Comparison of nocturia response to desmopressin treatment in elderly men with and without nocturnal polyuria in real-life practice

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1 ORIGINAL PAPER Comparison of nocturia response to desmopressin treatment in elderly men with and without nocturnal polyuria in real-life practice S.-L. Chen, 1,2 Y.-H. Huang, 2,3 T.-W. Hung, 2,4 Y.-C. Ou 5 1 Department of Urology, Chung Shan Medical University Hospital, Taichung, Taiwan 2 School of Medicine, Chung Shan Medical University, Taichung, Taiwan 3 Department of Physical Medicine and Rehabilitation, Chung Shan Medical University Hospital, Taichung, Taiwan 4 Department of Nephrology, Chung Shan Medical University Hospital, Taichung, Taiwan 5 Division of Urology, Department of Surgery, Taichung Veterans General Hospital, Taichung, Taiwan Correspondence to: Yen-Chuan Ou, #110, Chien- Kuo North Road, Section 1, Taichung 402, Taiwan Tel.: ext Fax: urologychen@gmail.com Disclosures All authors disclose no conflict of interest SUMMARY Objectives: To evaluate the safety and efficacy of low-dose desmopressin in elderly men with and without nocturnal polyuria (NP) in real-life practice. Methods: Patients with lower urinary tract symptoms (LUTS)/ benign prostate hyperplasia (BPH) who were 65 years old with refractory nocturia were enrolled in this study. We retrospectively analysed elderly men treated with adding desmopressin to current medications for nocturia according to category of the baseline nocturnal urine volume. The 48-h frequency volume chart (FVC), International Prostate Symptom Score (IPSS) and quality of life (QoL) were initially assessed and reevaluated 12 weeks later. Serum sodium level was checked 1 week, 4 weeks, and 12 weeks after initiation of desmopressin therapy or suspected hyponatremia event. The mean change in numbers of nocturnal voids was evaluated for efficacy of treatment. Results: A total of 136 patients were included with 55 in non-np group and 81 in NP group. Hypertension was more common in NP group in regard of comorbidities. During treatment period, there were significant reductions of nocturnal voids from to (p < 0.001) in non-np group and from to (p < 0.001) in NP group. The reduction in nocturnal voids was more significant in NP group ( vs , p = 0.003). The mean decrease in serum sodium levels were mmol/l (p < 0.001) in non-np group and mmol/l (p < 0.001) in NP group at the extreme value. Conclusions: Long-term treatment with low-dose desmopressin is safe and effective for nocturia with or without NP in elderly patients with LUTS/BPH during real-life practice. Patients should be well informed about the disease and are closely followed. What s known Nocturia is a common reason for interrupted sleep in elderly adults. As patients continue to grow, the complaint of nocturia will become more common and our patients will continue to demand effective and safe therapies to get them through the night. Nocturnal polyuria (NP) is a subclassification of nocturia characterised by nocturnal urine volume that is over 33% of the 24-h voided volume. Desmopressin has level 1 evidence and grade A recommendation for the treatment of nocturia because of NP. Randomised, placebo-controlled studies in adults with nocturia because of NP showed that desmopressin can significantly reduce the number of nocturnal voids, decreases the ratio of night/24-h urine volume. What s new This study revealed that noctutria continued to bother elderly men with lower urinary tract symptoms suggestive of benign prostate hyperplasia despite of stereotyped medical therapy. Adding on low-dose oral desmopressin in real-life practice was shown to be safe and effective for patients over 65 years with nocturia. It also demonstrated desmopressin reduced nocturnal void, IPSS total score and quality of life index not only in NP patients but also in non-np group in elderly men with comorbidities in reallife practice. Introduction Nocturia is defined as waking at night at least once to void (1). The condition is the most bothersome factor in the lower urinary tract symptoms (LUTS) and is associated with impaired quality of life (QoL) (2). Nocturnal polyuria (NP) is a subclassification of nocturia characterised by nocturnal urine volume (NVU) over than 33% of the 24-h voided volume. The prevalence of nocturia in aged men is high and % reported at least two voids per night in the literatures (3). Nocturia at least twice nightly is also reported by 35% of the population over 60 years of age (4) and by 69% of males and 49% of females over 80 years of age (5). Most importantly, nocturia contributes to morbidity in elderly people via an increased risk of nocturnal falls and bone fractures (6). Thus, how to manage nocturia seems to be a big issue in such population. Nocturia is a common manifestation of LUTS suggestive of benign prostate hyperplasia (BPH) (7) that is not only difficult to alleviate or cure but also resulting in 38% of patients treated surgically for benign prostatic obstruction (8). Most of the nocturia is considered as associated condition and thus treated by medications for BPH or overactive bladder (OAB) or such 372. doi: /ijcp.12786

