Oral Desmopressin in The Treatment of Nocturia in Aging Population: A Pilot Study

Nocturia is a condition in which a person frequently wakes up at night to pass urine. The disruption of sleep associated with nocturia has a severe negative impact on the quality of life of the patients [1], and is associated with daytime fatigue [2, 3], increased susceptibility to diseases [4] and poorer mental health [5]. Awakening at night to void also increases risk of falls [6] and hip fractures [7] in the elderly and is independently associated with increased mortality [8].

Nocturia is multifactorial but has a higher prevalence in older patients of both genders indicating age as a primary risk factor. It has been reported that up to 59% men and 62% women over 70 experience nocturia (more than 2 voids per night), compared to 16% to 18% respectively, for younger men and women (aged 20 to 40 years)[9]. Other underlying causes vary from non-urological conditions such as diabetes insipidus, hypoalbuminemia or chronic heart failure; and urological issues including bladder cancer [10]. Nocturia could be caused by a combination of these pathophysiologies or via other underlying conditions such as reduced nocturnal bladder capacity, global polyuria or nocturnal polyuria [11].

Nocturnal polyuria, or the over-production of urine at night, is the most common underlying cause for nocturia, with studies reporting its prevalence to be up to 76% in patients with nocturia [12,13]. Nocturnal polyuria is frequently secondary to the dysregulation in the levels of anti-diuretic hormone (ADH) [14]. ADH, also known as D-arginine vasopressin (DAVP), acts on the V2 receptors in the renal collecting duct to promote reabsorption of water from the nephron via aquaporins back into systemic circulation to maintain serum osmolality and volume [15]. ADH analogues (in the form of 1-desamino-8D-arginine vasopressin, DDAVP) have traditionally been used to treat central diabetes insipidus, bleeding disorders such as von Willebrand disease, and primary nocturnal enuresis in pediatrics. However, recent interest in its role for treating nocturia has spawned a growing body of literature examining the role and effect of desmopressin in its treatment. In healthy individuals, the levels of ADH have a circadian rhythm and are elevated nocturnally to control urine production, and this diurnal variation is often impaired in the elderly leading to increased diuresis [16].

Desmopressin is a synthetic analogue of ADH, but with a more potent antidiuresis effect due to its selective affinity for V2 receptors, unlike endogenous ADH that binds to both V1 and V2 receptors; and has a prolonged half-life [17,18]. Indeed, several studies have provided support for the use of desmopressin for the management of nocturia [19-21]. However, it has been recognized that the optimal dose of desmopressin differs among patients, especially associated with gender [22,23], and further research needs to be undertaken to support existing evidence on its use for the treatment of nocturia. In this two-phased study, which includes an open-labelled dose titration period, we provide further evidence for the effective use of desmopressin in nocturia in an elderly population.

An intention to treat (ITT) population of 211 patients were identified with nocturnal diuresis. Patients were included in the study when nocturia was indicated as voiding more than twice per night without urological pathologies. The main exclusion criteria were the presence of comorbidities including uncontrolled disease such as diabetes insipidus, cardiac disease, hypertension, use of diuretics, severe kidney diseases or diseases which influences medulla of kidney such as medullary cystic of kidney diseases, multiple sclerosis, urge incontinence, had undergone surgical treatment for BPH in last 6 months and known functional disease in urinary system for example neurogenic bladder. Following initial screening, an initial open-labelled period over 4 weeks for dose titration, followed by 1-week of washout was undertaken whereby patients received an increasing oral dose of Desmopressin starting at 0.1mg/day, till they responded to the treatment indicated by a >20% decrease in nocturnal diuresis. The effective dose was optimized from 0.1-0.2mg/day and only patients that obtained the 20% reduction in nocturnal diuresis were included from the initial 211 Intend-To-Treat (ITT) subjects.

A total of forty patients (22 females, 18 males) were recruited into the study with an average age of 61 and further screened for nocturia, defined as at least two voids per night and nocturnal polyuria - a nocturia index score of >1 (nocturnal urine volume/ functional bladder capacity; the latter being the largest single volume of urine measured at any time). The study took a randomized double-blind placebo-controlled approach (Figure 1). Following the 1-week washout period, patients were randomized to placebo or active treatment groups and received optimized dosage of oral Desmopressin or placebo tablets. The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori review and approval by Ajman, United Arab Emirates and the institutional ethical committee at the Gulf Medical College and University hospital. Written informed consent was obtained from each patient included in the study and for receiving their treatment protocol.

