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The KHA-CARI Guidelines Caring for Australasians with Renal Impairment Biochemical and Haematological Targets (October 2011) Page 1 Biochemical and Haematological Targets: Haemoglobin Levels in Patients Using Erthyropoiesis Stimulating Agents Date written: May 2011 Final submission: October 2011 Author: Lawrence McMahon, Rob MacGinley GUIDELINES a. We recommend against haemoglobin (Hb) targets above 130 g/L due to the strong association with increased morbidity and mortality in chronic kidney disease (CKD) (1A)*. b. For many anaemic patients with CKD we suggest a Hb target of between 100 and 115 g/L, balancing risks and benefits for each patient treated, in order to alleviate symptoms and reduce the risk of blood transfusion (2A)*. c. We suggest that in dialysis patients with anaemia due to CKD, an erythropoiesis stimulating agent (ESA) can be used to prevent the Hb falling below 95 g/L in order to avoid the need for blood transfusion (2B)* and to improve quality of life (2D)*. d. We suggest that ESAs are indicated for the partial correction of the anaemia of CKD in patients who are symptomatic or who may otherwise require blood transfusion (2A)*. UNGRADED SUGGESTIONS FOR CLINICAL CARE Treatment with Erythropoiesis Stimulating Agents (ESAs) Prior to the commencement of administration of ESAs, appropriate iron indices should be ensured. In addition, efforts should be made to control hyperparathyroidism, aluminium accumulation and/or significant systemic inflammation. Blood pressure levels should be controlled according to standard guidelines. For any individual patient who may require ESA therapy, the potential benefits must be balanced with the clinical risks. General Points Readers should refer to the PI (Product Information) brochures for the various ESAs currently available in Australia and/or New Zealand for information concerning mode and frequency of administration, and for side effects. All agents (apart from the newly listed epoetin lamba) currently have approval for both intravenous and subcutaneous administration. Increments in dosage should be considered if there is an inadequate increase in haemoglobin concentration (10 g/L) after a 4-week period. The haemoglobin concentration is usually checked at least monthly initially, and/or 1 month after a change in ESA dosage. Dosages in excess of 200 U/kg per week (or equivalent) in the setting of significant systemic inflammation are unlikely to elevate haemoglobin concentrations further. In the absence of inflammation,

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Page 1: Biochemical and Haematological Targets: … biochemical...Biochemical and Haematological Targets (October 2011) Page 2 assessment of Vitamin B12 and folate stores and/or exclusion

The KHA-CARI Guidelines – Caring for Australasians with Renal Impairment

Biochemical and Haematological Targets (October 2011) Page 1

Biochemical and Haematological Targets: Haemoglobin Levels in Patients Using Erthyropoiesis Stimulating Agents Date written: May 2011 Final submission: October 2011 Author: Lawrence McMahon, Rob MacGinley

GUIDELINES a. We recommend against haemoglobin (Hb) targets above 130 g/L due to the strong

association with increased morbidity and mortality in chronic kidney disease (CKD) (1A)*.

b. For many anaemic patients with CKD we suggest a Hb target of between 100 and 115 g/L, balancing risks and benefits for each patient treated, in order to alleviate symptoms and reduce the risk of blood transfusion (2A)*.

c. We suggest that in dialysis patients with anaemia due to CKD, an erythropoiesis stimulating agent (ESA) can be used to prevent the Hb falling below 95 g/L in order to avoid the need for blood transfusion (2B)* and to improve quality of life (2D)*.

d. We suggest that ESAs are indicated for the partial correction of the anaemia of CKD in patients who are symptomatic or who may otherwise require blood transfusion (2A)*.

UNGRADED SUGGESTIONS FOR CLINICAL CARE Treatment with Erythropoiesis Stimulating Agents (ESAs)

Prior to the commencement of administration of ESAs, appropriate iron indices should be ensured. In addition, efforts should be made to control hyperparathyroidism, aluminium accumulation and/or significant systemic inflammation. Blood pressure levels should be controlled according to standard guidelines. For any individual patient who may require ESA therapy, the potential benefits must be balanced with the clinical risks.

General Points Readers should refer to the PI (Product Information) brochures for the various ESAs currently

available in Australia and/or New Zealand for information concerning mode and frequency of administration, and for side effects. All agents (apart from the newly listed epoetin lamba) currently have approval for both intravenous and subcutaneous administration.

Increments in dosage should be considered if there is an inadequate increase in haemoglobin concentration (10 g/L) after a 4-week period. The haemoglobin concentration is usually checked at least monthly initially, and/or 1 month after a change in ESA dosage. Dosages in excess of 200 U/kg per week (or equivalent) in the setting of significant systemic inflammation are unlikely to elevate haemoglobin concentrations further. In the absence of inflammation,

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assessment of Vitamin B12 and folate stores and/or exclusion of occult bleeding may be required.

On average, after initiation of treatment, the rise in haemoglobin concentrations should not exceed 10 g/L per 2 week period). The haemoglobin concentration should be checked at least every month initially and iron stores at least every 3 months.

There are no studies that have ascertained whether CKD patients (including dialysis), who are ESA-naive, and who have a normal or high haemoglobin concentration have an increased risk of morbidity or mortality. Accordingly, these guidelines are specific for ESA-dependent patients with CKD.

IMPLEMENTATION AND AUDIT 1. The percentage of patients on ESAs reaching the target haemoglobin concentration should be

calculated against the total population treated with ESA‟s.

2. The number of patients not requiring ESA should be monitored, and patients followed for access thrombosis and mortality.

3. The percentage of patients requiring more than 20,000 units of epoetin alfa or epoetin beta or 100 µg of darbepoetin per week should be assessed and quantified against inflammatory markers.

4. The percentage of patients exceeding physiological haemoglobin concentrations on ESAs (both pre- and post-dialysis in haemodialysis patients) should be calculated.

5. The percentage of patients requiring cessation or reduction in epoetin dosage because of uncontrolled hypertension or an excessively rapid rise in haemoglobin levels (>10 g per 2 weeks) should be assessed.

