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Gut
1994;
35:
1294-1300
Cost
effectiveness
of
adjuvant
bile
salt
treatment
in
extracorporeal
shock
wave
lithotripsy
for
the
treatment
of
gall
bladder
stones
J
P
Nicholl,
B
Ross,
P
C
Milner,
J
E
Brazier,
L
Westlake,
B
Kohler,
E
Frost,
B
T
Williams,
A
G
Johnson
Abstract
The
relative
cost
effectiveness
of
adjuvant
urso
and
chenodeoxycholic
acid
treat-
ment
in
extracorporeal
shockwave
lithotripsy
(ESWL)
has
been
assessed
as
part
of
a
pragmatic
randomised
controlled
trial
of
ESWL
as
a
treatment
of
gall
bladder
stones.
Of
the
first
patients
with
gall
stone
volume
<4
cm3
randomised
to
ESWL
in
the
main
trial,
24
were
randomised
to
have
ESWL
alone
and
26
to
have
adjuvant
bile
acid
treatment,
one
of
whom
died
before
the
end
of
the
12
month
follow
up
period.
At
12
months
after
treatment,
differences
in
gall
stone
clearance
between
ESWL
alone
(3/24
(13%)
clear,
5
(21%)
referred
for
surgery)
and
ESWL
and
bile
acids
(6/25
(24%)
clear,
2
(8%)
referred
for
surgery)
were
not
significant
(p
=
0-36,
log
rank
test).
Patients
in
both
groups
had
substantial
and
signific.*.it
health
gains
(according
to
biliary
pain
frequency
and
severity,
Nottingham
Health
Profile
scores,
visual
analogue
scale
symptom
scores,
and
com-
plications)
but
there
were
no
significant
differences
between
the
groups.
Im-
provements
in
both
groups
usually
occurred
within
a
few
weeks
of
treatment
and
were
unrelated
to
gall
stone
clearance.
Costs
were
greater
in
the
bile
salt
group
(95%
confidence
intervals
for
estimated
cost
difference:
£90
to
£630).
If
the
purpose
of
treatment
is
symptom
relief
rather
than
gall
stone
clearance
then
adjuvant
bile
salt
treatment
seems
to
be
unnecessary.
(Gut
1994;
35:
1294-1300)
It
is
well
known
that
the
two
bile
salts,
urso
and
chenodeoxycholic
acids
can
dissolve
small
gall
bladder
stones'
and
their
combined
action
may
be
more
effective
than
either
alone.2
3
The
efficacy
of
these
acids
is
determined
primarily
by
the
composition
and
size
of
the
gall
stones,
with
a
more
favourable
response
in
small
uncalcified
stones.
With
this
in
mind,
it
has
been
conventional
since
the
initial
use
of
extra-
corporeal
shock
wave
lithotripsy
(ESWL)
for
gall
bladder
stones
to
give
adjuvant
bile
acids
to
speed
the
clearance
of
the
small
residual
fragments
that
result
from
ESWL.4
Although
most
researchers
have
found
improved
gall
stone
clearance
rates
using
urso
or
urso
and
chenodeoxycholic
acids
in
con-
junction
with
ESWL,5-7
good
clearance
has
also
been
found
with
ESWL
alone.8
9
Furthermore,
although
it
has
been
suggested
that
ursodeoxycholic
acid
may
be
effective
in
reducing
the
number
of
biliary
pain
episodes
after
ESWL
by
an
improvement
in
gall
stone
clearance
rates,'0
the
effect
of
adjuvant
bile
acid
treatment
on
health
generally
and
the
range
of
symptoms
commonly
associated
with
gall
stones
has
not
been
assessed.
Similarly,
the
health
benefits
of
ESWL
over
and
above
those
that
can
be
achieved
by
bile
salts
alone
have
not
been
formally
assessed.
As
part
of
the
larger
trial
comparing
the
cost
effectiveness
of
biliary
lithotripsy
and
cholectystectomy,"
we
were
able
to
undertake
a
pragmatic
randomised
controlled
study
of
the
cost
effectiveness
of
combined
adjuvant
oral
bile
acid
treatment
in
lithotripsy
on
patient
symptoms
and
general
health
status.
Methods
Over
the
two
years
from
April
1988
to
July
1990
all
symptomatic
patients
with
gall
bladder
stones
referred
to
the
nine
consultant
surgeons
at
the
Royal
Hallamshire
Hospital,
Sheffield,
England
and
in
the
latter
months
to
two
local
major
hospitals,
for
whom
elective
cholecystectomy
was
indicated
as
the
sole
major
operative
procedure
were
assessed
for
entry
to
the
trial.
Exclusion
criteria,
which
have
been
detailed
elsewhere,"
included
a
non-contracting
gall
bladder
(less
than
50%
volume
after
a
fatty
meal)
as
well
as
other
comorbidity,
but
there
was
not
restriction
on
the
number
or
size
of
stones
or
their
calcifica-
tion
and
many
patients
included
in
the
study
did
not
meet
the
'Munich
criteria'.4
Patients
who
consented
to
be
included
and
who
were
eligible
for
randomisation
in
the
main
trial
who
had
a
gall
stone
bulk
of
4000
mm3
or
less
were
randomised
to
either
cholecystectomy,
lithotripsy
alone
or
litho-
tripsy
and
bile
salts.
The
last
two
groups
form
the
bile
salt
subtrial
patients.
TREATMENT
REGIMENS
Patients
were
treated
with
up
to
a
maximum
of
3000
shocks
at
each
session
on
a
Wolf
Piezolith
2200/2300
without
sedation
or
anaesthesia.