The primary efficacy endpoint of this research was the proportion of patients who had a reduction by more than 50% in the mean number of nocturnal voids after treatment compared with baseline. Several secondary endpoints were also assessed which included the number of nocturnal voids, elevation of urine osmolality (according to the recommendations of Mount Sinai, New York on Urine Specific Gravity and Osmolality) and prolonged duration of the sleep period. A micturition diary was used to record the primary and secondary endpoints.

Statistical analysis was performed using the Statistical Package for Social Sciences (SPSS) v.11 for Windows software package (SPSS Inc., Chicago, USA). Data are expressed as mean group values with standard deviations at each time point. Clinical parameters were compared between groups across the treatment periods using mixed-effects, repeated-measures model with period, group and their interaction as fixed effects. Analysis of variance (ANOVA) was used to compare continuous variables. A value of p<0.05 was considered significant.

Patient demography and baseline characteristics were similar for both the desmopressin treated and placebo group for bladder capacity, nocturnal void number, nocturnal urine volume, mean sleep duration and female/male patient numbers. No adverse effects were demonstrated in either desmopressin or placebo treated groups and compliance with treatments were complete. In the treatment group, a clinical response (≥55% reduction in the mean number of nocturnal voids from 5 to 2 times) was achieved in 12 (60%) patients compared to 2 (10%) in the placebo group with voids from 5 to 4 times (OR=13.5, 95% CI 2.4 - 74.8; P=0.0014) (Figure 2).

Patients in the desmopressin treatment group had a significantly higher urine osmolality (810 ± 210 mOsmol/kg H2O) compared to the placebo group (630± 61 mOsmol/kg H2O, P=0.021; Figure 3). Nocturnal voiding volume was reduced by 44.3% (mean: 1.51mL/min to 0.84mL/min) in the treatment group compared to 4.1% (1.44mL/min to 1.38mL/min) in the placebo group (Figure 4). Patients in the active treatment group had improved sleep parameters, with 60% of them experiencing more than 5 hours unbroken sleep compared to 6% in the placebo group. The overall sleep duration was also significantly more in the desmopressin group (180±46 min) compared to placebo (42±12 min; P<0.001; Figure 5). No adverse events were recorded in the treatment group during the study duration.

Nocturia, if left untreated, can severely impact a patient’s quality of life by reducing the quality of sleep, and is associated with increased morbidity and mortality [8]. A clear understanding of the underlying etiology of nocturia is essential for choosing the correct treatment options and whilst lifestyle and behavioral changes may help some patients, pharmacotherapies remain the predominant option [15]. Nocturia is often attributed to nocturnal polyuria [13], which in turn is often a consequence of dysregulated ADH secretion through the night, especially in the elderly [24]. It is known that the pituitary gland decreases in size with age and corresponds to altered levels of ADH [25]. In elderly patients with nocturnal polyuria, ADH levels are suppressed to very low or undetectable levels at night resulting in 85% of 24hr-diuresis in extreme cases [16,26]. The majority of studies investigating nocturnal polyuria were designed in aging male subjects. In the present study we demonstrate that treatment of elderly patients of both genders with nocturnal polyuria using Desmopressin results in a reduction in nocturnal voids and voiding volume while increasing urine osmolality and improving sleep duration as a potential mechanism to improve quality of life and reduce associated comorbidities. The placebo and the treatment groups in this study suffered from nocturia and nocturnal polyuria (nocturia index score>1) and were well-matched for age, gender and other baseline characteristics including comorbidities diabetes insipidus and CVD. Desmopressin has shown to be effective in treating vasopressin-sensitive cranial diabetes insipidus and nocturnal enuresis, and since 2002, has been licensed for the treatment of nocturia in adults [15].

