Economic analysis of Noqturina® (oral lyophilisate) use in the symptomatic treatment of nocturia due to idiopathic nocturnal polyuria

Copyright
© 2018 PRO MEDICINA Foundation, Published by PRO MEDICINA Foundation
User License
The journal provides published content under the terms of the Creative Commons 4.0 AttributionInternational NonCommercial Use (CC BYNC 4.0) license.
Authors
Introduction:
Nocturia relates to the need to urinate at night
when micturition was preceded by sleep and immediately followed by a period of
sleep. The aim of this analysis is to examine the costeffectiveness of
desmopressin at a dose of 25 μg oral lyophilisate for
women and 50 μg oral lyophilisate for men
(DDAVP) in comparison to the best supportive care (BSC) used in Polish clinical
practice in the treatment of nocturia (≥2 nocturnal micturition) caused by
idiopathic nocturnal polyuria.
Methods:
The
economic analysis uses a model combining the aspects of the
partitionedsurvival model and statetransition model (STM). The projection was
carried out over a 30year time horizon, which corresponds to 120 quarterly
modelling cycles. The costs were calculated from a common perspective,
including expenses incurred by the public payer (Narodowy Fundusz Zdrowia,
National Health Found) and expenses incurred by the patient. Health effects of
medical technologies have been estimated on the basis of unit data from CS40
and CS41 studies. The literature, statistical databases and information
provided by clinical experts were used to develop the remaining input data,
including utility.
Results:
The ICER for DDAVP + BSC compared to BSC was 56.1 kPLN (13.0 kEUR) and is below the costeffectiveness threshold in force in Poland (135.5
kPLN; 31.2 kEUR). The multidirectional sensitivity analysis shows a profitability rate of
98.6%.
Conclusions:
The economic model shows that the addition of
orodispersible DDAVP to standard treatment allows reducing the expected number
of nocturnal micturition, improving the quality of life and reducing the number
of injuries and fractures in the group of patients with nocturia caused by
idiopathic nocturnal polyuria.
Considering the total direct medical costs of
treatment, desmopressin administered at a dose of 25 μg for women and 50 μg for
men is a costeffective therapy when added to the BSC.
INTRODUCTION
According to ICS (International Continence Society)
nocturia is defined as waking to pass urine during the main sleep period. [1] Nocturia is a disorder of diverse aetiology, however, one of its most
frequently recognized causes is nocturnal polyuria (considered as the
production of excessive amounts of urine during sleep). [2] The risk
of nocturia increases with age and in some studies women appeared more likely
to be affected than men. [3,4]
The consequences of nocturia include insomnia, lower
sleep quality, worsening of daytime functioning and an increased risk of falls
and injuries. [5] Two episodes of nocturia during the night cause a
significant reduction in the quality of life and in the group of people over 65
significantly increase the risk of falling down. [6,7]
In the analysis from 2010, it was estimated that the total annual cost of hip
fractures due to severe nocturia in 15 EU countries reaches even EUR 1 billion.
[8]
Desmopressin
(DDAVP) is a synthetic analogue of a natural antidiuretic hormone from
posterior pituitary gland. Desmopressin mimics the antidiuretic effect of
vasopressin, binds to V2 receptors in the kidney collective tubules and causes
the reabsorption of water into the body, which in turn reduces urine production
at night. Desmopressin is registered for the treatment of nocturia caused by
idiopathic nocturnal polyuria [9]. The efficacy of
DDAVP has been examined in two randomised double blinded studies CS40
i CS41 [2,10]. Both studies met the 2 coprimary endpoints
with statistically significant differences favouring desmopressin over the
3month period. In the female study (CS40) there was a reduction of micturions
of 1.46 in the DDAVP arm and 1.24 in the control group. In the male study
(CS41) there was a reduction of micturions of 1.25 in the DDAVP arm and 0.88 in
the control group. Moreover, in both studies there were time to first sleep
interruption increased and quality of life improved in the DDAVP arm in
comparison to placebo over 3month period.
Based on a survey conducted
among Polish clinical experts, it was found that clinical practice in Poland in
the described group of patients relies heavily on the use of behavioural
therapy. Experts also pointed out that in some patients pharmacotherapy may be
used, which also depends on the possibility of occurrence of nocturia in the
course of other diseases, such as: benign prostate hypertrophy, overactive
bladder syndrome, decompensated heart failure, diabetes or hypertension.
The
aim of this analysis is to examine the costeffectiveness of desmopressin 25 μg
for women and 50 μg for men (DDAVP) in comparison to the best supportive care