The
following
morning
the
state
of
the
gall
bladder,
extent
of
stone
fragmentation,
and
size
of
the
common
hepatic
duct
were
assessed
by
ultrasound.
The
target
fragment
size
was
less
than
3
mm
diameter
as
assessed
by
the
ultrasound,
and
the
schedule
was
repeated
on
Medical
Care
Research
Unit,
Department
of
Public
Health
Medicine,
Sheffield
University
Medical
School,
Sheffield
J
P
Nicholl
P
C
Milner
J
E
Brazier
L
Westlake
B
Kohler
B
T
Williams
Department
of
Radiology,
Royal
Hallamshire
Hospital,
Sheffield
B
Ross
E
Frost
Department
of
Surgery,
Royal
Hallamshire
Hospital,
Sheffield
A
G
Johnson
Correspondence
to:
Mr
J
Nicholl,
Medical
Care
Research
Unit,
Department
of
Public
Health
Medicine,
Sheffield
University
Medical
School,
Sheffield
S10
2RX.
Accepted
for
publication
21
December
1993
1294
group.bmj.com on July 16, 2011 - Published by gut.bmj.comDownloaded from
Cost
effectiveness
of
adjuvant
bile
salt
treatment
in
extracorporeal
shock
wave
lithotripsy
for
the
treatment
of
gall
bladder
stones
up
to
four
consecutive
days
until
adequate
fragmentation
occurred,
which
was
achieved
in
all
patients.
Patients
allocated
to
receive
bile
salts
started
them
two
weeks
before
lithotripsy
at
a
dose
of
chenodeoxycholic
acid
7.5
mg/kg,
and
ursodeoxycholic
acid
6.5
mg/kg,
both
being
taken
in
the
evening.
Six
months
after
treatment
patients
not
started
on
bile
salts
could
be
switched
over
if
this
was
thought
clinically
advisable.
OUTCOMES
AND
FOLLOW
UP
The
outcome
measures
were
McGill
pain
scores12
and Nottingham
Health
Profile
(NHP)
scores,13
visual
analogue
scale
(VAS)
symptom
scores,
and
complications,
measured
repeatedly
at
baseline,
and
at
two
weeks,
five
weeks,
three
months,
six
months,
and
12
months
after
treatment,
and
gall
stone
clearance
times.
VAS
biliary
pain
scores
were
also
collected
using
pain
diaries.
To
assess
gall
stone
clearance,
the
patients
were
followed
up
clinically
and
by
ultrasound
weekly
for
the
first
month
after
ESWL
and
then
at
monthly
intervals
until
one
year
after
ESWL.
Every
patient
whose
stones
had
not
cleared
or
who
had
not
been
referred
to
surgery
at
12
months
continued
to
be
followed
up
in
routine
clinics
and
gall
stone
clearance
times
have
been
recorded
whenever
clearance
has
occurred.
The
gall
bladder
was
taken
to
have
cleared
at
the
time
of
the
first
of
two
successive
follow
up
examinations
at
which
no
radiological
evidence
of
stone
fragments
was
found.
The
complications
recorded
were
those
that
might
have
been
associated
with
lithotripsy
or
bile
salts
(diarrhoea,
abdominal
pain,
biliary
colic,
or
acute
cholecystitis)
and
which
the
patient
reported
had
resulted
in
their
seeking
medical
assistance,
and
thereby
incurring
costs.
As
there
was
no
reliable
method
of
assessing
compliance
with
the
bile
salt
regimen,
compliance
was
not
assessed
at
follow
up.
In
a
pragmatic
trial
concerned
with
what
might
be
expected
to
happen
in
practice
this
is
not
important
with
regard
to
the
validity
of
the
results
but
does
put
a
limitation
on
their
interpretation.
PATIENT
NUMBERS
To
have
a
90%
chance
of
detecting
at
a
5%
significance
value
a
difference
of
three
months
in
mean
gall
stone
clearance
times,
the
bile
salt
subtrial
protocol
suggested
that
80
patients
should
be
randomly
assigned
to
lithotripsy
alone
or
lithotripsy
with
bile
salts
(40
in
each
group),
and
that
an
interim
assessment
should
be
carried
out
after
the
first
50
patients
had
been
randomised.14
Emerging
clinical
practice
elsewhere,
however,
had
begun
to
suggest
that
bile
salts
were
a
necessary
adjuvant
treatment
for
stone
clearance
and,
without
reference
to
the
trial
results,
random
assignment
in
the
bile
salt
subtrial
was
stopped
at
the
interim
assess-
ment
when
26
patients
had
been
randomised
to
lithotripsy
with
bile
salts
and
24
to
lithotripsy
alone.
STATISTICAL
ANALYSIS
The
results
have
been
analysed
by
intention
to
treat
in
accordance
with
the
pragmatic
nature
of
the
trial,
so
that
patients
in
the
lithotripsy
alone
arm
who
were
given
bile
salts
after
six
months
(as
permitted
in
the
treatment
protocols)
have
been
retained
in
the
lithotripsy
alone
arm
for
the
analysis.
Similarly,
patients
from
either
arm
who
were
referred
for
cholecystectomy
have
been
retained
in
the
analysis.
Patients
referred
for
cholecystectomy
preclude
a
simple
comparison
of
gall
stone
clearance
times.
Instead,
the
proportions
of
patients
in
each
subgroup
referred
for
chole-
cystectomy,
cleared,
or
not
cleared
by
12
months
have
been
compared,
and
also
gall
stone
clearance
time
curves
have
been
com-
puted
using
Kaplan-Meier
'survival'
estimates
and
compared
using
the
log
rank
test.
