Subcutaneous versus intravenous erythropoietin for long-term dialysis patients

  • Protocol
  • Intervention

Authors


Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

This review aims to look at the benefits (efficacy, tolerability and safety) and harms of subcutaneous versus intravenous erythropoiesis stimulating agents (ESA) for long-term adult (age 18 to 89 years) dialysis patients (both peritoneal and haemodialysis).

Background

Description of the condition

Anaemia is a common complication among patients with end-stage kidney disease (ESKD) (Eschbach 1985). Anaemia is caused by deficiency of erythropoietin (EPO), a glycoprotein produced by functioning nephrons. EPO acts on bone marrow to help mature precursor cells to mature as red blood cells. Human erythropoietin was purified, and its amino acid sequence described in the 1970s (Goldwasser 1976; Miyake 1977). Completion of a successful phase III clinical trial in 1989 prompted the US Food and Drug Administration to approve EPO for use in the treatment of anaemia of chronic kidney disease (CKD) (Eschbach 1989). EPO has since become the mainstay of anaemia management for people undergoing dialysis.

It has been estimated that at any given time 90% of prevalent dialysis patients need erythropoiesis-stimulating agent (ESA) therapy (Robinson 2012). Accordingly, several other ESAs have been introduced to the market: Epoetins (EPO-α, β, ϒ, ω) have the same amino acid sequence as endogenous EPO, but differ in the degree of glycosylation. Darbepoetin-α (epoetin analogue) is an exception, and differs from endogenous EPO at five amino acid positions and contains two additional glycosylation sites. Currently, 95% of dialysis patients in the United States are treated with EPO; and only about 4% are treated with darbepoetin (Robinson 2012).

Epoetin-α and β have comparable pharmacokinetics (Stockenhuber 1991). The terminal half-life of darbepoetin is estimated to be three times longer than intravenous epoetin-α. When studied in peritoneal dialysis patients, the time to peak concentration of darbepoetin was found to be more than double epoetin-α (54 vs. 16 to 24 hours) (Macdougall 2000) (Table 1). The newer continuous erythropoiesis receptor activator (CERA) is a post-translationally modified hyper-pegylated erythropoietin-β. The half-life of CERA is prolonged up to six days (Macdougall 2005) and can be administered once or twice a month (Sulowicz 2007).

Table 1. Pharmacokinetic properties of epoetins and their analogues. Adapted from Deicher and Horl 2004
  1. Adapted from Deicher 2004

 Epoetin-αEpoetin-βDarbepoetin-αPegylated epoetin
Half-life (t₁/₂)    
Intravenous route (hour)4 to 118.8 to 10.418 to 25.3 
Subcutaneous route (hour)19 to 25.32448144
Clearance (intravenous route) (mL/hour/kg)8.1 to 8.67.92.0 
Bioavailability (subcutaneous route) (%)30 to 3615 to 5037 

The United States Renal Data System (USRDS) has estimated the cost of ESA therapy at approximately USD 1.9 billion. With rising healthcare costs, and growing trends of bundling dialysis payment structures in Japan and the United States (Wish 2011), there is growing interest in limiting ESA usage.

Description of the intervention

ESAs (epoetins and darbepoetin) are approved for use by both subcutaneous and intravenous routes. In general, ESA administered intravenously has a shorter pharmacokinetic half-life (Table 1). Intravenous EPO requires more frequent dosing (generally three times a week) compared with subcutaneous administration (Besarab 1992). It may therefore be possible to reduce total ESA usage by using reliance on subcutaneous administration (Besarab 1992).

Widespread concern arose in the early 2000s following early reports from Europe that described pure red cell aplasia (PRCA) as a complication from subcutaneous use of EPO (Casadevall 2002). This lead to a shift from subcutaneous to intravenous route administration across dialysis facilities in North America, Europe, Japan, and Australia. Some potential advantages of subcutaneous use include lower dose requirements, and theoretically, a decreased risk of access thrombosis by avoiding exposure to high EPO concentrations and exacerbation of hypertension due to decreased peaks in EPO concentrations.

