DRAFT FOR CONSULTATION Management of hyperphosphataemia: NICE guideline DRAFT (October 2012) Page 1 of 248 Hyperphosphataemia in chronic kidney disease: management of hyperphosphataemia in patients with stage 4 or 5 chronic kidney disease NICE clinical guideline Draft for consultation, October 2012 This guideline was developed by the NICE Internal Clinical Guidelines Team following the short clinical guideline process. This document includes all the recommendations, details of how they were developed and summaries of the evidence they were based on.
Hyperphosphataemia in chronic kidney disease: management of hyperphosphataemia in patients with stage 4 or 5 chronic kidney disease. NICE clinical guideline Draft for consultation, October 2012
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DRAFT FOR CONSULTATION
Management of hyperphosphataemia: NICE guideline DRAFT (October 2012) Page 1 of 248
Hyperphosphataemia in chronic kidney disease: management of
hyperphosphataemia in patients with stage 4 or 5 chronic kidney disease
NICE clinical guideline
Draft for consultation, October 2012
This guideline was developed by the NICE Internal Clinical Guidelines Team
following the short clinical guideline process. This document includes all the
recommendations, details of how they were developed and summaries of the
evidence they were based on.
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Contents
Introduction ...................................................................................................... 3 Hyperphosphataemia ................................................................................... 3 Drug recommendations ................................................................................ 5
Who this guideline is for ............................................................................... 5 Patient-centred care ......................................................................................... 6 1 Recommendations .................................................................................... 8
1.1 List of all recommendations ................................................................ 8 2 Care pathway .......................................................................................... 11
3 Evidence review and recommendations .................................................. 12 3.1 Dietary management for people with stage 4 or 5 CKD who are not on dialysis ....................................................................................................... 12 3.2 Dietary management for people with stage 5 CKD who are on dialysis ....................................................................................................... 37 3.3 Patient information strategies ........................................................... 53 3.4 Use of phosphate binders in people with stage 4 or 5 CKD who are not on dialysis ............................................................................................. 79 3.5 Use of phosphate binders in people with stage 5 CKD who are on dialysis ..................................................................................................... 100 3.6 Use of supplements in people with stage 4 or 5 CKD who are not on dialysis ..................................................................................................... 200 3.7 Use of supplements in people with stage 5 CKD who are on dialysis ... ........................................................................................................ 202 3.8 Sequencing of treatments ............................................................... 215
4 Notes on the scope of the guideline ...................................................... 218
6 Other versions of this guideline ............................................................. 218 6.1 NICE pathway ................................................................................. 218 6.2 ‘Understanding NICE guidance’ ...................................................... 218
7 Related NICE guidance ......................................................................... 219 8 Updating the guideline ........................................................................... 219 9 References ............................................................................................ 220
10 Glossary and abbreviations ................................................................ 232 Appendix A Contributors and declarations of interests ................................ 238
Appendix B List of all research recommendations ....................................... 240 Appendix C Guideline scope ........................................................................ 244 Appendix D How this guideline was developed ........................................... 245
Appendix E Evidence tables ........................................................................ 246 Appendix F Full health economic report ....................................................... 247
Appendix G Clinical guideline technical assessment unit analysis (phosphate binders) ........................................................................................................ 248
Appendices C, D, E, F and G are in separate files.
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Introduction 1
Hyperphosphataemia 2
Chronic kidney disease (CKD) describes abnormal kidney function and/or 3
structure. It is common and often exists together with other conditions, such 4
as cardiovascular disease and diabetes. 5
The ‘National service framework for renal services’ adopted the US ‘National 6
Kidney Foundation kidney disease outcomes quality initiative’ (NKF-KDOQI) 7
classification of CKD. This classification divides CKD into 5 stages according 8
to the extent of a person’s loss of renal function. Stage 4 CKD is defined by a 9
glomerular filtration rate (GFR) of 15–30 ml/min/1.73 m2, and stage 5 by a 10
GFR of less than 15 ml/min/1.73 m2.1 11
CKD progresses to these more advanced stages in a small but significant 12
percentage of people. In 2010, the Health Survey for England reported a 13
prevalence of moderate to severe CKD (stages 3 to 5) of 6% in men and 7% 14
in women. CKD stages 4 and 5 were reported at a prevalence of 1% or less. 15
Although this figure might seem small, it translates to a prevalence of up to 16
520,000 people in England alone. 17
When CKD stage 5 advances to end-stage renal disease (ESRD), some 18
people progress to renal replacement therapy (RRT)2. The UK Renal Registry 19
reported that 49,080 adult patients were receiving RRT in the UK at the end of 20
2009. Of these, 25,796 were receiving RRT in the form of dialysis (a 21
population sometimes classified CKD stage 5D). 22
As kidney dysfunction advances, there is a higher risk of mortality and some 23
comorbidities become more severe. Hyperphosphataemia is one example of 24
this, and is because of insufficient filtering of phosphate from the blood by 25
1 A GFR of over 90 ml/min/1.73 m
2 is considered normal unless there is other evidence of kidney
disease. 2 Note: in this guideline, those who choose not to participate in an active treatment programme for their
ESRD (which would generally include RRT, diet, pain management etc), instead opting for
‘conservative management’, are considered to be a subset of the stage 5 population who are not on
Established advanced chronic renal failure, defined by an SCr > 600 µmol/l in
0.4 g/kg/day of mixed quality proteins
< 600 mg/day of phosphates
1 capsule/6 kg ideal body weight/day of ketoanalogues of essential amino acids
0.6 g/kg/day of mainly high biological value proteins
< 750 mg/day of phosphates
Ad-hoc/'when-required' calcium carbonate
Minimum of 3 months and maximum of 18 months, although data given for
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1 Note: Cianciaruso et al, 2008 and Cianciaruso et al, 2009 are 2 reports of the same study. Individual outcomes were included from only 1 of the 2 papers, to avoid double-
counting of the results: serum phosphate, adherence, need for additional phosphate management and serum PTH were extracted from Cianciaruso et al, 2008; malnutrition (adverse event) was extracted from Cianciaruso et al, 2009. 2 Note: Klahr et al, 1994 and Kopple et al, 1997 are 2 reports of the same study (the MDRD study). Individual outcomes were included from only 1 of the 2 papers to avoid
double-counting of the results: adherence was extracted from Klahr et al, 1994; hospitalisation (adverse event) was extracted from Kopple et al, 1997.
(% of prescription, calculated from urinary urea nitrogen)
12 months follow-up
1 RCT
European Study Group for the Conservative Management of Chronic Renal Failure, 1992
1
99 103 Absolute effect
Difference in medians = 23.4% higher
Very low
1Data were only extracted for those with ‘poor renal function’
Abbreviations: RCT, randomised controlled trial.
280
281
282
283
284
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Summary GRADE profile 4 Supplemented very-low-protein low-phosphate diet with (+ calcium) compared with low-protein 285
low-phosphate diet (+ calcium) 286
Outcome Number of Studies
Number of patients Effect Quality
Supplemented very-low-protein low-phosphate diet
(+ Ca supplement)
Low-protein low-phosphate diet
(+ Ca supplement)
Adherence to protein prescription
(% of prescription, calculated from urinary urea nitrogen)
12-month follow-up1
1 RCT
Snetselaar et al, 1994
2
363
22 Absolute effect
MD = 64.1% higher (95% CI: 47.2 to 81.0 higher)
Very low
Adherence to protein prescription
(% of prescription, calculated from 3-day diet diary)
12-month follow-up1
1 RCT
Snetselaar et al, 1994
2
363
22 Absolute effect
MD = 29.9% higher
Very low
Adherence to phosphate prescription
(% of prescription, calculated from 3-day diet diary)
12-month follow-up1
1 RCT
Snetselaar et al, 1994
2
363
22 Absolute effect
MD = 1% lower
Very low
1 Data provided are the weighted means of follow-up data collected throughout the 12-month study period
2 Data were only extracted for ‘Study B’
3 Study is a 3-arm trial; reviewer combined data for 2 arms (both VLPDs, but 1 supplemented with KAs, the other with essential AAs) into a weighted mean and, where
possible, pooled standard deviation, producing a pair wise comparison of sVLPD versus LPD
1 Actual intake in the intervention group falls in the ‘low-protein’ rather than the ‘very-low-protein’ range; actual protein intake in the intervention group was 0.66 g/kg/day and
0.72 g/kg/day in the control group (MD 0.06 lower [95% CI 0.43 lower to 0.31 higher i.e. not statistically significant])
supplementation than those on a low-protein diet with vitamin D 515
and ad-hoc phosphate binders (0/10 versus 3/9 respectively) 9. 516
Important outcomes 517
3.1.3.29 Very-low-quality evidence from 1 RCT of 19 patients found that 518
fewer patients on a very-low-protein diet supplemented with a 519
mixture of keto acids and amino acids and vitamin D required/were 520
prescribed phosphate binders than those on a low-protein diet with 521
vitamin D (0/10 versus 3/9 respectively)11. 522
10
Note: actual intake fell into the ‘low-protein’ rather than the ‘very-low-protein’ range; actual protein
intake in the intervention group was 0.66 g/kg/day and 0.72 g/kg/day in the control group (MD 0.06
lower [95% CI -0.43 to 0.31, that is, not statistically significant]). 11
Note: actual intake fell into the ‘low-protein’ rather than the ‘very-low-protein’ range; actual protein
intake in the intervention group was 0.66 g/kg/day and 0.72 g/kg/day in the control group (MD 0.06
lower [95% CI -0.43 to 0.31, that is, not statistically significant]).
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3.1.3.30 Very-low-quality evidence from 1 RCT of 42 patients showed that a 523
very-low-protein diet supplemented with a mixture of keto acids and 524
amino acids, vitamin D and ad-hoc phosphate binders to be 525
associated with a mean serum PTH level 33.9 pmol/l lower (95% CI 526
-43.5 to -24.3 i.e. statistically significant) than a low-protein diet with 527
vitamin D and ad-hoc phosphate binder use. 528
3.1.4 Evidence to recommendations 529
Relative value of different outcomes
The GDG discussed the relative importance of the outcomes and agreed that serum phosphate, adherence with dietary prescription, and adverse events such as malnutrition were critical for decision making. The need for additional phosphate management was considered important for decision making, but not critical.
Following the review of the evidence, malnutrition and adherence with treatment featured prominently in the GDG’s discussions.
In addition to being a surrogate outcome, the GDG noted that there is a lot of variability in PTH measurements, in both the level of PTH in the serum and the ability of laboratory techniques to detect these levels. Therefore, PTH was not deemed to be a sufficiently reliable basis from which to formulate recommendations.
Trade-off between benefits and harms
A very-low-protein diet supplemented with keto and amino acids was associated with the use of fewer concurrent phosphate binders and appeared to be effective in reducing serum phosphate. However, the GDG had concerns over the quality and applicability of the evidence. Many studies were powered for other outcomes, such as the preservation of renal function or patient responsiveness to erythropoietin, and most of the diets examined were accompanied by concurrent treatments, including phosphate binders and vitamin D, which could confound the observed effects. The GDG was unsure whether the beneficial effect observed was because of the diet or the calcium-based keto acids in the supplement, which may have phosphate-binding properties. Consequently, the supplement may overestimate the phosphate-lowering effect of the very-low-protein diet. As a result, the GDG did not have confidence in the findings of the studies in the context of managing hyperphosphataemia.
Despite significant protein restriction, malnutrition did not appear to be a significant problem with any of the diets reviewed. However, the GDG had concerns about the possible lack of sensitivity of the non-standardised definitions used in 1 of the papers, which may underestimate the actual incidence of malnutrition. In addition the GDG noted that adherence with the higher energy prescriptions used in the evidence seemed good, and because of this the long-term impact of protein restriction on nutritional status may be masked, requiring much longer follow-up periods to observe adverse effects relating to malnutrition. The GDG was also concerned that the studies may have had insufficient sample sizes, further reducing their sensitivity to detect malnutrition. The small number of events recorded support this suggestion.
Concerns relating to restricted diets also included ‘sub-clinical’
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malnutrition that may easily be missed in patients on low- or very-low-protein diets. It was noted that in current practice clinicians aim to maintain patients' dietary protein intake at or above the recommended minimum for CKD patients, rather than restrict nutritional intake in patients with advanced CKD.
It was noted that in the case of supplemented protein restricted diets the keto and amino acids may simply alleviate the harmful effects of very-low-protein diets, leading to the reduced rates of malnutrition and hospitalisation rates observed. There are a number of possible explanations for this association, such as a beneficial effect on nutritional status through substitution for the restricted protein or a positive impact relating to the alleged phosphate-binding properties of these supplements, although there is currently insufficient evidence available.
If patients are prescribed a very-low-protein diet supplemented with keto and amino acids, the GDG was concerned that non-adherence with the supplements might still lead to malnutrition; the additional pill burden of the supplements was a significant concern. However, no evidence on patient adherence with keto/amino acid supplements was found.
Adherence with protein restrictions was poor in all of the diets reviewed. There was no evidence on patients’ views (for example, quality of life), although the GDG felt the observed low adherence with protein restrictions to be indicative. It was felt that expecting patients to comply with protein restrictions, particularly given the unpalatability of such diets, is potentially unrealistic.
The GDG considered that the risks and disadvantages of a protein-restricted diet, with or without keto and amino acid supplementation, were greater than the benefit of the observed phosphate reduction and therefore did not feel it appropriate to recommend this kind of diet for the management of hyperphosphataemia in adults with advanced CKD. For the reasons outlined above, the GDG did not feel that the evidence was sufficient to recommend restricting protein intake below minimum recommended nutrient intake levels, the accepted standards used for protein intake in adults. Current recommended protein intake levels for adults with CKD stage 4 or 5 is a minimum of 0.75 g/kg of ideal body weight/day. Furthermore, given that very-low-protein diets supplemented with keto and amino acids also have a large pill burden, the GDG felt that phosphate binders would be more clinically appropriate than supplementation with keto and amino acids.
Although there was no evidence on the effectiveness of a low-phosphate diet without protein restriction (for example exchanging foods with a high phosphate to protein ratio for foods with a low phosphate to protein ratio), there was consensus among the GDG that this has been effective in their own clinical experience. The GDG considered that advising patients to reduce their intake of phosphate-rich foods is good clinical practice. The GDG also felt that the same principle could be extended to the nutritional supplements/substitutes currently used in CKD management to maintain protein intake, giving low-phosphate options where possible.
In children, the GDG felt that malnutrition is of much greater concern than hyperphosphataemia. Progressive CKD is often associated with decreased spontaneous dietary protein intake, which is a priority for
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treatment given the need to maintain growth and adequate nutritional status. For these reasons, as well as the lack of paediatric evidence available, the GDG could not recommend a diet based on protein restriction for children. Recommended intakes are instead age-specific according to reference nutrient intakes.
Economic considerations
This question was not prioritised for health economic analysis because the majority of resource inputs are outside the NHS and personal social services perspective.
Quality of evidence
No evidence was found for children.
For adults, little significant evidence was found to suggest that low-protein prescriptions are effective in managing serum phosphate, although it was felt that this could be a consequence of the poor quality of the evidence.
No evidence was found regarding the use of phosphate restriction alone demonstrating, for example, the effectiveness of a low-phosphate diet achieved without protein restriction or through the restriction of food and drink containing phosphate additives.
No evidence was found that compared a moderate protein restriction to high protein or ad libitum protein intake.
The GDG questioned the generalisability of the evidence to a UK setting (particularly dietary differences) because none of the studies are UK-based. The GDG also felt that the age of the studies may further reduce the generalisability of the evidence because of changes in practice over time.
The GDG was concerned about the reliability of the non-standardised definition of malnutrition used by 1 of the studies in place of widely recognised and accepted standards such as the Subjective Global Assessment of Nutrition (SGA) and Mini Nutritional Assessment (MNA). Adherence with dietary prescriptions was not regularly reported; instead, papers reported mean actual intakes for each group, which the reviewer then compared to prescriptions, producing a surrogate measure of adherence. The GDG also had concerns regarding the known variability of PTH measurements between laboratories; this variation is particularly concerning in the multicentre trials included, especially if those studies used multiple laboratories to analyse their biochemical outcomes.
It was noted that studies were often designed for purposes other than the management of hyperphosphataemia, such as slowing renal decline. For this reason, outcomes of interest were often secondary and concurrent treatments (such as phosphate binders or calcium/vitamin D supplementation) were often used, and at least 1 paper excluded those with metabolic imbalances such as hyperphosphataemia. Moreover, the ad-hoc phosphate binder use and vitamin D supplementation observed may be driving some of the results, particularly those for serum phosphate and PTH.
Reporting in many of the studies was poor. For example, details of study designs were often unclear and results were not always cited in the text of the papers, requiring the reviewer to read the data off available graphs. Additionally, it was not always clear what dietary advice was provided, in what manner it was provided, or who provided it. Unit-of-analysis errors were also common, with analyses not following the intent-to-treat principle.
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Other considerations
Keto and amino acid supplementation is not currently used in regular practice in the UK; the GDG felt that making recommendations about their use without further evidence on their safety and effectiveness would be premature.
Usual practice is to advise a reduction in certain types of food: generally those with a high phosphate to protein ratio, such as some dairy products and nuts, or food and drinks with high levels of phosphate additives, such as cola drinks or processed foods. The emphasis is more on the phosphate content of food and drinks rather than focusing on the restriction of protein.
The definition of ‘moderate-protein diet’ used in the analysis (0.75–1.2 g/kg/day) corresponds to the approximately normal level of protein intake for adults in the UK (although the top end of this range would be considered relatively high for CKD patients who are not on dialysis).
A distinction needs to be noted between a ‘moderate-protein diet’ and a ‘moderate-protein restriction’ because these are not the same intervention.
There is limited guidance regarding recommended nutrient intakes for phosphate in adults with CKD. There is some guidance available for children, but the evidence informing this guidance is limited.
The GDG noted relevant recommendations in ‘Chronic kidney disease’ (NICE clinical guideline 73).
Stable dialysis dose and modality, dietary intakes, body weight and biochemical markers for at least 3 months
All patients were on thrice weekly 4-hour standard bicarbonate haemodialysis
Baseline serum phosphate (mean SD):
Intervention = 2.7±0.4 mmol/l
Control = 2.6±0.2 mmol/l
Patients not asked to change their eating habits or their total protein/energy intakes
Partially replace dietary protein intake with a low-phosphorus, low-potassium whey protein concentrate (PROther), instructed to consume 30–40 g dissolved in liquid in place of usual daily portion sizes of protein-rich foods (including milk consumed at breakfast and meat, fish, eggs or dairy and poultry products consumed at lunch time)
Most patients received both phosphate binders (sevelamer, lanthanum carbonate, calcium carbonate, and aluminium hydroxide) and vitamin D analogues – continued pre-study regimen
Usual diet maintained
Most patients received both phosphate binders (sevelamer, lanthanum carbonate, calcium carbonate, and aluminium hydroxide) and vitamin D analogues – continued pre-study regimen
3 months
Blood samples taken before each dialysis session
Very-low-protein diet compared with moderate-protein diet
Jiang et al, 2009
RCT
Shanghai, China
n = 30
(29 analysed at month 12)
note: as trial had 3 arms, the moderate-protein diet group was split in 2 to give 2 pair-wise comparisons
Stable peritoneal dialysis for at least 1 month
Urine output of 800 ml or eGFR of 2 ml/min/1.73 m2
(calculated as an average of the creatinine and urea clearances by 24 hour urine) (that is, residual renal function)
Age 18–80 years
Baseline serum phosphate (mean SD):
Intervention = 1.46±0.35 mmol/l
Control = 1.28±0.32 mmol/l
See evidence tables in appendix E for full inclusion/exclusion criteria
0.6–0.8 g protein/kg ideal body weight/day 1.0–1.2 g protein/kg ideal body weight/day
12 months
Patients were assessed ‘serially’ for 12 months (data given for baseline, 1 month, 2 months, and then every 2 months)
Supplemented very-low-protein diet compared with moderate-protein diet
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1 Full study lasted 16 weeks: after 8 weeks on the intervention diet, the intervention group switched to the control diet and were observed for 8 weeks; the control group were
on the control diet for the duration of the 16-week study period. Data is only extracted from the initial 8-week RCT period, and not for the 8-week observation period following.
Abbreviations: BMI, body mass index; Ca x P product, calcium-phosphorus product; eGFR, estimated glomerular filtration rate; KA, keto acids; Kt/V, quantification of dialysis treatment adequacy; MPD, moderate-protein diet; RCT, randomised controlled trial; SD, standard deviation.