For
these
clearance
curves
the
patients
referred
for
cholecystectomy
have
been
treated
as
'with-
drawals'.
With
regard
to
biliary
pain,
NHP
scores,
and
gastrointestinal
and
other
symptoms,
each
patient's
response
to
treatment
can
be
described
by
'curves'
showing
the
change
in
each
outcome
measured
during
the
12
month
follow
up
period.
Both
the
mean
and
median
of
a
summary
measure
of
the
health
gain
during
the
'follow
up
period'
(and
95°/0
confidence
intervals15)
have
been
calculated,
and
the
distributions
of
the
summary
response
of
patients
in
the
two
treatment
groups
have
been
compared
using
re-randomisation
analysis
of
covariance
tests
of
differences
in
the
mean
response
adjusting
for
baseline
values.16
(Mean
responses
at
each
assessment
have
also
been
calculated
and
these
are
available
from
the
authors
on
request).
The
mean
summary
responses
of
the
two
treatment
groups
have
been
compared
rather
than
the
median
responses,
even
though
the
distributions
are
often
distinctly
skewed,
because
for
many
symptom
scores
the
median
response
is
zero
in
both
groups
even
though
one
group
has
fewer
respondents
or
fewer
severe
symptoms
among
responders
than
the
other
group.
Of
the
300
assessments
that
should
have
been
done
(50
patients
X
6
assessments),
only
three
were
missed.
In
a
few
cases
patients
also
failed
to
answer
all
the
questions
at
an
assessment.
COSTS
The
marginal
(or
extra)
costs
of
bile
salts
as
an
adjuvant
treatment
to
lithotripsy
were
estimated
as
the
difference
in
mean
cost
per
patient
between
the
bile
salt
arm
and
the
no
bile
salt
arm.
The
marginal
cost
is
therefore
the
sum
of
the
differences
in
all
costs,
and
not
only
the
difference
in
bile
salt
costs.
The
total
health
care
cost
for
each
patient
to
the
National
Health
Service
in
the
United
Kingdom
includes
the
costs
of
a
suitability
assessment,
lithotripsy
sessions,
ultrasound
sessions,
ward
stay,
bile
salts,
and
any
complications
requiring
health
services.
Little
1295
group.bmj.com on July 16, 2011 - Published by gut.bmj.comDownloaded from
Nicholl,
Ross,
Milner,
Brazier,
Westlake,
Kohler,
Frost,
Williams,
3tohnson
TABLE
I
Baseline
data
Treatment
group
Lithotripsy
Lithotripsy
alone
+
bile
salts
Number
randomised
24
26
Died
0
1
Number
of
patients
in
analysis
24
25
Personal
charactenrstics
Age
in
years
53
56
(median
(IQR))
(41-63)
(46-65)
Sex
(%
female)
79
68
Marital
status
(%
married)
96
92
Area
of
residence
(%
Sheffield)
92
76
Referral
hospital
(%
Hallamshire)
100
88
Waiting
time,
days
21
21
(median
(IQR))
(18-28)
(19-27)
Main
indication
(%
with
biliary
colic)
92
88
Stone
characteristics
%
With
calcified
stones
21
28
Number
of
stones
(/)
1
42
50
2-3
29
12
4
+
29
39
Stone
bulk
(mm3)
1065
1146
(median
(IQR))
(434-1931)
(550-2352)
Radius
of
largest
stone
(mm)
8 9
10.0
(median
(IQR))
(6-4-15-4)
(6-7-14.1)
difference
in
the
patient
time
costs
between
the
two
treatment
groups
was
expected
as
they
have
the
same
treatment
and
follow
up
regimens,
and
these
costs
were
not
con-
sidered
in
the
subtrial.
Confidence
intervals
for
the
difference
in
mean
costs
have
been
cal-
culated.
The
general
approach
to
costing
services
has
been
outlined
elsewhere.
Results
EXCLUSIONS
AND
BASELINE
COMPARISONS
Twenty
four
patients
were
randomised
to
lithotripsy
and
26
to
lithotripsy
with
bile
salts.
Only
one
patient,
randomised
to
lithotripsy
with
bile
salts,
who
died
from
lung
cancer
before
the
12
months
assessment
was
not
fol-
lowed
up
for
the
full
year.
Summary
scores
could
not
be
calculated
for
this
patient
and
the
patient
has
been
excluded
from
these
analyses.
The
two
subtrial
treatment
groups
had
similar
personal
and
stone
characteristics
(Table
I)..
GALL
STONE
CLEARANCE
By
the
end
of
12
months,
three
(13%)
patients
in
the
no
bile
salts
group
were
clear
of
gall
stones
and
five
(21%)
had
been
referred
for
surgery
(Fig
1A).
Among
the
26
patients
who
were
randomised
to
bile
salts
in
the
subtrial
one
had
died,
six
(24%)
had
cleared,
and
only
two
(8%)
had
been
referred
to
surgery.
None
of
the
patients
whose
gall
bladders
cleared
had
had
calcified
stones,
and
most
of
the
patients
who
cleared
(six
of
nine)
had
had
a
single
stone
initially.
Among
patients
with
a
single
uncalcified
stone
there
was
a
striking
contrast
in
clearance,
five
of
eight
(62-5%)
patients
in
the
bile
salt
group
had
cleared
at
12
months
compared
with
only
one
(12-5%)
of
eight
such
patients
in
the
no
bile
salt
group.
Excluding
the
patients
with
calcified
stones,
the
Kaplan-Meier
estimate
of
clearance
at
12
months
in
the
patients
not
started
on
bile
salts
was
16%
compared
with
35%
in
the
bile
salt
group
(Fig
1B).
