Study design
This was a retrospective modelling study based on a systematic review of published literature and information obtained from clinicians involved in managing nocturia in Germany, Sweden, and the UK.
Literature review
A systematic literature review was performed by searching EMBASE, PubMed, and Centre for Reviews and Dissemination databases for relevant publications on nocturia (i.e., ≥2 nocturnal voids) published between January 2010 and June 2015. The search terms focused on epidemiology, clinical and health outcomes, management, resource use, costs, and productivity. After applying various related search terms in the databases, 2617 abstracts were obtained. Of these, 2368 studies were excluded because of duplication or lack of relevance. This generated 249 publications to review in full. A manual literature search was subsequently conducted using the citations in the papers. Published studies that reported epidemiological data for only one gender were excluded from the analysis.
Due to the scarcity of country-specific studies, some data from other European and non-European countries were also extracted and analyzed. However, the included countries’ healthcare systems were similar to Germany, Sweden, and the UK. Country-specific prevalence rates stratified by age group and gender were only available for Sweden [15].
Mean prevalence rates were calculated for Germany and the UK using data from Finland [16], Sweden [15], and the USA [17], as they were the only available studies reporting age- and gender-specific prevalence. No data were collected for people aged ≥65 years in Sweden [15] and ≥80 years in Finland [16]. Hence, the prevalence rates for these age groups, stratified by gender, were extrapolated by using the last three available data points from each study (Tables 1 and 2). An annual incidence of 0.102 (i.e., number of new cases per population at risk in a given 12-month period), annual remission rate of 0.167 (i.e., proportion of patients in remission), and mortality data [pooled Hazard ratio (HR) = 1.29] pertaining to nocturia were obtained from published meta-analyses [18, 19].
Table 1 Prevalence rates of nocturia in Sweden [15]
Table 2 Estimated mean prevalence rates of nocturia used for Germany and the UK [15–17]
The incidence of the main serious adverse consequences of nocturia (i.e., falling and fracture) was generally reported for the older patient population. A weighted mean incidence for nocturia patients who fall during the night of 0.189 (i.e., proportion of patients who fall) was derived using data on patients aged ≥70 years [20, 21]. The distribution of fall-related fractures attributable to nocturia was applied to the incidence of fractures attributable to nocturia of 0.041 (i.e., proportion of patients with a fall-related fracture, both reported by Nakagawa et al. [22]) to estimate the annual number of patients who experience each fracture type in an average year. Based on these calculations, the incidence of fall-related accidents without subsequent fracture was estimated to be 0.148.
Patient management
Due to the limited availability of published data, information was obtained from surveys investigating the management of nocturia patients in various countries. The number of nocturia-related consultations, hospitalizations, and over-the-counter drugs was obtained from a cross-sectional real-world survey involving 635 physicians who were actively managing urological patients in France, Germany, Spain, the UK, and the USA [23, 24]. Additionally, data on drug treatments were obtained from a nocturia market assessment survey in Europe [25]. Estimates collected from these surveys are summarized in Table 3.
Table 3 Information obtained from the surveys
The clinical authors involved in managing nocturia patients in Germany, Sweden, and the UK estimated that due to differences between healthcare systems in these three countries, patients can have diverse treatment pathways. In Sweden and the UK, patients would initially see a family practitioner who might refer them to a urologist, a gynecologist, or a urogynecologist for further assessment. However, in Germany, patients can seek medical help directly from any physician without first seeing a family practitioner.
The basic diagnostic tests for nocturia [e.g., frequency–volume chart, symptom-score questionnaire, urinalysis, urinary flow rate, measurement of postvoid residual (PVR) urine] are the same in all three countries. However, ultrasound tests are generally not used to evaluate the cause of nocturia in Sweden, and usually no additional fee specifically for this test would be charged in Germany. Therefore, the cost of diagnostic ultrasound tests were excluded from the base-case analysis in all three countries. The clinical authors considered that once patients received a prescribed drug, they would need to take it on an ongoing basis until their symptoms disappeared. If a drug ceased to be efficacious, patients would either need to switch to another drug or take combined medication.
Nocturia patients can also suffer from other conditions (e.g., diabetes, arterial hypertension, cardiac diseases, depression, urinary tract infections) that usually precede the onset of nocturia [26]. However, because of disturbed nocturnal sleep, they also suffer from fatigue, loss of attention and productivity during the day, falls, and bone fracture.
Cost-of-illness models
Three country-specific cost-of-illness models comprising 12 one monthly cycles were constructed to estimate direct and indirect costs attributable to nocturia (≥2 nocturnal voids) in Germany, Sweden, and the UK in an average year (Fig. 1).
