Hyperphosphataemia in chronic kidney disease by Biblitoeca hrs

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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 5 Implementation ...................................................................................... 218 6 Other versions of this guideline ............................................................. 218 6.1 NICE pathway ................................................................................. 218 6.2 â&#x20AC;&#x2DC;Understanding NICE guidanceâ&#x20AC;&#x2122; ...................................................... 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

Hyperphosphataemia

Chronic kidney disease (CKD) describes abnormal kidney function and/or

structure. It is common and often exists together with other conditions, such

as cardiovascular disease and diabetes.

The ‘National service framework for renal services’ adopted the US ‘National

Kidney Foundation kidney disease outcomes quality initiative’ (NKF-KDOQI)

classification of CKD. This classification divides CKD into 5 stages according

to the extent of a person’s loss of renal function. Stage 4 CKD is defined by a

glomerular filtration rate (GFR) of 15–30 ml/min/1.73 m2, and stage 5 by a

GFR of less than 15 ml/min/1.73 m2.1

CKD progresses to these more advanced stages in a small but significant

percentage of people. In 2010, the Health Survey for England reported a

prevalence of moderate to severe CKD (stages 3 to 5) of 6% in men and 7%

in women. CKD stages 4 and 5 were reported at a prevalence of 1% or less.

Although this figure might seem small, it translates to a prevalence of up to

520,000 people in England alone.

When CKD stage 5 advances to end-stage renal disease (ESRD), some

people progress to renal replacement therapy (RRT)2. The UK Renal Registry

reported that 49,080 adult patients were receiving RRT in the UK at the end of

2009. Of these, 25,796 were receiving RRT in the form of dialysis (a

population sometimes classified CKD stage 5D).

As kidney dysfunction advances, there is a higher risk of mortality and some

comorbidities become more severe. Hyperphosphataemia is one example of

this, and is because of insufficient filtering of phosphate from the blood by 1

A GFR of over 90 ml/min/1.73 m2 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 dialysis.

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poorly functioning kidneys. This means that a certain amount of the phosphate

does not leave the body in the urine, instead remaining in the blood at

abnormally elevated levels.

High serum phosphate levels can directly and indirectly increase parathyroid

hormone secretion, leading to the development of secondary

hyperparathyroidism. Left untreated, secondary hyperparathyroidism

increases morbidity and mortality and may lead to renal bone disease, with

people experiencing bone and muscular pain, increased incidence of fracture,

abnormalities of bone and joint morphology, and vascular and soft tissue

calcification.

For adults with stage 4 or 5 CKD who are not on dialysis, the UK Renal

Association guidelines recommend that serum phosphate be maintained at

between 0.9 and 1.5 mmol/l. For adults with stage 5 CKD who are on dialysis,

it is recommended that serum phosphate levels be maintained at between 1.1

and 1.7 mmol/l. Because of the improved removal of phosphate from the

blood through dialysis, adults on dialysis have different recommended levels

to those with stage 4 or 5 CKD who are not on dialysis.

For children and young people with stage 4 CKD, the NKF-KDOQI guidelines

and European guidelines on the prevention and treatment of renal

osteodystrophy recommend that serum phosphate be maintained within

age-appropriate limits. For those with stage 5 CKD, including those on

dialysis, it is recommended that serum phosphate levels be maintained at

between 1.3 and 1.9 mmol/l for those aged 1â&#x20AC;&#x201C;12 years, and between 1.1 and

1.8 mmol/l during adolescence.

Standard management of hyperphosphataemia involves the use of both

pharmacological and non-pharmacological interventions, as well as the

provision of education and support. However, there is wide variation between

renal centres in the UK in how these interventions are used. At the end of

2009, data from the UK Renal Registry showed that only 61% of patients

receiving haemodialysis and 70% of patients receiving peritoneal dialysis

achieved serum phosphate levels within the recommended range. This,

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together with a rising prevalence of CKD, led to the development of this

clinical guideline on the management of hyperphosphataemia.

Drug recommendations

The guideline does not make recommendations on drug dosage; prescribers

should refer to the ‘British National Formulary’ for this information. The

guideline also assumes that prescribers will use a drug’s Summary of Product

Characteristics to inform decisions made with individual patients.

This guideline recommends some drugs for indications for which they do not

have a UK marketing authorisation at the date of publication, if there is good

evidence to support that use. Where recommendations have been made for

the use of drugs outside their licensed indications (‘off-label use’), these drugs

are marked with a footnote in the recommendations.

Who this guideline is for

This document is for healthcare professionals and other staff who care for

people with stage 4 or 5 CKD, including those with stage 5 CKD who are on

dialysis. Where it refers to children and young people, this applies to all

people younger than 18 years old. Where it refers to adults, this applies to all

people 18 years or older.

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Patient-centred care

This guideline offers best practice advice on the care of adults, children and

young people with stage 4 or 5 CKD who have, or are at risk of,

hyperphosphataemia.

Treatment and care should take into account patients’ needs and preferences.

People with CKD should have the opportunity to make informed decisions

about their care and treatment, in partnership with their healthcare

professionals. If patients do not have the capacity to make decisions,

healthcare professionals should follow the Department of Health’s advice on

consent and the code of practice that accompanies the Mental Capacity Act.

In Wales, healthcare professionals should follow advice on consent from the

Welsh Government.

If the patient is under 16, healthcare professionals should follow the guidelines

in the Department of Health’s ‘Seeking consent: working with children’.

Good communication between healthcare professionals and patients is

essential. It should be supported by evidence-based written information

tailored to the patient’s needs. Treatment and care, and the information

patients are given about it, should be culturally appropriate. It should also be

accessible to people with additional needs such as physical, sensory or

learning disabilities, and to people who do not speak or read English.

If the patient agrees, families and carers should have the opportunity to be

involved in decisions about treatment and care.

Families and carers should also be given the information and support they

need.

100

Care of young people in transition between paediatric and adult services

101

should be planned and managed according to the best practice guidance

102

described in the Department of Health’s ‘Transition: getting it right for young

103

people’.

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Adult and paediatric healthcare teams should work jointly to provide

105

assessment and services to young people with stage 4 or 5 CKD. Diagnosis

106

and management should be reviewed throughout the transition process, and

107

there should be clarity about who is the lead clinician to ensure continuity of

108

care.

109

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Recommendations

111

1.1

112

Please note: unless an age group is explicitly specified, the recommendation

113

applies to all age groups (children, young people and adults).

114

Dietary management: children, young people and adults

115

1.1.1

List of all recommendations

A specialist renal dietitian, supported by healthcare professionals

116

with the necessary skills and competencies, should carry out a

117

dietary assessment and give individualised information and advice

118

on dietary phosphate management.

119

1.1.2

Advice on dietary phosphate management should be tailored to

120

individual learning needs and preferences, rather than being

121

provided through a generalised or complex multicomponent

122

programme of delivery.

123

1.1.3

Give information about controlling intake of phosphate-rich foods

124

(in particular foods with a high phosphate content per gram of

125

protein, as well as food and drinks with high levels of phosphate

126

additives) to control serum phosphate, while avoiding malnutrition

127

by maintaining a protein intake at or above the minimum

128

recommended level. For those on dialysis, take into account

129

possible dialysate protein losses.

130

1.1.4

If a nutritional supplement is needed to maintain protein intake in

131

children and young people with hyperphosphataemia, offer a

132

supplement with a lower phosphate content, taking into account

133

patient preference.

134

Phosphate binders: children and young people

135

1.1.5

For children and young people, offer a calcium-based phosphate

136

binder as the first-line phosphate binder to control serum

137

phosphate in addition to dietary management.

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1.1.6

For children and young people, if a series of serum calcium

139

measurements shows a trend towards the age-adjusted upper limit

140

of normal, consider a calcium-based binder in combination with a

141

non-calcium-based binder, having taken into account other causes

142

of rising calcium levels.

143

1.1.7

For children and young people who remain hyperphosphataemic

144

despite adherence to a calcium-based phosphate binder, and

145

whose serum calcium goes above the age-adjusted upper limit of

146

normal, consider a combination of a calcium-based phosphate

147

binder and sevelamer hydrochloride3, having taken into account

148

other causes of raised calcium.

149

Phosphate binders: adults

150

1.1.8

to control serum phosphate in addition to dietary management.

151 152

1.1.9

For adults, consider calcium carbonate if calcium acetate is not tolerated or patients find it unpalatable.

153 154

For adults, offer calcium acetate as the first-line phosphate binder

1.1.10

For adults with stage 4 or 5 chronic kidney disease (CKD) who are not on dialysis and who are taking a calcium-based binder:

155 156

consider switching to a non-calcium-based binder if

157

calcium-based phosphate binders are not tolerated

158

consider either combining with, or switching to, a

159

non-calcium-based binder if hypercalcaemia develops (having

160

taken into account other causes of raised calcium), or if serum

161

parathyroid hormone levels are low.

162

1.1.11

For adults with stage 5 CKD who are on dialysis and remain hyperphosphataemic despite adherence to the maximum

163 3

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 Councilâ&#x20AC;&#x2122;s Good practice in prescribing medicines â&#x20AC;&#x201C; guidance for doctors for further information.

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recommended or tolerated dose of calcium-based phosphate

165

binders, consider either combining with, or switching to, a

166

non-calcium-based binder.

167

1.1.12

For adults with stage 5 CKD who are on dialysis and who are

168

taking a calcium-based binder, if serum phosphate is controlled by

169

the current diet and phosphate binder regimen but:

170

serum calcium goes above the upper limit of normal, or

171

serum parathyroid hormone levels are low,

172

consider switching the patient to either sevelamer hydrochloride or

173

lanthanum carbonate, having taken into account other causes of

174

raised calcium.

175

Phosphate binders: children, young people and adults

176

1.1.13

If a combination of phosphate binders is used, titrate the dosage to

177

achieve control of serum phosphate while taking into account the

178

effect of any calcium-based binders used on serum calcium levels

179

(also see recommendations 1.1.6, 1.1.7 and 1.1.10 to 1.1.12).

180

1.1.14

Use clinical judgement and take into account patient preference

181

when choosing whether to use a non-calcium-based binder as

182

monotherapy or in combination with a calcium-based binder (also

183

see recommendations 1.1.10 to 1.1.12).

184

1.1.15

Advise patients to take phosphate binders with food in order to control serum phosphate.

185 186

Review of treatments: children, young people and adults

187

1.1.16

If vitamin D or dialysis is introduced, review the patientâ&#x20AC;&#x2122;s diet and

188

phosphate binder requirement in order to maintain the control of

189

serum phosphate.

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Summary pathway

191 192 193

Person with stage 4 or 5 chronic kidney disease at risk of, or with, hyperphosphataemia

Dietary management

Review of treatments [1.1.16]

Dietary assessment, information and advice [1.1.1, 1.1.2, 1.1.3, 1.1.4]

Phosphate binder management [1.1.13, 1.1.14, 1.1.15]

First-line phosphate binder treatment for children and young people [1.1.5, 1.1.6]

First-line phosphate binder treatment for adults [1.1.8, 1.1.9]

Second-line phosphate binder treatment for children and young people [1.1.7]

Second-line phosphate binder treatment for adults [1.1.10, 1.1.11, 1.1.12]

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Evidence review and recommendations

195

For details of how this guideline was developed see appendix D.

196

3.1

Dietary management for people with stage 4 or 5 CKD who are not on dialysis

197 198

3.1.1

Review question

199

For people with stage 4 or 5 CKD who are not on dialysis, is the dietary

200

management of phosphate effective compared to placebo or other treatments

201

in managing serum phosphate and its associated outcomes? Which dietary

202

methods are most effective?

203

3.1.2

204

This review question focused on the use of dietary interventions in the

205

prevention and treatment of hyperphosphataemia in patients with stage 4 or 5

206

CKD who are not on dialysis. These interventions are based on varying

207

degrees of restriction in the intake of phosphate and/or protein, with or without

208

supplementation with keto and amino acids.

209

For this review question, papers were identified from a number of different

210

databases (Medline, Embase, Medline in Process, the Cochrane Database of

211

Systematic Reviews, the Cochrane Central Register of Controlled Trials and

212

the Centre for Reviews and Dissemination) using a broad search strategy,

213

pulling in all papers relating to the dietary management of

214

hyperphosphataemia in CKD. Only randomised controlled trials (RCTs) that

215

compared a dietary intervention with either a placebo or another comparator

216

in patients with stage 4 or 5 CKD who are not on dialysis were considered for

217

inclusion (appendix E).

218

Trials were excluded if:

Evidence review

219

the population included people with CKD stages 1 to 3 or

220

the population included people on dialysis.

221

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From a database of 3026 abstracts, 244 full-text articles were ordered

223

(including 107 identified through review of relevant bibliographies) and

224

13 papers describing 11 primary studies met the inclusion criteria

225

(Cianciaruso et al, 2008; Cianciaruso et al, 2008; Di Iorio et al, 2003;

226

European Study Group for the Conservative Management of Chronic Renal

227

Failure, 1992; Feiten et al, 2005; Ihle et al, 1989; Jungers et al, 1987; Klahr et

228

al, 1994; Kopple et al, 1997; Lindenau et al, 1990; Malvy et al, 1999; Mircescu

229

et al, 2007; Snetselaar et al, 1994). No paediatric studies meeting the

230

inclusion criteria were found. Table 1 lists the details of the included studies.

231

In order to define the interventions covered and aid an overarching analysis of

232

the dietary management of hyperphosphataemia, protein levels in

233

interventions that included protein restriction were categorised as follows

234

through discussion with the guideline development group (GDG):

235

less than or equal to 0.4 g of protein per kilogram of bodyweight per day:

236

very-low-protein diet

237

more than 0.4 g to less than or equal to 0.75 g of protein per kilogram of

238

bodyweight per day: low-protein diet

239

more than 0.75 g to less than or equal to 1.2 g of protein per kilogram of

240

bodyweight per day: moderate-protein diet

241

more than 1.2 g of protein per kilogram of bodyweight per day: high-protein

242

diet.

243 244

There was some pooling of studies, although this was limited because of the

245

presence of considerable heterogeneity. A prominent cause of such

246

heterogeneity was the widespread use of a number of concurrent

247

interventions that are known to impact the outcomes of interest. Additionally,

248

many studies were powered for purposes other than the management of

249

hyperphosphataemia, such as the preservation of renal function or patient

250

responsiveness to erythropoietin, further contributing to the heterogeneity

251

observed across the included studies.

252

Many papers did not report adherence, an outcome considered critical to

253

decision-making by the GDG, in a binary manner. Rather than defining a Management of hyperphosphataemia: NICE clinical guideline DRAFT (October 2012) Page 13 of 248

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patient as ‘adherent’ or ‘non-adherent’ with the dietary prescriptions, authors

255

often provided mean actual intakes for protein, energy and/or phosphate. In

256

order to use these continuous measures as indicators of adherence that could

257

be compared across studies and interventions, the reviewer converted these

258

mean actual intake levels into a percentage of the prescribed level. For

259

example: Prescribed protein intake

Reported mean Actual protein intake actual protein intake expressed as a percentage of the prescribed level

0.3 g/kg of body weight/day

0.42 g/kg of body weight/day

140% of prescription that is, actual intake exceeded prescription by 40%

260 261

Mean differences (MDs) were calculated for continuous outcomes and odds

262

ratios (ORs) for binary outcomes, as well as the corresponding 95%

263

confidence intervals where sufficient data were available. Where

264

meta-analysis was possible, a forest plot is also presented.

265

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Table 1 Summary of included studies for dietary management for people with stage 4 or 5 CKD who are not on dialysis Study

Population

Intervention

Control

Follow-up

Low-protein diet (+ ad-hoc binders + vitamin D) compared with moderate-protein diet (+ ad-hoc binders + vitamin D) Cianciaruso et al, 2008 RCT Naples, Italy

n = 423 (392 analysed) 2 Basal eGFR ≤ 30 ml/min/1.73 m Age 18 or older note: same population as Cianciaruso et 1 al, 2009 Baseline serum phosphate (mean SD): Intervention = 1.4±0.3 mmol/l Control = 1.2±0.2 mmol/l

Cianciaruso et al, 2009 RCT Naples, Italy

n = 423 (392 analysed) 2 Basal eGFR ≤ 30 ml/min/1.73 m Age 18 or older note: same population as Cianciaruso et 1 al, 2008 Baseline serum phosphate (mean SD): Intervention = 1.4±0.3 mmol/l Control = 1.2±0.2 mmol/l

0.55 g protein/kg/day At least 30 kcal/kg/day, reduced to a minimum of 25 kcal/kg/day in overweight patients, or if hypertension and hyperlipidaemia are present Calcium supplemented at 1000–1500 mg/day as calcium carbonate Further binders (calcium carbonate/sevelamer) prescribed where needed to treat hyperphosphataemia Ad-hoc prescription of vitamin D analogues when required

0.8 g protein/kg/day At least 30 kcal/kg/day, reduced to a minimum of 25 kcal/kg/day in overweight patients, or if hypertension and hyperlipidaemia are present Calcium supplemented at 1000–1500 mg/day as calcium carbonate Further binders (calcium carbonate/sevelamer) prescribed where needed to treat hyperphosphataemia Ad-hoc prescription of vitamin D analogues when required

18 months Monitored every 3 months

48 months Monitored every 3 months

Low-protein diet (+ ad-hoc binders) compared with ad libitum diet (moderate-protein intake as baseline) (+ ad-hoc binders) Ihle et al, 1989 RCT Melbourne, Australia

n = 72 (64 analysed) Mean Cr-EDTA clearance at baseline was 13.8±2.4 ml/min in the LPD group and 15 (±1.8) ml/min in the control group Baseline serum phosphate (mean SD): Intervention = 1.29±0.40 mmol/l Control = 1.35±0.21 mmol/l See evidence tables in appendix E for full inclusion/exclusion criteria

0.4 g of protein/kg body weight/day provided by foods of 75–80% biologic value 700 mg of phosphorus/day (30–40% less than conventional diet) 35–40 kcal/kg/day ‘When-required' phosphate binder use (calcium carbonate or aluminium hydroxide) to control phosphate levels

Ad libitum food intake with at least 0.75 g of protein/kg body weight/day 35–40 kcal/kg/day ‘When-required' phosphate binder use (calcium carbonate or aluminium hydroxide) to control phosphate levels

18 months Monitored monthly, although data provided for every 3 months

0.6 g/kg/day of protein ≥ 35 kcal/kg ideal body weight/day

1 year

Supplemented very-low-protein diet compared with low-protein diet European Study Group for the Conservative Management of Chronic Renal

n = 202 GFR < 20 ml/min Progressive renal failure during the 3 month run-in period

0.3 g protein/kg/day Keto/amino acid mixture ≥ 35 kcal/kg ideal body weight/day

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Failure, 1992 (only those with poor renal function) RCT

Baseline serum phosphate (mean SD): Intervention = no data available Control = no data available

Supplemented very-low-protein diet (+ Ca supplementation) compared with low-protein diet (+ Ca supplementation) Snetselaar et al, 1994 (MDRD pilot study B) RCT USA

n = 66 (58 analysed) Patients with advanced renal disease 2 GFR 7.5–24 ml/min/1.73 m Progressive increase in serum creatinine Aged 18 to 75 years

0.28 g protein/kg/day 4–9 mg phosphorus/kg/day 0.28 g keto acid/amino acid mixture (Cetolog)/kg/day or 0.22 g amino acid mixture (Aminess Novum)/kg/day 1500 mg calcium/day

0.575 g protein/kg/day – > 0.35 g/kg/day high biologic value dietary protein 5–10 mg phosphorus/kg/day 1500 mg calcium/day

2 years Monitored monthly

Baseline serum phosphate (mean SD): Intervention = no data available Control = no data available See evidence tables in appendix E for full inclusion/exclusion criteria Supplemented very-low-protein diet (+ vitamin D) compared with low-protein diet (+ Ca-based binders/supplements + vitamin D) Lindenau et al, 1990 RCT

n = 40 Patients with advanced renal failure CCr < 15 ml/min

0.4 g protein/kg body weight/day Mixture of KAs and AAs (Ketosteril) 20,000–40,000 U vitamin D/day

Baseline serum phosphate (mean SD): Intervention = 1.63±0.47 mmol/l Control = 1.41±0.25 mmol/l

0.6 g protein/kg body weight/day 750 mg calcium (as calcium carbonate or lactate) 20,000–40,000 U vitamin D/day

12 months

Supplemented very-low-protein diet (+ ad-hoc binders) compared with low-protein diet (+ ad-hoc binders) Feiten et al, 2005 RCT Sao Paulo, Brasil

n = 24 2

CCr 25 ml/min/1.73 m 18 or older Absence of catabolic illnesses, diabetes mellitus, auto-immune disease and malignant hypertension Baseline serum phosphate (mean SD): Intervention = 1.5±0.2 mmol/l Control = 1.5±0.3 mmol/l

Mircescu et al, 2007 RCT Bucharest, Romania

n = 53 (47 analysed) Non-diabetic adult patients with CKD 2 eGFR <30 ml/min/1.73 m Stable renal function at least 12 weeks before enrolment (i.e. a reduction in eGFR < 4 ml/min/year and well-controlled arterial BP) Good nutritional status (i.e. Subjective

0.3 g/kg/day of vegetable origin protein diet 1 tablet/5 kg ideal body weight/day, divided into 3 doses taken during meals, of keto acids and amino acids (Ketosteril) 30–35 kcal/kg ideal body weight/day ‘When-required' phosphate binder use to control phosphate levels

0.6 g/kg/day of protein (50% of high biological value) 30–35 kcal/kg ideal body weight/day ‘When-required' phosphate binder use to control phosphate levels

4 months All outcomes monitored monthly, except for iPTH which was measured at 2-month intervals

0.3 g/kg/day of vegetable proteins 1 capsule/5 kg ideal body weight/day of ketoanalogues of essential amino acids (Ketosteril®) Total recommended energy intake of 30 kcal/kg/day ‘When-required' prescription of calcium carbonate to maintain serum calcium and serum phosphate within the recommended

Continued conventional low-protein diet with 0.6 g/kg/day (including high biological value proteins) Total recommended energy intake of 30 kcal/kg/day ‘When-required' prescription of calcium carbonate to maintain serum calcium and serum phosphate within the recommended range

48 weeks Monitored monthly

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Global Assessment Score A/B and serum albumin >35 g/l)

range

Baseline serum phosphate (mean SD): Intervention = 1.9±0.7 mmol/l Control = 1.8±0.7 mmol/l See evidence tables in appendix E for full inclusion/exclusion criteria Di Iorio et al, 2003 RCT Italy

n = 20 (19 completed the study period) 2 Patients with CCr ≤ 25 ml/min/1.73 m Treated with LPD (0.6 g/kg body weight/day) and EPO for a period of 6 to 12 months Baseline serum phosphate (mean SD): Intervention = 1.2±0.3 mmol/l Control = 1.2±0.1 mmol/l See evidence tables in appendix E for full inclusion/exclusion criteria

Klahr et al, 1994 (MDRD study B) RCT USA

n = 255 2 GFR 13-24 ml/min/1.73 m Aged 18 to 70 years

Kopple et al, 1997 (MDRD study B)

n = 255 2 GFR 13-24 ml/min/1.73 m Aged 18 to 70 years

Baseline serum phosphate (mean SD): Intervention = no data available Control = no data available See evidence tables in appendix E for full inclusion/exclusion criteria Note: same population as Kopple et al, 2 1997 (MDRD study)

0.3 g/kg body weight/day of protein of vegetable origin Supplemented with a mixture of ketoanalogues and essential amino acids (Alfa Kappa) administered at the dose of 1 tablet/5 kg body weight 35 kcal/kg body weight/day Phosphate binders were administered to maintain serum phosphate levels ≤ 5.5 mg/dl

0.6 g/kg body weight/day of protein 35 kcal/kg body weight/day Phosphate binders were administered to maintain serum phosphate levels ≤ 5.5 mg/dl

18 months (although data were also available at 24 months for the sVLPD group only) Data provided for every 6 months

0.28 g protein/kg/day 0.28 g keto acid/amino acid mixture 4–9 g phosphorus/kg/day calcium carbonate prescribed for hyperphosphataemia 'as required'

0.58 g protein/kg/day (including 0.35 g/kg/day in essential AAs) 5–10 g phosphorus/kg/day calcium carbonate prescribed for hyperphosphataemia 'as required'

18 to 45 months

0.28 g protein/kg/day 0.28 g keto acid/amino acid mixture 4–9 g phosphorus/kg/day calcium carbonate prescribed for hyperphosphataemia 'as required'

0.58 g protein/kg/day (including 0.35 g/kg/day in essential AAs) 5–10 g phosphorus/kg/day calcium carbonate prescribed for hyperphosphataemia 'as required'

18 to 45 months Information on hospitalisation was obtained ‘routinely’ during study visits or if a study visit was missed

Supplemented very-low-protein diet (+ ad-hoc binders + vitamin D) compared with low-protein diet (+ ad-hoc binders + vitamin D) Jungers et al, 1987 RCT Paris, France

n = 19 (15 analysed) 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

Management of hyperphosphataemia: NICE clinical guideline DRAFT (October 2012)

0.6 g/kg/day of mainly high biological value proteins < 750 mg/day of phosphates Ad-hoc/'when-required' calcium carbonate

Page 17 of 248

Minimum of 3 months and maximum of 18 months, although data given for

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males or > 500 µmol/l in females, or a CCr 2 of 5–15 ml/min/1.73 m Slowly progressive rate of decline in renal function for at least 3 months Good general and nutritional condition Motivated to accept a low-protein diet and be available for follow-up Baseline serum phosphate (mean SD): Intervention = 1.64±0.24 mmol/l Control = 1.58±0.28 mmol/l Malvy et al, 1999 RCT Bordeaux, France

n = 50 (38 analysed) 2 CCr < 19 ml/min/1.73 m Baseline serum phosphate (mean SD): Intervention = 1.50±0.20 mmol/l Control = 1.62±0.35 mmol/l See evidence tables in appendix E for full inclusion/exclusion criteria

(Ketosteril®), divided into 3 doses taken during meals (average actual daily dose was 11.3±1.5 tablets/day) Vitamin D (at a dosage of 25–50 µg/day) used to maintain plasma phosphate levels below 1.7 mmol/l Total recommended energy intake of 35– 40 kcal/kg/day ‘When-required' binders (aluminium hydroxide) used to maintain plasma phosphate levels below 1.7 mmol/l

supplementation for hypocalcaemia Vitamin D (at a dosage of 50 µg/day) used to maintain plasma phosphate levels below 1.7 mmol/l Total recommended energy intake of 35– 40 kcal/kg/day ‘When-required' binders (aluminium hydroxide) used to maintain plasma phosphate levels below 1.7 mmol/l

‘the end of the study period’ Monitored monthly

0.3 g/kg/day of protein Supplement of ketoanalogues and hydroxyanalogues of amino acids (Ketosteril) Daily supplement of vitamin D3 (25– 50 mg) and nicotinic acid (25 mg) Calcium (1–4 g per day), and aluminium hydroxide were added depending on calcium and phosphate plasma levels

0.65 g/kg/day of protein Daily supplement of vitamin D3 (25– 50 mg) and nicotinic acid (25 mg) Calcium (1–4 g per day), and aluminium hydroxide were added depending on calcium and phosphate plasma levels

At least 3 months Monitored at baseline, once a month during the first 3 months, and then every 3 months thereafter

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 doublecounting 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. Abbreviations: AA, amino acids; CCr, creatinine clearance rate; CKD, chronic kidney disease; CrEDTA, chromium-ethylenediaminetetraacetic acid complex; eGFR, estimated glomerular filtration rate; GFR, glomerular filtration rate; iPTH, intact parathyroid hormone; KA, keto acids; LPD, low-protein diet; PTH, parathyroid hormone; RCT, randomised controlled trial; SCr, serum creatinine; SD, standard deviation; sVLPD, supplemented very low-protein diet.

267 268

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269 270

Summary GRADE profile 1 Low-protein diet (+ ad-hoc binders + vitamin D) compared with moderate-protein diet (+ ad-hoc binders + vitamin D) Outcome

Number of Studies

Number of patients Low protein (+ ad-hoc binders + vitamin D)

Moderate protein (+ ad-hoc binders + vitamin D)

Effect

Quality

Serum phosphate 18-month follow-up

1 RCT Cianciaruso et al, 2008

200

192

Absolute effect MD = 0.1 mmol/l higher (95% CI: 0 to 0.2 higher)

Very low

Adherence to protein prescription (% of patients adherent to dietary prescription) 18-month follow-up

1 RCT Cianciaruso et al, 2008

56/212 (26.4%)

103/211 (48.8%)

Relative effect OR = 0.38 (95%CI: 0.25 to 0.57) Absolute effect 22 fewer per 100 (14 to 30 fewer)

Moderate

Adherence to protein prescription (% of prescription, calculated from urinary urea nitrogen) 18-month follow-up

1 RCT Cianciaruso et al, 2008

200

192

Absolute effect MD = 21.6% higher (95% CI: 18.4 to 24.8 higher)

Very low

Adverse events â&#x20AC;&#x201C; malnutrition (% of patients reaching pre-defined malnutrition point) 48-month follow-up

1 RCT Cianciaruso et al, 2009

2/212 (0.94%)

1/211 (0.47%)

Relative effect

Very low

Need for additional phosphate management (% of patients who received phosphate binders [serum phosphate > 0.85â&#x20AC;&#x201C;1.85 mmol/l]) 18-month follow-up

1 RCT Cianciaruso et al, 2008

27%

36%

Relative effect OR = 0.66 (95% CI: 0.36 to 1.2) Absolute effect 9 fewer per 100 (19 fewer to 4 more)

Very low

Serum PTH 18-month follow-up

1 RCT Cianciaruso et al, 2008

200

192

Absolute effect MD =3.4 pmol/l lower (7.3 lower to 0.5 higher)

Very low

OR = 2 (95%CI: 0.18 to 22.23) Absolute effect 0 more per 100 (0 fewer to 9 more)

Abbreviations: CI, confidence interval; MD, mean difference; OR, odds ratio; RCT, randomised controlled trial.

271 272 273 274 275

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276 277

Summary GRADE profile 2 Low-protein low-phosphate diet (+ ad-hoc binders) compared with ad libitum diet (minimum: moderate-protein) (+ ad-hoc binders) Outcome

Number of Studies

Number of patients Low-protein lowphosphate diet (+ ad-hoc binders)

Ad libitum diet (minimum: moderateprotein) (+ ad-hoc binders)

Serum phosphate 18-month follow-up

1 RCT Ihle et al, 1989

Serum PTH (C-terminal radioimmunoassay) 18-month follow-up

1 RCT Ihle et al, 1989

Effect

Quality

Absolute effect

Very low

MD = 0.05 mmol/l lower (95% CI: 0.28 lower to 0.18 higher) Absolute effect

Very low

MD = 5.9 pmol/l lower (95% CI: 10.9 to 0.9 lower)

Abbreviations: CI, confidence interval; MD, mean difference; RCT, randomised controlled trial

278 279

Summary GRADE profile 3 Supplemented very-low-protein diet compared with low-protein diet Outcome

Adherence to protein prescription (% of prescription, calculated from urinary urea nitrogen) 12 months follow-up

Number of Studies

Number of patients Supplemented very-lowprotein diet

Low-protein diet

1 RCT European Study Group for the Conservative Management of Chronic Renal 1 Failure, 1992

103

Quality

Absolute effect

Very low

Difference in medians = 23.4% higher

Data were only extracted for those with â&#x20AC;&#x2DC;poor renal functionâ&#x20AC;&#x2122;

Abbreviations: RCT, randomised controlled trial.

280 281 282 283 284

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Effect

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285 286

Summary GRADE profile 4 Supplemented very-low-protein low-phosphate diet with (+ calcium) compared with low-protein low-phosphate diet (+ calcium) Outcome

Number of Studies

Number of patients

Adherence to protein prescription (% of prescription, calculated from urinary urea nitrogen) 1 12-month follow-up

1 RCT Snetselaar et al, 2 1994

Adherence to protein prescription (% of prescription, calculated from 3-day diet diary) 1 12-month follow-up

1 RCT Snetselaar et al, 2 1994

Absolute effect MD = 29.9% higher

Very low

Adherence to phosphate prescription (% of prescription, calculated from 3-day diet diary) 1 12-month follow-up

1 RCT Snetselaar et al, 2 1994

Absolute effect MD = 1% lower

Very low

Supplemented very-lowprotein low-phosphate diet (+ Ca supplement) 3

Effect

Quality

Absolute effect

Very low

Low-protein lowphosphate diet (+ Ca supplement) 22

MD = 64.1% higher (95% CI: 47.2 to 81.0 higher)

Data provided are the weighted means of follow-up data collected throughout the 12-month study period Data were only extracted for â&#x20AC;&#x2DC;Study Bâ&#x20AC;&#x2122; 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 2

Abbreviations: AAs, amino acids; CI, confidence interval; LPD, low-protein diet; MD, mean difference; RCT, randomised controlled trial; sVLPD, supplemented very-low-protein diet; VLPD, very-low-protein diet.

287 288 289 290 291 292 293 294

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295 296

Summary GRADE profile 5 Supplemented very-low-protein diet (+ vitamin D) compared with low-protein diet (+ calcium + vitamin D) Outcome

Number of Studies

Number of patients Supplemented very-lowprotein diet (+ vitamin D)

Low-protein diet (+ calcium + vitamin D)

Effect

Quality

Serum phosphate 12-month follow-up

1 RCT Lindenau et al, 1990

Absolute effect MD = 0.04 mmol/l lower (95% CI: 0.25 lower to 0.17 higher)

Very low

Serum iPTH 12-month follow-up

1 RCT Lindenau et al, 1990

Absolute effect MD = 9.8 pmol/l lower (95% CI: 15.8 to 3.8 lower)

Very low

Abbreviations: CI, confidence interval; iPTH, intact parathyroid hormone; MD, mean difference; RCT, randomised controlled trial.