(BSC) used in Polish clinical practice in the treatment of nocturia (≥2
nocturnal micturition) caused by idiopathic nocturnal polyuria.
MATERIALS AND METHODS
The economic analysis uses a hybrid model combining
aspects of the partitionedsurvival model (referred to as PSM, see Woods 2017 [11]) and the statetransition model (STM, see Williams 2017 [12]), i.e. a model
using the Markov chain. The projection was carried out over a 30year time
horizon, which corresponds to 120 quarterly modelling cycles. The costs were
calculated from a common perspective, including expenses incurred by the public
payer (Narodowy Fundusz Zdrowia, National Health Found) and expenses incurred
by the patient. The health outcomes generated in the model are the number of
years of life adjusted for quality (QALY), the number of life years, the number
of nocturnal micturition and the number of injuries and fractures. Costs and
health effects were discounted using the discount rates of 5% and 3.5%,
respectively recommended in Poland as part of the medical technology
assessment. [13]. The model was made with use of MS Excel 2013
software.
The
economic model consists of two interdependent models: PSM, which reflects the
number of nocturnal micturition and STM, in which patients in states generating
direct medical costs, including those using DDAVP and BSC, are counted. The PSM
model is based on the natural course of the disease, to which the health effect
of the technology currently applied is imposed, which in turn affects the
probabilities of transition between the STM states which depend, among others,
on the number of nocturnal micturitions of the patient.
The
structure of the STM model is shown in Figure 1 below.
Figure 1.
Structure of the STM model
Patients may start treatment in one of the DDAVP +
BSC or BSC states. Discontinuation of treatment may be due to the
occurrence of hyponatremia or a finding of ineffectiveness of treatment.
Patients who interrupt DDAVP + BSC due to hyponatremia may continue treatment
with BSC, whereas patients who stop BSC and patients who stop DDAVP + BSC due
to lack of treatment efficacy will not use any alternative therapy.
The
PSM model includes 6 health states corresponding to the number of nocturnal
micturition. Transitions between PSM states depend on the medical technology
that is used at the moment. The structure of this model is shown in Figure 2.
Figure 2.
Structure of the PSM model – The fluctuations of the disease
Modelling of the number of nocturnal micturition (M) is based on the assumption that it depends on two factors: the natural course of the disease (N) and the health effect of therapy (e), considered as the change in the number of nocturnal micturition, and these factors are additive, i.e.:
Where negative e corresponds to a reduction in voids. Assuming that N is a random variable, the probability distribution N was modelled using the parametric survival function depending on the age (t) and sex of the patient (g), given by the equation:
Where:
S (t) is a cumulative distribution of probability (e.g. logistic, lognormal or
Weibull distribution).
Using the cumulative distribution N in each cycle t, the vector was determined, hereinafter referred to as the natural distribution of nocturnal micturition, the elements of which represent the probability that a patient who is not treated at time t is in one of the M0M5 states of health. For example, for the M3 state, the expected one is in the range of ⟨3, 4), and therefore:
Figure 3 shows the natural distribution of nocturnal
micturition depending on age. This costeffectiveness analysis
only includes patients with N≥2, as this is generally considered as being a
threshold for bothersome nocturia.
Usually, in the partitioned survival model hazard ratios are used to reflect the health effects of the therapy. The hazard ratio causes the base survival curve to shift upwards or downwards, which corresponds to the extension or reduction of time to occurrence of the analysed event. This analysis uses an innovative approach of presenting health effects in the form of a transition matrix (E_{gj}). E_{gj} elements are probabilities of transition between M0M5 states within 3 months under the condition of sex and the use of medical technology j. The modified distribution of nocturnal micturition (M_{tg}) was determined from the formula:
Intuitively, the above equation means that the patient whose natural number of nocturnal micturitions at time t is N after the application of the therapy will have M nocturnal micturition. If the patient does not use any therapy, i.e. instead of E_{gj}, the identity matrix should be adopted then:
The
characteristics of health states included in the model are presented in the
table below:
Table 1.
Description of states included in the model
Model 
State 
State definition 
Expected
number of nocturnal micturition 
STM (medical costs) 
DDAVP+BSC 
DDAVP and behavioural therapy 
DDAVP health effect 
BSC 
Behavioural therapy 
BSC health effect 