Because
of
the
small
numbers,
however,
differences
between
treatment
groups
in
outcome
(surgery,
stone
free
or
not
stone
free)
at
12
months
could
have
occurred
by
chance
(p
=
0.15).
A
further
three
patients
in
the
no
bile
salts
group
and
two
patients
in
the
bile
salt
group
have
become
stone
free
since
the
end
of
the
12
month
trial
follow
up
period.
All
patients,
however,
in
the
no
bile
salt
group
who
had
not
cleared
or
had
not
been
referred
for
surgery
were
given
bile
salts
six
months
after
treatment
in
accordance
with
the
protocol
(n=
6)
or
after
12
months
(n=
10).
COMPLICATIONS
In
the
bile
salt
group
14
(54%)
patients
reported
complications
or
other
adverse
sequelae
of
intervention,
compared
with
11
(46%)
of
those
receiving
lithotripsy
alone,
a
non-significant
difference
(X2=0
51,
p>0
5).
The
groups
each
reported
26
contacts
with
medical
services
for
these
problems.
The
com-
monest
sequelae
were
biliary
colic
and
non-
specific
abdominal
pain.
1*0
08
06
-0-
ESWL
+
bile
acids
-*-
ESWL
alone
p
=
0-36 0.4
~
B
p
=
0-27
02
[
0.0
0
10
20
30
40
50
60
0
10
20
30 40
50
60
Time
after
treatment
(wk)
Time
after
treatment
(wk)
Figure
1:
(A)
Kaplan-Meier
estimates
of
the
proportion
of
patients
whose
gall
stones
had
not
cleared:
*p
value
from
log
rank
test
for
differences
in
clearance
at
52
weeks;
(B)
Kaplan-Meier
estimates
of
the
proportion
of
patients
with
uncalcified
stones
whose
gall
stones
had
not
cleared:
*p
value
from
log
rank
test
for
differences
in
clearance
at
52
weeks.
A
,_
1*0
08
a)
a)
4
0
c
0
0.
Q
20
06
_
04
_
02
_
0*0
1296
group.bmj.com on July 16, 2011 - Published by gut.bmj.comDownloaded from
Cost
effectiveness
of
adjuvant
bile
salt
treatment
in
extracorporeal
shock
wave
lithotripsy
for
the
treatment
of
gall
bladder
stones
1.6-
A
-
ESWL
+
bile
acids
1.4
-
-
|
-
ESWL
alone
12
-
0
1
0
LEXi)1|
P
=
0
90
08
-
02
_-
--
0
-20 -10
0
10
20 30
40
50
Time
after
treatment
(wk)
3.5r
3.0
V
2.5
F
20
F-
1
5
H
1.0
h
0.5
V
0
It
"
-.4
01
-20
-10
0
TO
20 30
40
50
Time
after
treatment
(wk)
Figure
2:
(A)
Average
number
of
biliary
pain
episodes
per
week
per
patient:
*p
value
for
the
difference
between
treatment
groups
in
numbers
of
pain
episodes
avoided;
(B)
average
number
of
biliary
pain
episodes
per
week
per
patient
reporting
some
pain
since
previous
assessment.
SYMPTOMS
AND
HEALTH
STATUS
After
treatment
both
groups
showed
a
signifi-
cant
reduction
in
the
mean
number
of
biliary
pain
episodes
experienced,
but
there
was
no
evidence
of
any
difference
between
the
treat-
ment
groups
(Fig
2A).
At
baseline,
21%
of
those
randomised
to
bile
salts
and
9%
of
those
randomised
to
ESWL
alone
reported
no
biliary
pain
episodes
in
the
previous
three
months.
At
the
12
month
assessment,
the
proportions
reporting
no
biliary
pain
in
the
previous
six
months
were
63%
and
57%/o
respectively.
Thus
the
reduction
in
the
mean
number
of
biliary
pain
episodes
per
patient
was
partly
the
result
of
fewer
patients
reporting
any
pain
episodes,
but
it
was
also
partly
the
result
of
there
being
fewer
episodes
per
patient
still
experiencing
pain
(Fig
2B).
Some
patients
who
had
pre-
viously
reported
pain
'nearly
every
day'
claimed
complete
relief
after
treatment
giving
rise
to
large
reductions
in
the
mean
number
of
episodes
pain
per
patient.
The
'average
patient'
(represented
by
the
median
response),
however,
avoided
fewer
than
the
mean
number
of
episodes.
There
was
no
evidence
of
any
difference
in
medians
between
the
two
groups
either.
Similarly,
the
pain
experience
after
treatment
as
recorded
in
the
patients'
pain
diaries
was
very
similar
in
the
two
groups.
There
were
similar
findings
with
regard
to
the
symptom
scores.
Most
symptoms
showed
a
substantial
improvement
in
mean
VAS
score
between
baseline
and
two
weeks,
and
there-
after
only
small
changes
were
seen
(see
Fig
3
for
example)
and
the
mean
summary
response
for
the
12
months
after
treatment
showed
significant
health
gains
for
most
symptoms.
For
10
of
14
symptoms
assessed
a
better
mean
summary
response
was
seen
in
the
no
bile
salt
group,
however,
after
adjusting
for
baseline
scores
none
of
the
differences
between
treatment
groups
were
significant
in
either
60
50
40
Feeling
sick
-0-
ESWL
+
bile
acids
-
-*-
ESWL
alone
-
---4
p=0.921
su
~
_
-20
10
0
10
20
30
40
50
60
Indigestion
50
40
-
p=0.20
30
20-
10
0
-20
-10
0
10
20
30
40
50
Fatty
food
upset
60
50
40
30
20
10
_
o
-
-20
60
50
40
30
---__
P
=
0-60
1
I
V'-77--7--7-
-10
0
10
20
30
40
50
Diarrhoea
P
=
0-09
20
-___
*
10
--
10
0
1
-1
,0
-20
-10
0
10 20
30
40
50
Time
after
treatment
(wk)
Time
after
treatment
(wk)
Figure
3:
Mean
VAS
symptom
score
at
six
assessment
times:
*p
values
for
the
difference
between
treatment
groups
in
the
summary
measure
of
health
gain.