297 298 299

Summary GRADE profile 6 Supplemented very-low-protein diet (+ ad-hoc binders) compared with low-protein diet (+ adhoc binders) Outcome

Number of Studies

Number of patients Supplemented very-lowprotein diet (+ ad-hoc binders)

Low-protein diet (+ adhoc binders)

Effect

Quality

Serum phosphate (pooled) 48.5-week follow-up (mean)

3 RCTs Feiten et al, 2005 Mircescu et al, 2007 Di Iorio et al, 2003

Absolute effect

Very low

Adherence to protein prescription (% of prescription, calculated from 3-day diet diary) 4-month follow-up

1 RCT Feiten et al, 2005

Absolute effect MD = 28.3% higher (95% CI: 1.7 lower to 58.3 higher)

Very low

Adherence to protein prescription (% of prescription, calculated from 1 urinary urea nitrogen) 4-month follow-up

1 RCT Feiten et al, 2005

Absolute effect

Very low

Adherence to protein prescription (% of prescription, calculated from 1 urinary urea nitrogen) 48-week follow-up

1 RCT Mircescu et al, 2007

Adherence to protein prescription (% of prescription, calculated from

1 RCT Klahr et al,

MD = 0.30 mmol/l lower (95% CI: 0.53 to 0.18 lower)

MD = 80/0% higher (95% CI: 56.1 to 103.9 higher) Absolute effect

Very low

MD = 8.4% higher (95% CI: 2.4 lower to 19.2 higher) Absolute effect Difference in medians = 27.7% higher

Management of hyperphosphataemia: NICE clinical guideline DRAFT (October 2012)

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Very low

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urinary urea nitrogen) 36-month follow-up

1994

2,3

Adherence to energy prescription (% of prescription, calculated from 1 3-day diet diary) 4-month follow-up

1 RCT Feiten et al, 2005

Absolute effect MD = 3.7% lower

Very low

Adherence to energy prescription (% of prescription, calculated from 1 3-day diet diary) 48-week follow-up

1 RCT Mircescu et al, 2007

Absolute effect MD = 2.7% higher (95% CI: 1.2 lower to 6.6 higher)

Very low

Adverse events – malnutrition (% of patients defined as malnourished according to SGA) 48-week follow-up

1 RCT Mircescu et al, 2007

13%

Relative effect OR = 1.34 (95% CI: 0.56 to 3.23) Absolute effect

Very low

Adverse events – hospitalisation (number of patients to undergo first hospitalisation during study) 34-month follow-up

1 RCT Kopple et al, 3,5 1997

28/126 (22.2%)

32/129 (24.8%)

Need for additional phosphate management (pooled) (number of patients who received phosphate binders) 33-week follow-up (mean)

2 RCTs Feiten et al, 2005 Mircescu et al

5/39 (12.8%)

25/38 (65.8%)

Relative effect OR = 0.07 (95% CI: 0.01 to 0.59) Absolute effect 54 fewer per 100 (13 to 64 fewer)

Very low

Serum PTH (pooled) (immunofluorometric assay/radioimmunoassay) 11-month follow-up (mean)

2 RCTs Feiten et al, 2005 Di Iorio et al, 2003

Absolute effect

Very low

10%

3 more per 100 (4 fewer to 16 more) Relative effect OR = 0.87 (95% CI: 0.49 to 1.55) Absolute effect

Very low

3 fewer per 100 (11 fewer to 9 more)

MD = 9.88 pmol/l (95% CI: 12.73 to 7.03 lower)

Data available for outcome inappropriate for meta-analysis across studies Same population as Kopple et al, 1997 3 Data only extracted from ‘Study B’ 4 Note: values were unchanged from baseline 5 Same population as Klahr et al, 1994 2

Abbreviations: CI, confidence interval; MD, mean difference; OR, odds ratio; PTH, parathyroid hormone; RCT, randomised controlled trial; SGA, subjective global assessment of nutrition.

300

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301 302

Summary GRADE profile 7 Supplemented very-low-protein diet (+ ad-hoc binders + vitamin D) compared with low-protein diet (+ ad-hoc binders + vitamin D) Outcome

Number of Studies

Number of patients Supplemented very-lowprotein diet (+ ad-hoc binders + vitamin D)

Low-protein diet (+ ad-hoc binders + vitamin D)

Effect

Quality

Serum phosphate (pooled) Follow-up unclear

2 RCTs Jungers et al, 1987 Malvy et al, 1999

Absolute effect

Very low

Adherence to protein prescription (% of prescription, calculated from urinary urea nitrogen) Follow-up unclear

1 RCT Jungers et al, 1987

Absolute effect MD = 45.0% higher (95% CI: 25.9 lower 1 to 115.9 higher)

Very low

Adverse events - need for additional calcium supplementation (number of patients who received calcium supplementation for hypocalcaemia) Follow-up unclear

1 RCT Jungers et al, 1987

0/10

3/9

Absolute effect 33 fewer per 100

Very low

Need for additional phosphate management (number of patients who received phosphate binders) Follow-up unclear

1 RCT Jungers et al, 1987

0/10

3/9

Absolute effect 33 fewer per 100

Very low

Serum PTH Follow-up unclear

1 RCT Malvy et al, 1999

Absolute effect MD = 33.9 pmol/l lower (95% CI: 43.5 to 24.3 lower)

Very low

MD = 0.30 mmol/l (95% CI: 0.58 to 0.01 lower)

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]) Abbreviations: CI, confidence interval; MD, mean difference; PTH, parathyroid hormone; RCT, randomised controlled trial.

303 304

See appendix E for the evidence tables and GRADE profiles in full.

Management of hyperphosphataemia: NICE clinical guideline DRAFT (October 2012)

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3.1.3

Evidence statements

306

For details of how the evidence is graded, see â&#x20AC;&#x2DC;The guidelines manualâ&#x20AC;&#x2122;.

307

Dietary management for people with stage 4 or 5 CKD who are not on

308

dialysis

309

A low-protein diet (+ ad-hoc binders) compared with a moderate-protein

310

diet (+ ad-hoc binders)

311

Critical outcomes

312

3.1.3.1

Very-low-quality evidence from 1 RCT of 392 patients showed a

313

low-protein diet with ad-hoc phosphate binder use to be associated

314

with a mean serum phosphate level 0.1 mmol/l higher (95%

315

confidence interval [CI] 0.0 to 0.2 i.e. statistically significant) than a

316

moderate-protein diet with ad-hoc phosphate binder use at 18

317

months.

318

3.1.3.2

Moderate-quality evidence from 1 RCT of 423 patients showed that

319

a low-protein diet with ad-hoc phosphate binder use was

320

associated with a smaller proportion of patients adherent to protein

321

prescription than a moderate-protein diet with ad-hoc phosphate

322

binder use (odds ratio [OR] 0.38 [95% CI 0.25 to 0.57 i.e.

323

statistically significant]).

324

3.1.3.3

Very low-quality evidence from the RCT of 392 patients showed

325

that, as a percentage of the prescribed protein intake, those on a

326

low-protein diet with ad-hoc phosphate binder use exceeded the

327

relevant prescription to a greater extent than those on a

328

moderate-protein diet with ad-hoc phosphate binder use (mean

329

difference [MD] 21.6% more [95% CI 18.4 to 24.8 i.e. statistically

330

significant]).

331

3.1.3.4

Very-low-quality evidence from 1 RCT of 423 patients did not show

332

a statistically significant difference in the incidence of malnutrition

333

over 48 months between those on a low-protein diet with ad-hoc

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phosphate binder use and those on a moderate-protein diet with

335

ad-hoc phosphate binder use (OR 2 [95% CI 0.18 to 22.23]).

336

Important outcomes

337

3.1.3.5

Very-low-quality evidence from 1 RCT of 392 patients did not show

338

a statistically significant difference in the number of patients that

339

required/were prescribed phosphate binders between those on a

340

low-protein diet and those on a moderate-protein diet (OR 0.66

341

[95% CI 0.36 to1.20]).

342

3.1.3.6

Very-low-quality evidence from 1 RCT of 392 patients did not show

343

a statistically significant difference in mean serum PTH level

344

between those on a low-protein diet with ad-hoc phosphate binder

345

use and those on a moderate-protein diet with ad-hoc phosphate

346

binder use at 18 months (mean serum PTH level 3.4 pmol/l lower in

347

the low-protein diet group [95% CI -7.3 to 0.5]).

348

A low-protein diet (+ ad-hoc binders) compared with an ad libitum diet

349

(moderate-protein intake prescribed as minimum) (+ ad-hoc binders)

350

Critical outcomes

351

3.1.3.7

Very-low-quality evidence from 1 RCT of 64 patients showed a low-

352

protein diet with ad-hoc phosphate binder use to be associated with

353

a mean serum phosphate level 0.05 mmol/l lower (95% CI -0.28 to

354

0.18) than an ad libitum diet with ad-hoc phosphate binder use at

355

18 months, although the effect was not statistically significant.

356

Important outcomes

357

3.1.3.8

Very-low-quality evidence from the RCT of 64 patients showed a

358

low-protein diet with ad-hoc phosphate binder use to be associated

359

with a mean serum PTH level 5.9 pmol/l lower (95% CI -10.9 to -0.9

360

i.e. statistically significant) than an ad libitum diet with ad-hoc

361

phosphate binder use at 18 months.

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A supplemented very-low-protein diet compared with a low-protein diet

363

Important outcomes

364

3.1.3.9

Very-low-quality evidence from 1 RCT of 202 patients showed that,

365

as a percentage of the prescribed protein intake, those on a very-

366

low-protein diet supplemented with a mixture of keto acids and

367

amino acids exceeded the relevant prescription to a greater extent

368

than those on a low-protein diet (difference in medians 23.4%

369

more).

370

A supplemented very-low-protein diet (+ Ca supplementation) compared

371

with a low-protein diet (+ Ca supplementation)

372

Critical outcomes

373

3.1.3.10

Very-low-quality evidence from 1 RCT of 58 patients showed that,

374

as a percentage of the prescribed protein intake, those on a

375

very-low-protein diet supplemented with a mixture of keto acids and

376

amino acids exceeded the relevant prescription to a greater extent

377

than those on a low-protein diet when estimated by urinary urea

378

nitrogen (MD 64.1% more [95% CI 47.2 to 81.0 i.e. statistically

379

significant])4.

380

3.1.3.11

Very-low-quality evidence from the same RCT of 58 patients

381

showed that, as a percentage of the prescribed protein intake,

382

those on a very-low-protein diet supplemented with a mixture of

383

keto acids and amino acids exceeded the relevant prescription to a

384

greater extent than those on a low-protein diet when estimated by

385

3-day diet diary (MD 29.9% more)3.

386

3.1.3.12

Very-low-quality evidence from the RCT of 58 patients comparing a

387

very-low-protein diet supplemented with a mixture of keto acids and

388

amino acids and calcium and a low-protein diet supplemented with

Note: actual intake in the intervention group fell into the ‘low-protein’ rather than the ‘very-lowprotein’ range (the difference in actual intake between the groups was, however, statistically significant).

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calcium, showed little difference in the deviation of mean

390

phosphate intake from that prescribed, with both groups

391

demonstrating good mean adherence5.

392

A supplemented very-low-protein diet (+ vitamin D) compared with a

393

low-protein diet (+ Ca-based binders/supplements + vitamin D)

394

Critical outcomes

395

3.1.3.13

Very-low-quality evidence from 1 RCT of 40 patients showed a

396

very-low-protein diet supplemented with a mixture of keto acids and

397

amino acids and vitamin D to be associated with a mean serum

398

phosphate level 0.04 mmol/l lower (95% CI -0.25 to 0.17) than a

399

low-protein diet supplemented with vitamin D at 12 months,

400

although the effect was not statistically significant.

401

Important outcomes

402

3.1.3.14

Very-low-quality evidence from the same RCT of 40 patients

403

showed a very-low-protein diet supplemented with a mixture of keto

404

acids and amino acids and vitamin D to be associated with a mean

405

serum PTH level 9.8 pmol/l lower (95% CI -15.8 to -3.8 i.e.

406

statistically significant) than a low-protein diet supplemented with

407

vitamin D at 12 months.

408

A supplemented very-low-protein diet (+ ad-hoc binders) compared with

409

a low-protein diet (+ ad-hoc binders)

410

Critical outcomes

411

3.1.3.15

Very-low-quality evidence from 3 RCTs analysing a total of 87

412

patients showed a very-low-protein diet supplemented with a

413

mixture of keto acids and amino acids and ad-hoc phosphate

414

binders to be associated with a mean serum phosphate level

415

0.30 mmol/l lower (95% CI -0.43 to -0.18 i.e. statistically significant) 5

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than a low-protein diet with ad-hoc phosphate binder use (mean

417

follow-up ~48.5 weeks).6

418

3.1.3.16

Very-low-quality evidence from 1 RCT of 23 patients showed that,

419

as a percentage of the prescribed protein intake, those on a

420

very-low-protein diet supplemented with a mixture of keto acids and

421

amino acids and ad-hoc phosphate binders exceeded the relevant

422

prescription to a greater extent than those on a low-protein diet with

423

ad-hoc phosphate binder use when estimated at 4 months by

424

urinary urea nitrogen (MD 80.0% more [95% CI 56.1 to 103.9 i.e.

425

statistically significant])5.

426

3.1.3.17

Very-low-quality evidence from the same RCT, in this case

427

analysing 22 patients, showed that as a percentage of the

428

prescribed protein intake, those on a very-low-protein diet

429

supplemented with a mixture of keto acids and amino acids and

430

ad-hoc phosphate binders exceeded the relevant prescription to a

431

greater extent than those on a low-protein diet with ad-hoc

432

phosphate binder use when estimated at 4 months by 3-day diet

433

diary, although this was not statistically significant (MD 28.3% more

434

[95% CI -1.7 to 58.3])7.

435

3.1.3.18

Very-low-quality evidence from 1 RCT of 45 patients showed that,

436

as a percentage of the prescribed protein intake, the extent to

437

which mean protein intake at 48 weeks exceeded the relevant

438

prescription was not statistically significantly different in those on a

439

very-low-protein diet supplemented with a mixture of keto acids and

440

amino acids and ad-hoc phosphate binders compared to those on a

441

low-protein diet with ad-hoc phosphate binder use (deviation of

442

8.4% more [95% CI -2.4 to 19.2]). 6

Note: actual intake in the intervention group fell into the ‘low-protein’ rather than the ‘very-lowprotein’ range, and fell into the ‘moderate-protein’ rather than the ‘low-protein’ range in the control group when measured by urinary urea nitrogen (the difference in actual intake between the groups was, however, statistically significant). 7 Note: actual intake in the intervention group fell into the ‘low-protein’ rather than the ‘very-lowprotein’ range when estimated at 4 months by 3-day diet diary (the difference in actual intake between the groups was, however, statistically significant).

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3.1.3.19

Very-low-quality evidence from 1 RCT of 44 patients showed that,

444

as a percentage of the prescribed protein intake, those on a

445

very-low-protein diet supplemented with a mixture of keto acids and

446

amino acids and ad-hoc phosphate binders exceeded the relevant

447

prescription to a greater extent than those on a low-protein diet with

448

ad-hoc phosphate binder use at 36 months (difference in medians

449

27.7% more)8.

450

3.1.3.20

Very-low-quality evidence from 1 RCT of 45 patients showed that,

451

as a percentage of the prescribed energy intake, those on a

452

very-low-protein diet supplemented with a mixture of keto acids and

453

amino acids and ad-hoc phosphate binders fell below the relevant

454

prescription to a greater extent than in those on a low-protein diet

455

with ad-hoc phosphate binder use at 4 months (MD 3.7% more).

456

3.1.3.21

Very-low-quality evidence from an RCT of 24 patients showed that,

457

as a percentage of the prescribed energy intake, those on a

458

very-low-protein diet supplemented with a mixture of keto acids and

459

amino acids and ad-hoc phosphate binders fell below the relevant

460

prescription to a lesser extent than in those on a low-protein diet

461

with ad-hoc phosphate binder use at 48 weeks, although this effect

462

was not statistically significant (MD 2.7% less [95% CI -1.2 to 6.6]).

463

3.1.3.22

Very-low-quality evidence from 1RCT of 45 patients showed that a

464

very-low-protein diet supplemented with a mixture of keto acids and

465

amino acids and ad-hoc phosphate binders was associated with a

466

larger proportion of patients defined as malnourished than among

467

those on a low-protein diet with ad-hoc phosphate binder use (OR

468

1.34 [95% CI 0.56 to 3.23]), although the difference was not

469

statistically significant and the proportions were the same as those

470

observed at baseline.

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DRAFT FOR CONSULTATION 471

3.1.3.23

Very-low-quality evidence from 1 RCT of 255 patients showed that

472

a very-low-protein diet supplemented with a mixture of keto acids

473

and amino acids and ad-hoc phosphate binders was associated

474

with a smaller proportion of patients undergoing first hospitalisation

475

than among those on a low-protein diet with ad-hoc phosphate

476

binder use (OR 0.87 [95% CI 0.49 to 1.55]), although the difference

477

was not statistically significant.

478

Important outcomes

479

3.1.3.24

Very-low-quality evidence from 2 RCTs of 77 patients in total

480

showed that a very-low-protein diet supplemented with a mixture of

481

keto acids and amino acids and ad-hoc phosphate binders was

482

associated with a smaller proportion of patients requiring the

483

prescription of phosphate binders than among those on a

484

low-protein diet with ad-hoc phosphate binder use (OR 0.07 [95%

485

CI 0.01 to 0.59 i.e. statistically significant])9.

486

3.1.3.25

Very-low-quality evidence from 2 RCTs analysing a total of

487

41 patients showed a very-low-protein diet supplemented with a

488

mixture of keto acids and amino acids and ad-hoc phosphate

489

binders to be associated with a mean serum PTH level 9.88 pmol/l

490

lower (95% CI -12.73 to -7.03 i.e. statistically significant) than a

491

low-protein diet with ad-hoc phosphate binder use (mean follow-up

492

11 months)8.

493

A supplemented very-low-protein diet (+ ad-hoc binders + vitamin D)

494

compared with a low-protein diet (+ ad-hoc binders + vitamin D)

495

Critical outcomes

496

3.1.3.26

Very-low-quality evidence from 2 RCTs analysing a total of 57 patients showed a very-low-protein diet supplemented with a

497 9

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DRAFT FOR CONSULTATION 498

mixture of keto acids and amino acids, vitamin D and ad-hoc

499

phosphate binders to be associated with a mean serum phosphate

500

level 0.30 mmol/l lower (95% CI -0.58 to -0.01 i.e. statistically

501

significant) than a low-protein diet with vitamin D and ad-hoc

502

phosphate binder use10.

503

3.1.3.27

Very-low-quality evidence from 1 RCT of 15 patients showed that,

504

as a percentage of the prescribed protein intake, those on a

505

very-low-protein diet supplemented with a mixture of keto acids and

506

amino acids, vitamin D and ad-hoc phosphate binders exceeded

507

the relevant prescription to a greater extent than those on a

508

low-protein diet with vitamin D and ad-hoc phosphate binder use,

509

although the difference was not statistically significant (MD 45.0%

510

more [95% CI -25.9 to 115.9])9.

511

3.1.3.28

Very-low-quality evidence from 1 RCT of 19 patients found that

512

fewer patients on a very-low-protein diet supplemented with a

513

mixture of keto acids and amino acids, vitamin D and ad-hoc

514

phosphate binders required/were prescribed calcium

515

supplementation than those on a low-protein diet with vitamin D

516

and ad-hoc phosphate binders (0/10 versus 3/9 respectively) 9.

517

Important outcomes

518

3.1.3.29

Very-low-quality evidence from 1 RCT of 19 patients found that

519

fewer patients on a very-low-protein diet supplemented with a

520

mixture of keto acids and amino acids and vitamin D required/were

521

prescribed phosphate binders than those on a low-protein diet with

522

vitamin D (0/10 versus 3/9 respectively)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]). 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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DRAFT FOR CONSULTATION 523

3.1.3.30

Very-low-quality evidence from 1 RCT of 42 patients showed that a

524

very-low-protein diet supplemented with a mixture of keto acids and

525

amino acids, vitamin D and ad-hoc phosphate binders to be

526

associated with a mean serum PTH level 33.9 pmol/l lower (95% CI

527

-43.5 to -24.3 i.e. statistically significant) than a low-protein diet with

528

vitamin D and ad-hoc phosphate binder use.

529

3.1.4

Evidence to recommendations

Relative value of different outcomes

Trade-off between benefits and harms

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 GDGâ&#x20AC;&#x2122;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. 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 nonstandardised 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 â&#x20AC;&#x2DC;sub-clinicalâ&#x20AC;&#x2122;

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DRAFT FOR CONSULTATION malnutrition that may easily be missed in patients on low- or very-lowprotein 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 patientsâ&#x20AC;&#x2122; 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 proteinrestricted 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 lowphosphate 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 phosphaterich 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 Management of hyperphosphataemia: NICE clinical guideline DRAFT (October 2012) Page 34 of 248

DRAFT FOR CONSULTATION

Economic considerations Quality of evidence

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. This question was not prioritised for health economic analysis because the majority of resource inputs are outside the NHS and personal social services perspective. No evidence was found for children. For adults, little significant evidence was found to suggest that lowprotein 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 lowphosphate 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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DRAFT FOR CONSULTATION 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).

530

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DRAFT FOR CONSULTATION 531

3.1.5

Recommendations and research recommendations for

532

dietary management for people with stage 4 or 5 CKD

533

who are not on dialysis

534

535 536

3.2

Dietary management for people with stage 5 CKD who are on dialysis

537 538

3.2.1

Review question

539

For people with stage 5 CKD who are on dialysis, is the dietary management

540

of phosphate effective in managing serum phosphate and its associated

541

outcomes compared to placebo or other treatments? Which dietary methods

542

are most effective?

543

3.2.2

544

This review question focused on the use of dietary interventions in the

545

prevention and treatment of hyperphosphataemia in patients with stage

546

5 CKD who are on dialysis. These interventions are based on varying degrees

547

of restriction in the intake of phosphate and/or protein, with or without

Evidence review

Note: recommendation 1.1.3 in full states â&#x20AC;&#x153;Give information about controlling intake of phosphaterich 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.â&#x20AC;? The aspects of recommendation 1.1.3 that relate to those on dialysis (including the highlighted final sentence, which has been removed from section 3.1.5 since this section relates only to people with stage 4 or 5 CKD who are not on dialysis) are covered in section 3.2.

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DRAFT FOR CONSULTATION 548

supplementation with keto and amino acids, or on the exchange of a

549

proportion of dietary protein with a low-phosphate protein substitute.

550

For this review question, papers were identified from a number of different

551

databases (Medline, Embase, Medline in Process, the Cochrane Database of

552

Systematic Reviews, the Cochrane Central Register of Controlled Trials and

553

the Centre for Reviews and Dissemination) using a broad search strategy,

554

pulling in all papers relating to the dietary management of

555

hyperphosphataemia in CKD. Only RCTs that compared a dietary intervention

556

with either a placebo or another comparator in patients with stage 5 CKD who

557

are on dialysis were considered for inclusion.

558

Trials were excluded if:

559

the population included people with CKD stages 1 to 4 or

560

the population included people with a diagnosis of CKD stage 5 who are

561

not on dialysis.

562

From a database of 3026 abstracts, 244 full-text articles were ordered

563

(including 107 identified through review of relevant bibliographies) and 3

564

papers describing 3 primary studies were selected (Guida et al, 2011; Jiang et

565

al, 2009; Li et al, 2011). No paediatric studies meeting the inclusion criteria

566

were found. Table 2 lists the details of the included studies.

567

Protein levels in dietary interventions that included protein restriction were

568

categorised as follows:

569

less than or equal to 0.8 g of protein per kilogram of bodyweight per day:

570

very-low-protein diet

571

more than 0.8 g to less than or equal to 1.0 g of protein per kilogram of

572

bodyweight per day: low-protein diet

573

more than 1.0 g to less than or equal to 1.2 g of protein per kilogram of

574

bodyweight per day: moderate-protein diet

575

more than 1.2 g of protein per kilogram of bodyweight per day: high-protein

576

diet.

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DRAFT FOR CONSULTATION 577

These definitions are different to those used in the analysis of dietary

578

interventions in patients with stage 4 or 5 CKD who are not dialysis because

579

of the different protein requirements of this population. A certain amount of

580

protein tends to be lost from the body through dialysis; therefore a high level

581

of protein restriction poses a greater concern over malnutrition. For this

582

reason, the lowest thresholds for protein intake are set at a higher level in

583

patients with stage 5 CKD who are on dialysis.

584

None of the papers reported adherence, an outcome considered critical to

585

decision-making by the GDG, in a binary manner. Rather than defining a

586

patient as ‘adherent’ or ‘non-adherent’ to the dietary prescriptions, authors

587

provided mean levels of actual protein intake. In order to use these continuous

588

measures as indicators of adherence that could be compared across studies

589

and interventions, the reviewer converted these mean actual intake levels into

590

a percentage of the prescribed level. For example: 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%

591 592

Mean differences (MDs) were calculated for continuous outcomes and odds

593

ratios (ORs) for binary outcomes, as well as the corresponding 95%

594

confidence intervals where sufficient data were available. There was no

595

pooling of studies because of the lack of similarity in the interventions used.

596 597

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DRAFT FOR CONSULTATION

598

Table 2 Summary of included studies for dietary management for people with stage 5 CKD who are on dialysis Study

Population

Intervention

Control

Follow-up

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 prestudy regimen

3 months Blood samples taken before each dialysis session

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)

Low-phosphorus protein supplement (+ binders) compared with usual diet (+ binders) Guida et al, 2011 RCT Italy

n = 27 Haemodialysis treatment for at least 6 months No allergy to cow’s milk protein Hyperphosphataemia (serum phosphate ≥ 6.5 mg/dl (i.e. ≥ 2.1 mmol/l)) 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

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 2

Urine output of 800 ml or eGFR of 2 ml/min/1.73 m (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 Supplemented very-low-protein diet compared with moderate-protein diet

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DRAFT FOR CONSULTATION

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

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)

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 1 weeks

Urine output of 800 ml or eGFR of 2 ml/min/1.73 m (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 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 lowcalcium dialysate (1.25 mEq/l) therapy to maintain normal serum calcium levels

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

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 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

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DRAFT FOR CONSULTATION

600

Summary GRADE profile 8 Low-phosphorus protein supplement compared with no intervention 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

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

Absolute effect MD = 28.9 pmol/l lower (95% CI:36.5 to 21.3 lower)

Very low

Abbreviations: CI, confidence interval; iPTH, intact parathyroid hormone; MD, mean difference; RCT, randomised controlled trial.

601 602

Summary GRADE profile 9 Very-low-protein diet compared with moderate-protein diet Outcome

Number of Studies

Number of patients

Effect

Quality

Very-low-protein diet

Moderate-protein diet

Serum phosphate 12-month follow-up

1 RCT Jiang et al, 2009

Absolute effect MD = 0.17 mmol/l lower (95% CI: 0.52 lower to 0.18 higher)

Very low

Adherence to protein prescription (% of prescription, calculated from 3-day diet diary) 12-month follow-up

1 RCT Jiang et al, 2009

Absolute effect MD = 15.5% higher

Very low

Adverse events â&#x20AC;&#x201C; malnutrition (% of patients malnourished, as defined by SGA) 12-month follow-up

1 RCT Jiang et al, 2009

Relative effect OR = 0.54 (95% CI: 0.25 to 1.17)

Very low

Adverse events â&#x20AC;&#x201C; hospitalisation (% of patients hospitalised) 12-month follow-up

1 RCT Jiang et al, 2009

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

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) Abbreviations: CI, confidence interval; iPTH, intact parathyroid hormone; LPD, low-protein diet; MD, mean difference; moderate-protein diet; OR, odds ratio; RCT, randomised controlled trial; SGA, subjective global assessment of nutrition; sLPD, supplemented low-protein diet.

603 604

Summary GRADE profile 10 Supplemented very-low-protein diet compared with moderate-protein diet Outcome

Number of Studies

Number of patients Supplemented verylow-protein diet

Moderate-protein diet

Effect

Quality

Serum phosphate 12-month follow-up

1 RCT Jiang et al, 2009

Absolute effect MD = 0.22 mmol/l lower (95% CI: 0.58 lower to 0.14 higher)

Very low

Adherence to protein prescription (% of prescription, calculated from 3-day diet diary) 12-month follow-up

1 RCT Jiang et al, 2009

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

20%

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

7/10

Relative effect

Very low

Serum iPTH

1 RCT

OR = 0.62 (95% CI: 0.12 to 3.21) Absolute effect 11 fewer per 100 (48 fewer to 18 more) 8

Management of Hyperphosphataemia: NICE clinical guideline DRAFT (October 2012)

Absolute effect

Very low

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DRAFT FOR CONSULTATION

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) Abbreviations: CI, confidence interval; iPTH, intact parathyroid hormone; LPD, low-protein diet; MD, mean difference; moderate-protein diet; OR, odds ratio; RCT, randomised controlled trial; SGA, subjective global assessment of nutrition; sLPD, supplemented low-protein diet.

605 606

Summary GRADE profile 11 Supplemented very-low-protein diet + phosphate restriction compared with moderate-protein diet Outcome

Number of Studies

Number of patients Supplemented very-lowprotein diet + phosphate restriction

Moderate-protein diet

Effect

Quality

Serum phosphate 8-week follow-up

1 RCT Li et al, 2011

Absolute effect MD = 0.5 mmol/l lower (95% CI: 0.7 to 0.3 lower)

Very low

Adherence to protein prescription (% of prescription, calculated from 3-day diet diary) 8-week follow-up

1 RCT Li et al, 2011

Absolute effect MD = 7.5% higher

Very low

Adherence to protein prescription (% of prescription, calculated from nPCR) 8-week follow-up

1 RCT Li et al, 2011

Absolute effect MD = 9.6% higher

Very low

Adverse events – malnutrition (% of patients malnourished, as defined by MNA of < 17) 8-week follow-up

1 RCT Li et al, 2011

0/20

Absolute effect

Very low

0 fewer per 100

Abbreviations: CI, confidence interval; MD, mean difference; MNA, mini-nutritional assessment; nPCR, normalised protein catabolic rate; RCT, randomised controlled trial.

607

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608

See appendix E for the evidence tables and GRADE profiles in full.

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DRAFT FOR CONSULTATION 609

3.2.3

Evidence statements

610

For details of how the evidence is graded, see ‘The guidelines manual’.

611

Dietary management for people with stage 5 CKD who are on dialysis

612

A low-phosphorus protein substitute compared with no intervention

613

Critical outcomes

614

3.2.3.1

Low-quality evidence from 1 RCT of 27 patients showed a diet in

615

which normal dietary protein is partially exchanged for a low-

616

phosphorus protein substitute to be associated with a mean serum

617

phosphate level 0.7 mmol/l lower (95% CI -1.0 to -0.4 i.e.

618

statistically significant) than in patients receiving no intervention

619

(that is, usual diet) at 3 months.

620

Important outcomes

621

3.2.3.2

Very-low-quality evidence from the RCT of 27 patients showed a

622

diet in which normal dietary protein is partially exchanged for a low-

623

phosphorus protein substitute to be associated with a mean serum

624

PTH level 28.9 pmol/l lower (95% CI -36.5 to -21.3 i.e. statistically

625

significant) than in patients receiving no intervention (that is, usual

626

diet) at 3 months.

627

A very-low-protein diet compared with a moderate-protein diet

628

Critical outcomes

629

3.2.3.3

Very-low-quality evidence from 1 RCT of 27 patients showed a

630

very-low-protein diet to be associated with a mean serum

631

phosphate level 0.17 mmol/l lower (95% CI -0.52 to 0.18) than in

632

patients on a moderate-protein diet at 12 months, although the

633

difference was not statistically significant13.

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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DRAFT FOR CONSULTATION 634

3.2.3.4

Very-low-quality evidence from the RCT of 27 patients showed that,

635

as a percentage of the prescribed protein intake, those on a very-

636

low-protein diet exceeded the relevant prescription to a greater

637

extent than those on a moderate-protein diet at 12 months

638

(MD 15.5% more)14.

639

3.2.3.5

Very-low-quality evidence from the RCT of 27 patients found that

640

8.2% fewer patients were defined as malnourished on a very-low-

641

protein diet compared to a moderate-protein diet (OR 0.54 [95% CI

642

0.25 to 1.17]), although the difference was not statistically

643

significant12.

644

3.2.3.6

Very-low-quality evidence from the RCT of 30 patients found that

645

15% fewer patients were hospitalised on a very-low-protein diet

646

compared to a moderate-protein diet (OR 0.46 [95% CI 0.08 to

647

2.54]), although the difference was not statistically significant12.

648

Important outcomes

649

3.2.3.7

Very-low-quality evidence from the RCT of 27 patients showed a

650

very-low-protein diet to be associated with a median serum PTH

651

level 1.8 pmol/l higher than in patients on a moderate-protein diet at

652

12 months12.

653

A very-low-protein diet supplemented with keto acids compared with a

654

moderate-protein diet

655

Critical outcomes

656

3.2.3.8

Very-low-quality evidence from 1 RCT of 26 patients showed a

657

very-low-protein diet supplemented with a mixture of keto acids and

658

amino acids to be associated with a mean serum phosphate level

659

0.22 mmol/l lower (95% CI -0.58 to 0.14) than in patients on a

660

moderate-protein diet at 12 months. 14

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DRAFT FOR CONSULTATION 661

3.2.3.9

Very-low-quality evidence from the RCT of 26 patients showed that,

662

as a percentage of the prescribed protein intake, those on a

663

very-low-protein diet supplemented with a mixture of keto acids and

664

amino acids exceeded the relevant prescription to a greater extent

665

than those on a moderate-protein diet when estimated by 3-day

666

diet diary at 12 months (MD 3% more).

667

3.2.3.10

Very-low-quality evidence from the RCT of 26 patients found that

668

20% fewer patients were defined as malnourished on a

669

very-low-protein diet supplemented with a mixture of keto acids and

670

amino acids compared to a moderate-protein diet (no patients in

671

the supplemented very-low-protein diet group were defined as

672

malnourished).

673

3.2.3.11

Very-low-quality evidence from 1 RCT of 30 patients found that

674

10% fewer patients were hospitalised among those on a

675

very-low-protein diet supplemented with a mixture of keto acids and

676

amino acids compared to those on a moderate-protein diet

677

(OR 0.62 [95% CI 0.12 to 3.21]), although the difference was not

678

statistically significant.

679

Important outcomes

680

3.2.3.12

Very-low-quality evidence from 1 RCT of 26 patients showed a

681

very-low-protein diet supplemented with a mixture of keto acids and

682

amino acids to be associated with a median serum PTH level

683

16.0 pmol/l lower than in patients on a moderate-protein diet at

684

12 months.

685

A very-low-protein diet supplemented with keto acids + phosphate

686

restriction compared with a moderate-protein diet

687

Critical outcomes

688

3.2.3.13

Very-low-quality evidence from 1 RCT of 40 patients showed a

689

very-low-protein and low-phosphate diet supplemented with a

690

mixture of keto acids and amino acids to be associated with a Management of hyperphosphataemia NICE clinical guideline DRAFT (October 2012) Page 48 of 248

DRAFT FOR CONSULTATION 691

mean serum phosphate level 0.5 mmol/l lower (95% CI -0.7 to -0.3

692

i.e. statistically significant) than in patients on a moderate-protein

693

diet at 12 months15,16.

694

3.2.3.14

Very-low-quality evidence from 1 RCT of 40 patients showed that,

695

as a percentage of the prescribed protein intake, those on a

696

very-low-protein and low-phosphate diet supplemented with a

697

mixture of keto acids and amino acids exceeded the relevant

698

prescription to a greater extent than those on a moderate-protein

699

diet when estimated by normalised protein catabolic rate at

700

8 weeks (MD 9.6% more)13.

701

3.2.3.15

Very-low-quality evidence from the same RCT showed that, as a

702

percentage of the prescribed protein intake, those on a

703

very-low-protein and low-phosphate diet supplemented with a

704

mixture of keto acids and amino acids exceeded the relevant

705

prescription to a greater extent than those on a moderate-protein

706

diet when estimated by 3-day diet diary at 8 weeks (MD 7.5%

707

more)17.

708

3.2.3.16

Very-low-quality evidence from 1 RCT of 40 patients found no

709

difference in the number of patients defined as malnourished on a

710

very-low-protein and low phosphate diet supplemented with a

711

mixture of keto acids and amino acids compared to a

712

moderate-protein diet (0 in both groups)13.