Hyponatremia after DDAVP or after BSC 
Diagnosis of
hyponatremia 
BSC health effect 

No treatment 
The patient does not use any therapy 
The natural course of the disease 

DEATH 
DEATH is an
absorbing condition, which means that after entering this state, the patient
cannot leave it. The transition to the DEATH state can occur from any state
and in any cycle. 
N/A 

PSM (micturitions number ) 
M0 
Micturitions number within the range <0.1) 
0.5 
M1 
Micturitions number within the range <1.2) 
1.5 

M2 
Micturitions number within the range <2.3) 
2.5 

M3 
Micturitions number within the range <3.4) 
3.5 

M4 
Micturitions number within the range <4.5) 
4.5 

M5 
Micturitions number is equal to or greater than 5 
5.5 
In
addition, one of the results of the model is the number of injuries caused by
falling. Falls are not a separate state in the model. It was assumed that at
any time the patient has a risk of falling depending on their age, sex and
number of micturition, and then the total number of falls in the analysis
horizon was estimated. The risk of falls depending on the age was estimated by
fitting the logit function to the data from the monograph POLSENIOR [14].
The risk of falling conditional on the number of micturitions
was estimated taking into account the respective odds ratios presented
in Stewart 1992 [7].
Population
The
economic analysis was carried out in the nocturnal population caused by
idiopathic nocturnal polyuria with at least 2 nocturnal micturitions.
Demographic
parameters were determined based on the Polish population pyramid in 2016 and
epidemiological studies. The initial age of patients and the percentage of
women and men in the population are shown in Table 5.
The probability of death was estimated on the basis
of the Polish tables of life expectancy for 2015 [15], taking into account in calculations the relative
risk of death for men and women related to the number of micturitions [16].
Health effects
The
natural course of the disease was modelled using data read from the graphs of
the Bosch 2010 publication [3]. Three parametric probability
distributions were adjusted to the data: loglogistic, lognormal and Weibull
distribution [17]. The basic analysis was performed with the
assumption of the Weibull distribution. In this way a model of shared survival
was obtained, which describes the probability of finding in the patient <i,
i + 1) nocturnal micturition in each cycle of the model (Figure 3).
Table 2.
Estimation of the parameters of the natural course of the disease
Parameter 
Loglogistic distribution 
Lognormal distribution 
Weibull
distribution 

Parameters of
the basic distribution 
alpha 
0.00 
5.14 
0,01 
beta 
3.44 
0.06 
2,71 

Hazard
parameters 
constant 
0.00 
6.85 
1,75 
gender (1 –
females, 0males) 
0.01 
0.08 
0,08 

Micturitions 
0.86 
0.98 
0,97 

Logarithm of
likelihood 
138,30 
198.70 
200.64 

Akaike
Information Criterion 
266,60 
387.39 
391.29 
The natural course of the disease: probability distribution nocturnal micturition depending on age (based on Bosch, 2010).
Transitions matrix corresponding to the health
effects of therapy were estimated on the basis of dataonfile from the two
pivotal CS40 and CS41 [2,10] studies. Transition probability
was determined by dividing the number of observed transitions from the Mi state
to the Mj state and the number of patients in the Mi state [Jones 2005].
Missing data, which constitute about 14% of observations, was imputed using a
probit model for an ordered multidimensional dependent variable.
Table 3.
Matrices corresponding to the probability of change in the number of micturitions in the DDAVP arm
Initial state 
Men 
Women 

End state 
End state 

<0.1) 
<1.2) 
<2.3) 
<3.4) 
<4.5) 
5+ 
<0.1) 
<1.2) 
<2.3) 
<3.4) 
<4.5) 
5+ 

<2.3) 
25.4% 
45.1% 
22.5% 
7.0% 
0.0% 
0.0% 
43.6% 
38.5% 
16.7% 
1.3% 
0.0% 
0.0% 
<3.4) 
18.8% 
25.0% 
43.8% 
12.5% 
0.0% 
0.0% 
27.7% 
38.3% 
27.7% 
2.1% 
2.1% 
2.1% 
<4.5) 
18.2% 
18.2% 
27.3% 
36.4% 
0.0% 
0.0% 
22.2% 
33.3% 
11.1% 
22.2% 
11.1% 
0.0% 
5+ 
0.0% 
0.0% 
60.0% 
20.0% 
20.0% 
0.0% 
0.0% 
0.0% 
0.0% 
100.0% 
0.0% 
0.0% 
Table 4.
Matrices corresponding to the probability of change in the number of micturitions in the BSC arm
Initial state 
Men 
Women 

End state 
End state 

<0.1) 
<1.2) 
<2.3) 
<3.4) 
<4.5) 
5+ 
<0.1) 
<1.2) 
<2.3) 
<3.4) 
<4.5) 
5+ 

<2.3) 
19.2% 
49.3% 
24.7% 
4.1% 
2.7% 
0.0% 
29.6% 
40.8% 
22.5% 
5.6% 
1.4% 
0.0% 
<3.4) 
6.5% 
26.1% 
41.3% 
21.7% 
4.3% 
0.0% 
16.7% 
40.5% 
28.6% 
7.1% 
7.1% 
0.0% 
<4.5) 
5.3% 
15.8% 
26.3% 
36.8% 
10.5% 
5.3% 
9.1% 
45.5% 
36.4% 
9.1% 
0.0% 
0.0% 
5+ 
0.0% 
33.3% 
33.3% 
33.3% 
0.0% 
0.0% 
0.0% 
0.0% 
50.0% 
0.0% 
50.0% 
0.0% 
The risk of hyponatremia (serum sodium less than 135 mmol/L)was estimated based on data from CS40 and CS41 studies [2,10].
Discontinuation
of treatment
The
probability of hyponatremia and discontinuation due to adverse reactions was
estimated based on data from clinical trials CS40 and CS41. It was assumed that
21% of patients after going through hyponatremia will not return to treatment.
Clinicians surveyed indicate that the lack of satisfaction with treatment effects is the cause of 40% discontinuation of patients who report to them. All the experts indicated that the patients they treated had already consulted 13 doctors in relation to nocturia. In the economic model, functionality was introduced allowing linking the effects of treatment with the probability of discontinuation, however, obtaining data to estimate these probabilities would require testing the preferences of the patients themselves, which would exceed the scope of this study. Therefore, the base analysis was based on the assumption that patients discontinue therapy if the number of micturition increases by at least 1, i.e.:
Where: δ_{ij }is the probability of discontinuation of treatment at the transition from the state of Mi to the state Mj.
Costs
The calculations included
the cost of desmopressin, the cost of monitoring, the cost of falls, and the
cost of adverse events. The cost of desmopressin was estimated as the average
of net sales prices from 13 countries in which it is reimbursed. Exfactory prices were made available by Ferring
Pharmaceuticals Poland Sp. z o.o. Other costs were estimated based on data from
the National Health Fund and the Ministry of Health as well as information
received from clinical experts.
Table 5.
Input data
Parameter 
Men 
Women 