U,
u1)
a0
Cu
0
.cl
(L)
0
z
a)
0
U)
c
Cu
a,
a)
2
0
C.)
CD
Cu
Cu
1
297
group.bmj.com on July 16, 2011 - Published by gut.bmj.comDownloaded from
Nicholl,
Ross,
Milner,
Brazier,
Westlake,
Kohler,
Frost,
Williams,
J7ohnson
Energy
-0--
ESWL
+
bile
acids
--&-
ESWL
alone
a--'
-W
=09
-
l
Pain
50
r
40
30
20
10
n
-5
0
5
10
15
20
25
30
35
40
45
50
55
-5
0
5
p
=
0.08]
I--0
I
10
15
20
25
30
35
40
45
50
55
Emotional
reaction
50r
50
_
40
30
.
20
10
0
-5
05
10
15
20
25
30 35
40
45
50
55
Sleep
kk
p
1-p0.15
1
l
-
--
-5
0
5
10
15
20
25
30
35
40
45
50
55
Time
after
treatment
(wk)
Figure
4:
Mean
NHP
scores
at
six
assessment
times.
*p
Values
for
the
difference
between
treatment
groups
in
the
summary
measure
of
health
gain.
direction.
A
difference
in
the
pattern
of
response
for
diarrhoea
(Fig
3)
was
brought
about
by
an
increase
in
mean
diarrhoea
score
in
the
bile
salt
group
between
baseline
and
two
weeks
after
treatment,
which
had
disappeared
by
five
weeks
probably
as
a
result
of
reductions
in
the
bile
salt
dose
in
patients
having
problems.
With
regard
to
the
Nottingham
Health
Profile
scores,
there
were
again
reductions
in
nearly
all
dimensions
in
both
groups
between
baseline
and
two
weeks
and
thereafter
little
change,
often
resulting
in
significant
health
gains
over
the
12
months
after
treatment.
The
immediate
health
gain
was
especially
notice-
able
for
energy,
pain,
and
emotional
reactions
(Fig
4)
with
only
small
reductions
in
the
other
dimensions.
Of
the
six
dimensions,
five
showed
a
better
mean
summary
response
in
the
lithotripsy
alone
group,
the
pain
dimension
being
the
exception.
Adjusted
for
baseline
response,
however,
none
of
the
differences
between
treatment
groups
in
either
the
pattern
of
response
or
summary
response
between
the
two
groups
were
significantly
different.
TABLE
II
Costs
per
patient
at
12
months
by
treatment
(1989/90
prices,
£
sterling)
ESWL
+
bile
acids
(n
=
25)
ESWL
alone
(n
=
24)
Quantity
per
Cost
Quantity
per
Cost
Service
patient
(,9
patient
(/9
Suitability
tests
1
83
1
83
Lithotripsy
sessions
2-8
402
3-2
454
Ultrasound
treatment
sessions
2-8
15
3-2
17
Ultrasound
follow
up
session
8-2
78
7
5
71
Ward
stay
4.0
512
4-3
549
Bile
salts
Prescription
681
Option
to
101
prescribe
after
6
months
Re-treatment
lithotripsy
sessions
None
0
1/24
6
Cholecystectomy
2/26
111
5/24
302
Other
complications
2/26
7
1/24
48
Mean
total
cost
1887
1631
Standard
deviation
525
734
Range
866-3028
821-3667
COSTS
The
mean
cost
of
the
bile
salt
group
exceeds
that
of
the
no
bile
salt
group
by
£343
at
six
months,
but
only
£256
at
12
months
(Table
II).
This
is
mainly
because
of
the
cost
of
the
larger
number
of
cholecystectomies
in
the
no
bile
salt
group
(five
of
24
v
two
of
26),
which
has
partly
offset
the
difference
in
bile
salt
costs
of
£580.
The
95%
confidence
intervals
for
the
difference
in
mean
cost
at
12
months
(-£90
to
+£630)
is
wide,
however,
because
of
the
small
numbers
in
the
trial;
and
the
interval
includes
zero
pointing
to
some
uncertainty
about
the
true
difference
in
costs.
A
sensitivity
analysis
found
that
the
esti-
mated
marginal
cost
of
bile
salts
as
an
adjuvant
treatment
to
lithotripsy
was
insensitive
to
large.
variations
in
the
unit
cost
estimates,
including
those
for
ward
stay,
medical
fees,
and
the
workload
of
the
lithotripter.
Unsurprisingly,
the
result
is
most
sensitive
to
the
price
of
bile
salts,
although
even
a
price
reduction
of
25%
would
not
reverse
the
direction
of
the
result.
A
higher
price
for
bile
salts
would,
of
course,
have
resulted
in
a
larger
and
possibly
signifi-
cant
difference
in
costs
in
favour
of
ESWL
alone.
Discussion
With
respect
to
gall
stone
clearance,
there
was
some
weak
though
not
significant
evidence
in
favour
of
bile
salts,
as
would
have
been
expected
a
priori.