BACKGROUND Anaemia is an almost universal accompaniment of CKD. Several of the co-morbidities associated with kidney failure have been primarily attributed to anaemia, including the development of left ventricular dysfunction, cardiac failure, reduced exercise capacity and reduced quality of life. Prior to the synthesis of epoetin, transfusion dependence was characterised by blood-borne infection, iron overload and sensitisation to HLA antigens, which limited transplantation opportunities.

With the availability of epoetin analogues (epoetin alfa, epoetin beta, darbepoetin alfa and others), collectively known as erythropoiesis-stimulating agents (ESAs), clinicians, patients and funders of health care require information about their effectiveness as well as the clinical consequences and economic impact of an increase in haemoglobin. These guidelines were developed to present and integrate the available evidence.

Target haemoglobin

Observational studies have uniformly demonstrated that people with innate higher haemoglobin concentrations enjoy better outcomes, including fewer hospitalizations and longer survival. Randomized controlled trials of patients receiving an ESA, on the other hand, show that the risk of stroke, hypertension and vascular thrombosis are greater when the target Hb is ≥ 130g/L. A meta analysis of all RCTs shows a strong trend in all-cause and cardiovascular mortality [1]. This effect could be related to the rate of increase in haemoglobin concentration, as well as to an overshoot of the target. Another possibility is that adverse cardiovascular events are not related to haemoglobin concentrations at all but are instead due to pleomorphic effects of ESAs through trophic effects on vascular endothelial or smooth muscle cells, particularly if precipitated by exposure to a higher

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ESA dose (e.g. iron deficiency). An association between high-dose ESA use and both accelerated tumour progression and shortened survival has been observed in patients with active malignancy.

Hence, as will be evident from analysis of the evidence below, it is now necessary for protagonists of higher haemoglobin targets to justify their claim in specific individuals. There are, for instance, no data to suggest that the minority of CKD patients who maintain their haemoglobin concentrations above the proposed target without the need for ESA should have their levels reduced by venesection; similarly, the appropriate haemoglobin target for patients with chronic airflow obstruction, for patients on peritoneal dialysis, the elderly, the very young, and those with sickle cell disease, thalassaemia or concurrent cyanotic cardiac disease may require specific targets yet to be determined.

Other issues remain and/or require further clarification. For haemodialysis patients, for instance, haemoglobin concentration is conventionally measured before dialysis. There are fears that excessive ultrafiltration may produce dangerously high haematocrit levels with associated intravascular red cell sludging or thrombosis if the baseline haematocrit is kept at more than 39% [2-4]. Changes in haematocrit from the start to end of dialysis can vary by as much as 3-6% [5, 6] depending on the volume of ultrafiltration and the timing of the post-dialysis sample. It would seem prudent to also measure the post-dialysis haemoglobin concentration in patients when the pre-dialysis level is above 130 g/L to ensure that haemoconcentration during dialysis does not exceed physiological limits.

Quality of Life

Investigation of ESAs and quality of life is complicated by the classification of patients, research design, the choice of instruments used to measure quality of life, and the definition of clinically meaningful improvement in quality-of life domains.

There has been a need to identify clinical benefits related to raising the haemoglobin concentration considering the recent suggestion of the negative effect of ESAs. Four trials have evaluated multiple patient-reported outcomes and quality of life indices. Although some individual measures showed improvement, the overall quality of life effects have been small and inconsistent.

The Normal Hematocrit Study showed a significant improvement on the physical-functioning scale of the Medical Outcomes Study 36-Item Short-Form General Health Survey (SF-36) but no significant effects on any of its other seven scales. The CHOIR Trial [7] did not show a significant improvement in any scale of the SF-36 Instrument in the High-Haemoglobin Group compared with the Low-Haemoglobin Group. The CREATE study [8] seems to be an outlier because quality of life deteriorated in the lower Hb arm and improved in patients assigned to the higher Hb. The TREAT study [9] showed a significant effect on the Functional Assessment of Cancer Therapy–Fatigue Instrument but not on quality of life assessments based on the SF-36.

Two systematic reviews suggest that there is little improvement in quality of life beyond a haemoglobin of 100 - 120 g/L [10, 11]. The improvement in some domains at a higher Hb target is of moderate clinical significance, when observed. For example, the TREAT Study showed a clinically meaningful improvement in fatigue scores occurred in 55% of patients assigned to darbepoetin alfa therapy compared with 50% in the placebo group [9].

SEARCH STRATEGY Databases searched: MeSH terms and text words for haemoglobin, hematocrit, and anaemia were combined with MeSH terms and text words for chronic kidney disease and renal replacement therapy. The searches were carried out in Medline (1966 to 1 February 2011) and in the Cochrane Controlled Trial Register.

Date of search/es: Medline and Cochrane Trial Register – February 2011.

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WHAT IS THE EVIDENCE?

Meta-analysis and Systematic Reviews Haemoglobin Targets Evidence regarding the benefits and risks of low (haemoglobin <100 g/L) versus high (haemoglobin 140 g/L) haemoglobin targets has been reviewed in a Cochrane systematic review of randomised controlled trials up until August 2006 [12]. Twenty two trials (3707 patients) were included. Hb >133 g/L was not associated with a reduction in the risk of all-cause mortality compared with 120 g/L in dialysis and pre-dialysis patients. In pre-dialysis patients, there was a significantly lower end of treatment creatinine clearance with Hb <120 g/L compared to >130 g/L (RR -4.17; 95% CI -6.33 - -2.02) but no significant difference in the risk of end-stage kidney disease (RR 1.05; 95% CI 0.50 - 2.22). Lower Hb targets resulted in an increased risk for seizures (RR 5.25; 95% CI 1.13 - 24.34) and a reduced risk of hypertensive episodes (RR 0.50; 95% CI 0.33 - 0.76). There were no significant differences in the risk of vascular access thrombosis.

