Nsw therapeutic Advisory Group Level 5, 376 Victoria Street po box 766




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NSW Therapeutic Advisory Group


Level 5, 376 Victoria Street

PO Box 766

Darlinghurst NSW 2010
Phone: 61 2 8382 2852
Fax: 61 2 8382 3529

Email: nswtag@stvincents.com.au



www.nswtag.org.au

Drugs for the treatment of secondary


hyperparathyroidism and hyperphosphataemia
Targeted Literature Review
June 2007


Contents

Summary 3

Background 3

Cinacalcet 3

Treatment recommendations 3

Use in children 4

Phosphate Binders 4

Treatment recommendations 4

Use in children 5

Introduction 6

Systematic Reviews and Guidelines 7

Cinacalcet 7

Clinical Evidence (2007 edition) 7

NICE 7

Cochrane 9



CARI (Caring for Australasians with

Renal Impairment) 10

NHS Health Technology Assessment

Programme 11

KDIGO (Kidney Disease: Improving

Global Outcomes) 11

Phosphate Binders 12

Clinical Evidence (2007 edition) 12

Scottish Medicines Consortium 13

CADTH 13


COCHRANE 14

CARI (Caring for Australasians with

Renal Impairment) 14

National Kidney Foundation (US) 16

Other reviews 18

Cinacalcet 18

Phosphate Binders 22

Clinical Studies 27

Cinacalcet 27

Efficacy 27

Use in Children 32

Predictors of response 32

Safety 32

Health economics, resources,

risk/benefit 32

Phosphate Binders 33

Efficacy 33

Use in Children 48

Predictors of response 50

Safety 50

Health economics, resources,

risk/benefit 54

Acknowledgments 58


2




Summary


This summary is not a position statement
and does not represent recommendations
from the NSW Therapeutic Advisory Group.
It is a summary of the main points from the
reviews, guidelines and articles identified in
a targeted review of the published literature
and presented in the main text of this

document.


Background

Elevated parathyroid hormone (PTH) levels from secondary hyperparathyroidism

(SHPT) are seen in around 40% of patients on dialysis for chronic renal failure. Very high levels of PTH develop in 1 in 10

patients on dialysis, defined as uncontrolled hyperparathyroidism (>800 pg/mL), with

nodular hyperplasia of the parathyroid
glands. In such cases, parathyroidectomy
may be considered. Elevated PTH leads to
high turnover bone disease (including the
typical features of osteitis fibrosa) and may
be present in up to 75% of people on
dialysis resulting in raised serum calcium,
phosphorus and calcium-phosphorus
product (calcium-phosphate product).
Fracture risk may be increased. Secondary
hyperparathyroidism (SHPT) may also be
complicated by calcification at a range of
sites, including cardiovascular calcification.
Left ventricular hypertrophy and dysfunction
may also result from raised PTH levels.
Such effects contribute to the increased
overall and cardiovascular mortality noted in
people with chronic kidney disease (CKD).

Prophylaxis is considered appropriate in asymptomatic patients with

hyperparathyroidism. International guidelines suggest target levels for serum PTH, calcium and phosphate

concentrations. The main treatment


approaches are to reduce serum phosphate
by using phosphate binding agents (and
dietary restriction) and to reduce PTH by
supplementation of vitamin D. The optimum
choice of phosphate binding agent is
unclear. Aluminium-containing agents may
contribute to increased aluminium toxicity
and are discouraged. Calcium-containing
binders were the mainstay of treatment until
concerns about associated risk of vascular
calcification in people on haemodialysis
arose. (Adapted from

http://www.hta.ac.uk/project/1499.asp)


Cinacalcet

Cinacalcet (Sensipar™) is approved by the TGA for treating the biochemical

manifestations of SHPT in patients with end-
stage renal disease (ESRD) receiving

dialysis. It operates by increasing


parathyroid sensitivity to serum calcium thus reducing secretion of PTH, which, in turn, reduces serum calcium.
Treatment recommendations

A Cochrane review (2006) of 8 randomised


controlled trials (RCTs - all presented in the
Clinical Studies section of this document)
concluded that calcimimetic treatment of
SHPT leads to significant improvements in
biochemical parameters associated with

increased mortality, cardiovascular risk and osteitis fibrosa. They state it can be

considered of potential but currently
unproven benefit to patient-based outcomes including cardiovascular mortality, renal osteodystrophy and fracture.
CARI (Caring for Australasians with Renal Impairment) guidelines (April 2006) state that cinacalcet should be used in

conjunction with standard therapies to


improve the proportion of dialysis patients who achieve target serum levels of PTH, calcium, phosphate and calcium-phosphate product. They note however, that rates of treatment withdrawal and the incidence of nausea and vomiting are higher for
cinacalcet than for placebo.

CARI guidelines also state that cinacalcet therapy of SHPT may reduce rates of

parathyroidectomy and fracture but has not been shown to influence hospitalisation,

cardiovascular mortality, all-cause mortality or quality of life. Clinical Evidence (2007)

adds that a pooled analysis found cinacalcet reduced the risk of cardiovascular

hospitalisation, fracture, and

parathyroidectomy compared with placebo.
It found no significant difference in overall
mortality between cinacalcet and placebo
though safety outcomes were not primary






outcomes of interest in the studies (see Cunningham et al 2005 abstract).