599
Jiang et al, 2009
RCT
Shanghai, China
n = 30
(28 analysed at month 12)
note: as trial had 3 arms, the MPD group has been split in 2 to give 2 pair-wise comparisons
Stable peritoneal dialysis for at least 1 month
Urine output of 800 ml or eGFR of 2 ml/min/1.73 m2
(calculated as an average of the creatinine and urea clearances by 24 hour urine) (that is, residual renal function)
Age 18–80 years
Baseline serum phosphate (mean SD):
Intervention = 1.48±0.36 mmol/l
Control = 1.28±0.32 mmol/l
See evidence tables in appendix E for full inclusion/exclusion criteria
0.6–0.8 g protein/kg ideal body weight/day
0.12 g KA (Ketosteril)/kg ideal body weight/day
1.0–1.2 g protein/kg ideal body weight/day
12 months
Patients were assessed ‘serially’ for 12 months (data given for baseline, 1 month, 2 months, and then every 2 months)
Supplemented very-low-protein diet + phosphate restriction compared with moderate-protein diet
Li et al, 2011
RCT
Shanghai, China
n = 40
Patients on maintenance haemodialysis 3 times/week for more than 3 months with Kt/V above 1.2 and no residual renal function
Patients who also had uncontrolled hyperphosphataemia – serum phosphate > 5.5 mg/dl (i.e. > 1.8mmol/l) – after 3 months of conventional calcium carbonate treatment and low-calcium dialysate (1.25 mEq/l) therapy to maintain normal serum calcium levels
Baseline serum phosphate (mean SD):
Intervention = 2.34±0.46 mmol/l
Control = 2.30±0.5 mmol/l
See evidence tables in appendix E for full inclusion/exclusion criteria
0.8 g of protein/kg ideal body weight/day
500 mg phosphate/day
12 pills of KA (Ketosteril)/day
30–35 kcal/kg/day
1.0–1.2 g protein/kg ideal body weight/day according to the patient’s normal diet
8 weeks
Monitored at baseline, 1 week, 2 weeks, 4 weeks and 8 weeks
1
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Summary GRADE profile 8 Low-phosphorus protein supplement compared with no intervention 600
Outcome Number of Studies
Number of patients Effect Quality
Low-phosphorus protein supplement
No intervention
Serum phosphate
3-month follow-up
1 RCT
Guida et al, 2011
15 12 Absolute effect
MD = 0.7 mmol/l lower (95% CI:1.0 to 0.4 lower)
Low
Serum iPTH
(immunoradiometric assay)
3-month follow-up
1 RCT
Guida et al, 2011
15 12 Absolute effect
MD = 28.9 pmol/l lower (95% CI:36.5 to 21.3 lower)
(% of prescription, calculated from 3-day diet diary)
12-month follow-up
1 RCT
Jiang et al, 2009
18 91
Absolute effect
MD = 15.5% higher
Very low
Adverse events – malnutrition
(% of patients malnourished, as defined by SGA)
12-month follow-up
1 RCT
Jiang et al, 2009
18 91
Relative effect
OR = 0.54 (95% CI: 0.25 to 1.17)
Very low
Adverse events – hospitalisation
(% of patients hospitalised)
12-month follow-up
1 RCT
Jiang et al, 2009
20 101
Relative effect
OR = 0.46 (95% CI: 0.08 to 2.54)
Very low
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Serum iPTH
12-month follow-up
1 RCT
Jiang et al, 2009
18 91
Absolute effect
Difference in medians = 1.8 pmol/l higher
Very low
Study is a 3-arm trial (LPD versus sLPD versus MPD); the reviewer has therefore broken down the data into 2 pair-wise comparisons, with the population of the common comparator (the MPD group) divided in 2 for the analysis: for LPD versus MPD, n (MPD) = 9; for sLPD versus MPD (see GRADE profile below), n (MPD) = 8 (except for ‘adverse events [hospitalisation]’: for LPD versus MPD, n [MPD] = 10; for sLPD versus MPD, n [MPD] = 10)
(% of prescription, calculated from 3-day diet diary)
12-month follow-up
1 RCT
Jiang et al, 2009
18 81 Absolute effect
MD = 3% higher
Very low
Adverse events – malnutrition
(% of patients malnourished, as defined by SGA)
12-month follow-up
1 RCT
Jiang et al, 2009
0% 20%1
Absolute effect
20 fewer per 100
Very low
Adverse events – hospitalisation
(% of patients hospitalised)
12-month follow-up
1 RCT
Jiang et al, 2009
5/20 7/101
Relative effect
OR = 0.62 (95% CI: 0.12 to 3.21)
Absolute effect
11 fewer per 100 (48 fewer to 18 more)
Very low
Serum iPTH 1 RCT 18 81 Absolute effect Very low
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12-month follow-up Jiang et al, 2009 Difference in medians = 16.0 pmol/l lower
Study is a 3-arm trial (LPD versus sLPD versus MPD); the reviewer has therefore broken down the data into 2 pair-wise comparisons, with the population of the common comparator (the MPD group) divided in 2 for the analysis: for sLPD versus MPD, n (MPD) = 8; for LPD versus MPD (see GRADE profile above), n (MPD) = 9 (except for ‘adverse events [hospitalisation]’: for LPD versus MPD, n [MPD] = 10; for sLPD versus MPD, n [MPD] = 10)
Management of hyperphosphataemia NICE clinical guideline DRAFT (October 2012) Page 47 of 248
3.2.3.4 Very-low-quality evidence from the RCT of 27 patients showed that, 634
as a percentage of the prescribed protein intake, those on a very-635
low-protein diet exceeded the relevant prescription to a greater 636
extent than those on a moderate-protein diet at 12 months 637
(MD 15.5% more)14. 638
3.2.3.5 Very-low-quality evidence from the RCT of 27 patients found that 639
8.2% fewer patients were defined as malnourished on a very-low-640
protein diet compared to a moderate-protein diet (OR 0.54 [95% CI 641
0.25 to 1.17]), although the difference was not statistically 642
significant12. 643
3.2.3.6 Very-low-quality evidence from the RCT of 30 patients found that 644
15% fewer patients were hospitalised on a very-low-protein diet 645
compared to a moderate-protein diet (OR 0.46 [95% CI 0.08 to 646
2.54]), although the difference was not statistically significant12. 647
Important outcomes 648
3.2.3.7 Very-low-quality evidence from the RCT of 27 patients showed a 649
very-low-protein diet to be associated with a median serum PTH 650
level 1.8 pmol/l higher than in patients on a moderate-protein diet at 651
12 months12. 652
A very-low-protein diet supplemented with keto acids compared with a 653
moderate-protein diet 654
Critical outcomes 655
3.2.3.8 Very-low-quality evidence from 1 RCT of 26 patients showed a 656
very-low-protein diet supplemented with a mixture of keto acids and 657
amino acids to be associated with a mean serum phosphate level 658
0.22 mmol/l lower (95% CI -0.58 to 0.14) than in patients on a 659
moderate-protein diet at 12 months. 660
14
Note: actual intake fell into the ‘low-protein’ rather than the ‘very-low-protein’ range; actual protein
intake in the very-low-protein diet group was 0.90 g/kg/day and 0.97 g/kg/day in the moderate-protein
diet group (MD 0.07 lower [95% CI -0.19 to 0.05]).
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3.2.3.9 Very-low-quality evidence from the RCT of 26 patients showed that, 661
as a percentage of the prescribed protein intake, those on a 662
very-low-protein diet supplemented with a mixture of keto acids and 663
amino acids exceeded the relevant prescription to a greater extent 664
than those on a moderate-protein diet when estimated by 3-day 665
diet diary at 12 months (MD 3% more). 666
3.2.3.10 Very-low-quality evidence from the RCT of 26 patients found that 667
20% fewer patients were defined as malnourished on a 668
very-low-protein diet supplemented with a mixture of keto acids and 669
amino acids compared to a moderate-protein diet (no patients in 670
the supplemented very-low-protein diet group were defined as 671
malnourished). 672
3.2.3.11 Very-low-quality evidence from 1 RCT of 30 patients found that 673
10% fewer patients were hospitalised among those on a 674
very-low-protein diet supplemented with a mixture of keto acids and 675
amino acids compared to those on a moderate-protein diet 676
(OR 0.62 [95% CI 0.12 to 3.21]), although the difference was not 677
statistically significant. 678
Important outcomes 679
3.2.3.12 Very-low-quality evidence from 1 RCT of 26 patients showed a 680
very-low-protein diet supplemented with a mixture of keto acids and 681
amino acids to be associated with a median serum PTH level 682
16.0 pmol/l lower than in patients on a moderate-protein diet at 683
12 months. 684
A very-low-protein diet supplemented with keto acids + phosphate 685
restriction compared with a moderate-protein diet 686
Critical outcomes 687
3.2.3.13 Very-low-quality evidence from 1 RCT of 40 patients showed a 688
very-low-protein and low-phosphate diet supplemented with a 689
mixture of keto acids and amino acids to be associated with a 690
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mean serum phosphate level 0.5 mmol/l lower (95% CI -0.7 to -0.3 691
i.e. statistically significant) than in patients on a moderate-protein 692
diet at 12 months15,16. 693
3.2.3.14 Very-low-quality evidence from 1 RCT of 40 patients showed that, 694
as a percentage of the prescribed protein intake, those on a 695
very-low-protein and low-phosphate diet supplemented with a 696
mixture of keto acids and amino acids exceeded the relevant 697
prescription to a greater extent than those on a moderate-protein 698
diet when estimated by normalised protein catabolic rate at 699
8 weeks (MD 9.6% more)13. 700
3.2.3.15 Very-low-quality evidence from the same RCT showed that, as a 701
percentage of the prescribed protein intake, those on a 702
very-low-protein and low-phosphate diet supplemented with a 703
mixture of keto acids and amino acids exceeded the relevant 704
prescription to a greater extent than those on a moderate-protein 705
diet when estimated by 3-day diet diary at 8 weeks (MD 7.5% 706
more)17. 707
3.2.3.16 Very-low-quality evidence from 1 RCT of 40 patients found no 708
difference in the number of patients defined as malnourished on a 709
very-low-protein and low phosphate diet supplemented with a 710
mixture of keto acids and amino acids compared to a 711
moderate-protein diet (0 in both groups)13. 712
713
714
15
Note: actual intake in the intervention group fell into the ‘low-protein’ rather than the ‘very-low-
protein’ range, and into the ‘high-protein’ rather than the ‘moderate-protein’ range in the control group
when estimated by the normalised protein catabolic rate (the difference in actual intake between the
groups was, however, statistically significant). 16
Phosphate intake was considerably reduced in the intervention group compared to the control (mean
difference [95% CI] at 8 weeks = -305 mg/day [-376 to -234]). 17
Note: actual intake in the intervention group fell into the ‘low-protein’ rather than the ‘very-low-
protein’ range when estimated by 3-day diet diary (the difference in actual intake between the groups
was, however, statistically significant).
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3.2.4 Evidence to recommendations 715
Relative value of different outcomes
The GDG discussed the relative importance of the outcomes and agreed that those considered critical or important for decision-making were the same as those in the review of dietary management in patients with CKD stage 4 or 5 who are not on dialysis.
Trade-off between benefits and harms
Protein restriction (without supplementation with keto and amino acids) had only a marginal positive impact upon serum phosphate and PTH; both increased during the study, only to a lesser extent than among those with a ‘normal’ protein intake. The effect of protein restriction without supplementation on the incidence of malnutrition and hospitalisation was not significantly different from that of people with a ‘normal’ protein intake. The GDG noted that adherence with the prescribed protein restriction was very poor, with no significant difference in the actual intake between the 2 groups. This was the likely cause of the similarity in the results of the 2 groups. The GDG was concerned that the risk of malnutrition on a protein restricted diet without supplementation could not be determined. The GDG was also concerned that the study may have been underpowered in terms of sample size, further reducing the sensitivity to detect malnutrition. The small number of events recorded support the suggestion that this study was underpowered.
The addition of keto and amino acid supplements to protein restricted diets did not have a significantly different effect on serum phosphate levels compared to those with a ‘normal’ protein intake, although it did significantly improve adherence, as well as the incidence of malnutrition and hospitalisation. However, the GDG was again concerned that the study may have been underpowered in terms of sample size, reducing their sensitivity to detect malnutrition.
Concerns relating to restricted diets also included ‘sub-clinical’ malnutrition that may easily be missed in those on low- or very-low-protein diets. It was noted that in current practice, clinicians aim to increase protein, or at least maintain patients’ dietary intakes at reference nutrient intake levels, rather than restrict nutritional intake in patients on dialysis.
The GDG noted that supplementation with keto and amino acids may simply mediate the harmful effects of very-low-protein diets, leading to the reduced rates of malnutrition and hospitalisation rates observed. There are a number of possible explanations for this association, such as a beneficial effect on nutritional status through substitution for the restricted protein or a positive impact relating to the alleged phosphate-binding properties of calcium-based keto acids, although there is currently insufficient evidence available.
If patients are prescribed a very-low-protein diet supplemented with keto and amino acids, the GDG was concerned that non-adherence with the supplements might still lead to malnutrition; the additional pill burden of these supplements was considered a significant concern in this area. However, no data were found on patient adherence with keto and/or amino acid supplements.
The GDG did not feel that the evidence for benefits outweighed the possible risks and disadvantages of significant protein restriction in these patients (whether supplemented by keto and amino acids or not), particularly given the lack of effect upon serum phosphate.
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Therefore the GDG did not feel it appropriate to recommend diets based on protein restriction for the management of hyperphosphataemia in adults on dialysis. The recommended nutrient intake for protein in adults on haemodialysis is a minimum of 1.1 g/kg of ideal body weight/day; the recommended nutrient intake for protein in adults on peritoneal dialysis is a minimum of 1.1 to 1.2 g/kg of ideal body weight/day. For the reasons outlined above, the GDG did not feel that the evidence was sufficient to recommend restricting protein intake below these levels. Furthermore, given that very-low-protein diets supplemented with keto and amino acids also have a large pill burden, the GDG felt that phosphate binders would be more clinically appropriate than supplementation with keto and amino acids.
In children, the GDG felt that malnutrition is a greater concern than hyperphosphataemia. Progressive CKD is often associated with decreases in spontaneous dietary protein intake and dialysis with a loss of protein from the body; effects that clinicians feel are a priority for treatment given the particular need to maintain growth and adequate nutritional status. For these reasons, accompanied by the lack of paediatric evidence available, the GDG could not recommend a diet based upon protein restriction for children. In addition, as the GDG felt that, for a variety of reasons, it would never be part of standard practice in the management of hyperphosphataemia to limit a child’s protein intake, it would be inappropriate to make such a recommendation. Recommended protein intakes are instead age-specific according to reference nutrient intakes, plus additional protein to attempt to compensate for the potential of dialytic and other protein losses.
Although observed within a short follow-up period, the GDG felt that, in the only study to examine it, limiting phosphate intake had a large impact in reducing serum phosphate, particularly when compared to the effectiveness of a similar intervention differing only in its lack of prescribed phosphate restriction. This result reflected the observations of the GDG in their own clinical and personal experience. The group considered advising patients to reduce their intake of phosphate-rich foods to reflect good clinical practice.
Exchanging a proportion of dietary protein with a low-phosphate protein substitute seems to be an effective intervention, with significant effects upon serum phosphate and PTH. The GDG was, however, concerned that the follow-up was relatively short, the sample size was small, and the study was not UK-based (Italy). These observations lead to reduced confidence in the results observed and uncertainty over the intervention’s long-term effects (for example, on nutritional status). There was also uncertainty as to the sustainability of the low-phosphate protein supplement as a long-term intervention, particularly since there is no data available on adherence or patients’ views on the intervention (such as quality of life data) and the GDG was unsure of its palatability. Additionally, it was felt that this could constitute further and unwelcome ‘medicalisation’ of the life of patients with advanced CKD.
The group felt that more evidence is required before a recommendation can be made for the use of such low-phosphate protein supplements as an intervention for the management of hyperphosphataemia. However, extending the principle that dietary restriction of food and drink rich in phosphate is desirable, the GDG
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felt that low-phosphate options should be considered in instances where patients require nutritional supplements and/or substitutes to maintain protein intake.
Economic considerations
This question was not prioritised for health economic analysis as the majority of resource inputs are outside of NHS personal social services perspective.
Quality of evidence
There was considerable variation across the 3 included papers in terms of design and the interventions used, and no evidence was found for children. The GDG noted that the limited evidence provided little for consideration. In particular, little significant or reliable evidence was found to suggest that low-protein prescriptions are effective in managing serum phosphate, although it was felt that this could be a consequence of the poor quality of the evidence and the general failure to meet the high requirements of protein restriction.
The GDG was also concerned with the applicability of the evidence to the NHS given that the papers were not UK-based, in particular the 2 based in China. It was felt that generalisability was further limited by the short follow-up periods in 2 of the papers and the relatively small sample sizes across all 3 papers.
The GDG raised concerns relating to the measures used for 2 of the outcomes. The incidence of adherence with dietary prescription was not regularly reported; instead, papers reported mean actual intakes for each group, which the reviewer then compared to prescriptions, producing a surrogate measure of adherence. The GDG also had reservations regarding the known variability of PTH measurements.
It was noted that 1 study was powered for purposes other than the management of serum phosphate, focusing instead on the preservation of residual renal function. Outcomes of interest in this study were therefore secondary.
In another study, the patients’ pre-study regimens of phosphate binders were continued. Although use was well-balanced at baseline, these concurrent treatments may have influenced the good results observed for serum phosphate and PTH in those on the low-phosphate protein substitute.
Reporting across the studies was poor. For example, details of study designs were often unclear and results were not always cited in the text of the papers, requiring the reviewer to read the data off available graphs. Additionally, it was not always clear what dietary advice was provided, in what manner it was provided, or who provided it. Unit-of-analysis errors were also common, with analyses not following the intent-to-treat principle.
Other considerations
Keto and amino acids supplementation is not currently used in practice in the UK; therefore, it was felt that making recommendations about their use without further evidence on their safety and effectiveness would be premature.
Usual practice is to advise a reduction in certain types of food: generally those with a high phosphate to protein ratio, such as some dairy products and nuts, or food and drinks with high levels of phosphate additives, such as cola drinks or processed foods. The emphasis is more on the phosphate content of food and drinks rather than focusing on the restriction of protein.
There is limited guidance available regarding recommended nutrient
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intakes for phosphate in adults with CKD. There is some guidance available for children, but the evidence informing this guidance is limited.
The GDG noted relevant recommendations in ‘Chronic kidney disease’ (NICE clinical guideline 73).
716
3.2.5 Recommendations and research recommendations for 717
dietary management for people with stage 5 CKD who are 718
on dialysis 719
Recommendations 720
Recommendation 1.1.3
Give information about controlling intake of phosphate-rich foods (in particular
foods with a high phosphate content per gram of protein, as well as food and
drinks with high levels of phosphate additives) to control serum phosphate,
while avoiding malnutrition by maintaining a protein intake at or above the
minimum recommended level. For those on dialysis, take into account
possible dialysate protein losses.
Recommendation 1.1.4
If a nutritional supplement is needed to maintain protein intake in children and
young people with hyperphosphataemia, offer a supplement with a lower
phosphate content, taking into account patient preference.
721
3.3 Patient information strategies 722
3.3.1 Review question 723
For people with stage 4 or 5 CKD, both those on dialysis and those who are 724
not, are patient information strategies effective at promoting adherence to 725
phosphate-lowering dietary interventions, or in the management of serum 726
phosphate and its associated outcomes? Which patient information strategies 727
management tools (such as medication charts, individualised menus and food 740
exchange lists) or competitions. 741
For this review question, papers were identified from a number of different 742
databases (Medline, Medline in Process, Embase, the Cochrane Database of 743
Systematic Reviews, the Centre for Reviews and Dissemination’s DARE and 744
HTA databases, and PsycINFO) using a broad search strategy, pulling in all 745
papers relating to the use of patient information and education interventions to 746
promote adherence to phosphate-lowering dietary interventions in patients 747
with CKD. RCTs, non-randomised controlled trials (non-RCTs) and controlled 748
before-and-after studies comparing a patient education intervention with either 749
no intervention or another comparator were considered for inclusion. 750
Trials were excluded if: 751
the population included people with CKD stages 1 to 3 or 752
the trial examined only the information to be covered by education, rather 753
than the strategy by which it should be delivered. 754
755
From a database of 1143 abstracts, 112 full-text articles were ordered 756
(including 9 identified through review of relevant bibliographies) and 9 papers 757
(7 RCTs, 1 cluster RCT and 1 non-RCT) describing 9 primary studies were 758
selected (Ashurst & Dobbie, 2003; Baraz et al, 2010; Campbell et al, 2008; 759
Chen et al, 2006; Ford et al, 2004; Morey et al, 2008; Shaw-Stuart & Stuart, 760
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2000; Sullivan et al, 2009; Tanner et al, 1998). No paediatric studies meeting 761
the inclusion criteria were found. Table 3 lists the details of the included 762
studies. 763
The reviewer analysed studies together where possible, producing a number 764
of pooled comparisons. These were structured as follows: 765
Patient education versus no intervention (beyond usual care) 766
Three papers were included in this pooled comparison (2 RCTs and 1 cluster 767
RCT). Data from the 2 RCTs could be meta-analysed for knowledge scores 768
and serum phosphate. The cluster RCT data for these outcomes could not be 769
included in the meta-analysis because of the unit-of-analysis error found 770
within the paper (data were analysed at the participant- rather than cluster-771
level, and insufficient information was available for the reviewer to correct 772
this). Therefore, this cluster RCT data, along with the other non-meta-773
analysed data from each paper, was recorded individually. 774
Interventions including counselling-based education versus written material 775
alone 776
Two papers were included in this pooled comparison (both RCTs). Because of 777
the absence of common outcomes between the papers, no meta-analysis was 778
performed; data for each outcome from each paper were recorded 779
individually. 780
Multiple component interventions versus single component interventions 781
Four papers were included in this pooled comparison (all RCTs). Data from all 782
4 papers could be meta-analysed for serum phosphate. The other, non-meta-783
analysed data from each paper were recorded individually. 784
Multiple component interventions versus specific single component 785
interventions 786
These comparisons were designed to further differentiate the more general 787
comparison above into the specific single component comparators of the 5 788
included papers: individual patient counselling alone (2 papers), written 789
material alone (1 paper) and video education alone (1 paper). Data from the 2 790
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papers comparing multiple component interventions against individual patient 791
counselling alone could be meta-analysed for serum phosphate. The other, 792
non-meta-analysed data from each paper were recorded individually. 793
Significant heterogeneity was observed across all of the included studies, 794
particularly in relation to the structure and content of the interventions studied. 795
There was also considerable variation in the locations of many of these 796
studies, with few conducted in the UK. 797
Many of the papers did not report adherence, an outcome considered critical 798
to decision-making by the GDG, in a binary manner. Rather than defining a 799
patient as ‘adherent’ or ‘non-adherent’ with the dietary prescriptions, authors 800
often provided mean levels of actual protein intake. In order to use these 801
continuous measures as indicators of adherence that could be compared 802
across studies and interventions, the reviewer converted these mean actual 803
intake levels into a percentage of the prescribed level. For example: 804
Prescribed protein intake
Reported mean actual protein intake
Actual protein intake expressed as a percentage of the prescribed level
0.6 g/kg of body weight/day
0.72 g/kg of body weight/day
120% of prescription
that is, actual intake exceeded prescription by 20%
805
Additionally, for the purpose of this review, the summary term 'self-806
management tool' has been used to collectively describe the aids used to help 807
patients in managing their dietary intake or serum phosphate levels in 808
response to the education provided. These tools range from a fridge magnet 809
detailing high-phosphate foods, to an individualised tracking chart that used 810
visual goals to engage patients in achieving phosphate control. 811
Mean differences (MDs) were calculated for continuous outcomes and odds 812
ratios (ORs) for binary outcomes, as well as the corresponding 95% 813
confidence intervals where sufficient data were available. Where meta-814
analysis was possible, a forest plot is also presented. 815
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Table 3 Summary of included studies on patient information strategies 816
Study Population Intervention Control
Follow-up
Regular individual oral counselling + written educational material + self-management tool (serum phosphate control) compared with no intervention (beyond usual care)
Ford et al, 2004
RCT
Louisiana, US
n = 70
(63 completed the study)
Haemodialysis patients
Mean serum phosphate of > 6.0 mg/dl (i.e. > 1.9 mmol/l) for 3 months prior to the study
Baseline serum phosphate
(mean SD):
Intervention = 2.2 0.2 mmol/l
Control = 2.3 0.4 mmol/l
See evidence tables in appendix E for full inclusion/exclusion criteria
In addition to routine care, 20–30 mins/month of diet education focusing on improving serum phosphate control
Education sessions:
Dietitian stressed the importance of all aspects of phosphate control: prevention of renal bone disease; foods high in phosphate; medications; importance of diet, dialysis and drug therapy
Educational tools (bright and attention-grabbing, and including analogies to which patients could relate) included: posters/flipcharts; picture handouts; puzzles; individualised phosphate tracking tool (self-monitoring phosphate levels using visual goals)
Routine care (no education):
Review of monthly laboratory report by the dietitian during monthly nutrition rounds
Although the dietitian did discuss abnormal phosphate levels with these patients, additional patient education materials were not provided
6 months
Monitored monthly
One-off individual oral counselling + written educational material + self-management tool (serum phosphate control) compared with no intervention (beyond usual care)
Sullivan et al, 2009
Cluster RCT
Ohio, US
n = 279
Long-term haemodialysis for at least 6 months
Most recent serum phosphate level and mean level for the previous 3 months both above 5.5 mg/dl (i.e. above 1.8 mmol/l)
18 years or older
Baseline serum phosphate
(mean SD):
Intervention = 2.3 0.4 mmol/l
Control = 2.3 0.3 mmol/l
See evidence tables in appendix E for full inclusion/exclusion criteria
Face-to-face education:
Coordinator met in person with each intervention patient during a dialysis treatment in the first month of the study
Provided approximately 30 minutes of education regarding phosphorus-containing additives and their effect on the phosphate content of foods
Educational device:
A small magnifier in a plastic case, on which common phosphorus-containing additives were printed
Patients were instructed to use the magnifier and list of additives when purchasing food to avoid any items whose ingredient lists include phosphorus-containing additives
Written material:
Continued to receive pre-study nutritional care from their facility’s registered dietitian, which included nutritional status assessment, monthly laboratory test result review (including serum phosphorus levels), and education regarding the renal diet (including the deleterious effects of hyperphosphataemia, dietary sources of phosphorus and ways to limit phosphorus intake)
A study coordinator telephoned control patients during the second month of the study and asked questions about how often they read nutrition facts labels and ingredient lists, ate meals from fast-food restaurants, and received phosphorus-related recommendations from their facility dietitian
Did not receive any education or feedback from
3 months
Monitoring unclear – at baseline and at 3 months?