Gender
(percentage) 
43.7% 
56.3% 

Patients
baseline age 
60.53 
64.21 

Risk of hyponatremia per cycle 
DDAVP 
14.5% 
10.9% 
BSC 
2.4% 
3.2% 

Relative risk (RR) of death due to at least 3
micturitions vs 2 or less micturitions 
1.9 
1.3 

The probability of discontinuation due to
hyponatremia in the DDAVP arm 
21% 

The probability of discontinuation due to
hyponatremia in the BSC arm 
0% 

Risk of
falling (OR) 
M0 
1.00 

M1 
1.46 

M2 
1.84 

M3M5 
2.15 

392.92 PLN (91.11 EUR) 

Fractures cost 
2,903.23
PLN (673.21 EUR) 

Mild hyponatremia cost 
106.53
PLN (24.70 EUR) 

Moderate hyponatremia cost 
864.23
PLN (200.40 EUR) 

Severe hyponatremia cost 
1,432.26
PLN (332.12 EUR) 

The cost of
BSC monitoring for the quarter 
15
PLN (3.48 EUR) 

The cost of DDAVP monitoring for the quarter up to
and including the 4th cycle 
49.50
PLN (11.48 EUR) 

The cost of
DDAVP monitoring for the quarter from the 5th cycle 
31.50
PLN (7.30 EUR) 
Utility values
In order to find utility values of the different health states, a systematic review was carried out in the Medline database (through the PubMed search) utilizing the following search strategy: ((utility OR utilities OR "qualityadjusted life year" OR "qualityadjusted life years" OR QALY OR Euroqol OR "standard gamble" OR "time tradeoff" OR SG OR TTO OR EQ5D OR EQ5D OR HUI OR "health utilities index") AND (Nocturia Or Nycturia Or "Frequent urination at night" Or "Urinate at night" Or "Nocturnal voids" Or "Nocturnal void" Or "Nocturnal polyuria" Or "Nighttime voids" Or "Nocturnal diuresis" Or "Nocturnal hyperuresis")). The utility values for the states of hyponatremia were estimated based on the number of micturitions considering the effectiveness of BSC and then reduced by the loss of utility associated with the occurrence of hyponatremia, which was determined based on Lee 2014 [18] Clinical experts asked to determine the duration of treatment for severe hyponatremia found that hospitalization lasts on average 4 days, which was consistent with the NFZ data for 2016: median hospitalization was 5 days, dominant 4 days [20]. Therefore, the utility in the hyponatremia state was modelled as the average of the utility resulting from the number of micturition in a given cycle.The articles included in this review were those that reported the estimates of HrQoL with respect to number of nocturnal micturions in adults with nocturia. The HrQoL must have been measured with EQ5D scale. Search strategy applied in the PubMed returned 35 abstracts which were reviewed by two independent reviewers. As a result two publications were identified: Kobelt 2003 and Andersson 2016 [21, 6] containing utility estimates measured using the EQ5D questionnaire. Using both publications, the average utility values in states M0M5 were determined. The reduction of utility related to injuries and fractures was determined based on the publication of Abimanyiochom 2015 [22].
Utilities are shown in Table 6 [Table 6]:
Table 6.
Utilities resulting from the number of micturition and disutilities associated with adverse events
Input type 
Health state / adverse
event 
Women 
Men 