Bile
salts
do
dissolve
stones
and
the
combined
treatment
may
act
additively
at
least
(if
not
synergistically)
and
in
a
larger
trial
it
is
probable
that
a
statistically
significant
benefit
in
clearance
times
would
have
been
found.
The
expectation
that
after
12
months
most
patients
would
have
cleared,
thus
permitting
us
to
compare
average
clearance
times,
rather
than
merely
the
proportion
who
had
cleared,
0
C
U)
c
50
40
30
20
10
0
a1)
0
U)
c
m
40
30
20
10
0
A1
111 111
111
1298
group.bmj.com on July 16, 2011 - Published by gut.bmj.comDownloaded from
Cost
effectiveness
of
adjuvant
bile
salt
treatment
in
extracorporeal
shock
wave
lithotripsy
for
the
treatment
of
gall
bladder
stones
with
just
40
patients
in
each
treatment
group,
was
unrealised.
Plainly,
the
low
clearance
rates
we
have
found
were
partly
because
of
the
heterogeneity
of
our
patients.
In
the
eight
patients
receiving
bile
salts
with
single
un-
calcified
stones,
five
(62.5%)
had
cleared
by
12
months.
But
in
patients
with
multiple
stones
or
calcified
stones,
little,
if
any,
clearance
occurred.
It
is
possible,
also,
that
our
patients
only
poorly
complied
with
their
bile
salt
treatment
regimens
and
that
this
has
diluted
the
apparent
effect
of
bile
salts.
It
is
difficult
to
see,
however,
why
compliance
should
have
been
worse
in
our
study
than
in
others,
and,
moreover,
in
routine
clinical
practice
one
could
not
expect
compliance
to
be
better
than
during
the
course
of
an
intensively
followed
up
trial.
As
well
as
being
related
to
adjuvant
bile
salt
treatment
and
the
stone
burden,
evidence
from
around
the
world
suggests
that,
as
would
be
expected,
clearance
is
related
to
the
fragment
size
achieved
by
ESWL,
which
may
depend
on
both
the
lithotripter
and
the
lithotripsy
regimen
used,
and
the
shock
wave
energy
used.'7
We
achieved
adequate
fragmentation18
in
all
trial
patients,
and
in
a
concurrent
study
of
a
highly
selected
group
of
patients
unsuitable
for
the
trial,
with
single
stones
<20
mm
in
diameter,
treated
by
ESWL
with
adjuvant
bile
salts,
we
achieved
a
12
month
clearance
of
95%
(unpublished
data).
It
is
unlikely
therefore
that
the
regimen
explains
the
low
clearance
rates
we
found
in
the
study.
Furthermore,
if
the
aim
of
treatment
is
symp-
tom
relief
then
clearance
itself
may
not
be
important.
Overall,
there
is
no
evidence
that
patients
meeting
our
broad
eligibility
criteria
who
had
adjuvant
bile
acid
treatment
from
the
outset
fared
better
in
terms
of
symptoms
than
patients
who
were
initially
treated
by
ESWL
alone,
with
adjuvant
bile
acids
only
intro-
duced
at
six
months
if
this
was
thought
clinically
necessary.
There
is
no
evidence
of
any
benefit
associated
with
bile
acids
with
respect
to
any
of
the
NHP
health dimensions,
nor
with
respect
to
any
of
14
gastrointestinal
and
other
symptoms
often
associated
with
gall
stone
disease,
or
with
respect
to
biliary
pain
(reflecting
the
finding
of
an
earlier
study
of
the
effect
of
ursodeoxycholic
acid
on
pain
experience
after
ESWLI0).
This
is
unlikely
to
be
the
result
of
the
trial
being
too
small.
What
differences
were
found
were
as
often
in
favour
of
the
no
bile
salts
group
as
the
bile
salts
group.
It
is
unlikely
that
the
lack
of
any
difference
in
improvement
in
self
reported
symptoms
and
health
status
between
the
treatment
groups
is
the
result
of
the
small
numbers
of
patients
whose
stones
cleared
in
either
treat-
ment
group.
If
this
were
the
explanation
then
we
would
expect
to
see
little
improvement
in
either
group.
We
have
seen,
however,
substantial
improvements
in
many
self
reported
symptoms,
including
pain,
and
most
dimensions
of
health,
equally
in
both
groups.
This
effect
cannot
have
been
caused
by
the
bile
salts
as
it
is
seen
in
both
groups.
It
cannot
be
the
result
of
stone
clearance
either,
because
it
seems
to
occur
almost
immediately
and
thus
before
any
stones
are
cleared.
Between
the
baseline
assessment
(usually
made
at
four
weeks
before
treatment)
and
two
weeks
after
treatment,
nearly
all
the
symptoms
have
resolved
as
much
as
they
will
ever
go
on
to
do
despite
the
fact
that
at
two
weeks
after
treat-
ment
virtually
all
lithotripsy
patients
still
have
stone
fragments
in
their
gall
bladders.
Fatty
food
intolerance,
for
example,
which
was
reported
on
average
as
about
40%-50%
as
severe
as
it
could
possibly
be
by
the
patients
at
baseline
was
reported
on
average
as
being
only
10%-
15%
as
severe
as
possible
just
two
weeks
after
treatment.
Twelve
months
later
the
VAS
scores
were
the
same
as
at
two
weeks
before
treatment.
Furthermore,
we
have
also
found
that
the
pattern
of
improvement
in
biliary
pain
episodes
is
the
same
in
patients
whose
gall
stones
clear
as
in
patients
whose
stones
never
clear.
1 1
It
is
possible
that
the
improvement
in
health,
which
is
rapid
and
similar
in
the
two
groups,
and
is
thus
neither
the
result
of
gall
stone
clear-
ance
or
bile
salts,
is
the
result
of
the
fragmenta-
tion
of
the
stones,
which
did
occur
similarly
in
the
two
groups.
