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not reported separately. The pooled analysis (1184 adults with end-stage renal disease [ESRD] receiving dialysis) found that

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.
Such results should be interpreted with

not primary outcomes of interest in the studies. Further prospective studies will be needed to evaluate whether reductions in PTH, calcium, and phosphorus

concentrations favourably influence
cardiovascular health and overall survival.
NICE

Source: www.nice.org.uk Cinacalcet for the


treatment of SHPT in patients with ESRD on
maintenance dialysis therapy. January 2007.

Summary of main findings:

Guidance

1. Cinacalcet is not recommended for


the routine treatment of SHPT in

patients with ESRD on maintenance dialysis therapy.

2. Cinacalcet is recommended for the
treatment of refractory SHPT in

patients with ESRD (including those with calciphylaxis) only in those:

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.

3. Response to treatment should be


monitored regularly and treatment

should be continued only if a


reduction in the plasma levels of
intact PTH of 30% or more is seen
within 4 months of treatment,
including dose escalation as
appropriate.

Clinical effectiveness

Seven RCTs in people with

hyperparathyroidism secondary to ESRD


who were receiving dialysis were found.
Significant improvements in mean levels of

PTH, calcium, phosphorus and the calcium-


phoshporus product (calcium-phosphate

product) with cinacalcet were found in most


of the studies. A pooled analysis of the 3
largest RCTs (n = 1136) showed that target
mean intact PTH levels (<26.5 pmol/litre

[250 pg/ml]) were reached in 40% of








patients randomised to cinacalcet,


compared with 5% of patients receiving
placebo (p < 0.001). Significantly more
patients who were treated with cinacalcet
had a reduction of at least 30% in mean
intact PTH levels compared with those
receiving standard care alone in all RCTs. A
post-hoc analysis of pooled data from 4
RCTs designed to investigate changes in
biochemical markers (n = 1184) assessed
the effects of cinacalcet compared with
placebo on the clinical outcomes of fracture,
cardiovascular hospitalisation, all-cause
hospitalisation, parathyroidectomy and
mortality. No statistically significant
differences were seen in overall mortality or
all-cause hospitalisation. However,
statistically significant differences were
observed in fracture, cardiovascular
hospitalisation, and parathyroidectomy
based on follow-up of 6-12 months. This
analysis also reported HRQOL

improvements.

Consideration of the evidence

The clinical trials of cinacalcet showed that it was effective in reducing levels of PTH and other biochemical markers, including serum calcium and phosphorus. A reduction in

adverse clinical outcomes associated with
raised PTH levels, such as bone fracture

and cardiovascular hospitalisation, had been observed in a post-hoc analysis of pooled safety data from several trials. However,

these trials were not designed to
demonstrate the clinical benefits of

treatment in terms of a reduction in adverse events, and there was a lack of data relating to long-term treatment with cinacalcet. The Committee was aware of observational

evidence to suggest that there is a
relationship between levels of PTH, calcium
and phosphate, and adverse clinical
outcomes. However, it noted that there is
considerable uncertainty about the extent to
which intervening to correct derangements
in the levels of PTH, calcium and phosphate
(in particular by lowering PTH levels) is
effective in reducing the risk of the adverse
outcomes. The Committee also noted that
many other factors relating to ESRD and its
underlying causes contribute to the
increased risk of serious adverse events for
people on dialysis, and that these add to the
uncertainty in predicting clinical benefits
from changes in surrogate markers.
Although cinacalcet can reduce the severity of major adverse events associated with

raised PTH levels, it does not replace the need for dietary restrictions and the use of other medications such as phosphate

binders and vitamin D sterols.

Recommendations for further research

The Committee identified a need for long-
term clinical studies that are designed to evaluate the effects of cinacalcet on clinical outcomes (in particular, fracture and

cardiovascular events) in people with ESRD. Studies to establish the multivariate

relationship between biochemical disruption
in SHPT and these clinical outcomes are
also recommended. The Committee also
noted that more research is needed on the
effects of cinacalcet in people with ESRD
with particular clinical needs, specifically

people with refractory secondary (or tertiary) hyperparathyroidism, people awaiting kidney transplants from living donors, people with calciphylaxis, people with recurrent

hyperparathyroidism after

parathyroidectomy, and people in whom surgical parathyroidectomy is

contraindicated.

