Intervention thresholds and ceilings can determine the haemoglobin outcome distribution in a haemodialysis population

Donald Richardson, Cherry Bartlett and Eric J. Will

Department of Renal Medicine, St James's University Hospital, Leeds, UK



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
We have explored the consequences of setting different thresholds and ceilings for erythropoietin dose changes in two randomized controlled studies of renal anaemia management based on an established algorithm.

Study 1. A large (n=236) unselected haemodialysis cohort was randomized to monthly intervention (increased erythropoietin (Epo)) at haemoglobin (Hb) levels falling below either 10.5 g/dl (group A) or 11.5 g/dl (group B) and followed for 6 months. The mean Hb was 0.6 g/dl higher in the 11.5 g/dl threshold group (11.1 g/dl vs 11.7 g/dl) at 6 months (P=0.001++). The Epo dose did not differ between them (median 133 IU/kg/week, Interquartile range (IQR) 86–217 and 140, IQR 74–227 respectively) (P=NS**).

Study 2. A large (n=211) unselected haemodialysis cohort was randomized to a reduction in Epo dose at Hb levels above either 12.0 g/dl (group C) or 13.0 g/dl (group D). The Hb outcome at 8 months differed between group C (mean 11.5 g/dl, SD 1.4) and group D (12.2, SD 2.1) (P=0.03++). The Epo dose did not significantly differ between groups C and D (median 60 IU/kg/week, IQR 32–142 and 71, IQR 38–117 respectively) (P=NS**).

Study 1 showed that an intervention threshold of 11.0 g/dl with a mean Hb outcome of 11.6 g/dl and SD 1.6 g/dl would produce the desired UK Renal Association Standards outcome of 85% Hb >=10.0 g/dl. Study 2 demonstrated that a ceiling of 12.0 g/dl narrowed the range of Hb values (P<0.001##), achieving a SD of 1.37 g/dl, and reduced the number of patients with a Hb >13.0 g/dl from 25 to 12%. This narrowing of the distribution has cost implications for reaching minimum standards in a haemodialysis population. Formal use of threshold and ceiling values for intervention within an anaemia management system enabled the haemodialysis population outcome mean and SD to be literally prescribed.

Keywords: haemodialysis; haemoglobin; intervention; outcome; thresholds



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
More is known of individual responses to erythropoietin (Epo) therapy than of strategies that predict haemoglobin (Hb) outcome distributions in haemodialysis cohorts. Outcome standards are being recommended with increasing frequency [1,2] yet the means to achieve and sustain them in haemodialysis populations are uncertain. Some standards are set as minima (values to be exceeded or a minimum percentage of patients are expected to exceed the value). The mean/median values for the group under treatment must inevitably be higher than these minima [1]. Such is the case with the standards for anaemia management set by both the UK Renal Association Standards Document and the European Best Practice Guidelines for the Management of Anaemia in Patients with Chronic Renal Failure [3]. A means of predicting treatment outcomes would enable better planning of services, with defined long-term costs.

Erythropoietin [4] and intravenous iron therapy [5] are known to improve the erythropoietic response in individuals and patient groups with renal disease. The percentage of hypochromic red cells is reported as both a useful marker of absolute and functional iron deficiency and useful predictor of response to intravenous iron therapy in the haemodialysis population [6,7]. We have reported previously the use of computer-aided algorithms to manage renal anaemia in a large haemodialysis cohort [8] and have employed the management system to improve the results in our patient population. We wished to determine the characteristics of a management system using these elements to achieve the ‘minimum standard’ haemoglobin of 85% >=10.0 g/dl (set by the UK Renal Association, and not dissimilar to those of DOQI, Hct 33–36%). We undertook a randomized, controlled study of two haemoglobin values below which erythropoietin therapy would be increased. These were defined as the threshold values. We then undertook a second randomized, controlled study of two haemoglobin values above which erythropoietin therapy would be decreased. These were defined as the ceiling values.

This paper is concerned simply with the methodology and consequences of erythropoietin intervention points, rather than any other elements of the management of renal anaemia. The treatment of iron deficiency using a computer-based algorithm in a haemodialysis population will be reported as part of another study.



