A Canadian Survey of Prescribing Practices of Erythropoiesis-Stimulating Agents in Dialysis-Dependent and Non-Dialysis-Dependent Chronic Kidney Disease

Abstract

French

Background:

Erythropoiesis-stimulating agents (ESAs) are commonly used to manage chronic kidney disease (CKD)-associated anemia. There is a paucity of clear guidelines on their use in patients with CKD and with history of stroke or malignancy.

Objective:

To identify hemoglobin targets/thresholds, ESA prescribing practices and patterns, and prescriber comfort in patients with CKD and with history of stroke or malignancy.

Study Design and Setting:

We administered an online, cross-sectional survey to nephrologists, nephrology trainees, nurse practitioners, and pharmacists affiliated with the Canadian Society of Nephrology (CSN) from March 11 to June 30, 2024.

Methods:

Survey questions were designed to determine the prescribing practices of ESAs for both general patients with CKD and those with CKD and history of stroke, active malignancy, or prior malignancy. Survey design was finalized using a 4-stage modified Delphi process. Ordinal regression was used to assess the association between baseline characteristics and prescriber comfort.

Results:

In all, 24% (127/540) of potential participants responded, with 121 responses included in the final survey analysis. Most respondents were nephrologists (67%, 81/121). Only 9%, 7%, and 4% of respondents reported having an institutional protocol for anemia management for patients with CKD and history of stroke, active malignancy, or previous malignancy, respectively. The most common hemoglobin target for general patients with CKD was 95 to 115 g/L. For those with history of stroke, active, or previous malignancy, it was 90 to 105 g/L. Self-reported prescriber comfort was greatest in general patients with CKD. Among all prescribers, comfort ratings were significantly lower when prescribing ESAs in those with stroke or malignancy. Nephrologists and nephrology trainees were more likely to report higher comfort ratings when prescribing ESAs in patients with CKD and active malignancy (odds ratio [OR] = 2.80, 95% confidence interval [CI] = 1.12-6.96) compared with nonphysicians.

Limitations:

There was a potential for nonresponse bias given the response rate of 24%. Sampling bias may have been introduced with convenience sampling of solely kidney care providers affiliated with the CSN.

Conclusion:

This study highlights the variability of ESA prescribing practices and anemia management across Canada in patients with CKD and with stroke or malignancy. Our findings emphasize the need for guidelines to manage ESA prescribing in these populations.

Keywords

chronic kidney disease anemia erythropoietin-stimulating agents maintenance dialysis stroke

Introduction

Anemia of chronic kidney disease (CKD) can lead to increased need for blood transfusions, higher risk of cardiovascular events, and decreased quality of life.¹ Erythropoiesis-stimulating agents (ESAs) are effective for treating anemia in CKD.^2,3 Currently, 2 ESAs are available in Canada, darbepoetin alfa (Aranesp) and epoetin alfa (Eprex).^4,5

Despite their benefits, ESAs are associated with serious adverse events which include stroke, cancer progression, vascular access thrombosis, and venous thromboembolism.^1-3,6-8 The increased risk of stroke was shown in the Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) which randomized patients with CKD, type 2 diabetes, and anemia to a target hemoglobin of 130 g/L (using darbepoetin alfa) or placebo with rescue darbepoetin alfa if hemoglobin levels fell below 90 g/L.⁷ Patients in the darbepoetin group experienced a 2-fold higher risk of stroke compared with placebo,⁷ confirmed in subsequent meta-analyses and possibly related to a higher target hemoglobin.^9,10 The TREAT trial also found that patients with a history of malignancy at baseline were more likely to die of cancer if randomized to darbepoetin alfa (14 vs 1 event).⁷

There are no clear guidelines on the use of ESAs in CKD populations with stroke or malignancy. In the 2012 Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guideline for anemia in CKD, “the cautious use of ESAs, if at all, [was] recommended in patients with history of malignancy or stroke,” but no definitive guidelines were provided regarding hemoglobin targets and ESA dosing.³ Furthermore, the strength of evidence for many of KDIGO’s recommendations was suboptimal.¹¹ A 2013 Canadian Society of Nephrology (CSN) commentary suggested that it would be reasonable to consider ESA initiation at lower hemoglobin levels (90 g/L) and use a lower hemoglobin range (90-105 g/L) in patients with a history of malignancy.¹¹ The commentary also recommended targeting a hemoglobin range of 90 to 105 g/L in those with a history of stroke.¹¹ We surmise the paucity of clear recommendations for ESA use has led to a wide array of practice patterns.

