Modelling

the

cost

effectiveness

of

tiotropium

salmeterol

and

ipratropium

for

the

treatment

of

chronic

obstructive

pulmonary

disease

in

Spain

Our

objective

was

to

assess

the

cost

effectiveness

of

bronchodilator

therapy

with

tiotropium

salmeterol

or

ipratropium

for

chronic

obstructive

pulmonary

disease

-LRB-

COPD

-RRB-

from

the

perspective

of

the

Spanish

National

Health

System

-LRB-

NHS

-RRB-

A

probabilistic

Markov

model

was

designed

wherein

patients

moved

between

moderate

severe

or

very

severe

COPD

and

had

the

risk

of

exacerbation

and

death

Probabilities

were

derived

from

clinical

trials

Spanish

healthcare

utilisation

costs

and

utilities

were

estimated

for

each

COPD

and

exacerbation

state

Outcomes

were

exacerbations

exacerbation-free

months

quality-adjusted

life

years

-LRB-

QALYs

-RRB-

and

cost

-LRB-

effectiveness

-RRB-

The

mean

-LRB-

SE

-RRB-

number

of

exacerbations

was

-LRB-

-RRB-

for

tiotropium

-LRB-

-RRB-

for

salmeterol

and

-LRB-

-RRB-

for

ipratropium

The

mean

-LRB-

SE

-RRB-

number

of

QALYs

was

-LRB-

-RRB-

-LRB-

-RRB-

and

-LRB-

-RRB-

respectively

Mean

-LRB-

SE

-RRB-

costs

were

-LRB-

-RRB-

for

tiotropium

-LRB-

-RRB-

for

salmeterol

and

-LRB-

-RRB-

for

ipratropium

-LRB-

values

-RRB-

Ipratropium

and

tiotropium

formed

the

cost-effectiveness

frontier

with

tiotropium

being

preferred

when

willingness

to

pay

-LRB-

WTP

-RRB-

exceeded

per

exacerbation-free

month

and

per

QALY

In

Spain

tiotropium

demonstrated

the

highest

expected

net

benefit

for

ratios

of

the

willingness

to

pay

per

QALY

well

within

accepted

limits

Introduction

Owing

to

the

chronic

progressing

nature

and

increasing

prevalence

of

chronic

obstructive

pulmonary

disease

-LRB-

COPD

-RRB-

its

treatment

will

undoubtedly

increase

pressure

on

the

drug

budgets

of

developed

countries

in

the

future

Several

new

and

competing

treatments

for

COPD

have

recently

been

introduced

or

may

soon

become

available

-LSB-

-RSB-

Healthcare

authorities

will

be

forced

to

decide

upon

reimbursement

of

these

medications

and

will

require

high-quality

information

about

the

costs

and

effectiveness

of

these

new

drugs

Pharmaco-economic

evaluations

provide

this

information

and

may

guide

the

positioning

of

new

drugs

in

the

treatment

spectrum

of

COPD

To

date

most

economic

evaluations

of

pharmacotherapy

for

COPD

have

been

conducted

alongside

randomised

controlled

trials

-LSB-

-RSB-

Consequently

their

time

horizon

has

been

restricted

to

the

duration

of

these

trials

which

is

usually

months

to

year

although

economic

evaluations

of

inhaled

bronchodilators

and

corticosteroids

piggybacked

to

clinical

trials

with

durations

of

only

weeks

have

been

reported

-LSB-

-RSB-

For

reimbursement

authorities

and

formulary

decision

makers

these

short-term

economic

evaluations

are

of

limited

value

because

COPD

requires

long-term

maintenance

treatment

on

a

daily

basis

Furthermore

these

policy

makers

will

need

results

that

represent

their

national

or

regional

setting

Because

it

is

not

feasible

to

conduct

long-term

empirical

cost-effectiveness

studies

in

all

potential

markets

some

sort

of

modelling

is

required

This

will

allow

expansion

of

the

time

horizon

beyond

that

of

a

clinical

trial

as

well

as

the

adapting

and

transferring

of

results

from

one

setting

to

another

Decision

analytical

modelling

has

become

an

accepted

approach

to

economic

evaluations

and

the

use

of

modelling

is

supported

by

nearly

all

pharmaco-economic

guidelines

issued

by

health

authorities

involved

in

decision

making

about

pricing

and

reimbursement

of

new

pharmaceuticals

including

Spain

-LSB-

-RSB-

This

study

investigates

the

cost

effectiveness

of

three

bronchodilators

for

the

maintenance

treatment

of

COPD

in

Spain

tiotropium

salmeterol

and

ipratropium

Bronchodilators

are

central

to

the

symptomatic

management

of

COPD

Bronchodilators

include

three

classes

of

medications

-LRB-

-RRB-

the

inhaled

-LRB-

-RRB-

the

inhaled

anticholinergics

and

-LRB-

-RRB-

the

oral

methylxanthines

All

three

classes

include

drugs

that

are

short

acting

or

long

acting

The

most

recently

launched

bronchodilator

is

tiotropium

an

anticholinergic

that

provides

h

bronchodilation

with

once-daily

dosing

It

was

developed

as

a

more

effective

and

more

convenient

alternative

to

ipratropium

the

most

frequently

used

short-acting

anticholinergic

bronchodilator

in

COPD

which

has

to

be

used

four

times

daily

At

the

time

tiotropium

became

available

salmeterol

which

is

used

twice

daily

was

the

most

effective

and

the

most

frequently

used

long-acting

bronchodilator

from

the

class

Orally

administered

methylxanthines

such

as

theophylline

are

not

recommended

for

routine

use

due

to

their

unfavourable

risk/benefit

ratios

In

a

series

of

multi-national

trials

tiotropium

was

directly

compared

with

either

placebo

-LSB-

-RSB-

ipratropium

-LSB-

-RSB-

or

salmeterol

-LSB-

-RSB-

The

above-mentioned

clinical

trials

have

