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What impact do traditional therapies for atherosclerosis (i.e. statins) have on vascular calcification?








Phosphate Binders

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:

One RCT found that sevelamer reduced the
progression of coronary artery and aortic
calcification compared with calcium salts at

52 weeks. One crossover RCT found no


difference in reduction of serum phosphorus
between sevelamer and calcium acetate.
The two RCTs found that sevelamer
reduced serum low density lipoprotein
cholesterol levels and the incidence of
hypercalcaemia compared with calcium
salts. We found no RCTs comparing
sevelamer versus aluminium or lanthanum
carbonate.

Benefits


Sevelamer versus calcium: We found two RCTs. The first multicentre RCT (open label; 200 adults with ESRD) compared sevelamer versus calcium salts (calcium carbonate and calcium acetate) for 52 weeks. It found that sevelamer significantly reduced the

progression of coronary artery and aortic


calcification (as measured by electron beam
tomography) compared with calcium salts at

52 weeks. It also found that serum low


density lipoprotein (LDL) cholesterol levels
significantly decreased with sevelamer
compared with calcium salts after 52 weeks.
The second RCT (open label, crossover trial
with 2 week hout period; 83 adults on
maintenance haemodialysis) compared
sevelamer versus calcium acetate for 8
weeks. The study did not present the results
before crossover. It found no significant
difference between groups in the reduction
of serum phosphate from baseline at the
end of treatment. In addition, serum LDL
cholesterol levels decreased significantly
more with sevelamer than with calcium
acetate. We found no RCTs.

Sevelamer versus lanthanum carbonate: We found no RCTs.

Harms

Sevelamer versus calcium: The first RCT found that both sevelamer and calcium salts were well tolerated. Significantly more



people experienced at least one
hypercalcaemic episode with calcium salts
compared with sevelamer over 52 weeks.
Serum bicarbonate concentrations were
significantly higher in the calcium treated
group. There was no significant difference
between groups in the risk of hospital

admission and the number of days spent in


hospital. The causes of hospital admission
were not reported. Post hoc analysis of this
RCT found that calcium salts significantly
reduced vertebral bone mineral density

compared with sevelamer. The second RCT reported no serious adverse effects with

either treatment. There was no significant difference between groups in

gastrointestinal complaints. It found that serum alkaline phosphatase was

significantly increased from baseline with sevelamer. During treatment with

sevelamer, 18/80 (23%) people required an evening dose of calcium carbonate to

maintain serum calcium concentrations, and 15/80 (18%) people developed

hypocalcaemia (serum calcium).


Sevelamer versus aluminium: We found no
RCTs.

Sevelamer versus lanthanum carbonate: We found no RCTs.

Comment

Traditional risk factors for coronary artery


disease account for only a portion of the
remarkable increase in cardiovascular
mortality observed in people receiving

dialysis. Disorders of mineral metabolism (i.e. abnormalities of calcium, phosphorus, PTH, and vitamin D) may play an important role in the accelerated atherosclerosis

unique to the dialysis population. Since the late 1980s, calcium salts have served as the conventional treatment for controlling

hyperphosphataemia. Several observational studies have shown a direct correlation

between elevated levels of serum
phosphorus and calcium, and higher

coronary artery calcification scores and mortality in people receiving chronic

haemodialysis. In clinical practice,
elevations in serum calcium and phosphorus
often limit the use of conventional calcium
salts and vitamin D analogues in controlling
abnormalities of mineral metabolism seen in
patients with ESRD. Thus, recent attention
has focused on the effects of non-calcium-
containing phosphate binders. Sevelamer is
also known to act as a bile acid sequestrant.
Hence, it is unclear whether the effects of






sevelamer on serum LDL cholesterol contributed significantly to the beneficial effects on vascular calcification. Further studies investigating the effects of

sevelamer on all-cause mortality and
cardiovascular events are currently in

progress. Studies investigating the effects of lanthanum carbonate on bone and mineral metabolism are currently in progress.


Scottish Medicines Consortium

Source: www.scottishmedicines.org.uk


Lanthanum carbonate 500, 750, 1000mg

chewable tablets (Fosrenol®).March 2007


Summary of main findings:

Advice to NHS boards in Scotland:

(Note, the SMC advises that the whole
document be read at their website rather

than summarised.) Lanthanum carbonate is accepted for restricted use within NHS

Scotland as a phosphate-binding agent for use in the control of hyperphosphataemia in chronic renal failure (CRF) patients on

haemodialysis or continuous ambulatory peritoneal dialysis. Lanthanum carbonate is as effective as calcium carbonate in

reducing phosphate to target levels. It is
restricted to use as a second-line agent in

patients where a non-aluminium, noncalcium phosphate binder is required.