In this study, we surveyed nephrology care practitioners across multiple centers within Canada on their individual and institution-specific practices on ESA use as well as hemoglobin targets in patients with dialysis-dependent or non-dialysis-dependent CKD and a history of ischemic stroke or malignancy. Our objectives were to:

Determine the hemoglobin targets/thresholds that are used for ESAs in patients with CKD and stroke or malignancy.

Identify patterns of ESA use in patients with CKD and stroke or malignancy such as maximum ESA doses prescribed or when therapy is interrupted.

Assess prescriber comfort in ESA prescribing.

We hypothesized that there would be significant variation in the use of ESAs and target hemoglobin values within these populations due to the lack of robust, established guidelines.

Methods

Study Design

We developed and administered a cross-sectional, online survey to a convenience sample of nephrologists (adult and pediatric), nephrology trainees, kidney pharmacists, and kidney nurse practitioners affiliated with the CSN. The CSN includes physicians and health care professionals who specialize in the care of people with kidney disease. The survey was created using the SurveyMonkey (www.surveymonkey.com) online platform (Supplemental Figure S1). All survey responses were anonymous and the survey could only be completed once per email and IP address. The survey was disseminated nationally by the CSN via unique weblink through their protected email list on March 11, 2024 to June 30, 2024 with 4 follow-up emails at 3, 7, 9, and 11 weeks to increase response rates. The Nova Scotia Health Research Ethics Board approved this study (#1029593).

Participants

Study participants who had an affiliation or membership with the CSN were enrolled. Participants were included if they had prescribed an ESA to a patient with CKD or kidney failure in the last 3 years. Nurse practitioners and pharmacists had to be affiliated with a kidney clinic or dialysis center.

Survey Domains

The survey consisted of a maximum of 48 questions and was divided into 4 domains to capture clinical practice patterns of ESA use in patients with CKD/kidney failure and in specific subgroups including those with previous ischemic stroke, active malignancy, or previous malignancy. Baseline demographic factors included age, professional designation, years in practice, province, experience in different areas of nephrology, and in which CKD populations participants have prescribed ESAs previously.

In the general ESA prescribing section of the survey (domain 1), participants rated their comfort with prescribing ESAs in CKD/kidney failure populations using a 5-point Likert scale ranging from 1 (strongly disagree) to 5 (strongly agree). Participants were asked about their institutional or individual hemoglobin targets and the maximum weekly dose of ESA that they are comfortable prescribing. We also included a question on who initially prescribes ESAs and who primarily adjusts ESA dosing at their institutions.

Survey domains 2 to 4 were specific to ESA prescribing in patients with history of stroke, active malignancy, or treated/cured malignancy. These sections included questions on whether participants prescribe ESAs in patients in these populations (yes/no), their comfort on prescribing ESAs (5-point Likert scale), hemoglobin targets, maximum weekly ESA dose, and how soon after a diagnosis are they comfortable starting or restarting an ESA.

Survey Design

The survey was finalized using a 4-stage modified Delphi process.¹² The first 2 stages of survey design involved 2 rounds of an expert panel reviewing an initial and revised draft of the survey. Each panel member provided feedback on whether to include, edit, or omit each question without ranking. The expert panel consisted of a nephrology trainee, 2 adult nephrologists, and a kidney pharmacist from the Central Zone of the Nova Scotia Health Renal Program. The third stage involved piloting the revised survey, using SurveyMonkey, to a convenience sample of 21 kidney practitioners from the same program (including physicians, a pharmacist, and nurse practitioner). Response rate was 76%. Respondents were able to provide open-ended feedback on inclusion/exclusion of questions, applicability, clarity, and item readability for all questions, but responses were not required. In the final stage, members of the expert panel reviewed feedback from the third stage for each question to reach a consensus for the final survey. While no set threshold was used, there was 100% consensus for all items included in the final survey. Informed consent was implied through a statement provided at the beginning of the survey.

Statistical Analysis

Responses from all completed surveys, including those with missing or skipped answers, were included in the analysis and complete case analysis was used in the event of missing data for a single question. Pilot survey responses were included in the analysis of survey data. These responses were also excluded in a sensitivity analysis.