Concerns about PRCA has prompted reinvestigation of policies concerning subcutaneous EPO use. Results have indicated that red cell aplasia reporting frequency has reduced in North America (Bennett 2004). Several investigators have successfully demonstrated reductions in EPO dose requirements by switching from intravenous to subcutaneous use.

The risks of injection site pain and PRCA need to be weighed carefully against benefits obtained from subcutaneous EPO use.

Why it is important to do this review

Well designed studies (Kaufman 1998; Muirhead 1992) have shown a reduction in EPO requirements and costs of treatment by using subcutaneous EPO. Others (Jensen 1996) have failed to show a benefit of subcutaneous EPO over intravenous use. Furthermore, there is a lack of consistent estimates of reduction in dosage requirements, and resulting cost savings that may be gained from switching from intravenous to subcutaneous EPO use. As dialysis facilities throughout the world grapple with decisions to switch from intravenous to subcutaneous administration of EPO, results from this review will help to provide guidance in decision making. Our review will also aim to collate and summarise the side effect profile of intravenous versus subcutaneous EPO treatment.

Objectives

This review aims to look at the benefits (efficacy, tolerability and safety) and harms of subcutaneous versus intravenous erythropoiesis stimulating agents (ESA) for long-term adult (age 18 to 89 years) dialysis patients (both peritoneal and haemodialysis).

Methods

Criteria for considering studies for this review

Types of studies

All randomised controlled trials (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 subcutaneous versus intravenous ESAs for long-term dialysis patients (both peritoneal and haemodialysis) will be included. ESAs studied will include erythropoietin-α, -β, -ϒ, -ω; darbepoetin-α and the newer pegylated erythropoietins.

Types of participants

Inclusion criteria

Studies evaluating use of either subcutaneous or intravenous ESAs in adults (aged 18 to 89 years) requiring long term dialysis (both peritoneal and haemodialysis) for treatment of anaemia of CKD will be included.

Exclusion criteria

Studies evaluating use of ESA for anaemia not related to CKD, such as malignancy or bone marrow disorders, will be excluded.

Studies involving children aged under 18 years will be excluded.

Types of interventions

Studies randomising participants to subcutaneous versus intravenous ESA will be included. Established EPO preparations to be included in this review are epoetins (EPO-α, -β, -ϒ, -ω), epoetin analogues (darbepoetin), or the newer pegylated epoetins. Concurrent treatment with oral or intravenous iron as well as adjunctive treatment with compounds that improve EPO responsiveness such as ascorbic acid or pentoxifylline will be permitted so long as the randomised intervention is subcutaneous versus intravenous EPO.

Types of outcome measures

Primary outcomes
  1. Change in EPO dose needed to achieve correction of haemoglobin to the desired level

  2. Quality of anaemia control: change in haemoglobin/haematocrit values on follow-up; numbers of blood transfusions; percentage of patients in appropriate haemoglobin/haematocrit target range; time to achieve target haemoglobin/haematocrit.

Secondary outcomes
  1. Hypertension measures: Change in systolic blood pressure, diastolic blood pressure and/or mean blood pressure level on follow-up

  2. Quality of life measures

  3. Estimates of cost of therapy

  4. Rates of access thrombosis

  5. Number and type of adverse effects

  6. Incidence of pure red cell aplasia

  7. Reports of pain due to subcutaneous administration

  8. Withdrawal due to adverse events

  9. Withdrawal due to lack of efficacy

  10. Withdrawal due to any reason

  11. Death.

Search methods for identification of studies

Electronic searches

We will search the Cochrane Renal Group's specialised register through contact with the Trials' Search Co-ordinator using search terms relevant to this review.