2 Desmopressin in nocturia with or without nocturnal polyuria 373 as with ablocker, 5a-reductase inhibitor and antimuscarinics in daily practice. Unfortunately, the response seems to be unsatisfactory. Desmopressin has been proven to be an effective treatment for nocturia with NP for years (9,10). However, an important adverse event was hyponatremia and the primary predictor for hyponatremia is age which makes the use of desmopressin in patients 65 years debatable (11). On the other hand, whether desmopressin is equally effective in patients with noctruria without NP also remains unclear. Hence we conduct this study with the objective to examine the effect and safety of desmopressin in refractory nocturia with and without NP among patients with a history of LUTS/BPH and comorbidities in a Veterans Affairs-based aged male population. Methods Study and patients selection This was a retrospective cohort study, and patients who were 65 years old and had LUTS suggestive of BPH with medical treatment were enrolled and followed prospectively from January 2006 to June History of comorbid illness was taken from patient and reconfirmed from previous medical documentation. Patients with urolithiasis, previous prostate-related surgery, active urinary tract infection were excluded. Standard medical treatments used for BPH were a-blocker, 5a-reductase inhibitor, imipramine and antimuscarinics as monotherapy or in combination. Oral desmopressin was added only in patients with refractory nocturia in spite of previous medications and no further improvement from these medications were expected, and they had experienced at least two nocturnal voids at screening while using the prescribed drugs. The dosage of desmopressin varied according to the discretion of the physician, usually beginning with 0.05 mg before going to bed at night. Dose increase was permitted upon patient request in 1-week intervals and was escalated to 0.2 mg if the NUV or nighttime frequency was not reduced. The dose never exceeded 0.2 mg, with a minimum dose of 0.05 mg. Use of concomitant drugs was allowed as long as patients did not change the dose. A digital rectal examination was performed to assess prostate size and serum prostate-specific antigen (PSA) value was obtained. The patients were required to have their serum sodium and potassium checked at baseline, 1 week, 4 weeks and 12 weeks after beginning desmopressin therapy or suspected hyponatremia event. The same protocol was repeated while changing desmopressin dosage. The data were analysed retrospectively. Nocturia was defined based on the International Continence Society 2002 definition. NP was also defined as nocturnal urine volume (NUV) that was > 33% of the total daily urine volume (12). Patients were asked to complete a 48-h frequency volume chart (FVC), including the time and volume of each void, bedtime and time of rising before desmopressin prescription. Efficacy and quality of life (QoL) parameters were assessed at baseline and 12 weeks after desmopressin use. Both patients and physicians evaluated the efficacy of desmopressin with International Prostate Symptom Score and IPSS-QoL questions (IPPS-Q8) completed by patients during the study. Safety was evaluated from reported adverse events and laboratory data with an emphasis on serum sodium levels. Statistical analysis was performed using SPSS â (SPSS for Windows Version 16.0, SPSS Inc., Chicago, IL, USA). The Wilcoxon signed-rank test was used for assessing statistical significance in changes in outcome parameters before and after treatment (Figure 1). The Fisher s exact test and Yate s correction of contingency were used as appropriate, with p < 0.05 considered significant mean Pre-tx nocturnal void Post-tx nocturnal void Non-PN NP Figure 1 Mean nocturnal voids changes before and after desmopressin treatment in both non-np and NP groups