Categorical variables were summarized as percentages and presented in the form of tables, histograms, and bar charts. In the primary analysis, survey responses were compared between all subpopulations. Non-normally distributed continuous variables such as Likert scale ratings on ESA prescribing comfort were reported as medians and interquartile ranges. Comparisons between subpopulations of baseline characteristics were done using the Wilcoxon rank sum test for continuous variables and Fisher exact test for categorical variables. A 2-sided P value of less than .05 was considered significant. A multivariable ordinal regression model was used to assess the association between baseline characteristics and prescriber comfort. Variables forced in this model included age (using a threshold of 40 years to reflect the start of middle age), professional designation (Nephrologist/Trainee vs other), years in practice (using a threshold of 15 years to reflect early versus late practice), or province of practice (Ontario vs other) without any interactions. Associations were reported with odds ratios and 95% confidence intervals. Statistical analyses were done using Stata IC, version 18 (StataCorp, College Station, Texas).

Results

Response Rate

Of the 540 potential participants, 127 responded to the survey (response rate: 24%) and 121 (22%) were included in the final analysis (Figure 1). A summary of completion rates for each question is shown in Supplemental Table S2. The average completion rate for all questions was 85%.

Figure 1.

Time sequence of survey responses.

Respondent Demographics

Demographic data are shown in Table 1. A total of 81 nephrologists (67%), 16 nephrology trainees/fellows (13%), 15 nurse practitioners (12%), 8 pharmacists (7%), and 1 physician assistant completed the survey (0.8%). Most respondents practiced in urban settings. All provinces were represented (Figure 2).

Table 1.

Demographic Characteristics of Survey Participants.

Characteristic^a	No. (%)n = 121 participants
Age range in years
<30	<5
30-39	43 (35.8)
40-49	32 (26.7)
50-59	32 (26.7)
60-69	9 (7.5)
≥70	<5
Professional designation
Nephrologist	81 (66.9)
Nephrology trainee	16 (13.2)
Nephrology nurse practitioner	14 (11.6)
Nephrology pharmacist	8 (6.6)
Nephrology physician assistant	<5
Years in practice
<5	21 (17.4)
5-9	30 (24.8)
10-14	20 (16.5)
15-19	16 (13.2)
20-24	18 (14.9)
≥25	16 (13.2)
Practice setting
Urban	114 (94.2)
Rural	7 (5.8)
Nephrology practice area
Hemodialysis	115 (95.0)
Home dialysis (Home HD or PD)	73 (60.3)
Renal clinics/outpatients	101 (83.5)
Kidney transplant	46 (38.0)
Nephrology inpatient services	100 (82.6)
Population ESAs prescribed
CKD category G3b to G5ND	103 (85.1)
CKD category G5D (HD or PD)	118 (97.5)
Kidney transplant (CKD G1T-5T)	37 (30.6)

Note. CKD = chronic kidney disease; HD = hemodialysis; PD = peritoneal dialysis; ND = nondialysis.

Certain categories are reported as <5 to avoid the potential identification of survey respondents.

Figure 2.

Survey respondent provinces of practice.

ESA Institutional Protocols

Sixty-four percent of respondents had an institutional protocol for general patients with CKD; whereas only 9%, 7%, and 4% had a protocol for individuals with history of stroke, active malignancy, or previous malignancy, respectively.

Hemoglobin Targets for CKD-Associated Anemia Managed With ESAs

In general CKD, 95 to 115 g/L was the most common hemoglobin target (46% of respondents, Figure 3). For patients with CKD and history of stroke, 90 to 105 g/L and 95 to 115 g/L were the 2 most common targets at 27% and 26%, respectively. For those with active and previous malignancy, 90 to 105 g/L was the most common target (27% and 26% of respondents, respectively).

Figure 3.

Institutional and personal preferred hemoglobin targets for CKD groups.

ESA Dosing

Prescribers were most comfortable with a maximum weekly dose of 150 µg of darbepoetin alfa for general CKD populations and those with previous malignancy and 100 µg of darbepoetin alfa for patients with CKD and either history of stroke or active malignancy (Table 2).

Table 2.

Maximum Weekly ESA Dose by Prescribers in CKD Groups.

CKD group	Maximum weekly ESA dose (%)^a
	IV or subcut. darbepoetin alfa^b				IV epoetin alfa^c				Subcut. epoetin alfa
	100 µg	150 µg	200 µg	No specified dose limit	10,000 units	20,000 units	30,000 units	No specified dose limit	7,500 units	15,000 units	25,000 units	No specified dose limit
General CKD	30 (24.8)	60 (49.6)	9 (7.4)	7 (5.8)	3 (2.5)	3 (2.5)	16 (13.2)	2 (1.7)	1 (0.8)	6 (5.0)	1 (0.8)	4 (3.3)
Stroke	40 (33.1)	25 (20.7)	5 (4.1)	19 (15.7)	6 (5.0)	4 (3.3)	4 (3.3)	5 (4.1)	2 (1.7)	2 (1.7)	0	2 (1.7)
Active Malignancy	30 (24.8)	22 (18.2)	5 (4.1)	22 (18.2)	4 (3.3)	4 (3.3)	4 (3.3)	6 (5.0)	1 (0.8)	2 (1.7)	0	3 (2.5)
Previous Malignancy	29 (24.0)	36 (29.8)	6 (5.0)	15 (12.4)	4 (3.3)	4 (3.3)	5 (4.1)	6 (5.0)	1 (0.8)	3 (2.5)	0	4 (3.3)