713 714

Note: actual intake in the intervention group fell into the ‘low-protein’ rather than the ‘very-lowprotein’ 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-lowprotein’ range when estimated by 3-day diet diary (the difference in actual intake between the groups was, however, statistically significant).

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DRAFT FOR CONSULTATION 715

3.2.4

Evidence to recommendations

Relative value of different outcomes Trade-off between benefits and harms

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. 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-lowprotein 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.

Management of hyperphosphataemia NICE clinical guideline DRAFT (October 2012) Page 50 of 248

DRAFT FOR CONSULTATION 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 agespecific 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 Management of hyperphosphataemia NICE clinical guideline DRAFT (October 2012) Page 51 of 248

DRAFT FOR CONSULTATION

Economic considerations Quality of evidence

Other considerations

felt that low-phosphate options should be considered in instances where patients require nutritional supplements and/or substitutes to maintain protein intake. This question was not prioritised for health economic analysis as the majority of resource inputs are outside of NHS personal social services perspective. 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 patientsâ&#x20AC;&#x2122; 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 lowphosphate 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-ofanalysis errors were also common, with analyses not following the intent-to-treat principle. 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

Management of hyperphosphataemia NICE clinical guideline DRAFT (October 2012) Page 52 of 248

DRAFT FOR CONSULTATION 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 â&#x20AC;&#x2DC;Chronic kidney diseaseâ&#x20AC;&#x2122; (NICE clinical guideline 73).

716 717

3.2.5

Recommendations and research recommendations for

718

dietary management for people with stage 5 CKD who are

719

on dialysis

720

Recommendations 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.

721 722

3.3

Patient information strategies

723

3.3.1

Review question

724

For people with stage 4 or 5 CKD, both those on dialysis and those who are

725

not, are patient information strategies effective at promoting adherence to

726

phosphate-lowering dietary interventions, or in the management of serum

727

phosphate and its associated outcomes? Which patient information strategies

728

are most effective?

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DRAFT FOR CONSULTATION 729

3.3.2

Evidence review

730

This review question focused on the use of patient information and education

731

interventions to promote adherence to phosphate-lowering dietary

732

interventions, in the context of both the prevention and treatment of

733

hyperphosphataemia, in patients with stage 4, 5 or 5D CKD. These

734

interventions ranged from the provision of written educational material, to

735

educational videos, to counselling sessions of varying frequency, delivered

736

one-on-one or to groups of patients. Other interventions consisted of

737

behavioural feedback and patient contracts or combinations of multiple

738

concurrent approaches, including 2 or more of the following: written

739

educational material, educational videos, counselling sessions, self-

740

management tools (such as medication charts, individualised menus and food

741

exchange lists) or competitions.

742

For this review question, papers were identified from a number of different

743

databases (Medline, Medline in Process, Embase, the Cochrane Database of

744

Systematic Reviews, the Centre for Reviews and Disseminationâ&#x20AC;&#x2122;s DARE and

745

HTA databases, and PsycINFO) using a broad search strategy, pulling in all

746

papers relating to the use of patient information and education interventions to

747

promote adherence to phosphate-lowering dietary interventions in patients

748

with CKD. RCTs, non-randomised controlled trials (non-RCTs) and controlled

749

before-and-after studies comparing a patient education intervention with either

750

no intervention or another comparator were considered for inclusion.

751

Trials were excluded if:

752

the population included people with CKD stages 1 to 3 or

753

the trial examined only the information to be covered by education, rather

754

than the strategy by which it should be delivered.

755 756

From a database of 1143 abstracts, 112 full-text articles were ordered

757

(including 9 identified through review of relevant bibliographies) and 9 papers

758

(7 RCTs, 1 cluster RCT and 1 non-RCT) describing 9 primary studies were

759

selected (Ashurst & Dobbie, 2003; Baraz et al, 2010; Campbell et al, 2008;

760

Chen et al, 2006; Ford et al, 2004; Morey et al, 2008; Shaw-Stuart & Stuart, Management of hyperphosphataemia NICE clinical guideline DRAFT (October 2012) Page 54 of 248

DRAFT FOR CONSULTATION 761

2000; Sullivan et al, 2009; Tanner et al, 1998). No paediatric studies meeting

762

the inclusion criteria were found. Table 3 lists the details of the included

763

studies.

764

The reviewer analysed studies together where possible, producing a number

765

of pooled comparisons. These were structured as follows:

766

Patient education versus no intervention (beyond usual care)

767

Three papers were included in this pooled comparison (2 RCTs and 1 cluster

768

RCT). Data from the 2 RCTs could be meta-analysed for knowledge scores

769

and serum phosphate. The cluster RCT data for these outcomes could not be

770

included in the meta-analysis because of the unit-of-analysis error found

771

within the paper (data were analysed at the participant- rather than cluster-

772

level, and insufficient information was available for the reviewer to correct

773

this). Therefore, this cluster RCT data, along with the other non-meta-

774

analysed data from each paper, was recorded individually.

775

Interventions including counselling-based education versus written material

776

alone

777

Two papers were included in this pooled comparison (both RCTs). Because of

778

the absence of common outcomes between the papers, no meta-analysis was

779

performed; data for each outcome from each paper were recorded

780

individually.

781

Multiple component interventions versus single component interventions

782

Four papers were included in this pooled comparison (all RCTs). Data from all

783

4 papers could be meta-analysed for serum phosphate. The other, non-meta-

784

analysed data from each paper were recorded individually.

785

Multiple component interventions versus specific single component

786

interventions

787

These comparisons were designed to further differentiate the more general

788

comparison above into the specific single component comparators of the 5

789

included papers: individual patient counselling alone (2 papers), written

790

material alone (1 paper) and video education alone (1 paper). Data from the 2 Management of hyperphosphataemia NICE clinical guideline DRAFT (October 2012) Page 55 of 248

DRAFT FOR CONSULTATION 791

papers comparing multiple component interventions against individual patient

792

counselling alone could be meta-analysed for serum phosphate. The other,

793

non-meta-analysed data from each paper were recorded individually.

794

Significant heterogeneity was observed across all of the included studies,

795

particularly in relation to the structure and content of the interventions studied.

796

There was also considerable variation in the locations of many of these

797

studies, with few conducted in the UK.

798

Many of the papers did not report adherence, an outcome considered critical

799

to decision-making by the GDG, in a binary manner. Rather than defining a

800

patient as ‘adherent’ or ‘non-adherent’ with the dietary prescriptions, authors

801

often provided mean levels of actual protein intake. In order to use these

802

continuous measures as indicators of adherence that could be compared

803

across studies and interventions, the reviewer converted these mean actual

804

intake levels into a percentage of the prescribed level. For example: 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%

805 806

Additionally, for the purpose of this review, the summary term 'self-

807

management tool' has been used to collectively describe the aids used to help

808

patients in managing their dietary intake or serum phosphate levels in

809

response to the education provided. These tools range from a fridge magnet

810

detailing high-phosphate foods, to an individualised tracking chart that used

811

visual goals to engage patients in achieving phosphate control.

812

Mean differences (MDs) were calculated for continuous outcomes and odds

813

ratios (ORs) for binary outcomes, as well as the corresponding 95%

814

confidence intervals where sufficient data were available. Where meta-

815

analysis was possible, a forest plot is also presented.

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DRAFT FOR CONSULTATION

816

Table 3 Summary of included studies on patient information strategies Study

Population

Intervention

Followup

Control

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:

Management of hyperphosphataemia: NICE clinical guideline DRAFT (October 2012)

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 phosphorusrelated 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

Management of hyperphosphataemia: NICE clinical guideline DRAFT (October 2012)

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; portionsized food aids

1 month Pre-and postinterventio n (at 1 month)

Patients received generic nutrition information for patients with CKD, as provided in regular practice

12 weeks Monitoring unclear – pre- and postinterventio n?

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 2 < 30 ml/min/1.73 m 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

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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

Management of hyperphosphataemia: NICE clinical guideline DRAFT (October 2012)

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 selfreport 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 postintervention

Video + oral counselling + competitive competition (serum phosphate control) compared with regular individual oral counselling + written material

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ShawStuart & 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:

Management of hyperphosphataemia: NICE clinical guideline DRAFT (October 2012)

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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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.

817 818

Summary GRADE profile 12 Patient education compared with no intervention (beyond usual care) 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

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= lowest reading behaviour score; 100 = highest possible reading behaviour score) 3-month follow-up Knowledge scores (pooled) 6-month follow-up

2 RCTs Tanner et al, 1998 Ford et al, 2004

Absolute effect MD = 8.50% (95% CI:5.88 lower to 22.88 higher)

Very low

Change in knowledge scores 3-month follow-up

1 cluster RCT Sullivan et al, 2009

145

134

Absolute effect MD = 3% higher (95% CI: 1 lower to 7 higher)

Very low

Change in knowledge scores 6-month follow-up

1 RCT Tanner et al, 1998

Absolute effect MD = 6.97% higher

Very low

Change in knowledge scores 6-month follow-up

1 RCT Ford et al, 2004

Absolute effect MD = 7.6% higher

Very low

2 RCTs Tanner et al, 1998 Ford et al, 2004

Absolute effect MD = 0.19 mmol/l lower (95% CI: 0.87 lower to 0.49 higher)

Very low

Serum phosphate 3-month follow-up

1 cluster RCT Sullivan et al, 2009

145

134

Absolute effect MD = 0.2 mmol/l lower (95% CI:0.3 lower to 0 higher)

Very low

Changes in beliefs and attitudes towards health - perceptions of selfefficacy for self-monitoring (Self-Efficacy Survey scores: 13–14 points = high; 15–26 points = moderate; 27–29 points = low) 6-month follow-up

1 RCT Tanner et al, 1998

Absolute effect 3 MD = 1.01 points higher

Very low

Changes in beliefs and attitudes towards health – health beliefs (Health Beliefs Survey scores: 9–10

1 RCT Tanner et al, 1998

Absolute effect 4 MD = 1.00 points higher

Very low

Serum phosphate (pooled) 6-month follow-up

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points = high; 11â&#x20AC;&#x201C;19 points = moderate; 20â&#x20AC;&#x201C;27 points = low) 6-month follow-up 1

Data available for outcome inappropriate for meta-analysis across studies 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' 2

Abbreviations: CI, confidence interval; MD, mean difference; RCT, randomised controlled trial.

819 820

Summary GRADE profile 13 Interventions including counselling compared with written material alone Outcome

Number of Studies

Number of patients Interventions including counselling

Written material alone

Effect

Quality

Adherence to protein prescription (% of prescription, calculated from 3-day diet diary) 12-week follow-up

1 RCT Campbell et al, 2008

Absolute effect

Very low

Adherence to energy prescription (% of prescription, calculated from 3-day diet diary) 12-week follow-up

1 RCT Campbell et al, 2008

Absolute effect MD = 9.4% higher

Very low

Serum phosphate 3-month follow-up

1 RCT Ashurst & Dobbie, 2003

Absolute effect MD = 0.34 mmol/l lower (95% CI: 0.58 to 0.10 lower)

Very low

MD = 0%

Abbreviations: CI, confidence interval; MD, mean difference; RCT, randomised controlled trial.

821

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822 823

Summary GRADE profile 14 Multiple component education/information interventions compared with single component education/information interventions Outcome

Number of Studies

Number of patients Multiple component education/information interventions

Single component education/information interventions

Effect

Quality

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

Absolute effect

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

Serum phosphate (pooled) 3-month follow-up (mean)

4 RCTs Chen et al, 2006 Morey et al, 2008 Ashurst & Dobbie, 2003 Baraz et al, 2010

130

126

Absolute effect MD = 0.09 mmol/l (95% CI: 0.23 lower to 0.04 higher)

MD = 0%

Management of hyperphosphataemia: NICE clinical guideline DRAFT (October 2012)

Very low

OR = 0.97 (95% CI: 0.06 to 16.17) Absolute effect 0 fewer per 100 (from 3 fewer to 31 more) Very low

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Serum phosphate (number of patients with serum phosphate within acceptable limits) 2-month follow-up

1 RCT Baraz et al, 2010

18/32

18/31

Relative effect OR = 0.93 (95% CI: 0.34 to 2.52) Absolute effect

Very low

2 fewer per 100 (from 26 fewer to 20 more)

Abbreviations: CI, confidence interval; MD, mean difference; OR, odds ratio; RCT, randomised controlled trial.

824 825 826

Summary GRADE profile 15 Multiple component education/information interventions compared with individual patient counselling alone Outcome

Number of Studies

Number of patients Multiple component education/information interventions

Individual patient counselling alone

Effect

Quality

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

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

Absolute effect MD = 0.01 mmol/l (95% CI: 0.1 lower to

Very low

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Morey et al, 2008

0.08 higher)

Abbreviations: CI, confidence interval; MD, mean difference; OR, odds ratio; RCT, randomised controlled trial.

827 828

Summary GRADE profile 16 Multiple component education/information interventions compared with written material alone Outcome

Serum phosphate 3-month follow-up

Number of Studies

Number of patients Multiple component education/information interventions

Written material alone

1 RCT Ashurst & Dobbie, 2003

Effect

Quality

Absolute effect MD = 0.34 mmol/l lower (95% CI: 0.58 to 0.10 lower)

Very low

Abbreviations: CI, confidence interval; MD, mean difference; RCT, randomised controlled trial.

829 830 831

Summary GRADE profile 17 Multiple component education/information interventions compared with video education alone Outcome

Number of Studies

Number of patients

Effect

Quality

Multiple component education/information interventions

Video education alone

Serum phosphate 2-month follow-up

1 RCT Baraz et al, 2010

Absolute effect MD = 0.05 mmol/l lower (95% CI: 0.22 lower to 0.13 higher)

Very low

Serum phosphate (number of patients with serum phosphate within acceptable limits) 2-month follow-up

1 RCT Baraz et al, 2010

18/32

18/31

Relative effect OR = 0.93 (95% CI: 0.34 to 2.52) Absolute effect 2 fewer per 100 (from 26 fewer to 20 more)

Very low

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Abbreviations: CI, confidence interval; MD, mean difference; OR, odds ratio; RCT, randomised controlled trial.

832 833 834

Summary GRADE profile 18 Oral counselling + video + competitive competition compared with regular individual oral counselling + written material Outcome

Serum phosphate 12-month follow-up

Number of Studies

Number of patients Oral counselling + video + competitive competition

Regular individual oral counselling + written material

1 observational study Shaw-Stuart & Stuart, 2000

Effect

Quality

Absolute effect

Very low

MD = 0.19 mmol/l lower (95% CI: 0.24 to 0.14 lower)

Abbreviations: CI, confidence interval; MD, mean difference.

835 836

See appendix E for the evidence tables and GRADE profiles in full.

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3.3.3

Evidence statements

838

For details of how the evidence is graded, see â&#x20AC;&#x2DC;The guidelines manualâ&#x20AC;&#x2122;.

839

Patient information strategies

840

Patient education compared with no intervention (beyond usual care)

841

Critical outcomes

842

3.3.3.1

Very-low-quality evidence from 1 cluster RCT of 279 patients

843

showed a greater increase in adherence-promoting behaviours in

844

those who had received a patient education intervention compared

845

to those who had not at 3 months. The frequency of reading

846

ingredients lists increased by 22% (95% CI 15 to 30 i.e. statistically

847

significant) and the frequency of reading nutritional fact labels

848

increased by 9% (95% CI 1 to 17 i.e. statistically significant) in the

849

patient education group compared to those who received usual

850

care only.

851

Important outcomes

852

3.3.3.2

Very-low-quality evidence from 2 RCTs analysing a total of

853

101 patients showed that at 6 months, mean knowledge scores

854

were 8.50% higher (95% CI 5.88 to 22.88 i.e. statistically

855

significant) in those who received a patient education intervention

856

compared to those who did not. Knowledge scores in the patient

857

education groups improved by 6.97% and 7.6% than in the 2

858

groups receiving usual care only.

859

3.3.3.3

Very-low-quality evidence from the cluster RCT of 279 patients

860

found that at 3 months, knowledge scores in the patient education

861

group improved by 3% (95% CI -1 to 7) than in those who received

862

usual care only, although the difference was not statistically

863

significant.

864 865

3.3.3.4

Very-low-quality evidence from the 2 RCTs of 100 patients showed patient education to be associated with a mean serum phosphate

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DRAFT FOR CONSULTATION 866

level 0.19 mmol/l lower (95% CI -0.87 to 0.49) at 6 months than in

867

patients who received usual care only, although the difference was

868

not statistically significant.

869

3.3.3.5

Very-low-quality evidence from the cluster RCT of 279 patients

870

found patient education to be associated with a mean serum

871

phosphate level 0.2 mmol/l lower (95% CI -0.3 to no difference i.e.

872

statistically significant) at 3 months than in patients who received

873

usual care only.

874

3.3.3.6

Very-low-quality evidence from 1 RCT of 38 patients showed no

875

difference in the changes observed in patients’ beliefs and attitudes

876

towards health, as measured by a ‘self-efficacy survey’ and a

877

‘health beliefs survey’, whether patients had received a patient

878

education intervention or usual care only.

879

Interventions including counselling compared with written material

880

alone

881

Critical outcomes

882

3.3.3.7

Very-low-quality evidence from 1 RCT of 50 patients showed that at

883

12 weeks there was no difference in the amount of deviation of the

884

mean protein intake (estimated by 3-day diet diary) from the

885

prescribed level of protein intake between those who received

886

counselling-based interventions and those who received the renal

887

units’ standard written educational material following a diet history,

888

with both means falling within the prescribed limits.

889

3.3.3.8

Very-low-quality evidence from the RCT of 50 patients showed that,

890

as a percentage of the prescribed energy intake, those who

891

received counselling-based interventions fell below the relevant

892

prescription to a greater extent than those who received the renal

893

units’ standard written educational material following a diet history,

894

when estimated by 3-day diet diary at 12 weeks (MD 9.4% less).

895

Important outcomes Management of hyperphosphataemia: NICE clinical guideline DRAFT (October 2012) Page 71 of 248

DRAFT FOR CONSULTATION 896

3.3.3.9

Very low-quality evidence from an RCT of 56 patients showed

897

counselling-based interventions to be associated with a mean

898

serum phosphate level 0.34 mmol/l lower (95% CI -0.58 to -0.10 i.e.

899

statistically significant) at 3 months than in patients who received

900

the renal unitsâ&#x20AC;&#x2122; standard written educational material following a

901

diet history.

902

Multiple component interventions compared with single component

903

interventions

904

Critical outcomes

905

3.3.3.10

Very-low-quality evidence from 1 RCT of 70 patients showed that

906

after 1 month significantly more patients who received multi-

907

component educational interventions were considered to be

908

adherent with dietary protein prescriptions than those who received

909

single-component educational interventions (OR 4.5 [95% CI 1.60

910

to 12.66 i.e. statistically significant]).

911

3.3.3.11

Very-low-quality evidence from the RCT of 70 patients showed that

912

at 1 month there was no difference in the amount of deviation of the

913

mean protein intake (estimated by 3-day diet diary) from the

914

prescribed level of protein intake between those who received

915

multi-component educational interventions and those who received

916

single-component educational interventions.

917

3.3.3.12

Very-low-quality evidence from 1 RCT of 67 patients showed that

918

after 6 months there was no statistically significant difference in the

919

number of patients who could have phosphate binders withdrawn

920

from their regimen between those who received multi-component

921

educational interventions and those who received single-

922

component educational interventions (OR 0.97 [95% CI 0.06 to

923

16.17]).

924

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DRAFT FOR CONSULTATION 925

Important outcomes

926

3.3.3.13

Very-low-quality evidence from 4 RCTs of 256 patients in total

927

showed no statistically significant difference in mean serum

928

phosphate levels between those who received multi-component

929

educational interventions and those who received single-

930

component educational interventions (mean serum phosphate level

931

0.09 mmol/l lower [95% CI -0.23 to 0.04; mean follow-up of

932

3 months]).

933

3.3.3.14

Very-low-quality evidence from 1 RCT of 63 patients showed that

934

after 2 months there was no statistically significant difference in the

935

number of patients considered to have serum phosphate within

936

acceptable limits between those who received multi-component

937

educational interventions and those who received single-

938

component educational interventions (OR 0.93 [95% CI 0.34 to

939

2.52]).

940

Multiple component interventions (one-off individual oral counselling +

941

written educational material + self-management tool; regular individual

942

oral counselling + written educational material) compared with

943

individual patient counselling alone

944

Critical outcomes

945

3.3.3.15

Very-low-quality evidence from 1 RCT of 70 patients showed that

946

after 1 month significantly more patients who received multi-

947

component educational interventions were adherent with dietary

948

protein prescriptions than those who received individual patient

949

counselling alone (OR 4.5 [95% CI 1.60 to 12.66 i.e. statistically

950

significant]).

951

3.3.3.16

Very-low-quality evidence from the RCT of 70 patients showed that

952

at 1 month there was no difference in the amount of deviation of the

953

mean protein intake (estimated by 3-day diet diary) from the

954

prescribed level of protein intake between those who received

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DRAFT FOR CONSULTATION 955

multi-component educational interventions and those who received

956

individual patient counselling alone.

957

3.3.3.17

Very-low-quality evidence from 1 RCT of 67 patients showed that

958

after 6 months there was no statistically significant difference in the

959

number of patients who could have phosphate binders withdrawn

960

from their regimen between those who received multi-component

961

educational interventions and those who received individual patient

962

counselling alone (OR 0.97 [95% CI 0.06 to 16.17]).

963

Important outcomes

964

3.3.3.18

Very-low-quality evidence from 2 RCTs of 137 patients in total

965

showed multi-component educational interventions to be

966

associated with a mean serum phosphate level 0.01 mmol/l lower

967

(95% CI -0.10 to 0.08) than patients who received individual patient

968

counselling alone (mean follow-up of 3 months), although the

969

difference was not statistically significant.

970

Multiple component interventions (one-off individual oral counselling +

971

written educational material + self-management tool) compared with

972

written material alone

973

Important outcomes

974

3.3.3.19

Very-low-quality evidence from 1 RCT of 56 patients showed multi-

975

component educational interventions to be associated with a mean

976

serum phosphate level 0.34 mmol/l lower (95% CI -0.58 to -0.10 i.e.

977

statistically significant) at 3 months than patients who received

978

written educational material alone.

979

Multiple component interventions (interactive group counselling +

980

written educational material) compared with video education alone

981

Important outcomes

982

3.3.3.20

983

Very-low-quality evidence from 1 RCT of 63 patients showed that after 2 months there was no statistically significant difference in the

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DRAFT FOR CONSULTATION 984

number of patients considered to have serum phosphate within

985

acceptable limits between those who received multi-component

986

educational interventions and those who received video education

987

alone (OR 0.93 [95% CI 0.34 to 2.52]).

988

3.3.3.21

Very-low-quality evidence from the RCT of 63 patients showed

989

multi-component educational interventions to be associated with a

990

mean serum phosphate level 0.05 mmol/l lower (95% CI -0.22 to

991

0.13) than in patients who received individual patient counselling

992

alone at 2 months, although the difference was not statistically

993

significant.

994

Oral counselling + video + competition compared with regular individual

995

oral counselling + written material

996

Important outcomes

997

3.3.3.22

Very-low-quality evidence from 1 non-RCT of 81 patients showed

998

the intervention (oral counselling and a video relating to serum

999

phosphate control, plus a competition) to be associated with a

1000

mean serum phosphate level 0.19 mmol/l lower (95% CI -0.24 to

1001

-0.14 i.e. statistically significant) at 12 months than that in patients

1002

who received the control (oral counselling and written material

1003

relating to dietary management and phosphate binder use for

1004

serum phosphate control).

1005

3.3.4

Evidence to recommendations

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 decisionmaking. 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 GDGâ&#x20AC;&#x2122;s discussions. Although important to decision making, it was felt that adherencepromoting 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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Trade-off between benefits and harms

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. 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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Economic considerations

Quality of evidence

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. 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. 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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Other considerations

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). 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).

1006

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3.3.5

patient information strategies

1008 1009

Recommendations and research recommendations for

Recommendations Recommendation 1.1.1 A specialist renal dietitian, supported by healthcare professionals with the necessary skills and competencies, should carry out a dietary assessment and give individualised information and advice on dietary phosphate management. Recommendation 1.1.2 Advice on dietary phosphate management should be tailored to individual learning needs and preferences, rather than being provided through a generalised or complex multicomponent programme of delivery.

1010 1011

3.4

Use of phosphate binders in people with stage 4 or 5 CKD who are not on dialysis

1012 1013

3.4.1

1014

For people with stage 4 or 5 CKD who are not on dialysis, are phosphate

1015

binders effective compared with placebo or other treatments in managing

1016

serum phosphate and its associated outcomes? Which is the most effective

1017

phosphate binder?

1018

3.4.2

1019

This review question focused on the use of phosphate-binding medications to

1020

prevent and treat hyperphosphataemia in patients with stage 4 or 5 CKD who

1021

are not on dialysis. These pharmacological interventions bind dietary

1022

phosphate when taken with food (that is, not on an empty stomach), and can

1023

broadly be defined as:

1024

Review question

Evidence review

calcium-based: calcium carbonate or calcium acetate, and

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non-calcium-based: sevelamer hydrochloride, sevelamer carbonate,

1026

lanthanum carbonate, aluminium hydroxide or magnesium carbonate.

1027 1028

For this review question, papers were identified from a number of different

1029

databases (Medline, Embase, Medline in Process, the Cochrane Database of

1030

Systematic Reviews and the Centre for Reviews and Dissemination) using a

1031

broad search strategy, pulling in all papers relating to the use of phosphate

1032

binders in the management of hyperphosphataemia in CKD. Only RCTs that

1033

compared a phosphate binder with either a placebo or another comparator in

1034

patients with stage 4 or 5 CKD who are not on dialysis were considered for

1035

inclusion. The first phase from crossover studies was considered for inclusion

1036

but only if the data were extractable from the overall results.

1037

Trials were excluded if:

1038

the population included people with stages 1 to 3 CKD; or

1039

the population included people on dialysis; or

1040

data were obtained through an open-label extension of an RCT.

1041 1042

From a database of 1480 abstracts, 300 full-text articles were ordered and 4

1043

papers were selected (Caglar et al, 2008; Qunibi et al, 2011; Russo et al,

1044

2007; Sprague et al, 2009). No paediatric studies meeting the inclusion

1045

criteria were found. Table 4 lists the details of the included studies.

1046

There was some pooling of studies, although there was considerable

1047

heterogeneity. One prominent cause was the widespread use of a range of

1048

concurrent interventions that are known to impact the outcomes of interest.

1049

Additionally, the time periods for which data were available varied widely

1050

between the studies.

1051

Mean differences (MDs) were calculated for continuous outcomes and relative

1052

risks (RRs) for binary outcomes, as well as the corresponding 95% confidence

1053

intervals where sufficient data were available. Meta-analyses were conducted

1054

either through the pooling of studies into single, direct pair-wise comparisons,

1055

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These interventions could then be compared, both directly and indirectly,

1057

against each other in multiple treatment comparisons (MTCs).

1058 1059

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1060 1061

Table 4 Summary of included studies for the use of phosphate binders in people with stage 4 or 5 CKD who are not on dialysis Study (Country)

Interventions

Follow-up

Target serum PO4/Ca (mmol/l)

Baseline PO4/Ca (mmol/l ± SD)

Outcomes

Conclusions

Caglar et al, 2008 RCT (Turkey)

Sevelamer hydrochloride versus Calcium acetate

8 weeks

PO4 <1.78

Sevelamer PO4: 2.52 ± 0.19 Ca: 2 ± 0.1 Calcium acetate PO4: 2.52 ± 0.23 Ca: 2.2 ± 0.1

Serum phosphate Serum calcium

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

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

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.

PO4: 1.65 ± 0.4 Ca: 2.27 ± 0.17 Placebo PO4: 1.65 ± 1.36 Ca: 2.2 ± 0.2

PO4: 1.74 ± 0.23 Ca: 2.24 ± 0.12

Abbreviations: Ca, calcium; Ca x PO4, calcium-phosphorus product; PO4, phosphate; RCT, randomised controlled trial; SD, standard deviation.

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1062 1063

Summary GRADE profile 19 Calcium acetate compared with placebo Outcome

Number of Studies

Number of patients

Effect

Quality

Calcium acetate

Placebo

Serum phosphate (number of patients in whom control of serum phosphate achieved) 12-week follow-up

1 RCT Qunibi et al, 2011

22/37 (59.5%)

15/41 (36.6%)

Relative effect RR = 1.63 (95% CI:1.00 to 2.63) Absolute effect 230 more per 1000 (0 to 596 more)

Very low

Adherence (% of prescribed pills taken) 12-week follow-up

1 RCT Qunibi et al, 2011

Absolute effect

Low

Serum calcium (number of patients with hypercalcaemia) 12-week follow-up

1 RCT Qunibi et al, 2011

5/37 (13.5%

MD = 0.70 lower (95% CI: 7.16 lower to 5.76 higher) 0/41 (0%)

Relative effect RR = 12.16 (95% CI: 0.7 to 212.64)

Very low

Abbreviations: CI, confidence interval; MD, mean difference; RCT, randomised controlled trial; RR, relative risk.

1064 1065

Summary GRADE profile 20 Calcium carbonate compared with sevelamer hydrochloride Outcome

Number of Studies

Number of patients Calcium carbonate

Sevelamer

Effect

Quality

Serum phosphate 2-year follow-up

1 RCT Russo et al, 2007

Absolute effect MD = 0.03 mmol/l lower (95% CI: 0.24 lower to 0.18 higher)

Very low

Serum calcium 2-year follow-up

1 RCT Russo et al, 2007

Absolute effect MD = 0.02 mmol/l higher (95% CI: 0.06 lower to 0.10 higher)

Very low

Coronary calcification scores

1 RCT Russo et al,

Absolute effect MD = 20 higher (95% CI: 262.96 lower

Very low

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2-year follow-up

2007

Annualised change in coronary calcification scores 2-year follow-up

1 RCT Russo et al, 2007

to 302.96 higher) 28

Absolute effect

Very low

MD = 146.66 higher (95% CI: 35.77 to 275.55 higher)

Abbreviations: CI, confidence interval; MD, mean difference; RCT, randomised controlled trial.

1066 1067

Summary GRADE profile 21 Lanthanum compared with placebo Outcome

Number of Studies

Number of patients Lanthanum

Placebo

Effect

Quality

Serum phosphate (number of patients in whom control of serum phosphate achieved) 8-week follow-up

1 RCT Sprague et al, 2009

25/56 (44.6%)

9/34 (26.5%)

Relative effect RR = 1.69 (95% CI: 0.9 to 3.17) Absolute effect 183 more per 1000 (26 fewer to 574 more)

Very low

Adverse events â&#x20AC;&#x201C; nausea and vomiting (number of patients to experience adverse event) 8-week follow-up

1 RCT Sprague et al, 2009

9/56 (16.1%)

4/34 (11.8%)

Relative effect

Very low

RR = 1.37 (95% CI: 0.46 to 4.10) Absolute effect 44 more per 1000 (64 fewer to 365 more)

Note: a small number of patients were CKD stage 3 in each group (Lanthanum 25%, Placebo 20.6%) Abbreviations: CI, confidence interval; RCT, randomised controlled trial; RR, relative risk.

1068 1069

Summary GRADE profile 22 Lanthanum compared with calcium acetate Outcome Serum phosphate (number of patients in whom control

Number of Studies

Number of patients Lanthanum

Calcium acetate

2 RCTs Qunibi et al,

25/56

22/37

Management of hyperphosphataemia: NICE clinical guideline DRAFT (October 2012)

Effect

Quality

Relative effect

Very low

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of serum phosphate achieved) 10-week follow-up (mean)

2011 Sprague et al, 2009

(44.6%)

(59.5%)

RR = 1.14 (95% CI: 0.31 to 4.15) Absolute effect 83 more per 1000 (410 fewer to 1000 more

Note: indirect comparison calculated by reviewer Abbreviations: CI, confidence interval; RCT, randomised controlled trial; RR, relative risk.

1070 1071

See appendix E for the evidence tables and GRADE profiles in full.

1072 1073

Multiple treatment comparisons (serum phosphate and serum calcium)

1074

As there was a lack of evidence allowing a direct comparison between all of the possible treatments, an MTC was carried out to aid

1075

the GDG decision making process (for further information on MTCs, please see the glossary on page 235). A total of 3 studies were

1076

included within the network allowing 4 treatments to be assessed against each other. The study by Russo et al was excluded from

1077

the model as the follow up time (104 weeks) was significantly longer than the other 3 studies within the network (mean follow up

1078

time, 9 weeks). The model used was based upon preliminary work carried out by NICE's technical support unit (appendix G). In

1079

brief, a standard network meta-analysis model in WinBUGS was used, utilising a previously published code (Dias et al, 201118).

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

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1080

The results below are those generated from a fixed effect analysis, which was recommended in the initial work carried out by the

1081

Technical Support Unit.

1082

Serum phosphate network map CKD patients stage 4 or 5

1 Study

1083 1084 1085

Abbreviations: CA, calcium acetate; LC, lanthanum carbonate; P, placebo; SH, sevelamer hydrochloride.

1086

Summary GRADE profile 23 Multiple treatment comparison- serum phosphate Outcome

Number of Studies

Serum phosphate (mean follow up 9 weeks)

3 RCTs

Limitations very serious

Inconsistency 2

serious

Indirectness serious

Imprecision serious

Quality very low

Caglar et al, 2008; Qunibi et al, 2011; Sprague et al, 2009 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 2

Abbreviations: RCT, randomised controlled trial.

1087

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1088

Mean difference matrix: serum phosphate Placebo

Lanthanum

Sevelamer hydrochloride

Calcium acetate

Placebo

-0.120 mmol/l (95%CI: -0.218 to -0.022)

-0.259 mmol/l (95%CI: -0.581 to 0.062)

-0.229 mmol/l (95%CI: -0.488 to 0.030)

Lanthanum

-0.140 mmol/l (95%CI: -0.475 to 0.196)

-0.109 mmol/l (95%CI: -0.387 to 0.168)

Sevelamer hydrochloride

0.030 mmol/l (95%CI: -0.161 to 0.222)

Calcium acetate

Abbreviations: CI, credibility interval.

1089 1090

Probability rank: serum phosphate Intervention

Probability best binder

Median rank (95% CI)

Sevelamer hydrochloride

0.560

1 (1, 4)

Calcium acetate

0.296

2 (1, 4)

Lanthanum carbonate

0.144

3 (1, 3)

Placebo

0.000

4 (3, 4)

Abbreviations: CI, credibility interval.

1091

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1092

Relative effectiveness compared to placebo: serum phosphate Calcium acetate Lanthanum carbonate -1

-0.5

0.5

MD (mmol/l) v. placebo

1093 1094 1095

Multiple treatment comparison: serum calcium

1 Study

1096 1097 1098 1099

Abbreviations: CA, calcium acetate; LC, lanthanum carbonate; P, placebo; SH, sevelamer hydrochloride.

Summary GRADE profile 24 Multiple treatment comparison - serum calcium Outcome Serum calcium (mean follow up 9 weeks) 1 2 3 4

Number of Studies 3 RCTs

Limitations very serious

Inconsistency 2

serious

Indirectness serious

Imprecision serious

Quality very low

Caglar et al, 2008; Qunibi et al, 2011; Sprague et al, 2009 Lack of detail on the randomisation, allocation and blinding within the studies Surrogate marker used GRADE rule of thumb sample size <400

Inconsistency could not be appraised Abbreviations: RCT, randomised controlled trial.