   Subjects and methods
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Study 1. Therapeutic thresholds for Epo dose increments
All hospital and satellite haemodialysis patients were included regardless of co-morbidity. Monthly pre-dialysis blood results for Hb, ferritin, and percentage hypochromic red cells (%HRC) were processed to provide recommendations for best therapy for the following month in terms of change to Epo dose or intravenous iron replacement. A clinician (DR) monitored the recommendation of the algorithm and assessed the patient for hypertension, resistant iron deficiency, resistant anaemia, and raised inflammatory markers each month. The protocol was followed unless a specific clinical reason for deviation could be detected and recorded. The system was designed to respond to signs of iron deficiency (absolute or functional) with intravenous iron saccharate prior to any increase in Epo dose. Once signs of iron deficiency had been corrected by criteria set for study 1 (vide infra), Epo doses were increased (by 1000 IU/dose) if Hb values fell below declared threshold levels. The choice of dose increments/decrements of 1000 IU (per dose administered) was a pragmatic one. Epo doses were not increased if the patient was hypertensive. Hypertension was defined as any pre-dialysis diastolic blood pressure >=100 mmHg in the preceding 14 days. A maximum Epo dose was set at 300 IU/kg/week. Doses were reduced in a decremental fashion at a ceiling Hb (14.0 g/dl; decrease Epo by 1000 IU/dose, 15.5 g/dl; halve Epo dose). All Epo was administered via the subcutaneous route.

Patients were randomized to intervention with an increase in Epo dose at Hb levels falling below 10.5 g/dl (group A) or 11.5 g/dl (group B) (the intervention thresholds) and followed for 6 months. Patients in each group were otherwise managed identically by the prevailing algorithm. The baseline characteristics for the population at entry into the study are given in Table 1Go. Transfusion criteria were the same for both groups: transfuse for Hb<6.0 g/dl or for symptomatic anaemia.


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Table 1. Baseline characteristics for groups A and B (study 1)

 

Iron protocol for study 1
Anaemic patients (Hb <threshold) with a ferritin <100 ng/ml (iron deficient) received iron saccharate (i.v. Fe) 100 mg/week for 8 weeks. If the ferritin remained <100 ng/ml a further 4-weeks dose of 100 mg/week was administered. For ferritin 100–250 ng/ml in anaemic patients and in ferritin <=250 ng/ml with a ‘normal’ Hb (Hb >=threshold), %HRC was assessed as a marker of functional iron deficiency. If the %HRC was >=5% (functionally iron deficient) iron saccharate 50 mg/week for 4 weeks was given. The initial values of ferritin and %HRC at which therapy was prescribed and the evidence base for response according to %HRC are described in our previous study [6]. When the ferritin was >250 ng/ml or %HRC <5% (iron replete) intravenous iron was discontinued.

Study 2. Therapeutic ceilings for Epo dose decrements
After an 8-month washout period at a unified threshold for intervention of 11.0 g/dl, a second randomization was performed. Patients were randomized to a reduction in Epo dose at Hb levels above 12.0 g/dl (group C) or 13.0 g/dl (group D) (the intervention ceilings). Patients in each group were otherwise managed identically by the prevailing algorithm. Study 2 was designed to investigate the effect of setting two different Hb ceilings for Epo dose decrement on the Hb outcome distribution and Epo expenditure. All hospital and satellite haemodialysis patients were included regardless of co-morbidity.

Epo dose decrements at the ceiling values were by 1000 IU/dose administered. If Hb values increased to above 15.5 g/dl at any time the Epo dose was halved as in study 1.

Iron protocol for study 2
A combination of low-dose maintenance therapy and incremental replacement dosing was used for iron-replete patients and those with signs of absolute/functional iron deficiency respectively. Ferritin <100 ng/ml (absolute iron deficiency) was treated with iron saccharate 50 mg thrice weekly. Treatment for ferritin 100–500 ng/ml depended upon evidence of functional iron deficiency as determined by %HRC. For %HRC <=2 (iron replete), iron saccharate 50 mg/week was administered, for %HRC >2–<5 (iron replete), 50 mg twice weekly, and for %HRC >=5 (functional iron deficiency), iron saccharate 50 mg thrice weekly was administered. For ferritin above 500 ng/ml (iron replete) intravenous iron therapy was withheld.

Statistics
Statistical significance was tested using the paired samples t-test+, independent samples t-test++ for equality of the means (P quoted for ‘equal variances not assumed’), the variance ratio test## (F test) for parametric data, the Wilcoxon signed-rank test*, the Mann–Whitney U-test** for non-parametric data, and the Chi-Squared test#.