Note. ESA = erythropoietin-stimulating agents; CKD = chronic kidney disease; IV =intravenous; subcut. = subcutaneous.

Total number of respondents (N) that chose each potential response are depicted.

Per manufacturer recommendations, the conversion between darbepoetin alfa and epoetin alfa is 200:1.¹³

Previous studies have shown a 25% to 30% reduction in dosing requirements when changing from IV to subcut. epoetin alfa.¹⁴

Prescribers most commonly chose a maximum weekly epoetin intravenous dose of 30 000 units or subcutaneous dose of 15 000 units in general patients with CKD. Most respondents chose the option of “no specified dose limit” when asked about weekly intravenous or subcutaneous epoetin dosing. The exception was for intravenous epoetin dosing in patients with CKD and stroke where the most common response was a maximum weekly dose of 10 000 units.

ESA Use in Patients With CKD and History of Stroke

Most (84%) respondents had prescribed ESAs in patients with CKD and history of stroke or transient ischemic attack (TIA); 41% did not hold or dose reduce the ESA in the setting of acute stroke, whereas 30% dose reduced the ESA and 22% stopped it completely. Figure 4 shows the duration of time prescribers typically wait following stroke or TIA before prescribing an ESA.

Figure 4.

How soon after initial stroke do survey respondents start ESA therapy if indicated.

ESA Use in Patients With CKD and Active Malignancy

A total of 74% of survey respondents had prescribed an ESA in a patient with CKD and an active malignancy, whereas 16% had not (11% provided no response). Participants were also asked if they were most likely to prescribe ESAs for patients with CKD who have an active malignancy managed conservatively or in a palliative manner. Sixty-two percent responded “yes,” 26% responded “no,” and 12% gave no response. When asked if the type of primary malignancy is taken into consideration when prescribing an ESA, 28% said “yes,” 24% said “no,” and 48% gave no response.

Most participants stopped or dose reduced the ESA if a patient on an ESA was diagnosed with an active malignancy (Supplement Figure S3) and resumed the ESA therapy once the malignancy was cured, treated or the patient was deemed to be palliative by their oncology team (Supplement Figure S4).

ESA Use in Patients With CKD and Previous Malignancy

Eighty-four percent of respondents prescribe ESAs to patients with CKD and history of malignancy, but waiting times before initiating therapy differed (Figure 5). Only 22% stated that they take into consideration malignancy type when prescribing.

Figure 5.

Length of time survey respondents wait before resuming ESA therapy in patients with CKD and history of malignancy.

ESA Prescriber Comfort

Prescriber comfort was greatest when using ESAs in general patients with CKD and lowest when using ESAs for patients with CKD and active malignancy (Table 3). There was a statistically significant difference in prescriber comfort when using ESAs in patients with CKD and history of stroke, active malignancy, or previous malignancy compared with general patients with CKD.

Table 3.

Likert Scale Ratings^a for ESA Prescribing Comfort in CKD Populations.

Question	Median rating	Interquartile range	P ^b
I am comfortable with prescribing ESAs in patients with dialysis-dependent or non-dialysis-dependent CKD	5	4-5	Reference
I am comfortable with prescribing ESAs in dialysis-dependent or non-dialysis-dependent patients with CKD and history of stroke	4	3-4	<.001
I am comfortable with prescribing ESAs in dialysis-dependent or non-dialysis-dependent patients with CKD and an active malignancy	3	2-4	<.001
I am comfortable with prescribing ESAs in dialysis-dependent or non-dialysis-dependent patients with CKD and history of previous malignancy	4	3-4	<.001

Note. ESA = erythropoietin-stimulating agent; CKD = chronic kidney disease.

Likert ratings: 1 = strongly disagree, 2 = disagree, 3 = neither agree nor disagree, 4 = agree, 5 = strongly agree.

Comparisons between 2 groups done using Wilcoxon rank sum test.