Utilities due to
micturitions 
Nocturia 
M0 
0.851 
0.885 
M1 
0.838 
0.871 

M2 
0.805 
0.838 

M3 
0.787 
0.820 

M4 
0.773 
0.807 

M5 
0.740 
0.773 

Reductions of QALY due to
adverse events 
Hyponatremia 
Mild 
0.059 

Moderate or severe 
0.136 

Fracture 
Cycle 1 
0.28 

Cycle 2 
0.11 

Cycle 3 
0.09 

Cycle 4 
0.07 

Cycle 5 
0.05 

Cycle 6 
0.04 

Cycle 7 
0.02 

Cycle 8 
0.00 
RESULTS
The results of the simulation suggest that the
addition of desmopressin to BSC will reduce the number of falls with an injury
by 0.05, extend the overall survival by 0.03 years and increase QALY by 0.10 in the lifetime horizon.
The
total cost of treatment of nocturia in the DDAVP + BSC arm amounted to approximately
9.9 kPLN (2.3 kEUR) in lifetime time horizon, while in the BSC arm the cost amounted to
4.4 kPLN (1.0 kEUR). The largest part of BSC costs was the cost of treating injuries and
fractures. The use of desmopressin is associated with a reduction in the cost
of injuries of an average of PLN 129 (EUR 30) and an increase in the cost of treatment
of hyponatremia by approximately PLN 462 (EUR 107) in the lifetime.
The ICER for DDAVP + BSC compared to BSC amounted to PLN 56.1 (EUR 13.0) thousand and is below the ICER threshold in force in Poland (PLN 134.5 thousand). The net sales price for the packaging, at which the ICER result reaches the value equal to the profitability threshold, is PLN 267.69.
Table 7.
The results of the economic analysis
Result 
DDAVP 
BSC 
DDAVP vs BSC 
QALY 
10.57 
10.48 
0.10 
LY 
12.87 
12.84 
0.03 
Number of injuries
and fractures 
1.45 
1.50 
0.05 
Total cost 
9,862 PLN (2,287 EUR) 
4,376 PLN (1,015 EUR) 
5,486 PLN (1,272 EUR) 
ICER 
N/A 
N/A 
56,086 PLN/QALY (13,005 EUR/QALY) 
ANALYSIS OF
SENSITIVITY
The
results of a oneway sensitivity analysis suggest that the initial age of
patients, the risk of death and discontinuation of treatment have the greatest
impact on the results.
Table 8.
Results of a oneway sensitivity analysis
Parameter 
Base case value 
Scenario 
ICER 
ICER change 

PLN/QALY 
EUR/QALY 

Baseline men age 
61.25 
50.00 
59,936.22 
13,898.25 
7% 
70.25 
49,942.99 
11,580.98 
11% 

Baseline women
age 
64.25 
53.00 
63,504.57 
14,725.7 
13% 
76.00 
47,355.11 
10,980.9 
16% 

RR of death for
men> = 3 micturition 
1.90 
1.00 
59,485.07 
13,793.64 
6% 
2.60 
53,964.5 
12,513.51 
4% 

RR of death for
women> = 3 micturition 
1.3 
1.00 
70,292.3 
16,299.66 
25% 
2.00 
39,371.08 
91,29.53 
30% 

Percentage of
hyponatremia patients returning to DDAVP 
0.79 
0.00 
69,734.05 
16,170.21 
24% 
1.00 
49,799.52 
11,547.71 
11% 
In
addition, the effect of treatment satisfaction on the ICER score was tested
using the Monte Carlo technique. Each transition from the state to the state j
may have a different risk of dissatisfaction, so to simplify the analysis, it
was assumed that the probability of discontinuation after transitioning from
the state
Where:
In the case of an optimization problem, each health condition has a fixed cost and a permanent health effect; therefore, the optimal strategy will be to stop treatment if the incremental cost for QALY in this state is above the profitability threshold and continuation of treatment if it is below the profitability threshold. This means that in the optimal strategy, δ_{ij} will only assume 0 or 1.
As a result of the Monte Carlo simulation, it was obtained that ICER is minimized when μ = 0.91 and σ = 0.02, which generates a discontinuation matrix in accordance with the strategy adopted in the basic analysis. This means that an optimal treatment strategy that ensures the best ratio of incremental costs to health effects is the discontinuation of treatment if the number of micturition increases by at least 1 (i.e. ). Deviation from this strategy in both directions results in a worsening of the ICER score. Assuming that all patients who are inefficiently treated continue therapy (i.e. δ_{ij}=0 for each pair i, j) the ICER result would be 175.4 kPLN, while in the case when patients stop treatment, when the number of micturition does not change or increases (i.e. ) the ICER result is 78.9 kPLN.
In
the multidirectional sensitivity analysis, the health effects of therapy,
initial age, risk of death and the probability of discontinuation due to
hyponatremia and lack of efficacy were tested.
Table 9.
Parameters tested in a multidirectional MonteCarlo sensitivity analysis
Result 
Distribution 
Data source 
Baseline age 
Discrete, based on
the probability of ≥2 nocturnal micturition in the range from 18 to 97 years. 
Own calculations based on Bosch 2010 [3] 
RR of death for
men> = 3 micturition 
Normal limited from
below at 1.4 and 2.6 from above. Average 1.9, standard deviation 4.22. 
Own calculations based on
Asplund 1999 [16] 
RR of death for
women> = 3 micturition 
Normal limited from
the bottom to 0.9 and 2.0 from above. Average 1.3, standard deviation 4.75 