The Cochrane Renal Group’s specialised register contains studies identified from:

  1. Quarterly searches of the Cochrane Central Register of Controlled Trials (CENTRAL)

  2. Weekly searches of MEDLINE OVID SP

  3. Handsearching of renal-related journals and the proceedings of major renal conferences

  4. Searching of the current year of EMBASE OVID SP

  5. Weekly current awareness alerts for selected renal journals

  6. 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 the Cochrane Renal Group. 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 the Cochrane Renal Group.

See Appendix 1 for search terms used.

Searching other resources

  1. Reference lists of nephrology textbooks, review articles and relevant studies.

  2. Letters seeking information about unpublished or incomplete trials to investigators known to be involved in previous studies.

Data collection and analysis

Selection of studies

The search strategy described will be used to obtain titles and abstracts of studies that may be relevant to the review. The titles and abstracts will be screened independently by two authors, who will discard studies that are not applicable, however studies and reviews that might include relevant data or information on trials will be retained initially. Two authors will independently assess retrieved abstracts and, if necessary the full text, of these studies to determine which studies satisfy the inclusion criteria.

Data extraction and management

Data extraction will be carried out independently by two authors using standard data extraction forms. Studies reported in non-English language journals will be translated before assessment. Where more than one publication of one study exists, reports will be grouped together and the publication with the most complete data will be used in the analyses. Where relevant outcomes are only published in earlier versions this data will be used. Any discrepancy between published versions will be highlighted.

Assessment of risk of bias in included studies

The following items will be independently assessed by two authors using the risk of bias assessment tool (Higgins 2011) (see Appendix 2).

  • Was there adequate sequence generation (selection bias)?

  • Was allocation adequately concealed (selection bias)?

  • Was knowledge of the allocated interventions adequately prevented during the study (detection bias)?

    • Participants and personnel

    • Outcome assessors

  • Were incomplete outcome data adequately addressed (attrition bias)?

  • Are reports of the study free of suggestion of selective outcome reporting (reporting bias)?

  • Was the study apparently free of other problems that could put it at a risk of bias?

Measures of treatment effect

For dichotomous outcomes (all-cause mortality, hypersensitivity reactions) results will be expressed as risk ratio (RR) with 95% confidence intervals (CI). Where continuous scales of measurement are used to assess the effects of treatment, such as mean blood pressure and quality of anaemia control, the mean difference (MD) will be used, or the standardised mean difference (SMD) if different scales have been used.

We expect to find studies that report change-from-baseline or final value scores. However, differences in mean final values will on average be the same as the difference in mean change scores. Therefore, studies reporting either change-from-baseline or final value scores will be included in our review. We will conduct separate subgroups since the mean values and standard deviations for the two types of outcome may differ substantially. The results will however be pooled together for reporting as mean difference only (not as SMD since the difference in standard deviation reflects not differences in measurement scale, but differences in the reliability of the measurements). If the use of change scores does increase precision, the studies presenting change scores will appropriately be given higher weights in the analysis than they would have received if final values had been used, as they will have smaller standard deviations.

Missing standard deviations for changes from baseline will be imputed using methods described by Higgins 2011.

Unit of analysis issues

We anticipate that in all identified studies the unit of analysis will be the individual participant.

Cluster-randomised trials will be identified and dealt with separately. If possible the analysis will be conducted at the same level as the allocation, using a summary measurement from each cluster and number of clusters as the sample size. The following information will be extracted if available:

  • the number of clusters (or groups) randomised to each intervention group; or the average (mean) size of each cluster

  • outcome data ignoring the cluster design for the total number of individuals (for example, number or proportion of individuals with events, or means and standard deviations); and

  • an estimate of the intra cluster (or intra class) correlation coefficient (ICC).

The ICC is an estimate of the relative variability within and between clusters (Higgins 2011) and is seldom available in published reports. If ICCs have been borrowed from external source sensitivity analyses will be performed to investigate the robustness of conclusions. Larger clusters often have smaller ICCs but even small values can have a substantial impact on confidence interval widths (and hence weights in a meta-analysis).