Table 4 shows prescriber comfort ratings when prescribing ESAs for each CKD subpopulation stratified by various baseline characteristics. Nephrologists and nephrology trainees were significantly more likely to report higher comfort scores when prescribing ESAs in those with active malignancy (odds ratio [OR] = 2.80 for each 1-point increase in Likert score rating, 95% confidence interval [CI] = 1.12-6.96) compared with nonphysicians (Table 5). There were no other demographic characteristics that were significantly associated with greater prescriber comfort across any CKD population.

Table 4.

Likert Scale Ratings^a for ESA Prescribing Comfort by Demographic Characteristic in Different CKD Populations.

	General	Stroke	Active malignancy	Previous malignancy
Characteristic	Median rating (interquartile range)	Median rating (interquartile range)	Median rating (interquartile range)	Median rating (interquartile range)
Age
<40	4 (4-4)	4 (3-4)	3 (2-4)	4 (4-4)
>40	4 (4-4)	4 (4-4)	3 (2-4)	4 (3-4)
Years in practice
<15	4 (4-4)	4 (4-4)	3 (2-4)	4 (3-4)
>15	4 (4-4)	4 (4-4)	3 (2-4)	4 (3-4)
Designation
Nephrologist or trainee	4 (4-4)	4 (4-4)	3 (2-4)	4 (3-4)
Other^b	4 (4-4)	4 (4-4)	2 (2-3)	4 (4-4)
Province of practice
Ontario	4 (4-4)	4 (3-4)	3 (2-4)	4 (3-4)
Other^c	4 (4-4)	4 (3-4)	3 (2-4)	4 (3-4)

Note. ESA = erythropoietin-stimulating agent; CKD =chronic kidney disease.

Likert ratings: 1 = strongly disagree, 2 = disagree, 3 = neither agree nor disagree, 4 = agree, 5 = strongly agree.

Nurse practitioners, pharmacists, physician assistants.

Alberta, British Columbia, Manitoba, New Brunswick, Newfoundland and Labrador, Nova Scotia, Prince Edward Island, Quebec, Saskatchewan.

Table 5.

Demographic Predictors of Greater ESA Prescriber Comfort in CKD Populations.

Demographic characteristic	CKD subpopulation
	General	Stroke	Active malignancy	Previous malignancy
	Odds ratio (95% confidence interval)
Age >40	0.68 (0.14-3.25)	2.12 (0.84-5.38)	1.52 (0.61-3.78)	0.73 (0.23-2.31)
Years in practice >15	2.03 (0.46-9.07)	1.25 (0.48-3.21)	0.50 (0.20-1.24)	1.17 (0.38-3.61)
Nephrologist or fellow/trainee	1.63 (0.39-6.87)	1.62 (0.70-3.78)	2.80 (1.12-6.96)	0.46 (0.12-1.75)
Ontario as province of practice	1.36 (0.46-3.98)	1.03 (0.50-2.10)	1.12 (0.54-2.32)	0.86 (0.36-2.07)

Note. ESA = erythropoietin-stimulating agent; CKD = chronic kidney disease.

Discussion

This national survey is the first to assess the ESA prescribing practices of nephrology care practitioners in patients with CKD and history of stroke, active malignancy, or previous malignancy. We identified that while most respondents have an institutional protocol for ESA use and anemia management for general patients with CKD at their center, less than 10% had an institutional protocol for patients with CKD and history of stroke, active malignancy, or previous malignancy.

A hemoglobin of 95 to 115 g/L was the most common institutional and preferred individual target for the general CKD population. There was a general trend toward using lower hemoglobin targets in patients with CKD and stroke or malignancy compared with the general CKD population. These practices align with the CSN commentary on the KDIGO clinical practice guideline for anemia in CKD and the anemia management protocol developed by the Canadian Kidney Knowledge Translation and Generation Network (CANN-NET).¹¹ The recommendation for lower hemoglobin targets in patients with CKD and stroke or malignancy was primarily based on the findings of higher mortality rates in patients assigned to darbepoetin alfa versus placebo in the TREAT trial.⁷ The CSN recommended targeting a hemoglobin range of 90 to 105 g/L in those with a history of stroke using findings from the post hoc analysis of TREAT and other randomized trials demonstrating higher stroke risk in those with previous history of stroke or TIA as well as individuals in higher target ESA trial arms.^11,15 The subsequent Proactive Intravenous Iron Therapy in Hemodialysis Patients (PIVOTAL) trial showed a similar signal where those randomized to the high-dose iron received lower ESA doses over the trial period compared with the low-dose group, and those randomized to this group experienced a lower risk of the composite outcome (nonfatal myocardial infarction, stroke, hospitalization, or death).¹⁶ We surmise that most Canadian practitioners are following the suggestions from the CSN and have adopted lower hemoglobin targets in these subpopulations.