CARI guidelines add that cinacalcet should be available for use by patients who require, but are medically unfit for parathyroidectomy or are waiting for elective

parathyroidectomy.

The National Institute for Health and Clinical Excellence (NICE) [2007 review] do not

recommended cinacalcet for the routine


treatment of SHPT in patients with ESRD
on maintenance dialysis therapy. They do

recommend it for the treatment of refractory SHPT in patients with ESRD (including

those with calciphylaxis) who have ‘very uncontrolled’ plasma levels of intact PTH (defined as greater than 85 pmol/litre [800 pg/ml]) that are refractory to standard

therapy, and a normal or high adjusted


serum calcium level, and in whom surgical
parathyroidectomy is contraindicated (in that
the risks of surgery are considered to
outweigh the benefits). They add that
response to treatment should be monitored
and treatment continued only if a reduction
in iPTH of 30% or more is seen within 4
months of treatment.
Cochrane, CARI and NICE all state that many other studies are required including RCTs over longer time periods to assess efficacy and safety of cinacalcet in ESRD. Trial endpoints should include

cardiovascular and all-cause mortality, hospitalisation, fracture and bone mineral density and the relationship between

biochemical disruption in SHPT and these
clinical outcomes needs to be elucidated.
The NICE review did not identify any cost-
effectiveness studies but they did review unpublished economic models, which

showed incremental cost-effectiveness ratios (ICERs) of £35,600 to £61,900 per quality-adjusted life year (QALY) gained (see body text for specifics). NICE

concluded that cinacalcet was unlikely to be
a cost-effective use of NHS resources in the
treatment of SHPT in patients with ESRD.

Use in children

No evidence was found for the use of cinacalcet in children.
Phosphate Binders

Sevelamer (Renagel™) is approved by the TGA for the management of

hyperphosphataemia in adult patients with stage 4 and 5 CKD. It is a non-calcium

containing phosphate binder which also reduces serum lipid levels.

Lanthanum (Fosrenol™) is approved by the TGA for the treatment of

hyperphosphataemia in adults with chronic renal failure (CRF) on haemodialysis or

continuous ambulatory peritoneal dialysis.

Treatment recommendations

CARI guidelines (2006), based on National Health and Medical research Council

(NHMRC) levels of evidence, recommend


the use of sevelamer when levels of calcium
are above the target range or when levels of
PTH are below the target range, but this is
only based on opinion - ie, low level of

evidence. They cite RCTs, which are included in the more comprehensive Canadian Agency for Drugs and

Technologies in Health (CADTH) systematic review published in 2006. This review

included 10 RCTs in its assessment with a total of 3,025 participants. They found no convincing evidence that substituting

sevelamer for calcium-based binders
reduced all-cause mortality, cardiovascular
mortality, hospitalisation, or the frequency of
symptomatic bone disease, and no evidence
that sevelamer improved quality of life.
While sevelamer therapy resulted in a
smaller decrease in phosphate levels, and
fewer episodes of hypercalcaemia,
compared with calcium-based phosphate
binders, the clinical significance of this is still
unknown. CARI comment that, in patients
prone to hypercalcaemia, there may be a
role for sevelamer but it is still unclear
whether sevelamer is associated with less
calcification in such cases and whether the
reduction in vascular calcification is due to
lower calcium levels or by concomitant
improvement in lipid profile. They state that
recent Japanese studies have shown good






phosphate control and patient tolerability with a combination of sevelamer and CaCO3 (see Koiwa et al 2005 abstract)

CADTH state that the cost effectiveness of
sevelamer is still uncertain. A cost per QALY
gained ranging from $127,000 to $278,100
was calculated, and the authors suggested a
possible restriction to patients ≥65 years old.

CARI comment that lanthanum is an


effective binder of dietary phosphate

compared with placebo (Joy & Finn 2003) and similar to CaCO3, with no trend towards adynamic bone disease (D’Haese et al

2003). There are no RCTs comparing
lanthanum with sevelamer. A recent

Prescrire review states that lanthanum is no more effective than other phosphate binders in terms of effects on mortality, incidence of fractures, or blood phosphorus level. In

trials, adverse events were more frequent with lanthanum than with the other

phosphorus chelators (gastrointestinal


disorders, headaches, seizures, and
encephalopathy). Longer-term studies

suggest lanthanum is well tolerated (see Altmann et al 2007, Finn 2006, Finn & Joy 2005). The Scottish Medicines Consortium (2007 review) adds that lanthanum

carbonate takes more than ten years to reach steady state in bone and that

accumulated lanthanum would be cleared


slowly if discontinued. Prescrire conclude
that when a phosphorus chelator is needed
to treat hyperphosphataemia in dialysis

patients with CRF, calcium carbonate is the first choice and sevelamer remains the best alternative.