Palmer et al in 2010 [1] conducted a meta-analysis of 27 trials. Risk of fatal and nonfatal stroke, vascular access thrombosis, and worsening hypertension was increased with a higher haemoglobin target. There was no statistically significant difference in the risk for all-cause mortality, serious cardiovascular events, or fatal and nonfatal myocardial infarction between those targeted with a higher versus a lower haemoglobin target. In the 10 studies conducted in people with CKD who were not dialysis-dependent, the risk for end-stage kidney disease requiring renal replacement therapy was not statistically different when haemoglobin target groups were compared. There was also no statistically significant difference in left ventricular mass at the end of treatment (4 trials; 1544 patients; mean difference, 0.14 g/m2) between treatment groups. Targeting a higher haemoglobin level was linked to a reduction in the need for red blood cell transfusions but more intravenous iron therapy. An increased mortality associated with higher haemoglobin targets using ESA treatment has also been demonstrated in patients with anaemia and cancer. Evidence for quality of life was suboptimal because of selective reporting, suggesting potential overestimation of the benefits of anaemia correction. Data from large and well-conducted trials did not support clinical efficacy for ESA therapy on quality of life.

In 2007, a meta-analysis of nine RCTs , enrolling a total of 5143 patients, was conducted by Phrommintikul et al [13]. There was a significantly higher risk of all-cause mortality (RR 1·17; 95% CI 1·01 - 1·35; p=0·031) and arteriovenous access thrombosis (RR 1·34, 95% CI 1·16 - 1·54; p=0·0001) in the higher haemoglobin target group than the lower in the fixed effects model. There was also a significantly higher risk of poorly controlled blood pressure (RR 1·27; 95% CI 1·08 - 1·50; p=0·004), although this was not significant in the random effects model (RR 1·31; 95% CI 0·97 - 1·78; p=0·075). The incidence of myocardial infarction similar in the two groups.

Quality of Life

Gandra et al [10] examined the impact of ESAs on energy and physical function in pre-dialysis patients. The study highlighted the methodological problems inherent in evaluating the impact of ESAs. There was considerable between-study heterogeneity in a variety of measures, including patient characteristics, starting Hb concentrations (Range 8.0 - 11.9 g/dL), target Hb concentrations, duration of follow up (8 - 96 weeks), choice of QoL instrument, and research design. One limitation of the review was that because there were few randomized placebo-controlled trials available, it relied heavily on open-label and single-arm studies, which are inherently more susceptible to bias. As such few conclusions can be drawn from this review.

Johansen et al (2010) [11] conducted a more extensive systematic review of trials reporting physical function and a meta-analysis of exercise tolerance in dialysis patients treated with ESAs.

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Twenty-eight studies of dialysis patients evaluated exercise tolerance were included of which 3 were RCTs.

The systematic review published by Clements et al in 2009 [14], reviewed SF-36 data across 9 trials to ascertain impacts on quality of life. Reporting of QoL data was generally incomplete. Data from each domain of the SF-36 were summarized. Statistically significant changes were noted in the physical function (weighted mean difference [WMD] 2.9; 95% CI 1.3 to 4.5), general health (WMD 2.7; 95% CI 1.3 to 4.2), social function (WMD 1.3; 95% CI −0.8 to 3.4), and mental health (WMD 0.4; 95% CI 0.1 to 0.8) domains favouring higher haemoglobin. None of the changes were considered clinically significant. The authors conclude that the study suggests that targeting a haemoglobin level in excess of 12.0 g/dL leads to small and not clinically meaningful improvements in HQOL.

The systematic review by Palmer et al (2010) [1] concluded the evidence for treatment effects on quality of life to be of low quality with a high risk of bias due to selective reporting of outcomes. For example only 2 of the 9 trials that used the SF-36 instrument, reported data for all 8 outcome domains. They noted that “the most recent, large, and well-designed trial” of Pfeffer et al (2009) [9], reported “no differences in mean change in scores between groups for energy or physical function Quality of life domains.”

Individual Trials Two groups of trials are available in the literature. In one, patients are randomised to two different doses of the same ESA to achieve and maintain two different haemoglobin targets. In the other, patients are randomised to an ESA versus a placebo or no treatment.

The Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) [9] is the largest placebo controlled study and was published after the Cochrane Review [12], however it was included in the Palmer et al (2010) systematic review [1]. Patients with diabetes mellitus and chronic kidney disease were randomised to either treatment of anaemia with darbepoetin up to a haemoglobin level of 13.0 g/dL versus placebo (with rescue treatment). The trial documented adverse consequences of using an ESA to raise haemoglobin concentrations. The trial enrolled 4038 patients; 2012 received darbepoetin alfa, and 2026 received placebo. The median haemoglobin concentrations achieved were 12.5 g/dL in the darbepoetin alfa group and 10.6 g/dL in the placebo group. There was no evidence of benefit and a trend toward overall harm with darbepoetin alfa following a median follow-up of 29 months. Death or a nonfatal cardiovascular event occurred in 31.4% of patients receiving darbepoetin alfa and 29.7% of patients receiving placebo. Although the finding was not significant (HR for darbepoetin alfa versus placebo: 1.05; 95% CI 0.94 to 1.17), there was a significant and substantial increase in the incidence of fatal or nonfatal stroke in the darbepoetin alfa group compared with the placebo group (5.0% versus 2.6%; HR 1.92; 95% CI 1.38 to 2.68; p < 0.001). There was also a significantly higher rate of thromboembolic events in the darbepoetin alfa group.

To identify clinical benefits related to raising the haemoglobin concentration, quality of life indices were examined. Although some individual measures showed improvement, the overall quality of life effects were small and inconsistent.

This data has now been recently reanalysed by Solomon et al (2010) [15] to look particularly at each patient‟s individual hematopoietic response. They were able, for the first 12 weeks of therapy, to define two subsets of patients, those with a poor response to ESA (thus needing a larger dose) and those with a good response. Patients who had a poor initial response to darbepoetin alfa had a lower average haemoglobin level at 12 weeks and during follow-up than did patients with a better haemoglobin response (a change in haemoglobin level ranging from 2 to 15% or more) (P<0.001 for both comparisons), despite receiving higher doses of darbepoetin alfa (median dose, 232 μg vs. 167 μg; P<0.001). Patients with a poor response, as compared with those with a better response, had higher rates of the composite cardiovascular end point (adjusted hazard ratio, 1.31; 95% confidence interval [CI], 1.09 to 1.59) or death (adjusted hazard ratio, 1.41;

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95% CI, 1.12 to 1.78). This lends evidence that ESA dosing alone may be a cause of the excess mortality.

