) | ⊕⊕⊝⊝ | Study limitation ⊝ Imprecision ⊝ |
| One or more red cell transfusions | |||||||
| CERA | Epoetin | 11 | 0 | 1.02 (0.72 to 1.46) | 1824 (5) | ⊕⊕⊝⊝ | Study limitation ⊝ Imprecision ⊝ |
| CERA | Darbepoetin | 11 | 2 fewer | 0.94 (0.55 to 1.61) | 1728 (6) | ⊕⊝⊝⊝ | Study limitation ⊝ Imprecision ⊝ Inconsistency ⊝ |
| CERA Q2W | CERA Q4W | 11 | 1 fewer | 0.91 (0.51 to 1.62) | 872 (3) | ⊕⊕⊝⊝ | Study limitation ⊝ Imprecision ⊝ |
| CERA lower dose | CERA higher dose | 28 | 88 more | 4.16 (0.89 to 19.53) | 125 (2) | ⊕⊝⊝⊝ | Study limitation ⊝ Imprecision ⊝ Inconsistency ⊝ |
| Vascular access thrombosis | |||||||
| CERA | Epoetin | 11 | 1 more (6 fewer to 15 more) | 1.09 (0.49 to 2.40) | 1419 (3) | ⊕⊝⊝⊝ | Study limitation ⊝ Imprecision ⊝ Inconsistency ⊝ |
| CERA | Darbepoetin | ‐ | ‐ | ‐ | ‐ | ‐ | ‐ |
| CERA Q2W | CERA Q4W | 9 | 1 fewer (4 fewer to 4 more) | 0.93 (0.61 to 1.41) | 822 (2) | ⊕⊕⊝⊝ | Study limitation ⊝ Imprecision ⊝ |
| CERA lower dose | CERA higher dose | ‐ | ‐ | ‐ | ‐ | ‐ | ‐ |
| Hypertension | |||||||
| CERA | Epoetin | 18 | 0 more (5 fewer to 7 more) | 1.01 (0.75 to 1.37) | 1821 (5) | ⊕⊕⊝⊝ | Study limitation ⊝ Imprecision ⊝ |
| CERA | Darbepoetin | 18 | 0 more (4 fewer to 5 more) | 1.00 (0.79 to 1.28) | 1752 (6) | ⊕⊕⊝⊝ | Study limitation ⊝ Imprecision ⊝ |
| CERA Q2W | CERA Q4W | 13 | 2 fewer (5 fewer to 3 more) | 0.85 (0.60 to 1.21) | 822 (2) | ⊕⊕⊝⊝ | Study limitation ⊝ Imprecision ⊝ |
| CERA lower dose | CERA higher dose | 54 | 30 fewer (50 fewer to 82 more) | 0.45 (0.08 to 2.52) | 89 (2) | ⊕⊕⊝⊝ | Study limitation ⊝ Imprecision ⊝ |
| CERA | PLACEBO | 7 | 2 fewer (4 fewer to 4 more) | 0.74 (0.37 to 1.50) | 235 (1) | ⊕⊕⊝⊝ | Study limitation ⊝ Imprecision ⊝ |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||||
| #We did not downgrade for reason of publication bias as insufficient studies contributed to treatment estimates to draw meaningful conclusions GRADE Working Group grades of evidence GRADE Working Group grades of evidence | |||||||
| CERA ‐ continuous erythropoiesis receptor activator | |||||||
| Study | Stage of CKD | Tool | Findings |
| CERA versus epoetin | |||
| Dialysis (HD, PD) | Short‐form 36 | Clinically meaningful changes from baseline (≥ 5 points) to week 13 and week 25 were noted in patients treated with CERA (score changes were reported in figure) Comparative effects for CERA versus epoetin on HRQOL were not reported | |
| Dialysis (HD, PD) | Korean version of Short‐form 36 | At week 13, a meaningful decrease (≥ 5 points) was observed on physical functioning for CERA group. At week 25, mean scores increased on all sub‐scales except role‐emotional for CERA group and clinically meaningful improvements was observed in vitality for CERA group (score changes were reported in figure) Comparative effects for CERA versus darbepoetin alfa on HRQOL were not reported | |
| CERA versus darbepoetin | |||
| Not on dialysis | Short‐form 36 | Relative to baseline, mean scores increased on each of the eight sub scales and summary scores in both treatment groups, representing an improvement in each parameter (score changes were reported in figure). Clinically meaningful improvements from baseline to weeks 13 and 29 (≥ 5 points) were observed for CERA once every 2 week in general health, vitality, role emotional, role physical (week 13 only), and social functioning and for darbepoetin alfa in vitality, role emotional, and role physical Comparative effects for CERA versus darbepoetin alfa on HRQOL were not reported | |
| CERA ‐ continuous erythropoiesis receptor activator; CKD ‐ chronic kidney disease; HD ‐ haemodialysis; HRQOL ‐ Health‐related quality of life; PD peritoneal dialysis | |||
| Study | Stage of CKD | Findings |
| CERA versus epoetin | ||