shown

that

tiotropium

provides

sustained

bronchodilation

reduces

exacerbation

rate

and

improves

dyspnoea

and

health-related

quality

of

life

when

compared

with

placebo

or

ipratropium

Improvements

in

lung

function

have

been

shown

to

be

significantly

better

with

tiotropium

than

with

salmeterol

-LSB-

-RSB-

Because

information

on

the

long-term

cost

effectiveness

of

these

bronchodilators

is

lacking

a

decision

analytical

model

was

developed

to

determine

the

cost

effectiveness

of

tiotropium

salmeterol

and

ipratropium

for

the

treatment

of

COPD

Efficacy

data

were

derived

from

the

above-mentioned

clinical

trials

and

the

potential

cost

effectiveness

of

inhaled

bronchodilator

therapy

was

assessed

in

scenario

analyses

The

model

was

populated

with

Spanish

epidemiological

data

on

COPD

Spanish

healthcare

utilisation

and

unit

costs

and

utilities

based

on

Spanish

population

values

Spain

was

chosen

because

cost-effectiveness

data

on

bronchodilator

therapy

from

a

Southern

European

country

were

lacking

Methods

The

model

This

model

can

be

characterised

as

a

Markov

model

-LSB-

-RSB-

It

builds

on

our

earlier

work

in

which

we

constructed

a

fully

probabilistic

Markov

model

to

assess

the

cost

effectiveness

of

tiotropium

salmeterol

and

ipratropium

-LSB-

-RSB-

All

mathematical

and

technical

details

of

this

model

have

been

published

elsewhere

-LSB-

-RSB-

In

brief

all

COPD

patients

were

classified

into

three

disease

states

of

increasing

severity

based

on

their

pre-bronchodilator

forced

expiratory

volume

in

s

-LRB-

-RRB-

moderate

COPD

-LRB-

the

percentage

of

the

predicted

value

-LRB-

pred

-RRB-

-RRB-

severe

COPD

-LRB-

pred

-RRB-

and

very

severe

COPD

-LRB-

pred

-RRB-

In

pre-specified

time

intervals

-LRB-

Markov

cycles

-RRB-

patients

move

between

disease

states

and

are

at

risk

of

experiencing

an

exacerbation

either

severe

or

non-severe

All

probabilities

to

move

between

disease

states

-LRB-

transition

probabilities

-RRB-

and

to

experience

exacerbations

that

went

into

the

model

were

obtained

directly

from

six

clinical

trials

comparing

tiotropium

with

salmeterol

ipratropium

or

placebo

-LRB-

study

codes

A

B

and

-RRB-

-LSB-

-RSB-

Transition

probabilities

and

exacerbation

probabilities

for

tiotropium

were

based

on

the

pooled

patient-level

data

from

all

six

clinical

trials

To

obtain

the

transition

and

exacerbation

probabilities

for

the

comparator

arms

we

applied

the

relative

difference

between

tiotropium

and

the

comparators

in

the

individual

trials

to

the

probabilities

of

tiotropium

that

were

derived

from

the

pooled

data

-LSB-

-RSB-

All

trials

used

similar

inclusion

and

exclusion

criteria

They

enrolled

patients

with

stable

moderate-to-severe

COPD

who

had

an

-LRB-

salmeterol-controlled

trials

-RRB-

of

predicted

normal

and

of

forced

vital

capacity

The

duration

of

these

trials

was

year

for

the

those

that

compared

tiotropium

with

placebo

and

ipratropium

and

months

for

the

trials

that

compared

tiotropium

with

salmeterol

In

total

patients

were

randomly

allocated

to

receive

tiotropium

and

patients

patients

and

patients

were

randomly

selected

to

receive

placebo

salmeterol

and

ipratropium

In

all

trials

the

same

definitions

of

an

exacerbation

and

its

severity

were

used

An

exacerbation

was

defined

as

a

new

onset

or

worsening

of

more

than

one

symptom

such

as

cough

sputum

dyspnoea

or

wheeze

lasting

for

at

least

days

Exacerbations

were

distinguished

into

severe

and

non-severe

exacerbations

A

severe

exacerbation

was

defined

as

incapacitating

or

inability

to

do

work

or

usual

activity

All

other

exacerbations

were

non-severe

Severity

was

assessed

by

the

clinical

investigator

The

risk

of

experiencing

an

exacerbation

varied

by

disease

state

and

treatment

group

Given

treatment

group

and

disease

state

exacerbation

probabilities

were

assumed

to

be

constant

over

time

-LSB-

-RSB-

The

current

model

expanded

the

time

horizon

from

year

to

years

and

aimed

to

assess

the

cost

effectiveness

of

tiotropium

salmeterol

and

ipratropium

for

treating

COPD

patients

in

Spain

To

reflect

the

progressive

nature

of

COPD

in

the

long

run

and

to

incorporate

mortality

an

additional

death

state

was

added

to

the

model

The

base-case

analysis

was

performed

from

the

perspective

of

the

Spanish

National

Health

Service

-LRB-

NHS

-RRB-

and

included

all

costs

covered

by

the

NHS

budget

in

euros

at

the

value

A

graphical

presentation

of

the

model

is

given

in

Fig.

In

addition

an

analysis

from

the

societal

perspective

was

performed

The

difference

between

the

societal

perspective

and

the

NHS

perspective

was

that

the

first

additionally

included

patients

co-payments

for

medications

and

the

costs

of

lost

production

from

day

of

sick

leave

onwards

however

it

excluded

value

added

tax

-LRB-

VAT

-RRB-

as

this

does

not

represent

a

cost

to

society.Fig

presentation

of

the

Markov

model

Backward

transitions

i.e.