Summary of clinical effectiveness:

The practical advantages of this new


treatment are that the tablets are taste
neutral, can be taken without fluid and

potentially fewer tablets may be required. There are no head to head studies with the only other non-aluminium, non-calcium

phosphate binder, sevelamer. In the 24
month, comparative study of tolerability with
standard treatment there was a higher
number of withdrawals in the lanthanum arm
compared to standard treatment (see Finn
2006 in the Safety section). Patients on
standard therapy were allowed to switch to a
different phosphate binder and still remain in
the study while no switching could be
allowed for patients on lanthanum and
therefore they could only discontinue from
the study. This was the explanation given for
the higher discontinuation rates. The
discontinuation rates in other studies were
also quite significant, however tolerability of
phosphate binder therapy is problematic and patients who had discontinued during the

early parts of the studies did have the option to re-titrate their lanthanum carbonate dose and re-enter the long-term extension

phases. Long-term effects on bone have still to be fully established. There is experience of lanthanum carbonate use out to six years but only in a small number of patients.

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

therefore it has not yet reached steady state in patients who have been treated so far and there is still some concern over the effects of long-term treatment on bone and other

tissue toxicity. Once lanthanum treatment has been discontinued, accumulated

lanthanum is cleared slowly from bone which potentially could prolong the time to resolution of adverse effects.
CADTH

Source: www.cadth.ca Manns B, et al. Sevelamer in patients with ESRD: a

systematic review and economic evaluation [Technology Report no 71]. Ottawa:

Canadian Agency for Drugs and


Technologies in Health; 2006.

Summary of main findings:

We did a systematic review to identify
relevant literature. Evidence of efficacy was
determined from randomized controlled trials
(RCTs). Evidence of harm was determined
from trials or registries where data was
gathered prospectively. Ten RCTs with a
total of 3,025 participants were included in
the efficacy analysis; 28 prospective trials
with a total of 3,983 participants were
identified and eligible for the review of harm.
One unpublished, randomized, unblinded
study of 2,103 dialysis patients was
designed to measure overall survival and
cardiovascular mortality.

Sevelamer was found to have no


demonstrated effect on health outcomes
compared with calcium-based phosphate
binders. There was 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. Sevelamer therapy resulted in






a smaller decrease in phosphate levels, and fewer episodes of hypercalcaemia of

unknown clinical significance, compared
with calcium-based phosphate binders.

There is uncertainty regarding the cost effectiveness of sevelamer. Even if

sevelamer is assumed to be more effective
than calcium-based phosphate binders, it is
associated with a cost per quality-adjusted
life year gained ranging from $127,000 to
$278,100. It is possible that sevelamer use,

restricted to patients ≥65 years old, might be more economically efficient, but improved effectiveness in this group requires

confirmation from future studies.

Funding sevelamer will require additional resources. The difference in cost per

patient between calcium carbonate and
sevelamer at usual daily doses is $4,127

annually. Substituting sevelamer for calcium carbonate for all patients with ESRD in

Canada would increase expenditures by
$70,620,616 annually. Restricting access to
those ≥65 years old, or based on
biochemical criteria, results in increased
expenditures between $14,712,628 and
$36,016,514.

COCHRANE


Source:

www.mrw.interscience.wiley.com/cochrane

Navaneethan SD, Chaukiyal P, Strippoli GF, et al. Phosphate binders for preventing and treating bone disease in chronic kidney

disease patients. (Protocol) Cochrane Database of Systematic Reviews 2006, Issue 2. Art. No.: CD006023.

Protocol:

This is the protocol for a review only - no results are yet available. The objectives are as follows:

1) The efficacy of the available aluminium salts, calcium salts, sevelamer

hydrochloride, lanthanum carbonate, iron salts and magnesium-based

phosphate binders in treatment of hyperphosphataemia.

2) To assess their impact on the

development of SHPT or low bone turnover


based on surrogate markers (PTH, bone
specifi alkaline phosphatase, osteocalcin or

other bone turnover markers) and the serum calcium, phosphate, the calcium-phosphate product, PTH levels. In addition, the


influence of these drugs would be assessed in relation to lipid profie, tissue calcifiation and common symptoms such as pruritis and bone or muscle pain.

3) To study the impact of these agents on BMD assessed by dual-energy X-ray

absorptiometry (DXA) or quantitative computerized tomography (QCT) and on bone turnover and mineralization based on histomorphometry and fracture rates.

4) To assess other patient-based 'hard' endpoints such as incidence of

cardiovascular events, number of hospital
admissions and all-cause mortality rates.

5) To assess the impact of various


phosphate binders on metastatic calcifiation
rates.

6) To assess cost effectiveness and quality of life.

7) Patient compliance with therapy and the incidence and nature of side effects.
CARI (Caring for Australasians with Renal Impairment)

Source: www.cari.org.au Use of phosphate


binders in chronic kidney disease (2006).