   Results
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Study 1. Thresholds
A haemodialysis population of 236 patients at entry was followed for 6 months. Thirty-five patients did not complete 6 months of study due to death (17), transplantation (10), conversion to continuous ambulatory peritoneal dialysis (CAPD) (7), and transfer to another hospital (1). The data showed no significant differences between the two groups (Table 2Go).


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Table 2. Reasons for not completing study 1

 
Epo doses were not increased on 17 occasions when the patient was hypertensive. Intolerance to treatment occurred in two patients. One developed vomiting shortly after receiving i.v. iron saccharate and was converted to iron dextran. The second developed migraine on Epo 6000 IU/week and the dose was set at a maximum of 3000 IU/week (71 IU/kg/week).

The population mean Hb increased from 10.2 g/dl to 11.4 g/dl (SD 1.8) (P<0.001+). Transfusion decreased from 47 units in 236 patients in month 1 to 23 units in 201 patients in month 6. Transfusion did not differ between groups A and B in any month**. The proportion of patients with an Hb >=10.0 g/dl increased from 50 to 80% at 6 months. A developing difference in Hb outcome between the two randomized groups was significant from the third month (P=0.001++) (Figures 1–3GoGoGo). The mean Hb differed in the two groups at 6 months by 0.6 g/dl (P=0.04++) having increased from baseline in both: group A, Hb 10.0 to 11.2 g/dl (SD 1.7 g/dl); group B, Hb 10.2 to 11.7 g/dl (SD 2.1 g/dl). The outcome mean Hb was above the respective threshold for intervention in both groups and the medians were 0.9 g/dl apart, close to the difference between the threshold values (Figure 3Go). There was no difference in the outcomes for ferritin or %HRC between the groups A and B** (Table 3Go). There was an increase in Epo dose in both groups during study 1 (group A, median 88 IU/kg/week (6000 IU/week) (IQR, 47–124) to 134 (9000 IU/week) (IQR 88–223) (P<0.001*) and group B, 72 (3000 IU/week) (IQR, 39–119) to 141 (9000 IU/week) (IQR, 75–228) (P=0.001*)). The Epo doses for groups A and B (quoted as means to enable cost calculations) at 6 months were 9916 and 10168 IU/week respectively and this difference was not statistically significant**.



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Fig. 1. Cumulative frequency curve for Hb in month 0 of threshold study.

 


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Fig. 2. Cumulative frequency curve for Hb in month 3 of threshold study.

 


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Fig. 3. Cumulative frequency curve for Hb in month 6 of threshold study.

 

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Table 3. Ferritin and %HRC outcomes by threshold group in study 1 (months 0–6). No significant difference between groups**

 

Study 2. Ceilings
The unselected haemodialysis population of 211 patients at entry was followed for 8 months (vide infra). There was no significant difference between the baseline characteristics of the two groups (Table 4Go).


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Table 4. Baseline characteristics for groups C and D (study 2)

 
Thirty-three patients did not complete 8 months of study: due to death (18), transplantation (7), conversion to CAPD (1), transfer to another hospital (6), recovery of renal function (1). There was no significant difference for failure to complete the study between the two groups (Table 5Go).


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Table 5. Reasons for not completing study 2

 
The population Hb increased from a mean of 11.4 g/dl (SD 1.8 g/dl) to 11.6 g/dl (SD 1.9) (P=0.02+). The ferritin increased from a median of 406 mg/ml (IQR, 259–491) to 542 mg/ml (IQR, 459–667) (P<0.01*). Transfusion rate for the 8 month period did not differ between Groups-C (17 of 103 patients) and D (23 of 118 patients)#. The haemoglobin outcomes developed a difference from 7 months (P=0.002++) and at 8 months the mean Hb outcome in group C (11.5 g/dl, SD 1.4) was lower than group D (12.2, SD 2.1) (P=0.001++) (Figures 4–6GoGoGo). The percentage of Hb values <10.0 g/dl were 13.5 and 15.5% respectively. Importantly, the standard deviation for Hb values was less for group C, with a standard deviation of 1.37 g/dl vs 2.07 g/dl for group D (P<0.001##). There was no difference in measured iron parameters between the two groups during the study (Table 6Go).



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Fig. 4. Cumulative frequency curve for Hb in month 0 of ceiling study.

 


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Fig. 5. Cumulative frequency curve for Hb in month 4 of ceiling study.

 


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Fig. 6. Cumulative frequency curve for Hb in month 8 of ceiling study.