from

very

severe

to

severe

COPD

and

from

severe

to

moderate

COPD

were

allowed

during

the

first

year

but

not

thereafter

The

circles

on

the

top

left

of

each

COPD

severity

state

indicate

that

the

patients

can

stay

in

the

same

state

Scenarios

The

first

year

of

the

model

incorporated

the

benefits

of

therapy

as

observed

in

the

clinical

studies

for

improvement

in

lung

function

which

delayed

the

progression

to

subsequent

COPD

severity

states

-LSB-

-RSB-

The

first

year

of

the

model

also

incorporated

the

reduction

in

the

number

of

exacerbations

that

were

found

in

the

clinical

trials

-LSB-

-RSB-

These

first

year

probabilities

are

shown

in

the

upper

part

of

Table

and

in

Table

Because

the

clinical

trials

did

not

provide

data

on

the

probabilities

to

move

between

disease

states

and

to

experience

exacerbations

after

the

first

year

the

model

was

used

to

run

three

scenarios

with

different

assumptions

on

transition

and

exacerbation

probabilities

for

years

to

In

the

base-case

scenario

the

decline

in

after

the

first

year

was

assumed

to

be

ml/year

-LSB-

-RSB-

in

all

treatment

groups

whereas

the

exacerbation

probabilities

remained

as

they

were

for

the

first

year

The

decline

of

ml

was

the

mean

annual

change

in

among

smokers

and

ex-smokers

in

the

Lung

Health

Study

-LSB-

-RSB-

The

lower

part

of

Table

shows

the

transition

probabilities

in

the

base-case

scenario

during

years

to

whereas

Table

shows

the

exacerbation

probabilities.In

the

second

scenario

both

transition

and

exacerbation

probabilities

of

the

first

year

were

assumed

to

remain

constant

during

years

to

In

other

words

the

first

year

probabilities

as

shown

in

Table

-LRB-

under

the

heading

Subsequent

cycle

probabilities

year

-RRB-

and

were

applied

to

the

later

years.In

the

third

scenario

it

was

assumed

that

disease

progression

and

exacerbation

risk

no

longer

differed

between

treatment

groups

after

the

first

year

Exacerbation

probabilities

for

tiotropium

salmeterol

and

ipratropium

were

assumed

to

be

equal

to

the

first

year

probabilities

of

the

ipratropium

group

-LRB-

columns

and

of

Table

-RRB-

The

assumption

on

lung

function

decline

was

the

same

as

in

the

base-case

scenario

Note

that

the

three

scenarios

do

not

differ

with

respect

to

the

first

year

During

the

first

year

both

forward

transitions

-LRB-

transitions

to

worse

disease

states

-RRB-

and

backward

transitions

-LRB-

transitions

to

better

disease

states

-RRB-

are

possible

In

the

base-case

and

third

scenario

backward

transitions

during

years

to

were

not

allowed

reflecting

the

progressive

nature

of

COPD

in

general

Further

note

that

no

differences

between

treatments

in

terms

of

mortality

risk

were

assumed.Table

-LRB-

SE

-RRB-

probabilities

to

move

between

disease

states

in

the

base-case

scenario

-LRB-

These

probabilities

were

also

used

in

scenario

In

scenario

the

subsequent

cycle

probabilities

for

year

were

applied

to

years

to

The

cycle

length

was

days

for

the

very

first

cycle

and

month

for

of

all

subsequent

cycles

-RRB-

To

From

TiotropiumSalmeterolIpratropiumModerateSevereVery

severeDeathModerateSevereVery

severeDeathModerateSevereVery

severeDeathFirst

cycle

probabilities

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Very

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Subsequent

cycle

probabilities

year

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Very

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Subsequent

cycle

probabilities

years

to

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Very

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Table

-LRB-

SE

-RRB-

exacerbation

probabilities

in

the

base-case

scenario

-LRB-

These

probabilities

were

also

used

in

scenario

In

scenario

the

probabilities

of

ipratropium

were

also

applied

to

tiotropium

and

salmeterol

during

years

to

-RRB-

Probability

of

experiencing

an

exacerbationProbability

that

the

exacerbation

will

be

severe

given

that

there

is

an

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Very

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Input

data

baseline

distribution

of

patients

among

disease

states

The

baseline

distribution

of

patients

among

the

disease

states

was

based

on

a

Spanish

study

by

Miravitlles

et

al.

-LSB-

-RSB-

Re-analysis

of

the

data

according

to

the

severity

definition

used

in

the

model

showed

that

of

COPD

patients

had

moderate

disease

had

severe

disease

and

had

very

severe

disease

A

disease

state

for

mild

COPD

was

not

included

in

the

model

because

mild

COPD

patients

did

not

participate

in

the

tiotropium

trials

Input

data

death

state

Probabilities

of

dying

were

based

on

all-cause

mortality

rates

among

Spanish

patients

with

severe

or

very

severe

COPD

as

published

by

Miravitlles

et

al.