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Each patient also received a handout for each fast-food restaurant the patient reported eating at more than once a month, tailored to the menus of common fast-food chains in the area. Each handout listed specific menu items to be avoided because they contained phosphorus additives, as well as better choices that were free of phosphorus additives and were compatible with other renal dietary requirements.
Study coordinator telephoned patients during the second month to reinforce the instructions and answer any questions
study coordinators
One-off individual oral counselling + written educational material + self-management tool (serum phosphate control) compared with written material alone
Ashurst & Dobbie, 2003
RCT
London, UK
n = 58
(56 analysed)
Dialysis patients with serum phosphate of at least one value above 1.7 mmol/l during 3-month monitoring
Over 18 years
Clinically stable
Baseline serum phosphate (mean):
Intervention = 1.96 mmol/l
Control = 1.98 mmol/l
See evidence tables in appendix E for full inclusion/exclusion criteria
Teaching session (approx 40 minutes in length), administered by a single, trained dietitian on an individual basis
Used an education tool to improve the patients’ knowledge of phosphate balance in dialysis patients and to assist patients in controlling their own phosphate level.
The education package, ‘A Patient’s Guide to Keeping Healthy: Managing Your Phosphate’ comprised:
A teaching booklet which included: a cartoon and written description of phosphate and calcium functions, absorption and excretion; information on PTH and vitamin D function, their interaction, ways to control their balance, and the consequences of increased levels in the body; therapeutic approaches to phosphate management and the patient’s role, including diet, dialysis and phosphate binders; emphasized the importance of adherence with treatment and medications
Medication record chart - a sheet given to each subject in both groups - one side had the patient’s personal details and phosphate binder prescription, as well as a table to be filled in with the medication dose taken at each meal, the other side had blood results for phosphate, calcium and Ca x P product and the normal
Written material delivered on the dialysis unit by the renal haemodialysis dietitian, who was not the research dietitian
Renal staff nurses or physicians refer those patients with persistent hyperphosphataemia for dietary advice.
The dietetic consultation involves a diet history to assess the patient’s intake, followed by phosphate restriction advice based on an A4 double-sided diet sheet. This diet sheet briefly explains about hyperphosphataemia and its association with bone disease; there is also a list of high-phosphate foods to be avoided and suitable low-phosphate alternatives.
Patients were given the same medication record chart as the intervention group
Patients in the control group were only told their biochemistry results if they asked or if they were above the recommended levels; they did not receive the education session nor the education booklet
3 months
Monitored monthly
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range for each
Refrigerator magnet
Patients were asked to complete the medication chart for 2 consecutive weeks
Gave appropriate individual advice about diet, medication adherence and lifestyle
One-off individual oral counselling + written educational material + self-management tool (dietary management) compared with individual oral counselling
Chen at al, 2006
RCT
Peking, China
n = 70
Patients on peritoneal dialysis for 3 months
Clinically stable
Baseline serum phosphate
(mean SD):
Intervention = 1.67 0.23 mmol/l
Control = 1.67 0.25 mmol/l
See evidence tables in appendix E for full inclusion/exclusion criteria
All patients received intensive training (‘traditional’ method) within 2 weeks of catheter implementation (patients enrolled 3 months after dialysis)
Detailed information about food contents and appropriate weight were taught by an experienced dietitian
Portion-sized food aids were used
Patients educated to maintain a daily protein intake level of 0.8–1.2 g/kg/day
Patients taught to correctly record their 3-day dietary intakes
In addition, intervention group patients received:
Education utilising: individualised menu from the dietitian based on food preferences; an exchange list as a reference – every food in 1 list contains an equivalent amount of protein; patients were taught how to correctly use their menu by referring to the exchange list; portion-sized food aids
All patients received intensive training (‘traditional’ method) within 2 weeks of catheter implementation (patients enrolled 3 months after dialysis)
Detailed information about food contents and appropriate weight were taught by an experienced dietitian
Portion-sized food aids were used
Patients educated to maintain a daily protein intake level of 0.8 to 1.2 g/kg/day
Patients taught to correctly record their 3-day dietary intakes
1 month
Pre-and post-intervention (at 1 month)
Regular individual oral counselling (dietary management) compared with written material alone
Campbell et al, 2008
RCT
Brisbane, Australia
n = 62
(50 analysed)
Adults (older than 18 years)
CKD with eGFR < 30 ml/min/1.73 m
2
Not previously seen by a dietitian for stage 4 CKD
Absence of malnutrition from a
Administered by a single dietitian
Individualised dietary prescription, including 125–146 kj/kg/day (i.e. 30–35 kcal/kg/day) and 0.75–1.0 g protein/kg/day
The patients were provided with an initial individual consultation at baseline of up to 60 minutes duration followed by a telephone consultation, commonly of 15–30 minutes duration, bi-weekly for the first month, then monthly
Patients received generic nutrition information for patients with CKD, as provided in regular practice
12 weeks
Monitoring unclear – pre- and post-intervention?
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cause other than CKD
Not expected to require RRT within 6 months
Baseline serum phosphate
(mean SD):
Intervention = no data available
Control = no data available
See evidence tables in appendix E for full inclusion/exclusion criteria
Structure:
1. Clinical Data
Initial: medical history; dialysis treatment plan; anthropometry; biochemistry
Follow-up: changes in medical treatment, medications etc; changes in biochemistry
2. Interview
Initial: nutrition assessment and appetite; evaluate food record; functional ability; psychosocial issues; readiness to change
Follow-up: 24-hour dietary recall; recall of changes made
3. Determine the treatment plan: discussion on the role and effect of diet on renal disease; nutrition prescription; development of goals and target strategies
4. Self-management training: goal setting; menu planning; education on identifying protein, energy and other nutrients; recipe modification; label reading
5. Expected outcomes: meeting set goals; making appropriate food choice; maintains body weight, muscle and fat stores; biochemistry within range
Regular individual oral counselling + written material (serum phosphate control) compared with one-off individual oral counselling
Morey et al, 2008
RCT
London, UK
n = 67
(60 completed the study)
On maintenance haemodialysis for > 6 months
Mean serum phosphate level persistently above of < 1.8 mmol/l over the 3-month review period
Age older than 18 years
Baseline serum phosphate
(mean SD):
Intervention = 2.05 0.5 mmol/l
Individual review by a specialist renal research dietitian – assessed/advised monthly from baseline until the end of the study period
Dietitian assessed subjects’ diets using diet histories, and made an approximation of dietary phosphate content and nutritional adequacy, as well as phosphate binder adherence by self-report against prescription
Subjects were advised and educated about dietary phosphate restriction and adherence with phosphate binder prescription while maintaining nutritional adequacy, and a variety of strategies were employed to encourage dietary modification, including: motivational counselling; negotiation; behaviour modification therapy; reminders; reinforcement; supportive care; both written
Individual review by a specialist renal research dietitian - assessed/advised infrequently, that is, at baseline and at the end of the study period
Dietitian assessed subjects’ diets using diet histories, and made an approximation of dietary phosphate content and nutritional adequacy, as well as phosphate binder adherence by self-report against prescription
Subjects were advised and educated about dietary phosphate restriction and adherence with phosphate binder prescription while maintaining nutritional adequacy
6 months
Monitored monthly
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Control = 2.24 0.5 mmol/l
See evidence tables in appendix E for full inclusion/exclusion criteria
and verbal
The research dietitian individualised strategies to each subject
Patients were educated on how to match phosphate binders to the phosphate content of a meal; the dietitian also liaised with the medical team to adjust phosphate binder prescriptions to better match the needs of the individual patient
Regular individual behavioural feedback and contracting (serum phosphate control) compared with no intervention (beyond usual care)
Tanner et al, 1998
RCT
Alabama, US
n = 40
(38 completed the study)
On haemodialysis for at least 2 months
Age range 26-78 years
A history of non-adherence for at least 1 month (non-adherence was defined as: interdialytic weight gain of 3 kg or greater on weekdays and 4 kg or greater on weekends for 6 of the 12 dialysis sessions and/or monthly serum phosphate levels of > 5.9 mg/dl (i.e. > 1.9 mmol/l))
Baseline serum phosphate
(mean SD):
Intervention = no data available
Control = no data available
See evidence tables in appendix E for full inclusion/exclusion criteria
Monthly progress reports and behavioural contracts were reviewed each month with subjects by the investigator; copies were given to the subjects
Monthly feedback included:
Posting of subject’s phosphorus level and number of acceptable IDWG on the monthly progress report – ‘smiley’ face stickers were used to represent acceptable values and ‘frown’ stickers for unacceptable values
The reports were used to educate subjects on acceptable and unacceptable phosphate values and IDWG
Provision of rewards, if indicated – subjects were provided with ‘smiley’ face stickers to wear for each criteria met, and an additional reward (stickers/candy) if both criteria were met
Instruction on recommended dietary behaviours
Setting of 1 or 2 monthly goals (increasing in complexity over time) to improve subjects’ phosphate and fluid control, which were written on a new contract; this contract was dated and signed by the investigator and subject
Review of previous month’s contract goals and progress – together, the subject and investigator identified reasons for non-adherence and/or improvement from the previous month
No intervention (usual care) 6 months
Serum phosphate data monitored (and provided for) each month; other outcomes were only monitored pre- and post-intervention
Video + oral counselling + competitive competition (serum phosphate control) compared with regular individual oral counselling + written material
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Shaw-Stuart & Stuart, 2000
Non-RCT
North Carolina, US
n = 81
Adult patients with end-stage renal failure
Currently receiving haemodialysis
Patients were not at risk for malnutrition
Baseline serum phosphate
(mean SD):
Intervention = 2.03 0.09 mmol/l
Control = 2.01 0.11 mmol/l
See evidence tables in appendix E for full inclusion/exclusion criteria
Educational program: ‘A Taste for Life’:
An educational, informational, motivational patient adherence program directed at dietary and medical regimens
Included: flip chart overviewing the basics of bone disease; ‘bone disease demonstrator’, which dramatised the progression of renal osteodystrophy without intervention; interactive educational modules; educational booklets; motivational posters; creative games and puzzles; videos
In-house educational materials depicting alternatives to high phosphate foods
In-centre achievement contest: ‘Bone Voyage’:
Group divided into teams: assembled to include a balanced sample of high and low adherence patients
Objective was to foster a competitive spirit and raise awareness of adherence in an effort to facilitate patient self-management
Pitted teams racing against each other in sailboats from a start to finish line on a game poster that hung in the centre
Movement of a team from start to finish depended on respective teams achieving goals set for the contest
Points were added up for each team, and at the end of the third month, the team with the most points won.
Prizes were awarded to winning teams and most improved patients each month and at the end of the 3 months
Patients were followed-up regularly by a staff dietitian and were counselled monthly concerning phosphate levels during the entire 9-month study period
Therapy was on an individual basis and involved:
Nutrition counselling consistent with the American Dietetic Association’s National Renal Diet
Instruction regarding the use of phosphate binders
In-house printed information supplemented verbal instruction
12 months
Monitored monthly
Oral interactive group counselling sessions + written material (general CKD + diet) compared with educational video viewed alone
Baraz et al, 2010
RCT
Tehran, Iran
n = 63
Aged older than 18 years
Receiving haemodialysis routinely 3 times a week
Receiving haemodialysis for at least 6 months
Patients invited to attend a class on the days after their haemodialysis sessions
Two educational sessions of up to 30 minutes
The principal investigator (a renal nurse expert) performed the teaching intervention
The education was didactic and interactive:
Individually approached during 2 consecutive dialysis sessions in a week
A 30-minute educational film was shown to each patient while they were having haemodialysis – each patient was started on haemodialysis, and then 1-2 hours after initiation of haemodialysis and ensuring that the patient was stable and
2 months
Monitored bi-monthly
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817
Summary GRADE profile 12 Patient education compared with no intervention (beyond usual care) 818
Outcome Number of Studies
Number of patients Effect Quality
Patient education No intervention (beyond usual care)
Changes in adherence-promoting behaviours - frequency of reading ingredients lists
(measured on scale from 0–100; 0 = lowest reading behaviour score; 100 = highest possible reading behaviour score)
3-month follow-up
1 cluster RCT
Sullivan et al, 2009
145 134 Absolute effect
MD = 22 higher (95% CI:15 to 30 higher)
Very low
Changes in adherence-promoting behaviours - frequency of reading nutritional fact labels
(measured on scale from 0–100; 0
1 cluster RCT
Sullivan et al, 2009
145 134 Absolute effect
MD = 9% higher (95% CI:1 to 17 higher)
Very low
Living in a home setting
Not received any educational intervention in the past
Baseline serum phosphate
(mean SD):
Intervention = 1.99 0.49 mmol/l
Control = 2.02 0.47 mmol/l
Patients could ask questions at the time of the class
An explicitly interactive portion of the program was held at the end of the class - in this part of the session, patients were encouraged to offer support to each other
At the end of group sessions, each patient received a teaching booklet (‘A Patient Guide to Controlling Dietary Regimen’) to take home
The 2 interventions had similar content, covering:
General knowledge about ESRD and dietary management for haemodialysis
Identification of restricted/non-restricted food
Fluid restrictions
Possible reasons for adherence and non-adherence
ready, they were invited to watch the film
The 2 interventions had similar content, covering:
General knowledge about ESRD and dietary management for haemodialysis
Identification of restricted/non-restricted food
Fluid restrictions
Reasons for adherence and possible reasons for non-adherence
Abbreviations: BMI, body mass index; Ca x P product, calcium-phosphorus product; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; IDWG, inter-dialytic weight gain; PTH, parathyroid hormone; RCT, randomised controlled trial; RRT, renal replacement therapy; SD, standard deviation.
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6-month follow-up 1 Data available for outcome inappropriate for meta-analysis across studies
2 Data extracted from the cluster RCT suffered from a unit-of-analysis error (analysed at the level of the individual patient, not at the level of the cluster); there was insufficient
data available for the reviewer to reduce the size of the trial to its effective sample size, and therefore the data will not be pooled with the other serum phosphate data 3 Scores in both groups, at both baseline and at 6 months, were interpreted as 'moderate'
4 Scores in both groups, at both baseline and at 6 months, were interpreted as 'high'
Single component education/information interventions
Adherence to protein prescription
(number of patients that reached prescribed targets were considered adherent - dietary protein intake greater than 0.8 g/kg/day and less than 1.2 g/kg/day)
1-month follow-up
1 RCT
Chen et al, 2006
20/35
(57.1%)
8/35
(22.9%)
Relative effect
OR = 4.5 (95% CI 1.6 to 12.66):
Absolute effect
34 more per 100 (9 more to 56 more)
Very low
Adherence to protein prescription
(% of prescription, calculated from 3-day diet diary)
1-month follow-up
1 RCT
Chen et al, 2006
35 35 Absolute effect
MD = 0%
Very low
Phosphate binder requirement
(number of patients in whom phosphate binders could be withdrawn)
(number of patients that reached prescribed targets were considered adherent - dietary protein intake greater than 0.8 g/kg/day and less than 1.2 g/kg/day)
1-month follow-up
1 RCT
Chen et al, 2006
20/35
(57.1%)
8/35
(22.9%)
Relative effect
OR = 4.5 (95% CI 1.6 to 12.66):
Absolute effect
34 more per 100 (9 more to 56 more)
Very low
Adherence to protein prescription
(% of prescription, calculated from 3-day diet diary)
1-month follow-up
1 RCT
Chen et al, 2006
35 35 Absolute effect
MD = 0%
Very low
Phosphate binder requirement
(number of patients in whom phosphate binders could be withdrawn)
6-month follow-up
1 RCT
Morey et al, 2008
1/34
(2.9%)
1/33
(3.0%)
Relative effect
OR = 0.97 (95% CI: 0.06 to 16.17)
Absolute effect
0 fewer per 100 (from 3 fewer to 31 more)
Very low
Serum phosphate (pooled)
3-month follow-up (mean)
1 RCT
Chen et al, 2006
69 68 Absolute effect
MD = 0.01 mmol/l (95% CI: 0.1 lower to
Very low
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written educational material + self-management tool) compared with 971
written material alone 972
Important outcomes 973
3.3.3.19 Very-low-quality evidence from 1 RCT of 56 patients showed multi-974
component educational interventions to be associated with a mean 975
serum phosphate level 0.34 mmol/l lower (95% CI -0.58 to -0.10 i.e. 976
statistically significant) at 3 months than patients who received 977
written educational material alone. 978
Multiple component interventions (interactive group counselling + 979
written educational material) compared with video education alone 980
Important outcomes 981
3.3.3.20 Very-low-quality evidence from 1 RCT of 63 patients showed that 982
after 2 months there was no statistically significant difference in the 983
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number of patients considered to have serum phosphate within 984
acceptable limits between those who received multi-component 985
educational interventions and those who received video education 986
alone (OR 0.93 [95% CI 0.34 to 2.52]). 987
3.3.3.21 Very-low-quality evidence from the RCT of 63 patients showed 988
multi-component educational interventions to be associated with a 989
mean serum phosphate level 0.05 mmol/l lower (95% CI -0.22 to 990
0.13) than in patients who received individual patient counselling 991
alone at 2 months, although the difference was not statistically 992
significant. 993
Oral counselling + video + competition compared with regular individual 994
oral counselling + written material 995
Important outcomes 996
3.3.3.22 Very-low-quality evidence from 1 non-RCT of 81 patients showed 997
the intervention (oral counselling and a video relating to serum 998
phosphate control, plus a competition) to be associated with a 999
mean serum phosphate level 0.19 mmol/l lower (95% CI -0.24 to 1000
-0.14 i.e. statistically significant) at 12 months than that in patients 1001
who received the control (oral counselling and written material 1002
relating to dietary management and phosphate binder use for 1003
serum phosphate control). 1004
3.3.4 Evidence to recommendations 1005
Relative value of different outcomes
The GDG discussed the possible outcomes and agreed that serum phosphate, changes in adherence-promoting behaviours, and adherence with dietary prescription were critical to their decision-making. Phosphate binder requirement, changes in knowledge and changes in beliefs and attitudes towards health were considered important, though not critical.
The lack of evidence led to limited differentiation in the relative value of these outcomes, although following review of the evidence serum phosphate featured prominently in the GDG’s discussions.
Although important to decision making, it was felt that adherence-promoting behaviours, knowledge and beliefs and attitudes towards health were only meaningful in the management of hyperphosphataemia in the context of an associated change in serum phosphate levels, rather than as endpoints themselves. In isolation,
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these outcomes do not necessarily translate directly into a meaningful effect in the management of serum phosphate. Therefore when interpreting data relating to these 3 outcomes the GDG looked for both a change in the outcomes and a concurrent significant difference in serum phosphate between trial arms.
Knowledge about phosphate-lowering dietary interventions was felt to be particularly far removed, or ‘indirect’, in its impact upon serum phosphate control and was therefore downgraded in quality as a surrogate outcome. The GDG felt that improving a person’s knowledge of a subject does not always bring about changes in that person’s behaviour. In this way, improved knowledge relating to the dietary management of hyperphosphataemia alone does not directly necessitate better adherence with dietary prescriptions or improvements in serum phosphate control.
Trade-off between benefits and harms
Patient education interventions that exceed ‘usual care’ had a positive effect on adherence, although the evidence was limited and of low quality. Greater improvements in knowledge and beliefs and attitudes towards health following these interventions appeared to be limited when compared to usual care, and serum phosphate levels were not significantly different between the 2 groups; again, the evidence was limited and of low (or very low) quality. The GDG felt that, despite its limitations, the evidence supported the view that usual care is sufficient in improving a patient’s serum phosphate control, and that interventions over and above this may not be necessary in routine practice.
In defining what constitutes good ‘usual’ practice, the GDG noted that counselling-based interventions were more effective than written material alone, although the evidence was of very low quality and there was some uncertainty over the statistical methods employed. The GDG felt that, in their experience and in conjunction with this evidence, advisory counselling sessions with patients represent good clinical practice. It was felt that counselling-based educational sessions represent an effective opportunity to explore different dietary management options with patients, as well as to monitor their suitability and progress. The GDG considered individualised approaches to be particularly important since different patients will have different diets, needs and preferences. These should be evaluated through dietary assessment, from which a treatment regimen can be developed. Additionally, people learn and respond to interventions in different ways and different approaches to dietary education and management may therefore need to be explored over the course of a patient’s treatment. However, it was felt that such exploration would not routinely require the use of an educational programme using multiple delivery methods (for example, including counselling sessions and comprehensive written material and videos/DVDs and self-management tools). Such interventions were not found to deliver a significant additional benefit over the effect seen following simpler, single-approach interventions, although again the quality of evidence was low or very low.