The observed effects of desmopressin in this study are comparable with previous reports. A similar two-phased study in men with a dose-titration and double-blind placebo-controlled period by [20], showed decreased nocturnal voids in 34% patients in the desmopressin group compared to 3% in the placebo [19]. performed a similar study in women and observed a 46% reduction in nocturnal voids compared to 7% in the placebo group [19]. A more recent, gender-independent study by [27], reported reduction of nocturnal voids in 33% following desmopressin administration compared to 11% in the placebo group [27]. All these studies were conducted in an older population akin to the patient cohort used in our study, and the results presented here extend the increasing evidence for the clinical use of desmopressin in improving the primary end points for nocturia in an elderly population. Supporting these findings, the present study observed that 60% patients in the desmopressin treatment group had a reduction in nocturnal voids in comparison to the placebo group where 10% patients experienced a reduction. Furthermore, we observed a reduction of 44.3% in nocturnal voiding volume from baseline following desmopressin administration, compared to 4.1% in the placebo group. This is comparable to previous reports of 44% reduction in a cohort of females [19], and 36% reduction observed in a male cohort [20]. To our knowledge, there has been no double-blind placebo-controlled study that reported a decrease in nocturnal voiding volume in a cohort consisting of both genders, where this pilot study pave the road toward a double-blind placebo-controlled study. Systematic review of studies in male patients with benign prostatic hyperplasia concluded that low-dose oral desmopressin therapy alone is an effective treatment for nocturia associated with lower urinary tract symptoms (LUTS) [28].

The increased reabsorption of water from the renal nephrons with desmopressin treatment, and the subsequent decrease in the nocturnal voiding volume results in a more concentrated urine. Indeed, we demonstrate an increase in urine osmolality in the desmopressin group compared to placebo. Although this has been demonstrated in a pediatric cohort for nocturnal enuresis [29], previous double-blind placebo-controlled studies in older adult populations have not reported this parameter [19, 20, 27].

Whilst reduction in nocturnal voids and nocturnal diuresis are essential for assessing the clinical efficacy of diuretic treatment, the changes in sleep parameters are vital to improving the QoL for the patients. In this study, treatment with desmopressin allowed 60% of patients more than 5 hours unbroken sleep, compared to 6% in the placebo group and significantly improved their sleep duration. This would undoubtedly benefit the patients QoL, but the use of established questionnaires to monitor work productivity and QoL would have been valuable for assessing the scale of the impact [30,31]. It has been demonstrated that 1 less nocturnal void and as little as 1 hour increased duration of first uninterrupted sleep period was associated with significant increases in QoL score [32]. Furthermore, an observational study assessing the relationship between nocturia and QoL revealed that an increasing number of nightly voids was associated with a deterioration of QoL scores, with significant differences particularly noted between 0-1 and ≥2 voids per night [33]. This suggests that to improve QoL, the treatment goal for patients should be to reduce nocturia to or below the threshold of 2 voids per night.

The present study has a few limitations. Following the initial open-labelled dose titration phase, the washout period could have been monitored empirically by measuring the return of nocturia parameters to baseline. This would have ensured no residual effect of desmopressin is carried over in the double-blind phase. Nonetheless, the one-week washout period is in keeping with other studies on desmopressin with an open-labelled dose titration phase [19, 20, 27]. Moreover, with a terminal half-life of 3.1hr and a clearance of 2.6mL/min/kg body weight [34,35], it is highly unlikely that desmopressin is retained past the wash-out period. The use of desmopressin has been associated with hyponatremia as serious potential adverse event, especially in the elderly [34]. Regular measurements of sodium levels during the open-labelled dose titration phase could have helped identify the patients that may have been at risk. Nevertheless, no adverse events were reported in this study, and close monitoring of symptoms such as headaches and weight increase would have helped identify any cases of hyponatremia. The efficacy of desmopressin in our patient cohort suggests that high proportion of them experienced nocturnal polyuria secondary to impaired ADH signaling. A baseline measurement of ADH concentrations in our patient cohort would have offered an insight into the etiology for nocturia in nonresponders from the treatment group.

In conclusion, in this two-phased randomized double-blind placebo-controlled study oral desmopressin treatment was welltolerated and effective in managing nocturia compared to placebo in an elderly population with nocturnal polyuria. The primary endpoint of nocturnal voiding was significantly improved along with voiding volume which resulted in increased duration of the first sleep period in the treatment group. These beneficial effects have the potential to improve quality of life, consistent with previous studies, and possibly reduce associated comorbidities in elderly patients with nocturnal polyuria.

Editorial support for this manuscript was provided by Astra- Health.

Aksam Yassin has received partial compensation for data entry and occasional honoraria from Bayer Pharma, Ferring Pharmaceuticals and GSK. No other conflicts of interest to report.

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