Cost effectiveness

The systematic review did not identify any published cost-effectiveness studies. An economic model and separate cost-

consequence analysis were submitted by


the manufacturer of cinacalcet, and the
Assessment Group developed its own

economic model. The manufacturer’s model resulted in an incremental cost-effectiveness ratio (ICER) of £35,600 per quality-adjusted life year (QALY) gained. The Assessment Group’s approach differed and they

calculated the ICER for cinacalcet at
£61,900 per additional QALY, though 2
further scenarios produced ICERs of

£43,000 and £38,900 per QALY gained,


excluding dialysis costs. Other analyses
looked at the cost effectiveness of two
strategies for discontinuing cinacalcet in
people whose PTH levels were not

controlled by treatment, and produced


ICERs of £44,000 and £57,400 per QALY.
The manufacturer also refined their analysis
based on strategies for adjusting dosage
according to PTH levels and treatment
discontinuation. The Committee concluded
that cinacalcet was unlikely to be a cost-
effective use of NHS resources in the
treatment of SHPT in patients with ESRD.






Also, they were not persuaded that these treatment strategies were clinically

practicable, and did not consider them an
acceptable approach to maximising the

clinical and cost effectiveness of treatment with cinacalcet.


Cochrane

Source:


www.mrw.interscience.wiley.com/cochrane

Strippoli GFM, Tong A, Palmer SC, et al.


Calcimimetics for SHPT in chronic kidney
disease patients. Cochrane Database of

Systematic Reviews 2006, Issue 4. Art. No.: CD006254.

Summary of main findings:

Main results

This review evaluated the benefits and
harms of calcimimetics for the prevention of
secondary hyperparathyroid bone disease
(including osteitis, fibrosa cystica and
adynamic bone disease) in dialysis patients
with CKD. Eight studies (1429 patients)
were identified, which compared a
calcimimetic agent plus standard therapy to
placebo plus standard therapy. The end of
treatment values of PTH (pg/mL) (MD -
290.79, 95% CI -360.23 to -221.34), serum
calcium (mg/dL) (MD -0.85, 95% CI -1.14 to

-0.56), serum phosphorus (mg/dL) (MD -

0.29, 95% CI -0.50 to -0.08) and the
calcium-phosphate product (mg2/dl2)(MD -

7.90, 95% CI -10.25 to -5.54) were


significantly lower with calcimimetics
compared to placebo. There was no

statistically significant reduction in the risk of all cause mortality with calcimimetics

compared to placebo/no treatment (5 trials, 1285 patients: RR 0.75, 95% CI 0.30 to

1.88). There was a significant increase in achieving a greater or equal to 30%

decrease in mean PTH level with
calcimimetics compared to placebo/no
treatment (4 trials, 1284 patients: RR 4.49, 95% CI 3.04 to 6.64). There were no
reported episodes of fractures in the
included studies. There was no statistically significant increase in the risk of

hypocalcaemia with calcimimetics compared to placebo/no treatment (4 trials, 868

patients: RR 2.89, 95% CI 0.71 to 11.73). There was no statistically significant

reduction in the risk of parathyroidectomy


with calcimimetics compared to placebo/no treatment (analysis 01.11 (1 trial, 395

patients): RR 0.07, 95%CI 0.00 to 1.43). No other significant effects on patient-based

endpoints were demonstrated except for the risk of hypotension which was significantly reduced with calcimimetics compared to

placebo (RR 0.53, 95%CI 0.36 to 0.79).