 

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Table 6. Ferritin and %HRC outcomes by ceiling group in study 2 (months 0–8). No significant difference between groups C and D apart from month 5 (HRC (P=0.02**) and ferritin (P=0.04**))

 
There was a decrease in Epo dose in both groups during study 2 (group C, 104 (IQR, 45–200) to 60 IU/kg/week (IQR 32–141) (P<0.01*) and group D, 108 (IQR, 43–167) to 71 IU/kg/week (IQR, 38–117) (P=0.02*)). The mean Epo doses for groups C and D were 5451 and 5672 IU/week respectively but this difference was not statistically significant.



   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
The management system produced a dramatic improvement in the population Hb profile over 6 months in study 1 through incremental use of Epo. The 1 g/dl difference in the set threshold values (for increments in Epo dosing) in the two groups led to two stable Hb distributions, with means separated by 0.6 g/dl (medians separated by 0.9 g/dl, and approximately 0.5 g/dl above the threshold value).

Despite a difference in the outcome Hbs in groups A and B there were no differences in Epo dose, ferritin, or %HRC between the two groups. There were very few interventions at the ceiling values during this 6-month period, suggesting a low risk of toxicity secondary to polycythaemia. The results did not depend on any prospective ‘target’ values, being simply the outcome of the algorithm applied at the two threshold values.

After study 1 was completed, the two groups were unified at an intervention threshold of 11.0 g/dl. With the subsequent mean predicted as 11.5 g/dl and a SD of ~1.7 g/dl, this system should have achieved ~85% of the population Hb values >=10.0 g/dl after 90 days on haemodialysis.

The algorithm of monthly Epo dose adjustments and i.v. iron saccharate supplements evolved in response to the high Epo requirements in study 1 and audit of the iron parameters resulting from the declared iron protocol during that period of study. In response to the earlier outcomes, persistent iron deficiency was subsequently managed with incremental iron dosing (up to 50 mg iron saccharate i.v. three times weekly) and iron-replete patients received maintenance iron (50 mg/week) to prevent the development of iron deficiency [8]. Because of these changes the prevalence of iron deficiency decreased by the time the second study was undertaken. This was demonstrated by the lower erythropoietin doses necessary to maintain the same Hb outcome during study 2 as at the end of study 1. However, all the patients randomized into each treatment group within each study were treated identically (with respect to iron supplements). The higher Epo requirements in study 1 are likely to have been secondary to a combination of attainment (increasing haemoglobins from lower levels to above a minimum standard) and the less aggressive iron replacement than in study 2. There is no reason to believe that the prevailing iron protocol influenced the results of the randomized studies.

The consequence of managing renal anaemia with erythropoietin and iron is always a distribution of Hb values for any dialysis patient cohort. Such distributions are typically Gaussian in character and have outcome SDs that are similar in most units across the UK. The UK Renal Registry data [9] for example suggested the possibility of determining in advance the mean Hb necessary to achieve defined standard values (e.g. a mean of 11.5 g/dl for 85% >=10.0 g/dl). Similar predictions can be made from cross-sectional and longitudinal data [10,11]. The latest guidelines from the European Renal Association [3] (Preface 1.3 and Guideline 5A) acknowledge that the population mean value must be significantly higher than the minimum standard in order to achieve distributions compliant with that standard, but no formal methods are currently available to manipulate the distributions predictably.

The studies in this paper were designed to explore the consequences of erythropoietin intervention at two lower threshold and two upper ceiling Hb values, in an iron-replete dialysis population. The principle was less concerned with target values being used as ‘aiming points’, than with the Hb values at which Epo doses should be increased or decreased in order to shape the outcome distribution. Because of inertia in the declining values and momentum in the values that are rising there is a need to choose the points at which interventions effectively throw the Hb back towards the middle of the distribution. Intervention on declining values must clearly precede transgression of 10 g/dl (UK Renal Association Standard) in order to maintain the distribution. Likewise the momentum of the erythropoietic tissue, under Epo/iron stimulation, means that a relatively low ceiling must be chosen to limit overshoot into higher values. These are pre-emptive (pro-active) rather than reactive interventions; a clinical response is elicited before marginal values are ever reached.