Percentage of hyponatremia patients returning
to DDAVP 
Uniform from 63% to 100% 
The lower bound of the support is estimated based on the average pooled from clinicists' answers in the survey. The upper bound is the highest possible value for the parameter. 
Tolerance of
micturition number 
Normal, average 0.9, standard deviation 1.35 
Arbitrarily selected
distribution parameters that give a wide dispersion of the parameter around
the average. 
The
mean incremental health effect of sensitivity analysis is 0.082 QALY (95% CI
0.0800.083), while the average incremental cost of therapy is PLN 4,955.61
(95% CI 4,9414,970), therefore ICER is 60.5 (95% CI 52.2 – 68.7) kPLN / QALY.
Assuming the variability of the main structural factors of the model, both
costs and health effects are characterized by exceptional stability, due to
which the probability that the ICER is below the threshold is 95.5%.
Figure 4.
The results of a multidimensional sensitivity analysis
DISCUSSION
The economic analysis takes into account the key
aspects in which the nocturia affects the patient's life: a decrease in the
quality of life, an increased risk of falling and the risk of death. In
addition, literature suggests that fatigue related to sleep deprivation results
in reduced productivity during the day, which may result in early retirement.
[21] It has also been shown that the loss of productivity is on par
with many other chronic diseases. [23] This effect may be particularly
important in case of younger people suffering from nocturia. Other
psychological aspects of nocturia, which are difficult to assess are
irritation, loss of control (e.g. fear of falling, fear of increasing nocturnal
micturition) and the necessity to adapt to life with nocturia (e.g. limiting
fluid intake or avoiding visits and sleeping in places where access to the
toilet can be difficult). [8]
The
analysis was started with the implementation of a systematic review covering
the Medline and CEAR databases, the purpose of which was to find other economic
analyses regarding the profitability of using DDAVP in the analysed indication,
however, no publications matching the inclusion criteria were found. Another
unpublished economic analysis has been described in two SMC recommendations
regarding financing of DDAVP in Scotland, first in January 2017 and then after
the resubmission of the application by the responsible entity in the
recommendation in July 2017 [24,25].
The first recommendation stated that the incremental
QALY was 0.223 and the incremental cost of GBP 1 600 in the horizon of 35
years, as compared to the standard of care. Thus, the ICER value amounted to
GBP 7,168, or about 34,400 PLN [24]. After submitting the application
again, in which the applicant took into account SMC's comments to the
methodology of economic analysis, the results of the economic analysis have
changed. The incremental QALY amounted to 0.136 while the incremental cost was
GBP 1,300 in the horizon of 19 years. Thus, the ICER value amounted to GBP
9,538, or approximately 45.8 kPLN.
The main limitations of the analysis indicated by
the SMC concerned the symmetry of modelling the natural course of the disease,
health effects. The symmetry of modelling means that the disease process is
consistently represented in the evaluated therapeutic strategies [26]. In the Scottish submitted analysis, the SMC model initially did not
adequately reflect the natural course of the disease. Therefore, the final
analysis introduces the possibility of remission, i.e. reduction of the number
of nocturnal micturitions below 2 in the DDAVP arm based on data from studies
for desmopressin and BSC resulting from the natural course of the disease. Our
analysis proposes modelling the natural course of the disease using an
econometric model tailored to epidemiological data. This approach guarantees
that the disease process is modelled symmetrically in both analysis arms. In
contrast to Scottish analysis, the disease process has a progressive character.
The expected natural number of micturitions in this model increases with age.
The
second key difference involved the method of modelling treatment
discontinuation. In the Scottish submission, it was assumed that after two
years of using DDAVP, treatment would be discontinued if the symptoms of the
disease did not return after one week of discontinuation. SMC highlighted the
uncertainty and difficulty of implementing such a rule in clinical practice. In
this model, treatment is continued as long as it is effective and the
phenomenon of discontinuation of ineffective treatment in clinical practice has
been confirmed by clinical experts.
The similarities, however, should include the
approach to estimating the number of micturition. In all analyses, it was
assumed that reduction of micturition would reduce the risk of injury.
Demonstrating the causal relationship is a methodological challenge for
clinical trials, due to the complexity of processes, low incidence and the
random nature of events. Therefore, in medicine it is recognized that a given