The largest single trial for ESA versus ESA was published by Besarab et al in 1998 [16]. In this

trial, patients were randomised to a high („normal‟) haemoglobin target (140 16 g/L) versus a

lower haemoglobin target of 100 3 g/L. Patients with significant cardiovascular disease were specifically selected because it was assumed that these would benefit from the raised haemoglobin target. However, the trial showed reduced survival in the group with the higher haemoglobin target (RR 0.82, 95%CI 0.68, 0.99).

Another trial, which included both ESA versus ESA and ESA versus no treatment groups was published in 2003 by Furuland et al [17]. The authors concluded that there was an improvement in the quality of life of patients treated with „normal‟ haemoglobin targets but no difference was found between the lower and higher targets in terms of overall mortality, incidence of thrombovascular events and incidence of vascular access thrombosis. This trial included both pre- and post-dialysis patients. However, the authors of the Cochrane systematic review [12] found the quality of both these studies to be suboptimal because of unclear allocation concealment and no blinding of study participants.

The Australian and New Zealand pre-dialysis study was published in 2004 [18]. This study enrolled 155 patients with CKD, with a creatinine clearance of 15 to 50 mL/min and an entry haemoglobin of 110 to 120 g/L (female) or 110 to 130 g/L (male); 28% of patients were diabetic. Target haemoglobin levels were 90 to 100 g/L (low) and 120 to 130 g/L. Achieved haemoglobin concentrations were 108 ± 13 g/L and 121 ± 14 g/L for low and high target groups respectively. The primary endpoint was change in left ventricular mass index. There was no difference between the target groups for the primary endpoint on an intention to treat analysis, although for those patients who did achieve protocol target (n = 15 and 37, respectively), a significant difference in the left ventricular mass index was found favouring the higher target group. There was no apparent benefit in quality of life in the higher target group. No patients died.

Parfrey et al published the results of a study of 596 relatively new-onset (mean duration 10 months) haemodialysis patients in 2005 [19]. The study was double-blinded and examined left ventricular volume index (echocardiogram) and quality of life over 2 years. The mean age of patients was 50.8 years and 18% were diabetic. Targeted haemoglobins were 9.5 to 11.5 g/dL (low group) and 13.5 to 14.5 g/dL (high group). Target concentrations were achieved by week 24. No advantage was found in being randomized to the higher target, however, vitality was improved. Greater rates of pain, surgery and dizziness were seen in the lower target group and headache and cerebrovascular events were more frequent in the higher group. Vascular access loss was not significantly different between the two groups.

Two CKD studies, recognised by the acronyms CHOIR and CREATE, were published in 2006 [7, 8].

CHOIR enrolled 1432 patients with a mean age of 66 ± 13 years, of whom 55% had significant cardiovascular disease [7]. The intended target was to receive epoetin alfa treatment sufficient to achieve and maintain a haemoglobin of 13.5 or 11.3 g/dL. In CHOIR, an increased rate of death and heart failure were observed in patients targeted to a higher Hb (13.5 g/dL). The mean eGFR was 27 ± 9 mL/min/1.73m2 and almost 50% of patients were diabetic. Patients were followed for 30 months. Anaemia was treated with epoetin alfa and mean doses were approximately 5000 Units (low haemoglobin target, 11.3 g/dL) and 12,000 Units (high haemoglobin target, 13.5 g/dL) per week.

CREATE enrolled 603 patients with a mean age of 59 ± 14 years [8]. The Early Treatment Group received epoetin-beta therapy immediately for a target Hb 13 to 15 g/dL. The Late Anaemia Correction Group did not receive treatment until the Hb was < 10.5 g/dL, with a target of 10.5 to 11.5 g/dL. There was no benefit or overall increased risk for mortality or cardiovascular complications in the active treatment group. Significant cardiovascular disease at baseline was 36% and 26% of patients had diabetes. The eGFR was between 15 and 35 mL/min/1.73m2. Patients were followed for 36 months and anaemia was largely prevented with target

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haemoglobins of 11 and 14 g/dL. Epoetin beta was used with weekly doses of 2000 and 5000 Units per week (low versus high target).

The Canadian Erythropoietin Study Group evaluated the treatment of severe anaemia and found a significant increase in 6-minute walking in the combined epoetin alfa groups compared with placebo, but no significant difference between the High- and Low-Hb Target groups [20].

The double-blind Canadian- European RCT in 596 „healthy‟ patients also found no difference between the High- and Low-Hb Target groups [19]. Similar results were observed for KDQ physical function scores in these 2 studies. However, statistically significant improvements of moderate clinical significance were observed in the High-Hb Target groups for the SF-36 Vitality subscore and KDQOL Fatigue scores compared with the Low-Hb Group.

Cohort and Case Control Studies

There is additional data in pre-dialysis CKD patients but it is less comprehensive. Various studies [21-23] have demonstrated that most patients have developed left ventricular hypertrophy by the time end stage kidney disease is reached. In dialysis patients, all-cause and cardiac mortality was lowest at a haematocrit between 33% and 36% both before and after adjusting for severity of disease, in a retrospective database analysis of over 75,000 patients [24] although higher haematocrits were not assessed. Similar findings have been reported in other epidemiological studies [25-27].

SUMMARY OF EVIDENCE Substantial evidence now indicates that targeting (without necessarily achieving) haemoglobin concentrations above 130 g/L with ESAs in patients with CKD results in an increased mortality and morbidity with little benefit (compared to targeting concentrations below 120 g/L) and at a higher cost. There is no definitive basis for establishing an upper value of a target range for Hb and as such the recommended range represents interpretation of the results available from RCTs. As noted in the meta-analysis of Palmer et al the lower and higher Hb intervention targets have increased with time such that in the more recent RCTs, the lower targets are of the same order as the higher targets in the earlier trials. An upper value of 115 g/L represents a value roughly equal to the highest values achieved in the low Hb target treatment arms (i.e. control) [1].