3 374 Desmopressin in nocturia with or without nocturnal polyuria Results In total, 136 eligible patients were identified (age years) who had been prescribed mg desmopressin in tablet form (Minirin, Ferring) to be taken at bedtime. The data of enrolled 136 patients were divided into two groups (55 in non-np group and 81 in NP group) according to their NUV before desmopressin treatment. No significant statistical differences were noted in patient age, medical comorbidities (except for hypertension), a-blocker use, antimuscarinics use, 5a-reductase inhibitor use, imipramine use, IPSS scores, number of nocturnal voids, baseline serum sodium level, duration and dose of desmopressin use (Table 1). The duration of desmopressin use in non-np and NP group was months and months. In non-np group: Seven patients (7/55) satisfied with 0.05 mg desmopressin and continued with this dose until study end. Forty-four (44/55) increased dose from 0.05 to 0.1 mg, one (1/55) to 0.15 mg and three (3/55) to 0.2 mg. In NP group: Ten patients (10/81) satisfied with 0.05 mg desmopressin and continued with this dose until study end. Sixtytwo (62/81) increased dose from 0.05 to 0.1 mg, two (2/81) to 0.15 mg and seven (7/81) to 0.2 mg. No significantly statistical difference was observed with regard to the treatment dose of desmopressin. During treatment period, there were significant reductions of nocturnal voids from to (p < 0.001) in non-np group and from to (p < 0.001) in NP group (Figure 1). The reduction was more significant in NP group ( vs , p = 0.003). There were 31 (56.4%) patients reduced to 2 nocturnal voids in non-np group and 58 (71.6%) in NP group (p = 0.099). However, the extent of nocturnal voids 2 was 35(63.6%) in non-np group, and 71 (87.7%) in NP group (p = 0.002) (Figure 2). The total IPSS scores decreased from to (p < 0.001) in non-np group and from to (p < 0.001) in NP group (Figure 2). The IPSS-Q8 decreased from to (p < 0.001) in non-np group and from to (p < 0.001) in NP group. But no difference in total IPSS and IPSS-Q8 changes were noted between both groups (Table 2). The mean decreases in serum sodium level were mmol/l (p < 0.001) in non-np group and mmol/l (p < 0.001) in NP group at the extreme value during follow-up. But the reduction level in serum sodium and in below 135 mmol/l were not significant between both groups (p = and 0.159). There were two cases of significant hyponatremia (i.e. < 125 mmol/l), each in both groups, who claimed to have no symptoms and Table 1 Demographic characteristics of nocturia with or without NP Non-NP (n = 55) NP (n = 81) p Age (years) PSA ng/ml Use a-blocker 43 (78.2%) 64 (79%) Use 5ARI 8 (14.5%) 17 (21%) Use antimuscarinics 19 (34.5%) 21 (26.3%) Use imipramine 17 (30.9%) 23 (28.4%) BPO 43 (79.6%) 68 (85%) Prostate cancer 10 (18.5%) 10 (12.5%) DM 2 (3.7%) Hypertension 6 (11.1%) 25 (31.2%) 0.012* CVA 3 (5.6%) 4 (5%) Insomnia 10 (18.5%) 6 (7.5%) Renal insufficiency 4 (7.4%) 1 (1.2%) Urothelail cancer 1 (1.9%) 3 (3.7%) Dose of desmopressin Mean SD (mg) mg mg mg mg 3 7 Treatment duration (months) *Statistically significant p < NP, nocturnal polyuria; 5ARI, 5a-reductase inhibitor; BPO, benign prostate obstruction.

4 Desmopressin in nocturia with or without nocturnal polyuria 375 Figure 2 Percentage of nocturnal voids reduction according to the extent of reduced 1 episode, reduced 2 episodes and reduced to 2 episodes in both non-np and NP groups Table 2 Efficacy and safety parameter changes before and after desmopressin treatment Non-NP (n = 55) NP (n = 81) p Nocturnal voids Pretreatment Posttreatment *** *** Reduced episodes ** one episode 47 (85.5%) 78 (96.3%) 0.050* two episodes 35 (63.6%) 71 (87.7%) 0.002** Reduced episodes to two episodes 31 (56.4%) 58 (71.6%) IPSS Pretreatment Posttreatment Reduced IPSS *** *** QoL Pretreatment Posttreatment Reduced QoL *** *** Adverse event (except hyponatremia) 3 (5.5%) 6 (7.4%) Side effect: nausea (1), dizziness (1), oliguria (1); headache (3), diarrhoea (1), oliguria (1), incontinence (1). *Statistically significant p = **Statistically significant p < ***Statistically significant p < NP, nocturnal polyuria; IPSS, International Prostate Symptom Score; QoL, quality of life. insisted on being allowed to continue the treatment (Table 3). After normalisation of serum sodium values, the doses in both patients were reduced to 0.05 mg. Nine patients (6.61%) experienced AEs, of those nausea (1), dizziness (1), oliguria (1) in non- NP group and headache (3), diarrhoea (1), oliguria (1) and incontinence (1) in NP group (Table 2). No patients discontinued desmopressin because of adverse events including hyponatremia. Discussion Our study revealed that