Given the broad, in-depth knowledge required in formulating effective, individualised therapeutic options, the GDG felt that a specialist renal dietitian would be the most appropriate person to conduct a patient’s dietary assessment and offer them individualised advice. It was also felt that early contact with a dietitian is important as a means of
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preventing patient misinformation, for example what constitutes phosphate-rich food and drink. The risks of misinformation can also be mediated by appropriately trained, multidisciplinary healthcare professionals/teams, who also play an important role in a patient’s ongoing dietary education, reinforcing nutritional advice and providing support on a more day-to-day basis. It is important for patients, especially those in the early stages of CKD, to understand the need to manage their health and minimise the risks they face. Education empowers many patients to take steps to limit such risks and, in this instance, to minimise the impact of high phosphate levels on their bones and vasculature.
The GDG highlighted that, although no evidence was found for this population; children need to be considered separately because parents and/or carers provide food and drink, and because their dietary needs change as they get older. Therefore parents and/or carers should also be educated, and the monitoring and revision of advice will need to be more frequent depending on the age of the child and their nutritional and clinical status. Because of the specific nature of children’s dietary needs and habits, the GDG felt that a specialist renal dietitian, specifically a paediatric specialist renal dietitian, would be the most appropriate person to conduct a child’s dietary assessment and offer the individualised advice. The multidisciplinary health professionals and teams that support a child’s ongoing dietary management should be similarly aware of the specific requirements of children with CKD, and the ways in which these change over time.
The GDG also felt that it is important to include information relating to phosphate binder use, giving the specific example of the need to take binders with high-phosphate snacks and not simply with meals, as well as the need to match binder dose with the phosphate load in the snack or meal.
Economic considerations
Early contact with a dietitian will require adequate availability.
It is not just dietitians who play a role in patient education; nurses, doctors and psychologists also play an important role, and these healthcare professionals should be appropriately trained. Dietitians will have a role in educating and supporting them.
The GDG noted that substantial resources and costs would be incurred in the development of complex, non-individualised programmes of multiple, concurrent educational approaches, with little evidence for additional benefit.
Quality of evidence
No studies compared the intervention of interest against a true ‘no intervention’ comparator, only usual care.
Limited evidence was found for those not on dialysis (only 1 study), and no evidence on education interventions in children was found.
Definitions of usual care varied across the studies, and were not always clear or explicit.
A significant amount of heterogeneity/diversity was observed across the interventions examined; it was difficult to pool studies to produce overarching interpretations of effectiveness. Content, in addition to the structure of the interventions, varied widely across the studies; for example, some interventions focused on serum phosphate control through diet, some on serum phosphate control more generally (for example, the use of binders), and some on more general dietary
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management in CKD (for example, information on fluid intake). There were differences between the papers in the populations studied. Most notably, some studies included only those expected to be adherent, some only those expected to be non-adherent.
The GDG questioned how applicable the evidence is to a UK setting, particularly since many of the studies were not conducted in the UK.
Adherence with dietary prescription was not regularly reported; instead, papers reported mean actual intakes for each group, which the reviewer then compared to prescriptions, producing a surrogate measure of adherence.
Reporting in many of the studies was poor: details of study designs were often unclear, results were not always cited in the text of the papers, requiring the reviewer to read the data off available graphs, and 1 paper did not contain a statistics section leaving uncertainty as to the measure of variance used. Unit-of-analysis errors were also common, with analyses not following the intent-to-treat principle, and 2 studies had follow-up periods that the GDG considered too short (less than 3 months).
Other considerations
In the context of the evidence reviewed, the ‘standard care’ provided seems to be sufficient for educating patients, although what constitutes ‘standard care’ is likely to vary across the UK. Concerns were raised that some patients receive a level of care that is below the standard of the studies reviewed, particularly in the long periods of time they wait to receive dietary advice.
Nurses play a significant role in the education process. They may have the most contact and often the greatest rapport with patients, and are important members of the multidisciplinary teams in reinforcing and supporting implementation of the nutritional advice developed by the dietitian.
The GDG noted relevant recommendations in ‘Chronic kidney disease’ (NICE clinical guideline 73).
No significant differences in serum Ca or PO4 levels as a result of binder assignment, although the non-significant serum Ca levels and Ca x PO4 levels were lower in the sevelamer group.
Qunibi et al, 2011
RCT
(USA)
Calcium acetate
versus
Placebo
12 weeks PO4
1.45 to 0.87
Ca
2.54 to 2.12
Calcium acetate
PO4: 1.65 ± 0.4
Ca: 2.27 ± 0.17
Placebo
PO4: 1.65 ± 1.36
Ca: 2.2 ± 0.2
Serum phosphate
Proportion with controlled serum phosphate
Serum calcium
Hypercalcaemia
Adherence
Calcium acetate was effective in reducing serum PO4 over a 12 week period.
Serum Ca was significantly higher in the calcium acetate group compared to the placebo group.
Russo et al, 2007
RCT
(Italy)
Control diet only
versus
Calcium carbonate
versus
Sevelamer hydrochloride
104 weeks None given Calcium carbonate
PO4: 1.48 ± 0.48
Ca: 2.24 ± 0.17
Sevelamer
PO4: 1.55 ± 0.55
Ca: 2.3 ± 0.05
Serum phosphate
Serum calcium
Coronary artery calcification
Progression of coronary artery calcification was slowed in those receiving calcium carbonate but that there was no progression in those treated with sevelamer.
Sprague et al, 2009
RCT
(USA)
Lanthanum carbonate
versus
Placebo
8 weeks PO4
<1.49
Lanthanum
PO4: 1.71 ± 0.22
Ca: 2.22 ± 0.15
Placebo
PO4: 1.74 ± 0.23
Ca: 2.24 ± 0.12
Serum phosphate
Proportion with controlled serum phosphate
Serum calcium
Adverse events
Lanthanum was effective in controlling serum PO4 compared to placebo.
There was a slight increase in serum Ca in the lanthanum group.
The safety profile was similar between the treatments.
Abbreviations: Ca, calcium; Ca x PO4, calcium-phosphorus product; PO4, phosphate; RCT, randomised controlled trial; SD, standard deviation.
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1062
Summary GRADE profile 19 Calcium acetate compared with placebo 1063
Outcome Number of Studies
Number of patients Effect Quality
Calcium acetate Placebo
Serum phosphate
(number of patients in whom control of serum phosphate achieved)
See appendix E for the evidence tables and GRADE profiles in full. 1071
1072
Multiple treatment comparisons (serum phosphate and serum calcium) 1073
As there was a lack of evidence allowing a direct comparison between all of the possible treatments, an MTC was carried out to aid 1074
the GDG decision making process (for further information on MTCs, please see the glossary on page 235). A total of 3 studies were 1075
included within the network allowing 4 treatments to be assessed against each other. The study by Russo et al was excluded from 1076
the model as the follow up time (104 weeks) was significantly longer than the other 3 studies within the network (mean follow up 1077
time, 9 weeks). The model used was based upon preliminary work carried out by NICE's technical support unit (appendix G). In 1078
brief, a standard network meta-analysis model in WinBUGS was used, utilising a previously published code (Dias et al, 201118). 1079
18
Dias, S et al (2011) NICE DSU Technical support Document 2: a generalised linear modelling framework for pair wise and network meta-analysis NICE Decision Support
Outcome Number of Studies Limitations Inconsistency Indirectness Imprecision Quality
Serum calcium (mean follow up 9 weeks)
3 RCTs1 very serious2 serious5 serious3 serious4 very low
1 Caglar et al, 2008; Qunibi et al, 2011; Sprague et al, 2009 2 Lack of detail on the randomisation, allocation and blinding within the studies 3 Surrogate marker used 4 GRADE rule of thumb sample size <400 5
Inconsistency could not be appraised
Abbreviations: RCT, randomised controlled trial.
-1 -0.5 0 0.5 1
Lanthanum carbonate
Calcium acetate
MD (mmol/l) v. placebo
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received sevelamer hydrochloride at 2 years (MD 0.03 mmol/l 1135
higher [95% CI –0.24 to 0.18]). 1136
Important outcomes 1137
3.4.3.5 Very-low-quality evidence from the RCT of 55 patients showed no 1138
statistically significant difference in mean serum calcium between 1139
those that received calcium carbonate and those that received 1140
sevelamer at 2 years (MD 0.02 mmol/l higher [95% CI –0.06 to 1141
0.10]). 1142
3.4.3.6 Very-low-quality evidence from the RCT of 55 patients showed no 1143
statistically significant difference in mean coronary artery 1144
calcification scores between those that received calcium carbonate 1145
and those that received sevelamer at 2 years (MD 20 higher [95% 1146
CI –262.96 to 302.96]) 1147
3.4.3.7 Very-low-quality evidence from the RCT of 55 patients showed 1148
calcium carbonate to be associated with a mean annualised 1149
change in coronary artery calcification scores 146.66 greater (95% 1150
CI 35.77 to 257.55 i.e. statistically significant) than that associated 1151
with sevelamer. 1152
Lanthanum compared with placebo 1153
Critical outcomes 1154
3.4.3.8 Very-low-quality evidence from 1 RCT of 90 patients showed no 1155
statistically significant difference in the number of participants that 1156
achieved serum phosphate control during the 8-week study period 1157
between those that received lanthanum and those that received 1158
placebo (RR 1.69 higher [95% CI 0.90 to 3.17]). 1159
Important outcomes 1160
3.4.3.9 Very-low-quality evidence from the RCT of 90 patients showed no 1161
statistically significant difference in the number of participants who 1162
experienced nausea and vomiting during the 8-week study period 1163
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between those that received lanthanum and those that received 1164
placebo (RR 1.37 higher [95% CI 0.46 to 4.10]). 1165
Lanthanum compared with calcium acetate 1166
Critical outcomes 1167
3.4.3.10 Very-low-quality evidence from 1 indirect comparison of 93 patients 1168
from 2 RCTs showed no statistically significant difference in the 1169
number of participants that achieved serum phosphate control 1170
during a mean 10-week study period between those that received 1171
lanthanum and those that received calcium acetate (RR 1.14 1172
[95% CI 0.31 to 4.15]). 1173
Multi treatment comparison: serum phosphate 1174
Critical outcome 1175
3.4.3.11 Evidence from 1 MTC, containing 3 studies of very low quality, 1176
suggested that sevelamer hydrochloride had a 56% probability 1177
(median rank 1 [95% CI 1, 4]) of being the best treatment to control 1178
serum phosphate at 9 weeks, in patients with stage 4 or 5 CKD, 1179
with calcium acetate having a 29.6% probability (median rank 2 1180
[95% CI 1, 4]). 1181
Multi treatment comparison: serum calcium 1182
Important outcome 1183
3.4.3.12 Evidence from 1 MTC, containing 3 studies of very low quality, 1184
suggested that placebo had a 93.6% probability (median rank 1 1185
[95%CI 1, 2]) of being the best treatment to control serum calcium 1186
at 9 weeks in patients with stage 4 or 5 CKD, with sevelamer 1187
hydrochloride acetate having a 5.2% probability (median rank 3 1188
[95% CI 1, 3]) and lanthanum carbonate having a 1.2% probability 1189
(median rank 2 [95% CI 2, 3]). 1190
1191
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3.4.4 Evidence to recommendations 1192
Relative value of different outcomes
The GDG discussed the relative importance of the outcomes and agreed that all-cause mortality, cardiovascular-related mortality, serum phosphate and adherence were critical for decision making.
Adverse events (including nausea and vomiting, constipation, diarrhoea, abdominal distension and upper abdominal pain), serum calcium and cardiovascular calcification scores were also considered important for decision making, though not critical.
Serum PTH was raised by some as potentially important, though the GDG also noted that there is a lot of variability in PTH measurements, both in the sense of the actual levels of PTH in the serum and in the ability of laboratory techniques to detect these levels. Therefore, serum PTH was not deemed to be a sufficiently reliable basis from which to formulate recommendations.
Serum phosphate, serum calcium and cardiovascular calcification scores were considered surrogate measures.
Trade-off between benefits and harms
Early intervention to prevent or manage high phosphate levels was considered key to preventing downstream complications resulting from the poor management of serum calcium and PTH. The GDG therefore emphasised the importance of starting phosphate binder therapy early, and stressed that this should be in the context of concurrent dietary management of serum phosphate.
The evidence showed that the phosphate binders examined were all effective in lowering serum phosphate in adults compared to placebo, with a 56% probability that sevelamer hydrochloride is better than calcium acetate or lanthanum. Although no significant difference was observed between lanthanum and calcium acetate in terms of achieving serum phosphate control, the Multiple Treatment Comparison (MTC) suggested calcium acetate to be more likely to have the best mean serum phosphate level (30% versus 14% probability of being the best). It was noted, however, that the median ranking of these binders had wide credibility intervals that reduced the GDG's confidence in the significance of these results.
Sevelamer hydrochloride, lanthanum and calcium acetate were all associated with a raise in serum calcium in comparison to placebo, with calcium acetate raising it the most.
There was no significant difference between sevelamer hydrochloride and calcium carbonate in their effectiveness at controlling serum phosphate, although sevelamer hydrochloride is more effective than calcium carbonate in limiting coronary artery calcification.
The GDG felt that the large body of evidence found for the use of phosphate binders in patients with CKD stage 5 but who are also on dialysis (see section 3.5) was a stronger foundation from which to make recommendations than the small, limited evidence base found during this review. Additionally, the GDG felt that continuity of care was important to both patient well-being and therapeutic success. Because of this, they felt it would be inappropriate to use the limited evidence identified in this review to recommend a different phosphate binder for pre-dialysis patients than that recommended for those on dialysis, which was supported by a more substantial evidence base. Calcium acetate's consistently good performance in the review of phosphate binder use in dialysis patients led the GDG to recommend
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it as the first-line phosphate binder for that population. The GDG felt it was appropriate to extrapolate these results to patients with CKD stage 4 or 5, and this, combined with calcium acetate's relatively good performance in the serum phosphate MTC outlined above, led the GDG to recommend calcium acetate as the first-line choice of phosphate binder in both pre-dialysis and dialysis patients.
However, in patients that cannot tolerate calcium acetate (for example, those who find it difficult to swallow tablets or experience side effects), the GDG felt that calcium carbonate would be an effective alternative first-line phosphate binder.
The GDG noted that metabolites and toxins are less likely to accumulate in patients with CKD stages 4 and 5 than in patients who require dialysis since residual renal function allows a greater capacity for their elimination from the body. This means that the clinical concerns associated with calcium-based phosphate binders in terms of higher serum calcium levels were lower in this population, and longer-term use of calcium-based phosphate binders was felt to be less of an issue.
Despite this, the GDG noted that a non-calcium-based binder could still be of use in reducing the daily intake of elemental calcium in those who are hypercalcaemic, have low serum PTH or in whom calcium-based binders are not tolerated. The lack of evidence in this area led the GDG to conclude that the choice of non-calcium-based binder should be determined through clinical judgement and patient preference. Because of the residual renal function discussed above, the clinical concerns associated with aluminium hydroxide and magnesium carbonate19 in terms of the potential build-up and deposition of metabolites and toxins in the body are less in pre-dialysis patients. Therefore, the GDG felt comfortable allowing their inclusion as non-calcium-based options alongside sevelamer hydrochloride and lanthanum carbonate. However, some members of the GDG also felt that regular monitoring of serum aluminium may be beneficial in those receiving aluminium hydroxide.
Although no evidence was found concerning the effectiveness of phosphate binders in children, the GDG felt that a calcium-based binder would be desirable as the first-line phosphate binder used in children. This is because children require additional calcium for their growing bones, but also to avoid the effects of secondary hyperparathyroidism that can arise in young patients with chronically low serum calcium levels. However, in children with high serum calcium or at risk from hypercalcaemia, a combination of a calcium-based and a non-calcium-based binder should be used as the first-line binder regimen. In this way, serum phosphate can be controlled to the desired level without further raising the serum calcium, but also without allowing calcium to decrease to levels that lead to the adverse effects outlined above.
In some children taking a calcium-based binder, serum phosphate can still remain above the recommended level and serum calcium may reach the age-adjusted upper limit of normal. In these patients it was
19
Note: magnesium carbonate is only licensed as a combination with calcium acetate; therefore it
cannot currently be used as monotherapy in the UK.
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felt that no further increases should be made to the dose of calcium-based binders. Instead, a non-calcium-based binder could be added to the regimen. As with first-line combination phosphate binder therapy, this second-line combination aims to raise phosphate control to the desired level without further raising the serum calcium.
Currently, the only non-calcium-based binder licensed for use in children is aluminium hydroxide. However, although searched for, no evidence meeting the defined inclusion criteria was found for the use of aluminium hydroxide in children with stage 4 or 5 CKD who are not on dialysis. There was also a lack of evidence found for the use of aluminium hydroxide in those who are on dialysis that might have been extrapolated to the population of interest. The only paediatric trial found examined the effectiveness of sevelamer against calcium carbonate over an 8-month period, and showed sevelamer to be as effective at lowering serum phosphate and associated with lower serum calcium level. Although this trial was conducted in children on dialysis (see section 3.5), the GDG felt it appropriate to extrapolate the evidence to those who are pre-dialysis, particularly since no evidence was found for non-calcium-based binders in this population. Furthermore, while the GDG had concerns over the toxicity of aluminium, it was also noted that the licence is not for longer-term indications. For these reasons, the GDG felt that recommending sevelamer hydrochloride over aluminium hydroxide was appropriate, despite its use being off-label in children. The GDG also felt that the total replacement of calcium-based binders with a non-calcium-based binder would be inappropriate in children because of their higher calcium requirements.
If considering the use of non-calcium-based binders because of high serum calcium levels in patients on calcium-based binders, the GDG felt it important to emphasise the necessity of reviewing other sources of calcium, such as vitamin D, calcium supplements or dietary calcium, before making any changes. They noted that in some cases it might be easier to make small changes to these sources of elemental calcium than changing (and ensuring adherence to) the phosphate binder regimen. For example, it may be the case that a patient is on a high dose of vitamin D, and a reduction in this may be the most appropriate course of action.
Economic considerations
There was insufficient evidence to provide a worthwhile model for adults with CKD stage 4 or 5 who are not on dialysis, and for children.
Quality of evidence
No data were found for age groups other than adults, although for this population only 4 papers examining 4 comparisons were identified.
Following the application of GRADE, overall evidence quality was low or very low across the outcomes.
Three of the studies had similar follow-up times and could be combined in a meta-analysis. The fourth study, however, was not considered appropriate for inclusion because of its significantly longer length.
A range of co-treatments were used across the studies, including calcium supplements, vitamin D and low-protein diets. The GDG noted their potential influence as confounders.
Reporting in many of the studies was poor. For example, details of study designs were often unclear and results were not always cited in the text of the papers, requiring the reviewer to read the data off
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available graphs. Unit-of-analysis errors were also common, with analyses not following the intent-to-treat principle.
Other considerations
It was noted that dietary management is particularly important in these patients, and should continue to be a key component of regimens designed to manage hyperphosphataemia in CKD stages 4 and 5.
1193
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3.4.5 Recommendations and research recommendations for 1194
use of phosphate binders in people with stage 4 or 5 CKD 1195
who are not on dialysis 1196
Recommendations 1197
Recommendation 1.1.5
For children and young people, offer a calcium-based phosphate binder as the
first-line phosphate binder to control serum phosphate in addition to dietary
management.
Recommendation 1.1.6
For children and young people, if a series of serum calcium measurements
shows a trend towards the age-adjusted upper limit of normal, consider a
calcium-based binder in combination with a non-calcium-based binder, having
taken into account other causes of rising calcium levels.
Recommendation 1.1.7
For children and young people who remain hyperphosphataemic despite
adherence with a calcium-based phosphate binder, and whose serum calcium
goes above the age-adjusted upper limit of normal, consider a combination of
a calcium-based phosphate binder and sevelamer hydrochloride20, having
taken into account other causes of raised calcium.
Recommendation 1.1.8
For adults, offer calcium acetate as the first-line phosphate binder to control
serum phosphate in addition to dietary management.
Recommendation 1.1.9
For adults, consider calcium carbonate if calcium acetate is not tolerated or
20
At the time of consultation (October 2012), sevelamer hydrochloride did not have a UK marketing
authorisation for this indication. The prescriber should follow relevant professional guidance, taking
full responsibility for the decision. The patient should provide informed consent, which should be
documented. See the General Medical Council’s Good practice in prescribing medicines – guidance for
See appendix E for the evidence table and GRADE profile in full. 1287
1288
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Table 6 Summary of included studies for the use of phosphate binders in adults with stage 5 CKD who are on dialysis 1289
Study (Country) Interventions Follow-up Target PO4 / Ca
(mmol/l)
Baseline PO4 / Ca (mmol/l ± SD)
Outcomes Conclusions
Al-Baaj et al, 2005
RCT
(UK)
Lanthanum carbonate
versus
Placebo
4 weeks PO4
1.3 to 1.8
Lanthanum
PO4: 1.54 ± 0.29
Placebo
PO4: 1.68 ± 0.27
Achieved phosphate control
Serum phosphate
Adherence
Lanthanum is effective in controlling serum phosphate.
Asmus et al, 2005
RCT
(Germany)
Sevelamer hydrochloride
versus
Calcium carbonate
2 years PO4
1 to 1.6
Ca
< 2.6
Sevelamer
PO4: 2.4 ± 0.6
Ca: 2.4 ± 0.1
Calcium carbonate PO4: 2.3 ± 0.2
Ca: 2.2 ± 0.5
Achieved phosphate control
Serum phosphate
Serum calcium
Coronary artery calcification
Calcium carbonate was associated with increases in coronary artery calcification and the number of participants suffering hypercalcaemic events.
Both treatments lowered serum phosphate.
Babarykin et al, 2004
RCT
(Latvia)
Calcium carbonate bread
versus
Calcium acetate
8 weeks PO4
1.5 to 1.7
Calcium carbonate bread
PO4: 2.57 ± 0.47
Ca: 2 ± 0.25
Calcium acetate
PO4: 2.1 ± 0.18
Ca: 2.15 ± 0.2
Serum calcium
Serum phosphate
Calcium carbonate bread was able to control serum phosphate and serum calcium as effectively as calcium acetate.
Barreto et al, 2008
RCT
(Brazil)
Calcium acetate
versus
Sevelamer hydrochloride
12 months PO4
1.13 to 1.78
Calcium acetate
PO4: 2.3 ± 0.45
Sevelamer
PO4: 2.3 ± 0.7
Serum phosphate
Coronary artery calcification
No differences were observed in coronary artery calcification between the sevelamer and calcium acetate groups.
There was no difference between the treatments in terms of controlling serum phosphate.