Lower hemoglobin targets were most likely to be used in patients with CKD and active malignancy where practitioners had the specific goal of limiting need for red blood cell transfusion rather than targeting the usual goal of a hemoglobin of 95 to 115 g/L. It has been theorized that tumor cell erythropoietin receptor activation may directly lead to pathological cancer angiogenesis and tumor proliferation.¹⁷ The Cochrane Review in 2012 assessed the effects of ESAs in the treatment of anemia in malignancy patients (receiving or not receiving therapy). They found that although there was a slight signal toward ESAs being associated with increased risk of tumor progression, there was insufficient evidence to support an effect of ESAs on tumor progression.¹⁸ This may explain practice variability with hemoglobin targets; some may place greater weight on this risk and use either lower targets or hold the ESA altogether depending on patient values or preferences.

The decision for blood transfusion is often dependent on clinical context, patient-related factors, and a balance of competing risks versus benefits. Despite no established hemoglobin threshold for patients with cancer, the American Society of Clinical Oncology and American Society of Hematology (ASCO/ASH) recommends that ESAs be increased to target the lowest hemoglobin concentration to reduce the need for blood transfusion.¹⁹ Most transfusion guidelines across multiple societies advise a hemoglobin threshold of 70 g/L in asymptomatic patients.²⁰ We surmise that our survey participants more commonly target a hemoglobin threshold less than 95 to 115 g/L but greater than at least 70 g/L to balance excessive ESA dosing with avoidance of blood transfusion.

Most survey respondents used darbepoetin alfa in their institutions and were comfortable to a maximum dose of 150 µg/wk in both general patients with CKD and those with previous malignancy, but only 100 µg/wk in those with active cancer or history of stroke. This dosing variability may again relate to extrapolations from prior clinical trials. For those with prior stroke, practitioners may be concerned about direct endothelial effects associated with ESAs which may be more pronounced at higher doses. A post hoc analysis of the Correction of Anemia with Epoetin Alfa in Chronic Kidney Disease trial (CHOIR) suggested that adverse events are related to ESA dose and not hemoglobin levels.²¹ In the case for active malignancy, certain cancer types, such as head and neck or genitourinary, may be more likely to propagate when exposed to an ESA, and therefore, this may cause prescribers to limit total doses that are used.^22,23

Despite most survey participants having experience prescribing ESAs in patients with CKD and stroke or malignancy, their comfort levels when using ESAs in these populations were lower than for general patients with CKD. Comfort levels were lowest for using ESAs in patients with CKD and active malignancy. With the lack of clear guidelines, decisions regarding ESA initiation or dose adjustment are often solely placed on the prescriber or practice group. Prescribers are tasked with balancing the risks and harms of therapy on their own, obtaining informed consent, and factoring patient preference into their clinical decisions. Prescribers also may have had less exposure to managing anemia in patients with CKD and stroke or malignancy during their training as these patients are generally more complex than general patients with CKD, leading to fewer opportunities for experiential learning.

We did not find that most baseline characteristics were associated with higher/lower comfort in most populations. This may be explained by consistency around institutional practice. While most survey respondents do not have an anemia management or ESA protocol in their institution for patients with CKD and stroke or malignancy, it is common for practice styles to be similar within practice groups and in particular shared care settings. Therefore, varying demographic characteristics such as age or years in practice would not change ESA prescribing behaviors. The one exception was among those with active malignancy, where nephrologists/nephrology trainees were more likely to have higher prescribing comfort compared with nonphysicians. As institutional ESA protocols for patients with CKD and malignancy are rare, decisions regarding anemia management for this group may preferentially be deferred to the physicians in the multidisciplinary team. Nephrology fellows directly train under nephrologists which may also help improve their self-reported confidence when using ESAs in this population.

Our study has several strengths. Survey design was done using a 4-stage modified Delphi process, incorporating a local pilot of the survey, where a multidisciplinary expert panel provided input regarding question formulation and selection. This process allowed the panel to systemically reach a consensus during survey design and the use of content experts helped to improve face validity of our survey. Our survey was able to capture respondents from all provinces in Canada across numerous centers and included nonphysician ESA prescribers such as nurse practitioners and pharmacists, thus improving generalizability.