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1100 1101

Mean difference matrix: serum calcium Placebo

Lanthanum

Sevelamer hydrochloride

Calcium acetate

Placebo

0.050 mmol/l (95%CI: 0.006 to 0.094)

0.080 mmol/l (95%CI: -0.017 to 0.177)

0.170 mmol/l (95%CI: 0.090 to 0.250)

Lanthanum

0.030 mmol/l (95%CI: -0.076 to 0.136)

0.120 mmol/l (95%CI: 0.029 to 0.211)

Sevelamer hydrochloride

0.090 mmol/l (95%CI: 0.035 to 0.145)

Calcium acetate

1102 1103

Probability rank: serum calcium Intervention

Probability best

Median rank (95%CI)

Placebo

0.936

1 (1, 2)

Lanthanum carbonate

0.012

2 (2, 3)

Sevelamer hydrochloride

0.052

3 (1, 3)

Calcium acetate

0.000

4 (4, 4)

1104

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1105

Relative effectiveness compared to placebo: serum calcium Calcium acetate Sevelamer hydrochloride Lanthanum carbonate

-1

-0.8

-0.6

-0.4

-0.2

0.2

0.4

0.6

0.8

MD (mmol/l) versus placebo 1106 1107

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3.4.3

Evidence statements

1109

For details of how the evidence is graded, see ‘The guidelines manual’.

1110

Use of phosphate binders in people with stage 4 or 5 CKD who are not

1111

on dialysis

1112

Calcium acetate compared with placebo

1113

Critical outcomes

1114

3.4.3.1

Very-low-quality evidence from 1 RCT of 78 patients showed

1115

calcium acetate to be associated with a greater proportion of

1116

participants that had that achieved serum phosphate control than

1117

that associated with placebo at 12 weeks (RR 1.63 [95% CI 1.00 to

1118

2.63 i.e. statistically significant]).

1119

3.4.3.2

Low-quality evidence from the RCT of 78 patients showed no

1120

statistically significant difference in the degree of adherence

1121

between those that received calcium acetate and those that

1122

received placebo (MD 0.70% of prescription lower [95% CI –7.16 to

1123

5.76]).

1124

Important outcomes

1125

3.4.3.3

Very-low-quality evidence from the RCT of 78 patients showed no

1126

statistically significant difference in the proportion of participants

1127

with hypercalcaemia at 12 weeks between those that received

1128

calcium acetate and those that received placebo (RR 12.16 [95%

1129

CI 0.7 to 212.64]).

1130

Calcium carbonate compared with sevelamer hydrochloride

1131

Critical outcomes

1132

3.4.3.4

Very-low-quality evidence from 1 RCT of 55 patients showed no

1133

statistically significant difference in mean serum phosphate

1134

between those that received calcium carbonate and those that

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DRAFT FOR CONSULTATION 1135

received sevelamer hydrochloride at 2 years (MD 0.03 mmol/l

1136

higher [95% CI –0.24 to 0.18]).

1137

Important outcomes

1138

3.4.3.5

Very-low-quality evidence from the RCT of 55 patients showed no

1139

statistically significant difference in mean serum calcium between

1140

those that received calcium carbonate and those that received

1141

sevelamer at 2 years (MD 0.02 mmol/l higher [95% CI –0.06 to

1142

0.10]).

1143

3.4.3.6

Very-low-quality evidence from the RCT of 55 patients showed no

1144

statistically significant difference in mean coronary artery

1145

calcification scores between those that received calcium carbonate

1146

and those that received sevelamer at 2 years (MD 20 higher [95%

1147

CI –262.96 to 302.96])

1148

3.4.3.7

Very-low-quality evidence from the RCT of 55 patients showed

1149

calcium carbonate to be associated with a mean annualised

1150

change in coronary artery calcification scores 146.66 greater (95%

1151

CI 35.77 to 257.55 i.e. statistically significant) than that associated

1152

with sevelamer.

1153

Lanthanum compared with placebo

1154

Critical outcomes

1155

3.4.3.8

Very-low-quality evidence from 1 RCT of 90 patients showed no

1156

statistically significant difference in the number of participants that

1157

achieved serum phosphate control during the 8-week study period

1158

between those that received lanthanum and those that received

1159

placebo (RR 1.69 higher [95% CI 0.90 to 3.17]).

1160

Important outcomes

1161

3.4.3.9

Very-low-quality evidence from the RCT of 90 patients showed no

1162

statistically significant difference in the number of participants who

1163

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DRAFT FOR CONSULTATION 1164

between those that received lanthanum and those that received

1165

placebo (RR 1.37 higher [95% CI 0.46 to 4.10]).

1166

Lanthanum compared with calcium acetate

1167

Critical outcomes

1168

3.4.3.10

Very-low-quality evidence from 1 indirect comparison of 93 patients

1169

from 2 RCTs showed no statistically significant difference in the

1170

number of participants that achieved serum phosphate control

1171

during a mean 10-week study period between those that received

1172

lanthanum and those that received calcium acetate (RR 1.14

1173

[95% CI 0.31 to 4.15]).

1174

Multi treatment comparison: serum phosphate

1175

Critical outcome

1176

3.4.3.11

Evidence from 1 MTC, containing 3 studies of very low quality,

1177

suggested that sevelamer hydrochloride had a 56% probability

1178

(median rank 1 [95% CI 1, 4]) of being the best treatment to control

1179

serum phosphate at 9 weeks, in patients with stage 4 or 5 CKD,

1180

with calcium acetate having a 29.6% probability (median rank 2

1181

[95% CI 1, 4]).

1182

Multi treatment comparison: serum calcium

1183

Important outcome

1184

3.4.3.12

Evidence from 1 MTC, containing 3 studies of very low quality,

1185

suggested that placebo had a 93.6% probability (median rank 1

1186

[95%CI 1, 2]) of being the best treatment to control serum calcium

1187

at 9 weeks in patients with stage 4 or 5 CKD, with sevelamer

1188

hydrochloride acetate having a 5.2% probability (median rank 3

1189

[95% CI 1, 3]) and lanthanum carbonate having a 1.2% probability

1190

(median rank 2 [95% CI 2, 3]).

1191

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DRAFT FOR CONSULTATION 1192

3.4.4

Evidence to recommendations

Relative value of different outcomes

Trade-off between benefits and harms

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. 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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DRAFT FOR CONSULTATION 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 calciumbased 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 predialysis 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 calciumbased 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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Economic considerations Quality of evidence

felt that no further increases should be made to the dose of calciumbased 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. 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. 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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Other considerations

available graphs. Unit-of-analysis errors were also common, with analyses not following the intent-to-treat principle. 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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DRAFT FOR CONSULTATION 1194

3.4.5

Recommendations and research recommendations for

1195

use of phosphate binders in people with stage 4 or 5 CKD

1196

who are not on dialysis

1197

Recommendations 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

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DRAFT FOR CONSULTATION patients find it unpalatable. Recommendation 1.1.10 For adults with stage 4 or 5 chronic kidney disease (CKD) who are not on dialysis and who are taking a calcium-based binder: consider switching to a non-calcium-based binder if calcium-based phosphate binders are not tolerated consider either combining with, or switching to, a non-calcium-based binder if hypercalcaemia develops (having taken into account other causes of raised calcium), or if serum parathyroid hormone levels are low. 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). 1198 1199

Research recommendations

1200

See appendix B for full details of research recommendations.

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Research recommendation B1 Which binders are most effective in controlling serum phosphate in adults with stage 4 or 5 CKD who are not on dialysis? Research recommendation B2 In adults with stage 4 or 5 CKD, including those on dialysis, what is the longterm 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 B4 Which binders are most effective in controlling serum phosphate in children with stage 4 or 5 CKD who are not on dialysis? 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? 1201 1202

3.5

Use of phosphate binders in people with stage 5 CKD who are on dialysis

1203 1204

3.5.1

Review question

1205

For people with stage 5 CKD who are on dialysis, are phosphate binders

1206

effective compared to placebo or other treatments in managing serum

1207

phosphate and its associated outcomes? Which is the most effective

1208

phosphate binder?

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DRAFT FOR CONSULTATION 1209

3.5.2

Evidence review

1210

This review question focused on the use of phosphate-binding medications to

1211

prevent and treat hyperphosphataemia in patients with stage 5 CKD who are

1212

on dialysis. These pharmacological interventions bind dietary phosphate when

1213

taken with food, that is, not on an empty stomach), and can broadly be

1214

defined as:

1215

calcium-based: calcium carbonate or calcium acetate; and

1216

non-calcium-based: sevelamer hydrochloride, sevelamer carbonate,

1217

lanthanum carbonate, aluminium hydroxide or magnesium carbonate.

1218 1219

For this review question, papers were identified from a number of different

1220

databases (Medline, Embase, Medline in Process, the Cochrane Database of

1221

Systematic Reviews and the Centre for Reviews and Dissemination) using a

1222

broad search strategy, pulling in all papers relating to the use of phosphate

1223

binders in the management of hyperphosphataemia in CKD. Only RCTs that

1224

compared a phosphate binder with either a placebo or another comparator in

1225

patients with stage 5 CKD who are on dialysis were considered for inclusion.

1226

Trials were excluded if:

1227

the population included people with CKD stages 1 to 4 or

1228

the population included people with a diagnosis of CKD stage 5 who are

1229

not on dialysis or

1230

data were obtained through an open-label extension of an RCT.

1231 1232

From a database of 1480 abstracts, 300 full-text articles were ordered and

1233

46 papers were included in the review (Al-Baaj et al, 2005; Asmus et al, 2005;

1234

Barbarykin et al 2004; Barreto et al, 2008; Block et al, 2005; Braun et al, 2004;

1235

Chertow et al, 1997; Chertow et al, 2002; Chertow et al, 2003; Chiang et al,

1236

2005; Chow et al, 2007; de Francisco et al, 2010; de Santo et al, 2006;

1237

Emmett et al, 1991; Evenepoel et al, 2009; Ferreira et al, 2008; Finn et al,

1238

2004; Finn & the Lanthanum Study Group, 2006; Fishbane et al, 2010;

1239

Freemont et al, 2005; Galassi et al, 2006; Hervas et al, 2003; Hutchison et al,

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DRAFT FOR CONSULTATION 1240

2005; Iwasaki et al, 2005; Janssen et al, 1995; Janssen et al, 1996; Joy et al,

1241

2003; Kakuta et al, 2011; Katopodis et al, 2006; Koiwa et al, 2005a; Koiwa et

1242

al, 2005b; Lin et al, 2011; Liu et al, 2006; Malluche et al, 2008; Navarro-

1243

Gonzalez et al, 2011; Qunibi et al, 2008; Raggi et al, 2004; Ring et al, 1993;

1244

Salusky et al, 2005; Shigematsu & the Lanthanum Carbonate Research

1245

Group, 2008a; Shigematsu & the Lanthanum Carbonate Research Group,

1246

2008b; Spasovski et al, 2006; Spiegel et al, 2007; Suki et al, 2007; Tzanakis

1247

et al, 2008; Wilson et al, 2009). Tables 5 and 6 list the details of the included

1248

studies.

1249

The reviewer was unable to extract the serum phosphate data from 1 study

1250

(Finn & the Lanthanum Study Group, 2006) comparing lanthanum carbonate

1251

against ‘standard therapy’ (the participants’ pre-study binder regimens) due to

1252

its presentation in uninterpretable graphs. It was felt that this study was a

1253

significant part of the evidence base due to its long follow-up of 2 years and

1254

large population of 1359 participants. The reviewer contacted the authors of

1255

the study but was unable to obtain the data required to include this study in

1256

the analyses of serum phosphate data.

1257

Only 1 of the papers located explicitly considered the use of phosphate

1258

binders in the management hyperphosphataemia in children who are on

1259

dialysis. The evidence for this population is presented separately from that for

1260

adults because of the different considerations required in determining a child’s

1261

treatment regimen. Foremost amongst these is the need to support a child’s

1262

development and growth, and the different nutrient and mineral requirements

1263

this entails.

1264

There was some pooling of the 46 studies conducted in adults, although this

1265

suffered from considerable heterogeneity. One prominent cause of this was

1266

the widespread use of a range of concurrent interventions that are known to

1267

impact the outcomes of interest. Additionally, time periods for which data were

1268

available varied widely between the studies, and thresholds for the definition

1269

of dichotomous outcomes, such as the incidence of hypercalcaemia or the

1270

achievement of serum phosphate control, were not always consistent.

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DRAFT FOR CONSULTATION 1271

Mean differences (MDs) were calculated for continuous outcomes, hazard

1272

ratios (HRs) were calculated for all-cause and cardiovascular-related

1273

mortality, and relative risks (RRs) were calculated for all other binary

1274

outcomes. Corresponding 95% confidence intervals are given where sufficient

1275

data were available.

1276

Meta-analyses were conducted either through the pooling of studies into

1277

single, direct pair-wise comparisons, or through the pooling of 3 or more

1278

interventions into a network meta-analysis. These interventions could then be

1279

compared, both directly and indirectly, against each other in multiple treatment

1280

comparisons (MTCs). Where possible, these MTCs enabled the GDG to

1281

quantitatively rank the phosphate binders according to their impact on the

1282

outcomes of interest.

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1283

Table 5 Summary of included studies for the use of phosphate binders in children with stage 5 CKD who are on dialysis Study (Country)

Interventions

Follow-up

Target PO4/Ca (mmol/l)

Baseline PO4/Ca (mmol/l ± SD)

Outcomes

Conclusions

Salusky et al, 2005 RCT

Calcium carbonate versus Sevelamer hydrochloride

8 months

PO4 1.24 to 1.94 Ca 2.1 to 2.54

Calcium carbonate PO4: 1.91±0.5 Ca: 2.25±0.15 Sevelamer

Serum phosphate Serum calcium

Both treatments controlled serum phosphate and calcium. However, sevelamer controlled serum calcium closer to the lower end of the normal range.

PO4: 1.81±0.38 Ca: 2.25±0.15 Abbreviations: Ca, calcium; PO4, phosphate; RCT, randomised controlled trial.

1284 1285

Summary GRADE profile 25 Calcium carbonate compared with sevelamer in children Outcome

Number of Studies

Number of patients

Effect

Quality

Calcium carbonate

Sevelamer hydrochloride

Serum phosphate 8-month follow-up

1 RCT Salusky et al, 2005

Absolute effect MD = 0.16 mmol/l higher (95% CI: 0.16 lower to 0.48 higher)

Very low

Serum calcium 8-month follow-up

1 RCT Salusky et al, 2005

Absolute effect MD = 0.20 mmol/l higher (95% CI: 0.1 to 0.32 higher)

Very low

Abbreviations: CI, confidence interval; MD, mean difference; RCT, randomised controlled trial.

1286 1287

See appendix E for the evidence table and GRADE profile in full.

1288

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1289

Table 6 Summary of included studies for the use of phosphate binders in adults with stage 5 CKD who are on dialysis 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

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

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

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

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

PO4: 1.68 ± 0.27

PO4: 2.57 ± 0.47 Ca: 2 ± 0.25 Calcium acetate PO4: 2.1 ± 0.18 Ca: 2.15 ± 0.2 PO4 1.13 to 1.78

Calcium acetate PO4: 2.3 ± 0.45 Sevelamer PO4: 2.3 ± 0.7

18 months

PO4 < 2.10 Ca

Sevelamer PO4: 1.68 ± 0.52 Ca: 2.32 ± 0.25

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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

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.

PO4: 2.13 ± 0.68 Ca: 2.32 ± 0.22 Placebo PO4: 2.32 ± 0.77 Ca: 2.4 ± 0.12

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Chiang et al, 2005 RCT (Taiwan)

Lanthanum versus Placebo

4 weeks

PO4 0.6 to 1.8

Chow et al, 2007 RCT (China)

Sevelamer hydrochloride high-dose versus Sevelamer hydrochloride low-dose

6 months

PO4 <1.78

de Francisco et al, 2010 RCT (Germany, Poland, Portugal, Romania and Spain)

Calcium acetate + magnesium carbonate versus Sevelamer hydrochloride

6 months

de Santo et al, 2006 RCT (Italy)

Sevelamer hydrochloride versus Calcium carbonate

Emmett et al, 1991 RCT (USA)

Evenepoel et al,

Lanthanum PO4: 1.77 ± 0.11 Placebo

Serum phosphate Proportion achieving phosphate control

Lanthanum was effective in controlling serum phosphate.

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.

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.

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.

Calcium acetate versus Placebo

2 weeks

PO4 1.45 to 1.78

Calcium acetate

Serum calcium Serum phosphate

Calcium acetate was associated with a decrease in serum phosphate and an increase in serum calcium.

Sevelamer hydrochloride

12 weeks

PO4

Sevelamer

Serum calcium

Both treatments significantly

PO4: 1.83 ± 0.16

PO4: 2.42 ± 0.54 Ca: 2.2 ± 0.18 Placebo PO4: 2.29 ± 0.45 Ca: 2.25 ± 0.22

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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

Ferreira et al, 2008 RCT (Portugal)

Sevelamer hydrochloride versus Calcium-based binder

12 months

PO4 1 to 1.6 Ca < 2.6

Finn et al, 2004 RCT (USA)

Lanthanum carbonate at various doses versus Placebo

6 weeks

Finn et al, 2006 RCT (USA, Puerto Rico, Poland and South Africa)

Lanthanum carbonate versus Standard therapy

Fishbane et al, 2010 RCT (USA)

Sevelamer carbonate powder versus Sevelamer hydrochloride tablets

PO4: 2.42 ± 0.45 Ca: 2.38 ± 0.15 Calcium acetate

Serum phosphate Risk of hypercalcaemia

reduced serum phosphate. Hypercalcaemia was experienced by more calcium acetate patients.

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.

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.

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.

6 months

PO4 1.13 to 1.78

Sevelamer carbonate powder

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

PO4: 2.4 ± 0.45 Ca: 2.39 ± 0.12

PO4: 2.36 ± 0.41 Ca: 2.25 ± 0.17 Sevelamer tablets PO4: 2.44 ± 0.41 Ca: 2.25 ± 0.17

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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.

Iwasaki et al, 2005 RCT (Japan)

Sevelamer hydrochloride + calcium carbonate (low-dose) versus Sevelamer hydrochloride

8 weeks

None given

Sevelamer + calcium carbonate (low-dose) PO4: 2.23 ± 0.26 Ca: 2.23 ± 0.26 Sevelamer + calcium

Serum calcium Serum phosphate Adverse events

Serum phosphate significantly decreased in the high dose group only.

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carbonate (highdose) PO4: 2.42 ± 0.26 Ca: 2.47 ± 0.15

+ calcium carbonate (high-dose)

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

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.

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.

PO4: 1.65 ± 1.36 Ca: 2.2 ± 0.2 PO4 < 1.91

Lanthanum

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.

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.

Joy et al, 2003 RCT (USA)

Lanthanum carbonate versus Placebo

4 weeks

Kakuta et al, 2011 RCT (Japan)

Sevelamer hydrochloride versus Calcium carbonate

Katopodis et al, 2006 RCT

Sevelamer hydrochloride versus Aluminium hydroxide

PO4: 1.76 ± 0.47 Ca: 2.20 ± 0.16 Placebo PO4: 1.82 ± 0.53 Ca: 2.17 ± 0.18

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Aluminium hydroxide PO4: 2.28 ± 0.39 Ca: 2.27 ± 0.2

(Greece)

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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Standard therapy PO4: 2.62 ± 0.65 Ca: 2.3 ± 0.28

(USA, Puerto Rico, Poland, South Africa)

calcium at most visits.

NavarroGonzalez 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

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

Serum calcium Serum phosphate

Both treatments controlled serum phosphate. There was no difference between the treatments in terms of serum calcium.

Serum phosphate Adverse event Risk of hypercalcaemia

Both treatments are effective in controlling serum phosphate, but lanthanum is associated with a lower incidence of

PO4: 2.1 ± 0.61 Ca: 2.2 ± 0.2 Sevelamer PO4: 2.13 ± 0.48 Ca: 2.2 ± 0.17

PO4: 2.30 ± 0.59 Ca: 2.40 ± 0.31 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

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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 dosedependent manner. The incidence of drug-related adverse events was also dosedependent.

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

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

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.

PO4: 2.12 ± 0.28

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Ca: 2.28 Âą 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 1291

Summary GRADE profile 26 Calcium acetate compared with placebo Outcome

Number of Studies

Number of patients

Effect

Quality

Calcium acetate

Placebo

Serum phosphate 2-week follow-up

1 RCT Emmett et al, 1991

Absolute effect MD = 0.62 mmol/l lower (95% CI: 0.90 to 0.34 lower)

Very low

Serum calcium 2-week follow-up

1 RCT Emmett et al, 1991

Absolute effect MD = 0.15 mmol/l higher (95% CI: 0.05 to 0.25 higher)

Very low

Effect

Quality

Absolute effect MD = 0.09 mmol/l lower (95% CI: 0.45 lower to 0.27 higher)

Very low

Abbreviations: CI, confidence interval; MD, mean difference; RCT, randomised controlled trial.

1292 1293

Summary GRADE profile 27 Calcium acetate compared with calcium carbonate Outcome Serum phosphate 3-week follow-up

Number of Studies

Number of patients Calcium acetate

Calcium carbonate

1 RCT Ring et al,1993

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Serum calcium 3 weeks follow-up

1 RCT Ring et al,1993

Serum calcium (number of patients with hypercalcaemia) 12 months follow-up

1 RCT Janssen et al, 1996

9/14 (64.3%)

Absolute effect

Very low

MD = 0.09 mmol/l higher (95% CI: 0.13 lower to 0.31 higher) 12/13 (92.3%)

Relative effect

Very low

RR = 0.70 (95% CI: 0.46 to 1.06) Absolute effect 277 fewer per 1000 (from 498 fewer to 55 more)

Abbreviations: CI, confidence interval; MD, mean difference; RCT, randomised controlled trial; RR, relative risk.

1294 1295

Summary GRADE profile 28 Calcium carbonate bread compared with calcium acetate Outcome

Number of Studies

Number of patients

Effect

Quality

Calcium carbonate bread

Calcium acetate

Serum phosphate 8-week follow-up

1 RCT Babarykin et al, 2004

Absolute effect MD = 0.35 mmol/l lower (95% CI: 0.40 to 0.30 lower)

Very low

Serum calcium 8-week follow-up

1 RCT Babarykin et al, 2004

Absolute effect MD = 0.65 mmol/l lower (95% CI: 0.75 to 0.55 lower)

Very low

Abbreviations: CI, confidence interval; MD, mean difference; RCT, randomised controlled trial.

1296 1297

Summary GRADE profile 29 Calcium carbonate compared with sevelamer + calcium carbonate Outcome

Number of Studies

Number of patients Calcium carbonate

Effect

Quality

Sevelamer + calcium

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carbonate Serum phosphate 4-week follow-up

1 RCT Koiwa et al, 2005

Serum calcium 4-week follow-up

1 RCT Koiwa et al, 2005

Absolute effect

Very low

MD = 0.31 mmol/l higher (95% CI: 0.05 to 0.57 higher) 26

Absolute effect

Very low

MD = 0.02 mmol/l higher (95% CI: 0.12 lower to 0.16 higher)

Abbreviations: CI, confidence interval; MD, mean difference; RCT, randomised controlled trial.

1298 1299 1300

Summary GRADE profile 30 Sevelamer hydrochloride + calcium carbonate (high-dose) compared with sevelamer hydrochloride + calcium carbonate (low-dose) Outcome

Number of Studies

Number of patients

Effect

Quality

Sevelamer + calcium carbonate (high-dose)

Sevelamer + calcium carbonate (low-dose)

Serum phosphate 8-week follow-up

1 RCT Iwasaki et al, 2005

Absolute effect MD = 0.10 mmol/l lower (95% CI: 0.34 lower to 0.14 higher)

Very low

Adverse events - abdominal distension (number of patients to experience adverse event) 8-week follow-up

1 RCT Iwasaki et al, 2005

8/21 (38.1%)

9/30 (30%)

Relative effect RR = 1.27 (95% CI: 0.59 to 2.75) Absolute effect 81 more per 1000 (from 123 fewer to 525 more)

Very low

Adverse events - constipation (number of patients to experience adverse event) 8-week follow-up

1 RCT Iwasaki et al, 2005

10/21 (47.6%)

13/30 (43.3%)

Relative effect RR = 1.10 (95% CI: 0.6 to 2.02) Absolute effect

Very low

Serum calcium

1 RCT

43 more per 1000 (from 173 fewer to 442 more) 21

Management of hyperphosphataemia: NICE clinical guideline DRAFT (October 2012)

Absolute effect

Very low

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8-week follow-up

Iwasaki et al, 2005

MD = 0.02 mmol/l lower (95% CI: 0.13 lower to 0.09 higher)

Abbreviations: CI, confidence interval; MD, mean difference; RCT, randomised controlled trial; RR, relative risk.

1301 1302

Summary GRADE profile 31 Sevelamer hydrochloride compared with placebo Outcome

Number of Studies

Number of patients

Effect

Quality

Sevelamer

Placebo

Serum phosphate 2-week follow-up

1 RCT Chertow et al, 1997

Absolute effect

Very low

Adherence (% of prescribed pills taken) 2-week follow-up

1 RCT Chertow et al, 1997

Adverse Events â&#x20AC;&#x201C; diarrhoea (number of patients to experience adverse event) 2-week follow-up

1 RCT Chertow et al, 1997

0/24 (0%)

1/12 (8.3%)

Relative effect RR = 0.17 (95% CI: 0.01 to 3.96) Absolute effect 69 fewer per 1000 (from 82 fewer to 247 more)

Very low

Adverse Events - nausea and vomiting (number of patients to experience adverse event) 2-week follow-up

1 RCT Chertow et al, 1997

1/24 (4.2%)

1/12 (8.3%)

Relative effect RR = 0.5 (95% CI: 0.03 to 7.32) Absolute effect 42 fewer per 1000 (from 81 fewer to 527 more)

Very low

Adverse events - upper abdominal pain (number of patients to experience adverse event) 2-week follow-up

1 RCT Chertow et al, 1997

0/24 (0%)

1/12 (8.3%)

Relative effect RR = 0.17 (95% CI: 0.01 to 3.96) Absolute effect

Very low

Serum calcium 2-week follow-up

1 RCT Chertow et al,

MD = 0.52 mmol/l lower (95% CI: 0.96 to 0.08 lower) 12

Absolute effect

Very low

MD = 4% higher (95% CI: 6.75 lower to 14.75 higher)

69 fewer per 1000 (from 82 fewer to 247 more) 24

Management of hyperphosphataemia: NICE clinical guideline DRAFT (October 2012)

Absolute effect

Very low

MD = 0.03 mmol/l lower (95% CI: 013

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1997

lower to 0.07 higher)

Abbreviations: CI, confidence interval; MD, mean difference; RCT, randomised controlled trial; RR, relative risk.

1303 1304

Summary GRADE profile 32 Sevelamer hydrochloride compared with calcium-based binders Outcome

Number of Studies

Number of patients Sevelamer

Calcium-based binders

Effect

Quality

Mortality 44-week follow-up

1 RCT Suki et al, 2007

267/1053 (25.4%)

275/1050 (26.2%)

Relative effect HR = 0.93 (95% CI: 0.79 to 1.1) Absolute effect 16 fewer per 1000 (from 49 fewer to 22 more)

Low

Mortality - in those > 65 years 44-week follow-up

1 RCT Suki et al, 2007

578

598

Relative effect HR = 0.77 (95% CI: 0.61 to 0.96)

Very low

Mortality - in those < 65 years 44-week follow-up

1 RCT Suki et al, 2007

472

455

Relative effect

Very low

Cardiovascular mortality 44-week follow-up

1 RCT Suki et al, 2007

142/1053 (13.5%)

147/1050 (14%)

Relative effect

Cardiovascular mortality - in those > 65 years 44-week follow-up

1 RCT Suki et al, 2007

578

598

Relative effect HR = 0.78 (95% CI: 0.58 to 1.05)

Very low

Cardiovascular mortality - in those < 65 years 44-week follow-up

1 RCT Suki et al, 2007

472

455

Relative effect HR = 1.19 (95% CI: 0.82 to 1.73)

Very low

Adverse events - nausea and

1 RCT

1/1053

1/1050

Relative effect

Very low

HR = 1.18 (95% CI: 0.91 to 1.53)

Management of hyperphosphataemia: NICE clinical guideline DRAFT (October 2012)

Very low

HR = 0.93 (95% CI: 0.74 to 1.17) Absolute effect 9 fewer per 1000 (from 34 fewer to 22 more)

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vomiting (number of patients to experience adverse event) 3.75-year follow-up

Suki et al, 2007

(0.09%)

(0.1%)

RR = 1.00 (95% CI: 0.06 to 15.92) Absolute effect 0 fewer per 1000 (from 1 fewer to 14 more)

Serum calcium (number of patients with hypercalcaemia) 8-month follow-up

9 RCTs Block et al, 2005 Braun et al, 2004 Chertow et al, 2002 Chertow et al, 2003 Evenepoel et al, 2009 Koiwa et al, 2005 Lin et al, 2011 Liu et al, 2006 Qunibi et al, 2008

73/538 (13.6%)

161/497 (32.4%)

Relative effect RR = 0.40 (95% CI: 0.31 to 0.52) Absolute effect 194 fewer per 1000 (from 155 fewer to 224 fewer)

Very low

Coronary artery calcification scores 12- to 21-month follow-up

7 RCTs Asmus et al, 2005 Barreto et al, 2008 Block et al, 2005 Braun et al, 2004 Kakuta et al, 2011 Qunibi et al, 2008

369

382

Absolute effect

Low

Management of hyperphosphataemia: NICE clinical guideline DRAFT (October 2012)

MD = 124.13 lower (95% CI: 205.88 to 42.38 lower)

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Raggi et al, 2004 Coronary artery calcification scores – in those with baseline CAC > 30 12- to18-month follow-up

3 RCTs Bareto et al, 2008 Block et al, 2005 Braun et al, 2004

Absolute effect MD = 210.52 lower (382.36 to 38.69 lower)

Very low

Coronary artery calcification scores – in those with diabetes 2-year follow-up

1 RCT Galassi et al, 2006

Absolute effect MD = 289.00 lower (651.99 lower to 73.99 higher)

Very low

Coronary artery calcification scores – in those without diabetes 2 years follow-up

1 RCT Galassi et al, 2006

Absolute effect

Very low

MD = 100.00 lower (256.33 lower to 56.23 higher)

Abbreviations: CAC, coronary artery calcification score; CI, confidence interval; MD, mean difference; RCT, randomised controlled trial; RR, relative risk; HR, hazard ratio.

1305 1306

Summary GRADE profile 33 Sevelamer hydrochloride compared with calcium carbonate Outcome

Number of Studies

Number of patients Sevelamer

Calcium carbonate

Serum phosphate 4-week follow-up

1 RCT Koiwa et al, 2005

Adherence (number of patients considered adherent) 12-month follow-up

1 RCT Braun et al, 2004

39/46 (84.8%)

Effect

Quality

Absolute effect

Very low

MD = 0.04 mmol/l higher (95% CI: 0.20 lower to 0.28 higher) 30/36 (83.3%)

Management of hyperphosphataemia: NICE clinical guideline DRAFT (October 2012)

Relative effect

Very low

RR = 1.02 (95% CI: 0.84 to 1.23) Absolute effect 17 more per 1000 (from 133 fewer to 192 more

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5/29 (17.2%)

2/27 (7.4%)

Relative effect RR = 2.33 (95% CI: 0.49 to 11.01) Absolute effect

Adverse events - abdominal distension (number of patients to experience adverse event) 4-week follow-up

1 RCT Koiwa et al, 2005

Very low

Adverse events â&#x20AC;&#x201C; constipation (number of patients to experience adverse event) 4- to 52-week follow-up

2 RCTs Kakuta et al, 2011 Koiwa et al, 2005

16/120 (13.3%)

4/119 (3.4%)

Relative effect

Serum calcium 4-week follow-up

1 RCT Koiwa et al, 2005

Absolute effect MD = 0.24 mmol/l lower (95% CI: 0.37 to 0.11 lower)

Very low

Coronary artery calcification scores 12-month follow-up

3 RCTs Asmus et al, 2005 Braun et al, 2004 Kakuta et al, 2011

109

Absolute effect MD = 250.11 lower (95% CI: 480.63 to 19.59 lower)

Very low

99 more per 1000 (from 38 fewer to 741 more) Very low

RR = 3.40 (95% CI: 1.34 to 8.63) Absolute effect 81 more per 1000 (from 11 more to 256 more)

Abbreviations: CI, confidence interval; MD, mean difference; RCT, randomised controlled trial; RR, relative risk.

1307 1308

Summary GRADE profile 34 Sevelamer hydrochloride compared with calcium acetate Outcome

Number of Studies

Number of patients Sevelamer

Calcium acetate

Serum phosphate 8-week follow-up

1 RCT Liu et al, 2006

Management of hyperphosphataemia: NICE clinical guideline DRAFT (October 2012)

Effect

Quality

Absolute effect MD = 0.23 mmol/l higher (95% CI: 0.10 lower to 0.56 higher)

Very low

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42/52 (80.8%)

39/54 (72.2%)

Relative effect RR = 1.62 (95% CI: 0.65 to 4.02) Absolute effect

Adherence (number of patients considered adherent) 12-month follow-up

1 RCT Chertow et al, 2003

Very low

Adverse events â&#x20AC;&#x201C; constipation (number of patients to experience adverse event) 12-month follow-up

2 RCTs Chertow et al, 2003 Qunibi et al, 2008

16/154 (10.4%)

14/157 (8.9%)

Relative effect

Adverse events â&#x20AC;&#x201C; diarrhoea (number of patients to experience adverse event) 12-month follow-up

2 RCTs Chertow et al, 2003 Qunibi et al, 2008

26/154 (16.9%)

29/157 (18.5%)

Relative effect RR = 0.91 (95% CI: 0.56 to 1.47) Absolute effect 17 fewer per 1000 (from 81 fewer to 87 more)

Low

Adverse events - nausea and vomiting (number of patients to experience adverse event) 12-month follow-up

2 RCTs Chertow et al, 2003 Qunibi et al, 2008

54/154 (35.1%)

63/157 (40.1%)

Relative effect RR = 0.86 (95% CI: 0.61 to 1.21) Absolute effect 56 fewer per 1000 (from 156 fewer to 84 more)

Low

Adverse events - upper abdominal pain (number of patients to experience adverse event) 12-month follow-up

1 RCT Qunibi et al, 2008

8/100 (8%)

4/103 (3.9%)

Relative effect

Low

Serum calcium 8-week follow-up

1 RCT Liu et al, 2006

Absolute effect MD = 0.15 mmol/l lower (95% CI: 0.3 lower to 0.00 higher)

Very low

Coronary artery calcification scores 12- to 21-month follow-up

2 RCTs Barreto et al, 2008 Qunibi et al,

158

179

Absolute effect MD = 23.04 lower (95% CI: 124.44 lower to 78.36 higher)

Very low

448 more per 1000 (from 253 fewer to 1000 more)

Management of hyperphosphataemia: NICE clinical guideline DRAFT (October 2012)

Low

RR = 1.15 (95% CI: 0.38 to 3.48) Absolute effect 13 more per 1000 (from 55 fewer to 221 more)

RR = 2.06 (95% CI: 0.64 to 6.63) Absolute effect 41 more per 1000 (from 14 fewer to 219 more)

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2008 Abbreviations: CI, confidence interval; MD, mean difference; RCT, randomised controlled trial; RR, relative risk.