Block et al, 2005
RCT
(USA)
Sevelamer hydrochloride
versus
Calcium-based binders
18 months PO4
< 2.10
Ca
Sevelamer
PO4: 1.68 ± 0.52
Ca: 2.32 ± 0.25
Serum calcium
Serum phosphate
Risk of hypercalcaemia
No difference was observed in those with little evidence of calcification at baseline. However, in those with mild calcification
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< 2.54 Calcium-based binders
PO4: 1.74 ± 0.45
Ca: 2.32 ± 0.2
Coronary artery calcification there was evidence of a more rapid progression in those on calcium-based binders.
There were no differences in serum phosphate, but there was a higher risk of hypercalcaemia in those on calcium-based binders.
Braun et al, 2004
RCT
(Germany)
Sevelamer hydrochloride
versus
Calcium carbonate
12 months PO4
1 to 1.6
Ca
< 2.6
Sevelamer
PO4: 1.65 ± 0.4
Ca: 2.34 ± 0.15
Calcium carbonate
PO4: 1.65 ± 1.36
Ca: 2.32 ± 0.14
Serum calcium
Serum phosphate
Coronary artery calcification
Adherence
Risk of hypercalcaemia
Reductions in serum phosphate were similar in both groups.
Calcium carbonate resulted in more instances of hypercalcaemia and was associated with increases in coronary artery calcification.
Chertow et al, 1997
RCT
(USA)
Sevelamer hydrochloride
versus
Placebo
2 weeks None given
Sevelamer
PO4: 2.13 ± 0.68
Ca: 2.32 ± 0.22
Placebo
PO4: 2.32 ± 0.77
Ca: 2.4 ± 0.12
Serum calcium
Serum phosphate
Adherence
Adverse events
Sevelamer significantly reduced serum phosphate and was not significantly associated with changes in serum calcium.
There was no difference in the incidence of adverse events between sevelamer and placebo.
Chertow et al, 2002
RCT
(USA)
Sevelamer hydrochloride
versus
Calcium based binders
12 months PO4
0.97 to 1.61
Ca
2.12 to 2.62
Sevelamer
PO4: 2.45 ± 0.58
Ca: 2.35 ± 0.17
Calcium-based binders
PO4: 2.39 ± 0.61
Ca: 2.32 ± 0.17
Serum calcium
Serum phosphate
Adherence
Risk of hypercalcaemia
Sevelamer was equivalent to calcium in controlling serum phosphate.
However, serum calcium was higher in the calcium group and hypercalcaemia was more common.
Chertow et al, 2003
RCT
(USA)
Sevelamer hydrochloride
versus
Calcium acetate
12 months PO4
0.97 to 1.61
Ca
2.12 to 2.62
Sevelamer
PO4: 2.45 ± 0.61
Ca: 2.34 ± 0.17
Calcium acetate
PO4: 2.48 ± 0.17
Ca: 2.34 ± 0.17
Serum calcium
Serum phosphate
Adverse events
Adherence
Coronary artery calcification
Risk of hypercalcaemia
Calcium acetate was associated with increased hypercalcaemia and calcification.
The reduction in serum phosphate was equivalent in both treatments.
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Chiang et al, 2005
RCT
(Taiwan)
Lanthanum
versus
Placebo
4 weeks PO4
0.6 to 1.8
Lanthanum
PO4: 1.77 ± 0.11
Placebo
PO4: 1.83 ± 0.16
Serum phosphate
Proportion achieving phosphate control
Lanthanum was effective in controlling serum phosphate.
Chow et al, 2007
RCT
(China)
Sevelamer hydrochloride high-dose
versus
Sevelamer hydrochloride low-dose
6 months PO4
<1.78
Sevelamer high-dose
PO4: 2.38 ± 0.38
Sevelamer low-dose
PO4: 2.25 ± 0.31
Serum phosphate
Proportion achieving phosphate control
Adherence
Serum phosphate was significantly lower in the high dose group. However, the proportion of patients achieving phosphate control was not significantly different.
de Francisco et al, 2010
RCT
(Germany, Poland, Portugal, Romania and Spain)
Calcium acetate + magnesium carbonate
versus
Sevelamer hydrochloride
6 months PO4
> 1.78
Ca
2.1 to 2.37
Calcium acetate + magnesium carbonate
PO4: 2.46 ± 0.40
Ca: 2.14 ± 0.23
Sevelamer
PO4: 2.48 ± 0.47
Ca: 2.19 ± 0.18
Serum calcium
Serum phosphate
There was no difference in the control of serum phosphate.
There were small increases in serum calcium in the calcium acetate + magnesium carbonate group.
de Santo et al, 2006
RCT
(Italy)
Sevelamer hydrochloride
versus
Calcium carbonate
6 months PO4
<1.78
Ca
2.12 to 2.62
Sevelamer
PO4: 2.38 ± 0.35
Ca: 2.28 ± 0.19
Calcium carbonate
PO4: 2.42 ± 0.34
Ca: 2.28 ± 0.24
Serum calcium
Serum phosphate
Both treatments were effective in reducing serum phosphate.
There was a slight rise in serum calcium in those receiving calcium carbonate.
Emmett et al, 1991
RCT
(USA)
Calcium acetate
versus
Placebo
2 weeks PO4
1.45 to 1.78
Calcium acetate
PO4: 2.42 ± 0.54
Ca: 2.2 ± 0.18
Placebo
PO4: 2.29 ± 0.45
Ca: 2.25 ± 0.22
Serum calcium
Serum phosphate
Calcium acetate was associated with a decrease in serum phosphate and an increase in serum calcium.
Evenepoel et al, Sevelamer hydrochloride 12 weeks PO4 Sevelamer Serum calcium Both treatments significantly
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2009
RCT
(Belgium, Denmark, France, Italy, Spain, The Netherlands and UK)
versus
Calcium acetate
0.97 to 1.78
Ca
2.1 to 2.59
PO4: 2.42 ± 0.45
Ca: 2.38 ± 0.15
Calcium acetate
PO4: 2.4 ± 0.45
Ca: 2.39 ± 0.12
Serum phosphate
Risk of hypercalcaemia
reduced serum phosphate.
Hypercalcaemia was experienced by more calcium acetate patients.
Ferreira et al, 2008
RCT
(Portugal)
Sevelamer hydrochloride
versus
Calcium-based binder
12 months PO4
1 to 1.6
Ca
< 2.6
Sevelamer
PO4: 1.91 ± 0.6
Ca: 2.33 ± 0.27
Calcium-based binders
PO4: 1.74 ± 0.48
Ca: 2.38 ± 0.27
Serum calcium
Serum phosphate
Both serum phosphate and serum calcium were well controlled in both groups.
Finn et al, 2004
RCT
(USA)
Lanthanum carbonate at various doses
versus
Placebo
6 weeks PO4
< 1.78
No details Serum phosphate
Proportion achieving phosphate control
Lanthanum carbonate was effective in lower serum phosphate. Significant reductions were observed in the 1350 and 2250 mg/day groups compared to placebo.
Finn et al, 2006
RCT
(USA, Puerto Rico, Poland and South Africa)
Lanthanum carbonate
versus
Standard therapy
2 years PO4
< 1.9
Lanthanum
Ca: 2.41 ± 0.26
Standard therapy
Ca: 2.37 ± 0.40
Proportion achieving phosphate control
Serum calcium
Adverse events
Lanthanum’s efficacy in controlling serum phosphate is similar to that of other therapies.
However, higher serum calcium levels were observed in those using standard therapies.
Fishbane et al, 2010
RCT
(USA)
Sevelamer carbonate powder
versus
Sevelamer hydrochloride tablets
6 months PO4
1.13 to 1.78
Sevelamer carbonate powder
PO4: 2.36 ± 0.41
Ca: 2.25 ± 0.17
Sevelamer tablets
PO4: 2.44 ± 0.41
Ca: 2.25 ± 0.17
Serum phosphate
Serum calcium
Adverse events
Adherence
Once a day sevelamer carbonate powder was not as effective in reducing serum phosphate as thrice daily sevelamer tablets. However, the powder did reduce levels significantly, reaching the KDOQI phosphate targets in most patients.
There were a greater number of
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upper GI-related events in those taking the powder.
Freemont et al, 2005
RCT
(UK)
Lanthanum carbonate
versus
Calcium carbonate
12 months None given
Lanthanum
PO4: 1.72 ± 0.4
Ca: 2.24 ± 0.2
Calcium carbonate
PO4: 1.87 ± 0.52
Ca: 2.29 ± 0.32
Serum calcium
Serum phosphate
Proportion achieving phosphate control
Adverse events
Both treatments were equally effective in controlling serum phosphate and serum calcium, although there were more instances of hypercalcaemia in the calcium carbonate group.
Galassi et al, 2006
RCT
(USA)
Sevelamer hydrochloride
versus
Calcium-based binders
2 years None given
Sevelamer
PO4: 1.60 ± 0.42
Ca: 2.30 ± 0.68
Calcium-based binders
PO4: 2.30 ± 0.15
Ca: 1.7 ± 0.45
Serum phosphate
Serum calcium
Coronary artery calcification
Serum phosphate was similar in both groups. However, serum calcium and coronary artery calcification increased in those receiving calcium-based binders.
Hervas et al, 2003
RCT
(Spain)
Sevelamer hydrochloride
versus
Calcium acetate
32 weeks None given
Sevelamer
PO4: 2.61 ± 0.52
Ca: 2.45
Calcium acetate
PO4: 2.42 ± 0.48
Ca: 2.45
Serum calcium
Serum phosphate
Sevelamer is effective in lowering serum phosphate.
Hutchison et al, 2005
RCT
(UK, Germany, Belgium, The Netherlands)
Lanthanum carbonate
versus
Calcium carbonate
20 weeks PO4
< 1.8
Lanthanum
PO4: 2.67 ± 0.63
Calcium carbonate
PO4: 2.67 ± 0.63
Serum phosphate
Proportion achieving phosphate control
Risk of hypercalcaemia
Adverse events
Serum phosphate control was similar in both groups. However, there was a greater incidence of hypercalcaemia in the calcium carbonate group.
Serum phosphate significantly decreased in the high dose group only.
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+ calcium carbonate (high-dose)
carbonate (high-dose)
PO4: 2.42 ± 0.26
Ca: 2.47 ± 0.15
Janssen et al, 1995
RCT
(Netherlands)
Calcium acetate
versus
Calcium carbonate
12 months PO4
< 1.6
Ca
> 2.2
Calcium acetate
PO4: 2.95 ± 0.86
Ca: 2.30 ± 0.2
Calcium carbonate
PO4: 2.45 ± 0.54
Ca: 2.3 ± 0.18
Serum calcium
Serum phosphate
Serum phosphate did not differ between the groups
Janssen et al, 1996
RCT
(Netherlands)
Calcium acetate
versus
Calcium carbonate
12 months PO4
< 1.6
Ca
2.2 to 3.0
Calcium acetate
PO4: 1.65 ± 0.4
Ca: 2.27 ± 0.17
Placebo
PO4: 1.65 ± 1.36
Ca: 2.2 ± 0.2
Serum phosphate
Serum calcium
Proportion achieving phosphate control
Risk of hypercalcaemia
There was no difference between the treatments in terms of phosphate-binding capacity.
Calcium carbonate appeared to be associated with more hypercalcaemic episodes than calcium acetate.
Joy et al, 2003
RCT
(USA)
Lanthanum carbonate
versus
Placebo
4 weeks PO4
< 1.91
Lanthanum
PO4: 1.76 ± 0.47
Ca: 2.20 ± 0.16
Placebo
PO4: 1.82 ± 0.53
Ca: 2.17 ± 0.18
Serum phosphate
Serum calcium
Proportion achieving phosphate control
Adverse events
Lanthanum was effective in controlling serum phosphate.
The number of drug-related adverse events was similar between the 2 groups.
Kakuta et al, 2011
RCT
(Japan)
Sevelamer hydrochloride
versus
Calcium carbonate
12 months PO4
< 2.1
Ca
< 2.54
Sevelamer
PO4: 1.82 ± 0.18
Ca: 2.44 ± 0.2
Calcium carbonate
PO4: 1.86 ± 0.25
Ca: 2.42 ± 0.16
Serum calcium
Serum phosphate
Adverse events
Coronary artery calcification
Sevelamer appeared to slow the increase in coronary artery calcification.
The control of biochemical parameters was similar in both groups.
Katopodis et al, 2006
RCT
Sevelamer hydrochloride
versus
Aluminium hydroxide
8 weeks None given
Sevelamer
PO4: 2.38 ± 0.43
Ca: 2.3 ± 0.2
Serum phosphate
Serum calcium
Adverse events
Similar reductions in serum phosphate were observed over the course of the study.
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(Greece) Aluminium hydroxide PO4: 2.28 ± 0.39
Ca: 2.27 ± 0.2
There were no differences in the control of calcium.
Koiwa et al, 2005a
RCT
(Japan)
Sevelamer hydrochloride
versus
Sevelamer +calcium carbonate
versus
Calcium carbonate
4 weeks PO4
< 1.78
Ca
2.1 to 2.37
Sevelamer
PO4: 2.09 ± 0.28
Ca: 2.15 ± 0.22
Sevelamer + calcium carbonate
PO4: 1.92 ± 0.54
Ca: 2.28 ± 0.17
Calcium carbonate
PO4: 2.2 ± 0.39
Ca: 2.28 ± 0.17
Proportion achieving phosphate control
Serum phosphate
Serum calcium
Adverse events
Risk of hypercalcaemia
There was an additive effect of sevelamer in the treatment of hyperphosphataemia with calcium carbonate.
Koiwa et al, 2005b
RCT
(Japan)
Sevelamer hydrochloride + calcium carbonate
versus
Calcium carbonate
4 weeks None given
Sevelamer + calcium carbonate
PO4: 1.91 ± 0.39
Calcium carbonate
PO4: 2.0 ± 0.29
Serum phosphate Serum phosphate levels were lower in those treated with sevelamer + calcium carbonate.
Lin et al, 2011
RCT
(Taiwan)
Sevelamer hydrochloride
versus
Calcium acetate
8 weeks PO4
1.13 to 1.78
Ca
< 2.74
Not applicable Adverse events
Adherence
Risk of hypercalcaemia
More hypercalcaemic events were recorded in the calcium acetate group.
Liu et al, 2006
RCT
(Taiwan)
Sevelamer hydrochloride
versus
Calcium acetate
8 weeks PO4
1.13 to 1.94
Sevelamer
PO4: 2.62 ± 0.79
Ca: 2.26 ± 0.30
Calcium acetate
PO4: 2.62 ± 0.74
Ca: 2.25 ± 0.37
Serum phosphate
Serum calcium
Proportion achieving phosphate control
Risk of hypercalcaemia
Serum phosphate did not differ between the 2 treatments.
The number of patients experiencing hypercalcaemic events was significantly higher in the calcium acetate group.
Malluche et al, 2008
RCT
Lanthanum carbonate
versus
Standard therapy
24 months PO4
< 1.91
Lanthanum
PO4: 2.45 ± 0.48
Ca: 2.2 ± 0.24
Serum phosphate
Serum calcium
There was similar phosphate control with both treatments.
However, standard treatment was associated with higher serum
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(USA, Puerto Rico, Poland, South Africa)
Standard therapy
PO4: 2.62 ± 0.65
Ca: 2.3 ± 0.28
calcium at most visits.
Navarro-Gonzalez et al, 2011
RCT
(Spain)
Sevelamer hydrochloride
versus
Calcium acetate
12 weeks None given
Sevelamer
PO4: 1.74 ± 0.32
Ca: 2.25 ± 0.17
Calcium acetate
PO4: 1.65 ± 0.19
Ca: 2.25 ± 0.12
Serum phosphate
Serum calcium
Both serum phosphate and serum calcium decreased significantly in both groups.
Qunibi et al, 2008
RCT
(USA)
Calcium acetate
versus
Sevelamer hydrochloride
12 months PO4
1.13 to 1.78
Calcium acetate
PO4: 2.1 ± 0.61
Ca: 2.2 ± 0.2
Sevelamer
PO4: 2.13 ± 0.48
Ca: 2.2 ± 0.17
Serum phosphate
Serum calcium
Adverse events
Coronary artery calcification
Risk of hypercalcaemia
Both treatments were effective in controlling serum phosphate and serum calcium.
There did not appear to be any differences it coronary artery calcification progression.
Raggi et al, 2004
RCT
(USA, Germany and Austria)
Sevelamer hydrochloride
versus
Calcium-based binders
12 months PO4
0.97 to 1.61
Ca
2.12 to 2.62
Calcium acetate
PO4: 1.65 ± 0.4
Ca: 2.27 ± 0.17
Placebo
PO4: 1.65 ± 1.36
Ca: 2.2 ± 0.2
Coronary artery calcification Patients prescribed sevelamer had lower calcification scores than those on calcium-based binders at 52 weeks.
Ring et al, 1993
RCT
(Denmark)
Calcium acetate
versus
Calcium carbonate
3 weeks None given
Calcium acetate
PO4: 2.09 ± 0.25
Ca: 2.48 ± 0.16
Calcium carbonate
PO4: 2.30 ± 0.59
Ca: 2.40 ± 0.31
Serum calcium
Serum phosphate
Both treatments controlled serum phosphate.
There was no difference between the treatments in terms of serum calcium.
Shigematsu et al, 2008a
RCT
(Japan)
Lanthanum carbonate
versus
Calcium carbonate
8 weeks PO4
1.13 to 1.78
Ca
Lanthanum
PO4: 2.7 ± 0.45
Calcium carbonate
Serum phosphate
Adverse event
Risk of hypercalcaemia
Both treatments are effective in controlling serum phosphate, but lanthanum is associated with a lower incidence of
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< 2.59 PO4: 2.71 ± 0.46
hypercalcaemia.
Shigematsu et al, 2008b
RCT
(Japan)
Lanthanum carbonate 750 to 3000mg/day
versus
Placebo
6 weeks PO4
1.13 to 1.78
See evidence table Proportion achieving phosphate control
Serum phosphate
Adverse events
Serum phosphate was significantly reduced in a dose-dependent manner.
The incidence of drug-related adverse events was also dose-dependent.
Spasovski et al, 2006
RCT
(Macedonia)
Lanthanum carbonate
versus
Calcium carbonate
12 months PO4
< 1.8
Ca
< 2.6
Lanthanum
PO4: 1.58 ± 0.25
Ca: 2.13 ± 0.2
Calcium carbonate
PO4: 1.76 ± 0.39
Ca: 2.27 ± 0.23
Serum calcium
Serum phosphate
Risk of hypercalcaemia
There were no significant differences in serum levels of calcium or phosphate.
Spiegel et al, 2007
RCT
(USA)
Magnesium carbonate
versus
Calcium acetate
12 weeks PO4
< 1.78
Magnesium carbonate
PO4: 2.1 ± 0.27
Ca: 2.06 ± 0.13
Calcium acetate
PO4: 2.13 ± 0.19
Ca: 2.1 ± 0.19
Proportion achieving phosphate control
Serum phosphate
Serum calcium
Both treatments equally controlled serum phosphate.
Serum calcium was significantly higher in those taking calcium acetate.
Suki et al, 2007
RCT
(USA)
Sevelamer hydrochloride
versus
Calcium-based binders
3.75 years None given
None given Adverse events
Mortality
All-cause and specific mortality rates were not significantly different. Only in those over the age of 65 was there a significant effect of sevelamer in lowering the mortality rate.
Tzanakis et al, 2008
RCT
(Greece)
Magnesium carbonate
versus
Calcium carbonate
6 months PO4
< 1.78
Ca
< 2.62
Magnesium carbonate
PO4: 2.14 ± 0.28
Ca: 2.35 ± 0.13
Calcium carbonate
PO4: 2.12 ± 0.28
Proportion achieving phosphate control
Serum phosphate
Serum calcium
Risk of hypercalcaemia
Both treatments controlled serum phosphate.
There were fewer instances of hypercalcaemia in those receiving magnesium carbonate.
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Ca: 2.28 ± 0.11
Wilson et al, 2009
RCT
(USA, Puerto Rico, Poland and South Africa)
Lanthanum carbonate
versus
Standard treatment
2.6 years PO4
< 1.9
Not applicable Mortality Overall mortality was similar in both groups, but the results suggested a survival benefit for those aged over 65 years.
Abbreviations: Ca, calcium; GI, gastrointestinal; PO4, phosphate; RCT, randomised controlled trial; SD, standard deviation.
1290
Summary GRADE profile 26 Calcium acetate compared with placebo 1291
Management of hyperphosphataemia: NICE clinical guideline DRAFT (October 2012) Page 130 of 248
Multiple treatment comparisons (serum phosphate and serum calcium) 1326
As there was a lack of evidence allowing a direct comparison between all of the possible treatments, a series of MTCs were carried 1327
out to aid the GDG decision-making process process (for further information on MTCs, please see glossary on page 235). Due to 1328
the use of continuous measures and the wide range of follow-up times presented within the evidence base, it was not possible to 1329
develop a single network which assessed all of the treatments at the various different time-points. Therefore, a series of network 1330
analyses were carried out at 3 months (90 days), 6 months (180 days) and 12 months (360 days). These analyses utilised the data 1331
available at each of these time points, and as a result, the interventions under consideration at each of these time points varied. In 1332
order to facilitate the construction of complete networks, it was decided that the comparators, “Standard Therapy” and “Calcium 1333
Based Binder”, should be analysed as a meta-class, “Any/Calcium based binders”. This assumption was made on the basis that 1334
within the relevant trials21 over 75% of the binders taken within the standard therapy arms were actually calcium based. MTC 1335
analyses were also carried out on the dichotomous outcomes of proportion of people with phosphate controlled and the risk of 1336
hypercalcaemia. 1337
The models used were based upon preliminary work carried out by NICE's technical support unit (appendix G). In brief, a standard 1338
network meta-analysis model in WinBUGS was used, utilising a previously published code (Dias et al 201122). The results 1339
presented below are those generated from a fixed effect analysis, which was recommended in the initial work carried out by the 1340
Technical Support Unit. 1341
21
Finn 2006, Malluche 2008 22
Dias, S et al (2011) NICE DSU Technical support Document 2: a generalised linear modelling framework for pair wise and network meta-analysis NICE Decision Support Unit available from http://www.nicedsu.org.uk
Management of hyperphosphataemia: NICE clinical guideline DRAFT (October 2012) Page 132 of 248
Summary GRADE profile 44 Quality of comparisons within the network 1349
Outcome Number of Studies Limitations Inconsistency Indirectness Imprecision Quality
Serum phosphate (follow up 90 days)
13 RCTs1 very serious
2,3 serious
5 serious
4 no serious very low
1 Barreto et al, 2008; Block et al, 2005; Braun et al, 2004; De Francisco et al, 2010; De Santo et al, 2006; Evenepoel et al, 2009; Ferreira et al, 2008; Fishbane et al, 2010;
Hutchison et al, 2005; Janssen et al, 1996; Malluche et al, 2008; Navarro-Gonzalez et al, 2011; Spiegel et al, 2007
2 Lack of detail on the randomisation
3 Studies were either not blinded or details were not provided
4 Surrogate marker used
5 Inconsistency could not be appraised
Abbreviations: RCT, randomised controlled trial.