| Dialysis (HD) | Overall adverse events during the study were mild to moderate, among which thrombosed arteriovenous shunt was considered as the most specific complication to the given medications, nevertheless incidence remained low | |
| Dialysis (HD, PD) | The incidence of adverse events did not differ between groups (P > 0.05) | |
| Dialysis (HD, PD) | The incidence of adverse events did not differ between groups (P = 0.12).The most common serious adverse events were sepsis, pneumonia and arteriovenous graft thrombosis. Only 6 patients had serious adverse events that were judged to be treatment‐related (three and two with CERA every 2 and 4 weeks, respectively, and one with epoetin; P = 0.40) | |
| Dialysis (HD) | Overall and frequently reported adverse events during the correction phase were comparable between the two study arms. Serious adverse events were reported 14 events in 10 patients (26.3%) in CERA and 7 events in 6 patients (15.4%) in epoetin beta group. None of them was judged to be related with study drugs | |
| Dialysis (HD, PD) | The most commonly reported adverse events were hypertension, procedural hypotension (induced by dialysis), nasopharyngitis, headache, and diarrhoea. Most events were mild or moderate in intensity and distributed evenly across groups. The incidence of treatment‐related adverse events was low in all groups (once monthly CERA 6%; twice monthly CERA 4%; epoetin 2%) | |
| Dialysis (PD) | The overall incidence of adverse events was similar between the two treatment groups; at least one adverse event was experienced by 94.5% and 94.6% of patients in the CERA and epoetin groups, respectively. Most events were mild to moderate in intensity | |
| CERA versus darbepoetin | ||
| Dialysis (HD) | Overall adverse events during the study were mild to moderate, among which thrombosed arteriovenous shunt was considered as the most specific complication to the given medications, nevertheless incidence remained low | |
| Not on dialysis | The number of patients who experienced one or more adverse events was similar between groups and typical of this patient population. The most commonly reported adverse events included hypertension, peripheral oedema, diarrhoea, and nasopharyngitis. Most events were mild or moderate and very few were considered treatment related (CERA 7.5%; darbepoetin alfa 5.6%) | |
| Not on dialysis | Most adverse events experienced by patients in each study arm were reported to be mild to moderate intensity, and rates were comparable between the two groups. The most frequently reported adverse events were hypertension, renal impairment, hyperkalaemia, upper respiratory tract infection and constipation. Numerically more patients in the darbepoetin alfa arm experienced resinous adverse events compared with patients in the CERA arm (12% versus 6% respectively). No patient had a serious adverse event that was judged to be treatment related | |
| Dialysis (HD) | The incidence of adverse events did not differ between groups (P = 0.55). Six were judged to be related to treatment (four with CERA and two with darbepoetin alfa, respectively). Serious adverse events were comparable in the two groups (P = 0.71). The most common serious adverse events were arteriovenous fistula site complication, arteriovenous fistula thrombosis and sepsis. No patient had serious adverse events that was judged to be treatment related | |
| Dialysis (HD) | The overall incidences of adverse and serious adverse events were similar between the two treatment groups and typical of the patient population. The most commonly reported adverse events were diarrhoea, nasopharyngitis and influenza. Serious adverse events were considered to be related to study treatment in one patient in the CERA group (arteriovenous graft thrombosis) and three patients in the darbepoetin group (arteriovenous graft thrombosis, arteriovenous fistula site haemorrhage and cerebral infarction) | |