1309 1310

Summary GRADE profile 35 Sevelamer hydrochloride compared with sevelamer hydrochloride + calcium carbonate Outcome

Number of Studies

Number of patients Sevelamer

Sevelamer + calcium carbonate

Serum phosphate 4-week follow-up

1 RCT Koiwa et al, 2005

Serum calcium 4-week follow-up

1 RCT Koiwa et al, 2005

Effect

Quality

Absolute effect

Very low

MD = 0.35 mmol/l higher (95% CI: 0.17 to 0.53 higher) 26

Absolute effect MD = 0.22 mmol/l lower (95% CI: 0.36 to 0.08 lower)

Very low

Effect

Quality

Abbreviations: CI, confidence interval; MD, mean difference; RCT, randomised controlled trial.

1311 1312

Summary GRADE profile 36 Sevelamer compared with aluminium hydroxide Outcome

Number of Studies

Number of patients Sevelamer

Aluminium hydroxide

Serum phosphate 8-week follow-up

1 RCT Katopodis et al, 2011

Absolute effect MD = 0.12 mmol/l higher (95% CI: 0.15 lower to 0.39 higher)

Very low

Adverse events â&#x20AC;&#x201C; constipation (number of patients to experience adverse event) 8-week follow-up

1 RCT Katopodis et al, 2011

2/15 (13.3%)

0/15 (0%)

Relative effect RR = 5.00 (95% CI: 0.26 to 96.13)

Very low

Management of hyperphosphataemia: NICE clinical guideline DRAFT (October 2012)

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Serum calcium 8-week follow-up

1 RCT Katopodis et al, 2011

Absolute effect MD = 0.01 mmol/l lower (95% CI: 0.12 lower to 0.10 higher)

Very low

Abbreviations: CI, confidence interval; MD, mean difference; RCT, randomised controlled trial; RR, relative risk.

1313 1314

Summary GRADE profile 37 Sevelamer hydrochloride compared with sevelamer carbonate Outcome

Number of Studies

Number of patients Sevelamer hydrochloride

Sevelamer carbonate

Effect

Quality

Adherence (number of patients considered adherent) 24-week follow-up

1 RCT Fishbane et al, 2010

127/148 (85.8%)

66/72 (91.7%)

Relative effect RR = 0.94 (95% CI: 0.85 to 1.03) Absolute effect 55 fewer per 1000 (from 137 fewer to 27 more)

Very low

Adverse events â&#x20AC;&#x201C; constipation (number of patients to experience adverse event) 24-week follow-up

1 RCT Fishbane et al, 2010

4/72 (5.6%)

1/141 (0.71%)

Relative effect

Very low

Adverse events â&#x20AC;&#x201C; diarrhoea (number of patients to experience adverse event) 24-week follow-up

1 RCT Fishbane et al, 2010

4/72 (5.6%)

12/141 (8.5%)

Relative effect RR = 0.65 (95% CI: 0.22 to 1.95) Absolute effect 30 fewer per 1000 (from 66 fewer to 81 more)

Very low

Adverse events - nausea and vomiting (number of patients to experience adverse event) 24-week follow-up

1 RCT Fishbane et al, 2010

3/72 (4.2%)

22/141 (15.6%)

Relative effect RR = 0.27 (95% CI: 0.08 to 0.86) Absolute effect 114 fewer per 1000 (from 22 fewer to 144 fewer)

Very low

RR = 7.83 (95% CI: 0.89 to 68.8) Absolute effect 48 more per 1000 (from 1 fewer to 481 more)

Abbreviations: CI, confidence interval; MD, mean difference; RCT, randomised controlled trial; RR, relative risk.

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1315 1316

Summary GRADE profile 38 Sevelamer hydrochloride high-dose compared with sevelamer hydrochloride low-dose Outcome

Number of Studies

Number of patients Sevelamer high-dose

Sevelamer low-dose

Adherence (number of patients considered adherent) 6-week follow-up

1 RCT Chow et al, 2007

8/9 (88.9%)

16/18 (88.9%)

Effect

Quality

Relative effect RR = 1 (95% CI: 0.75 to 1.33) Absolute effect 0 fewer per 1000 (from 222 fewer to 293 more)

Very low

Effect

Quality

Absolute effect

Very low

Abbreviations: CI, confidence interval; MD, mean difference; RCT, randomised controlled trial; RR, relative risk.

1317 1318

Summary GRADE profile 39 Lanthanum compared with placebo Outcome

Number of Studies

Number of patients Lanthanum

Placebo

Serum phosphate 4- to 7-week follow-up

4 RCTs Al Baaj et al, 2005 Chiang et al, 2005 Joy et al, 2003 Shigematsu et al, 2008

207

125

Adherence (number of patients considered adherent) 4-week follow-up

1 RCT Al-Baaj et al, 2005

16/17 (94.1%)

18/19 (94.7%)

Relative effect RR = 0.99 (95% CI: 0.85 to 1.16) Absolute effect 9 fewer per 1000 (from 142 fewer to 152 more)

Very low

Adverse event â&#x20AC;&#x201C; constipation

1 RCT

24/111

1/31

Relative effect

Very low

MD = 0.66 mmol/l lower (95% CI: 0.86 to 0.47 lower)

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(number of patients to experience adverse event) 6-week follow-up

Shigematsu et al, 2008

(21.6%)

(3.2%)

RR = 6.70 (95% CI: 0.94 to 47.6) Absolute effect 184 more per 1000 (from 2 fewer to 1000 more)

Adverse event â&#x20AC;&#x201C; diarrhoea (number of patients to experience adverse event) 4- to 104-week follow-up

3 RCTs Shigematsu et al, 2008 Finn et al, 2004 Joy et al, 2002

12/273 (4.4%)

13/107 (12.1%)

Relative effect RR = 0.32 (95% CI: 0.15 to 0.66) Absolute effect 83 fewer per 1000 (from 41 fewer to 103 fewer)

Very low

Adverse event - nausea and vomiting (number of patients to experience adverse event) 4- to 104-week follow-up

3 RCTs Shigematsu et al, 2008 Finn et al, 2004 Joy et al, 2002

71/273 (26%)

15/107 (14%)

Relative effect

Very low

Adverse event - upper abdominal pain (number of patients to experience adverse event) 6- to 104-week follow-up

2 RCTs Finn et al, 2004 Shigematsu et al, 2008

9/224 (4%)

1/63 (1.6%)

Relative effect RR = 1.48 (95% CI: 0.26 to 8.57) Absolute effect

Serum calcium 8-week follow-up

1 RCT Al-Baaj et al, 2005

RR = 2.12 (95% CI: 0.27 to 16.53) Absolute effect 157 more per 1000 (from 102 fewer to 1000 more) Very low

8 more per 1000 (from 12 fewer to 120 more) 44

Absolute effect MD = 0.09 mmol/l higher (95% CI: 0.01 to 0.17 higher)

Very low

Effect

Quality

Relative effect HR = 0.86 (95% CI: 0.68 to 1.08)

Low

Abbreviations: CI, confidence interval; MD, mean difference; RCT, randomised controlled trial; RR, relative risk.

1319 1320

Summary GRADE profile 40 Lanthanum compared with any other binder Outcome Mortality 40-month follow-up

Number of Studies

Number of patients Lanthanum

Any other binder

1 RCT Wilson et al,

135/680 (19.9%)

157/674 (23.3%)

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2009

Mortality - in those > 65 years 40-month follow-up

1 RCT Wilson et al, 2009

Absolute effect 29 fewer per 1000 (from 68 fewer to 16 more) 44/163 (27%)

68/173 (39.3%)

Relative effect HR = 0.68 (95% CI: 0.46 to 0.99) Absolute effect

Very low

105 fewer per 1000 (from 3 fewer to 188 fewer) Mortality - in those < 65 years 40-month follow-up

1 RCT Wilson et al, 2009

91/507 (17.9%)

89/501 (17.8%)

Relative effect HR = 1.00 (95% CI: 0.75 to 1.34) Absolute effect 0 fewer per 1000 (from 41 fewer to 53 more)

Very low

Adverse events - diarrhoea (number of patients to experience adverse event) 2-year follow-up

1 RCT Finn et al, 2006

164/682 (24%)

217/677 (32.1%)

Relative effect RR = 0.75 (95% CI: 0.63 to 0.9) Absolute effect 80 fewer per 1000 (from 32 fewer to 119 fewer)

Low

Adverse events - nausea and vomiting (number of patients to experience adverse event) 2-year follow-up

1 RCT Finn et al, 2006

434/682 (63.6%)

470/677 (69.4%)

Relative effect RR = 0.92 (95% CI: 0.85 to 0.99) Absolute effect

Low

Adverse events - upper abdominal pain (number of patients to experience adverse event) 2-year follow-up

1 RCT Finn et al, 2006

56 fewer per 1000 (from 7 fewer to 104 fewer) 119/682 (17.4%)

161/677 (23.8%)

Relative effect

Very low

RR = 0.68 (95% CI: 0.52 to 0.88) Absolute effect 76 fewer per 1000 (from 29 fewer to 114 fewer)

Abbreviations: CI, confidence interval; RCT, randomised controlled trial; RR, relative risk; HR, Hazard ratio.

1321

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1322

Summary GRADE profile 41 Lanthanum compared with calcium carbonate Outcome

Number of Studies

Number of patients

Effect

Quality

Lanthanum

Calcium carbonate

Serum phosphate 8-week follow-up

1 RCT Shigematsu et al, 2008

126

132

Absolute effect MD = 0.08 mmol/l higher (95% CI: 0.03 lower to 0.19 higher)

Very low

Adverse events - abdominal distension (number of patients to experience adverse event) 8-week follow-up

1 RCT Shigematsu et al, 2008

3/126 (2.4%)

5/132 (3.8%)

Relative effect RR = 0.63 (95% CI: 0.15 to 2.58) Absolute effect

Very low

Adverse events â&#x20AC;&#x201C; constipation (number of patients to experience adverse event) 8- to 52-week follow-up

3 RCTs Freemont et al, 2005 Hutchison et al, 2005 Shigematsu et al, 2008

40/708 (5.6%)

33/448 (7.4%)

Relative effect RR = 0.77 (95% CI: 0.48 to 1.21) Absolute effect 17 fewer per 1000 (from 38 fewer to 15 more)

Very low

Adverse events â&#x20AC;&#x201C; diarrhoea (number of patients to experience adverse event) 20- to 52-week follow-up

2 RCTs Freemont et al, 2005 Hutchison et al, 2005

71/582 (12.2%)

30/316 (9.5%)

Relative effect RR = 1.26 (95% CI: 0.84 to 1.89) Absolute effect 25 more per 1000 (from 15 fewer to 84 more)

Very low

Adverse events - nausea and vomiting (number of patients to experience adverse event) 8- to 52-week follow-up

3 RCTs Freemont et al, 2005 Hutchison et al, 2005 Shigematsu et al, 2008

221/708 (31.2%)

76/448 (17%)

Relative effect RR = 2.17 (95% CI: 1.02 to 4.6) Absolute effect

Very low

Adverse events - upper abdominal pain (number of patients to experience adverse event) 8-week follow-up

1 RCT Shigematsu et al, 2008

4/126 (3.2%)

14 fewer per 1000 (from 32 fewer to 60 more)

198 more per 1000 (from 3 more to 611 more) 7/132 (5.3%)

Management of hyperphosphataemia: NICE clinical guideline DRAFT (October 2012)

Relative effect

Very low

RR = 0.60 (95% CI: 0.18 to 2) Absolute effect 21 fewer per 1000 (from 43 fewer to 53

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more) Serum calcium (number of patients with hypercalcaemia) 8-month follow-up (mean)

4 RCTs Freemont et al, 2005 Hutchison et al, 2005 Shigematsu et al, 2008 Spasovski et al, 2006

12/715 (1.7%)

122/456 (26.8%)

Relative effect

Very low

RR = 0.09 (95% CI: 0.03 to 0.27) Absolute effect 243 fewer per 1000 (from 195 fewer to 260 fewer)

Abbreviations: CI, confidence interval; MD, mean difference; RCT, randomised controlled trial; RR, relative risk.

1323 1324

Summary GRADE profile 43 Magnesium carbonate compared with calcium carbonate Outcome

Serum calcium (number of patients with hypercalcaemia) 6-month follow-up

Number of Studies

Number of patients Magnesium carbonate

Calcium carbonate

1 RCT Tzanakis et al, 2008

9/14 (64.3%)

12/13 (92.3%)

Effect

Quality

Relative effect RR = 0.37 (95% CI: 0.17 to 0.76) Absolute effect 582 fewer per 1000 (from 222 fewer to 766 fewer)

Very low

Abbreviations: CI, confidence interval; RCT, randomised controlled trial; RR, relative risk .

1325

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1326

Multiple treatment comparisons (serum phosphate and serum calcium)

1327

As there was a lack of evidence allowing a direct comparison between all of the possible treatments, a series of MTCs were carried

1328

out to aid the GDG decision-making process process (for further information on MTCs, please see glossary on page 235). Due to

1329

the use of continuous measures and the wide range of follow-up times presented within the evidence base, it was not possible to

1330

develop a single network which assessed all of the treatments at the various different time-points. Therefore, a series of network

1331

analyses were carried out at 3 months (90 days), 6 months (180 days) and 12 months (360 days). These analyses utilised the data

1332

available at each of these time points, and as a result, the interventions under consideration at each of these time points varied. In

1333

order to facilitate the construction of complete networks, it was decided that the comparators, “Standard Therapy” and “Calcium

1334

Based Binder”, should be analysed as a meta-class, “Any/Calcium based binders”. This assumption was made on the basis that

1335

within the relevant trials21 over 75% of the binders taken within the standard therapy arms were actually calcium based. MTC

1336

analyses were also carried out on the dichotomous outcomes of proportion of people with phosphate controlled and the risk of

1337

hypercalcaemia.

1338

The models used were based upon preliminary work carried out by NICE's technical support unit (appendix G). In brief, a standard

1339

network meta-analysis model in WinBUGS was used, utilising a previously published code (Dias et al 2011 22). The results

1340

presented below are those generated from a fixed effect analysis, which was recommended in the initial work carried out by the

1341

Technical Support Unit. 21

Finn 2006, Malluche 2008 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 22

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1342 1343 1344

Network binder map serum phosphate at 90 days patients CKD stage 5 on dialysis A total of 13 studies were included within the network allowing 8 treatments to be assessed against each other. 1 study

LC 1 study

Any/CB

1 study

2 studies 2 studies

1 study

3 studies

1 study

CAMG

1345 1346 1347 1348

Abbreviations: Any/CB, Any/calcium-based binder; CA, calcium acetate; CAMG, calcium acetate + magnesium carbonate; CC, calcium carbonate; LC, lanthanum carbonate; MG, magnesium carbonate; SC, sevelamer carbonate; SH, sevelamer hydrochloride

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1349

Summary GRADE profile 44 Quality of comparisons within the network Outcome

Number of Studies

Serum phosphate (follow up 90 days)

13 RCTs

Limitations very serious

Inconsistency 2,3

serious

Indirectness serious

Imprecision

Quality

no serious

very low

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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1352

Mean difference matrix: serum phosphate at 90 days Calcium Carbonate

Any / calciumbased 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 / calciumbased 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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1354

Probability rank: serum phosphate at 90 days Intervention

Probability best binder

Median rank (95%CI)

Sevelamer carbonate

0.991

1 (1, 1)

Calcium acetate+magnesium carbonate

0.000

2 (2, 3)

Magnesium carbonate

0.009

3 (2, 8)

Sevelamer hydrochloride

0.000

4 (3, 6)

Calcium acetate

0.000

5 (3, 6)

Any / calcium-based binders

0.000

5 (3, 7)

Calcium carbonate

0.000

7 (5, 8)

Lanthanum carbonate

0.000

8 (7, 8)

Abbreviations: CI, credibility interval.

1355 1356

Relative effectiveness compared to calcium carbonate: serum phosphate at 90 days

1357

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1358 1359 1360

Network binder map serum Phosphate at 180 days patients CKD stage 5 on dialysis A total of 12 studies were included within the network allowing 8 treatments to be assessed against each other.

LC 1 study

MG 1 study

1 study

Any/CB

2 studies

CC 2 studies

2 studies

SH 1 study

1 study

CAMG

1361 1362 1363 1364

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1365

Summary GRADE profile 45 Quality of comparisons within the network Outcome

Number of Studies

Serum phosphate (follow up 180 days)

12 RCTs

Limitations very serious

Inconsistency 2,3

serious

Indirectness serious

Imprecision

Quality

no serious

very low

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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1367

Mean difference matrix: serum phosphate at 180 days Calcium carbonate

Any / calciumbased binders

Lanthanum carbonate

Sevelamer hydrochloride

Calcium acetate

Calcium acetate+ magnesium carbonate

Sevelamer carbonate

Magnesium carbonate

Calcium carbonate

-0.065 mmol/l (95%CI: -0.262, 0.132)

0.006 mmol/l (95%CI: 0.132, 0.145)

-0.098 mmol/l (95%CI: -0.263, 0.066)

-0.097 mmol/l (95%CI: -0.389, 0.194)

-0.148 mmol/l (95%CI: -0.378, 0.081)

-0.088 mmol/l (95%CI: -0.298, 0.120)

-0.070 mmol/l (95%CI: -0.253, 0.113)

Any / calciumbased binders

0.072 mmol/l (95%CI: 0.127, 0.269)

-0.033 mmol/l (95%CI: -0.192, 0.126)

-0.032 mmol/l (95%CI: -0.339, 0.273)

-0.083 mmol/l (95%CI: -0.308, 0.142)

-0.023 mmol/l (95%CI: -0.228, 0.181)

-0.005 mmol/l (95%CI: -0.275, 0.264)

Lanthanum carbonate

-0.104 mmol/l (95%CI: -0.297, 0.087)

-0.103 mmol/l (95%CI: -0.415, 0.207)

-0.154 mmol/l (95%CI: -0.404, 0.096)

-0.094 mmol/l (95%CI: -0.327, 0.136)

-0.076 mmol/l (95%CI: -0.306, 0.153)

Sevelamer hydrochloride

0.001 mmol/l (95%CI: -0.268, 0.269)

-0.050 mmol/l (95%CI: -0.209, 0.110)

0.010 mmol/l (95%CI: -0.119, 0.138)

0.028 mmol/l (95%CI: -0.218, 0.275)

Calcium acetate

-0.051 mmol/l(95%CI: 0.364, 0.262)

0.009 mmol/l (95%CI: -0.289, 0.307)

0.027 mmol/l (95%CI: -0.318, 0.372)

Calcium acetate+ magnesium carbonate

0.060 mmol/l (95%CI: -0.145, 0.264)

0.078 mmol/l (95%CI: -0.216, 0.373)

Sevelamer carbonate

0.018 mmol/l (95%CI: -0.259, 0.297)

Magnesium carbonate

1368 1369

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1370

Probability rank: serum phosphate at 180 days Intervention

Probability best binder

Median rank (95%CI)

Calcium acetate+magnesium carbonate

0.363

2 (1, 8)

Sevelamer hydrochloride

0.032

4 (1, 7)

Calcium acetate

0.255

4 (1, 8)

Sevelamer carbonate

0.100

4 (1, 8)

Any / calcium-based binders

0.071

5 (1, 8)

Magnesium carbonate

0.163

5 (1, 8)

Lanthanum carbonate

0.013

7 (2, 8)

Calcium carbonate

0.003

7 (3, 8)

Abbreviations: CI, credibility interval.

1371 1372

Relative effectiveness compared to calcium carbonate: serum phosphate at 180 days

1373

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1374 1375

Multiple treatment comparison: serum phosphate at 360 days

1376

A total of 13 studies were included within the network allowing 5 treatments to be assessed against each other.

2 studies

1 study

Any/CB

3 studies

2 studies

3 studies

1377 1378 1379

Abbreviations: Any/CB, Any/calcium-based binder; CA, calcium acetate; CC, calcium carbonate; LC, lanthanum carbonate; SH, sevelamer hydrochloride

1380

Summary GRADE profile 46 Quality of comparisons within the network Outcome Serum phosphate (follow up 360 days)

Number of Studies 13 RCTs

Limitations very serious

Inconsistency 2,3

serious

Indirectness serious

Imprecision

Quality

no serious

very low

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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1382

Mean difference matrix: serum phosphate at 360 days Calcium carbonate

Any / calcium-based binders

Lanthanum carbonate

Sevelamer hydrochloride

Calcium acetate

Calcium carbonate

0.073 mmol/l (95%CI: 0.058, 0.203)

0.191 mmol/l (95%CI: 0.030, 0.353)

0.031 mmol/l (95%CI: 0.047, 0.109)

-0.029 mmol/l (95%CI: 0.182, 0.124)

Any / calcium-based binders

0.118 mmol/l (95%CI: 0.063, 0.300)

-0.042 mmol/l (95%CI: 0.153, 0.069)

-0.102 mmol/l (95%CI: 0.276, 0.073)

Lanthanum carbonate

-0.160 mmol/l (95%CI: 0.331, 0.010)

-0.220 mmol/l (95%CI: 0.436, -0.005)

Sevelamer hydrochloride

-0.060 mmol/l (95%CI: 0.194, 0.075)

Calcium acetate

1383 1384

Probability rank: serum phosphate at 360 days Intervention

Probability best binder

Median rank (95%CI)

Calcium acetate

0.612

1 (1, 4)

Calcium carbonate

0.303

2 (1, 4)

Sevelamer hydrochloride

0.036

3 (1, 4)

Any / calcium-based binders

0.046

4 (1, 5)

Lanthanum carbonate

0.004

5 (3, 5)

Abbreviations: CI, credibility interval.

1385

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1386

Relative effectiveness compared to calcium carbonate: serum phosphate at 360 days Calcium acetate Sevelamer hydrochloride Lanthanum carbonate Any / calcium-based binders

-1 1387 1388

-0.5

0.5

MD (mmol/l) v. calcium carbonate

1389

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1390

Multiple treatment comparison: serum calcium at 90 days

1391

A total of 10 studies were included within the network allowing 7 treatments to be assessed against each other.

CC 2 studies 2 studies

1 study

Any/CB

3 studies

1 study

CAMG 1392 1393 1394 1395 1396

Abbreviations: Any/CB, Any/calcium-based binder ; CA, calcium acetate; CAMG, calcium acetate + magnesium carbonate; CC, calcium carbonate; LC, lanthanum carbonate; MG, magnesium carbonate; SH, sevelamer hydrochloride

1397

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1398

Summary GRADE profile 47 Quality of comparisons within the network Outcome

Number of Studies

Serum calcium (follow up 90 days)

10 RCTs

Limitations very serious

Inconsistency 2,3

serious

Indirectness serious

Imprecision

Quality

no serious

very low

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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1400

Mean difference matrix: serum calcium at 90 days Calcium carbonate

Any / calciumbased binders

Lanthanum carbonate

Sevelamer hydrochloride

Calcium acetate

Calcium acetate+ magnesium carbonate

Magnesium carbonate

Calcium carbonate

-0.080 mmol/l (95%CI: -0.200, 0.040)

-0.170 mmol/l (95%CI: -0.293, 0.048)

-0.120 mmol/l (95%CI: -0.181, 0.058)

-0.050 mmol/l (95%CI: -0.127, 0.028)

-0.037 mmol/l (95%CI: -0.114, 0.040)

-0.060 mmol/l (95%CI: -0.215, 0.095)

Any / calcium-based binders

-0.090 mmol/l (95%CI: -0.116, 0.064)

-0.040 mmol/l (95%CI: -0.143, 0.063)

0.030 mmol/l (95%CI: -0.083, 0.143)

0.042 mmol/l (95%CI:-0.070, 0.156)

0.020 mmol/l (95%CI: -0.156, 0.195)

Lanthanum carbonate

0.050 mmol/l (95%CI: -0.056, 0.157)

0.120 mmol/l (95%CI: 0.004, 0.236)

0.133 mmol/l (95%CI: 0.018, 0.249)

0.110 mmol/l (95%CI: -0.068, 0.287)

Sevelamer hydrochloride

0.070 mmol/l (95%CI: 0.023, 0.117)

0.083 mmol/l (95%CI: 0.036, 0.130)

0.060 mmol/l (95%CI: -0.082, 0.202)

Calcium acetate

0.013 mmol/l (95%CI: -0.054, 0.079)

-0.010 mmol/l (95%CI: -0.145, 0.124)

Calcium acetate+ magnesium carbonate

-0.023 mmol/l (95%CI: -0.173, 0.127)

Magnesium carbonate

1401 1402

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1403

Probability rank: serum calcium at 90 days Intervention

Probability best binder

Median rank (95%CI)

Lanthanum carbonate

0.771

1 (1, 3)

Sevelamer hydrochloride

0.141

2 (1, 4)

Any / calcium-based binders

0.000

3 (2, 7)

Magnesium carbonate

0.089

4 (1, 7)

Calcium acetate

0.000

5 (3, 7)

Calcium acetate+magnesium carbonate

0.000

5 (3, 7)

Calcium carbonate

0.000

7 (4, 7)

Abbreviations: CI, credibility interval.

1404 1405

Relative effectiveness compared to calcium carbonate: serum calcium at 90 days

1406 1407

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1408

Multiple treatment comparison: serum calcium at 180 days

1409

A total of 9 studies were included within the network allowing 8 treatments to be assessed against each other.

MG 1 study

1 study

1 study 2 studies

1 study

Any/CB 1 study

SC 1410 1411 1412 1413 1414

1 study

CAMG

Abbreviations: Any/CB, any/calcium-based binder ;CA, calcium acetate; CAMG, calcium acetate + magnesium carbonate;; CC, calcium carbonate; LC, lanthanum carbonate; MG, magnesium carbonate; SH, sevelamer hydrochloride; SC, sevelamer carbonate

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1415

Summary GRADE profile 48 Quality of comparisons within the network Outcome

Number of Studies

Serum calcium (follow up 180 days)

9RCTs

Limitations very serious

Inconsistency 2,3

serious

Indirectness serious

Imprecision

Quality

no serious

very low

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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1417

Mean difference matrix: serum calcium at 180 days Calcium carbonate

Any / calciumbased binders

Lanthanum carbonate

Sevelamer hydrochloride

Calcium acetate

Calcium acetate+ magnesium carbonate

Sevelamer carbonate

Magnesium carbonate

Calcium carbonate

-0.155 mmol/l (95%CI: -0.284, -0.027)

-0.259 mmol/l (95%CI: -0.392, -0.129)

-0.115 mmol/l (95%CI: -0.183, -0.048)

-0.179 mmol/l (95%CI: -0.315, -0.043)

-0.048 mmol/l (95%CI: -0.128, 0.031)

-0.135 mmol/l (95%CI: -0.222, -0.049)

-0.260 mmol/l (95%CI: -0.328, -0.192)

Any / calciumbased binders

-0.104 mmol/l (95%CI: -0.131, -0.078)

0.040 mmol/l (95%CI: -0.069, 0.149)

-0.024 mmol/l (95%CI: -0.204, 0.155)

0.107 mmol/l (95%CI: -0.010, 0.224)

0.020 mmol/l (95%CI: -0.102, 0.140)

-0.105 mmol/l (95%CI: -0.250, 0.041)

Lanthanum carbonate

0.144 mmol/l (95%CI: 0.032, 0.256)

0.080 mmol/l (95%CI: -0.101, 0.261)

0.211 mmol/l (95%CI: 0.092, 0.331)

0.124 mmol/l (95%CI: 0.000, 0.248)

-0.001 mmol/l (95%CI: -0.148, 0.148)

Sevelamer hydrochloride

-0.064 mmol/l (95%CI: -0.206, 0.078)

0.067 mmol/l (95%CI: 0.025, 0.109)

-0.020 mmol/l (95%CI: -0.074, 0.034)

-0.145 mmol/l (95%CI: -0.241, -0.048)

Calcium acetate

0.131 mmol/l (95%CI: -0.017, 0.279)

0.044 mmol/l (95%CI: -0.108, 0.196)

-0.081 mmol/l (95%CI: -0.233, 0.071)

Calcium acetate+ magnesium carbonate

-0.087 mmol/l (95%CI: -0.155, -0.019)

-0.212 mmol/l (95%CI: -0.316, -0.107)

Sevelamer carbonate

-0.125 mmol/l (95%CI: -0.235, -0.014)

Magnesium carbonate

1418 1419

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1420

Probability rank: serum calcium at 180 days Intervention

Probability best binder

Median rank (95%CI)

Lanthanum carbonate

0.463

2 (1, 3)

Magnesium carbonate

0.456

2 (1, 4)

Calcium acetate

0.081

3 (1, 7)

Any / calcium-based binders

0.000

4 (2, 7)

Sevelamer carbonate

0.001

5 (3, 6)

Sevelamer hydrochloride

0.000

5 (4, 6)

Calcium acetate+magnesium carbonate

0.000

7 (6, 8)

Calcium carbonate

0.000

8 (7, 8)

Abbreviations: CI, credibility interval.

1421 1422

Relative effectiveness compared to calcium carbonate: serum calcium at 180 days

1423

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1424

Multiple treatment comparison: serum calcium at 360 days

1425

A total of 12 studies were included within the network allowing 5 treatments to be assessed against each other.

2 studies

Any/CB

2 studies

1 study

2 studies

3 studies

1426 1427 1428 1429

Abbreviations: Any/CB, Any/Calcium Based binder; CA, calcium acetate; CC, calcium carbonate; LC, lanthanum carbonate; SH, sevelamer hydrochloride

1430

Summary GRADE profile 49 Quality of comparisons within the network Outcome

Number of Studies

Serum calcium (follow up 360 days)

12RCTs

Limitations very serious

Inconsistency 2,3

serious

Indirectness serious

Imprecision

Quality

no serious

very low

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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1432

Mean difference matrix: serum calcium at 180 days Calcium carbonate

Any / calcium-based binders

Lanthanum carbonate

Sevelamer hydrochloride

Calcium acetate

Calcium carbonate

-0.016 mmol/l (95%CI: 0.062, 0.030)

-0.083 mmol/l (95%CI: -0.131, -0.034)

-0.099 mmol/l (95%CI: -0.133, -0.065)

-0.049 mmol/l (95%CI: 0.100, 0.002)

Any / calcium-based binders

-0.066 mmol/l (95%CI: -0.090, -0.042)

-0.083 mmol/l (95%CI: -0.119, -0.046)

-0.033 mmol/l (95%CI: 0.086, 0.020)

Lanthanum carbonate

-0.016 mmol/l (95%CI: -0.058, 0.025)

0.033 mmol/l (95%CI: -0.023, 0.090)

Sevelamer hydrochloride

0.050 mmol/l (95%CI: 0.011, 0.089)

Calcium acetate

1433 1434

Probability rank: serum calcium at 360 days Intervention

Probability best binder

Median rank (95%CI)

Sevelamer hydrochloride

0.775

1 (1, 2)

Lanthanum carbonate

0.220

2 (1, 3)

Calcium acetate

0.005

3 (2, 4)

Any / calcium-based binders

0.000

4 (3, 5)

Calcium carbonate

0.000

5 (4, 5)

Abbreviations: CI, credibility interval.

1435

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1436

Relative effectiveness compared to calcium carbonate: serum calcium at 360 days

1437 1438 1439

Multiple treatment comparison: proportion of patients achieving phosphate control

1440

A total of 15 studies were included within the network allowing 9 treatments to be assessed against each other. One of the trials

1441

included within the analysis was concerned with different dosages of sevelamer hydrochloride and this data was included within

1442

that one node.

1443

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Any-B 1 study

MG 1 study

1 study 1 study

1 study

2 studies

5 studies

SH+CC

SH 1 study

SC 1444 1445 1446 1447 1448

Abbreviations: Any-B, any binder; CA, calcium acetate; CC, calcium carbonate; LC, lanthanum carbonate; MG, magnesium carbonate; P, placebo; SH, sevelamer hydrochloride; SH+CC, sevelamer hydrochloride + calcium carbonate; SC, Sevelamer carbonate

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1449

Summary GRADE profile 50 Quality of comparisons within the network Outcome

Number of Studies

Proportion of patients achieving phosphate control

15RCTs

Limitations very serious

Inconsistency 2,3

serious

Indirectness serious

Imprecision

Quality

no serious

very low

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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1451

Hazard ratio matrix: proportion achieving phosphate control Placebo

Calcium carbonate

Any binder

Lanthanum carbonate

Sevelamer hydrochloride

Calcium acetate

Sevelamer hydrochloride+ calcium carbonate

Sevelamer carbonate

Magnesium carbonate

Placebo

0.274 (95%CI: 0.194, 0.387)

0.238 (95%CI: 0.176, 0.324)

0.284 (95%CI: 0.210, 0.384)

0.338 (95%CI: 0.155, 0.739)

0.317 (95%CI: 0.143, 0.707)

0.133 (95%CI: 0.051, 0.330)

0.470 (95%CI: 0.190, 1.173)

0.209 (95%CI: 0.077, 0.566)

Calcium carbonate

0.868 (95%CI: 0.726, 1.040)

1.034 (95%CI: 0.873, 1.227)

1.230 (95%CI: 0.613, 2.486)

1.154 (95%CI: 0.562, 2.379)

0.485 (95%CI: 0.198, 1.123)

1.715 (95%CI: 0.745, 3.987)

0.761 (95%CI: 0.300, 1.933)

Any binder

1.191 (95%CI: 1.124, 1.261)

1.417 (95%CI: 0.691, 2.928)

1.330 (95%CI: 0.634, 2.797)

0.558 (95%CI: 0.224, 1.319)

1.973 (95%CI: 0.842, 4.678)

0.876 (95%CI: 0.340, 2.262)

Lanthanum carbonate

1.190 (95%CI: 0.581, 2.452)

1.116 (95%CI: 0.534, 2.343)

0.469 (95%CI: 0.188, 1.105)

1.656 (95%CI: 0.709, 3.920)

0.736 (95%CI: 0.286, 1.899)

Sevelamer hydrochloride

0.941 (95%CI: 0.609, 1.431)

0.393 (95%CI: 0.157, 0.939)

1.390 (95%CI: 0.887, 2.242)

0.618 (95%CI: 0.223, 1.736)

Calcium acetate

0.419 (95%CI: 0.158, 1.052)

1.483 (95%CI: 0.797, 2.816)

0.658 (95%CI: 0.245, 1.810)

Sevelamer hydrochloride + calcium carbonate

3.553 (95%CI: 1.326, 9.923)

1.574 (95%CI: 0.474, 5.426)

Sevelamer carbonate

0.443 (95%CI: 0.144, 1.368)

Magnesium carbonate

1452

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1453

Probability rank: proportion achieving phosphate control Intervention

Probability best binder

Median rank (95%CI)

Sevelamer hydrochloride + calcium carbonate

0.732

1 (1, 5)

Magnesium carbonate

0.212

2 (1, 8)

Any binder

0.042

3 (1, 6)

Calcium carbonate

0.001

4 (3, 7)

Lanthanum carbonate

0.000

5 (3, 8)

Calcium acetate

0.009

6 (2, 8)

Sevelamer hydrochloride

0.003

6 (2, 8)

Sevelamer carbonate

0.001

8 (4, 9)

Placebo

0.000

9 (8, 9)

Abbreviations: CI, credibility interval.