1350
1351
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Mean difference matrix: serum phosphate at 90 days 1352
Calcium Carbonate
Any / calcium-based binders
Lanthanum carbonate
Sevelamer hydrochloride
Calcium acetate
Calcium acetate + magnesium carbonate
Sevelamer carbonate
Magnesium carbonate
Calcium Carbonate
- -0.129 mmol/l (95%CI: -0.281, 0.023)
0.068 mmol/l (95%CI: -0.034, 0.170)
-0.158 mmol/l (95%CI: -0.292, -0.023)
-0.154 mmol/l (95%CI: -0.315, 0.007)
-0.341 mmol/l (95%CI: -0.525, -0.157)
-0.648 mmol/l (95%CI: -0.809, -0.486)
-0.225 mmol/l (95%CI: -0.592, 0.141)
Any / calcium-based binders
- - 0.197 mmol/l (95%CI: 0.048, 0.346)
-0.028 mmol/l (95%CI: -0.153, 0.096)
-0.025 mmol/l (95%CI: -0.179, 0.129)
-0.212 mmol/l (95%CI: -0.389, -0.035)
-0.519 mmol/l (95%CI: -0.672, -0.365)
-0.096 mmol/l (95%CI: -0.458, 0.267)
Lanthanum carbonate
- - - -0.226 mmol/l (95%CI: -0.374, -0.077)
-0.222 mmol/l (95%CI: -0.396, -0.050)
-0.409 mmol/l (95%CI: -0.604, -0.214)
-0.716 mmol/l (95%CI: -0.890, -0.542)
-0.293 mmol/l (95%CI: -0.665, 0.078)
Sevelamer hydrochloride
- - - - 0.003 mmol/l (95%CI: -0.088, 0.094)
-0.184 mmol/l (95%CI: -0.310, -0.059)
-0.490 mmol/l (95%CI: -0.580, -0.401)
-0.068 mmol/l (95%CI: -0.407, 0.273)
Calcium acetate
- - - - - -0.187 mmol/l (95%CI: -0.343, -0.032)
-0.494 mmol/l (95%CI: -0.621, -0.366)
-0.071 mmol/l (95%CI: -0.397, 0.256)
Calcium acetate + magnesium carbonate
- - - - - - -0.306 mmol/l (95%CI: -0.460, -0.153)
0.116 mmol/l (95%CI: -0.245, 0.481)
Sevelamer carbonate
- - - - - - - 0.423 mmol/l (95%CI: 0.072, 0.774)
Magnesium carbonate
- - - - - - - -
1353
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Summary GRADE profile 45 Quality of comparisons within the network 1365
Outcome Number of Studies Limitations Inconsistency Indirectness Imprecision Quality
Serum phosphate (follow up 180 days)
12 RCTs1 very serious
2,3 serious
5 serious
4 no serious very low
1 Barreto, et al 2008; Block, et al 2005; Braun, et al 2004; De Francisco, et al 2010; De Santo, et al 2006; Fishbane, et al 2010; Ferreira, et al 2008; Hutchison, et al 2005;
Janssen, et al 1995; Janssen, et al 1996; Malluche, et al 2008; Tzanakis, et al 2008. 2
Lack of detail on the randomisation 3 Studies were either not blinded or details were not provided
4 Surrogate marker used
5 Inconsistency could not be appraised
Abbreviations: RCT, randomised controlled trial.
1366
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Mean difference matrix: serum phosphate at 180 days 1367
Summary GRADE profile 46 Quality of comparisons within the network 1380
Outcome Number of Studies Limitations Inconsistency Indirectness Imprecision Quality
Serum phosphate (follow up 360 days)
13 RCTs1 very serious
2,3 serious
5 serious
4 no serious very low
1 Barreto et al, 2008; Block et al, 2005; Braun et al, 2004; Chertow et al, 2002; Chertow et al, 2003; Ferreira et al, 2008; Freemont et al, 2005; Kakuta et al, 2011; Janssen et
al, 1995; Janssen et al, 1996; Malluche et al, 2008; Qunibi et al, 2008; Spasovski et al, 2006 2 Lack of detail on the randomisation
3 Studies were either not blinded or details were not provided
4 Surrogate marker used
5 Inconsistency could not be appraised
Abbreviations: RCT, randomised controlled trial.
1381
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Mean difference matrix: serum phosphate at 360 days 1382
Management of hyperphosphataemia: NICE clinical guideline DRAFT (October 2012) Page 143 of 248
Summary GRADE profile 47 Quality of comparisons within the network 1398
Outcome Number of Studies Limitations Inconsistency Indirectness Imprecision Quality
Serum calcium (follow up 90 days)
10 RCTs1 very serious
2,3 serious
5 serious
4 no serious very low
1 Barreto et al, 2008; Braun et al, 2004; De Francisco et al, 2010; De Santo et al, 2006; Evenepoel et al, 2009; Ferreria et al, 2006; Finn et al, 2006; Malluche et al, 2008;
Navarro-Gonzalez et al, 2011; Spiegel et al, 2007 2
Lack of detail on the randomisation 3 Studies were either not blinded or details were not provided
4 Surrogate marker used
5 Inconsistency could not be appraised
Abbreviations: RCT, randomised controlled trial.
. 1399
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Mean difference matrix: serum calcium at 90 days 1400
Management of hyperphosphataemia: NICE clinical guideline DRAFT (October 2012) Page 147 of 248
Summary GRADE profile 48 Quality of comparisons within the network 1415
Outcome Number of Studies Limitations Inconsistency Indirectness Imprecision Quality
Serum calcium (follow up 180 days)
9RCTs1 very serious
2,3 serious
5 serious
4 no serious very low
1 Barreto et al, 2008; De Francisco et al, 2010; De Santo et al, 2006; Ferreria et al, 2006; Fishbane et al, 2010; Finn et al, 2006; Janssen et al, 1995; Malluche et al, 2008;
Tzankis et al, 2008 2 Lack of detail on the randomisation
3 Studies were either not blinded or details were not provided
4 Surrogate marker used
5 Inconsistency could not be appraised
Abbreviations: RCT, randomised controlled trial.
1416
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Mean difference matrix: serum calcium at 180 days 1417
Relative effectiveness compared to calcium carbonate: serum calcium at 180 days 1422
1423
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Multiple treatment comparison: serum calcium at 360 days 1424
A total of 12 studies were included within the network allowing 5 treatments to be assessed against each other. 1425
SH
CA
CCLC
Any/CB
2 studies
3 studies
1 study
2 studies
2 studies
2 studies
1426 1427 Abbreviations: Any/CB, Any/Calcium Based binder; CA, calcium acetate; CC, calcium carbonate; LC, lanthanum carbonate; SH, sevelamer hydrochloride 1428
1429
Summary GRADE profile 49 Quality of comparisons within the network 1430
Outcome Number of Studies Limitations Inconsistency Indirectness Imprecision Quality
Serum calcium (follow up 360 days)
12RCTs1 very serious
2,3 serious
5 serious
4 no serious very low
1 Barreto et al, 2008; Braun et al, 2004; Chertow et al, 2002; Chertow et al, 2003; Ferreria et al, 2006; Finn et al, 2006; Freemont et al, 2005; Janssen et al, 1995; Kakuta et al,
2011; Malluche et al, 2008; Qunibi et al, 2008; Spasovski et al, 2006 2 Lack of detail on the randomisation
3 Studies were either not blinded or details were not provided
4 Surrogate marker used
5 Inconsistency could not be appraised
Abbreviations: RCT, randomised controlled trial.
1431
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Mean difference matrix: serum calcium at 180 days 1432
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Summary GRADE profile 50 Quality of comparisons within the network 1449
Outcome Number of Studies Limitations Inconsistency Indirectness Imprecision Quality
Proportion of patients achieving phosphate control
15RCTs1 very serious
2,3 serious
5 serious
4 no serious very low
1 Al-Baaj et al, 2005; Chiang et al, 2005; Chow 2007; Evenepoel 2009; Finn et al, 2004; Finn et al, 2006; Fishbane et al, 2010; Hutchison et al, 2005; Janssen et al, 1996; Joy
et al, 2003; Koiwa et al, 2005; Liu et al, 2006; Shigematsu et al, 2008; Spiegel et al, 2007; Tzanakis et al, 2008. 2
Lack of detail on the randomisation 3 Studies were either not blinded or details were not provided
4 Surrogate marker used
5 Inconsistency could not be appraised
Abbreviations: RCT, randomised controlled trial.
1450
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Hazard ratio matrix: proportion achieving phosphate control 1451
Management of hyperphosphataemia: NICE clinical guideline DRAFT (October 2012) Page 159 of 248
Summary GRADE profile 51 Quality of comparisons within the network 1464
Outcome Number of Studies Limitations Inconsistency Indirectness Imprecision Quality
Risk of hypercalcaemia 16RCTs1 very serious
2,3 serious
5 serious
4 no serious very low
1 Asmus et al, 2005; Block et al, 2005; Braun et al, 2006; Chertow et al, 2002; Chertow et al, 2003; Evenepoel et al, 2009; Freemont et al,2005; Hutchison et al, 2005; Janssen
et al, 1996; Koiwa et al, 2005; Lin et al, 2011; Liu et al, 2006; Qunibi et al, 2008; Shigematsu et al, 2008; Spasovski et al, 2006; Tzanakis et al, 2008 2 Lack of detail on the randomisation
3 Studies were either not blinded or details were not provided
Sevelamer hydrochloride £25,823 3.842 £10,652 0.121 £87,916 a extendedly dominated: indicates that the specified strategy has a higher ICER than at least one other 2108
option, when we estimate the additional value each provides over and above that which can be 2109 achieved with a common (cheaper, less effective) comparator 2110
Calcium acetate appears to provide good value for money compared with 2111
calcium carbonate, providing an average health gain of around one-eighth of a 2112
QALY at an additional cost of just over £1000, equating to an incremental cost 2113
effectiveness ratio (ICER) of approximately £8000 per QALY gained. 2114
Sevelamer hydrochloride was found to be the most effective treatment; 2115
however, the additional health gains predicted, when compared with calcium 2116
acetate, come at a cost of almost £90,000 per QALY. The simulated cohort 2117
receiving lanthanum carbonate accrued very similar health gains to that 2118
receiving calcium acetate, but at much higher cost. It is said to be extendedly 2119
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dominated, in this analysis, which indicates that – regardless of the assumed 2120
maximum acceptable ICER threshold – better value can be achieved by using 2121
Lanthanum carbonate (no switch) £23,615 3.731 dominatedb
Sevelamer hydrochloride (no switch) £25,823 3.842 dominatedb
a extendedly dominated: indicates that the specified strategy has a higher ICER than at least one other 2141
option, when we estimate the additional value each provides over and above that which can be 2142 achieved with a common (cheaper, less effective) comparator 2143
b dominated: indicates that one or more treatment options are both cheaper and more effective than the 2144
specified strategy 2145
Figure 3 Cost–utility plane for sequential use 2146
2147
As in the first-line-only setting, reliance on calcium acetate as an initial binder 2148
appears to provide good value for money: such strategies tend to provide 2149
conspicuously greater QALY gains than those based on calcium carbonate at 2150
a net cost that is either modestly increased or reduced. 2151
£5.0K
£10.0K
£15.0K
£20.0K
£25.0K
£30.0K
3.55 3.65 3.75 3.85
Co
sts
QALYs
CC CA SHLC CC -> SH CC -> LCCA -> SH CA -> LC £20K/QALY£30K/QALY Frontier
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If remaining on calcium acetate indefinitely is considered a clinically 2152
appropriate option, it may be hard to justify switching to a non-calcium-based 2153
binder, instead, even in people with raised serum calcium. This is because, 2154
although switching strategies are associated with QALY gains, the extra 2155
acquisition costs of the non-calcium-based binders make the opportunity cost 2156
of adopting them represent an ineffective use of NHS resources (the ICER for 2157
best-value alternative – switching from calcium acetate to sevelamer 2158
hydrochloride – approaches £40,000 per QALY gained). 2159
For patients who are unable to tolerate calcium acetate, the cost effectiveness 2160
of switching to non-calcium-based binders should be judged against the only 2161
plausible alternative, which is indefinite treatment with calcium carbonate. 2162
Because calcium carbonate is a less effective choice than calcium acetate, 2163
this comparison is more favourable to the calcium-free alternatives, with 2164
ICERs in the range of £20,000–£30,000 per QALY. 2165
If calcium-based binders are considered to be fundamentally contraindicated 2166
in any individual case, the only remaining options in the decision-space are 2167
sevelamer hydrochloride and lanthanum carbonate. The relative cost-2168
effectiveness of strategies switching from calcium-based binders to either of 2169
these alternatives is difficult to distinguish. Although the model estimates an 2170
ICER of £26,090 for the comparison between the two, this is based on 2171
extremely small differences in costs and QALYs, and it is notable that the two 2172
options have similar ICERs compared with a common baseline of indefinite 2173
calcium acetate treatment (£38,078 per QALY gained for switching to 2174
sevelamer hydrochloride and £42,683 per QALY gained for switching to 2175
lanthanum carbonate). Accordingly, if either treatment is considered 2176
acceptable value for money, it is very likely that the other would have to be 2177
judged similarly. 2178
In one-way sensitivity analysis, very few alterations to individual model 2179
parameters affected the apparent superiority of indefinite calcium acetate 2180
therapy when compared with strategies that transferred people to a non-2181
calcium-based binder when their serum calcium reached a given threshold. 2182
Analyses in which that threshold was raised from its base-case value of 2183
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2.54 mmol/l were associated with some improvement in estimated value for 2184
money for switching strategies; however, even when the threshold was as 2185
high as 3 mmol/l, the ICER for switching to either drug remained above 2186
£30,000 per QALY gained. Conversely, switching people to non-calcium-2187
based binders at a lower threshold made switching strategies appear less cost 2188
effective. 2189
Three other parameters had a potentially important impact on findings. 2190
Switching strategies were associated with ICERs between £20,000 and 2191
£30,000 per QALY gained when: 2192
sevelamer hydrochloride or lanthanum carbonate were at the lower (most 2193
effective) bounds of their credibility intervals for impact on serum calcium 2194
after one year; or 2195
calcium acetate was at the higher (least effective) bound of its credibility 2196
interval for the same parameter; or 2197
low calcium levels were associated with a very substantially increased 2198
mortality risk compared with people with normal serum calcium. 2199
Details are provided in appendix F. 2200
For the comparison of strategies switching to sevelamer hydrochloride and 2201
those switching to lanthanum carbonate, plausible alterations to a large 2202
number of parameters result in the apparent superiority of one or other option 2203
over the other. This reinforces the view that it is difficult to distinguish between 2204
these options, from a health-economic perspective; additional research on the 2205
relative effectiveness of the treatments would be necessary, if it is judged 2206
worthwhile to establish which is superior. 2207
Discussion 2208
Principal findings 2209
The base-case economic model suggests that calcium acetate, when 2210
compared with calcium carbonate, sevelamer hydrochloride and lanthanum 2211
carbonate, is likely to be the preferred first-line phosphate binder for the 2212
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management of hyperphosphataemia in people with CKD stage 5 who are on 2213
dialysis. 2214
When second-line treatment options are taken into account, the most effective 2215
strategies are those commencing with calcium acetate but switching to 2216
sevelamer hydrochloride or lanthanum carbonate if hypercalcaemia develops. 2217
However, remaining on calcium acetate remains a viable option from a health-2218
economic perspective and, in comparison, the switching approaches are 2219
associated with substantially increased costs. Therefore, if all simulated 2220
strategies are seen as realistic options, it is unlikely that the health gains 2221
provided by the more expensive binders are sufficient to counterbalance the 2222
extra expense they entail (unless it can be assumed that society’s maximum 2223
acceptable ICER threshold is approximately £40,000 per QALY). There may 2224
be an exception to this conclusion for people who are unable to tolerate 2225
calcium acetate; in this circumstance, switching to sevelamer hydrochloride or 2226
lanthanum carbonate in those with hypercalcaemia could be seen as an 2227
effective use of resources when compared with the alternative of indefinite 2228
treatment with calcium carbonate. 2229
In patients for whom calcium-based-binders are considered to be 2230
fundamentally contraindicated, the only remaining options in the decision-2231
space are sevelamer hydrochloride and lanthanum carbonate. Under this 2232
circumstance, either option is likely to be judged acceptable, from a health 2233
economic perspective. 2234
Limitations of the analysis 2235
The model has good validity over its first year, accurately reflecting 2236
biochemical measures seen in the trials underpinning it. It also makes a 2237
relatively good prediction of observed survival with the treatments of interest 2238
over the first 3 years of treatment. However, beyond the first year of the 2239
model, biochemical profiles are estimated on the basis of extrapolation and 2240
simplification and, while this approach had its face validity endorsed by the 2241
GDG, it is impossible to tell how well the model fits the (unknown) reality. 2242
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Similarly, it is arguable that, as they extend into the future, the biochemical 2243
profiles of occasional simulated patients become implausible (especially as 2244
regards modelled serum calcium, which may rise very high in a few 2245
instances). However, this is only a problem if it results in implausible effects: if 2246
the level of risk that is predicted is realistic, then it does not matter that the 2247
value of the predictor may be unlikely. For this reason, it should be 2248
remembered that the sole purpose of biochemical parameters in the model is 2249
to estimate the risks faced by patients. 2250
The use of serum phosphate and serum calcium alone as determinants of 2251
treatment effect is an acknowledged simplification of a highly complex 2252
biological interaction. Moreover, it is well known that serum calcium is a 2253
suboptimal index of calcium balance in humans, perhaps especially those with 2254
advanced kidney disease (Houillier et al. 2006). If people who are exposed to 2255
excess calcium intake in their phosphate binding regimen are subject to 2256
greater risks than can be inferred from their serum calcium levels, the model 2257
will underestimate the benefit of switching such people to calcium-free 2258
binders. 2259
When simulating second-line treatment for people experiencing 2260
hypercalcaemia, the model is necessarily reliant on evidence of the 2261
effectiveness of treatments in a broader population. If people with 2262
hypercalcaemia respond differently to treatment than those without, it follows 2263
that the model over- or underestimates the treatment effect that can be 2264
achieved in reality; it is possible that different cost–utility conclusions would be 2265
reached if more specific evidence were available. 2266
It is a significant weakness of this analysis that it has not proved 2267
computationally feasible to undertake full probabilistic sensitivity analysis, to 2268
explore the implications of parameter uncertainty for decision-making. A wide 2269
range of one-way sensitivity analyses was undertaken; this enables a fair 2270
degree of inference on the impact of such ‘second-order’ uncertainty and, in 2271
the light of these analyses, it is possible to state with some confidence that the 2272
options identified as optimal in the base-case analysis would be associated 2273
with the highest probability of cost effectiveness in a fully probabilistic 2274
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analysis. However, it is not possible to quantify these probabilities in the 2275
absence of such an analysis. 2276
It is possible that the model somewhat underestimates the effectiveness of 2277
lanthanum carbonate in both first- and second-line settings, since it was not 2278
possible to include data on phosphate control from what is by far the largest 2279
and longest trial of the drug in the evidence-base (Finn & the Lanthanum 2280
Study Group, 2006; see 3.5.2 above). It is speculated that, were these data 2281
available to incorporate into analysis, apparent differences between 2282
treatments – perhaps especially sevelamer hydrochloride and lanthanum 2283
carbonate in the first-line setting – would be somewhat attenuated. However, 2284
the use of lanthanum carbonate would still be associated with a very high 2285
ICER, compared with calcium acetate: an additional gain of at least 0.3 2286
QALYs would be necessary to counterbalance the costs estimated here, 2287
assuming conventional cost–utility thresholds, and there is no evidence that 2288
an underestimate of such magnitude is plausible. 2289
It is regrettable that there was insufficient evidence to provide a worthwhile 2290
model for people in CKD stages 4 and 5 who have not yet commenced 2291
dialysis, or for children at any stage of disease. There was also insufficient 2292
evidence to perform any meaningful modelling to support a recommendation 2293
on aluminium hydroxide, magnesium carbonate or sevelamer carbonate. 2294
3.5.5 Evidence to recommendations 2295
Relative value of different outcomes
The GDG discussed the relative importance of the outcomes and agreed that those considered critical or important for decision-making were the same as those in the review of phosphate binder effectiveness in patients with CKD stage 4 or 5 who are not on dialysis. However, the GDG also felt that as the cut off points that defined "phosphate control" or "hypercalcaemia" varied between the studies it was more appropriate to focus upon the continuous measures of serum phosphate and calcium as these would be more objective.
Trade-off between benefits and harms
The evidence showed that the phosphate binders examined were all effective in lowering serum phosphate compared with placebo. According to the results of the MTC, no binder was clearly the most effective in terms of impact on serum phosphate levels at the time points considered, although calcium acetate consistently did well. The GDG noted that at 90 days calcium acetate appeared to not be as effective as other binders. However, the GDG considered 90 days to be the minimum follow up time from which decisions could be made,
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and therefore felt that more weight should be given to the longer term analyses. A significant number of patients were considered to have achieved serum phosphate control when treated with sevelamer in conjunction with calcium carbonate. There was also a significant number who were considered to have achieved serum phosphate control amongst those treated with magnesium carbonate.
Both sevelamer and lanthanum appear to reduce the risk of death in those older than 65 years.
Non-calcium-based binders were associated with lower serum calcium levels, with sevelamer and magnesium carbonate performing particularly well. Calcium carbonate consistently performed least well. Calcium carbonate was also associated with a greater risk of hypercalcaemia compared with the other calcium-based phosphate binder, calcium acetate. Although the study that demonstrated this was small in size, the GDG believed this to have biological plausibility because absorption of calcium is lower from calcium acetate than from calcium carbonate because of its lower elemental calcium content. Lanthanum appeared to be associated with a lower risk of hypercalcaemia than sevelamer and magnesium carbonate, although these non-calcium-based binders were better than the calcium-based binders.
Sevelamer was better than calcium-based binders in controlling coronary calcification scores. However, when the effectiveness of the 2 calcium-based binders was considered separately, sevelamer was only better than calcium carbonate; there was no statistically significant difference in coronary calcification scores between sevelamer and calcium acetate.