CARI suggest that future research needs to
include mortality studies with sevelamer and
lanthanum in comparison with calcium salts.
Also, a cost-benefit analysis of sevelamer
vs. calcium salts should be undertaken as
well as bone biopsy studies of patients

treated long-term with lanthanum to satisfy safety concerns.


Use in children

Published studies on the use of phosphate binding agents in children are scarce. In general, the evidence from adult studies is not necessarily directly applicable to


paediatric age groups (especially younger ages). The need for longer-term

effectiveness and safety data on relevant clinical (eg, bone disease, vascular

calcification, mortality) versus surrogate (eg, calcium and phosphate levels) outcomes is even more relevant in paediatrics because of the likelihood of a different (and, currently, largely unknown) adverse effect profile

compared with adults and the fact that


younger patients will be on treatment for a
relatively longer time. Civilibal et al showed
that that serum phosphorus and the
cumulative exposure to calcium-containing
phosphate binders were the most significant
independent predictors in the development
of coronary artery calcification in children
with ESRD. Thus, non-calcium based
phosphate binders might have an advantage
in this regard; however, the small study by
Pieper et al showed that sevelamer may
increase metabolic acidosis compared with
calcium acetate. The clinical significance of
this on factors such as growth and
development are as yet unknown and larger
controlled trials are required.




g. (a or e) and f combined (11 results - this



Introduction

This document contains summary data from published reviews, guidelines and articles to help drug and therapeutic committees make decisions about use of cinacalcet,

sevelamer and lanthanum. It is not a Position Statement and does not represent recommendations from the NSW
Therapeutic Advisory Group.
The data was collated after searching
websites of organizations/publications
including Cochrane, National Institute for
Health and Clinical Excellence (NICE),

Scottish Intercollegiate Guidelines Network (SIGN), The Canadian Agency for Drugs and Technologies in Health (CADTH),

Clinical Evidence, National Heath Service Health Technology Assessment Programme (NHS HTA Programme), National Guideline Clearing House (NGC), Scottish Medicines Consortium (SMC), Medical Journal of

Australia (MJA), National Health and


Medical research Council (NHMRC) and
Medscape (March 2007). Specialist
nephrology guidelines were also sourced:
Caring for Australiasians with Renal
Impairment (CARI), Kidney Disease
Outcomes Quality Initiative (K/DOQI), British Renal Association, Canadian Society of
Nephrology, European Best Practice
Guidelines (all accessible from

www.kdigo.org).


An Embase search (1996 to 2007 week 15) was also performed using the following

MESH terms:

a. “kidney disease” or “chronic kidney
disease” or “hyperphoshphatemia” or

“secondary hyperparathyroidism” (24764 results).

b.”cinacalcet” or “calcimimetic agent” or “r568” or “calcium channel stimulating agent” or “amg073” or “N[3(2 chlorophenyl)propyl] 1(3 methoxyphenyl)ethylamine” or
“calcimimetic agent” or n (3[2

chlorophenyl]propyl) alpha methyl 3


methoxybenzylamine” (1016 results)

c. a and b combined (299 results)

d. “sevelamer” or “lanthanum carbonate” or “lanthanum” (2095 results)

e. a and d combined (389 results)

f. “case control studies” or “cohort analyses” (50889 results).

search was performed to locate additional safety information not otherwise found in the other searches).

h. (b or d) and (child or adolescent or infant)

- this search was conducted to find any paediatric studies with cinacalcet or

lanthanum or sevelamer. It yielded no more results than those identified in the other

searches).

All of the results were assessed, and abstracts of the selected papers are presented in this document.
Summaries of systematic reviews and
guidelines are reproduced verbatim where
possible, but may have been edited for
conciseness. The abstracts of review
articles and clinical studies are taken
verbatim from Embase (background
information may have been deleted) and are
presented chronologically (latest studies
first). Full references are given so that
readers may consult these if required.




caution because the safety outcomes were



Systematic Reviews and Guidelines
Cinacalcet

Clinical Evidence (2007 edition)

Source: Hall YN, Chertow GM. End stage
renal disease. Available at Books @ OVID,

http://gateway.ut.ovid.com/gw1/ovidweb.cgi

Summary of main findings:

Two randomized controlled trials (RCTs)
found that cinacalcet improved control of
secondary hyperparathyroidism (SHPT)
compared with placebo at 26 weeks.

Benefits


Cinacalcet versus placebo: The first RCT
(Block et al 2004) compared cinacalcet

versus placebo for 26 weeks (efficacy was measured from week 13 to week 26). It

found that cinacalcet significantly improved control of SHPT compared with placebo. The second RCT (Lindberg et al 2005)

found that cinacalcet significantly improved control of SHPT compared with placebo.

Harms

Cinacalcet versus placebo: The first RCT found that adverse events were common and occurred at a similar frequency with cinacalcet and with placebo. The second RCT reported a higher incidence of



gastrointestinal side effects in people
receiving cinacalcet compared with placebo

Comment


The second RCT found that the efficacy of cinacalcet was similar for peritoneal dialysis and haemodialysis. We identified one

pooled analysis of safety data (Cuningham et al 2005) from four RCTs, two of which were phase II trials and had participant

overlap with the two RCTs described in the
benefits section above, and therefore are

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