Conclusions

The authors concluded that calcimimetic treatment of SHPT leads to significant

improvements in biochemical parameters that observational studies have shown to be associated with increased mortality,

cardiovascular risk and osteitis fibrosa. The


authors stated several reservations relating
to the current RCTs (including trial design,
duplicate publication and study duration)
and said that calcimimetic therapy of SHPT
can be considered of potential but currently

unproven benefit to patient-based outcomes including cardiovascular mortality, renal

osteodystrophy and fracture. RCTs with
adequate power and longer treatment

duration are required to determine the most appropriate use of this important new class of drugs.

Surrogate validation

The argument in favor of calcimimetic use hinges on the acceptance of improvements in Ca-P metabolism and levels of PTH as valid surrogates of clinically important

outcomes such as mortality. However, not
all surrogates are valid proxies of clinically
important patient-centered outcomes. In

order for a surrogate to be valid, two criteria must be met. First, there must be a strong, independent and consistent association

between the surrogate and the clinically important outcome, which comes from observational studies. For calcium,

phosphorus and PTH this criterion has been met from a number of large-scale cohort and cross sectional studies. Second, and more importantly, for a surrogate to be valid there must also be evidence that using an

intervention changes a surrogate (eg,
reduction of PTH with a calcimimetic) and
results in an expected change in the patient-
based outcome distal to the surrogate in the
same causal pathway for the disease in
question (e.g. reduction of deaths with a
calcimimetic). This criterion requires a RCT,
which measures both the surrogate and the
hard endpoint. Our study has shown that the
second criterion has not yet been met for


9


calcimimetics. Critics of the second criterion argue that it is too stringent and will mean potentially life-saving interventions will be withheld. Proponents invoke the usual

arguments for superiority of RCTs compared with observational studies (selection bias

and unmeasured confounders) to estimate the true effects of interventions. In addition some interventions that positively affect a surrogate have been reported to have

possible harmful effects on the major
patient-based outcome. A recent example is that high dose erythropoietin increases
hemoglobin levels in patients with metastatic breast cancer but has also been associated with an increase in the risk of death and
disease progression in this population. Such results suggest that validation of surrogates in disease specific populations, should be
mandatory when adopting novel

interventions and that trial results based on unvalidated surrogates should be used

cautiously.
CARI (Caring for Australasians with Renal Impairment)

Source: www.cari.org.au Use of calcimimetic drugs (2006).

Guidelines (NHMRC levels of evidence):

a. Treatment with cinacalcet reduces levels of PTH, calcium, phosphate and the

calcium-phosphate product in patients with SHPT due to dialysis-dependent CKD.

(Level ll evidence)

b. Treatment with cinacalcet is not reported to influence requirements for standard drug therapy of SHPT. However, a greater

proportion of patients treated with the


addition of cinacalcet achieve K/DOQI and CARI target levels of PTH, calcium,
phosphate and the calcium-phosphate product. (Level ll evidence)

c. When using cinacalcet, patients on


dialysis with mild or moderate SHPT are

more likely to achieve target levels of PTH, calcium, phosphate and the calcium-

phosphate product than patients with severe SHPT. (Level ll evidence)

d. Rates of treatment withdrawal and the


incidence of nausea and vomiting are higher
for cinacalcet than for placebo. (Level ll evidence)

Suggestions for clinical care (based on Level III and IV evidence):

The use of cinacalcet in patients on dialysis is associated with a reduction in bone

turnover and bone marrow fibrosis. (Level lll evidence)

Cinacalcet should not be used in patients on dialysis with intact-PTH levels below the

target range (Opinion). The use of cinacalcet may be associated with development of

adynamic bone disease when iPTH values are < 10.6 pmol/L (< 100 pg/mL). (Level lll evidence)

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. (Post-hoc analysis of Level ll evidence)

A therapeutic trial of cinacalcet is warranted for dialysis-dependent patients with SHPT when sustained levels of iPTH and the

calcium-phosphate product remain above target levels despite optimal standard

therapy. (Opinion)