factor is the cause of an event if increases its incidence [27]. The
existence of a statistically significant relationship between the number of
micturition and the risk of falls, injuries and fractures has been confirmed by
a number of studies [5,7,29]. In addition,
the problem of falls in the elderly is significant enough [14] that
omitting the risk of falls in the analysis would also be a limitation.
As with any economic analysis it is subject to some
limitation. Firstly, clinical efficacy of DDAVP was based on data from CS40 and
CS41 trials that lasted 3 months each. The lack of longterm studies prevents from assessment of extrapolations on the lifetime horizon. Secondly,
some costs may be partially duplicated, e.g. costs of monitoring and costs of
hyponatremia both include cost of blood tests. Thirdly, cost of desmopressin
was based on the mean price from other countries and may be different in Poland
due to local regulations (i.e. margins, taxations). Another limitation is that the analysis is performed for Polish population meanwhile utilities are derived from qualuty of life studies carried out in the United Kingdom and Sweden. While there are noticeable similiarities between these populations in term of factors determining quality of life, for example HrQoL decreases with age and is generally worse among women than men the differences concern some detailed qualityoflife dimensions that deteriorate. For example problems raleted to anxiety and depression are reported by 30% more respondents in Poland than in Sweden and by 50% more respondents than in Great Britain [30]. It may be hypothesized that due to presence of different comorbidities the impact of nocturia on HrQoL may as well differer between these countries. However, the extent and the direction in which it may affect the ICER is difficult to determine. Finally, it was
assumed that patients with an increase in number of micturitions will
discontinue the treatment. Despite that it seems to be a logical strategy of
discontinuation, it is just an assumption made by the authors of this analysis
and has not been verified by any research. Moreover, it is an optimal strategy
and a deviation from it in any direction will cause an increase of ICER.
CONCLUSIONS
The
economic model shows that the addition of DDAVP to standard treatment allows
reducing the expected number of nocturnal micturition, improving the quality of
life and reducing the number of injuries and fractures in the group of patients
with nocturia caused by idiopathic nocturnal polyuria.
Taking into account the total direct medical costs of treatment, desmopressin administered at a dose of 25 μg for women and 50 μg for men is at 56 kPLN (13 kEUR) well below the accepted Polish ICER threshold of 135 kPLN (31 kEUR), thus a costeffective therapy added to the BSC. As part of a multidimensional sensitivity analysis, the critical assumptions of the model were tested using conservative confidence intervals for the tested parameters. The results of the sensitivity analysis show limited changes to changes in the input parameters.
ABBREVIATIONS
BSC – best supportive care
CEAR – CostEffectiveness Analysis Registry
DDAVP – desmopressin
HrQoL – healthrelated quality of life
ICER – incremental costeffectiveness ratio
ICS  International Continence Society
DRG  diagnosisrelated group
LY  life years
PSM – partitionedsurvival model
QALY  quality adjusted life years
SMC – Scottish Medicines Consortium
STM – statetransition model
CONFLICT OF INTERESTS
The publication was prepared at the request of Ferring Pharmaceuticals Poland Sp. z o. o. who financed the work. The authors declared no other type of conflict of interest.
 van Kerrebroeck P, Abrams P, Chaikin D, Donovan J, Fonda D, Jackson S, Jennum P, Johnson T, Lose G, Mattiasson A, Robertson G, Weiss J; Standardisation Subcommittee of the International Continence Society. The standardisation of terminology in nocturia: report from the Standardisation Subcommittee of the International Continence Society. Neurourol Urodyn. 2002;21 (2), 17983
 Weiss J., Herschorn S., Albei C., van der Meulen E., Efficacy and safety of low dose desmopressin orally disintegrating tablet in men with nocturia: results of a multicenter, randomized, doubleblind, placebo controlled, parallel group study, J Urol 2013; 190 (3), 965972
 Bosch J., Weiss J., The prevalence and causes of nocturia, J Urol 2010, 194 (2), 440446
 Irwin D., Milsom I., Hunskaar S., Reilly K., Kopp Z., Herschorn S.,
Coyne K., Kelleher C., Hampel C., Artibani W., Abrams P., Populationbased survey of urinary incontinence, overactive bladder,
and other lower urinary tract symptoms in five countries: results of the EPIC
study, Eur Urol, 2006, 50 (6),13061315
 Asplund R., Nocturia:
consequences for sleep and daytime activities and associated risks,
European Urology Supplements, 2005, 3 (6), 2432
 Andersson F., Anderson P., HolmLarsen T., Piercy J., Everaert K.,
Holbrook T., Assessing the impact of