Little evidence showed statistically significant differences relating to the incidence of adverse events. However, when compared against other binders, lanthanum had a reduced risk of experiencing a number of the adverse events of interest: diarrhoea, upper abdominal pain, and nausea and vomiting. Additionally, sevelamer carbonate was associated with a greater risk of nausea and vomiting when compared with sevelamer hydrochloride. There were also concerns regarding the long-term effects of lanthanum, such as its possible deposition in bone, although no evidence was found for this since it was not an agreed outcome of interest.
Because of its effectiveness in lowering serum phosphate, it was felt that calcium acetate would be an effective choice of first-line treatment in adults. However, in patients that cannot tolerate calcium acetate (for example, those who find it difficult to swallow tablets or experience side effects), the GDG felt that calcium carbonate would be an effective alternative first-line phosphate binder.
The GDG also noted that there may be some subgroups that would be at particular risk of the adverse effects of hypercalcaemia and cardiovascular calcification that can result from the use of calcium-based phosphate binders. Using experience and knowledge gained from their own clinical practice, it was noted that these at-risk patients would likely be defined by the presence of vascular calcification, high serum calcium and/or low serum PTH levels. For some of these patients, non-calcium-based binders could be considered, although it was noted that defining thresholds for these biochemical parameters is difficult. In the case of serum calcium and PTH, it was felt that there
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is not sufficient evidence or consensus in practice to categorically define what constitutes too high or too low. Clinicians should use their clinical judgement to determine acceptable levels, using indicators such as trends observed across a series of measurements, as well as relative levels of other biochemical markers that are known to impact serum calcium or PTH levels. In the case of PTH, current guidance from the Renal Association states that the target range for dialysis patients is between 2 and 9 times the upper limit of normal for the intact PTH assay used. In terms of vascular calcification, the rare use of tests to determine its extent (particularly for the sole reason of determining vascular calcification in CKD patients being treated for hyperphosphataemia) and the absence of cheap, simple and reliable screening tests for vascular calcification precluded the GDG from including this parameter in their recommendations.
Additionally, although no significant difference in adherence was observed with any of the binders examined, the GDG was concerned that the large size of the calcium acetate tablets used in the UK, together with the unpalatability of calcium acetate and calcium carbonate, may reduce adherence to these phosphate binders in particular, and therefore further limit their suitability for some patients.
In some patients, serum phosphate can remain above the recommended level despite adherence with calcium-based binders. If they have reached the maximum recommended (or tolerated) daily dose of calcium-based binders23 it was felt that no further increases in the dose of calcium-based binder should be made. Instead, a non-calcium-based binder may need to be added to the regimen, producing a combination. The aim would be for the added phosphate-binding capacity to raise phosphate control to the desired level without exceeding the recommended daily intake for elemental calcium.
For patients taking calcium-based binders in whom hypercalcaemia has developed, it was felt that the calcium-based binders should be stopped, and non-calcium-based binders started in their place. Although no direct evidence was found for this ‘sequencing’ of binders, the clinical experience of the GDG and the results of the health economic model constructed for this guideline supported this course of action. The health economic model demonstrated that in patients for whom calcium-based binders are not an option, both sevelamer hydrochloride and lanthanum carbonate would be cost-effective candidates for this switch in adults, although there was insufficient evidence to include other non-calcium-based binders (such as aluminium hydroxide) in the evaluation.
Alternatively, it may be considered appropriate to replace a proportion of the calcium-based binder dose with non-calcium-based binders, producing a lower calcium combination without impairing the control of serum phosphate.
23
The GDG felt it important to explicitly define the upper threshold of the calcium-based binder dose
by both the maximum recommended dose in the BNF and, alternatively, by the actual dose that could
be tolerated by the patient. This resulted from the divergence noted between the BNF's maximum
recommended daily dose of calcium acetate (12 tablets) and the dose usually tolerated by patients in
their own clinical experience (4–6 tablets). This disparity raised concerns among the GDG over the
impact on patients of aiming to dose calcium acetate up to the BNF's upper limit before considering
alternative phosphate binder combinations.
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Evidence for the effectiveness of different combinations of binders was limited, addressing only 2 combinations: sevelamer hydrochloride with calcium carbonate (3 studies of 4 to 8 weeks duration), and calcium acetate with magnesium carbonate (1 study of 6 months duration). Both of these combinations seemed to be effective at controlling serum phosphate in patients with normal serum calcium levels, and the binders involved consistently performed well across the effectiveness analyses. The limited nature of the evidence, combined with the lack of evidence for combinations in hypercalcaemic patients, prevented the GDG from selecting one combination over the other, preferring instead to leave the decision to patient preference and clinical judgement.
In children, the one comparison for which evidence was found showed that sevelamer and calcium carbonate are both effective in controlling serum phosphate. Calcium carbonate was also associated with increased serum calcium levels. Children need additional calcium for growing bones and to avoid the effects of secondary hyperparathyroidism that can arise in young patients with chronically low serum calcium. For these reasons, a calcium-based binder would also be desirable as a first-line treatment in children. However, in children who have had a series of calcium measurements that show a trend towards hypercalcaemia, a non-calcium-based binder could help to avoid the adverse effects of prolonged hypercalcaemia.
Additionally, it was felt that no further increases in the dose of calcium-based binder should be made if children taking calcium-based binders remain hyperphosphataemic and have also become hypercalcaemic. Instead, the addition of a non-calcium-based binder to the regimen should be considered in order to achieve phosphate control at the desired level without exceeding the recommended levels for calcium.
Currently, the only non-calcium-based binder licensed for use in children is aluminium hydroxide. However, despite its use being off-label in children, the GDG felt that recommending sevelamer hydrochloride over aluminium hydroxide was appropriate, because they had no evidence for the use of aluminium hydroxide in children. The only paediatric trial found examined the effectiveness of sevelamer against calcium carbonate over an 8-month period, and showed sevelamer to be as effective at lowering serum phosphate and associated with a lower serum calcium level. Furthermore, the GDG had concerns over the toxicity of aluminium, as well as the fact that its licence is not for longer-term indications. The GDG felt that the total replacement of calcium-based binders with a non-calcium-based binder would be inappropriate in children because of their higher calcium requirements.
If considering the use of non-calcium-based binders because of high serum calcium levels in patients on calcium-based binders, the GDG felt it important to emphasise the necessity of reviewing possible causes of high calcium, such as dialysate calcium content, vitamin D, calcium supplements or dietary calcium, before making any changes to the choice of binder. They noted that in some cases it might be easier to make small changes to these sources of elemental calcium than changing (and ensuring adherence to) the phosphate binder regimen. For example, it may be the case that a patient has a high calcium concentration in their dialysate or be on a high dose of vitamin D, and a reduction in one of these may be the most appropriate
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course of action.
Economic considerations
First-line use of phosphate binders:
A cost–utility model was built based on effectiveness data from a network meta-analysis comparing various phosphate binders. The model suggests that calcium acetate is likely to be the preferred option, as it provides appreciable benefit, when compared with calcium carbonate, at a relatively modest additional cost (ICER of approximately £8000 per QALY gained). While the use of non-calcium-based binders may be associated with some extension of quality-adjusted life expectation compared with first-line calcium acetate, this gain is insufficient to justify the additional costs of the proprietary binders, when judged according to conventional standards (very high ICERs of around £90,000 per QALY gained or greater were estimated).
There is some uncertainty about the validity of the model’s extrapolations beyond the first year of follow-up (it was only possible to inform the first year’s treatment effect directly from the literature). However, the model is expected to be robust to inter-individual variability in parameter values because first-order uncertainty is properly captured in the approach that was adopted.
Second-line use of phosphate binders (sequencing following first-line use of calcium acetate):
The cost–utility model was also used to compare the use of different sequences of phosphate binders, with patients starting on calcium acetate. When their serum calcium level rose above a given level (2.54 mmol/l, in the base case), simulated patients either stayed on calcium acetate or were moved to sevelamer hydrochloride or lanthanum carbonate. The results suggest that, although switching to a non-calcium-based binder in this circumstance is likely to result in additional quality-adjusted life-expectancy, this comes at an additional cost that is unlikely to be judged an acceptable use of NHS resources for patients for whom remaining on calcium acetate is clinically viable (ICERs of approximately £40,000 per QALY or greater).
Therefore, the GDG felt that the model supported the use of non-calcium-based binders only in patients for whom the increased calcium intake associated with calcium-based binder use is considered particularly harmful. In patients with hypercalcaemia or low serum PTH, or in patients unable to tolerate calcium-based binders, the GDG felt it was appropriate to remove the calcium-based binders from the decision space – that is, to regard the use of binders that increase calcium load fundamentally contraindicated. The remaining second-line phosphate binders for consideration within the model – sevelamer hydrochloride and lanthanum carbonate – both appear to be cost-effective in patients for whom calcium-based binders are contraindicated.
Although the GDG noted that combinations of different phosphate binders may be used in practice, the model was not able to explore the cost-effectiveness of this approach, due to an absence of evidence on the effectiveness of such combinations.
Quality of evidence
Following the application of GRADE, overall evidence quality was low or very low across the outcomes.
Only one study examining one comparison (sevelamer compared with
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calcium carbonate) was found for age groups other than adults.
Although some evidence for a small number of combinations was found, the evidence did not reflect the wide range of combinations commonly used in UK practice. Furthermore, the combination of sevelamer and calcium carbonate (examined in a number of included studies) would not generally be used.
In making recommendations on the use of combinations of calcium-based and non-calcium-based binders in patients who are above the upper range of normal through calcium-based binder monotherapy, the GDG noted the lack of evidence for combinations in hypercalcaemic patients.
Although magnesium carbonate appeared to perform well in the control of serum phosphate and calcium, the GDG raised concerns about the possible adverse effects – such as diarrhoea – that might be associated with it. The possible adverse effects were not extracted from the single trial examining the effectiveness of magnesium carbonate. This, in conjunction with the small sample size of the trial found, meant that the GDG did not feel the evidence was sufficient to make any recommendations for the use of magnesium carbonate.
No evidence was included on the toxicity of lanthanum, despite concerns, such as its possible deposition in the bones.
Only one paper was found that examined the effectiveness of aluminium hydroxide (used as a comparator for sevelamer). The paper reported data for serum phosphate, the incidence of constipation as an adverse event and serum calcium, although the short 8-week follow-up period and the small sample size meant that the GDG did not feel confident in making recommendations on its use.
A number of different co-treatments were used across the studies. These included ‘rescue’ binders (used when serum phosphate levels became too high), vitamin D, cinacalcet, and phosphate- and/or protein-restricted diets. These concurrent treatments were also considered potential confounders. Additionally, the GDG noted that there were variations, where reported, in the length of time patients were on dialysis prior to starting the trials.
Concerns over the timings of follow-up measurements were also raised. Firstly, the time points used in the MTCs – 90 days, 180 days and 360 days – suffered from approximately 10 days’ variation above or below the stated time point. This primarily resulted from differences in the measures used to define time in each study (days versus weeks versus months). Furthermore, the studies that formed the MTC networks often entailed different follow-up intervals. This meant that the networks changed over time, both in terms of the comparisons covered and the studies involved. It was felt that this may have contributed to the variations in binder ranking over the different time periods analysed.
For serum calcium, lanthanum could not be included in the MTC until 360 days because of the absence of a ‘connector’. When it does enter the network, it was felt that lanthanum did not perform as well as expected. It was suggested that this might have resulted from its connection to the network by ‘any other binder’, which performs particularly poorly, potentially pulling down lanthanum’s relative performance to the other interventions. Additionally, the reviewer was unable to extract serum phosphate data from 1 study comparing
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lanthanum carbonate against ‘standard therapy’ due to its presentation in uninterpretable graphs. It was felt that this study was a significant part of the evidence base due to its long follow-up of 2 years and large population of 1359 participants. However, despite contacting the authors of the study, the reviewer was unable to obtain the data required to include this study in the MTCs for serum phosphate or in the health economic model.
A variety of thresholds were used to define dichotomous outcomes, although the thresholds were sufficiently similar for relative comparisons to still be considered useful. Significant variation was observed in the definitions used for hypercalcaemia in particular, although the thresholds used to define a patient’s achievement of phosphate control also differed in a number of papers.
The GDG felt that the sub-group analysis conducted on patients with a baseline coronary calcification score of more than 30 might not have been a clinically relevant distinction.
Reporting in many of the studies was poor. For example, details of study designs were often unclear and results were not always cited in the text of the papers, requiring the reviewer to read the data off available graphs. Unit-of-analysis errors were also common, with analyses not following the intent-to-treat principle.
Other considerations
Patients on nocturnal, long-hours dialysis may have sufficient phosphate removal to preclude the need for intensive phosphate management interventions. However, their phosphate status should still be closely monitored. Some patients may need interventions to increase their phosphate levels if hypophosphataemia occurs.
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3.5.6 Recommendations and research recommendations for 2296
use of phosphate binders in adults with stage 5 CKD who 2297
are on dialysis 2298
Recommendations 2299
Recommendation 1.1.5
For children and young people, offer a calcium-based phosphate binder as the
first-line phosphate binder to control serum phosphate in addition to dietary
management.
Recommendation 1.1.6
For children and young people, if a series of serum calcium measurements
shows a trend towards the age-adjusted upper limit of normal, consider a
calcium-based binder in combination with a non-calcium-based binder, having
taken into account other causes of rising calcium levels.
Recommendation 1.1.7
For children and young people who remain hyperphosphataemic despite
adherence with a calcium-based phosphate binder, and whose serum calcium
goes above the age-adjusted upper limit of normal, consider a combination of
a calcium-based phosphate binder and sevelamer hydrochloride24, having
taken into account other causes of raised calcium.
Recommendation 1.1.8
For adults, offer calcium acetate as the first-line phosphate binder to control
serum phosphate in addition to dietary management.
Recommendation 1.1.9
For adults, consider calcium carbonate if calcium acetate is not tolerated or
24
At the time of consultation (October 2012), sevelamer hydrochloride did not have a UK marketing
authorisation for this indication. The prescriber should follow relevant professional guidance, taking
full responsibility for the decision. The patient should provide informed consent, which should be
documented. See the General Medical Council’s Good practice in prescribing medicines – guidance for
Management of hyperphosphataemia: NICE clinical guideline DRAFT (October 2012) Page 199 of 248
patients find it unpalatable.
Recommendation 1.1.11
For adults with stage 5 CKD who are on dialysis and remain
hyperphosphataemic despite adherence to the maximum recommended or
tolerated dose of calcium-based phosphate binders, consider either combining
with, or switching to, a non-calcium-based binder.
Recommendation 1.1.12
For adults with stage 5 CKD who are on dialysis and who are taking a
calcium-based binder, if serum phosphate is controlled by the current diet and
phosphate binder regimen but:
serum calcium goes above the upper limit of normal, or
serum parathyroid hormone levels are low,
consider switching the patient to either sevelamer hydrochloride or lanthanum
carbonate, having taken into account other causes of raised calcium.
Recommendation 1.1.13
If a combination of phosphate binders is used, titrate the dosage to achieve
control of serum phosphate while taking into account the effect of any
calcium-based binders used on serum calcium levels (also see
recommendations 1.1.6, 1.1.7 and 1.1.10 to 1.1.12).
Recommendation 1.1.14
Use clinical judgement and take into account patient preference when
choosing whether to use a non-calcium-based binder as monotherapy or in
combination with a calcium-based binder (also see recommendations 1.1.10
to 1.1.12).
2300
Research recommendations 2301
See appendix B for full details of research recommendations. 2302
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Research recommendation B2
In adults with stage 4 or 5 CKD, including those on dialysis, what is the long-
term effectiveness and safety of aluminium hydroxide in controlling serum
phosphate?
Research recommendation B3
In adults and children with stage 4 or 5 CKD, including those on dialysis, what
is the long-term effectiveness and safety of magnesium carbonate in
controlling serum phosphate?
Research recommendation B5
For adults with stage 4 or 5 CKD, including those on dialysis, what is the most
effective sequence or combination of phosphate binders to control serum
phosphate?
2303
3.6 Use of supplements in people with stage 4 or 5 CKD 2304
who are not on dialysis 2305
3.6.1 Review question 2306
For people with stage 4 or 5 CKD who are not on dialysis, are prescribed 2307
supplements, alone or in conjunction with other interventions, effective 2308
compared to placebo or other treatments in managing serum phosphate and 2309
its associated outcomes? Which are the most effective supplements? 2310
3.6.2 Evidence review 2311
This review question focused on the use of supplements in the prevention and 2312
treatment of hyperphosphataemia in patients with stage 4 or 5 CKD who are 2313
not on dialysis. These supplements could consist of a variety of vitamins and 2314
minerals. 2315
For this review question, papers were identified from a number of different 2316
databases (Medline, Embase, Medline in Process, the Cochrane Database of 2317
Systematic Reviews and the Centre for Reviews and Dissemination) using a 2318
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broad search strategy, pulling in all papers relating to the management of 2319
hyperphosphataemia in CKD using supplements . Only RCTs that compared a 2320
supplementation intervention with either a placebo or another comparator in 2321
patients with stage 4 or 5 CKD who are not on dialysis were considered for 2322
inclusion. 2323
Trials were excluded if: 2324
the population included people with CKD stages 1 to 3 or 2325
the population included people on dialysis or 2326
supplementation was intended for any reason other than for the 2327
management of hyperphosphataemia. 2328
2329
From a database of 2020 abstracts, 20 full-text articles were ordered, though 2330
no papers were found to be suitable for inclusion in the analysis. 2331
Supplementation using vitamin D and its metabolites was also not considered 2332
for this review and was excluded at the scoping stage. It was felt that their 2333
effectiveness is not disputed and they are already an accepted and cost-2334
effective part of standard clinical practice. 2335
3.6.3 Evidence statements 2336
3.6.3.1 No evidence on the clinical effectiveness of supplements in the 2337
management of hyperphosphataemia in people with CKD stages 4 2338
or 5 who are not on dialysis was identified. 2339
3.6.4 Evidence to recommendations 2340
Relative value of different outcomes
The GDG discussed the relative importance of the outcomes and agreed that those considered critical or important for decision-making were the same as those in the reviews of phosphate binder effectiveness.
Trade-off between benefits and harms
No evidence was found to examine the benefits and harms of using supplements in the management of hyperphosphataemia in people with stage 4 or 5 CKD who are not on dialysis.
However, the GDG felt that the evidence found in patients with CKD stage 5 who are on dialysis could be extrapolated to this population because it is likely that the efficacy of the intervention would be similar, regardless of whether the person was on dialysis or not. See ‘3.7 Use of supplements in people with stage 5 CKD who are on
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dialysis’ for the review of this evidence.
Economic considerations
Because the GDG did not feel that the available evidence supported the use of supplements, it was not necessary to conduct a cost-effectiveness analysis for this question.
Quality of evidence
No evidence was identified for the use of supplements in the management of hyperphosphataemia in people with stage 4 or 5 CKD who are not on dialysis.
Other considerations
2341
3.7 Use of supplements in people with stage 5 CKD who 2342
are on dialysis 2343
3.7.1 Review question 2344
For people with stage 5 CKD who are on dialysis, are prescribed 2345
supplements, alone or in conjunction with other interventions, effective 2346
compared to placebo or other treatments in managing serum phosphate and 2347
its associated outcomes? Which is the most effective prescribed supplement? 2348
3.7.2 Evidence review 2349
This review question focused on the use of supplements in the prevention and 2350
treatment of hyperphosphataemia in patients with stage 5 CKD who are on 2351
dialysis. These supplements could consist of a variety of vitamins and 2352
minerals, though in the evidence located included: nicotinamide, calcium and 2353
L-carnitine supplementation. 2354
For this review question, papers were identified from a number of different 2355
databases (Medline, Embase, Medline in Process, the Cochrane Database of 2356
Systematic Reviews and the Centre for Reviews and Dissemination) using a 2357
broad search strategy, pulling in all papers relating to the management of 2358
hyperphosphataemia in CKD using supplements. Only RCTs that compared a 2359
supplement with either a placebo or another comparator in patients with stage 2360
5 CKD who are on dialysis were considered for inclusion. 2361
Trials were excluded if: 2362
the population included people with CKD stages 1 to 4 or 2363
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the population included people with CKD stage 5 who were not on dialysis 2364
or 2365
supplementation was intended for any reason other than for the 2366
management of hyperphosphataemia. 2367
2368
From a database of 2020 abstracts, 20 full-text articles were ordered and 2369
5 papers describing 5 primary studies were selected (Young et al, 2009; 2370
Shahbazian et al, 2011; Rudnicki et al, 1993; Chertow et al, 1999; Cibulka et 2371
al, 2007). No paediatric studies meeting the inclusion criteria were found. 2372
Table 9 lists the details of the included studies. 2373
Supplementation using vitamin D and its metabolites was also not considered 2374
for this review and was excluded at the scoping stage. It was felt that their 2375
effectiveness is not disputed and they are already an accepted and cost-2376
effective part of standard clinical practice. 2377
There was pooling of the 2 studies comparing nicotinamide supplementation 2378
against placebo, although there was some heterogeneity present. This 2379
heterogeneity resulted from the use of different concurrent interventions that 2380
are known to impact the outcomes of interest, but also the different types of 2381
dialysis used. 2382
Where meta-analysis was possible, a forest plot is also presented. Mean 2383
differences (MDs) were calculated for continuous outcomes and odds ratios 2384
(ORs) for binary outcomes, as well as the corresponding 95% confidence 2385
intervals where sufficient data were available. 2386
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Table 9 Summary of included studies for the use of supplements in people with stage 5 CKD who are on dialysis 2387
Study Population Intervention Control Follow-up
Nicotinamide compared with placebo
Young et al, 2009
RCT
Missouri, US
Randomised = 17 (intervention = 8; control = 9)
Analysed = 14 (intervention = 7; control = 7)
Age > 18 years
On peritoneal dialysis for > 3 months
Dose of phosphate binder(s) stable over the previous 2 weeks
Plasma phosphate > 4.9 mg/dl (i.e. 1.6 mmol/l) based on the most recent laboratory data within 1 month of enrolment (note: this threshold is within recommended phosphate levels, though at the upper end)
Patients with phosphate values > 3.9 mg/dl meeting all other inclusion criteria were eligible, if consenting, for a reduction in the current phosphate binder dose followed by repeat screening within 2–4 weeks; they were then eligible for continued participation if the repeat phosphate value exceeded 4.9 mg/dl
Baseline serum phosphate (mean SD):
Intervention = 1.65±0.32 mmol/l
Control = 1.74±0.23 mmol/l
See evidence tables in appendix E for full inclusion/exclusion criteria
Nicotinamide (250 mg per capsule) and placebo were packaged as identically appearing capsules
Dosing increased throughout study period: study medication or placebo was started at 250 mg twice daily, increased to 500 mg twice daily after 2 weeks and to 75 0 mg twice daily after 4 weeks
Changes in phosphate binder dose were not allowed except if phosphate values exceeded 6.5 mg/dl (i.e. 2.1 mmol/l) or fell below 3 mg/dl (i.e. 1.0 mmol/l)
Active vitamin D and cinacalcet doses were required to remain stable - i.e. followed pre-study protocol
Placebo packaged as identically appearing capsules
Dosing increased throughout study period: study medication or placebo was started at 250 mg twice daily, increased to 500 mg twice daily after 2 weeks and to 750 mg twice daily after 4 weeks
Changes in phosphate binder dose were not allowed except if phosphate values exceeded 6.5 mg/dl (i.e. 2.1 mmol/l) or fell below 3 mg/dl (i.e. 1.0 mmol/l)
Active vitamin D and cinacalcet doses were required to remain stable - i.e. followed pre-study protocol
8 weeks
Serum phosphate and corrected calcium measured every 2 weeks
Incidence of adverse events (diarrhoea) recorded for the 8-week study period
Shahbazian et al, 2011
RCT
Ahvaz, Iran
Randomised = 48 (intervention = 24; control = 24)
Analysed = 48
Age ≥ 18 years
Fasting serum phosphate ≥ 5 mg/dl (i.e. ≥ 1.6 mmol/l) (note: this threshold is within recommended phosphate levels, though at the very upper end)
Maintaining on haemodialysis for more than 2 months
Constant dosage of phosphate binders during past 2
Immediate release nicotinamide tablets (500 mg)
During the first 4 weeks, nicotinamide was administered 500 mg/day, and then it was administered 1,000 mg/day in weeks 5 to 8.