1454

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1455

Relative effectiveness compared to placebo: proportion achieving phosphate control

1456 1457

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1458

Multiple treatment comparison: risk of hypercalcaemia

1459

A total of 16 studies were included within the network allowing 7 treatments to be assessed against each other.

C-Based

5 studies

CA 1 study

2 studies

2 studies 4 studies

1 study

SH+CC 1460 1461 1462 1463

CC 1 study

Abbreviations: C-Based, calcium based; CA, calcium acetate; CC, calcium carbonate; LC, lanthanum carbonate; MG, magnesium carbonate; SH, sevelamer hydrochloride; SH+CC, sevelamer hydrochloride + calcium carbonate

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1464

Summary GRADE profile 51 Quality of comparisons within the network Outcome

Number of Studies

Risk of hypercalcaemia

16RCTs

Limitations very serious

Inconsistency 2,3

serious

Indirectness

serious

Imprecision

Quality

no serious

very low

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 4 Surrogate marker used 5 Inconsistency could not be appraised Abbreviations: RCT, randomised controlled trial.

1465 1466

Hazard ratio matrix: risk of hypercalcaemia Calcium carbonate

Calcium-based binders

Lanthanum carbonate

Sevelamer hydrochloride

Calcium acetate

Sevelamer hydrochloride + calcium carbonate

Magnesium carbonate

Calcium carbonate

1.412 (95%CI: 0.704, 2.915)

0.059 (95%CI: 0.031, 0.104)

0.436 (95%CI: 0.282, 0.663)

1.031 (95%CI: 0.612, 1.742)

0.386 (95%CI: 0.177, 0.795)

0.231 (95%CI: 0.080, 0.593)

Calcium-based binders

0.042 (95%CI: 0.016, 0.103)

0.309 (95%CI: 0.171, 0.531)

0.732 (95%CI: 0.365, 1.413)

0.272 (95%CI: 0.098, 0.715)

0.163 (95%CI: 0.045, 0.532)

Lanthanum carbonate

7.347 (95%CI: 3.600, 15.910)

17.440 (95%CI: 8.062, 39.900)

6.521 (95%CI: 2.488, 17.180)

3.912 (95%CI: 1.164, 12.250)

Sevelamer hydrochloride

2.366 (95%CI: 1.638, 3.466)

0.885 (95%CI: 0.384, 1.957)

0.531 (95%CI: 0.169, 1.497)

Calcium acetate

0.373 (95%CI: 0.152, 0.874)

0.223 (95%CI: 0.068, 0.660)

Sevelamer hydrochloride + calcium carbonate

0.600 (95%CI: 0.166, 2.036)

Magnesium carbonate

1467

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1468

Probability rank: risk of hypercalcaemia Intervention

Probability best binder

Median rank (95%CI)

Lanthanum carbonate

0.986

1 (1, 1)

Magnesium carbonate

0.014

2 (2, 4)

Sevelamer hydrochloride+calcium carbonate

0.000

3 (2, 4)

Sevelamer hydrochloride

0.000

4 (2, 4)

Calcium carbonate

0.000

5 (5, 7)

Calcium acetate

0.000

6 (5, 7)

Calcium-based binders

0.000

7 (5, 7)

Abbreviations: CI, credibility interval

1469 1470

Relative effectiveness compared to calcium carbonate: risk of hypercalcaemia

1471

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1472

See appendix E for the evidence tables and GRADE profiles in full.

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3.5.3

Evidence statements

1474

For details of how the evidence is graded, see â&#x20AC;&#x2DC;The guidelines manualâ&#x20AC;&#x2122;.

1475

Use of phosphate binders in children with stage 5 CKD who are on

1476

dialysis

1477

Calcium carbonate compared with sevelamer

1478

Critical outcomes

1479

3.5.3.1

Very-low-quality evidence from 1 RCT of 29 patients showed no

1480

statistically significant difference in mean serum phosphate level

1481

between those that received calcium carbonate and those that

1482

received sevelamer at 8 months (MD 0.16 mmol/l higher ([95% CI -

1483

0.16 to 0.48]).

1484

Important outcomes

1485

3.5.3.2

Very-low-quality evidence from the RCT of 29 patients showed

1486

calcium carbonate to be associated with a mean serum calcium

1487

level 0.20 mmol/l higher (95% CI 0.10 to 0.32 i.e. statistically

1488

significant) than that associated with sevelamer at 8 months.

1489

Use of phosphate binders in adults with stage 5 CKD who are on dialysis

1490

Calcium acetate compared with placebo

1491

Critical outcomes

1492

3.5.3.3

Very-low-quality evidence from 1 RCT of 68 patients showed

1493

calcium acetate to be associated with mean serum phosphate

1494

levels 0.62 mmol/l lower (95% CI -0.90 to -0.34 i.e. statistically

1495

significant) at 2 weeks than that associated with placebo.

1496

Important outcomes

1497

3.5.3.4

1498

Very-low-quality evidence from the RCT of 68 patients showed calcium acetate to be associated with mean serum calcium levels

Management of hyperphosphataemia: NICE clinical guideline DRAFT (October 2012) Page 162 of 248

DRAFT FOR CONSULTATION 1499

0.15 mmol/l higher (95% CI 0.05 to 0.25 i.e. statistically significant)

1500

at 2 weeks than that associated with placebo.

1501

Calcium acetate compared with calcium carbonate

1502

Critical outcomes

1503

3.5.3.5

Very-low-quality evidence from 1 RCT of 15 patients showed no

1504

statistically significant difference in mean serum phosphate levels

1505

at 3 weeks between those that received calcium acetate and those

1506

that received calcium carbonate (MD 0.09 mmol/l lower [95% CI -

1507

0.45 to 0.27]).

1508

Important outcomes

1509

3.5.3.6

Very-low-quality evidence from the RCT of 15 patients showed no

1510

statistically significant difference in mean serum calcium levels at

1511

3 weeks between those that received calcium acetate and those

1512

that received calcium carbonate (MD 0.09 mmol/l higher [95% CI -

1513

0.13 to 0.31]).

1514

3.5.3.7

Very-low-quality evidence from 1 RCT of 27 patients showed no

1515

statistically significant difference in the risk of hypercalcaemia

1516

between those that received calcium acetate and those that

1517

received calcium carbonate over 12 months (RR 0.70 [95% CI 0.46

1518

to 1.06]).

1519

Calcium carbonate bread compared with calcium acetate

1520

Critical outcomes

1521

3.5.3.8

Very-low-quality evidence from 1 RCT of 53 patients showed

1522

calcium carbonate bread to be associated with mean serum

1523

phosphate levels 0.35 mmol/l lower (95% CI -0.40 to -0.30 i.e.

1524

statistically significant) at 8 weeks than that associated with calcium

1525

acetate.

1526

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DRAFT FOR CONSULTATION 1527

Important outcomes

1528

3.5.3.9

Very-low-quality evidence from the RCT of 53 patients showed

1529

calcium carbonate bread to be associated with mean serum

1530

calcium levels 0.65 mmol/l lower (95% CI -0.75 to -0.55 i.e.

1531

statistically significant) at 8 weeks than that associated with calcium

1532

acetate.

1533

Calcium carbonate compared with sevelamer + calcium carbonate

1534

Critical outcomes

1535

3.5.3.10

Very-low-quality evidence from 1 RCT of 46 patients showed

1536

calcium carbonate alone to be associated with mean serum

1537

phosphate levels 0.31 mmol/l higher (95% CI 0.05 to 0.57 i.e.

1538

statistically significant) at 4 weeks than that associated with

1539

sevelamer and calcium carbonate.

1540

Important outcomes

1541

3.5.3.11

Very-low-quality evidence from the RCT of 46 patients showed no

1542

statistically significant difference in mean serum calcium levels at

1543

4 weeks between those that received calcium carbonate alone and

1544

those that received sevelamer and calcium carbonate (MD

1545

0.02 mmol/l higher [95% CI -0.12 to 0.16 ]).

1546

Sevelamer + calcium carbonate (high-dose) compared with sevelamer +

1547

calcium carbonate (low-dose)

1548

Critical outcomes

1549

3.5.3.12

Very-low-quality evidence from 1 RCT of 51 patients showed no

1550

statistically significant difference in mean serum phosphate levels

1551

at 8 weeks between those that received a high dose of sevelamer

1552

and calcium carbonate and those that received a low dose of

1553

sevelamer and calcium carbonate (MD 0.10 mmol/l lower [95% CI -

1554

0.34 to 0.14]).

1555 Management of hyperphosphataemia: NICE clinical guideline DRAFT (October 2012) Page 164 of 248

DRAFT FOR CONSULTATION 1556

Important outcomes

1557

3.5.3.13

Very-low-quality evidence from the RCT of 51 patients showed no

1558

statistically significant difference in the risk of experiencing

1559

abdominal distension between those that received a high dose of

1560

sevelamer and calcium carbonate and those that received a low

1561

dose of sevelamer and calcium carbonate over 8 weeks (RR 1.27

1562

[95% CI 0.59 to 2.75]).

1563

3.5.3.14

Very-low-quality evidence from the RCT of 51 patients showed no

1564

statistically significant difference in the risk of experiencing

1565

constipation between those that received a high dose of sevelamer

1566

and calcium carbonate and those that received a low dose of

1567

sevelamer and calcium carbonate over 8 weeks (RR 1.10 [95% CI

1568

0.60 to 2.02]).

1569

3.5.3.15

Very-low-quality evidence from the RCT of 51 patients showed no

1570

statistically significant difference in mean serum calcium levels at

1571

8 weeks between those that received a high dose of sevelamer and

1572

calcium carbonate and those that received a low dose of sevelamer

1573

and calcium carbonate (MD 0.02 mmol/l higher [95% CI -0.34 to

1574

0.14]).

1575

Sevelamer compared with placebo

1576

Critical outcomes

1577

3.5.3.16

Very-low-quality evidence from 1 RCT of 36 patients showed

1578

sevelamer to be associated with a mean serum phosphate level

1579

0.52 mmol/l lower (95% CI -0.96 to -0.08 i.e. statistically significant)

1580

at 2 weeks than that associated with placebo.

1581

3.5.3.17

Very-low-quality evidence from the RCT of 36 patients showed no

1582

statistically significant difference in degree of adherence to

1583

prescription over 2 weeks between those that received sevelamer

1584

and those that received placebo (MD 4.00% above prescription

1585

[95% CI -6.75 to 14.75]). Management of hyperphosphataemia: NICE clinical guideline DRAFT (October 2012) Page 165 of 248

DRAFT FOR CONSULTATION 1586

Important outcomes

1587

3.5.3.18

Very-low-quality evidence from the RCT of 36 patients showed no

1588

statistically significant difference in the risk of experiencing

1589

diarrhoea over 2 weeks between those that received sevelamer

1590

and those that received placebo (RR 0.17 [95% CI 0.01 to 3.96]).

1591

3.5.3.19

Very-low-quality evidence from the RCT of 36 patients showed no

1592

statistically significant difference in the risk of experiencing upper

1593

abdominal pain over 2 weeks between those that received

1594

sevelamer and those that received placebo (RR 0.17 [95% CI 0.01

1595

to 3.96]).

1596

3.5.3.20

Very-low-quality evidence from the RCT of 36 patients showed no

1597

statistically significant difference in the risk of experiencing nausea

1598

and vomiting over 2 weeks between those that received sevelamer

1599

and those that received placebo (RR 0.50 [95% CI 0.03 to 7.32]).

1600

3.5.3.21

Very-low-quality evidence from the RCT of 36 patients showed no

1601

statistically significant difference in mean serum calcium levels at

1602

2 weeks between those that received sevelamer and those that

1603

received placebo (MD 0.03 mmol/l lower [95% CI -0.13 to 0.07]).

1604

Sevelamer compared with calcium-based binders

1605

Critical outcomes

1606

3.5.3.22

Low-quality evidence from 1 RCT of 2103 patients showed no

1607

statistically significant difference in mortality over 44 months

1608

between those that received sevelamer and those that received

1609

calcium-based binders (HR 0.93 [95% CI 0.79 to 1.10]).

1610

3.5.3.23

Very-low-quality evidence from the RCT of 2103 patients showed

1611

no statistically significant difference in cardiovascular mortality over

1612

44 months between those that received sevelamer and those that

1613

received calcium-based binders (HR 0.93 [95% CI 0.74 to 1.17]).

Management of hyperphosphataemia: NICE clinical guideline DRAFT (October 2012) Page 166 of 248

DRAFT FOR CONSULTATION 1614

3.5.3.24

Very-low-quality evidence from a sub-group of 1176 patients aged

1615

over 65 in the RCT of 2103 patients showed sevelamer to be

1616

associated with a smaller risk of mortality over 44 months than that

1617

associated with calcium-based binders (HR 0.77 [95% CI 0.61 to

1618

0.96 i.e. statistically significant]).

1619

3.5.3.25

Very-low-quality evidence from a sub-group of 1176 patients aged

1620

over 65 in the RCT of 2103 patients showed no statistically

1621

significant difference in cardiovascular mortality over 44 months

1622

between those that received sevelamer and those that received

1623

calcium-based binders (HR 0.78 [95% CI 0.58 to 1.05]).

1624

3.5.3.26

Very-low-quality evidence from a sub-group of 927 patients aged

1625

under 65 in the RCT of 2103 patients showed no statistically

1626

significant difference in mortality over 44 months between those

1627

that received sevelamer and those that received calcium-based

1628

binders (HR 1.18 [95% CI 0.91 to 1.53]).

1629

3.5.3.27

Very-low-quality evidence from a sub-group of 927 patients aged

1630

under 65 in the RCT of 2103 patients showed no statistically

1631

significant difference in cardiovascular mortality over 44 months

1632

between those that received sevelamer and those that received

1633

calcium-based binders (HR 1.19 [95% CI 0.82 to 1.73]).

1634

Important outcomes

1635

3.5.3.28

Very-low-quality evidence from the RCT of 2103 patients showed

1636

no statistically significant difference in the risk of experiencing

1637

nausea and vomiting over 3.75 years between those that received

1638

sevelamer and those that received calcium-based binders (RR 1.00

1639

[95% CI0.06 to 15.92]).

1640

3.5.3.29

Very-low-quality evidence from 9 RCTs of 1035 patients in total

1641

showed sevelamer to be associated with a smaller risk of

1642

hypercalcaemia over a mean of 8 months than that associated with

Management of hyperphosphataemia: NICE clinical guideline DRAFT (October 2012) Page 167 of 248

DRAFT FOR CONSULTATION 1643

calcium-based binders (RR 0.40 [0.31 to 0.52 i.e. statistically

1644

significant]).

1645

3.5.3.30

Low-quality evidence from 7 RCTs of 751 patients in total showed

1646

sevelamer to be associated with mean coronary artery calcification

1647

scores 124.13 lower (95% CI -205.88 to -42.38 i.e. statistically

1648

significant) than that associated with calcium-based binders when

1649

followed-up for 12 to 21 months.

1650

3.5.3.31

Very-low-quality evidence from a sub-group of 158 patients from

1651

3 RCTs who had baseline coronary artery calcification scores

1652

below 30 showed sevelamer to be associated with mean coronary

1653

artery calcification scores 210.52 lower (95% CI -382.36 to -38.69

1654

i.e. statistically significant) than that associated with calcium-based

1655

binders when followed-up for 12 to 18 months.

1656

3.5.3.32

Very-low-quality evidence from a sub-group of 64 patients with

1657

diabetes from 1 RCT showed no statistically significant difference in

1658

mean coronary artery calcification scores at 2 years between those

1659

that received sevelamer and those that received calcium-based

1660

binders (MD 289.00 lower [95% CI -651.99 to 73.99]).

1661

3.5.3.33

Very-low-quality evidence from a sub-group of 45 patients without

1662

diabetes from 1 RCT showed no statistically significant difference in

1663

mean coronary artery calcification scores at 2 years between those

1664

that received sevelamer and those that received calcium-based

1665

binders (MD 100.00 lower [95% CI -256.33 to 56.23]).

1666

Sevelamer compared with calcium carbonate

1667

Critical outcomes

1668

3.5.3.34

Very-low-quality evidence from 1 RCT of 36 patients showed no

1669

statistically significant difference in mean serum phosphate levels

1670

at 4 weeks between those that received sevelamer and those that

1671

received calcium carbonate (MD 0.04 mmol/l higher [95% CI -0.20

1672

to 0.28]). Management of hyperphosphataemia: NICE clinical guideline DRAFT (October 2012) Page 168 of 248

DRAFT FOR CONSULTATION 1673

3.5.3.35

Very-low-quality evidence from 1 RCT of 82 patients showed no

1674

statistically significant difference in adherence over 12 months

1675

between those that received sevelamer and those that received

1676

calcium carbonate (RR 1.02 [95% CI 0.84 to 1.23]).

1677

Important outcomes

1678

3.5.3.36

Very-low-quality evidence from 1 RCT of 56 patients showed no

1679

statistically significant difference in risk of experiencing abdominal

1680

distension over 4 weeks between those that received sevelamer

1681

and those that received calcium carbonate (RR 2.33 [95% CI 0.49

1682

to 11.01]).

1683

3.5.3.37

Very-low-quality evidence from 2 RCT of 239 patients in total

1684

showed sevelamer to be associated with a greater risk of

1685

experiencing constipation than that associated with calcium

1686

carbonate (RR 3.40 [95% CI 1.34 to 8.63 i.e. statistically

1687

significant]), when followed up for 4 to 52 weeks.

1688

3.5.3.38

Very-low-quality evidence from 1 RCT of 36 patients showed

1689

sevelamer to be associated with mean calcium level 0.24 mmol/l

1690

lower (95% CI -0.37 to â&#x20AC;&#x201C; 0.11 i.e. statistically significant) at 4 weeks

1691

than that associated with calcium carbonate.

1692

3.5.3.39

Very-low-quality evidence from 3 RCTs of 197 patients in total

1693

showed sevelamer to be associated with mean coronary artery

1694

calcification scores 250.11 lower (95% CI -480.63 to -19.59 i.e.

1695

statistically significant) than that associated with calcium carbonate

1696

at 12 months.

1697

Sevelamer compared with calcium acetate

1698

Critical outcomes

1699

3.5.3.40

1700

Very-low-quality evidence from 1 RCT of 70 patients showed no statistically significant difference in mean serum phosphate level

Management of hyperphosphataemia: NICE clinical guideline DRAFT (October 2012) Page 169 of 248

DRAFT FOR CONSULTATION 1701

between those that received sevelamer and those that received

1702

calcium acetate (MD 0.23 mmol/l higher [95% CI -0.10 to 0.56]).

1703

3.5.3.41

Very-low-quality evidence from 1 RCT of 106 patients showed no

1704

statistically significant difference in adherence over 12 months

1705

between those that received sevelamer and those that received

1706

calcium acetate (RR 1.62 [95% CI 0.65 to 4.02]).

1707

Important outcomes

1708

3.5.3.42

Low-quality evidence from 2 RCTs of 311 patients in total showed

1709

no statistically significant difference in risk of experiencing

1710

constipation over 12 months between those that received

1711

sevelamer and those that received calcium acetate (RR 1.15 [95%

1712

CI 0.38 to 3.48]).

1713

3.5.3.43

Low-quality evidence from the 2 RCTs of 311 patients in total

1714

showed no statistically significant difference in risk of experiencing

1715

nausea and vomiting over 12 months between those that received

1716

sevelamer and those that received calcium acetate (RR 0.86 [95%

1717

CI 0.61 to 1.21]).

1718

3.5.3.44

Low-quality evidence from the 2 RCTs of 311 patients in total

1719

showed no statistically significant difference in risk of experiencing

1720

diarrhoea over 12 months between those that received sevelamer

1721

and those that received calcium acetate (RR 0.91 [95% CI 0.56 to

1722

1.47]).

1723

3.5.3.45

Low-quality evidence from 1 RCT of 203 patients showed no

1724

statistically significant difference in risk of experiencing upper

1725

abdominal pain over 12 months between those that received

1726

sevelamer and those that received calcium acetate (RR 2.06 [95%

1727

CI 0.64 to 6.63]).

1728 1729

3.5.3.46

Very-low-quality evidence from 1 RCT of 70 patients showed no statistically significant difference in mean serum calcium level

Management of hyperphosphataemia: NICE clinical guideline DRAFT (October 2012) Page 170 of 248

DRAFT FOR CONSULTATION 1730

between those that received sevelamer and those that received

1731

calcium acetate (MD 0.15 mmol/l lower [95% CI -0.30 to 0.00]).

1732

3.5.3.47

Very-low-quality evidence from 2 RCTs of 337 patients in total

1733

showed no statistically significant difference in mean coronary

1734

artery calcification scores when followed-up for 12 to 21 months

1735

between those that received sevelamer and those that received

1736

calcium acetate (MD 23.04 lower [95% CI -124.44 to 78.36]).

1737

Sevelamer compared with sevelamer + calcium carbonate

1738

Critical outcomes

1739

3.5.3.48

Very-low-quality evidence from 1 RCT of 42 patients showed

1740

sevelamer alone to be associated with mean serum phosphate

1741

levels 0.35 mmol/l higher (95% CI 0.17 to 0.53 i.e. statistically

1742

significant) at 4 weeks than that associated with sevelamer and

1743

calcium carbonate.

1744

Important outcomes

1745

3.5.3.49

Very-low-quality evidence from the RCT of 42 patients showed

1746

sevelamer alone to be associated with mean serum calcium levels

1747

0.22 mmol/l lower (95% CI -0.36 to -0.08 i.e. statistically significant)

1748

at 4 weeks than that associated with sevelamer and calcium

1749

carbonate.

1750

Sevelamer compared with aluminium hydroxide

1751

Critical outcomes

1752

3.5.3.50

Very-low-quality evidence from 1 RCT of 30 patients showed no

1753

statistically significant difference in mean serum phosphate levels

1754

at 8 weeks between those that received sevelamer and those that

1755

received aluminium hydroxide (MD 0.12 mmol/l lower [95% CI -0.15

1756

to 0.39]).

1757

Management of hyperphosphataemia: NICE clinical guideline DRAFT (October 2012) Page 171 of 248

DRAFT FOR CONSULTATION 1758

Important outcomes

1759

3.5.3.51

Very-low-quality evidence from the RCT of 30 patients showed no

1760

statistically significant difference in the risk of experiencing

1761

constipation between those that received sevelamer and those that

1762

received aluminium hydroxide over 8 weeks (RR 5.00 [95% CI 0.26

1763

to 96.13]).

1764

3.5.3.52

Very-low-quality evidence from the RCT of 30 patients showed no

1765

statistically significant difference in mean serum calcium levels at

1766

8 weeks between those that received sevelamer and those that

1767

received aluminium hydroxide (MD 0.01 mmol/l lower [95% CI -0.12

1768

to 0.10]).

1769

Sevelamer hydrochloride compared with sevelamer carbonate

1770

Critical outcomes

1771

3.5.3.53

Very-low-quality evidence from 1 RCT of 220 patients showed no

1772

statistically significant difference in adherence over 24 weeks

1773

between those that received sevelamer hydrochloride and those

1774

that received sevelamer carbonate (RR 0.94 [95% CI 0.85 to 1.03]).

1775

Important outcomes

1776

3.5.3.54

Very-low-quality evidence from 1 RCT of 213 patients showed no

1777

statistically significant difference in the risk of experiencing

1778

diarrhoea over 24 weeks between those that received sevelamer

1779

hydrochloride and those that received sevelamer carbonate (RR

1780

0.65 [95% CI 0.22 to 1.95]).

1781

3.5.3.55

Very-low-quality evidence from the RCT of 213 patients showed no

1782

statistically significant difference in the risk of experiencing

1783

constipation over 24 weeks between those that received sevelamer

1784

hydrochloride and those that received sevelamer carbonate (RR

1785

7.83 [95% CI 0.89 to 68.80]).

Management of hyperphosphataemia: NICE clinical guideline DRAFT (October 2012) Page 172 of 248

DRAFT FOR CONSULTATION 1786

3.5.3.56

Very-low-quality evidence from the RCT of 213 patients showed

1787

sevelamer hydrochloride to be associated with a smaller risk of

1788

experiencing nausea and vomiting over 24 weeks than that

1789

associated with sevelamer carbonate (RR 0.27 [95% CI 0.08 to

1790

0.86 i.e. statistically significant]).

1791

Sevelamer (high-dose) compared with sevelamer (low-dose)

1792

Critical outcomes

1793

3.5.3.57

Very-low-quality evidence from 1 RCT of 27 patients showed no

1794

statistically significant difference in adherence over 6 months

1795

between those that received a high dose of sevelamer and those

1796

that received a low dose of sevelamer (RR 1.00 [95% CI 0.75 to

1797

1.33]).

1798

Lanthanum compared with placebo

1799

Critical outcomes

1800

3.5.3.58

Very-low-quality evidence from 4 RCTs of 332 patients in total

1801

showed lanthanum to be associated with a mean serum phosphate

1802

level 0.66 mmol/l lower (95% CI -0.86 to -0.47 i.e. statistically

1803

significant) than that associated with placebo when followed up for

1804

4 to 7 weeks.

1805

3.5.3.59

Very-low-quality evidence from 1 RCT of 36 patients showed no

1806

statistically significant difference in adherence over 4 weeks

1807

between those that received lanthanum and those that received

1808

placebo [RR 0.99 (95% CI 0.85 to 1.16]).

1809

Important outcomes

1810

3.5.3.60

Very-low-quality evidence from 3 RCTs of 380 patients in total

1811

showed lanthanum to be associated with a smaller risk of

1812

experiencing diarrhoea than that associated with placebo (RR 0.32

1813

[95% CI 0.15 to 0.66 i.e. statistically significant]), when followed-up

1814

for 4 to 104 weeks.

Management of hyperphosphataemia: NICE clinical guideline DRAFT (October 2012) Page 173 of 248

DRAFT FOR CONSULTATION 1815

3.5.3.61

Very-low-quality evidence from the 3 RCTs of 380 patients in total

1816

showed no statistically significant difference in the risk of

1817

experiencing nausea or vomiting between those that received

1818

lanthanum and those that received placebo (RR 2.12 [95% CI 0.27

1819

to 16.53]), when followed-up for 4 to 104 weeks.

1820

3.5.3.62

Very-low-quality evidence from 2 RCTs of 287 patients in total

1821

showed no statistically significant difference in the risk of

1822

experiencing upper abdominal pain between those that received

1823

lanthanum and those that received placebo (RR 1.48 [95% CI 0.26

1824

to 8.57]), when followed-up for 6 to 104 weeks.

1825

3.5.3.63

Very-low-quality evidence from 1 RCT of 142 patients showed no

1826

statistically significant difference in the risk of experiencing

1827

constipation over 6 weeks between those that received lanthanum

1828

and those that received placebo (RR 6.70 [95% CI 0.94 to 47.60]).

1829

3.5.3.64

Very-low-quality evidence from 1 RCT of 93 patients showed

1830

lanthanum to be associated with a mean serum calcium level

1831

0.09 mmol/l higher (95% CI 0.01 to 0.17 i.e. statistically significant)

1832

at 8 weeks than that associated with placebo.

1833

Lanthanum compared with any other binder

1834

Critical outcomes

1835

3.5.3.65

Low-quality evidence from 1 RCT of 1354 patients showed no

1836

statistically significant difference in mortality over 40 months

1837

between those that received lanthanum and those that received

1838

other binders [HR 0.86 (95% CI 0.68 to 1.08]).

1839

3.5.3.66

Very-low-quality evidence from a sub-group of 336 patients aged

1840

over 65 in the RCT of 1354 patients showed lanthanum to be

1841

associated with a smaller risk of mortality over 40 months than that

1842

associated with other binders (HR 0.68 [95% CI 0.46 to 0.99 i.e.

1843

statistically significant]).

Management of hyperphosphataemia: NICE clinical guideline DRAFT (October 2012) Page 174 of 248

DRAFT FOR CONSULTATION 1844

3.5.3.67

Very-low-quality evidence from a sub-group of 1008 patients aged

1845

under 65 in the RCT of 1354 patients showed no statistically

1846

significant difference in mortality over 40 months between those

1847

that received lanthanum and those that received other binders (HR

1848

1.00 [95% CI 0.75 to 1.34]).

1849

Important outcomes

1850

3.5.3.68

Low-quality evidence from 1 RCT of 1359 patients showed

1851

lanthanum to be associated with a smaller risk of experiencing

1852

diarrhoea over 2 years than that associated with other binders (RR

1853

0.75 [95% CI 0.63 to 0.90 i.e. statistically significant]).

1854

3.5.3.69

Very-low-quality evidence from 1 RCT of 1359 patients showed

1855

lanthanum to be associated with a smaller risk of experiencing

1856

upper abdominal pain over 2 years than that associated with other

1857

binders (RR 0.68 [95% CI 0.52 to 0.88 i.e. statistically significant]).

1858

3.5.3.70

Low-quality evidence from 1 RCT of 1359 patients showed

1859

lanthanum to be associated with a smaller risk of experiencing

1860

nausea and vomiting over 2 years than that associated with other

1861

binders (RR 0.92 [95% CI 0.85 to 0.99 i.e. statistically significant]).

1862

Lanthanum compared with calcium carbonate

1863

Critical outcomes

1864

3.5.3.71

Very-low-quality evidence from 1 RCT of 258 patients showed no

1865

statistically significant difference in mean serum phosphate levels

1866

at 8 weeks between those that received lanthanum and those that

1867

received calcium carbonate (MD 0.08 mmol/l higher [95% CI -0.03

1868

to 0.19]).

1869

Important outcomes

1870

3.5.3.72

Very-low-quality evidence from 4 RCTs of 1171 patients in total

1871

showed lanthanum to be associated with a lower risk of

1872

hypercalcaemia over a mean of 8 months than that associated with Management of hyperphosphataemia: NICE clinical guideline DRAFT (October 2012) Page 175 of 248

DRAFT FOR CONSULTATION 1873

calcium carbonate (RR 0.09 [95% CI 0.03 to 0.27 i.e. statistically

1874

significant]).

1875

3.5.3.73

Very-low-quality evidence from 3 RCTs of 1156 patients in total

1876

showed no statistically significant difference in the risk of

1877

experiencing constipation between those that received lanthanum

1878

and those that received calcium carbonate (RR 0.77 [95% CI 0.48

1879

to 1.21]).

1880

3.5.3.74

Very-low-quality evidence from the 3 RCTs of 1156 patients in total

1881

showed lanthanum to be associated with a greater risk of

1882

experiencing nausea and vomiting than that associated with

1883

calcium carbonate (RR 2.17 [95% CI 1.02 to 4.60 i.e. statistically

1884

significant]), when followed up for 8 to 52 weeks.

1885

3.5.3.75

Low-quality evidence from 2 RCTs of 898 patients in total showed

1886

no statistically significant difference in the risk of experiencing

1887

diarrhoea between those that received lanthanum and those that

1888

received calcium carbonate (RR 1.26 [95% CI 0.84 to 1.89]), when

1889

followed up for 20 to 52 weeks.

1890

3.5.3.76

Very-low-quality evidence from 1 RCT of 258 patients showed no

1891

statistically significant difference in the risk of experiencing

1892

abdominal distension over 8 weeks between those that received

1893

lanthanum and those that received calcium carbonate (RR 0.63

1894

[95% CI 0.15 to 2.58]).

1895

3.5.3.77

Low-quality evidence from the RCT of 258 patients showed no

1896

statistically significant difference in the risk of experiencing upper

1897

abdominal pain over 8 weeks between those that received

1898

lanthanum and those that received calcium carbonate (RR 0.60

1899

[95% CI 0.18 to 2.00]).

1900

Management of hyperphosphataemia: NICE clinical guideline DRAFT (October 2012) Page 176 of 248

DRAFT FOR CONSULTATION 1901

Magnesium carbonate compared with calcium carbonate

1902

Important outcomes

1903

3.5.3.78

Very-low-quality evidence from 1 RCT of 27 patients showed

1904

magnesium carbonate to be associated with a lower risk of

1905

hypercalcaemia over 6 months than that associated with calcium

1906

carbonate (RR 0.37 [0.17 to 0.76 i.e. statistically significant]).

1907

Multi treatment comparison: serum phosphate

1908

Critical outcome

1909

3.5.3.79

Serum phosphate at 90 days

1910

Evidence from 1 MTC of 8 treatments, containing 13 studies of low

1911

or very low quality, suggested that sevelamer carbonate had a

1912

99.1% probability.

1913

3.5.3.80

Serum phosphate at 180 days

1914

Evidence from 1 MTC of 8 treatments, containing 12 studies of low

1915

or very low quality suggested that calcium acetate with magnesium

1916

carbonate had a 36.3% probability (median rank 2 [95%CI 1, 8]) of

1917

being the best treatment to control serum phosphorus at 180 days

1918

in patients with CKD stage 5 on dialysis, with calcium acetate

1919

having a 25.5% probability (median rank 4 [95% CI 1, 8]),

1920

magnesium carbonate 16.3% probability (median rank 5 [95%CI 1,

1921

8]).

1922

3.5.3.81

Serum phosphate at 360 days

1923

Evidence from 1 MTC of 5 treatments, containing 13 studies of low

1924

or very low quality suggested that calcium acetate had a 61.2%

1925

probability (median rank 1 [95%CI 1, 4]) of being the best treatment

1926

to control serum phosphorus at 360 days in patients with CKD

1927

stage 5 on dialysis, with calcium carbonate having a 30.3%

1928

probability (median rank 2 [95% CI 1, 4]).

Management of hyperphosphataemia: NICE clinical guideline DRAFT (October 2012) Page 177 of 248

DRAFT FOR CONSULTATION 1929

Multi treatment comparison: achieving phosphate control

1930

Critical outcome

1931

3.5.3.82

Evidence from 1 MTC of 9 treatments, containing 15 studies of low

1932

or very low quality suggested that sevelamer hydrochloride plus

1933

calcium carbonate had a 73.2% probability (median rank 1 [95%CI

1934

1, 5]) of being the best treatment to achieve phosphate control in

1935

patients with CKD stage 5 on dialysis, with magnesium carbonate

1936

having a 21.2% probability (median rank 2 [95%CI 1, 8]).

1937

Multi treatment comparison: serum calcium

1938

Important outcome

1939

3.5.3.83

Serum calcium at 90 days

1940

Evidence from 1 MTC of 7 treatments, containing 10 studies of low

1941

or very low quality suggested that Lanthanum Carbonate had a

1942

77.1% probability (median rank 1 [95%CI 1, 3]) of being the best

1943

treatment to control serum calcium at 90 days in patients with CKD

1944

stage 5 on dialysis, with sevelamer hydrochloride having a 14.1%

1945

probability (median rank 2 [95%CI 1, 4]).

1946

3.5.3.84

Serum calcium at 180 days

1947

Evidence from 1 MTC of 8 treatments, containing 9 studies of low

1948

or very low quality suggested that Lanthanum carbonate had a

1949

46.3% probability (median rank 2 [95%CI 1, 3]) of being the best

1950

treatment to control serum calcium at 180 days in patients with

1951

CKD stage 5 on dialysis, with Magnesium Carbonate having a

1952

45.6% probability (median rank 2 [95% CI 1, 4]).