-LSB-

-RSB-

The

data

from

this

study

were

re-analysed

using

the

same

cut-off

values

for

the

predicted

of

severe

and

very

severe

COPD

that

were

used

in

the

model

The

all-cause

mortality

rate

was

found

to

be

per

among

patients

with

severe

COPD

-LSB-

-RSB-

and

the

relative

mortality

risk

in

patients

with

very

severe

COPD

compared

with

severe

COPD

was

found

to

be

for

a

mean

decline

in

predicted

of

Under

the

assumption

of

constant

proportional

hazards

the

relative

mortality

risk

of

patients

in

the

trials

was

estimated

to

be

for

very

severe

COPD

and

for

moderate

COPD

compared

with

severe

COPD

We

applied

these

relative

risks

to

the

all-cause

mortality

rate

of

per

among

patients

with

severe

COPD

to

derive

the

mortality

rates

and

subsequently

the

probabilities

of

dying

among

patients

with

moderate

and

very

severe

COPD

These

probabilities

were

the

same

for

all

treatment

groups

Input

data

utilities

To

reflect

the

impaired

quality

of

life

of

patients

with

COPD

we

attached

utility

weights

to

each

disease

severity

state

These

utilities

were

obtained

from

the

scores

at

baseline

in

a

subset

of

patients

randomly

accepted

into

the

UPLIFT

trial

-LRB-

n

-RRB-

-LSB-

-RSB-

These

scores

were

valued

using

the

Spanish

tariff

-LSB-

-RSB-

A

value

of

represents

perfect

health

whereas

represents

death

Mean

-LRB-

SE

-RRB-

utilities

at

baseline

of

the

UPLIFT

trial

were

calculated

to

be

-LRB-

-RRB-

in

patients

with

moderate

disease

-LRB-

-RRB-

in

patients

with

severe

disease

and

-LRB-

-RRB-

in

patients

with

very

severe

disease

During

the

months

in

which

patients

experienced

an

exacerbation

the

utility

value

was

reduced

by

in

the

case

of

a

non-severe

exacerbation

-LSB-

-RSB-

and

by

in

the

case

of

a

severe

exacerbation

-LSB-

-RSB-

Each

year

the

number

of

quality-adjusted

life-years

-LRB-

QALYs

-RRB-

was

calculated

as

the

sum

of

the

multiplications

of

the

number

of

months

in

a

particular

disease

state

and

the

utility

of

that

disease

state

divided

by

Input

data

costs

The

details

and

results

of

the

cost

estimates

are

presented

in

Table

Estimates

of

healthcare

utilisation

were

primarily

derived

from

two

studies

performed

in

Spain

that

had

measured

resource

use

and

costs

of

the

treatment

of

patients

with

COPD

-LSB-

-RSB-

Data

from

these

studies

were

re-analysed

to

estimate

resource

use

and

costs

by

disease

severity

and

exacerbation

severity

using

similar

definitions

as

applied

in

the

model

In

the

model

healthcare

utilisation

associated

with

COPD

maintenance

therapy

varied

by

disease

severity

Healthcare

utilisation

during

exacerbations

varied

by

the

severity

of

the

exacerbation

-LRB-

severe

or

non-severe

-RRB-

Calculations

were

conservative

in

assuming

that

costs

per

disease

severity

state

and

costs

per

severe

or

non-severe

exacerbation

were

equal

across

treatment

groups

Resources

for

maintenance

therapy

included

visits

to

respiratory

physicians

inside

and

outside

the

hospital

visits

to

the

general

practitioner

pulmonary

function

tests

blood

tests

imaging

tests

and

respiratory

medications

Resources

associated

with

a

non-severe

exacerbation

included

general

practitioner

and

respiratory

physician

visits

and

medications

Besides

physician

visits

and

outpatient

medications

resources

associated

with

severe

exacerbations

also

included

hospital

admissions

and

visits

to

the

emergency

room

-LRB-

ER

-RRB-

department

Costs

of

pulmonary

function

and

other

tests

as

well

as

costs

of

medications

that

were

prescribed

during

inpatient

stay

or

during

ER

visits

were

not

measured

separately

because

they

were

included

in

the

overall

costs

per

in-patient

day

and

the

costs

per

ER

visit.Table

healthcare

utilisation

-LRB-

HU

-RRB-

unit

costs

and

mean

-LRB-

SE

-RRB-

total

costs

of

maintenance

therapy

and

exacerbations

from

the

NHS

perspective

for

Spain

in

euros

at

the

value

-LRB-

HU

healthcare

utilisation

RP

respiratory

physician

GP

general

practitioner

ICU

intensive

care

unit

exa

exacerbation

-RRB-

Maintenance

therapy

Unit

costsModerate

COPDSevere

COPDVery

severe

COPDHU

per

patient

per

yearTotal

costsHU

per

patient

per

yearTotal

costsHU

per

patient

per

yearTotal

costsVisit

RP

in

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Visit

RP

outside

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Visit

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Thorax

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Blood

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Blood

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Influenza

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Oral

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Inhaled

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Total

costs

per

patient

per

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

ExacerbationsUnit

costsNon-severe

exacerbationSevere

exacerbationStudy

medication

costs

per

dayHU

per

exaTotal

costsHU

per

exaTotal

-LRB-

-RRB-

-LRB-

-RRB-

Emergency

-LRB-

-RRB-

Visit

-LRB-

-RRB-

-LRB-

-RRB-

Visit

RP

in

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Oral

-LRB-

-RRB-

-LRB-

-RRB-

Inhaled

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

NHS

sick