Although, this approach can dramatically reduce the sample size and therefore the power of the study; the idea is to reduce the size of each trial to its effective sample size (Higgins 2011). The effective sample size of a single intervention group in a cluster-randomised trial is its original sample size divided by a quantity called the ‘design effect’. The design effect is 1 + (M – 1) ICC, where M is the average cluster size and ICC is the intra cluster correlation coefficient. A common design effect is usually assumed across intervention groups. For dichotomous data both the number of participants and the number experiencing the event will be divided by the same design effect. The resulting data will be rounded to whole numbers for entry into RevMan. For continuous data only the sample size need be reduced; means and standard deviations should remain unchanged.

Dealing with missing data

Any further information required from the original author will be requested by written correspondence (e.g. emailing and/or writing to corresponding author/s) and any relevant information obtained in this manner will be included in the review. Evaluation of important numerical data such as screened, randomised patients as well as intention-to-treat, as-treated and per-protocol population will be carefully performed. Attrition rates, for example drop-outs, losses to follow-up and withdrawals will be investigated. Issues of missing data and imputation methods (for example, last-observation-carried-forward) will be critically appraised (Higgins 2011).

Assessment of heterogeneity

Heterogeneity will be 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% correspond to low, medium and high levels of heterogeneity. We will consider P values of < 0.10 as statistically significant.

Assessment of reporting biases

If possible, funnel plots will be used to assess for the potential existence of small study bias (Higgins 2011).

Data synthesis

Data will be pooled using the random-effects model but the fixed-effect model will also be used to ensure robustness of the model chosen and susceptibility to outliers.

Subgroup analysis and investigation of heterogeneity

Subgroup analysis will be used to explore possible sources of heterogeneity (such as dialysis modality). Heterogeneity among participants could be related to age and renal pathology (such as serum albumin levels, and percentage of patients with diabetes). Heterogeneity in treatments could be related to prior agent(s) used and the agent, dose and duration of therapy (such as type of ESA administered, presence and degree of iron therapy, and non-iron co-interventions). Adverse effects will be tabulated and assessed with descriptive techniques, as they are likely to be different for the various agents used. Where possible, the risk difference with 95% CI will be calculated for each adverse effect, either compared to no treatment or to another agent.

Sensitivity analysis

We will perform sensitivity analyses in order to explore the influence of the following factors on effect size:

  • repeating the analysis excluding unpublished studies

  • repeating the analysis taking account of risk of bias, as specified

  • repeating the analysis excluding any very long or large studies to establish how much they dominate the results

  • repeating the analysis excluding studies using the following filters: diagnostic criteria, language of publication, source of funding (industry versus other), country.

Acknowledgements

The authors would like to acknowledge the help of the editorial team and at the Cochrane Renal Group and the referees in conducting this systematic review.

Appendices

Appendix 1. Electronic search strategies

DatabaseSearch terms
CENTRAL
  1. MeSH descriptor Erythropoietin explode all trees

  2. (erythropoietin):ti,ab,kw in Clinical Trials

  3. (epo):ti,ab,kw in Clinical Trials

  4. (darbepoetin):ti,ab,kw in Clinical Trials

  5. (epoetin):ti,ab,kw in Clinical Trials

  6. (cera):ti,ab,kw in Clinical Trials

  7. (rhuepo):ti,ab,kw in Clinical Trials

  8. (#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7)

  9. MeSH descriptor Injections, this term only

  10. MeSH descriptor Injections, Subcutaneous, this term only

  11. MeSH descriptor Injections, Intravenous, this term only

  12. MeSH descriptor Injections, Intradermal, this term only

  13. (subcutaneous*):ti,ab,kw in Clinical Trials

  14. (intravenous*):ti,ab,kw in Clinical Trials

  15. (iv or sc or sq):ti,ab,kw in Clinical Trials

  16. (#9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15)