1953

3.5.3.85

Serum calcium at 360 days

1954

Evidence from 1 MTC of 5 treatments, containing 12 studies of low

1955

or very low quality suggested that sevelamer hydrochloride had a

1956

77.5% probability (median rank 1 [95%CI 1, 2]) of being the best

1957

treatment to control serum calcium at 360 days in patients with Management of hyperphosphataemia: NICE clinical guideline DRAFT (October 2012) Page 178 of 248

DRAFT FOR CONSULTATION 1958

CKD stage 5 on dialysis, with lanthanum carbonate having a 22%

1959

probability (median rank 2 [95% CI 1, 3]).

1960

Multi treatment comparison: risk of hypercalcaemia

1961

Important outcome

1962

3.5.3.86

Evidence from 1 MTC of 7 treatments, containing 16 studies of low

1963

or very low quality suggested that lanthanum carbonate had a

1964

98.6% (median rank 1 [95% CI 1, 1]) probability of being the best

1965

treatment to reduce the chance of hypercalcaemia in patients with

1966

CKD stage 5 on dialysis, with magnesium carbonate having a 1.4%

1967

probability (median rank 2 [95% CI 2, 4]).

1968

3.5.4

Health economic modelling

1969

This is a summary of the modelling carried out for this review question. See

1970

appendix F for full details of the modelling carried out for the guideline.

1971

Decision problems

1972

Two questions were addressed, based on the literature that had been

1973

identified in the review of clinical effectiveness evidence:

1974

For adults with stage 5 CKD on dialysis, which phosphate binder(s) provide

1975

cost-effective first-line management of hyperphosphataemia and its

1976

associated outcomes?

1977

For adults with stage 5 CKD on dialysis, what is the cost effectiveness of

1978

various sequences of phosphate binders in the management of

1979

hyperphosphataemia?

1980

Both questions were explored using the same model structure. An initial

1981

attempt was made to model the use of different phosphate binders in people

1982

in CKD stage 4 and people in CKD stage 5 but not on dialysis; however,

1983

insufficient data were available to estimate the effectiveness of different

1984

binders in this population (see section 3.5.2). Similarly, there were insufficient

1985

data to undertake a separate model exploring the cost effectiveness of

1986

different phosphate binders in children.

Management of hyperphosphataemia: NICE clinical guideline DRAFT (October 2012) Page 179 of 248

DRAFT FOR CONSULTATION 1987

Therefore, the analysis presented directly applies to adults with CKD stage 5

1988

on dialysis, and (to an extent) was extrapolated to people with CKD stage 4 or

1989

5 who are not on dialysis, and children.

1990

Methods

1991

The model used an individual patient (â&#x20AC;&#x2DC;discrete eventâ&#x20AC;&#x2122;) simulation approach,

1992

capturing costs and effects associated with a series of discrete health states.

1993

Discrete event simulation was considered to be the most appropriate structure

1994

for the analysis because of the complex relationships between biochemical

1995

intermediate outcomes (such as blood phosphate and calcium concentrations)

1996

and long-term, patient-relevant outcomes such as cardiovascular events,

1997

fractures and death. Figure 1 presents a simplified representation of the

1998

model structure, which was based on the natural history of CKD 5 and inputs

1999

from the GDG.

cohort starts here

CV event

transplantation

CKD 5 (on dialysis)

dead

fracture

parathyroidectomy

posttransplantation

post-PTx

2000 2001

Figure 1 Model structure

2002

In simulating the course of an individual patient, a virtual patient is created

2003

and assigned several characteristics, including age, sex, baseline serum

2004

phosphate level and baseline serum calcium level, with these data drawn from

2005

distributions reflecting patients in the UK Renal Registry.

2006

Based on these baseline characteristics, the model estimates the phosphate

2007

and calcium profiles of the simulated individual receiving 1 year's treatment Management of hyperphosphataemia: NICE clinical guideline DRAFT (October 2012) Page 180 of 248

DRAFT FOR CONSULTATION 2008

with calcium carbonate, which is then used as a common baseline with

2009

reference to which the effects of all other treatments are estimated. Treatment

2010

effects relative to calcium carbonate are drawn from 6 network meta-analyses

2011

reported in section 3.4.2 (phosphate and calcium at 3 different time points: 3

2012

months, 6 months and 1 year). The data underpinning these analyses enabled

2013

consideration of 4 different phosphate binders: calcium carbonate, calcium

2014

acetate, sevelamer hydrochloride and lanthanum carbonate. Insufficient data

2015

were available to derive conclusions on the use of sevelamer carbonate,

2016

aluminium hydroxide, magnesium carbonate.

2017

In the absence of evidence of treatment effects beyond 1 year's follow-up, it

2018

was necessary to rely on extrapolation and assumption to extend the

2019

phosphate and calcium profiles of simulated patients beyond 1 year. In the

2020

model's base case, phosphate levels are assumed to remain constant,

2021

whereas calcium levels are assumed to continue to rise (or fall) at the same

2022

rate observed on average in year 1. Alternative assumptions were tested in

2023

sensitivity analysis (for full details, see appendix F).

2024

Having estimated a simulated patient's biochemical profile, the model uses

2025

these measures as surrogate predictors to calculate event probabilities. The

2026

events that were deemed relevant for this analysis were:

2027

all-cause mortality

2028

cardiovascular events

2029

requirement for parathyroidectomy, and

2030

fractures.

2031

These events are shown in red, outlined arrows in Error! Reference source

2032

not found., indicating that the transitions are directly related to biochemical

2033

parameters (and, hence, treatment effects).

2034

The estimates used to calculate the probability of the relevant events were

2035

obtained from a systematic review of observational prognostic studies. We

2036

identified 36 studies in people with CKD (stage 4 or 5) relating serum

2037

phosphate and serum calcium to the events of interest in a single multivariate

2038

model. A meta-analysis of the various measures of effect was not performed Management of hyperphosphataemia: NICE clinical guideline DRAFT (October 2012) Page 181 of 248

DRAFT FOR CONSULTATION 2039

because it would be inappropriate to pool estimates that come from a

2040

heterogeneous collection of multivariable models. Instead, the evidence was

2041

systematically appraised and the most appropriate individual study(s) were

2042

selected. For full details of systematic review of prognostic studies, see

2043

appendix F.

2044

Adverse events associated with the different phosphate binders – a proportion

2045

of which lead to discontinuation due to intolerance – were also simulated, on

2046

the basis of reported event-rates in the pooled literature.

2047

Once the incidence of events (and consequent state-transitions) was

2048

estimated, costs and quality-of-life values were attached to the events and

2049

health-states and aggregated for each simulated individual's lifetime.

2050

The cost of the binders themselves was calculated with reference to the

2051

average dose at which each was delivered to achieve the clinical effect

2052

observed in the evidence base. Calculated costs as used in the model are

2053

shown in Table 7.

2054

Table 7 Cost of phosphate binders used in model Binder

Average daily dose (g)

Cost per g (£)

Cost per day (£)

Calcium carbonate

3.66

0.07

0.27

Calcium acetate

4.82

0.11

0.52

Sevelamer hydrochloride

5.22

0.82

5.22

Lanthanum carbonate

1.93

2.25

4.36

2055 2056

In the analyses presented here, cohorts of 250,000 virtual patients were

2057

simulated for each treatment arm. Finally, the average cost and quality-of-life

2058

values for each cohort were calculated.

2059

The model was implemented in Visual Basic for Applications, using Microsoft

2060

Excel as a ‘front-end’, in which parameters are specified and results collected

2061

and analysed. Costs and benefits were discounted at 3.5% per annum each.

Management of hyperphosphataemia: NICE clinical guideline DRAFT (October 2012) Page 182 of 248

DRAFT FOR CONSULTATION 2062

Treatments simulated

2063

First-line binders

2064

To provide a cost–utility estimate for different phosphate binders used as

2065

first-line agents, a simplified scenario was assumed in which patient cohorts

2066

were assigned to a single binder. Aside from dropout due to adverse events,

2067

no switching or addition of different binders was simulated, and serum

2068

phosphate and calcium levels were allowed to change based on the observed

2069

effect in the evidence base without additional intervention. Importantly, this

2070

means that the calcium level of simulated patients receiving calcium-based

2071

binders was allowed to rise indefinitely (which is likely to be at odds with

2072

current practice).

2073

Sequential use of binders

2074

As well as estimating the costs and effects of first-line treatment with various

2075

phosphate binders, the model was configured to simulate cohorts receiving

2076

predetermined sequences of binders, with patients switching between them as

2077

time progresses. Because the GDG believed that the main reason for

2078

switching in practice is hypercalcaemia associated with the use of

2079

calcium-based binders, the scenario of greatest interest was one in which

2080

people switched from a calcium-based to a non-calcium-based binder when

2081

simulated serum calcium levels exceeded 2.54 mmol/l (based on GDG

2082

advice). In this scenario, the sequences modelled are:

2083

Calcium carbonate  sevelamer hydrochloride

2084

Calcium carbonate  lanthanum carbonate

2085

Calcium acetate  sevelamer hydrochloride

2086

Calcium acetate  lanthanum carbonate

2087

Calcium carbonate alone (no switch)

2088

Calcium acetate alone (no switch)

2089

Sevelamer hydrochloride alone (no switch)

2090

Lanthanum carbonate alone (no switch)

2091

The latter 4 strategies were included in the decision space to estimate the

2092

potential opportunity costs of switching treatment at all. Management of hyperphosphataemia: NICE clinical guideline DRAFT (October 2012) Page 183 of 248

DRAFT FOR CONSULTATION 2093

Sequences were modelled on basis of generic evidence (based on the

2094

network meta-analyses) because of lack of primary evidence on sequential

2095

use of binders.

2096

Types of analysis

2097

At the time of reporting, detailed exploration of parameter uncertainty

2098

(probabilistic sensitivity analysis) has not been feasible because of the

2099

additional computational burden introduced by the discrete event simulation

2100

approach. However, it should be emphasised that, because first-order

2101

uncertainty is properly captured in this model, the impact of inter-individual

2102

variability in parameter values is reflected in the base-case analysis.

2103

Results: first line

2104

In its base case (Table 8), the economic model suggested that calcium-based

2105

phosphate binders are likely to be preferred to either sevelamer hydrochloride

2106

or lanthanum carbonate in the first-line management of hyperphosphataemia.

2107

Table 8 Cost–utility results for first-line use Discounted Costs (£)

Effects (QALYs)

Calcium carbonate

£14,151

3.597

Calcium acetate

£15,171

3.721

Lanthanum carbonate

£23,615

3.731

Sevelamer hydrochloride

£25,823

3.842

Binder

Incremental Costs (£)

Effects (QALYs)

£1020

ICER (£ / QALY)

0.124

£8197

extendedly dominated £10,652

0.121

£87,916

2108 2109 2110

2111

Calcium acetate appears to provide good value for money compared with

2112

calcium carbonate, providing an average health gain of around one-eighth of a

2113

QALY at an additional cost of just over £1000, equating to an incremental cost

2114

effectiveness ratio (ICER) of approximately £8000 per QALY gained.

2115

Sevelamer hydrochloride was found to be the most effective treatment;

2116

however, the additional health gains predicted, when compared with calcium

2117

acetate, come at a cost of almost £90,000 per QALY. The simulated cohort

2118

receiving lanthanum carbonate accrued very similar health gains to that

2119

receiving calcium acetate, but at much higher cost. It is said to be extendedly

Management of hyperphosphataemia: NICE clinical guideline DRAFT (October 2012) Page 184 of 248

DRAFT FOR CONSULTATION 2120

dominated, in this analysis, which indicates that – regardless of the assumed

2121

maximum acceptable ICER threshold – better value can be achieved by using

2122

calcium acetate and/or sevelamer hydrochloride.

2123

Figure 2 illustrates these results on the cost–utility plane. £30.0K

Costs

£25.0K £20.0K £15.0K £10.0K

£5.0K 3.55

CC SH £20K/QALY Frontier

CA LC £30K/QALY

3.75

3.85

3.65 QALYs

2124 2125

Figure 2 Cost–utility plane for first-line use

2126

In one-way sensitivity analysis, calcium acetate remained good value for

2127

money compared with calcium carbonate, except when the difference in

2128

serum calcium at 12 months was varied so that calcium acetate was

2129

associated with higher levels than calcium carbonate (mean difference

2130

+0.002 mmol/l, compared with a base-case point-estimate of −0.049 mmol/l).

2131

Independently varying all other parameters within plausible ranges had no

2132

effect on the implied decision.

2133

The finding that sevelamer hydrochloride and lanthanum carbonate are

2134

associated with high opportunity costs is entirely robust to individual

2135

parameter variations: none had a qualitative impact on model results, with all

2136

ICERs remaining far greater than £30,000 per QALY gained.

Management of hyperphosphataemia: NICE clinical guideline DRAFT (October 2012) Page 185 of 248

DRAFT FOR CONSULTATION 2137

Results: sequential use

2138

Base-case cost–utility results for the sequential treatment scenarios are

2139

tabulated in Table 9. Figure 3 illustrates these results on the cost–utility plane.

2140

Table 9 Cost–utility results for sequential use Discounted Costs (£)

Effects (QALYs)

Calcium carbonate (no switch)

£14,151

3.597

Calcium acetate (no switch)

£15,171

3.721

Calcium acetate  lanthanum carbonate

£18,965

3.810

extendedly dominated

Calcium carbonate  lanthanum carbonate

£19,124

3.765

dominated

Calcium acetate  sevelamer hydrochloride

£19,856

3.844

Calcium carbonate  sevelamer hydrochloride

£20,132

3.798

dominated

Lanthanum carbonate (no switch)

£23,615

3.731

dominated

Sevelamer hydrochloride (no switch)

£25,823

3.842

dominated

Binder sequence

2141 2142 2143 2144 2145

Incremental

Costs (£) £1020

£4684

Effects ICER (QALYs) (£ / QALY) 0.124

£8197 a

0.123

£38,078

extendedly dominated: indicates that the specified strategy has a higher ICER than at least one other option, when we estimate the additional value each provides over and above that which can be achieved with a common (cheaper, less effective) comparator dominated: indicates that one or more treatment options are both cheaper and more effective than the specified strategy

£30.0K

Costs

£25.0K

£20.0K

£15.0K CC LC CA -> SH £30K/QALY

£10.0K

£5.0K 3.55

3.65

CA CC -> SH CA -> LC Frontier

3.75

SH CC -> LC £20K/QALY

3.85

QALYs

2146 2147

Figure 3 Cost–utility plane for sequential use

2148

As in the first-line-only setting, reliance on calcium acetate as an initial binder

2149

appears to provide good value for money: such strategies tend to provide

2150

conspicuously greater QALY gains than those based on calcium carbonate at

2151

a net cost that is either modestly increased or reduced. Management of hyperphosphataemia: NICE clinical guideline DRAFT (October 2012) Page 186 of 248

DRAFT FOR CONSULTATION 2152

If remaining on calcium acetate indefinitely is considered a clinically

2153

appropriate option, it may be hard to justify switching to a non-calcium-based

2154

binder, instead, even in people with raised serum calcium. This is because,

2155

although switching strategies are associated with QALY gains, the extra

2156

acquisition costs of the non-calcium-based binders make the opportunity cost

2157

of adopting them represent an ineffective use of NHS resources (the ICER for

2158

best-value alternative – switching from calcium acetate to sevelamer

2159

hydrochloride – approaches £40,000 per QALY gained).

2160

For patients who are unable to tolerate calcium acetate, the cost effectiveness

2161

of switching to non-calcium-based binders should be judged against the only

2162

plausible alternative, which is indefinite treatment with calcium carbonate.

2163

Because calcium carbonate is a less effective choice than calcium acetate,

2164

this comparison is more favourable to the calcium-free alternatives, with

2165

ICERs in the range of £20,000–£30,000 per QALY.

2166

If calcium-based binders are considered to be fundamentally contraindicated

2167

in any individual case, the only remaining options in the decision-space are

2168

sevelamer hydrochloride and lanthanum carbonate. The relative cost-

2169

effectiveness of strategies switching from calcium-based binders to either of

2170

these alternatives is difficult to distinguish. Although the model estimates an

2171

ICER of £26,090 for the comparison between the two, this is based on

2172

extremely small differences in costs and QALYs, and it is notable that the two

2173

options have similar ICERs compared with a common baseline of indefinite

2174

calcium acetate treatment (£38,078 per QALY gained for switching to

2175

sevelamer hydrochloride and £42,683 per QALY gained for switching to

2176

lanthanum carbonate). Accordingly, if either treatment is considered

2177

acceptable value for money, it is very likely that the other would have to be

2178

judged similarly.

2179

In one-way sensitivity analysis, very few alterations to individual model

2180

parameters affected the apparent superiority of indefinite calcium acetate

2181

therapy when compared with strategies that transferred people to a non-

2182

calcium-based binder when their serum calcium reached a given threshold.

2183

Analyses in which that threshold was raised from its base-case value of Management of hyperphosphataemia: NICE clinical guideline DRAFT (October 2012) Page 187 of 248

DRAFT FOR CONSULTATION 2184

2.54 mmol/l were associated with some improvement in estimated value for

2185

money for switching strategies; however, even when the threshold was as

2186

high as 3 mmol/l, the ICER for switching to either drug remained above

2187

ÂŁ30,000 per QALY gained. Conversely, switching people to non-calcium-

2188

based binders at a lower threshold made switching strategies appear less cost

2189

effective.

2190

Three other parameters had a potentially important impact on findings.

2191

Switching strategies were associated with ICERs between ÂŁ20,000 and

2192

ÂŁ30,000 per QALY gained when:

2193

sevelamer hydrochloride or lanthanum carbonate were at the lower (most

2194

effective) bounds of their credibility intervals for impact on serum calcium

2195

after one year; or

2196

calcium acetate was at the higher (least effective) bound of its credibility

2197

interval for the same parameter; or

2198

low calcium levels were associated with a very substantially increased

2199

mortality risk compared with people with normal serum calcium.

2200

Details are provided in appendix F.

2201

For the comparison of strategies switching to sevelamer hydrochloride and

2202

those switching to lanthanum carbonate, plausible alterations to a large

2203

number of parameters result in the apparent superiority of one or other option

2204

over the other. This reinforces the view that it is difficult to distinguish between

2205

these options, from a health-economic perspective; additional research on the

2206

relative effectiveness of the treatments would be necessary, if it is judged

2207

worthwhile to establish which is superior.

2208

Discussion

2209

Principal findings

2210

The base-case economic model suggests that calcium acetate, when

2211

compared with calcium carbonate, sevelamer hydrochloride and lanthanum

2212

carbonate, is likely to be the preferred first-line phosphate binder for the

Management of hyperphosphataemia: NICE clinical guideline DRAFT (October 2012) Page 188 of 248

DRAFT FOR CONSULTATION 2213

management of hyperphosphataemia in people with CKD stage 5 who are on

2214

dialysis.

2215

When second-line treatment options are taken into account, the most effective

2216

strategies are those commencing with calcium acetate but switching to

2217

sevelamer hydrochloride or lanthanum carbonate if hypercalcaemia develops.

2218

However, remaining on calcium acetate remains a viable option from a health-

2219

economic perspective and, in comparison, the switching approaches are

2220

associated with substantially increased costs. Therefore, if all simulated

2221

strategies are seen as realistic options, it is unlikely that the health gains

2222

provided by the more expensive binders are sufficient to counterbalance the

2223

extra expense they entail (unless it can be assumed that societyâ&#x20AC;&#x2122;s maximum

2224

acceptable ICER threshold is approximately ÂŁ40,000 per QALY). There may

2225

be an exception to this conclusion for people who are unable to tolerate

2226

calcium acetate; in this circumstance, switching to sevelamer hydrochloride or

2227

lanthanum carbonate in those with hypercalcaemia could be seen as an

2228

effective use of resources when compared with the alternative of indefinite

2229

treatment with calcium carbonate.

2230

In patients for whom calcium-based-binders are considered to be

2231

fundamentally contraindicated, the only remaining options in the decision-

2232

space are sevelamer hydrochloride and lanthanum carbonate. Under this

2233

circumstance, either option is likely to be judged acceptable, from a health

2234

economic perspective.

2235

Limitations of the analysis

2236

The model has good validity over its first year, accurately reflecting

2237

biochemical measures seen in the trials underpinning it. It also makes a

2238

relatively good prediction of observed survival with the treatments of interest

2239

over the first 3 years of treatment. However, beyond the first year of the

2240

model, biochemical profiles are estimated on the basis of extrapolation and

2241

simplification and, while this approach had its face validity endorsed by the

2242

GDG, it is impossible to tell how well the model fits the (unknown) reality.

Management of hyperphosphataemia: NICE clinical guideline DRAFT (October 2012) Page 189 of 248

DRAFT FOR CONSULTATION 2243

Similarly, it is arguable that, as they extend into the future, the biochemical

2244

profiles of occasional simulated patients become implausible (especially as

2245

regards modelled serum calcium, which may rise very high in a few

2246

instances). However, this is only a problem if it results in implausible effects: if

2247

the level of risk that is predicted is realistic, then it does not matter that the

2248

value of the predictor may be unlikely. For this reason, it should be

2249

remembered that the sole purpose of biochemical parameters in the model is

2250

to estimate the risks faced by patients.

2251

The use of serum phosphate and serum calcium alone as determinants of

2252

treatment effect is an acknowledged simplification of a highly complex

2253

biological interaction. Moreover, it is well known that serum calcium is a

2254

suboptimal index of calcium balance in humans, perhaps especially those with

2255

advanced kidney disease (Houillier et al. 2006). If people who are exposed to

2256

excess calcium intake in their phosphate binding regimen are subject to

2257

greater risks than can be inferred from their serum calcium levels, the model

2258

will underestimate the benefit of switching such people to calcium-free

2259

binders.

2260

When simulating second-line treatment for people experiencing

2261

hypercalcaemia, the model is necessarily reliant on evidence of the

2262

effectiveness of treatments in a broader population. If people with

2263

hypercalcaemia respond differently to treatment than those without, it follows

2264

that the model over- or underestimates the treatment effect that can be

2265

achieved in reality; it is possible that different costâ&#x20AC;&#x201C;utility conclusions would be

2266

reached if more specific evidence were available.

2267

It is a significant weakness of this analysis that it has not proved

2268

computationally feasible to undertake full probabilistic sensitivity analysis, to

2269

explore the implications of parameter uncertainty for decision-making. A wide

2270

range of one-way sensitivity analyses was undertaken; this enables a fair

2271

degree of inference on the impact of such â&#x20AC;&#x2DC;second-orderâ&#x20AC;&#x2122; uncertainty and, in

2272

the light of these analyses, it is possible to state with some confidence that the

2273

options identified as optimal in the base-case analysis would be associated

2274

with the highest probability of cost effectiveness in a fully probabilistic Management of hyperphosphataemia: NICE clinical guideline DRAFT (October 2012) Page 190 of 248

DRAFT FOR CONSULTATION 2275

analysis. However, it is not possible to quantify these probabilities in the

2276

absence of such an analysis.

2277

It is possible that the model somewhat underestimates the effectiveness of

2278

lanthanum carbonate in both first- and second-line settings, since it was not

2279

possible to include data on phosphate control from what is by far the largest

2280

and longest trial of the drug in the evidence-base (Finn & the Lanthanum

2281

Study Group, 2006; see 3.5.2 above). It is speculated that, were these data

2282

available to incorporate into analysis, apparent differences between

2283

treatments â&#x20AC;&#x201C; perhaps especially sevelamer hydrochloride and lanthanum

2284

carbonate in the first-line setting â&#x20AC;&#x201C; would be somewhat attenuated. However,

2285

the use of lanthanum carbonate would still be associated with a very high

2286

ICER, compared with calcium acetate: an additional gain of at least 0.3

2287

QALYs would be necessary to counterbalance the costs estimated here,

2288

assuming conventional costâ&#x20AC;&#x201C;utility thresholds, and there is no evidence that

2289

an underestimate of such magnitude is plausible.

2290

It is regrettable that there was insufficient evidence to provide a worthwhile

2291

model for people in CKD stages 4 and 5 who have not yet commenced

2292

dialysis, or for children at any stage of disease. There was also insufficient

2293

evidence to perform any meaningful modelling to support a recommendation

2294

on aluminium hydroxide, magnesium carbonate or sevelamer carbonate.

2295

3.5.5

Evidence to recommendations

Relative value of different outcomes

Trade-off between benefits and harms

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. 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,

Management of hyperphosphataemia: NICE clinical guideline DRAFT (October 2012) Page 191 of 248

DRAFT FOR CONSULTATION 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 calciumbased 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 Management of hyperphosphataemia: NICE clinical guideline DRAFT (October 2012) Page 192 of 248

DRAFT FOR CONSULTATION 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 noncalcium-based binder may need to be added to the regimen, producing a combination. The aim would be for the added phosphatebinding 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 â&#x20AC;&#x2DC;sequencingâ&#x20AC;&#x2122; 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 costeffective 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 (4â&#x20AC;&#x201C;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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DRAFT FOR CONSULTATION 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 calciumbased 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 offlabel 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 Management of hyperphosphataemia: NICE clinical guideline DRAFT (October 2012) Page 194 of 248

DRAFT FOR CONSULTATION

Economic considerations

Quality of evidence

course of action. 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 noncalcium-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 noncalcium-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. 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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DRAFT FOR CONSULTATION 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 calciumbased 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 Management of hyperphosphataemia: NICE clinical guideline DRAFT (October 2012) Page 196 of 248

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Other considerations

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. 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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DRAFT FOR CONSULTATION 2296

3.5.6

Recommendations and research recommendations for

2297

use of phosphate binders in adults with stage 5 CKD who

2298

are on dialysis

2299

Recommendations 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

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DRAFT FOR CONSULTATION 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 2301

Research recommendations

2302

See appendix B for full details of research recommendations.

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Research recommendation B2 In adults with stage 4 or 5 CKD, including those on dialysis, what is the longterm 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 2304

3.6

Use of supplements in people with stage 4 or 5 CKD who are not on dialysis

2305 2306

3.6.1

Review question

2307

For people with stage 4 or 5 CKD who are not on dialysis, are prescribed

2308

supplements, alone or in conjunction with other interventions, effective

2309

compared to placebo or other treatments in managing serum phosphate and

2310

its associated outcomes? Which are the most effective supplements?

2311

3.6.2

2312

This review question focused on the use of supplements in the prevention and

2313

treatment of hyperphosphataemia in patients with stage 4 or 5 CKD who are

2314

not on dialysis. These supplements could consist of a variety of vitamins and

2315

minerals.

2316

For this review question, papers were identified from a number of different

2317

databases (Medline, Embase, Medline in Process, the Cochrane Database of

2318

Systematic Reviews and the Centre for Reviews and Dissemination) using a

Evidence review

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DRAFT FOR CONSULTATION 2319

broad search strategy, pulling in all papers relating to the management of

2320

hyperphosphataemia in CKD using supplements . Only RCTs that compared a

2321

supplementation intervention with either a placebo or another comparator in

2322

patients with stage 4 or 5 CKD who are not on dialysis were considered for

2323

inclusion.

2324

Trials were excluded if:

2325

the population included people with CKD stages 1 to 3 or

2326

the population included people on dialysis or

2327

supplementation was intended for any reason other than for the

2328

management of hyperphosphataemia.

2329 2330

From a database of 2020 abstracts, 20 full-text articles were ordered, though

2331

no papers were found to be suitable for inclusion in the analysis.

2332

Supplementation using vitamin D and its metabolites was also not considered

2333

for this review and was excluded at the scoping stage. It was felt that their

2334

effectiveness is not disputed and they are already an accepted and cost-

2335

effective part of standard clinical practice.

2336

3.6.3

Evidence statements

2337

3.6.3.1

No evidence on the clinical effectiveness of supplements in the

2338

management of hyperphosphataemia in people with CKD stages 4

2339

or 5 who are not on dialysis was identified.

2340

3.6.4

Evidence to recommendations

Relative value of different outcomes Trade-off between benefits and harms

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. 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 â&#x20AC;&#x2DC;3.7 Use of supplements in people with stage 5 CKD who are on

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Economic considerations Quality of evidence

dialysisâ&#x20AC;&#x2122; for the review of this evidence. Because the GDG did not feel that the available evidence supported the use of supplements, it was not necessary to conduct a costeffectiveness analysis for this question. 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 2342

3.7

Use of supplements in people with stage 5 CKD who are on dialysis

2343 2344

3.7.1

2345

For people with stage 5 CKD who are on dialysis, are prescribed

2346

supplements, alone or in conjunction with other interventions, effective

2347

compared to placebo or other treatments in managing serum phosphate and

2348

its associated outcomes? Which is the most effective prescribed supplement?

2349

3.7.2

2350

This review question focused on the use of supplements in the prevention and

2351

treatment of hyperphosphataemia in patients with stage 5 CKD who are on

2352

dialysis. These supplements could consist of a variety of vitamins and

2353

minerals, though in the evidence located included: nicotinamide, calcium and

2354

L-carnitine supplementation.

2355

For this review question, papers were identified from a number of different

2356

databases (Medline, Embase, Medline in Process, the Cochrane Database of

2357

Systematic Reviews and the Centre for Reviews and Dissemination) using a

2358

broad search strategy, pulling in all papers relating to the management of

2359

hyperphosphataemia in CKD using supplements. Only RCTs that compared a

2360

supplement with either a placebo or another comparator in patients with stage

2361

5 CKD who are on dialysis were considered for inclusion.

2362

Trials were excluded if:

2363

Review question

Evidence review

the population included people with CKD stages 1 to 4 or Management of hyperphosphataemia: NICE clinical guideline DRAFT (October 2012) Page 202 of 248

DRAFT FOR CONSULTATION 2364

the population included people with CKD stage 5 who were not on dialysis

2365

2366

supplementation was intended for any reason other than for the

2367

management of hyperphosphataemia.

2368 2369

From a database of 2020 abstracts, 20 full-text articles were ordered and

2370

5 papers describing 5 primary studies were selected (Young et al, 2009;

2371

Shahbazian et al, 2011; Rudnicki et al, 1993; Chertow et al, 1999; Cibulka et

2372

al, 2007). No paediatric studies meeting the inclusion criteria were found.

2373

Table 9 lists the details of the included studies.

2374

Supplementation using vitamin D and its metabolites was also not considered

2375

for this review and was excluded at the scoping stage. It was felt that their

2376

effectiveness is not disputed and they are already an accepted and cost-

2377

effective part of standard clinical practice.

2378

There was pooling of the 2 studies comparing nicotinamide supplementation

2379

against placebo, although there was some heterogeneity present. This

2380

heterogeneity resulted from the use of different concurrent interventions that

2381

are known to impact the outcomes of interest, but also the different types of

2382

dialysis used.

2383

Where meta-analysis was possible, a forest plot is also presented. Mean

2384

differences (MDs) were calculated for continuous outcomes and odds ratios

2385

(ORs) for binary outcomes, as well as the corresponding 95% confidence

2386

intervals where sufficient data were available.

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2387

Table 9 Summary of included studies for the use of supplements in people with stage 5 CKD who are on dialysis Study

Population

Intervention

Control

Follow-up

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

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

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

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

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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 3 150,000/mm ), 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.

Management of hyperphosphataemia: NICE guideline DRAFT (October 2012)

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

Page 205 of 248

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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

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

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

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.

2388

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2389

Summary GRADE profile 52 Niacinamide compared with placebo Outcome

Number of Studies

Number of patients

Effect

Quality

Serum phosphate (pooled) 8-week follow-up

2 RCTs Shahbazian et al, 2011 Young et al, 2009

Absolute effect MD = 0.30 mmol/l lower (95% CI:0.42 to 0.17 lower)

Very low

Change in serum phosphate 8-week follow-up

1 RCT Young et al, 2009

Absolute effect MD = 0.36 mmol/l lower (95% CI: 0.64 to 0.07 lower)

Very low

Serum phosphate (number of patients to experience an increase in serum phosphate from baseline to the end of the study period) 8-week follow-up

1 RCT Young et al, 2009

1/7 (14.3%)

5/7 (71.4%)

Relative effect OR = 0.07 (95% CI: 0.01 to 0.97) Absolute effect

Very low

Adverse events â&#x20AC;&#x201C; diarrhoea (number of patients to experience diarrhoea) 8-week follow-up

2 RCTs Shahbazian et al, 2011 Young et al, 2009

5/32 (15.6%)

0/33 (0%)

Relative effect OR = 6.78 (95% CI: 0.73 to 62.69)

Very low

Serum calcium 8-week follow-up

1 RCT Young et al, 2009

Absolute effect MD = 0.05 mmol/l lower (95% CI: 0.21 lower to 0.11 higher)

Very low

Niacinamide

Placebo

57 fewer per 100 (1 fewer to 69 fewer)

The 2 studies had different co-treatments, received by both the intervention and control groups: Shahbazian et al, 2011: pre-study calcium carbonate regimen (note: unclear if calcium carbonate was used as a binder or as a supplement) Young et al, 2009: pre-study phosphate binder, active vitamin D and cinacalcet regimens Abbreviations: CI, confidence interval; MD, mean difference; OR, odds ratio; RCT, randomised controlled trial.

2390

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2391 2392

Summary GRADE profile 53 Sevelamer hydrochloride + calcium supplementation (+ pre-study vitamin D regimen) compared with sevelamer hydrochloride (+ pre-study vitamin D regimen) Outcome

Number of Studies

Number of patients Sevelamer hydrochloride + calcium supplementation (+ pre-study vitamin D regimen)

Sevelamer hydrochloride (+ pre-study vitamin D regimen)

1 RCT Chertow et al, 1999

2/36 (5.6%)

Serum phosphate 12-week follow-up

1 RCT Chertow et al, 1999

Change in serum phosphate 12-week follow-up

Mortality (number of deaths among patients hospitalised during study) 12-week follow-up

Serum phosphate (number of patients to achieve a therapeutic response - serum phosphate at or below washout level or <1.78mmol/l) 12-week follow-up Change in serum calcium 12-week follow-up Serum calcium (% of patients to experience hypercalcaemia) 12-week follow-up

Effect

Quality

0/35 (0%)

Relative effect OR = 0.21 (95% CI: 0.01 to 4.44)

Very low

Absolute effect MD = 0.31 mmol/l lower (95% CI: 0.59 to 0.04 lower)

Very low

1 RCT Chertow et al, 1999

Absolute effect MD = 0.03 mmol/l lower (95% CI: 1.83 lower to 1.77 higher)

Very low

1 RCT Chertow et al, 1999

35/36 (97.2%)

33/35 (94.3%)

Relative effect OR = 1.03 (95% CI: 0.14 to 7.75) Absolute effect 0 more per 100 (from 24 fewer to 5 more)

Very low

1 RCT Chertow et al, 1999

Absolute effect MD = 0.08 mmol/l higher (95% CI:0.01 lower to 0.16 higher)

Very low

1 RCT Chertow et al, 1999

21.1%

2.4%

Relative effect OR = 10.88 (95% CI: 2.77 to 42.70) Absolute effect 19 more per 100 ( 4 to 49 more)

Very low

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

Management of hyperphosphataemia: NICE guideline DRAFT (October 2012)

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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]) Abbreviations: CI, confidence interval; MD, mean difference; OR, odds ratio; RCT, randomised controlled trial.