| CERA lower versus higher doses | ||
| Dialysis (HD) | The most commonly reported adverse events were gastrointestinal disorders, infections, nervous system and vascular disorders. Most events were mild or moderate in intensity | |
| Dialysis (HD) | The adverse events manifested were similar among the dose groups investigated | |
| Not on dialysis | The most commonly reported adverse events were hypertension, urinary tract infection and kidney failure. The majority of events were mild or moderate in intensity | |
| CERA versus placebo | ||
| Not on dialysis | Adverse events with a suspected relation to the study drug occurred in 22% and 16% of patients randomised to CERA and placebo, respectively | |
| CERA ‐ continuous erythropoiesis receptor activator; CKD ‐ chronic kidney diease; HD ‐ haemodialysis; PD ‐ peritoneal dialysis | ||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 All‐cause mortality Show forest plot | 5 | 1846 | Risk Ratio (IV, Random, 95% CI) | 1.07 [0.73, 1.57] |
| 2 Major adverse cardiovascular event Show forest plot | 1 | Risk Ratio (IV, Random, 95% CI) | Totals not selected | |
| 3 Vascular access thrombosis Show forest plot | 3 | 1419 | Risk Ratio (IV, Random, 95% CI) | 1.09 [0.49, 2.40] |
| 4 Cancer Show forest plot | 2 | 903 | Risk Ratio (IV, Random, 95% CI) | 0.82 [0.18, 3.67] |
| 5 Hypertension Show forest plot | 5 | 1821 | Risk Ratio (IV, Random, 95% CI) | 1.01 [0.75, 1.37] |
| 6 Hyperkalaemia Show forest plot | 1 | Risk Ratio (IV, Random, 95% CI) | Totals not selected | |
| 7 Blood transfusion Show forest plot | 5 | 1824 | Risk Ratio (IV, Random, 95% CI) | 1.02 [0.72, 1.46] |
| 8 Iron supplementation Show forest plot | 2 | 437 | Risk Ratio (IV, Random, 95% CI) | 1.03 [0.91, 1.15] |
| 9 Haemoglobin (end of treatment) Show forest plot | 6 | 1626 | Mean Difference (IV, Random, 95% CI) | ‐0.12 [‐0.34, 0.10] |
| 10 Haemoglobin (change during treatment) Show forest plot | 4 | 1510 | Mean Difference (IV, Random, 95% CI) | 0.08 [‐0.04, 0.19] |
| 11 Achieved haemoglobin level target Show forest plot | 5 | 1133 | Risk Ratio (IV, Random, 95% CI) | 1.03 [0.94, 1.12] |
| 12 Exceeding haemoglobin level target Show forest plot | 1 | Risk Ratio (IV, Random, 95% CI) | Totals not selected | |
| 13 Epoetin dose (end of treatment) Show forest plot | 2 | 194 | Std. Mean Difference (IV, Random, 95% CI) | ‐2.11 [‐3.60, ‐0.62] |
| 14 One or more hospital admissions Show forest plot | 1 | Risk Ratio (IV, Random, 95% CI) | Totals not selected | |
| 15 Serum ferritin at end of follow‐up Show forest plot | 2 | 194 | Std. Mean Difference (IV, Random, 95% CI) | 0.14 [‐0.43, 0.71] |
| 16 Transferrin saturation at end of follow‐up Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 All‐cause mortality Show forest plot | 5 | 1657 | Risk Ratio (IV, Random, 95% CI) | 1.11 [0.75, 1.65] |
| 2 Cardiovascular mortality Show forest plot | 2 | 633 | Risk Ratio (IV, Random, 95% CI) | 1.68 [0.74, 3.78] |
| 3 Major adverse cardiovascular event Show forest plot | 2 | 551 | Risk Ratio (IV, Random, 95% CI) | 5.56 [0.99, 31.30] |
| 4 Hypertension Show forest plot | 6 | 1725 | Risk Ratio (IV, Random, 95% CI) | 1.00 [0.79, 1.28] |
| 5 Hyperkalaemia Show forest plot | 3 | 854 | Risk Ratio (IV, Random, 95% CI) | 1.23 [0.63, 2.39] |
| 6 Achieved haemoglobin level target Show forest plot | 5 | 1251 | Risk Ratio (IV, Random, 95% CI) | 1.10 [0.93, 1.29] |
| 7 Haemoglobin (end of treatment) Show forest plot | 4 | 750 | Mean Difference (IV, Random, 95% CI) | 0.03 [‐0.13, 0.18] |