Older patients and those with more advanced cardiovascular disease and/or diabetes are at highest risk, which appears to pertain to both dialysis and pre-dialysis patients. In addition, there appears to be an increased risk of hypertension and arteriovenous access thrombosis in patients targeted for higher haemoglobin concentrations without substantial evidence of benefit in quality of life or normalisation of exercise capacity. The ESA dosage and associated cost of achieving and maintaining higher haemoglobin concentrations is significantly greater.

WHAT DO THE OTHER GUIDELINES SAY?

Kidney Disease Outcomes Quality Initiative: The Hb target is the intended aim of ESA therapy for the individual patient with CKD. In clinical practice, achieved Hb results vary considerably from the Hb target.

In the opinion of the Work Group, selection of the Hb target and selection of the Hb level at which ESA therapy is initiated in the individual patient should include consideration of potential benefits (including improvement in quality of life and avoidance of transfusion) and potential harms (including the risk of life threatening adverse events). (Clinical Practice RECOMMENDATION)

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In the opinion of the Work Group, in dialysis and nondialysis patients with CKD receiving ESA therapy, the selected Hb target should generally be in the range of 11.0 to 12.0 g/dL. (Clinical Practice RECOMMENDATION)

In dialysis and nondialysis patients with CKD receiving ESA therapy, the Hb target should not be greater than 13.0 g/dL. (Clinical Practice GUIDELINE - MODERATELY STRONG EVIDENCE)

Canadian Society of Nephrology (CSN): The target haemoglobin during epoetin therapy is advised to be between 110 and 120 g/L for

both men and women. It is suggested that epoetin be used before and after initiation of dialysis as well as in patients with failing transplants, if necessary.

British Renal Association (BRA) 2006:

Patients with CKD should achieve an outcome distribution of haemoglobin of 10.5-12.5 g/dl. (Evidence).

Adjustments to ESA doses should be considered when Hb is <11 or >12g.dl.in order that the population distribution has the maximum proportion of patients in the range 10.5-12.5 as is possible (Evidence)

European Best Practice Guidelines (EBPG) 2004: Patients with chronic kidney disease (CKD) should maintain a target haemoglobin (Hb)

concentration of >11 g/dl [haematocrit (Hct) >33%] (Level B) (Target Rationale) - Exact target Hb concentrations >11 g/dl should be defined for individual patients, taking gender, age, ethnicity, activity and co-morbid conditions into account. In HD patients, pre-dialysis Hb concentrations above 14 g/dl are not desirable due to the risks associated with the effects arising from post-dialysis haemoconcentration. (Level C) –

Hb concentrations >12 g/dl are not recommended for patients with severe cardiovascular disease [defined as class III and above of the New York Heart Association Classification of Congestive Heart Failure unless continuing severe symptoms (e.g. angina) dictate otherwise.(Level A)

Until data become available, it seems prudent to recommend a cautious approach to raising Hb concentrations to levels >12 g/dl in patients with diabetes, especially with concurrent peripheral vascular disease. (Level C)

International Guidelines: KDIGO: No recommendation.

SUGGESTIONS FOR FUTURE RESEARCH There is a consistent trend towards higher morbidity and mortality in patients targeted to a haemoglobin concentration above 130 g/L. This is invariably associated with a higher ESA dosage in most studies, and there is now a need to ascertain whether the higher Hb concentration, or other factors are primarily responsible for the higher morbidity and mortality.

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CONFLICT OF INTEREST Lawrence McMahon and Rob MacGinley have no relevant financial affiliations that would cause a conflict of interest according to the conflict of interest statement set down by CARI.

*EXPLANATION OF GRADES The evidence and recommendations in this KHA-CARI guideline have been evaluated and graded following the approach detailed by the GRADE working group (www.gradeworkinggroup.org). A description of the grades and levels assigned to recommendations is provided below.

Final grade for overall quality of evidence

Overall Evidence Grade

Description

A High quality of evidence.

We are confident that the true effect lies close to that of the estimate of the effect.

B Moderate quality of evidence. The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.

C Low quality of evidence. The true effect may be substantially different from the estimate of the effect.

D Very low quality of evidence. The estimate of effect is very uncertain, and often will be far from the truth.

Nomenclature and description for grading recommendations

Grade Implications

Patients Clinicians Policy

Level 1 “We recommend” Most people in your situation would want the recommended course of action and only a small proportion would not

Most patients should receive the recommended course of action

The recommendation can be adopted as a policy in most situations

Level 2 “We suggest” The majority of people in your situation would want the recommended course of action, but many would not

Different choices will be appropriate for different patients. Each patient needs help to arrive at a management decision consistent with her or his values and preferences

The recommendation is likely to require debate and involvement of stakeholders before policy can be determined

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REFERENCES

1. Palmer SC, Navaneethan SD, Craig JC et al. Meta-analysis: erythropoiesis-stimulating agents in patients with chronic kidney disease. Annals of Internal Medicine. 2010; 153: 23-33.

2. Junor BJ. Hematocrit above 30% in continuous ambulatory peritoneal dialysis patients treated with erythropoietin is harmful. Peritoneal Dialysis International. 1993; 13 Suppl 2: S535-7.

3. Raine AE. Hypertension, blood viscosity, and cardiovascular morbidity in renal failure: implications of erythropoietin therapy. Lancet. 1988; 1: 97-100.

4. Shinaberger JH, Miller JH, and Gardner PW. Erythropoietin alert: risks of high hematocrit hemodialysis. ASAIO Transactions. 1988; 34: 179-84.

5. Boobes Y. Pre-dialysis or post-dialysis hematocrit to monitor EPO treatment? . Nephrology. 1997; 3: S306.

6. Laudat K, Paulitschke M, Riedel E et al. Complete correction of renal anemia – no increased risk in access thrombosis or thromboembolic events in hemodialysis patients. Journal of the American Society of Nephrology 1998; 9: 219A.