This study does have some limitations. While we did have 127 respondents, our response rate was only 24% which raises the possibility of nonresponse bias for our study. Previous surveys disseminated through the CSN had a response rate closer to 30%; however, response rates from affiliated nephrologists were comparable.²⁴ Our survey was disseminated through the CSN to its current active members which may have introduced sampling bias. The third stage of our survey design consisted of the circulation of a revised version of the survey to a convenience sample within the Nova Scotia Health Central Zone Renal Program which may have been another potential source for sampling bias. We also did not include any questions related to hypoxia-inducible factor prolyl hydroxylase inhibitors as these agents are not approved for use within Canada. Patient perspectives, shared decision-making, or other relevant patient factors were also not explored within our survey domains. Finally, our survey assessed self-reported prescribing behaviors which may be different than the actual prescribing behaviors employed by our participants.

Conclusion

Our study highlighted that ESAs are routinely used in patients with CKD and history of stroke or malignancy, as well as the target hemoglobin concentrations and maximum ESA doses used in these subpopulations. The lack of institutional protocols likely contributed to the wide range of practice patterns seen in our survey. We found that health care providers have lower comfort ratings when using ESAs in patients with CKD and stroke or malignancy compared with general patients with CKD. Nephrologists and nephrology trainees/fellows had greater self-reported confidence ratings in using ESAs for patients with CKD and active malignancy compared with nurse practitioners and pharmacists.

Due to the lack of clear guidelines in the use of ESAs in these specific populations, our survey identified potential knowledge gaps in the anemia management practices of Canadian nephrology practitioners. The hemoglobin targets identified by this study may be used for future prospective studies to evaluate benefits of ESAs in treating CKD-associated anemia versus the risk of stroke or malignancy in these important subgroups. Future studies should also consider patient perspectives to better understand patient-reported outcomes and risk tolerances as ESA treatment decisions in patients with CKD and stroke or malignancy are often a balance between benefit and harm.

Supplemental Material

sj-docx-1-cjk-10.1177_20543581261437775 – Supplemental material for A Canadian Survey of Prescribing Practices of Erythropoiesis-Stimulating Agents in Dialysis-Dependent and Non-Dialysis-Dependent Chronic Kidney Disease

Supplemental material, sj-docx-1-cjk-10.1177_20543581261437775 for A Canadian Survey of Prescribing Practices of Erythropoiesis-Stimulating Agents in Dialysis-Dependent and Non-Dialysis-Dependent Chronic Kidney Disease by Rammdeep Saini, Keigan More, Jo-Anne S. Wilson, David A. Clark, Amanda J. Vinson, David Collister, Mark Canney and Karthik K. Tennankore in Canadian Journal of Kidney Health and Disease

Footnotes

Acknowledgements

The authors thank all clinicians and allied health staff who assisted with this study.

ORCID iDs

Rammdeep Saini

Keigan More

Jo-Anne S. Wilson

David A. Clark

Amanda J. Vinson

Mark Canney

Karthik K. Tennankore

Ethical Considerations

This study was approved by the Nova Scotia Health Research Ethics Board (#1029593).

Consent to Participate

Informed consent was implied through a statement provided at the beginning of the survey.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Supplemental Material

Supplemental material for this article is available online.

References

Lamerato

James

van Haalen

, et al. Epidemiology and outcomes in patients with anemia of CKD not on dialysis from a large US healthcare system database: a retrospective observational study. BMC Nephrol. 2022;23:166. doi:10.1186/s12882-022-02778-8.

Aapro

Gascón

Patel

, et al. Erythropoiesis-stimulating agents in the management of anemia in chronic kidney disease or cancer: a historical perspective. Front Pharmacol. 2019;9:1498. doi:10.3389/fphar.2018.01498.

Kidney Disease: Improving Global Outcomes (KDIGO) Anemia Work Group. KDIGO clinical practice guideline for anemia in chronic kidney disease. Kidney Inter. 2012; Suppl 2:279-335. doi:10.1038/kisup.2012.40.

Amgen Canada. Aranesp® (darbepoetin alfa injection) product monograph. Amgen Canada Inc. Updated October 27, 2023. https://www.amgen.ca/about/-/media/Themes/CorporateAffairs/Redesign/Amgen-ca/Amgen-ca/pdf/products/en/aranesp_pm.pdf. Accessed April 4, 2025.

Janssen Inc. Eprex® (epoetin alfa) product monograph. Janssen Inc. Updated October 3, 2017. https://pdf.hres.ca/dpd_pm/00041771.PDF. Accessed April 4, 2025.

Singh

Szczech

Tang

, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006;355(20):2085-2098.