| 8 Haemoglobin (change during treatment) Show forest plot | 2 | 261 | Mean Difference (IV, Random, 95% CI) | 0.15 [‐0.05, 0.36] |
| 9 Epoetin dose (end of treatment) Show forest plot | 4 | 632 | Std. Mean Difference (IV, Random, 95% CI) | 0.24 [‐0.30, 0.77] |
| 10 Exceeding haemoglobin level target Show forest plot | 1 | Risk Ratio (IV, Random, 95% CI) | Totals not selected | |
| 11 Time within the target haemoglobin range Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 12 Need for one or more dose increase Show forest plot | 1 | Risk Ratio (IV, Random, 95% CI) | Totals not selected | |
| 13 Need for one or more dose decrease Show forest plot | 1 | Risk Ratio (IV, Random, 95% CI) | Totals not selected | |
| 14 Blood transfusion Show forest plot | 6 | 1728 | Risk Ratio (IV, Random, 95% CI) | 0.94 [0.55, 1.61] |
| 15 Iron supplementation Show forest plot | 2 | 798 | Risk Ratio (IV, Random, 95% CI) | 0.99 [0.95, 1.03] |
| 16 Serum ferritin at the end of follow‐up Show forest plot | 2 | 131 | Std. Mean Difference (IV, Random, 95% CI) | 0.03 [‐0.31, 0.37] |
| 17 Transferrin saturation at end of follow‐up Show forest plot | 2 | 131 | Mean Difference (IV, Random, 95% CI) | 0.45 [‐1.39, 2.29] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 All‐cause mortality Show forest plot | 2 | 822 | Risk Ratio (IV, Random, 95% CI) | 0.97 [0.56, 1.66] |
| 2 Vascular access thrombosis Show forest plot | 2 | 822 | Risk Ratio (IV, Random, 95% CI) | 0.93 [0.61, 1.41] |
| 3 Hypertension Show forest plot | 2 | 822 | Risk Ratio (IV, Random, 95% CI) | 0.85 [0.60, 1.21] |
| 4 Hyperkalaemia Show forest plot | 1 | 380 | Risk Ratio (IV, Random, 95% CI) | 0.5 [0.05, 5.47] |
| 5 Haemoglobin (end of treatment) Show forest plot | 2 | 653 | Mean Difference (IV, Random, 95% CI) | 0.15 [0.00, 0.31] |
| 6 Haemoglobin (change during treatment) Show forest plot | 2 | 701 | Mean Difference (IV, Random, 95% CI) | 0.03 [‐0.12, 0.18] |
| 7 Achieved haemoglobin level target Show forest plot | 1 | 381 | Risk Ratio (IV, Random, 95% CI) | 0.96 [0.90, 1.03] |
| 8 Cancer Show forest plot | 1 | 380 | Risk Ratio (IV, Random, 95% CI) | 7.0 [0.36, 134.60] |
| 9 Blood transfusion Show forest plot | 3 | 872 | Risk Ratio (IV, Random, 95% CI) | 0.91 [0.51, 1.62] |
| 10 Epoetin dose (end of treatment) Show forest plot | 1 | 42 | Mean Difference (IV, Random, 95% CI) | ‐11.20 [‐35.52, 13.12] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 All‐cause mortality Show forest plot | 1 | Risk Ratio (IV, Random, 95% CI) | Totals not selected | |
| 2 Hypertension Show forest plot | 2 | 89 | Risk Ratio (IV, Random, 95% CI) | 0.45 [0.08, 2.52] |
| 3 Blood transfusion Show forest plot | 2 | 125 | Risk Ratio (IV, Random, 95% CI) | 4.16 [0.89, 19.53] |
| 4 Haemoglobin (change during treatment) Show forest plot | 4 | 250 | Mean Difference (IV, Random, 95% CI) | ‐1.26 [‐1.77, ‐0.74] |
| 5 Need for one or more dose decrease Show forest plot | 1 | Risk Ratio (IV, Random, 95% CI) | Totals not selected | |
| 6 Need for one or more dose increase Show forest plot | 2 | 125 | Risk Ratio (IV, Random, 95% CI) | 4.16 [0.89, 19.53] |
| 7 Achieved haemoglobin level target Show forest plot | 1 | Risk Ratio (IV, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Major adverse cardiovascular event Show forest plot | 1 | Risk Ratio (IV, Random, 95% CI) | Totals not selected | |
| 2 Cancer Show forest plot | 1 | Risk Ratio (IV, Random, 95% CI) | Totals not selected | |
| 3 Hypertension Show forest plot | 1 | Risk Ratio (IV, Random, 95% CI) | Totals not selected | |
| 4 Hyperkalaemia Show forest plot | 1 | Risk Ratio (IV, Random, 95% CI) | Totals not selected | |
| 5 End of treatment eGFR [mL/min/1.73 m²] Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