  17. MeSH descriptor Renal Dialysis explode all trees

  18. MeSH descriptor Hemofiltration explode all trees

  19. MeSH descriptor Kidney Failure, Chronic, this term only

  20. (dialysis):ti,ab,kw in Clinical Trials

  21. (haemodialysis or haemodialysis):ti,ab,kw in Clinical Trials

  22. (hemofiltration or haemofiltration):ti,ab,kw in Clinical Trials

  23. (hemodiafiltration or haemodiafiltration):ti,ab,kw in Clinical Trials

  24. (PD or CAPD or CCPD or APD):ti,ab,kw in Clinical Trials

  25. (end-stage kidney or end-stage renal or endstage kidney or endstage renal):ti,ab,kw in Clinical Trials

  26. (ESKD or ESKF or ESRD or ESRF):ti,ab,kw in Clinical Trials

  27. (#17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23 OR #24 OR #25 OR #26)

  28. (#8 AND #16 AND #27)

MEDLINE (OVID)
  1. exp Erythropoietin/

  2. erythropoietin.tw.

  3. EPO.tw.

  4. cera.tw.

  5. darbepoetin.tw.

  6. epoetin.tw.

  7. or/1-6

  8. Injections/

  9. Injections, Subcutaneous/

  10. Injections, Intradermal/

  11. Injections, Intravenous/

  12. subcutaneous$.tw.

  13. intravenous$.tw.

  14. (iv or sc or sq).tw.

  15. or/8-14

  16. exp Renal Dialysis/

  17. exp Hemofiltration/

  18. Kidney Failure, Chronic/

  19. dialysis.tw.

  20. (haemodialysis or haemodialysis).tw.

  21. (hemofiltration or haemofiltration).tw.

  22. (hemodiafiltration or haemodiafiltration).tw.

  23. (PD or CAPD or CCPD or APD).tw.

  24. (end-stage kidney or end-stage renal or endstage kidney or endstage renal).tw.

  25. (ESKD or ESKF or ESRD or ESRF).tw.

  26. and/7,15,25

EMBASE (OVID)
  1. erythropoietin/

  2. erythropoietin.tw.

  3. epoetin.tw.

  4. EPO.tw.

  5. darbepoetin.tw.

  6. cera.tw.

  7. or/1-6

  8. intravenous drug administration/

  9. subcutaneous drug administration/

  10. drug administration route/

  11. subcutaneous$.tw.

  12. intravenous$.tw.

  13. (iv or sc or sq).tw.

  14. or/8-13

  15. exp Renal Replacement Therapy/

  16. (haemodialysis or haemodialysis).tw.

  17. (hemofiltration or haemofiltration).tw.

  18. (hemodiafiltration or haemodiafiltration).tw.

  19. dialysis.tw.

  20. (PD or CAPD or CCPD or APD).tw.

  21. Chronic Kidney Disease/

  22. Kidney Failure/

  23. Chronic Kidney Failure/

  24. (end-stage renal or end-stage kidney or endstage renal or endstage kidney).tw.

  25. (ESRF or ESKF or ESRD or ESKD).tw.

  26. or/15-25

  27. and/7,14,26

Appendix 2. Risk of bias assessment tool

Potential source of biasAssessment criteria

Random sequence generation

Selection bias (biased allocation to interventions) due to inadequate generation of a randomised sequence

Low risk of bias: Random number table; computer random number generator; coin tossing; shuffling cards or envelopes; throwing dice; drawing of lots; minimization (minimization may be implemented without a random element, and this is considered to be equivalent to being random).
High risk of bias: Sequence generated by odd or even date of birth; date (or day) of admission; sequence generated by hospital or clinic record number; allocation by judgement of the clinician; by preference of the participant; based on the results of a laboratory test or a series of tests; by availability of the intervention.
Unclear: Insufficient information about the sequence generation process to permit judgement.