Pfeffer

Burdmann

Chen

, et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med. 2009;361(21):2019-2032. doi:10.1056/nejmoa0907845.

Parfrey

Foley

Wittreich

Sullivan

Zagari

Frei

Double-blind comparison of full and partial anemia correction in incident hemodialysis patients without symptomatic heart disease. J Am Soc Nephrol. 2005;16(7):2180-2189. doi:10.1681/ASN.2004121039.

Palmer

Navaneethan

Craig

, et al. Meta-analysis: erythropoiesis-stimulating agents in patients with chronic kidney disease. Ann Intern Med. 2010;153(1):23-33.

10.

Koulouridis

Alfayez

Trikalinos

Balk

Jaber

BL.

Dose of erythropoiesis-stimulating agents and adverse outcomes in CKD: a metaregression analysis. Am J Kidney Dis. 2013;61(1):44-56. doi:10.1053/j.ajkd.2012.07.014.

11.

Moist

Troyanov

White

, et al. Canadian Society of Nephrology commentary on the 2012 KDIGO clinical practice guideline for anemia in CKD. Am J Kidney Dis. 2013;62(5):860-873. doi:10.1053/j.ajkd.2013.08.001.

12.

Nasa

Jain

Juneja

Delphi methodology in healthcare research: how to decide its appropriateness. World J Methodol. 2021;11(4):116-129. doi:10.5662/wjm.v11.i4.116.

13.

Roger

Cooper

What is the practical conversion dose when changing from epoetin alfa to darbepoetin outside of clinical trials. Nephrology. 2004;9(4):223-228. doi:10.1111/j.1440-1797.2004.00261.x.

14.

Prasad

Jafari

Toppings

Gross

Kappel

Economic benefits of switching from intravenous to subcutaneous epoetin alfa for the management of anemia in hemodialysis patients. Can J Kidney Health Dis. 2020;7:2054358120927532. doi:10.1177/2054358120927532.

15.

Skali

Parving

Parfrey

, et al. Stroke in patients with type 2 diabetes mellitus, chronic kidney disease, and anemia treated with darbepoetin alfa: the trial to reduce cardiovascular events with Aranesp therapy (TREAT) experience. Circulation. 2011;124:2903-2908. doi:10.1161/CIRCULATIONAHA.

16.

Macdougall

White

Anker

, et al. Intravenous iron in patients undergoing maintenance hemodialysis. N Engl J Med. 2019;380(5):447-458. doi:10.1056/nejmoa1810742.

17.

Hazzan

Shah

Hong

Sakhiya

Wanchoo

Fishbane

Treatment with erythropoiesis-stimulating agents in chronic kidney disease patients with cancer. Kidney Int. 2014;86(1):34-39. doi:10.1038/ki.2013.528.

18.

Tonia

Mettler

Robert

, et al. Erythropoietin or darbepoetin for patients with cancer. Cochrane Database Syst Rev. 2012;12:1-505. doi:10.1002/14651858.CD003407.pub5.

19.

Bohlius

Bohlke

Castelli

, et al. Management of cancer-associated anemia with erythropoiesis-stimulating agents: ASCO/ASH clinical practice guideline update. Blood Adv. 2019;3(8):1197-1210. doi:10.1182/bloodadvances.2018030387.

20.

Carson

Stanworth

Guyatt

, et al. Red blood cell transfusion: 2023 AABB international guidelines. JAMA. 2023;330(19):1892-1902. doi:10.1001/jama.2023.12914.

21.

Szczech

Barnhart

Inrig

, et al. Secondary analysis of the CHOIR trial epoetin-α dose and achieved hemoglobin outcomes. Kidney Int. 2008;74(6):791-798. doi:10.1038/ki.2008.295.

22.

Aapro

Jelkmann

Constantinescu

Leyland-Jones

Effects of erythropoietin receptors and erythropoiesis-stimulating agents on disease progression in cancer. Br J Cancer. 2012;106(7):1249-1258. doi:10.1038/bjc.2012.42.

23.

Huang

Lin

, et al. Erythropoiesis-stimulating agents and incident malignancy in chronic kidney and end-stage renal disease: a population-based study. Clin Transl Sci. 2022;15(9):2195-2205. doi:10.1111/cts.13353.

24.

Collister

Healey

Conen

, et al. Canadian nephrologist views regarding stroke and systemic embolism prevention in dialysis patients with nonvalvular atrial fibrillation: a survey. Can J Kidney Health Dis. 2019;6:2054358118821945. doi:10.1177/2054358118821945.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

2.13 MB