For each country, prevalence data (Tables 1 and 2) were used to estimate the annual number of patients aged 20–89 years who experience ≥2 nocturnal voids. Using published incidence rates, remission rates, and mortality HRs, our analysis estimated the annual number of newly diagnosed patients, patients who go into remission (i.e., experiencing <2 nocturnal voids) and discontinue treatment, and patients who die as a consequence of their nocturia (i.e., difference between the annual number of nocturia patients who die and the annual number of deaths in the general population using a mortality HR for nocturia [19]; background mortality for causes other than nocturia was not captured in the model). Hence, within the models, existing patients enter the model in the first month. New patients and patients in remission enter and leave the patient pool each month during the year. Additionally, deaths can occur in each month. The annual number of patients who enter or leave the pool each month in the three groups were distributed evenly throughout the year (by dividing annual incidence, remission, and mortality data by 12). Therefore, the size of the open cohort of patients at any one time depended on the number of newly diagnosed patients, patients who started treatment in a previous period, patients who died, and patients who went into remission. Annual amounts of healthcare resource use and corresponding costs were estimated separately for new patients and patients diagnosed with nocturia in previous years. However, the relative risk (RR) of having a fall or fracture was assumed to be the same for both newly diagnosed and existing patients.
In the base-case analysis, all patients from previous years were assumed to continue treatment for the year unless they went into remission or died. However, newly diagnosed patients were assumed to have to wait to see a specialist physician in accordance with country-specific average waiting times [27–29]. Moreover, patients generally received only lifestyle advice and a voiding diary to complete at the first visit. Accordingly, it was assumed that newly diagnosed patients would not start treatment until their second visit to a clinician, which would take place ~1 month after the first appointment. This impacts on the number of clinician visits and length of treatment experienced by newly diagnosed patients in the study year in the models. The number of falls and fractures and associated costs were estimated for both newly diagnosed and existing patients ≥70 years of age.
Indirect societal costs arising from absenteeism (i.e., being absent from work) and presenteeism (i.e., attending work when unwell, thus not working productively) were estimated for both newly diagnosed and existing patients aged between 20 and 64 years. Incremental values of absenteeism and presenteeism were estimated by calculating differences between nocturia patients [23, 30] and the general population [30–32] for each country. The costs of absenteeism and presenteeism were derived using national average monthly salaries [33] and the estimated incremental number of months that patients of working age are absent from work or do not work productively due to nocturia.
Due to a lack of data, presenteeism in the UK could not be estimated. Furthermore, based on findings from the available sources [23, 30, 31], people with nocturia in Germany and Sweden do not appear to be absent from work more than the general population. Therefore, it was assumed that there were no indirect costs arising from absenteeism due to nocturia in these two countries.
Resource use and costs
Resource use was obtained from various sources: the two abovementioned surveys [23, 25], the clinical authors, and published literature [20–22]. Some data were not available; thus, the following assumptions were made:
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If a patient was referred to a specialist, only one additional specialist visit was assumed.
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Patients would initially visit their family practitioner in Sweden and the UK.
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Patients who have a fall would visit an accident and emergency department; those with fractures would require some type of fracture-related procedure in a hospital.
Unit costs at 2014–2015 prices were obtained from published sources (Table 4) and applied to the resource use estimates in the models to estimate the total annual direct cost of healthcare resource use and the annual indirect societal cost arising from presenteeism and absenteeism attributable to nocturia in the individual countries. If cost data was only available from previous years, values were uprated to 2014–2015 prices.
Table 4 Unit costs at 2014–2015 prices used in the base-case analysis
Sensitivity and scenario analyses
To assess whether any variable had a major impact on total direct or indirect costs of nocturia, one-way sensitivity analyses were performed on all model inputs. Base-case values were decreased and increased by 25 %. Various scenarios were also assessed to estimate the effect of increasing or decreasing the values of groups of variables (e.g., unit costs of drugs, number of visits in a year) and including the cost of an ultrasound test in the diagnostic tests. In addition, the impact of including the cost of treating depression, a condition that is suggested to have a bidirectional association with nocturia [34], was examined. In this scenario it was assumed that 10.82 % of patients had depression (a weighted mean estimated using Miyazato et al. (2014) [35] and Tikkinen et al. (2010) [36]) and needed corresponding treatment. Probabilistic sensitivity analysis was also undertaken to evaluate parameter uncertainty within the models. This involved 10,000 iterations of the models by simultaneously varying the different inputs. To estimate random values of inputs, the standard error (SE) was assumed to be 10 % around the mean values, and relevant distributions were assigned to the deterministic values. Beta distribution was used for probabilities, log-normal distribution for resource use estimates, and time variables and gamma distribution for costs enabling distributions of annual direct and indirect costs to be estimated.