Parathyroidectomy should be considered for patients given a therapeutic trial of

cinacalcet who do not achieve target levels of PTH, calcium, phosphate or the calcium-


phosphate product. In particular,

parathyroidectomy should be considered for patients with sustained levels of iPTH > 85 pmol/L (> 800 pg/mL), or sustained levels of iPTH > 50 pmol/L (> 470 pg/mL) in addition to levels of corrected serum calcium,

phosphate or the calcium-phosphate product above the target ranges. (Opinion)

Cinacalcet should be available for use in


patients who require but are medically unfit

for parathyroidectomy, or who are waiting for elective parathyroidectomy. (Opinion)

Implementation and audit

In Australia and New Zealand, the use of


cinacalcet will depend on availability and the
cost to dialysis patients. 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 the
calcium-phosphate product, as described
elsewhere in the guidelines. Cinacalcet






should be available for use by patients who require, but are medically unfit for

parathyroidectomy or are waiting for elective parathyroidectomy (see Suggestions for

Clinical Care).

Suggestions for future research:

RCTs over longer time periods are needed to assess the continuing efficacy and safety of cinacalcet. Trial endpoints should include cardiovascular and all-cause mortality,

hospitalisation, fracture and bone mineral density. A longer study with larger patient numbers is required to assess influences of cinacalcet on bone histomorphometry. The potential for cinacalcet to be used at earlier stages of CKD and following renal

transplantation requires evaluation. To date,


calcimimetics have been evaluated as an
addition to standard therapy but studies to
assess cinacalcet plus lower dose vitamin D
are underway. An evaluation of cinacalcet
versus standard therapies would be useful,
particularly in early CKD when cinacalcet
may reduce progression of parathyroid

hyperplasia in addition to improving the attainment of biochemical targets.


NHS Health Technology
Assessment Programme

Source: http://www.hta.ac.uk/project/1499.asp The clinical and cost-effectiveness of cinacalcet hydrochloride for the treatment of SHPT in

patients with ESRD on maintenance dialysis therapy.

Details:


This report is due to be published in May
2007. It has been commissioned by the HTA
programme on behalf of NICE on a call-off
contract basis. This project will draw
together all relevant evidence on cinacalcet
in a systematic review. It will also assess
whether the introduction of cinacalcet is
likely to represent good value for money to
the NHS.
KDIGO (Kidney Disease:
Improving Global Outcomes)
Source: www.kdigo.org Clinical Practice
Guidelines for the Diagnosis, Evaluation,
Prevention and Treatment of Chronic Kidney Disease-Related Mineral and Bone

Disorders (CKD-MBD).


Details:

This report is due to be published in 2008. The major issues to be addressed will be to find: the most sensitive and specific

biochemical, bone and calcification tests for diagnosis of CKD-MBD; target levels for

biochemical measures of CKD-MBD; the


prevalence of CKD-MBD at various stages
of CKD; the validity of the classification of
CKD-MBD in predicating morbidity and

mortality; the most efficacious and safe treatment options for the various

components of CKD-MBD.

Treatment options to be assessed will be:

A. Treatment strategies for hyperphosphatemia

Which therapy is best for the control of hyperphosphatemia?

What are the major side effects of oral phosphate binders?

What role do non-binder therapies play?

B. Treatment strategies for hyperparathyroidism

Which therapy (oral calcium supplements,


vitamin D oral vs. IV vs. type, calcimimetics,
direct parathyroid injection of active vitamin
D compounds, parathyroidectomy) is best
for lowering elevated PTH, avoiding over-
suppressed PTH, [minimizing] side effects?

C. Treatment strategies for bone:

What is the efficacy of standard anti osteoporotic therapies including

bisphosphonates, calcitonin, estrogen,


SERMs, and intermittent PTH on bone

mineral density by DEXA, qCT and on bone fractures?

What impact do therapies for control of serum phosphorus, calcium, and PTH have on bone as assessed by histology, DEXA, or qCT, on bone fractures and strength?

D. Treatment strategies for vascular calcification:

What impact do therapies for control of serum phosphorus, calcium, and PTH have on vascular calcification?

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