7. Singh AK, Szczech L, Tang KL et al. Correction of anemia with epoetin alfa in chronic kidney disease. New England Journal of Medicine. 2006; 355: 2085-98.

8. Drueke TB, Locatelli F, Clyne N et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. New England Journal of Medicine. 2006; 355: 2071-84.

9. Pfeffer MA, Burdmann EA, Chen C-Y et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. New England Journal of Medicine. 2009; 361: 2019-32.

10. Gandra SR, Finkelstein FO, Bennett AV et al. Impact of erythropoiesis-stimulating agents on energy and physical function in nondialysis CKD patients with anemia: a systematic review. American Journal of Kidney Diseases. 2010; 55: 519-34.

11. Johansen KL, Finkelstein FO, Revicki DA et al. Systematic review and meta-analysis of exercise tolerance and physical functioning in dialysis patients treated with erythropoiesis-stimulating agents. American Journal of Kidney Diseases. 2010; 55: 535-48.

12. Strippoli GFM, Navaneethan SD, Craig JC et al. Haemoglobin and haematocrit targets for the anaemia of chronic kidney disease. Cochrane Database of Systematic Reviews. Issue 4. Art. No.: CD003967. 2006.

13. Phrommintikul A, Haas SJ, Elsik M et al. Mortality and target haemoglobin concentrations in anaemic patients with chronic kidney disease treated with erythropoietin: a meta-analysis. Lancet. 2007; 369: 381-8.

14. Clement FM, Klarenbach S, Tonelli M et al. The impact of selecting a high hemoglobin target level on health-related quality of life for patients with chronic kidney disease: a systematic review and meta-analysis. Archives of Internal Medicine. 2009; 169: 1104-12.

15. Solomon SD, Uno H, Lewis EF et al. Erythropoietic response and outcomes in kidney disease and type 2 diabetes. New England Journal of Medicine. 2010; 363: 1146-55.

16. Besarab A, Bolton WK, Browne JK et al. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. New England Journal of Medicine. 1998; 339: 584-90.

17. Furuland H, Linde T, Ahlmen J et al. A randomized controlled trial of haemoglobin normalization with epoetin alfa in pre-dialysis and dialysis patients. Nephrology Dialysis Transplantation. 2003; 18: 353-61.

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18. Roger SD, McMahon LP, Clarkson A et al. Effects of early and late intervention with epoetin alpha on left ventricular mass among patients with chronic kidney disease (stage 3 or 4): results of a randomized clinical trial. Journal of the American Society of Nephrology. 2004; 15: 148-56.

19. Parfrey PS, Foley RN, Wittreich BH et al. Double-blind comparison of full and partial anemia correction in incident hemodialysis patients without symptomatic heart disease. Journal of the American Society of Nephrology. 2005; 16: 2180-9.

20. Canadian Erythropoietin Study Group. Effect of recombinant human erythropoietin therapy on blood pressure in hemodialysis patients. Canadian Erythropoietin Study Group. American Journal of Nephrology. 1991; 11: 23-6.

21. Collins AJ, Ma JZ, Xia A et al. Trends in anemia treatment with erythropoietin usage and patient outcomes. American Journal of Kidney Diseases. 1998; 32: S133-41.

22. Foley RN, Parfrey PS, Harnett JD et al. Clinical and echocardiographic disease in patients starting end-stage renal disease therapy. Kidney International. 1995; 47: 186-92.

23. Foley RN, Parfrey PS, Harnett JD et al. The impact of anemia on cardiomyopathy, morbidity, and and mortality in end-stage renal disease. American Journal of Kidney Diseases. 1996; 28: 53-61.

24. Ma JZ, Ebben J, Xia H et al. Hematocrit level and associated mortality in hemodialysis patients. Journal of the American Society of Nephrology. 1999; 10: 610-9.

25. Locatelli F, Conte F, and Marcelli D. The impact of haematocrit levels and erythropoietin treatment on overall and cardiovascular mortality and morbidity--the experience of the Lombardy Dialysis Registry. Nephrology Dialysis Transplantation. 1998; 13: 1642-4.

26. Xia H, Ebben J, Ma JZ et al. Hematocrit levels and hospitalization risks in hemodialysis patients. Journal of the American Society of Nephrology. 1999; 10: 1309-16.

27. Madore F, Lowrie EG, Brugnara C et al. Anemia in hemodialysis patients: variables affecting this outcome predictor. Journal of the American Society of Nephrology. 1997; 8: 1921-9.

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APPENDICES

Table 1. Characteristics of included studies

Study ID N Study design

Description - Participants and Interventions

Follow up

Comments and results

Strippoli et al (2006) [12]

22 RCTs (3707 participants)

Systematic review (to August 2006), meta-analysis

RCTs and quasi-RCTs of different Hb and HCT targets achieved by any means (EPO alfa or beta, darbepoietin alfa, blood transfusion) in CKD patients (pre-dialysis, haemodialysis, peritoneal dialysis). Two study groups: 1). High versus low Hb target achieved with high versus low EPO doses; and 2). High versus low Hb target achieved by EPO treatment versus placebo or no treatment).

Minimum 2 months of treatment duration.