leave

-LRB-

-RRB-

Total

costs

per

-LRB-

-RRB-

-LRB-

-RRB-

For

medications

and

oxygen

HU

is

expressed

in

number

of

days

during

which

the

medication

or

oxygen

was

usedaOf

all

severe

exacerbations

required

hospital

admission

Of

those

were

to

the

ICU

The

length

of

stay

on

ICU

is

days

and

the

length

of

stay

on

non-ICU

is

days

Hence

and

bOnly

medications

prescribed

in

ambulatory

settings

Costs

of

medications

administered

in

hospital

and

at

emergency

rooms

are

included

in

costs

of

hospital

stay/emergency

room

visitcAverage

labour

costs

per

day

in

Spain

are

Of

Spanish

COPD

patients

have

paid

employment

The

NHS

covers

of

these

labour

costs

during

days

of

the

sick

leave

episode

and

from

day

onwards

Of

severe

exacerbations

are

associated

with

sick

leave

longer

than

days

The

duration

of

these

absence

spells

is

days

So

-LRB-

-RRB-

Unit

costs

of

healthcare

resources

were

obtained

from

the

SOIKOS

health

database

and

have

been

described

in

detail

elsewhere

-LSB-

-RSB-

They

were

updated

to

using

the

Spanish

General

Consumer

Price

Index

Acquisition

costs

of

pulmonary

drugs

from

the

NHS

perspective

were

based

on

public

prices

and

calculated

as

the

ex-factory

prices

multiplied

by

a

mark-up

of

to

convert

these

prices

to

public

prices

-LSB-

-RSB-

The

co-payment

of

of

the

public

price

for

the

people

in

the

work

force

was

excluded

It

was

estimated

that

of

Spanish

COPD

patients

had

to

pay

these

co-payments

because

they

were

still

in

the

work

force

-LSB-

-RSB-

From

a

societal

perspective

the

drug

costs

included

co-payment

but

excluded

the

VAT

that

is

included

in

the

public

prices

Costs

of

tiotropium

salmeterol

and

ipratropium

from

the

NHS

perspective

were

and

per

day

respectively

From

the

societal

perspective

these

costs

were

for

tiotropium

for

salmeterol

and

for

ipratropium

The

NHS

covers

the

costs

of

absence

from

work

due

to

illness

from

the

day

of

sick

leave

onwards

The

NHS

pays

of

gross

salary

during

days

to

and

from

day

onwards

When

we

were

calculating

costs

from

the

NHS

perspective

these

costs

were

added

to

the

costs

of

all

severe

exacerbations

with

sick

leave

longer

than

days

-LRB-

approximately

of

all

severe

exacerbations

-RRB-

The

costs

from

the

societal

perspective

included

the

costs

of

lost

production

during

all

days

of

absence

from

paid

work

The

resulting

mean

-LRB-

SE

-RRB-

annual

costs

of

maintenance

therapy

from

an

NHS

perspective

were

-LRB-

-RRB-

for

a

patient

with

moderate

COPD

-LRB-

-RRB-

for

a

patient

with

severe

COPD

and

-LRB-

-RRB-

for

a

patient

with

very

severe

COPD

The

corresponding

values

from

the

societal

perspective

were

-LRB-

-RRB-

-LRB-

-RRB-

and

-LRB-

-RRB-

The

mean

-LRB-

SE

-RRB-

costs

of

exacerbations

from

the

NHS

perspective

were

-LRB-

-RRB-

for

a

non-severe

exacerbation

and

-LRB-

-RRB-

for

a

severe

exacerbation

From

a

societal

perspective

these

costs

were

-LRB-

-RRB-

and

-LRB-

-RRB-

respectively

COPD

severity

To

investigate

the

impact

of

COPD

severity

on

the

cost

effectiveness

of

the

bronchodilators

we

ran

sensitivity

analyses

with

the

base-case

scenario

assuming

that

at

the

start

of

the

model

of

the

patients

had

either

moderate

severe

or

very

severe

COPD

Discounting

Because

of

time

preference

costs

and

effects

that

will

arise

in

the

future

are

usually

valued

lower

than

costs

and

effects

in

the

present

Discounting

is

used

to

calculate

the

present

value

of

future

costs

and

effects

In

accordance

with

proposed

Spanish

guidelines

an

annual

discount

rate

of

has

been

adopted

-LSB-

-RSB-

In

the

base-case

analysis

costs

and

health

outcomes

were

discounted

at

the

same

rate

whereas

in

sensitivity

analyses

discount

rates

of

for

both

costs

and

effects

and

for

costs

combined

with

for

effects

were

applied

In

scenarios

and

the

same

discount

rate

was

used

as

in

the

base-case

scenario

Probabilistic

sensitivity

analysis

To

facilitate

the

interpretation

of

results

of

economic

analyses

the

reporting

of

uncertainty

associated

with

costs

and

outcomes

is

equally

important

as

reporting

the

point

estimates

of

these

parameters

Hence

the

model

was

designed

fully

probabilistic

and

uncertainty

around

the

probabilities

to

move

between

disease

states

the

probabilities

to

experience

exacerbations

utilities

and

healthcare

utilisation

was

addressed

by

defining

a

probability

distribution

for

each

input

parameter

-LSB-

-RSB-

The

uncertainty

around

these

input

parameters

was

propagated

through

the

model

simultaneously

by

conducting

second-order

Monte

Carlo

simulations

This

means

making

random

draws

of

the

uncertain

parameters

from

their

probability

distribution

running

the

model

for

each

set

of

parameters

that

is

drawn

and

collecting

the

outputs

from

each

run

-LSB-

-RSB-

The

current

results

were

based

on

iterations

The

main

outcome

measures

of

the

model

were

mean

and

standard

error

-LRB-

SE

being

the

standard

deviation

of

the

iterations

-RRB-

of

the

costs

per

patient

exacerbation-free

months

and

quality-adjusted

life

years

The

presentation

of

incremental

cost

effectiveness

was

based

on

the

hierarchy

of

outcomes

i.e.