Guidelines (NHMRC levels of evidence):

a. Calcium-containing phosphate binders are effective. (Level II evidence)

b. Calcium acetate (CA) is more effective


than calcium carbonate. (Level I evidence)

c. Calcium salt-based binders should be


minimised when serum calcium is above the target range (2.4 mmol/L) or serum PTH is below the upper limit of the reference range. (Level II evidence)

d. Sevelamer is an effective phosphate binder. (Level II evidence)

e. Lanthanum is an effective phosphate binder. (Level II evidence)

Suggestions for Clinical Care (based on Level III and IV evidence):

Factors influencing the choice and
effectiveness of a phosphate binder include serum PTH, tendency towards

hypercalcaemia, side effects, diet and


compliance of the patient. (Opinion)

Initial management of serum phosphate


levels above the target range (> 1.6 mmol/L)
should include optimization of dialysis, when






possible, by increasing the duration and/or the number of treatments (Level III

evidence), dietary advice and efforts to
ensure patient compliance with medications. (Opinion)

Calcium-containing phosphate binders


should be the initial choice in patients with
levels of serum calcium < 2.4 mmol/L and
PTH in the target range (Opinion), but
should be avoided when levels of PTH are
below the target range. (Level lll evidence)
Calcium carbonate (CaCO3) should be
taken before or with meals and may be less
effective than CA when used with inhibitors
of gastric acidity. (Level III evidence)
Aluminium salts should be avoided when
PTH is below the target range (Level lll
evidence). Aluminium use is associated with
an increased risk of low bone turnover and
abnormal bone mineralisation and should be
avoided in at-risk patients, including
children. (Level III evidence)

Monitoring of serum aluminium levels at regular intervals is suggested when

aluminium-containing binders are used. If no aluminium-containing binders are used, it is sufficient to monitor reverse osmosis water supplies for heavy metal contamination, and perform serum aluminium levels and

desferrioxamine testing in patients when the clinical state suggests that aluminium

toxicity is possible.

Calcium citrate may increase aluminium


absorption and should be avoided (Level III evidence)

The use of sevelamer should be considered when levels of calcium are above the target range. (Opinion)

The use of sevelamer should be considered when levels of PTH are below the target

range. (Opinion)

Compared with calcium, magnesium-
containing salts are an alternative but less
efficient phosphate binder. (Level III
evidence)

There are few long-term studies of safety. If used, serum magnesium levels should be monitored. Consider the use of low

magnesium dialysate (Opinion)
Care should be taken to avoid

hypercalcaemia when calcium salts are used in conjunction with calcitriol or vitamin D analogues. (Opinion)

A maximum daily dose of calcium salts to be used in CKD is not suggested in this

guideline.

Summary of the evidence (sevelamer and lanthanum only):

Sevelamer is a newer agent recently


available in Australia. Available trial data
suggests that sevelamer is an equivalent but
not better binder of phosphate, compared
with calcium salts. There is evidence that
sevelamer use leads to less hypercalcaemia
than calcium salts. Sevelamer also lowers
LDL cholesterol. It is associated with a lower
serum bicarbonate level in kidney disease
patients. One trial examined vascular
calcification over a 1-year period and found
less calcification with sevelamer than with
CaCO3 (Chertow et al 2002). Mortality data
is awaited. Another major study is the CARE
study (Qunibi et al 2004), an RCT of 98
patients randomised to CA or sevelamer.
This well-conducted study showed that CA
was able to control serum phosphate and
the calcium-phosphate product better than
sevelamer, at less cost. In patients prone to
hypercalcaemia, there may be a role for
sevelamer. Less coronary calcification
progression over 52 weeks was seen for
sevelamer (+ 6% increase) vs CaCO3 (+
23% increase) in the study by Chertow et al
(2002). Calcification score is a surrogate
marker for cardiovascular events and hard
endpoint data is awaited. Some studies with
sevelamer have required the use of
supplemental calcium to maintain serum
calcium levels. It is 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. Recent
Japanese studies have shown good

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

Lanthanum is a new rare metal salt,
phosphate binder. There is evidence that
lanthanum is an effective binder of dietary
phosphate compared with placebo (Joy &
Finn 2003). A 12-month clinical study in
humans showed no trend towards the
development of adynamic bone disease with
this salt, although rat studies had suggested
that this may occur (Behets et al 2004). The
same study showed lanthanum equivalence
with CaCO3 in the control of serum
phosphate (D’Haese et al 2003). Serum and
bone levels of lanthanum did increase over






the 12 months in the lanthanum-treated group, although not to a large degree. The CaCO3 group had more episodes of

hypercalcaemia compared with the
lanthanum group, although mean serum
calcium levels were not significantly
different.

Implementation and audit:

Implementation should be on the basis of
achieving target serum levels of calcium (<

2.4 mmol/L), phosphate (< 1.6 mmol/L) and PTH (not less than the upper limit of the

reference range). As episodes of
hypercalcaemia may be a marker for
vascular calcification, dialysis units should
review blood results monthly in order to
minimize hypercalcaemic episodes and
improve serum phosphate control. The
number of patients with levels out of range

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