The authors note that the review was not able to include the CREATE [8] or CHOIR [7] studies and the findings are largely influenced by the single Besarab et al (1998) [16] study. Overall the review identified major limitations in the number of RCTs, small sample sizes and suboptimal methods quality. Mortality and cardiovascular outcomes: Hb ≥ 133 g/L compared with 120 g/L (pre-dialysis and dialysis) was not associated with a significant reduction in the risk of all-cause mortality. There were no significant differences in any fatal or non-fatal cardiovascular outcomes including vascular access thrombosis with the exception of a reduced risk of hypertension episodes in the placebo group in EPO vs placebo/no treatment trials (RR 0.50, 95% CI 0.33 to 0.76). Toxicity and other outcomes: A higher risk of seizures was reported in the placebo group of the 4 EPO versus placebo trials reporting this outcome (RR 5.25, 95% CI 1.13 to 24.34). There was no significant difference in the occurrence of seizures between the EPO treatment groups in the Besarab et al (1998) [16] study. Renal Outcomes: There was a significantly higher end of treatment creatinine clearance with higher Hb targets in comparison to lower Hb targets in the EPO versus EPO trials ) MD -4.17, 95% CI -6.33 to -2.02) and no difference in the EPO versus placebo trial. There was no significant difference between low and high Hb targets for all other renal outcomes (where reported), including ESKD requiring RRT. Quality of Life: The authors concluded that the QoL data was problematic due to use of non-validated scales, lack of pre-specification of events to be analysed and restriction to reporting of positive results. No pooled analysis was possible.

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Study ID N Study design

Description - Participants and Interventions

Follow up

Comments and results

Palmer et al (2010) [1]

27 RCTs (10 452 participants)

Systematic review (to November 2009), meta-analysis

RCTs where CKD patients were allocated to either ESA versus placebo or no treatment or different ESA doses to achieve a higher or lower Hb target.

Minimum 3 months treatment duration.

This review is an up-date of Strippoli et al (2006) and includes the CHOIR and CREATE [7, 8] studies as well as the large (n= 4038) TREAT study [9]. Mortality and cardiovascular outcomes: Higher Hb target associated with significantly increased risk of stroke (RR 1.51, 95% CI 1.03 to 2.21), hypertension (RR 1.67, CI 1.31 to 2.12) and vascular access thrombosis (RR 1.33, CI 1.16 to 1.53) compared to lower Hb. The point estimates of risks for all cause mortality and serious cardiovascular events were greater in the higher Hb target group compared to the lower Hb target group, however the differences were not significant. Patients assigned to higher Hb targets were less likely to require a blood transfusion (RR 0.61, CI 0.49 to 0.77) but more likely to require intravenous iron therapy (RR 1.57, CI 1.13, 2.20). Quality of Life: The evidence for effects on quality of life of poor quality and subject to selective reporting. No conclusions were therefore made. Overall the authors consider there is no evidence that higher Hb targets in the range 110 to 120 g/L are associated with benefit, rather the evidence indicates associations with possible or absolute harms across major clinical outcomes.

Phrommintikul et al (2007) [13]

9 RCTs (5143 participants)

Systematic review (November 2006), meta-analysis

RCTs where > 100 CKD patients were randomised to different Hb targets with treatment for anaemia in both groups achieved using an ESA.

Minimum of 3 months treatment duration.

Given the exclusions on size and requirement for ESA treatment in both groups, this review represents a subset of studies identified by both Strippoli et al (2006) [12] and Palmer et al (2010) [1]. No assessment of QoL was undertaken due to differences in measures used between studies. The risk of all-cause mortality was significantly greater in the higher Hb group (RR 1.17, 95% CI 1.01 to 1.35) than the lower Hb target group being dominated by the large Besarab et al (1998) [16] study. The higher target Hb concentration in the studies was 120 to 160 g/L. The risk of poorly controlled blood pressure was significantly greater in the higher Hb group compared to the lower Hb group (RR 1.27, 95% CI 1.08 to 1.50). There was a significantly increased risk of arteriovenous access thrombosis in the higher Hb group compared to the lower Hb group (RR 1.34, 95% CI 1.16 to 1.54).

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Study ID N Study design

Description - Participants and Interventions

Follow up

Comments and results

Gandra 2010 [10]

2 double blind RCTS (124 participants); 5 open label RCTs (2746 participants); 6 open-label single arm or parallel-group (2140 participants).

Systematic review (2008)

Non dialysis CKD patients with anaemia. Prospective trials of ESA treatment with baseline and follow up of patient reported outcome measures of energy or physical function.

Minimum 2 months treatment duration.

Seven studies used SF36, 4 LASA, 2 unspecified VAS and 1 used the KDQ. Eight of 11 studies reported statistically significant improvements in energy (effect size ranged from small (0.24) to large (1.90) in ESA-treated groups and was moderate in each arm of the low versus high Hb groups). Ten of 14 studies reported statistically significant improvements in physical function (effect size ranged from small (0.37) to large (2.38) in ESA-treated groups and was negligible to moderate in each arm of the low versus high Hb groups.

Johansen et al (2010) [11]

Exercise tolerance: 5 RCTs (777 participants); 23 cohort studies (315 participants). Physical function: 5 RCTs (626 participants), 8 cohort studies (1898 participants)

Systematic review, meta analysis (2008)

CKD patients receiving dialysis and treatment with an ESA. RCTs and observational studies including pre- and post-treatment measures of functional and/or physical function or exercise tolerance.

Minimum 2.4 months

Exercise tolerance (VO2peak) – maximal or submaximal testing or a 6-minute walk test. Physical function end points – most commonly used were KPS, KDQ, SIP and SF36. Exercise tolerance are all small (i.e. <30) with the exception of Parfrey et al (2005) [19] which had 596 participants. Meta-analysis of 15 studies (including RCTs and cohort studies) showed a significant VO2peak increase of 28% (95% CI 18.6 to 29.0%) before and after ESA initiation. There was no significant difference between VO2peak for studies comparing high and low Hb targets (3 studies). Only 4 small cohort studies met criteria for inclusion in the meta-analysis of physical function. A significant change in the KPS scores from baseline with ESA treatment was reported (10.3%, the 95% CI was not reported). Overall meaningful assessment is limited by the small size of trials, the lack of control groups for exercise tolerance and wide variety of instruments used to assess physical function. The clinical significance of reported improvements in physical function and exercise tolerance is not discussed.

Clement (2009) [14]

11 RCTs (5214 participants)

Systematic review (December 2006), meta-analysis

RCTs of ≥30 CKD patients allocated to either ESA versus placebo or no treatment or different ESA doses to achieve a higher or lower Hb target and reporting HRQoL using a validated measure.