each

treatment

option

was

compared

with

the

next

best

treatment

option

in

terms

of

effectiveness

The

uncertainty

around

costs

and

effects

was

further

explored

by

plotting

of

the

iterations

on

incremental

cost-effectiveness

planes

-LRB-

CE-planes

-RRB-

-LSB-

-RSB-

and

by

presenting

cost-effectiveness

acceptability

curves

-LSB-

-RSB-

and

frontiers

-LSB-

-RSB-

The

acceptability

curve

presents

the

probability

that

a

treatment

is

the

most

cost

effective

of

the

three

treatments

at

different

threshold

values

for

cost

effectiveness

-LRB-

ceiling

ratio

-RRB-

whereas

the

cost-effectiveness

acceptability

frontier

demonstrates

which

of

the

three

treatments

should

be

adopted

because

it

results

in

the

highest

expected

net

benefit

given

the

ceiling

ratio

The

net

benefit

is

calculated

as

the

total

costs

-LRB-

C

-RRB-

minus

the

effects

-LRB-

E

-RRB-

multiplied

by

the

ceiling

ratio

-LRB-

C

-LRB-

E

ceiling

ratio

-RRB-

-RRB-

-LSB-

-RSB-

The

model

was

programmed

in

Microsoft

EXCEL

Results

Health

outcomes

The

results

of

the

Markov

simulation

for

the

different

scenarios

are

presented

in

Table

In

the

base-case

scenario

the

mean

-LRB-

SE

-RRB-

number

of

exacerbations

in

years

was

-LRB-

-RRB-

in

the

tiotropium

group

-LRB-

-RRB-

in

the

salmeterol

group

and

-LRB-

-RRB-

in

the

ipratropium

group

The

corresponding

mean

-LRB-

SE

-RRB-

number

of

exacerbation-free

months

was

-LRB-

-RRB-

in

the

tiotropium

group

-LRB-

-RRB-

in

the

salmeterol

group

and

-LRB-

-RRB-

in

the

ipratropium

group

Estimates

of

the

number

-LRB-

SE

-RRB-

of

QALYs

were

-LRB-

-RRB-

-LRB-

-RRB-

and

-LRB-

-RRB-

respectively

In

all

scenarios

differences

in

exacerbation-free

months

and

QALYs

between

treatment

groups

were

consistently

in

favour

of

the

tiotropium

group

Applying

the

first

year

probabilities

to

all

subsequent

years

-LRB-

scenario

-RRB-

increased

the

difference

in

exacerbation-free

months

between

tiotropium

and

the

other

treatment

groups

to

approximately

and

the

difference

in

QALYs

to

approximately

Assuming

similar

exacerbation

probabilities

across

treatment

groups

in

year

to

-LRB-

scenario

-RRB-

reduced

the

differences

between

treatment

groups

considerably

In

this

analysis

the

difference

in

exacerbation-free

months

between

tiotropium

and

the

other

treatment

groups

was

just

above

and

the

difference

in

QALYs

was

about

There

was

almost

no

difference

in

health

outcomes

between

ipratropium

and

salmeterol

in

this

scenario.Table

of

the

Markov

simulation

for

the

base-case

analysis

from

the

NHS

perspective

covering

a

time

period

of

years

The

table

gives

mean

-LRB-

SE

-RRB-

or

mean

-LRB-

confidence

interval

-RRB-

QALY

quality-adjusted

life

year

Tio

tiotropium

Salm

salmeterol

Ipra

Ipratropium

exa

exacerbations

CE-ratio

cost-effectiveness

ratio

exa-free

exacerbation-free

Costs

In

the

base-case

scenario

from

the

NHS

perspective

mean

-LRB-

SE

-RRB-

total

costs

over

years

were

lowest

in

the

ipratropium

group

with

-LRB-

-RRB-

per

patient

-LRB-

Table

-RRB-

Costs

were

-LRB-

-RRB-

in

the

salmeterol

group

and

-LRB-

-RRB-

in

the

tiotropium

group

The

higher

costs

in

the

tiotropium

and

salmeterol

group

were

largely

due

to

the

higher

costs

of

study

medication

Compared

with

those

of

ipratropium

the

costs

of

study

medication

were

-LRB-

-RRB-

higher

in

the

tiotropium

group

and

-LRB-

-RRB-

higher

in

the

salmeterol

group

Savings

in

other

categories

of

costs

mainly

exacerbation-related

costs

offset

approximately

half

of

these

additional

study

medication

costs

Because

of

a

smaller

difference

in

exacerbation

rate

between

treatment

groups

in

scenario

the

difference

in

total

costs

between

ipratropium

on

the

one

hand

and

tiotropium

and

salmeterol

on

the

other

hand

increased

by

and

respectively

The

impact

of

applying

the

first-year

transition

probabilities

to

years

to

-LRB-

scenario

-RRB-

on

the

differences

in

costs

between

treatment

groups

was

much

less

-LRB-

Table

-RRB-

Cost

effectiveness

In

the

base-case

scenario

from

the

NHS

perspective

estimates

of

the

incremental

costs

per

exacerbation-free

month

were

when

tiotropium

was

compared

with

salmeterol

and

when

salmeterol

was

compared

with

ipratropium

The

corresponding

incremental

costs

per

QALY

were

and

respectively

The

distribution

of

the

results

of

the

model

iterations

on

the

CE-planes

is

also

reported

in

Table

The

comparisons

between

tiotropium

and

salmeterol

show

that

the

majority

of

simulations

-LRB-

approximately

-RRB-

lie

in

the

upper-right

quadrants

signifying

better

health

outcomes

and

higher

costs

for

tiotropium

The

CE-planes

comparing

salmeterol

with

ipratropium

show

that

about

of

the

dots

are

found

in

the

upper-left

and

about

in

the

upper-right

quadrant

signifying

similar

health

outcomes

and

higher

costs

for

salmeterol

Figure

shows

the

cost-effectiveness

acceptability

curves

in

the

base-case

scenario

from

the

NHS

perspective

The

curves

show

that

in

terms

of

exacerbation-free

months

ipratropium

has

the

highest

probability

of

being

cost

effective

when

the

threshold

value

for

cost

per

additional

exacerbation-free

month

is

below

In

terms

of

QALYs

ipratropium

has

the

highest

probability

of

being

the

most

cost

effective

for

all

threshold

values

for

cost

per

QALY

below

Above

these

values

tiotropium

has

the

highest

probability

of

being

cost

effective

However

when

the

distribution

of

the

cost-effectiveness

ratio

is

skewed

as

is

the

case

in

the

presented

analyses

the

treatment

with

the

highest

probability

of

being

cost

effective

is

not

always

the

treatment

with

the

highest

expected

net

benefit

-LSB-

-RSB-

In

Fig.

the

cost-effectiveness

acceptability

frontier

is

drawn

in

bold

The

frontier

follows

the

curve

of

the

treatment

with

the

highest

expected

net

benefit

for

a

given

value

of

the

cost-effectiveness

threshold

Hence

it

indicates

which

treatment

should

be

chosen

because

it

is

optimal

The

bold

curve

demonstrates

that

both

ipratropium

and

tiotropium

are

on

the

frontier

For

any

ceiling

ratio

above

per

exacerbation-free

month

and

above

per

QALY

tiotropium

is

the

preferred

treatment

option

In

scenario

these

threshold

values

were

lower

and

respectively

whereas

the

corresponding

values

in

scenario

were

and

The

point

on

the

frontier

where

the

most

optimal

treatment

switches

from

ipratropium

to

tiotropium

in

Fig.