In case of adverse effects, phosphate level ≤ 3.5 (i.e. 1.1 mmol/l) or > 8 mg/dl (i.e. 2.6 mmol/l), thrombocytopenia
Placebo tablets
Usual doses of calcium carbonate - i.e. followed pre-study protocol (note: unclear if calcium carbonate taken as a supplement or a phosphate binder)
8 weeks
Serum phosphate and corrected calcium measured every 4 weeks
Incidence of
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weeks
Patients had residual renal function of < 10 ml/min
Dialysate concentration of calcium was similar for all patients (in these centres, only 1 kind of dialysate is used)
Baseline serum phosphate (mean SD):
Intervention = 1.91±0.19 mmol/l
Control = 1.88±0.11 mmol/l
See evidence tables in appendix E for full inclusion/exclusion criteria
(platelet counts less than 150,000/mm
3), or clinical findings of
low platelet count, the research committee decided on adjusting the dose or other necessary measures
Usual doses of calcium carbonate - i.e. followed pre-study protocol (note: unclear if calcium carbonate taken as a supplement or a phosphate binder)
adverse events (diarrhoea) recorded for the 8-week study period
Sevelamer hydrochloride + calcium supplementation compared with sevelamer hydrochloride alone
Chertow et al, 1999
RCT
US
Randomised = 71 (intervention = 36; control = 35)
Analysed = 71
Age ≥ 18 years
Thrice weekly haemodialysis for at least 3 months
Regular calcium- and/or aluminium-based phosphate binders, with or without vitamin D metabolite replacement therapy at stable doses for at least 1 month before screening; all pre-study phosphate binders discontinued 2 weeks before treatment phase
Participants whose serum phosphate concentration rose to 6.0 mg/dl (i.e. 1.9 mmol/l) or above after 2-week phosphate binder washout period were entered into treatment phase; participants whose serum phosphate rose to above 12 mg/dl (i.e. 3.9 mmol/l) were entered immediately into the treatment phase without necessarily completing the 2-week washout
Baseline serum phosphate (mean SD):
Intervention = 2.51 0.10 mmol/l
Control = 2.75 0.13 mmol/l
See evidence tables in appendix E for full inclusion/exclusion criteria
900 mg of elemental calcium taken in the form of calcium carbonate once nightly on a on an empty stomach
Initial dose of sevelamer hydrochloride (RenaGel) was determined by the highest level of serum phosphate during the 2-week phosphate binder washout period: 2 x 465 mg capsules 3 times daily with meals for serum phosphate concentrations > 6.0 mg/dl (i.e. 1.9 mmol/l) and < 7.5 mg/dl (i.e. 2.4 mmol/l); 3 x 465 mg capsules 3 times daily with meals for serum phosphate concentrations > 7.5 mg/dl (i.e. 2.4 mmol/l) and < 9.0 mg/dl (i.e. 2.9 mmol/l); 4 x 465 mg capsules 3 times daily with meals for serum phosphate concentrations > 9.0 mg/dl (i.e. 2.9 mmol/l)
Sevelamer hydrochloride doses were titrated up and down by 3 capsules per day every 3 weeks (at 3, 6 and 9 weeks after treatment commencement), with the goal of achieving serum phosphate concentrations between 2.5 (i.e. 0.6 mmol/l) and 5.5 mg/dl (i.e.
Initial dose of sevelamer hydrochloride (RenaGel) was determined by the highest level of serum phosphate during the 2-week phosphate binder washout period: 2 x 465 mg capsules 3 times daily with meals for serum phosphate concentrations > 6.0 mg/dl (i.e. 1.9 mmol/l) and < 7.5 mg/dl (i.e. 2.4 mmol/l); 3 x 465 mg capsules 3 times daily with meals for serum phosphate concentrations > 7.5 mg/dl (i.e. 2.4 mmol/l) and < 9.0 mg/dl (i.e. 2.9 mmol/l); 4 x 465 mg capsules 3 times daily with meals for serum phosphate concentrations > 9.0 mg/dl (i.e. 2.9 mmol/l)
Sevelamer hydrochloride doses were titrated up and down by 3 capsules per day every 3 weeks (at 3, 6 and 9 weeks after treatment commencement), with the goal of achieving serum phosphate concentrations between 2.5 (i.e. 0.6 mmol/l) and 5.5 mg/dl (i.e. 1.8 mmol/l)
Participants were asked to maintain their usual eating habits without any intentional changes in dietary
12 weeks
Incidence of mortality and adverse events (vomiting, nausea, constipation, and diarrhoea) recorded for the 12-week study period
Serum phosphate and calcium measured weekly
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2388
1.8 mmol/l)
Participants were asked to maintain their usual eating habits without any intentional changes in dietary restrictions
Participants were not permitted to take any aluminium-based products, or any additional calcium-based products
Vitamin D metabolite doses were maintained at baseline levels except in the event of significant hypo- or hypercalcaemia
restrictions
Participants were not permitted to take any calcium- or aluminium-based products
Vitamin D metabolite doses were maintained at baseline levels except in the event of significant hypo- or hypercalcaemia
L-carnitine supplementation compared with placebo
Cibulka et al, 2007
RCT
Czech Republic
Randomised = 112
Analysed = 83 (intervention = 44; control = 39)
Criteria for randomisation:
Regular haemodialysis – 4 hours 3 times weekly
All patients had a GFR < 0.2 ml/sec (i.e. < 12 ml/min)
Baseline serum phosphate (median (range)):
Intervention = 1.74 mmol/l (0.71 – 3.71)
Control = 1.71 mmol/l (1.02 – 3.50)Exclusion criteria (for those who were randomised but who were not included in the analysis): kidney transplant; non-adherence; change of residence; restitution of kidney function; change in vitamin D dose during trial
15 mg of L-carnitine/kg of body weight in a short intravenous infusion after each haemodialysis session (i.e. 3 times weekly)
All patients received calcium carbonate phosphate binder therapy
Patients continued pre-study vitamin D treatment
Isotonic solution of sodium chloride in a short intravenous infusion after each haemodialysis session (i.e. 3 times weekly)
All patients received calcium carbonate phosphate binder therapy
Patients continued pre-study vitamin D treatment
6 months
Incidence of mortality recorded for the 6-month study period
Serum phosphate and calcium measured every 3 months
Abbreviations: Ca, calcium ions; GFR, glomerular filtration rate; HIV, human immunodeficiency virus; RCT, randomised controlled trial; SD, standard deviation.
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Summary GRADE profile 52 Niacinamide compared with placebo 2389
Outcome Number of Studies
Number of patients Effect Quality
Niacinamide1
Placebo1
Serum phosphate (pooled)
8-week follow-up
2 RCTs
Shahbazian et al, 2011
Young et al, 2009
31 31 Absolute effect
MD = 0.30 mmol/l lower (95% CI:0.42 to 0.17 lower)
Note: the 2 groups were not comparable in terms of their serum phosphate at the start of the treatment period (the mean difference was statistically significant at -0.24 mmol/l (95% CI -0.29 to -0.19)), nor their serum calcium x phosphorus product (both were higher in the control group). It also appears that there was a greater prevalence of
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hypercalcaemia in the intervention group at the start of treatment. Additionally, vitamin D use different at baseline, but the difference was not statistically significant (intervention group = 60% use vitamin D versus 42% in control group [p = 0.16])
Management of hyperphosphataemia: NICE guideline DRAFT (October 2012) Page 211 of 248
3.7.3.5 Very-low-quality evidence from 1 RCT of 14 participants showed no 2426
statistically significant difference in mean serum corrected calcium 2427
level between those that received nicotinamide supplementation 2428
and those that received placebo at 8 weeks (MD 0.05 mmol/l lower 2429
[95% CI -0.21 to 0.11]). 2430
Sevelamer hydrochloride + calcium supplementation compared with 2431
sevelamer hydrochloride 2432
Critical outcomes 2433
3.7.3.6 Very-low-quality evidence from 1 RCT of 71 participants showed no 2434
statistically significant difference in the number of deaths during the 2435
12-week study period between those that received sevelamer 2436
hydrochloride and calcium supplementation and those that received 2437
sevelamer hydrochloride alone (OR 0.21 [95% CI 0.01 to 4.44]). 2438
3.7.3.7 Very-low-quality evidence from 1 RCT of 71 participants showed 2439
sevelamer hydrochloride and calcium supplementation to be 2440
associated with a mean serum phosphate level 0.31 mmol/l lower 2441
(95% CI -0.59 to -0.04 i.e. statistically significant) than that 2442
associated with sevelamer hydrochloride alone at 6 months25. 2443
3.7.3.8 Very-low-quality evidence from 1 RCT of 71 participants showed no 2444
statistically significant difference in the mean change in serum 2445
phosphate levels during the 6-month study period between those 2446
that received sevelamer hydrochloride and calcium 2447
supplementation and those that received sevelamer hydrochloride 2448
alone (MD 0.03 mmol/l lower [95% CI -1.83 to 1.77]). 2449
3.7.3.9 Very-low-quality evidence from 1 RCT of 71 participants showed no 2450
statistically significant difference in the number of patients to 2451
achieve a therapeutic response (defined as serum phosphate at or 2452
25
Note: the difference in mean serum phosphate at treatment initiation was statistically significant
between the 2 groups, with a mean in the group taking sevelamer hydrochloride with supplemental
calcium of 2.51 mmol/l and of 2.75 mmol/l in the group taking sevelamer hydrochloride alone (MD -
0.24 mmol/l (95% CI -0.29 to -0.19)).
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below the participant’s pre-binder washout level or < 1.78 mmol/l) 2453
during the 12-week study period between those that received 2454
sevelamer hydrochloride and calcium supplementation and those 2455
that received sevelamer hydrochloride alone (OR 1.03 [95% CI 2456
0.14 to 7.75]). 2457
Important outcomes 2458
3.7.3.10 Very-low-quality evidence from 1 RCT of 71 participants showed no 2459
statistically significant difference in the mean change in serum 2460
calcium levels during the 6-month study period between those that 2461
received sevelamer hydrochloride and calcium supplementation 2462
and those that received sevelamer hydrochloride alone (MD 2463
0.08 mmol/l higher [95% CI -0.01 to 0.16]). 2464
3.7.3.11 Very-low-quality evidence from 1 RCT of 71 participants showed 2465
that a greater proportion of participants that received sevelamer 2466
hydrochloride and calcium supplementation experienced 2467
hypercalcaemia during the 12-week study period than among those 2468
that received sevelamer hydrochloride alone (OR 10.88 [95% CI 2469
2.77 to 42.70 i.e. statistically significant]). 2470
L-carnitine supplementation compared with placebo 2471
Critical outcomes 2472
3.7.3.12 Very-low-quality evidence from 1 RCT of 83 participants showed no 2473
statistically significant difference in the number of deaths during the 2474
6-month study period between those that received L-carnitine 2475
supplementation and those that received placebo (OR 0.63 [95% 2476
CI 0.21 to 1.89]). 2477
3.7.3.13 Very-low-quality evidence from 1 RCT of 83 participants showed 2478
received L-carnitine supplementation to be associated with a 2479
median serum phosphate level 0.08 mmol/l lower than that 2480
associated with placebo. 2481
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2482
Important outcomes 2483
3.7.3.14 Very-low-quality evidence from 1 RCT of 83 participants showed 2484
L-carnitine supplementation to be associated with a median serum 2485
calcium level 0.04 mmol/l lower than that associated with placebo. 2486
3.7.4 Evidence to recommendations 2487
Relative value of different outcomes
The GDG discussed the relative importance of the outcomes and agreed that those considered critical or important for decision-making were the same as those in the reviews of phosphate binder effectiveness.
Trade-off between benefits and harms
From the 2 studies identified, the GDG noted that nicotinamide appears to be effective in lowering serum phosphate levels. Fewer patients experienced an increase in these levels when taking nicotinamide, instead achieving a greater mean decrease in serum phosphate over the study period and lower mean levels at the endpoint. It also appeared that the incidence of diarrhoea was not significantly different between those taking the supplement and those taking placebo. However, the GDG felt that the study periods involved (both studies lasted for 8 weeks) and the sizes of the samples used (14 and 48 patients) were not sufficient to detect a significant difference in the risk of experiencing side effects. The GDG was concerned that the side effects of nicotinamide could be comparable to those associated with nicotinic acid, including: nausea, vomiting, abdominal pain and dyspepsia; flushing; pruritus and rash. No evidence was found on these adverse effects. Additionally, no data were found concerning the mortality, adherence or quality of life associated with this supplement.
One study was found to examine the effectiveness of calcium supplementation in controlling serum phosphate. The comparison was made between sevelamer hydrochloride supplemented with calcium carbonate and sevelamer hydrochloride alone. The GDG distinguished calcium carbonate’s use as a supplement from its use as a binder by the timing of its consumption; calcium carbonate supplementation is taken on an empty stomach and calcium carbonate binders are taken with meals.
The addition of supplemental calcium to sevelamer hydrochloride was associated with a significantly lower mean serum phosphate level at the study’s end compared to sevelamer hydrochloride alone. However, the GDG concluded that this was not due to the intervention’s greater effectiveness in controlling serum phosphate because the intervention group had a significantly lower mean serum phosphate level at the start of treatment. This view was further supported by the finding that there was not a significant difference between the mean changes in serum phosphate of the 2 groups over the course of the study.
The GDG noted that the use of additional calcium supplementation did, however, result in an increase in hypercalcaemic events and an
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almost statistically significant increase in mean serum calcium. The GDG felt that there were considerable concerns over when calcium carbonate should and should not be given, and how this might link to the binders that an individual may or may not be given. The available evidence only supports the use of calcium carbonate as a phosphate binder (reviewed in section 3.5), taken with food not on an empty stomach. The GDG noted that the need to take any phosphate binder with a meal, as opposed to as a supplement on an empty stomach, was an important step in ensuring therapeutic success.
The GDG felt that the evidence outlined above could be extrapolated to those with CKD stages 4 and 5 who are not on dialysis and to children.
Economic considerations
Because the GDG did not feel that the available evidence supported the use of supplements, it was not necessary to conduct a cost-effectiveness analysis for this question.
Quality of evidence
No data were available for age groups other than adults.
No evidence was found relating to cardiovascular calcification scores, adherence and quality of life, and the GDG also noted the short length of follow-up in the trials that studied mortality.
A range of co-treatments were used across the studies, and concerns were noted over their potential influence as confounders. In particular, heterogeneity was noted for the two studies pooled in order to assess the effectiveness of nicotinamide. The co-treatments in one paper consisted of the patients’ pre-study phosphate binder, vitamin D and cinacalcet regimens, and the patients’ pre-study calcium carbonate regimen in the other. Additionally, the types of dialysis used were different in the two papers: peritoneal dialysis and maintenance haemodialysis, respectively.
Reporting in many of the studies was poor. For example, details of study designs were often unclear and results were not always cited in the text of the papers, requiring the reviewer to read the data off available graphs. Unit-of-analysis errors were also common, with analyses not following the intent-to-treat principle.
Other considerations
The use of supplementation in the management of hyperphosphataemia could add further to the treatment burden already experienced by patients on a demanding regimen.
2488
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3.7.5 Recommendations and research recommendations for 2489
use of supplements in people with stage 5 CKD who are 2490
on dialysis 2491
Recommendations 2492
Recommendation 1.1.15
Advise patients to take phosphate binders with food in order to control serum
phosphate.
2493
3.8 Sequencing of treatments 2494
3.8.1 Review question 2495
In the management of hyperphosphataemia in people with stage 4 or 5 CKD, 2496
in what order should available treatments be considered? What are the clinical 2497
indications for commencing each? 2498
3.8.2 Evidence review 2499
This review question focused on the sequencing of interventions in the 2500
prevention and treatment of hyperphosphataemia in patients with stage 4 or 5 2501
CKD, including those on dialysis. These interventions could include dietary 2502
interventions, phosphate binders, supplements including vitamin D, and 2503
dialysis. 2504
For this review question, papers were identified from a number of different 2505
databases (Medline, Embase, Medline in Process, the Cochrane Database of 2506
Systematic Reviews, the Health Technology Assessment Database (HTA) 2507
and the Database of Abstracts of Reviews of Effects (DARE). A broad search 2508
strategy was used, pulling in all papers relating to the sequencing of 2509
interventions in the management of hyperphosphataemia in patients with 2510
trials, cohort studies, cross-sectional studies and case-control studies were 2512
eligible for inclusion. 2513
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Trials were excluded if: 2514
the population included people with stages 1 to 3 CKD or 2515
they did not compare a sequence of interventions with another sequence of 2516
interventions. 2517
2518
From a database of 1868 abstracts, 16 full-text articles were ordered, 2519
although no papers were found to be suitable for inclusion in the analysis. 2520
2521
3.8.3 Evidence statements 2522
3.8.3.1 No evidence was identified on the sequencing of interventions in 2523
order to maximise the management of hyperphosphataemia in 2524
people with stage 4 or 5 CKD, nor in people with stage 5 CKD who 2525
are on dialysis. 2526
3.8.4 Health economic modelling 2527
Health economic analysis within this guideline focused on evaluation of 2528
phosphate binders for people with stage 5 CKD who are on dialysis. These 2529
results assisted the GDG in making recommendations regarding the 2530
sequencing of phosphate binders. See section 3.5.4 and appendix F for full 2531
details on the health economic analysis and modelling carried out for the 2532
guideline. 2533
3.8.5 Evidence to recommendations 2534
Relative value of different outcomes
The GDG discussed the relative importance of the outcomes and agreed that those considered critical or important for decision-making were the same as those in the reviews of phosphate binder effectiveness.
Trade-off between benefits and harms
Although no evidence was found concerning the relative effectiveness of different treatment sequences, the GDG reached a consensus regarding best practice, using their clinical knowledge and experience. The GDG felt strongly that the two key interventions for the management of hyperphosphataemia in people with advanced CKD are, as first-line, dietary management and, as second-line, phosphate binders. They also emphasised the cyclical nature of this sequence, stressing that clinicians should continue to periodically review the dietary and binder regimens throughout the treatment pathway.
The GDG noted that dialysis efficacy and vitamin D and its analogues
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are known to influence serum phosphate control. However, it was felt that these are not part of the primary treatment sequence of hyperphosphataemia, rather they fall in parallel. By this the GDG meant that, while they impact serum phosphate, these interventions would be brought in to the treatment pathway for reasons other than hyperphosphataemia: for example, vitamin D for management of serum calcium, serum PTH and/or hyperparathyroidism, and dialysis for severe decline in renal function. For this reason, the GDG did not feel it appropriate to specify the clinical conditions in which vitamin D or dialysis should be initiated within the treatment of hyperphosphataemia. However, acknowledging their impact upon serum phosphate (and other relevant biochemical parameters, such as serum calcium), they noted that diet and binder prescriptions should be reviewed when vitamin D or dialysis regimens are initiated or adjusted.
GDG discussions regarding the sequencing of phosphate binders were included in earlier reviews (see sections 3.4 and 3.5).
Economic considerations
No health economic evidence was available to inform the GDG’s consideration of the optimal sequence of different modes of treatment. However, the de novo health economic model developed to examine the cost–utility of phosphate binders provided evidence on the cost-effectiveness of different sequences of binders (see section 3.5.4). It should be noted that, in the GDG’s experience, different phosphate binders may be used in combination, rather than wholesale switching from one to another. The model was not able to explore the cost-effectiveness of different combinations of phosphate binders due to a complete absence of evidence on the effectiveness of such combinations.
Quality of evidence
No evidence was found to examine the effectiveness of different treatment sequences for the management of hyperphosphataemia in people with stage 4 or 5 CKD, including those on dialysis.
Other considerations
2535
3.8.6 Recommendations and research recommendations for 2536
sequencing of treatments 2537
Recommendations 2538
Recommendation 1.1.16
If vitamin D or dialysis is introduced, review the patient’s diet and phosphate
binder requirement in order to maintain the control of serum phosphate.
2539
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Research recommendations 2540
See appendix B for full details of research recommendations. 2541
Research recommendation B5
For adults with stage 4 or 5 CKD, including those on dialysis, what is the most
effective sequence or combination of phosphate binders to control serum
phosphate?
2542
4 Notes on the scope of the guideline 2543
NICE guidelines are developed in accordance with a scope that defines what 2544
the guideline will and will not cover. The scope of this guideline is given in 2545
appendix C. 2546
5 Implementation 2547
NICE has developed tools to help organisations implement this guidance. 2548
Note: these details will apply when the guideline is published. 2549
6 Other versions of this guideline 2550
6.1 NICE pathway 2551
The recommendations from this guideline have been incorporated into a NICE 2552
pathway. Note: these details will apply when the guideline is published. 2553
6.2 ‘Understanding NICE guidance’ 2554
A summary for patients and carers (‘Understanding NICE guidance’) is 2555
available. 2556
For printed copies, phone NICE publications on 0845 003 7783 or email 2557
[email protected] (quote reference number N[xxxx]). Note: these 2558
details will apply when the guideline is published. 2559