Certainly
if
there
were
a
critical
stone
number,
size,
shape,
or
even
orientation
that
triggered
symptomatic
gall
stone
disease
then
it
could
be
possible
that
stone
fragmentation
by
lithotripsy
would
quickly
relieve
symptoms.
Another
possibility
is
that
the
rapid
improvement
in
health
is
the
result
of
lithotripsy
acting
as
a
placebo.
Presumably,
a
placebo
effect
is
possible
if
the
classic
symptoms
and
health
problems,
which
are
reported
to
be
associated
with
gall
stone
disease,
and
which
we
have
measured
here,
are
only
weakly
associated
with
the
presence
or
absence
of
gall
stones.
There
is
evidence
that
this
is
the
case
both
in
the
fact
that
most
people
with
gall
stones
are
symptomless,19
and
that
many
people
having
had
their
gall
bladders
(and
stones)
removed
continue
to
experience
symptoms,20
as
well
as
the
fact
that
the
preva-
lence
of
upper
right
quadrant
pain
has
been
found
to
be
unrelated
to
the
presence
of
stones
in
the
gall
bladder.21
The
fact,
however,
that
the
benefits
of
treatment
that
we
saw
were
often
sustained
over
12
months
may
argue
against
a
placebo
effect.
The
two
main
cost
differences
between
the
treatment
groups
were
for
bile
acids
and
chole-
cystectomy.
Bile
acids
may
not
be
costly
on
a
daily
basis,
but
accumulated
over
a
12
month
period
they
represented
one
third
of
the
total
costs
in
the
bile
salt
trial
arm.
The
higher
number
of
cholecystectomies
in
the
treatment
group
not
started
with
bile
salts
could
r
sult
from
this
group's
lower
gall
stone
cle
rance
rate.
The
higher
cost,
however,
of
bile
salts
in
the
bile
salt
arm
were
only
partially
offset
by
the
cost
of
these
extra
cholecystectomies
in
the
no
bile
salt
arm.
The
comparative
costs
of
the
two
regimens
were
found
to
be
insensitive
to
large
variations
in
the
unit
cost
estimates,
and
therefore
the
comparative
costs
are
probably
1299
group.bmj.com on July 16, 2011 - Published by gut.bmj.comDownloaded from
1300
Nicholl,
Ross,
Milner,
Brazier,
Westlake,
Kohler,
Frost,
Williams,
J7ohnson
relevant
in
most
situations
although
the
overall
level
of
costs
may
be
different.
Our
results
suggest
that
bile
salts
do
not
improve
the
effectiveness
of
lithotripsy
in
terms
of
symptom
relief.
It
is
possible,
however,
that
they
do
improve
stone
clearance.
Plainly,
then,
the
extra
costs
of
the
bile
salts
can
only
be
justified
if
the
proportion
of
patients
needing
to
be
referred
for
surgery
is
reduced
by
adjuvant
bile
salt
treatment.
Our
results
do
not
suggest
that
this
is
the
case,
but
the
number
are
small
and
the
confidence
intervals
for
the
cost
differences
wide.
Nevertheless,
if
the
aim
of
treatment
is
symptom
relief
then
clearance
would
seem
to
be
unimportant
and
bile
salts
unnecessary.
We
are
grateful
to
the
consultant
surgeons
(Messrs
G
L
Cohen,
W
P
Morgan,
J
Jacobs,
A
J
Shorthouse,
W
Morris-Jones,
C
J
Stoddard,
A
Raftery,
C
H
Talbot,
W
E
G
Thomas,
Professor
R
G
Clark,
Professor
K
Rogers,
J
A
R
Smith,
and
M
Simms),
who
participated
in
this
study
and
also
permitted
us
access
to
their
patients;
and
to
CP
Pharmaceuticals
for
supplying
the
bile
salts.
In
addition
we
are
grateful
to
Dr
Stephen
Birch
for
his
help
with
the
initial
stages
of
the
economic
evaluation,
for
the
assistance
of
members
of
the
finance,
information,
and
pharmacy
depart-
ments,
Royal
Hallamshire
Hospital
in
calculating
the
costs
of
treatment,
Linda
Hawkesworth
for
administrative
support,
and
to
Maria
Platts
for
assisting
with
data
collection.
The
Department
of
Health
funded
this
research,
and,
along
with
Trent
Regional
Health
Authority,
provide
core
funding
for
the
Medical
Care
Research
Unit.
We
are
grateful
to
both
bodies
for
their
continuing
support.
1
Fronim
H,
Roat
JW,
Gonzales
V,
et
al.
Comparative
efficacy
and
side
effects
of
urso-deoxycholic
and
cheno-deoxy-
cholic
acids
in
dissolving
gallstones.
A
double-blind
con-
trolled
study.
Gastroenterology
1983;
85:
1257-64.
2
Podda
M,
Zuin
M,
Batterzati
PM,
et
al.
Efficacy
and
safety
of
a
combination
of
cheno-deoxycholic
acid
and
urso-
deoxycholic
acid
for
gallstone
dissolution.
Gastroenterology
1989;
96:
222-39.
3
Uribe
M,
Sanchez
JM,
Davila B,
Mendez
N,
Merikanski
A,
Bosques
F.
Rapid
dissolution
of
gallstone
fragments
after
high
doses
of
the
combination
of
urso-deoxycholic
acid
and
cheno-deoxycholic
acid
plus
early
shock
wave
re-
treatment:
a
comparison
with
cheno-deoxycholic
acid.