Due to lack of standardised reporting, only studies using SF36 were suitable for meta-analysis. SF36 was used in 9 of the 11 trials. Of these 6 studies were able to be included in a meta-analysis and of these only 3 reported data for all SF36 domains. Small improvements in 4 out of 8 domains were found, however the Weighted Mean Differences from baseline were all less than those considered to be clinically significant (i.e. all < 5-point change). The authors conclude that the review does not support Hb targets >120 mg/L on the basis of improvement in HQOL. In addition, selective reporting, variation in HQOL instruments and lack of directly measured data on utility are major weaknesses.

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Table 2 – Evidence Profile

Quality Assessment Summary of findings

Importance No. of patients

b Effect

Quality No. of studies and

design

Study Limitations

Inconsistency Indirectness Imprecision Other Considerations Intervention (Higher Hb)

Control (Lower Hb)

Relative (95% CI)

Absolute c

Outcome: All cause mortality

18 RCTs a

Serious limitations (1)

No serious limitation

No serious limitation

No serious limitation

Cumulative meta-analysis (Palmer et al 2010) indicates the point estimates of increased risk of mortality to have been consistent since the first large trial of Besarab et al in 1998. Only the earlier small studies showed large confidence intervals and point estimates less than 1.

731 / 4951 677 / 5000 RR 1.09 (0.99-1.20)

Range from 2 fewer to 27 more per 1000

High (6) Critical

Outcome: Serious cardiovascular events

7 RCTs a

Serious limitations (1)

No serious limitation

No serious limitation

No serious limitation

Cumulative meta-analysis (Palmer et al 2010) indicates the point estimates of increased risk of serious cardio vascular events to have been consistent since the trial of Rossert et al in 2006. Trials since this time have included 96% of the total participants.

878 / 3438 800 / 3442 RR 1.15 (0.98-1.33)

Range from 5 fewer to 77 more per 1000

High (6) Critical

Outcome: Stroke

6 RCTs a

Serious limitations (1)

No serious limitation

No serious limitation

No serious limitation.

127 / 3529 77 / 3525 RR 1.51 (1.03-2.21)

11 more per 1,000

Moderate Critical

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Quality Assessment Summary of findings

Importance No. of patients

b Effect

Quality No. of studies and

design

Study Limitations

Inconsistency Indirectness Imprecision Other Considerations Intervention (Higher Hb)

Control (Lower Hb)

Relative (95% CI)

Absolute c

Outcome: Hypertension

12 RCTs a

Serious limitations (1)

Serious limitations (4)

No serious limitation

No serious limitation

833 / 3524 677 / 3584 RR 1.67 (1.31-2.12)

127 more per 1,000

Low Important

Outcome: Vascular access thrombosis

8 RCTs a

Serious limitations (1)

No serious limitation

No serious limitation

No serious limitation

Cumulative meta analysis by Palmet et al (2010) shows consistently significant point estimates greater than 1 for all trials except for the small early Canadian EPO trial in 1990.

337 / 3433 250 / 3411 RR 1.33 (1.16-1.53)

24 more per 1,000

High (6) Important

Outcome: ESKD Requiring RRT

10 RCTs a

Serious limitations (1)

No serious limitation

No serious limitation

No serious limitation

704 / 3619 687 / 3699 RR 1.08 (0.97-1.20)

Range from 5 fewer to 37 more per 1000

Moderate Important

Outcome: Qol all instruments

15 RCTs d

Very serious limitations (2)

No serious limitation

No serious limitation

No serious limitation

Not able to compare across studies due to differing instruments and selective reporting. However, no clinically important effects on QoL are noted.

4742 4735 NA Not able to be estimated

Very low Important

18 Non RCT e

Very serious limitations (3)

No serious limitation

No serious limitation

No serious limitation

Total 2,321 NA Not able to be estimated

Very low Important

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Quality Assessment Summary of findings

Importance No. of patients

b Effect

Quality No. of studies and

design

Study Limitations

Inconsistency Indirectness Imprecision Other Considerations Intervention (Higher Hb)

Control (Lower Hb)

Relative (95% CI)

Absolute c

Outcome: QoL SF36

9 RCTs (dialysis and

pre-dialysis) f

Very Serious limitations (2)

No serious limitation

No serious limitation

No serious limitation

Ability to compare across trials is limited by selective reporting of SF36 domains.

4345 4389 NA Not able to be estimated

Very low Important

5 RCTs (pre-

dialysis) g

Very serious limitations (2)

No serious limitation

No serious limitation

No serious limitation

Ability to compare across studies limited by selective reporting and missing data.

2591 NA

MD 8.9, 4.3 (Vitality) in 2 trials with sig diff. MD 12.6, 5.5, 1.1 (Physical fn.domain) in 3 trials with sig diff. MD 7.9, -1.1 (PCS) in 2 trials with sig diff.

Very low Important

Outcome: Karnofsky Performance Scale i

4 Non RCT h

Very serious limitations (3)

No serious limitation

No serious limitation

Serious limitations (5)

546 NA

Mean change from baseline 10.5% (4.7-16.3)

Very low Important

RR – Relative risk – calculated assuming control rate across all trials. MD – Mean difference. NA – Not applicable. a. References [1, 12, 13]. Only Palmer et al (2010) includes all RCTs. b. Numbers are for all trials i.e. Placebo vs ESA and ESA vs ESA. Sub analysis by Palmer et al (2010) showed no difference between trial design or patient group (dialysis vs pre dialysis. c. Based on control rate across all trials. d. References. [1, 10-12, 14] e. References. [10, 11] f. References. [1, 12] g. Reference [10] h. Reference [11] i. Clinician rated score

Evidence quality footnotes (1) Lack of blinding, unclear with respect to allocation concealment and intention to treat analysis. (2) Lack of blinding, unclear with respect to allocation concealment and intention to treat analysis, selective reporting. (3) Lack of control group and selective reporting. (4) Significant heterogeneity attributable to variation in study design. (5) All trials are very small with short follow up. (6) On the basis of findings of cumulative meta-analysis the quality is considered high rather than moderate.