corresponds

to

the

base-case

incremental

cost-effectiveness

ratio

for

the

comparison

between

these

two

bronchodilators

Figure

also

shows

that

although

tiotropium

has

the

highest

probability

of

being

the

most

optimal

treatment

this

probability

is

at

maximum

This

is

the

value

at

which

the

acceptability

curve

of

tiotropium

using

QALYs

becomes

asymptotic.Fig

acceptability

curves

and

frontier

of

the

costs

per

exacerbation-free

month

and

the

cost

per

QALY

Ceiling

ratio

threshold

value

for

the

cost-effectiveness

ratio

in

euros

The

curves

in

grey

represent

the

probability

that

a

treatment

is

cost

effective

for

a

given

value

of

the

ceiling

ratio

In

the

case

of

skewed

distributions

of

the

ratio

the

treatment

with

the

highest

probability

of

being

cost

effective

is

not

always

the

treatment

with

the

highest

expected

net

benefit

The

acceptability

frontier

-LRB-

in

black

-RRB-

shows

which

treatment

is

associated

with

the

highest

expected

net

benefit

for

each

value

of

the

ceiling

ratio

Societal

perspective

From

the

societal

perspective

overall

mean

-LRB-

SE

-RRB-

costs

increased

in

all

treatment

groups

to

-LRB-

-RRB-

for

tiotropium

-LRB-

-RRB-

for

salmeterol

and

-LRB-

-RRB-

for

ipratropium

However

the

savings

in

exacerbation

costs

generated

by

tiotropium

and

salmeterol

compared

with

ipratropium

were

higher

from

a

societal

perspective

than

from

the

NHS

perspective

Consequently

from

the

societal

perspective

the

difference

in

overall

costs

between

the

treatment

groups

was

reduced

Also

the

incremental

costs

per

exacerbation-free

month

were

reduced

to

for

the

comparison

tiotropium

versus

salmeterol

and

for

the

comparison

salmeterol

versus

ipratropium

The

incremental

cost

per

QALY

were

reduced

to

for

the

comparison

tiotropium

versus

salmeterol

and

for

the

comparison

salmeterol

versus

ipratropium

Tiotropium

had

the

highest

expected

net

benefit

for

any

value

of

the

cost-effectiveness

threshold

above

per

exacerbation-free

month

and

above

per

QALY

Below

these

values

ipratropium

is

preferred

Impact

of

COPD

severity

When

the

model

was

run

separately

for

patients

with

either

moderate

severe

or

very

severe

COPD

it

showed

that

the

threshold

value

above

which

tiotropium

had

the

highest

expected

net

benefit

increased

with

the

severity

of

COPD

The

threshold

values

for

the

costs

per

QALY

above

which

tiotropium

became

the

preferred

option

were

for

moderate

COPD

for

severe

COPD

and

for

very

severe

COPD

Below

these

values

ipratropium

was

preferred

Tiotropium

had

the

highest

expected

net

benefit

when

the

ceiling

ratios

for

cost

per

exacerbation

free

month

were

for

moderate

COPD

for

severe

COPD

and

for

very

severe

COPD

Below

these

values

ipratropium

had

the

highest

expected

net

benefit

Discount

rates

Because

discounting

affects

both

health

outcomes

and

costs

the

effect

of

discounting

in

this

study

was

small

Analyses

based

on

discount

rates

of

and

showed

almost

similar

cost-effectiveness

ratios

Discounting

health

outcomes

at

a

lower

rate

than

costs

led

to

cost-effectiveness

ratios

that

were

slightly

more

in

favour

of

tiotropium

Discussion

Bronchodilators

form

the

main

therapy

for

the

symptomatic

relief

of

respiratory

symptoms

in

COPD

patients

In

this

study

we

have

constructed

a

decision

analytical

model

to

synthesise

clinical

trial

data

on

the

effectiveness

of

bronchodilator

treatment

We

have

shown

how

scenario

analyses

can

be

used

to

extend

the

time

horizon

of

the

cost-effectiveness

study

beyond

that

of

the

clinical

trials

In

addition

we

have

shown

how

a

model

can

be

populated

with

country-specific

data

to

obtain

estimates

of

the

cost-effectiveness

of

bronchodilators

in

the

Spanish

setting

This

comprehensive

country

adaptation

and

extension

of

the

existing

short-term

Markov

model

-LSB-

-RSB-

required

much

more

than

just

the

imputation

of

Spanish

unit

costs

We

searched

for

Spanish

sources

for

almost

every

type

of

input

data

ranging

from

the

distribution

of

COPD

severity

stages

mortality

the

proportion

of

COPD

patients

in

the

work

force

utilities

resource

use

and

unit

costs

We

re-analysed

patient-level

data

from

previously

published

Spanish

studies

on

prevalence

mortality

and

resource

utilisation

-LSB-

-RSB-

to

ensure

that

these

Spanish

data

matched

the

model

's

definitions

of

COPD

severity

and

exacerbation

severity

This

included

obtaining

point

estimates

as

well

as

distributions

of

these

input

data

The

strength

of

the

Spanish

data

is

also

that

mainly

patients

from

general

practices

were

included

thus

reflecting

the

routine

care

setting

closely

The

majority

of

Spanish

patients

are

treated

by

general

practitioners

and

the

proportion

of

patients

referred

to

specialist

care

by

pulmonologists

is

smaller

than

in

many

other

west

European

countries

-LSB-

-RSB-

This

may

be

related

to

the

gate-keeping

function

of

the

general

practitioner

in

Spain

that

is

not

enforced

in

some

other

European

countries

The

base-case

scenario

showed

that

tiotropium

was

associated

with

an

approximately

reduction

in

exacerbations

when

compared

with

salmeterol

Salmeterol

was

associated

with

reduction

in

exacerbations

when

compared

with

ipratropium

Differences

between

the

three

treatment

groups

in

terms

of

QALYs

were

small

That

was

expected

given

the

time

horizon

and

treatments

that

do

not

directly

affect

survival

The

distribution

of

dots

on

the

CE-planes

showed

that

the

higher

effectiveness

of

salmeterol

over

ipratropium

was

associated

with

more

uncertainty

than

the

higher

effectiveness

of

tiotropium

over

salmeterol

because

for

the

latter

comparison

a

larger

proportion

of

the

dots

was

found

on

the

right

side

of

the

CE

plane

Beside

effectiveness

the

choice

between

bronchodilators

must

involve

many

considerations

including

economic

considerations

of

costs

and

cost

effectiveness

The

final

result

of

this

cost-effectiveness

analysis

is

an

acceptability

frontier

that

demonstrated

that

tiotropium

has

the

highest

expected

net

benefit

for

a

threshold

value

of

the

costs

per

QALY

that

is

well

within

the

limits

of

other

adopted

therapies

in

Spain

-LSB-

-RSB-

and

in

other

countries

like

the

UK

-LSB-

-RSB-

This

threshold

value

increases

with

the

severity

of

COPD

because

the

differences

between

treatments

in

the

probabilities

of

developing

a

-LRB-

severe

-RRB-

exacerbation

decrease

as

COPD

severity

increases

Nevertheless

the

cost-effectiveness

threshold

in

the

most

severely

affected

patients

is

still

relatively

low

The

threshold

value

for

costs

per

additional

exacerbation-free

month

of

above

which

tiotropium

becomes

the

optimal

choice

in

Spain

is

higher

than

the

ceiling

ratios

above

which

tiotropium

became

most

cost

effective

in

the

Netherlands

-LRB-

-RRB-

and

Canada

-LRB-

-RRB-

in

the

model

-LSB-

-RSB-

Similarly

when

QALYs

were

used

as

the

outcome

measure

the

ceiling

ratio

of

per

QALY

above

which

tiotropium

is

the

preferred

option

in

Spain

is

also

higher

than

in

The

Netherlands

and

Canada

where

tiotropium

became

the

preferred

option

when

decision

makers

could

afford

to

pay

more

than

and

for

a

QALY

respectively

This

difference

between

these

countries

is

largely

driven

by

the

relatively

low

acquisition

costs

of

ipratropium

in

Spain

which

is

related

to

the

fact

that

there

is

no

widespread

use

of

the

more

expensive

dry

powder

formulation

of

ipratropium

In

addition

the

savings

due

to

the

reduction

in

exacerbations

by

tiotropium

and

salmeterol

are

less

because

the

costs

of

treating

a

severe

exacerbation

in

Spain

are

lower

than

in

The

Netherlands

and