nocturia on healthrelated qualityoflife and utility: results of an
observational survey in adults., J Med Econ 2016.,
19(12), 12001206
 Stewart R., Moore M., May F., Marks R., Hale W., Nocturia: a risk factor for falls in the elderly, J Am Geriatr Soc 1992; 40 (12), 12171220.
 HolmLarsen T., The Economic
Impact of Nocturia, Neurourol Urodyn, 2014, 33 (Suppl 1), S10–S14
 Summary of Product’s Characteristics of Noqturina^{® }(in Polish), available at:
https://www.lekiinformacje.pl/content/noqturina  Sand P.K., Dmochowski R.R., Reddy J., Meulen E.A., Efficacy and safety of low dose desmopressin orally disintegrating tablet in women with nocturia: results of a multicenter, randomized, doubleblind, placebo controlled, parallel group study, J Urol 2013; 190 (3), 958964
 Woods B., Sideris E., Palmer S., Latimer N., Soares M., NICE DSU technical support document 19: partitioned survival analysis for decision modelling in health care: a critical review. 2017, available at: http://scharr.dept.shef.
ac.uk/nicedsu/wpcontent/ uploads/sites/7/2017/06/ PartitionedSurvivalAnalysis finalreport.pdf  Williams C., Lewsey J., Mackay D., Briggs A., Estimation of survival probabilities for use in costeffectiveness
analyses: a comparison of a multistate modeling survival analysis approach
with partitioned survival and markov decisionanalytic modeling. Med Decis Making 2017, 37 (4), 427–439.
 Agencja Oceny Technologii
Medycznych i Taryfikacji, Wytyczne oceny technologii medycznych (HTA, ang.
health technology assessment), Warszawa 2016, available at:
http://www.aotm.gov.pl/www/wpcontent/uploads/wytyczne_hta/2016/20160913_Wytyczne_AOTMiT.pdf  Skalska A., Wizner B., KlichRączka A., Piotrowicz
K., Grodzicki T., Upadki i ich następstwa
w populacji osób starszych w Polsce. Złamania bliższego końca kości udowej i
endoprotezoplastyka stawów biodrowych, Monografia projektu PolSenior 2012,
275294,
 Demography database of the Central Statistical Office (pl. Baza demografia Głównego Urzędu Statystycznego), available at:
http://demografia.stat.gov.pl/bazademografia/  Asplund R., Mortality in the elderly in relations to nocturnal micturition, BJU International 1999, 84 (3), 297301
 Frątczak E., Sienkiewicz
U., Babiker H., Analiza historii zdarzeń.
Elementy teorii, wybrane przykłady zastosowań. Szkoła Główna Handlowa w
Warszawie – Oficyna Wydawnicza, Warszawa 2009; 79110.
 Jones M., Estimating Markov
transition matrices using proportions data: an application to credit risk,
International Monetary Fund 2005, WP/05/2019, available at: https://www.imf.org/external/pubs/ft/wp/2005/wp05219.pdf
 Lee M., Kang H., Park S., Kim H., Han E., Lee E., Costeffectiveness of tolvaptan for euvolemic or hypervolemic hyponatremia, Clin Ther 2014, 36 (9), 11831194
 Narodowy Fundusz Zdrowia, DRG Statistics, available at:
https://prog.nfz.gov.pl/appjgp/  Kobelt G., Borgström F., Mattiasson A., Productivity, vitality and utility in a group of healthy professionally active individuals with nocturia, BJU International 2003, 91 (3), 190195
 AbimanyiOchom J., Watts J., Borgstrom F., Nicholson G., ShoreLorenti C., Stuart A., Zhang Y., Iuliano S., seeman E., Prince R., March L., Cross M., Winzenberg T., Laslett L., Duque G., Ebeling R., Sanders K., Changes in quality of life associated with fragility fractures: autralian arm of the international cost and utility related to osteoporotic fractures study (AusICUROS), Osteoporos Int 2015, 26 (6), 17811790
 Miller P., Hill H., Andersson F., Nocturia work productivity and activity impairment compared with other common chronic diseases, Pharmacoeconomics 2016, 34 (12): 12771297
 Scottish
Medicines Consortium, desmopressin 25
microgram, 50 microgram oral lyophilisate (Noqdirna®) SMC No. (1218/17),
available at:
https://www.scottishmedicines.org.uk/files/advice/desmopressin_oral_lyophilisate_Noqdirna_FINAL_Jan_2017Revised030217_for_website.pdf  Scottish
Medicines Consortium, Resubmission, desmopressin 25 microgram, 50 microgram oral
lyophilisate (Noqdirna®) SMC No. (1218/17), Advice following a resubmission
available at:
https://www.scottishmedicines.org.uk/files/advice/desmopressin_Noqdirna_Resubmission_FINAL_July_2017_for_website.pdf  Siebert U., Alagoz O., Bayoumi A., Jahn B., Owens D., Cohen D., Kuntz
K., Statetransition modelling: A report
of the ISPORSMDM modelling good research practices task force3, Value Health 2012, 15 (6), 812820
 Daya S., Characteristics of good
causation studies, Semin Reprod Med. 2003, 21 (1), 7383.
 Asplund R., Hip fractures, nocturia, and nocturnal polyuria in the elderly, Ach Gerontol Geriatr 2006, 43 (3), 319326
 Nakagawa H, Niu K, Hozawa A, Ikeda Y, Kaiho Y, OhmoriMatsuda K, Nakaya N, Kuriyama S, Ebihara S, Nagatomi R, Tsuji I, Arai Y., Impact of nocturia on bone fracture and mortality in older individuals: a japanese longitudinal cohor study, J Urol. 2010, 184 (4), 14131418
 Golicki D., Niewada M., Jakubczyk M., Wrona W., Hermanowski T., Self‑assessed health status in Poland: EQ‑5D findings from the Polish valuation study, Pol Arch Med Wewn. 2010; 120 (78): 276281