Allocation concealment

Selection bias (biased allocation to interventions) due to inadequate concealment of allocations prior to assignment

Low risk of bias: Randomisation method described that would not allow investigator/participant to know or influence intervention group before eligible participant entered in the study (e.g. central allocation, including telephone, web-based, and pharmacy-controlled, randomisation; sequentially numbered drug containers of identical appearance; sequentially numbered, opaque, sealed envelopes).
High risk of bias: Using an open random allocation schedule (e.g. a list of random numbers); assignment envelopes were used without appropriate safeguards (e.g. if envelopes were unsealed or non-opaque or not sequentially numbered); alternation or rotation; date of birth; case record number; any other explicitly unconcealed procedure.
Unclear: Randomisation stated but no information on method used is available.

Blinding of participants and personnel

Performance bias due to knowledge of the allocated interventions by participants and personnel during the study

Low risk of bias: No blinding or incomplete blinding, but the review authors judge that the outcome is not likely to be influenced by lack of blinding; blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken.
High risk of bias: No blinding or incomplete blinding, and the outcome is likely to be influenced by lack of blinding; blinding of key study participants and personnel attempted, but likely that the blinding could have been broken, and the outcome is likely to be influenced by lack of blinding.
Unclear: Insufficient information to permit judgement

Blinding of outcome assessment

Detection bias due to knowledge of the allocated interventions by outcome assessors.

Low risk of bias: No blinding of outcome assessment, but the review authors judge that the outcome measurement is not likely to be influenced by lack of blinding; blinding of outcome assessment ensured, and unlikely that the blinding could have been broken.
High risk of bias: No blinding of outcome assessment, and the outcome measurement is likely to be influenced by lack of blinding; blinding of outcome assessment, but likely that the blinding could have been broken, and the outcome measurement is likely to be influenced by lack of blinding.
Unclear: Insufficient information to permit judgement

Incomplete outcome data

Attrition bias due to amount, nature or handling of incomplete outcome data.

Low risk of bias: No missing outcome data; reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias); missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes not enough to have a clinically relevant impact on observed effect size; missing data have been imputed using appropriate methods.
High risk of bias: Reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes enough to induce clinically relevant bias in observed effect size; ‘as-treated’ analysis done with substantial departure of the intervention received from that assigned at randomisation; potentially inappropriate application of simple imputation.
Unclear: Insufficient information to permit judgement

Selective reporting

Reporting bias due to selective outcome reporting

Low risk of bias: The study protocol is available and all of the study’s pre-specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre-specified way; the study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre-specified (convincing text of this nature may be uncommon).
High risk of bias: Not all of the study’s pre-specified primary outcomes have been reported; one or more primary outcomes is reported using measurements, analysis methods or subsets of the data (e.g. subscales) that were not pre-specified; one or more reported primary outcomes were not pre-specified (unless clear justification for their reporting is provided, such as an unexpected adverse effect); one or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta-analysis; the study report fails to include results for a key outcome that would be expected to have been reported for such a study.
Unclear: Insufficient information to permit judgement

Other bias

Bias due to problems not covered elsewhere in the table

Low risk of bias: The study appears to be free of other sources of bias.
High risk of bias: Had a potential source of bias related to the specific study design used; stopped early due to some data-dependent process (including a formal-stopping rule); had extreme baseline imbalance; has been claimed to have been fraudulent; had some other problem.
Unclear: Insufficient information to assess whether an important risk of bias exists; insufficient rationale or evidence that an identified problem will introduce bias.

Contributions of authors

  1. Draft the protocol: AKG, VA

  2. Study selection: AKG, SN, VA

  3. Extract data from studies: AKG, VA

  4. Enter data into RevMan: VA, SN, AKG

  5. Carry out the analysis: AKG, VA

  6. Interpret the analysis:AKG

  7. Draft the final review: AKG, VA

  8. Disagreement resolution: SN

  9. Update the review: AKG

Declarations of interest

None known.

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