In:
Paumgartner
G,
Sauderbruch
T,
Sackmann
M,
Burhenne
JH,
eds.
Lithotripsy
and
related
techniques
for
gallstone
treat-
ment.
St
Louis,
MO:
Mosby
Year
Books,
1991:
119-24.
4
Sackmann
M,
Delius
M,
Sauerbruch
T,
et
al.
Shockwave
lithotripsy
for
gallstones.
The
first
175
patients.
N
Engl
Jf
Med
1998;
318:
393-7.
5
Schoenfield
U.
Contribution
of
urso-deoxycholic
acid
to
extracorporeal
shock
wave
lithotripsy
of
gallbladder
stones.
In:
Paumgartner
G,
Sauderbruch
T,
Sackmann
M,
Burhenne
HJ,
eds.
Lithotripsy
and
related
techniques
for
gallstone
treatment.
St
Louis,
MO:
Mosby
Year
Books,
1991:
93-5.
6
Darzi
A,
Leahy
A,
O'Morain
C,
Tanner
WA,
Keane
FBV.
Gallstone
clearance:
a
randomised
study
of
extracorporeal
shock
wave
lithotripsy
and
chemical
dissolution.
BrJ
Surg
1990;
7:
1265-7.
7
Kordac
V,
Benes
J,
Chmel
J,
Katab
M,
Stuka
C.
Dissolution
therapy
is
necessary
after
lithotripsy
of
gallbladder
stones
by
shock
waves.
In:
Paumgartner
G,
Sauderbruch
T,
Sackmann
M,
Burhenne
HJ,
eds.
Lithotripsy
and
related
techniques
for
gallstone
treatment.
St
Louis,
MO:
Mosby
Year
Books,
1991:
109-2.
8
Burhenne
HJ.
Treatment
results
of
extracorporeal
lithotripsy
without
adjuvant
dissolution.
Presented
at
IV
international
symposium
on
biliary
stone
therapy.
Rochester,
Minnesota;
1991.
9
Maher
JW,
Sumners
RW,
Dean
TR,
Swift
J,
Heitshuzen
D,
Quinn
G.
Early
results
of
combined
electrohydraulic
shock
wave
lithotripsy
and
oral
litholytic
therapy
of
gallbladder
stones
at
the
University
of
Iowa.
In:
Paumgartner
G,
Sauderbruch
T,
Sackmann
M,
Burhenne
HJ,
eds.
Lithotripsy
and
related
techniques
for
gallstone
treat-
ment.
St
Louis,
MO:
Mosby
Year
Books,
1991:
113-8.
10
Sumners
RW,
Wilkie
J,
Maher
JW,
Dean
T.
Biliary
pain
after
extracorporeal
shockwave
lithotripsy:
effect
of
urso-deoxycholic
acid
and
stone
fragments.
In:
Paumgartmer
G,
Sauderbruch
T,
Sackmann
M,
Burhenne
HJ,
eds.
Lithotripsy
and
related
techniques
for
gallstone
treat-
ment.
St
Louis,
MO:
Mosby
Year
Books,
1991:
87-91.
11
Nicholl
JP,
Brazier
JE,
Milner
PC,
et
al.
A
randomised
con-
trolled
trial
of
the
cost-effectiveness
of
lithotripsy
and
open
cholecystectomy
as
treatments
for
gallbladder
stones.
Lancet
1992;
ii:
801-7.
12
Melzack
R.
The
McGill
pain
questionnaire:
major
proper-
ties
and
scoring
methods.
Pain
1975;
1:
277-99.
13
Hunt
SM,
McEwen
J,
McKenna
SP.
Measuring
health
status.
Beckenham,
Kent:
Croom
Helm,
1986.
14
Milner
PC,
Nicholl
JP,
Westlake
L,
et
al.
The
evaluation
of
lithotripsy
as
a
treatment
for
gallstones:
a
randomised
controlled
trial
approach
in
England.
J
Lithotripsy
and
Stone
Disease
1989;
1:
122-32.
15
Effron
A.
Bootstrap
and
Jacknife
procedures.
The
American
Statistician
1983;
37:
36-48.
16
Manly
BFJ.
Randomisation
and
Monte
Carlo
methods
in
biology.
Chapman
and
Hall,
London:
1991.
17
Mori
H,
Malone
DE,
McGrath
FP,
et
al.
Optimising
gall-
bladder
stone
lithotripsy:
an
international
survey.
Radiology
1992;
184:
735-9.
18
Sackmann
M,
Pauletzki
J,
Sauerbruch
T,
et
al.
The
Munich
gallbladder
lithotripsy
study:
results
of
the
first
five
years
with
711
patients.
Ann
Intern
Med
1991;
114:
290-6.
19
Heaton
KW,
Braddon
FEM,
Mountford
RA,
Hughes
AO,
Emmett
PM.
Symptomatic
and
silent
gall
stones
in
the
community.
Gut
1991;
32:
316-20.
20
Anonymous.
Cholecystectomy:
the
dissatisfied
customer.
[Editorial].
Lancet
1988;
i:
339.
21
Jorgensen
T.
Abdominal
symptoms
and
gallstone
disease:
an
epidemiological
investigation.
Hepatology
1989;
9:
856-60.
group.bmj.com on July 16, 2011 - Published by gut.bmj.comDownloaded from
doi: 10.1136/gut.35.9.1294
1994 35: 1294-1300Gut
J P Nicholl, B Ross, P C Milner, et al.
bladder stones.
lithotripsy for the treatment of gall
treatment in extracorporeal shock wave
Cost effectiveness of adjuvant bile salt
http://gut.bmj.com/content/35/9/1294
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