Our studies demonstrate the ability of a formal management system to produce different outcome distributions by using threshold and ceiling values for Epo dose intervention. The threshold study (study 1) produced two outcome distributions with mean values separated by just over 0.5 g/dl from 3–6 months. The ceiling study (study 2) again separated the outcome distributions through the use of a ceiling value 1 g/dl and 2 g/dl greater than the then unified threshold value of 11.0 g/dl (with outcome means approximating to the midpoints between threshold and ceiling values in each group). The utilization of the lower ceiling value, with the same threshold at 11.0 g/dl, decreased the dispersion (SD) of the 12 g/dl-ceiling group compared to the 13.0 g/dl ceiling group. The ability to reduce the spread of outcome values is important in regard to both safety and cost-effectiveness. To narrow the distributions further will require the investigation of differential Epo dosing and frequency. Methods based on standard algorithms will allow this further study, as well as, for example, examining the timing interval for monitoring and intervention.

The different Hb outcome for groups A and B, and groups C and D respectively, despite comparable values for erythropoietin doses and iron parameters, requires further discussion. We suggest that the differences may be explained by the increased frequency of Epo dose interventions made in groups B and C (Figures 7Go, 8Go). The number of Epo dose interventions are dependent on the level at which the threshold/ceiling is set relative to the population Hb distribution at that time. For instance, in group B, with a threshold set at 11.5 g/dl, a larger proportion of the population had values that fell below this threshold at the beginning of the study than for the threshold set at 10.5 g/dl. This hypothesis, based on the proportion of interventions in Epo dose, might also explain why, with a greater frequency of interventions occurring in study 1 (with initially the majority of patients' values <11.0 g/dl), there was a separation in the two groups by month 3. However, in study 2 the proportion of each group's Hb results that were above the ceiling values (resulting in an Epo dose intervention) was smaller and the Hb distributions did not separate significantly until 7 months of study.



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Fig. 7. Stacked bar chart for interventions at threshold values in study 1, months 1–6.

 


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Fig. 8. Stacked bar chart for interventions at ceiling values in study 2, months 1–8.

 
These studies in the St James's renal population were undertaken at a particular time in an anaemia treatment cycle, and the intervention values chosen here might not produce the same results in other patient cohorts. Studies within individual units should ultimately provide the local evidence base for optimal design of renal anaemia management systems. This is an opportunity for local clinical research.

It appears that a management system might be evolved in order to achieve any desired anaemia outcome in a given renal population. The goal is to develop clinical best practice in a predictable manner, through audit of outcomes produced by accurately defined clinical pathways. This work indicates that formal principles can be used to design Hb outcome distributions in advance and provides a basis for further development of procedural aids in managing the anaemia of chronic renal disease [12].



   Acknowledgments
 
Dr Richardson was sponsored by the Yorkshire Kidney Research Fund.



   Notes
 
Correspondence and offprint requests to: Dr Donald Richardson, Renal Research Registrar, St James's University Hospital, Beckett Street, Leeds LS9 7TF, UK. Back



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

  1. Standards Subcommittee of the Renal Association. Treatment of adult patients with renal failure. In: Recommended Standards and Audit Measures, 2nd edn. Royal College of Physicians, 1997; 24–25
  2. NKF-DOQI Clinical Practice Guidelines for the Treatment of Anemia of Chronic Renal Failure. New York, National Kidney Foundation, 1997
  3. Working Party for European Best Practice Guidelines for the Management of Anaemia in Patients with Chronic Renal Failure. Nephrol Dial Transplant1999; 14 [suppl. 5]: 1–50[Free Full Text]
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  7. Macdougall IC, Cavill I, Hulme B et al. Detection of functional iron deficiency during erythropoietin treatment: a new approach. Br Med J1992; 304: 225–226[ISI][Medline]
  8. Richardson D, Bartlett C, Jones C, Will EJ. An evolving computer-aided algorithm for the management of renal anemia in a hemodialysis cohort. J Am Soc Nephrol1999; 10: A0917 (Abstract)
  9. UK RENALREG 1998. UK Renal Registry, Bristol, UK
  10. Health Care Financing Administration. 1998 Annual Report, End Stage Renal Disease Core Indicators Project. Department of Health and Human Services, Health Care Financing Administration, Office of Clinical Standards and Quality, Baltimore, Maryland, December, 1998; 29–39
  11. DeOreo PB, Eschbach JW. Implementation of the anemia guidelines. Adv Renal Replace Ther1999; 6: 18–27[ISI][Medline]
  12. Will EJ, Cameron SJ. European guidelines for renal anaemia—predicting 85% compliance. Nephrol Dial Transplant2000; 15: 439–440[Free Full Text]
Received for publication: 6. 1.00
Revision received 7. 7.00.