Canada

This

is

caused

by

a

smaller

proportion

of

patients

hospitalised

as

well

as

a

shorter

length

of

stay

As

a

result

tiotropium

generated

very

small

net

savings

in

the

Netherlands

and

similar

costs

to

the

other

two

bronchodilators

in

Canada

whereas

it

increased

total

costs

in

Spain

Nevertheless

in

the

three

countries

investigated

the

economic

evaluations

indicated

that

the

health

benefits

gained

with

tiotropium

are

either

at

almost

no

additional

costs

or

at

costs

that

appear

reasonable

and

acceptable

given

other

adopted

treatments

-LSB-

-RSB-

Our

base-case

scenario

was

conservative

with

respect

to

lung

function

decline

as

we

assigned

a

similar

decline

of

ml/year

to

the

patients

in

all

treatment

groups

after

the

first

year

We

chose

this

to

be

the

best

assumption

for

the

base-case

scenario

because

there

is

little

evidence

in

the

literature

that

bronchodilators

alter

the

rate

of

decline

of

lung

function

-LSB-

-RSB-

However

frequent

exacerbations

seem

to

accelerate

the

decline

in

lung

function

-LSB-

-RSB-

Therefore

our

base-case

scenario

might

have

underestimated

the

long-term

effect

of

a

bronchodilator

that

reduces

the

number

and

severity

of

exacerbations

For

that

reason

we

developed

the

second

scenario

which

is

the

least

conservative

because

we

assumed

that

the

differences

in

lung

function

decline

and

exacerbation

rates

between

the

three

treatments

that

were

observed

during

the

first

year

would

remain

during

the

years

thereafter

This

scenario

is

most

favourable

for

tiotropium

and

we

see

the

threshold

value

above

which

tiotropium

becomes

most

cost

effective

drop

to

per

exacerbation-free

month

and

per

QALY

In

addition

to

this

optimistic

scenario

we

developed

a

very

conservative

scenario

by

completely

eliminating

the

difference

in

exacerbation

rate

between

the

treatment

groups

after

the

first

year

and

assuming

that

exacerbation

rates

would

resemble

the

rate

observed

in

the

ipratropium

group

This

third

scenario

also

assumed

a

similar

decline

in

lung

function

across

treatment

groups

of

ml/year

This

third

scenario

is

conservative

because

exacerbations

were

the

main

drivers

of

cost

effectiveness

The

threshold

value

above

which

tiotropium

becomes

most

cost

effective

in

this

third

scenario

increases

to

for

an

additional

exacerbation-free

month

and

for

a

QALY

yet

is

still

below

acceptable

limits

reported

for

the

Spanish

setting

Below

that

ipratropium

was

most

cost

effective

Altogether

these

three

scenarios

give

the

range

within

which

to

expect

the

cost

effectiveness

of

these

bronchodilators

Note

that

we

had

no

scenarios

assuming

a

differential

effect

of

the

treatments

on

for

example

utilities

or

costs

of

a

single

exacerbation

because

the

evidence

of

such

effects

is

lacking

Furthermore

all

scenarios

had

a

time

horizon

of

years

to

meet

the

requirements

of

many

European

reimbursement

authorities

who

prefer

extensions

to

time

horizons

reflecting

their

budgeting

process

-LRB-

typically

for

years

-RRB-

Lifetime

models

that

primarily

aim

to

compare

medications

are

soon

outdated

by

the

development

of

new

therapeutic

options

When

the

cost-effectiveness

analysis

was

conducted

from

a

societal

perspective

the

threshold

value

above

which

tiotropium

is

the

preferred

option

is

reduced

considerably

to

per

exacerbation-free

month

and

per

QALY

This

improved

cost

effectiveness

is

primarily

related

to

increasing

exacerbation

costs

because

of

the

inclusion

of

the

costs

of

production

losses

Hence

a

reduced

exacerbation

rate

is

associated

with

higher

savings

The

NHS

perspective

also

included

sick

leave

benefits

paid

for

by

the

NHS

from

day

onwards

However

this

applies

only

to

severe

exacerbations

where

it

was

less

than

of

its

costs

In

contrast

from

a

societal

perspective

costs

of

production

losses

are

of

the

costs

of

a

severe

exacerbation

and

of

the

costs

of

a

non-severe

exacerbation

We

chose

two

outcome

measures

that

are

among

the

most

relevant

in

the

lives

of

patients

with

COPD

being

free

of

exacerbations

and

having

a

good

quality

of

life

The

concept

of

an

exacerbation-free

month

is

comparable

to

the

concept

of

a

symptom-free

day

which

is

a

frequently

used

outcome

measure

in

asthma

-LSB-

-RSB-

As

it

is

a

positive

outcome

-LRB-

i.e.

more

is

better

-RRB-

its

cost-effectiveness

ratio

is

easier

to

interpret

than

the

ratio

cost

per

exacerbation

avoided

In

general

the

number

of

exacerbations

is

not

a

good

outcome

measure

to

use

in

long-term

models

especially

when

treatment

improves

survival

This

outcome

measure

will

bias

the

treatment

which

improves

survival

because

patients

can

experience

exacerbations

during

the

life

years

gained

In

contrast

the

number

of

exacerbation-free

months

takes

account

of

the

fact

that

the

added

years

of

life

are

partly

lived

free

of

exacerbations

The

model

as

well

as

the

currently

presented

long-term

model

has

been

used

in

reimbursement

negotiations

in

several

countries

The

major

strength

of

this

model

is

its

transparency

We

have

fully

disclosed

the

model

structure

as

well

as

all

the

input

Costs

per

exacerbation

and

costs

per

disease

state

do

not

differ

between

the

three

treatment

groups

and

mortality

rates

by

disease

severity

were

also

set

equally

for

all

treatment

groups

Hence

the

difference

in

cost

effectiveness

is

driven

by

the

difference

in

acquisition

costs

of

the

study

drugs

and

the

difference

in

their

effectiveness

i.e.

the

difference

in

the

probabilities

to

move

between

disease

states

and

the

differences

in

exacerbation

risks

For

the

first

year

of

the

model

estimates

of

effectiveness

were

directly

obtained

from

patient-level

data

from

clinical

trials

Hence

estimates

of

probabilities

were

not

based

on

expert

opinion

or

literature

as

is

often

the

case

in

modelling

studies

We

acknowledge

that

differences

may

exist

between

trial

results

from

which

we

derived

the

model

input

and

the

effectiveness

of

therapy

in

routine

daily

practice

A

model

can

be

used

to

adapt

the

trial

data

to

better

represent

daily

practice

Particularly

compliance

is

known

to

be

worse

in

daily

practice

However

not

accounting

for

compliance

was

conservative

for

tiotropium

and

salmeterol

since

once-daily

and

twice-daily

dosing

is

more

likely

to

be

accompanied

by

long-term

compliance

than

is

four-times

daily

dosing

in

chronic

diseases

-LSB-

-RSB-

Owing

to

the

double-blind

double-dummy

design

of

the

clinical

trials

the

dosing

frequency

was

the

same

in

the

treatment

groups

and

any

impact

of

dosing

frequency

on

outcomes

was

eliminated

In

conclusion

our

model

has

demonstrated

that

tiotropium

is

the

treatment

with

the

highest

expected

net

benefit

if

decision

makers

can

afford

to

spend

additional

budget

to

gain

additional

health

benefits

The

threshold

value

of

the

costs

per

QALY

at

which

tiotropium

becomes

the

preferred

treatment

is

well

within

acceptable

limits

-LRB-

i.e.

from

the

NHS

perspective

and

from

the

societal

perspective

-RRB-

O O O B I O O O O O O O O O O O O O O O B O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B I O O B O O O O O O O B O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O B O O O O O O B O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O B O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O B I O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B I O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O B O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O B O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

bronchodilators
model
cost effectiveness
spain

chronic obstructive pulmonary disease (copd)