2393 2394 2395

Summary GRADE profile 54 L-carnitine supplementation (+ calcium carbonate + pre-study vitamin D regimen) compared with placebo (+ calcium carbonate + pre-study vitamin D regimen) Outcome

Number of Studies

Number of patients L-carnitine supplementation (+ calcium carbonate + pre-study vitamin D regimen)

Placebo (+ calcium carbonate + pre-study vitamin D regimen) 9/39

Effect

Quality

Relative effect

Very low

Mortality (number of deaths among patients) 6-month follow-up

1 RCT Cibulka et al, 2007

7/44

Serum phosphate 6-month follow-up

1 RCT Cibulka et al, 2007

Absolute effect Difference in medians = 0.08 mmol/l lower

Very low

Serum calcium 6-month follow-up

1 RCT Cibulka et al, 2007

Absolute effect Difference in medians = 0.04 mmol/l lower

Very low

OR = 0.63 (95% CI: 0.21 to 1.89) Absolute effect 7 fewer per 100 (17 fewer to 13 more)

Abbreviations: CI, confidence interval; OR, odds ratio; RCT, randomised controlled trial.

2396 2397

See appendix E for the evidence tables and GRADE profiles in full.

Management of hyperphosphataemia: NICE guideline DRAFT (October 2012)

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DRAFT FOR CONSULTATION 2398

3.7.3

Evidence statements

2399

For details of how the evidence is graded, see ‘The guidelines manual’.

2400

Use of supplements in people with stage 5 CKD who are on dialysis

2401

Niacinamide compared with placebo

2402

Critical outcomes

2403

3.7.3.1

Very-low-quality evidence from 2 RCTs of 62 participants in total

2404

showed nicotinamide supplementation to be associated with a

2405

mean serum phosphate level 0.30 mmol/l lower (95% CI -0.42 to

2406

-0.17 i.e. statistically significant) than that associated with placebo

2407

at 8 weeks.

2408

3.7.3.2

Very-low-quality evidence from 1 RCT of 14 participants showed

2409

that at 8 weeks’ nicotinamide supplementation was associated with

2410

a mean decrease in serum phosphate levels of 0.23 mmol/l (SD

2411

0.29) and placebo with a mean increase in serum phosphate levels

2412

of 0.13 mmol/l (SD 0.26) (MD 0.36 mmol/l lower [95% CI -0.64 to

2413

-0.07 i.e. statistically significant]).

2414

3.7.3.3

Very-low-quality evidence from 1 RCT of 14 participants showed

2415

that a smaller proportion of participants that received nicotinamide

2416

supplementation experienced an increase in serum phosphate from

2417

baseline to the end of the 8-week study period than among those

2418

that received placebo (OR 0.07 [95% CI 0.01 to 0.97 i.e.

2419

statistically significant]).

2420

Important outcomes

2421

3.7.3.4

Very-low-quality evidence from 2 RCTs of 65 participants showed

2422

no statistically significant difference in the proportion of participants

2423

that experienced diarrhoea during the 8-week study period,

2424

between those that received nicotinamide supplementation and

2425

those that received placebo (OR 6.78 [95% CI 0.73 to 62.69]).

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DRAFT FOR CONSULTATION 2426

3.7.3.5

Very-low-quality evidence from 1 RCT of 14 participants showed no

2427

statistically significant difference in mean serum corrected calcium

2428

level between those that received nicotinamide supplementation

2429

and those that received placebo at 8 weeks (MD 0.05 mmol/l lower

2430

[95% CI -0.21 to 0.11]).

2431

Sevelamer hydrochloride + calcium supplementation compared with

2432

sevelamer hydrochloride

2433

Critical outcomes

2434

3.7.3.6

Very-low-quality evidence from 1 RCT of 71 participants showed no

2435

statistically significant difference in the number of deaths during the

2436

12-week study period between those that received sevelamer

2437

hydrochloride and calcium supplementation and those that received

2438

sevelamer hydrochloride alone (OR 0.21 [95% CI 0.01 to 4.44]).

2439

3.7.3.7

Very-low-quality evidence from 1 RCT of 71 participants showed

2440

sevelamer hydrochloride and calcium supplementation to be

2441

associated with a mean serum phosphate level 0.31 mmol/l lower

2442

(95% CI -0.59 to -0.04 i.e. statistically significant) than that

2443

associated with sevelamer hydrochloride alone at 6 months25.

2444

3.7.3.8

Very-low-quality evidence from 1 RCT of 71 participants showed no

2445

statistically significant difference in the mean change in serum

2446

phosphate levels during the 6-month study period between those

2447

that received sevelamer hydrochloride and calcium

2448

supplementation and those that received sevelamer hydrochloride

2449

alone (MD 0.03 mmol/l lower [95% CI -1.83 to 1.77]).

2450

3.7.3.9

Very-low-quality evidence from 1 RCT of 71 participants showed no

2451

statistically significant difference in the number of patients to

2452

achieve a therapeutic response (defined as serum phosphate at or 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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DRAFT FOR CONSULTATION 2453

below the participantâ&#x20AC;&#x2122;s pre-binder washout level or < 1.78 mmol/l)

2454

during the 12-week study period between those that received

2455

sevelamer hydrochloride and calcium supplementation and those

2456

that received sevelamer hydrochloride alone (OR 1.03 [95% CI

2457

0.14 to 7.75]).

2458

Important outcomes

2459

3.7.3.10

Very-low-quality evidence from 1 RCT of 71 participants showed no

2460

statistically significant difference in the mean change in serum

2461

calcium levels during the 6-month study period between those that

2462

received sevelamer hydrochloride and calcium supplementation

2463

and those that received sevelamer hydrochloride alone (MD

2464

0.08 mmol/l higher [95% CI -0.01 to 0.16]).

2465

3.7.3.11

Very-low-quality evidence from 1 RCT of 71 participants showed

2466

that a greater proportion of participants that received sevelamer

2467

hydrochloride and calcium supplementation experienced

2468

hypercalcaemia during the 12-week study period than among those

2469

that received sevelamer hydrochloride alone (OR 10.88 [95% CI

2470

2.77 to 42.70 i.e. statistically significant]).

2471

L-carnitine supplementation compared with placebo

2472

Critical outcomes

2473

3.7.3.12

Very-low-quality evidence from 1 RCT of 83 participants showed no

2474

statistically significant difference in the number of deaths during the

2475

6-month study period between those that received L-carnitine

2476

supplementation and those that received placebo (OR 0.63 [95%

2477

CI 0.21 to 1.89]).

2478

3.7.3.13

Very-low-quality evidence from 1 RCT of 83 participants showed

2479

received L-carnitine supplementation to be associated with a

2480

median serum phosphate level 0.08 mmol/l lower than that

2481

associated with placebo.

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DRAFT FOR CONSULTATION 2482 2483

Important outcomes

2484

3.7.3.14

Very-low-quality evidence from 1 RCT of 83 participants showed

2485

L-carnitine supplementation to be associated with a median serum

2486

calcium level 0.04 mmol/l lower than that associated with placebo.

2487

3.7.4

Evidence to recommendations

Relative value of different outcomes Trade-off between benefits and harms

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. 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 carbonateâ&#x20AC;&#x2122;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 studyâ&#x20AC;&#x2122;s end compared to sevelamer hydrochloride alone. However, the GDG concluded that this was not due to the interventionâ&#x20AC;&#x2122;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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Economic considerations Quality of evidence

Other considerations

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. Because the GDG did not feel that the available evidence supported the use of supplements, it was not necessary to conduct a costeffectiveness analysis for this question. 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 patientsâ&#x20AC;&#x2122; pre-study phosphate binder, vitamin D and cinacalcet regimens, and the patientsâ&#x20AC;&#x2122; 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. 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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DRAFT FOR CONSULTATION 2489

3.7.5

Recommendations and research recommendations for

2490

use of supplements in people with stage 5 CKD who are

2491

on dialysis

2492

Recommendations Recommendation 1.1.15 Advise patients to take phosphate binders with food in order to control serum phosphate.

2493 2494

3.8

Sequencing of treatments

2495

3.8.1

Review question

2496

In the management of hyperphosphataemia in people with stage 4 or 5 CKD,

2497

in what order should available treatments be considered? What are the clinical

2498

indications for commencing each?

2499

3.8.2

2500

This review question focused on the sequencing of interventions in the

2501

prevention and treatment of hyperphosphataemia in patients with stage 4 or 5

2502

CKD, including those on dialysis. These interventions could include dietary

2503

interventions, phosphate binders, supplements including vitamin D, and

2504

dialysis.

2505

For this review question, papers were identified from a number of different

2506

databases (Medline, Embase, Medline in Process, the Cochrane Database of

2507

Systematic Reviews, the Health Technology Assessment Database (HTA)

2508

and the Database of Abstracts of Reviews of Effects (DARE). A broad search

2509

strategy was used, pulling in all papers relating to the sequencing of

2510

interventions in the management of hyperphosphataemia in patients with

2511

CKD. RCTs, quasi-RCTs, systematic reviews, non-randomised controlled

2512

trials, cohort studies, cross-sectional studies and case-control studies were

2513

eligible for inclusion.

Evidence review

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DRAFT FOR CONSULTATION 2514

Trials were excluded if:

2515

the population included people with stages 1 to 3 CKD or

2516

they did not compare a sequence of interventions with another sequence of

2517

interventions.

2518 2519

From a database of 1868 abstracts, 16 full-text articles were ordered,

2520

although no papers were found to be suitable for inclusion in the analysis.

2521 2522

3.8.3

Evidence statements

2523

3.8.3.1

No evidence was identified on the sequencing of interventions in

2524

order to maximise the management of hyperphosphataemia in

2525

people with stage 4 or 5 CKD, nor in people with stage 5 CKD who

2526

are on dialysis.

2527

3.8.4

Health economic modelling

2528

Health economic analysis within this guideline focused on evaluation of

2529

phosphate binders for people with stage 5 CKD who are on dialysis. These

2530

results assisted the GDG in making recommendations regarding the

2531

sequencing of phosphate binders. See section 3.5.4 and appendix F for full

2532

details on the health economic analysis and modelling carried out for the

2533

guideline.

2534

3.8.5

Evidence to recommendations

Relative value of different outcomes Trade-off between benefits and harms

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. 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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DRAFT FOR CONSULTATION

Economic considerations

Quality of evidence

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). 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 costeffectiveness 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 costeffectiveness of different combinations of phosphate binders due to a complete absence of evidence on the effectiveness of such combinations. 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 2536 2537 2538

3.8.6

Recommendations and research recommendations for sequencing of treatments

Recommendations 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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DRAFT FOR CONSULTATION 2540

Research recommendations

2541

See appendix B for full details of research recommendations.

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 2543

Notes on the scope of the guideline

2544

NICE guidelines are developed in accordance with a scope that defines what

2545

the guideline will and will not cover. The scope of this guideline is given in

2546

appendix C.

2547

2548

NICE has developed tools to help organisations implement this guidance.

2549

Note: these details will apply when the guideline is published.

2550

Other versions of this guideline

2551

6.1

NICE pathway

2552

The recommendations from this guideline have been incorporated into a NICE

2553

pathway. Note: these details will apply when the guideline is published.

2554

6.2

2555

A summary for patients and carers (‘Understanding NICE guidance’) is

2556

available.

2557

For printed copies, phone NICE publications on 0845 003 7783 or email

2558

publications@nice.org.uk (quote reference number N[xxxx]). Note: these

2559

details will apply when the guideline is published.

Implementation

‘Understanding NICE guidance’

Management of hyperphosphataemia: NICE guideline DRAFT (October 2012) Page 218 of 248

DRAFT FOR CONSULTATION 2560

We encourage NHS and third sector, including voluntary, organisations to use

2561

text from this booklet in their own information about stage 4 or 5 CKD.

2562

2563

Published

Related NICE guidance

2564

Peritoneal dialysis. NICE clinical guideline 125 (2011).

2565

Anaemia management in people with chronic kidney disease. NICE clinical

2566

guideline 114 (2011).

2567

Medicines adherence: Involving patients in decisions about prescribed

2568

medicines and supporting adherence. NICE clinical guideline 76 (2009).

2569

Chronic kidney disease. NICE clinical guideline 73 (2008).

2570

Cinacalcet for the treatment of secondary hyperparathyroidism in patients

2571

with end-stage renal disease on maintenance dialysis therapy. NICE

2572

technology appraisal guidance 117 (2007).

2573

Under development

2574

NICE is developing the following guidance (details available from the NICE

2575

website):

2576

Chronic kidney disease (update). NICE clinical guideline. Publication date

2577

to be confirmed.

2578

Acute kidney injury. NICE clinical guideline. Publication date August 2013.

2579

Updating the guideline

2580

NICE clinical guidelines are updated so that recommendations take into

2581

account important new information. New evidence is checked 3 years after

2582

publication, and healthcare professionals and patients are asked for their

2583

views; we use this information to decide whether all or part of a guideline

2584

needs updating. If important new evidence is published at other times, we

2585

may decide to do a more rapid update of some recommendations. Please see

2586

our website for information about updating the guideline.

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DRAFT FOR CONSULTATION 2587

8.1

References

2588 2589

Dietary management for people with stage 4 or 5 CKD who are not on dialysis

2590

Cianciaruso B; Pota A; Pisani A; Torraca S; Annecchini R; Lombardi P;

2591

Capuano A; Nazzaro P; Bellizzi V; Sabbatini M. (2008) Metabolic effects of

2592

two low protein diets in chronic kidney disease stage 4-5--a randomized

2593

controlled trial. Nephrology Dialysis Transplantation 23(2): 636-644 [ref ID:

2594

555]

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Dialysis Therapy 12: 55-61 [ref ID: 5096]

2913

Spasovski GB; Sikole A; Gelev S; Masin-Spasovska J; Freemont T; Webster

2914

I; Gill M; Jones C; De Broe ME; D'Haese PC. (2006) Evolution of bone and

2915

plasma concentration of lanthanum in dialysis patients before, during 1 year of

2916

treatment with lanthanum carbonate and after 2 years of follow-up.

2917

Nephrology Dialysis Transplantation 21: 2217-24 [ref ID: 5128]

2918

Spiegel DM; Farmer B; Smits G; Chonchol M. (2007) Magnesium carbonate is

2919

an effective phosphate binder for chronic hemodialysis patients: a pilot study.

2920

Journal of Renal Nutrition 17: 416-22 [ref ID: 5132]

2921

Suki WN; Zabaneh R; Cangiano JL; Reed J; Fischer D; Garrett L; Ling BN;

2922

Chasan-Taber S; Dillon MA; Blair AT; Burke SK. (2007) Effects of sevelamer

2923

and calcium-based phosphate binders on mortality in hemodialysis patients.

2924

Kidney International 72: 1130-7 [ref ID: 5163]

2925

Tzanakis IP; Papadaki AN; Wei M; Kagia S; Spadidakis VV; Kallivretakis NE;

2926

Oreopoulos DG. (2008) Magnesium carbonate for phosphate control in

2927

patients on hemodialysis. A randomized controlled trial. International Urology

2928

& Nephrology 40: 193-201 [ref ID: 5221]

2929 2930 2931

UK Renal Registry. thirteenth annual report. 2010. http://www.renalreg.com/Reports/2010.html

2932

Wilson R; Zhang P; Smyth M; Pratt R. (2009) Assessment of survival in a 2-

2933

year comparative study of lanthanum carbonate versus standard therapy.

2934

Current Medical Research & Opinion 25: 3021-8 [ref ID: 5278]

2935 2936

Use of supplements in people with stage 4 or 5 CKD who are not on dialysis

2937

No studies found

2938

Use of supplements in people with stage 5 CKD who are on dialysis

2939

Chertow GM; Dillon M; Burke SK; Steg M; Bleyer AJ; Garrett BN; Domoto DT;

2940

Wilkes BM; Wombolt DG; Slatopolsky E. A randomised trial of sevelamer Management of hyperphosphataemia: NICE guideline DRAFT (October 2012) Page 231 of 248

DRAFT FOR CONSULTATION 2941

hydrochloride (RenaGel) with and without supplemental calcium. Clinical

2942

Nephrology 51(1): 18-26 (1999) [ref ID: 9336]

2943

Cibulka R; Racek J; Pikner R; Rajdl D; Trefil L; Vesala E; Studenovska M;

2944

Siroka R. Effect of L-carnitine supplementation on secondary

2945

hyperparathyroidism and bone metabolism in hemodialyzed patients. Calcified

2946

Tissue International 81: 99-106 (2007) [ref ID: 9357]

2947

Shahbazian H; Zafar Mohtashami A; Ghorbani A; Abbaspour MR; Belladi

2948

Musavi SS; Hayati F; Lashkarara GR. Oral niacinamide reduces serum

2949

phosphate, increases HDL, and induces thrombocytopenia in hemodialysis

2950

patients: a double-blind racndomised controlled trial. Nefrologia 31(1): 58-65

2951

(2011) [ref ID: 10763]

2952

Young DO; Cheng SC; Delmez JA; Coyne DW. The effect of oral niacinamide

2953

on plasma phosphate levels in peritoneal dialysis patients. Peritoneal Dialysis

2954

International 29: 562-7 (2009) [ref ID: 11182]

2955

Sequencing of treatments

2956

No studies found

2957 2958

Glossary and abbreviations

2959

Glossary

2960

Chronic kidney disease

2961

The term ‘chronic kidney disease’ describes abnormal kidney function and/or

2962

structure. It is defined as ‘chronic’ as the condition is long-lasting and often

2963

progresses over time.

2964

The US ‘National Kidney Foundation kidney disease outcomes quality

2965

initiative’ (NKF-KDOQI) classification divides CKD into 5 stages according to

2966

the extent of a person’s loss of renal function. Stages 4 and 5, the stages

2967

covered in this guideline, are the most advanced stages of the condition.

2968

Stage 4 is defined by a glomerular filtration rate (GFR) of 15–

Management of hyperphosphataemia: NICE guideline DRAFT (October 2012) Page 232 of 248

DRAFT FOR CONSULTATION 2969

30 ml/min/1.73 m2, and stage 5 by a GFR of less than 15 ml/min/1.73 m2. A

2970

GFR of over 90 ml/min/1.73 m2 is considered normal unless there is other

2971

evidence of kidney disease.

2972

A decline in or absence of kidney function leads to a range of adverse effects,

2973

including: fluid retention, anaemia, abnormal levels of lipids in the blood,

2974

protein–energy malnutrition and disturbances in bone and mineral

2975

metabolism. Additionally, chronic kidney disease often exists together with

2976

other conditions, such as cardiovascular disease and diabetes.

2977

Dietary management

2978

Dietary management is, in general, a non-pharmacological approach to

2979

managing hyperphosphataemia involving the adjustment of a patient’s diet to

2980

reduce the amount of phosphate they consume. This can be achieved, for

2981

example, by reducing the intake of food and drinks with a high phosphate to

2982

protein ratio, such as some dairy products and nuts, or a high level of

2983

phosphate additives, such as cola drinks or processed foods. However, it is

2984

also important that a patient’s nutritional status is maintained at a healthy

2985

level.

2986

Dialysis

2987

Dialysis is an artificial process for filtering waste and excess water from the

2988

blood. It is a form of renal replacement therapy and is often initiated when

2989

chronic kidney disease advances to end-stage renal disease, in which there is

2990

a complete or almost complete loss of renal function.

2991

Extended dominance

2992

In health economic modelling, each intervention is compared to the next most

2993

effective alternative by calculating the incremental cost-effectiveness ratio

2994

(ICER). Extended dominance occurs when the ICER for a given treatment

2995

alternative is higher than that of the next, more effective, alternative. A

2996

treatment option that is extendedly dominated, that is has a higher ICER and

2997

lower effectiveness, will almost always be rejected in favour of a treatment

2998

option with a lower ICER and greater effectiveness.

Management of hyperphosphataemia: NICE guideline DRAFT (October 2012) Page 233 of 248

DRAFT FOR CONSULTATION 2999

Hypercalcaemia

3000

Hypercalcaemia is the abnormal elevation of calcium in the blood. The

3001

condition arises because of insufficient filtering of calcium from the blood by

3002

poorly functioning kidneys. This, in turn, means that a certain amount of the

3003

calcium does not leave the body in the urine, instead remaining in the blood.

3004

Other causes of hypercalcaemia include a high intake of calcium, for example

3005

through the diet or medications, and high levels of vitamin D or parathyroid

3006

hormone, which increase the absorption of calcium in the intestine and its

3007

release from bone. Calcium is also obtained from dialysate in haemodialysis.

3008

High serum calcium levels can lead to increases in morbidity and mortality

3009

through, for example, abnormalities of bone and joint morphology, increased

3010

vascular and soft tissue calcification, and cardiovascular disease.

3011

Hyperphosphataemia

3012

Hyperphosphataemia is an abnormal elevation of phosphate in the blood. The

3013

condition arises because of insufficient filtering of phosphate from the blood

3014

by poorly functioning kidneys. This, in turn, means that a certain amount of the

3015

phosphate does not leave the body in the urine, instead remaining in the

3016

blood.

3017

Dietary phosphate intake can further contribute to hyperphosphataemia; food

3018

and drink with a large phosphate to protein ratio, such as dairy products, or a

3019

large amount of phosphate additives are of particular concern in patients with

3020

chronic kidney disease.

3021

High serum phosphate levels can directly and indirectly increase parathyroid

3022

hormone secretion, leading to the development of secondary

3023

hyperparathyroidism and increases in morbidity and mortality.

3024

Hyperphosphataemia can contribute to an increased incidence of fracture,

3025

abnormalities of bone and joint morphology, vascular and soft tissue

3026

calcification, and cardiovascular disease.

Management of hyperphosphataemia: NICE guideline DRAFT (October 2012) Page 234 of 248

DRAFT FOR CONSULTATION 3027

Multiple treatment comparison

3028

Well-conducted randomised controlled trials are the â&#x20AC;&#x2DC;gold standardâ&#x20AC;&#x2122; for directly

3029

comparing the effectiveness of different treatments. However, for some

3030

conditions there are many different treatments available, many of which have

3031

not been directly compared in head-to-head trials.

3032

If there is a lack of evidence from direct comparison trials, or the available

3033

evidence is limited, results from different trials can be used to indirectly

3034

estimate the effects of a treatment relative to each of the other treatments. In

3035

this way, a multiple treatment comparison uses a network of the available

3036

direct and indirect comparisons to provide an overall picture of the available

3037

treatments. Indirect comparisons can also be used to strengthen the

3038

estimates of effect gained from direct comparisons.

3039

Phosphate binders

3040

Phosphate binders are pharmacological interventions that bind to dietary

3041

phosphate while it is in the stomach, preventing its absorption into the blood.

3042

Instead, the bound phosphate is passed out of the body in the faeces.

3043

A range of phosphate binders are licensed in the UK, though they can broadly

3044

be defined as calcium-based and non-calcium-based. They are available as

3045

pills, chewable tablets, capsules and powders.

3046

Because the phosphate-binding action occurs in the stomach, it is important

3047

that these medications are taken with food and not on an empty stomach.

3048

Self-management tool

3049

For the purpose of this guideline, the summary term 'self-management tool'

3050

was used to collectively describe the aids used to help patients to manage

3051

their dietary intake or serum phosphate levels alongside education or

3052

counselling.

3053

These tools ranged from a fridge magnet detailing high-phosphate foods, to

3054

an individualised tracking chart that uses visual goals to engage patients in

3055

achieving phosphate control.

Management of hyperphosphataemia: NICE guideline DRAFT (October 2012) Page 235 of 248

DRAFT FOR CONSULTATION 3056

Supplements

3057

Supplements are a potentially wide range of substances, including vitamins

3058

and minerals. A supplement is often defined as a preparation intended to

3059

provide nutrients that may be missing from a personâ&#x20AC;&#x2122;s diet or may not be

3060

consumed in sufficient quantities. However, in this guideline supplements

3061

were defined as vitamins, minerals and other substances that control serum

3062

phosphate through effects other than phosphate-binding.

3063

It should be noted that in the case of calcium, its classification as a phosphate

3064

binder was distinguished from that as a supplement through the timing of its

3065

administration. As defined in this guideline, calcium-based phosphate binders

3066

are taken with food while calcium supplements are taken on an empty

3067

stomach when the phosphate-binding effect will be limited.

3068

Please see the NICE glossary for an explanation of terms not described

3069

above.

3070

Abbreviations Abbreviation

Term

Amino acid

ACR

Albumin to creatinine ratio

Any-B C-based

Any binder Calcium-based binder

Calcium acetate

CAMG

Calcium acetate with magnesium carbonate

CC CCr

Calcium carbonate Creatinine clearance

CHF

Chronic heart failure

Confidence interval / credibility interval

CKD

Chronic kidney disease

Cardiovascular

eGFR

Estimated glomerular filtration rate

ESRD

End-stage renal disease

GDG GFR

Guideline development group Glomerular filtration rate

Gastrointestinal

GRADE

Grading of Recommendations Assessment, Development and Evaluation

Management of hyperphosphataemia: NICE guideline DRAFT (October 2012) Page 236 of 248

DRAFT FOR CONSULTATION HR

Hazard ratio

ICER IDWG

Incremental cost effectiveness ratio Interdialytic weight gain

Keto acid

Lanthanum carbonate

LPD MD

Low-protein diet Mean difference

Magnesium carbonate

MNA

Multi-nutritional assessment

MPD MTC

Moderate-protein diet Multiple treatment comparison

nPCR

Normalised protein catabolic rate

Odds ratio

P PTH

Placebo Parathyroid hormone

PTx

Parathyroidectomy

QALY

Quality-adjusted life year

RCT RR

Randomised controlled trial Relative risk

RRT

Renal replacement therapy

Sevelamer carbonate

SCr SD

Serum creatinine Standard deviation

SGA

Subjective Global Assessment of nutrition

Sevelamer hydrochloride

sLPD sVLPD

Supplemented low-protein diet Supplemented very-low-protein diet

Kidney transplant

VLPD

Very-low-protein diet

3071 3072

Management of hyperphosphataemia: NICE guideline DRAFT (October 2012) Page 237 of 248

DRAFT FOR CONSULTATION 3073

Appendix A Contributors and declarations of interests

3074

The Guideline Development Group

3075

Gary McVeigh (Chair)

3076

Professor of Cardiovascular Medicine, Queenâ&#x20AC;&#x2122;s University Belfast

3077

David Bennett-Jones

3078

Consultant - Renal Medicine, University Hospitals Coventry & Warwickshire

3079

Shelley Cleghorn

3080

Principal Paediatric Nephrology Dietitian, Great Ormond Street Hospital for

3081

Children

3082

Roy Connell

3083

Clinical Nurse Specialist - Paediatric dialysis, Nottingham University Hospital

3084

Indranil Dasgupta

3085

Consultant Physician and Nephrologist, Birmingham Heartlands Hospital

3086

Sylvia Grace

3087

Renal Dietitian, University Hospitals Coventry & Warwick NHS Trust

3088

Clair Huckerby

3089

Pharmaceutical Adviser - Medicines Management Lead, NHS Dudley

3090

Nora Kerigan

3091

Dialysis Adequacy Practitioner, Lancashire Teaching Hospitals NHS Trust

3092

Fiona Loud

3093

Patient and carer member, The Kidney Alliance

3094

Nicholas Palmer

3095

Patient and carer member, National Kidney Federation

3096

Rukshana Shroff

3097

Consultant in Paediatric Nephrology, Great Ormond Street Hospital for

3098

Children

Management of hyperphosphataemia: NICE guideline DRAFT (October 2012) Page 238 of 248

DRAFT FOR CONSULTATION 3099

Internal Clinical Guidelines Technical Team

3100

An Internal Clinical Guidelines Technical team was responsible for this

3101

guideline throughout its development. It prepared information for the Guideline

3102

Development Group, drafted the guideline and responded to consultation

3103

comments.

3104

Emma Banks

3105

Project Manager

3106

Mendwas Dzingina

3107

Technical Analyst (Health Economics)

3108

Sarah Glover

3109

Information Specialist

3110

Michael Heath

3111

Programme Manager

3112

Lucy Hoppe

3113

Assistant Technical Analyst

3114

Dylan Jones

3115

Technical Adviser

3116

Gabriel Rogers

3117

Technical Adviser (Health Economics)

3118

NICE Centre for Clinical Practice

3119

Laura Donegani

3120

Guideline Commissioning Coordinator

3121

Louise Millward

3122

Associate Director

3123

Sarah Palombella

3124

Editor

Management of hyperphosphataemia: NICE guideline DRAFT (October 2012) Page 239 of 248

DRAFT FOR CONSULTATION 3125

Rachel Ryle

3126

Guideline Commissioning Manager

3127

Judith Thornton

3128

Technical Lead

3129

Erin Whittingham

3130

Assistant Project Manager, Patient & Public Involvement Programme

3131

Declarations of interests GDG Member

Interest Declared

Gary McVeigh

None

David Bennett Jones Shelley Cleghorn Roy Connell Indril Dasgupta

None

Sylvia Grace Clair Huckerby Nora Kerigan Fiona Loud Nicholas Palmer Rukshana Shroff

None None Chief Investigator in the UK for the Steering study which is an observational study of Osvaren (calmag) in dialysis patients. None None None None None None

Type of Interest

Decisions Taken

Non Personal Pecuniary

Leave the room prior to any decisions and recommendations made

3132 3133

Appendix B List of all research recommendations

3134

The Guideline Development Group has made the following recommendations

3135

for research, based on its review of evidence, to improve NICE guidance and

3136

patient care in the future.

Management of hyperphosphataemia: NICE guideline DRAFT (October 2012) Page 240 of 248

DRAFT FOR CONSULTATION 3137

Phosphate binders in patients with CKD stage 4 or 5

3138 3139

Which binders are most effective in controlling serum phosphate in adults with

3140

stage 4 or 5 CKD who are not on dialysis?

3141

Why this is important

3142

Limited evidence was found on the use of phosphate binders in adults with

3143

stage 4 or 5 CKD. While it is possible in some instances to extrapolate from

3144

the evidence on people with stage 5 CKD who are on dialysis, it is not ideal.

3145

Therefore a series of RCTs should be conducted to examine the comparative

3146

effectiveness of various phosphate binders against each other for the

3147

management of serum phosphate in adults with stage 4 or 5 CKD. These

3148

trials should examine the long-term (ideally 12-month) effects of the various

3149

binders on outcomes such as serum phosphate, serum calcium, adverse

3150

events and the ability of the binders to control serum phosphate and calcium

3151

within the given ranges.

3152

3153

Effectiveness and safety of aluminium hydroxide in adults

3154

In adults with stage 4 or 5 CKD, including those on dialysis, what is the long-

3155

term effectiveness and safety of aluminium hydroxide in controlling serum

3156

phosphate?

3157

Why this is important

3158

Limited evidence was found on the efficacy of aluminium hydroxide in adults

3159

and no evidence was found on the long-term efficacy and safety of aluminium

3160

hydroxide. A series of RCTs should be conducted separately in adults with

3161

stages 4 or 5 CKD, including those on dialysis. These trials should be run for

3162

a minimum of 12 months and should examine the effect of aluminium

3163

hydroxide on outcomes such as serum phosphate, serum calcium, adverse

3164

events and the ability of the binders to control serum phosphate and calcium

3165

within the given ranges. In addition, specific data should be collected on

3166

aspects relating to aluminium toxicity. Management of hyperphosphataemia: NICE guideline DRAFT (October 2012) Page 241 of 248

DRAFT FOR CONSULTATION 3167

Effectiveness and safety of magnesium carbonate

3168 3169

In adults and children with stage 4 or 5 CKD, including those on dialysis, what

3170

is the long-term effectiveness and safety of magnesium carbonate in

3171

controlling serum phosphate?

3172

Why this is important

3173

Limited evidence was found on the use of magnesium carbonate to control

3174

serum phosphate. However, the evidence that was assessed suggested that

3175

magnesium carbonate could be very effective in controlling serum phosphate.

3176

A series of RCTs should be conducted separately in adults and children with

3177

stages 4 or 5 CKD, including those on dialysis. These trials should be run for

3178

a minimum of 12 months and should examine the effect of magnesium

3179

carbonate on outcomes such as serum phosphate, serum calcium, adverse

3180

events and the ability of the binders to control serum phosphate and calcium

3181

within the given ranges. In addition, specific data should be collected on

3182

aspects relating to magnesium toxicity.

3183

3184

Which binders are most effective in controlling serum phosphate in children

3185

with stage 4 or 5 CKD who are not on dialysis?

3186

Why this is important

3187

Limited evidence was found on the use of phosphate binders in children with

3188

stage 5 CKD who are on dialysis, and none was found for those with stage 4

3189

or 5 CKD who are not on dialysis. Therefore a series of RCTs should be

3190

conducted that examine the comparative effectiveness of various phosphate

3191

binders against each other for the management of serum phosphate in

3192

children with stage 4 or 5 CKD. These trials should examine the long-term

3193

(ideally 12-month) effects of the various binders on outcomes such as serum

3194

phosphate, serum calcium, adverse events and the ability of the binders to

3195

control serum phosphate and calcium within the given ranges.

Phosphate binders in children

Management of hyperphosphataemia: NICE guideline DRAFT (October 2012) Page 242 of 248

DRAFT FOR CONSULTATION 3196 3197

Sequencing and combining of phosphate binders

3198

For adults with stage 4 or 5 CKD, including those on dialysis, what is the most

3199

effective sequence or combination of phosphate binders to control serum

3200

phosphate?

3201

Why this is important

3202

It is thought that the longer people remain on calcium-based binders, the

3203

greater their risk of developing hypercalcaemia. However, no evidence was

3204

found on the most appropriate sequence or combination of phosphate binders

3205

a person should receive to control serum phosphate and serum calcium. A

3206

series of RCTs should be conducted separately in adults with stages 4 or 5

3207

CKD, including those on dialysis. These trials should be run for a minimum of

3208

12 months and should examine comparative effectiveness of various

3209

sequences and combinations of available phosphate binders on outcomes

3210

such as serum phosphate, serum calcium, adverse events and the ability of

3211

the binders to control serum phosphate and calcium within the given ranges.

3212

Management of hyperphosphataemia: NICE guideline DRAFT (October 2012) Page 243 of 248

DRAFT FOR CONSULTATION 3213

Appendix C Guideline scope

3214

See separate file.

3215

Management of hyperphosphataemia: NICE guideline DRAFT (October 2012) Page 244 of 248

DRAFT FOR CONSULTATION 3216

Appendix D How this guideline was developed

3217

See separate file.

3218

Management of hyperphosphataemia: NICE guideline DRAFT (October 2012) Page 245 of 248

DRAFT FOR CONSULTATION 3219

Appendix E Evidence tables

3220

See separate file.

3221

Management of hyperphosphataemia: NICE guideline DRAFT (October 2012) Page 246 of 248

DRAFT FOR CONSULTATION 3222

Appendix F Full health economic report

3223

See separate file.

3224

Management of hyperphosphataemia: NICE guideline DRAFT (October 2012) Page 247 of 248

DRAFT FOR CONSULTATION 3225

Appendix G Clinical guideline technical assessment

3226

unit analysis (phosphate binders)

3227

See separate file.

3228

Management of hyperphosphataemia: NICE guideline DRAFT (October 2012) Page 248 of 248