noctutria continued to bother elderly men with LUTS/BPH despite of stereotyped medical therapy. Adding on low-dose oral desmopressin in real-life practice was shown to be safe and effective for patients over 65 years with nocturia. It reduced nocturnal void, IPSS total score and QoL index not only in NP patients but also in non-np group. Nocturia is one of the most bothersome urinary symptoms in elderly people (13). Many elderly people have difficulty returning to sleep after interruption. It is reported that nocturia is associated with a twofold increase in the risk of fall in ambulatory elderly. Nocturia also has wide-ranging implications for patients quality of life (QoL), productivity, longer term physical and mental health, and possibly

5 376 Desmopressin in nocturia with or without nocturnal polyuria Table 3 Serum sodium and potassium changes before and after desmopressin treatment Non-NP (n = 55) NP (n = 81) p Serum sodium mmol/l Pretreatment Posttreatment *** *** Reduced sodium Pretreatment hyponatremia (< 135 mmol/l) 2 (3.6%) 2 (2.5%) Posttreatment hyponatremia (< 135 mmol/l) 12 (21.8%) 28 (34.6%) mmol/l 7 (12.7%) 21 (25.9%) mmol/l 4 (7.3%) 6 (7.4%) <125 mmol/l 1 (1.8%) 1 (1.2%) Serum potassium mmol/l Pretreatment ** Posttreatment Reduced potassium **Statistically significant p < ***Statistically significant p < NP, nocturnal polyuria. mortality (14). These findings were confirmed more recently in a prospective cohort study of 692 community-dwelling elderly people with a mean age of 74.5 years where nocturia three voids was associated with a 28% increased risk of falls over 3 years (15). LUTS are one of the major causes of nocturia in older men (16), while the pathophysiology of nocturia is considered multifactorial. NP as a result of age-associated changes in the circadian rhythm of urine excretion is the main mechanisms of nocturia (17,18). As a consequence of different definitions, the prevalence of NP in nocturia was reported to be % (19). The ICS has adopted a definition of NP as a proportion of the 24-h urine voided at night being > 20 33%; this threshold is age-dependent, with 20% for younger subjects and 33% for the elderly (12). With this definition, studies have shown that in at least 25% of elderly men with nocturia who are referred to urologists, the main factor contributing to nocturia is not bladder outflow obstruction or detrusor instability, but a syndrome known as NP of elderly people (20,21). Weiss et al. reported NP and excessive urine production remains up to 93% of nocturia in elderly patients (22). Yet, most of the reports enrolled only the Caucasian population. Marriappan et al. had compared Asians and Caucasian men with nocturia. Asian men were found to have a reduced nocturnal bladder capacity with lesser nocturnal production while Caucasian men suffered from more NP (23). Our study population presented with 55/136 (40%) in nocturia without NP and 81/136 (60%) in nocturia with NP. Our results were compatible with previous study in revealing that NP was a factor in nocturia in 43% of the patients evaluated, 57% had decreased NBC and 36% had a mixed aetiology (22). Nocturia does not completely respond to LUTS/ BPH medical treatment of benign prostate obstruction (BPO). These include behavioural interventions, a-blockers, 5a-reductase inhibitors, antimuscarinics and combination of these treatments (24), based on multiple aetiologies of nocturia in ageing men (25). Accordingly, the International Consultation on Incontinence renewed the grade A, Level 1 recommendation for desmopressin as the only treatment for nocturia of polyuric origin (26). Wang et al. demonstrated that low-dose oral desmopressin can be an effective and well-tolerated treatment for NP in patients with LUTS from BPO (27). However, the trials are defined by relatively strict patient exclusion criteria which limit the extrapolation of desmopressin effect in NP during real life practice. Aged men usually presented with LUTS/BPH and associated comorbidities. Researches for desmopressin response in nocturia without NP are also scarce and debatable. Ho et al. had reported a short-term and small patient population which demonstrated desmopressin to be an effective alternative in nocturia without NP refractory to antimuscarinics (28). Our report with more study population revealed that desmopressin was statistically effective in reducing nocturnal voids in both groups in a longer treatment period ( months in non-np, months in NP). Animal study had observed desmopressin induced increase in nighttime voided volume as a result of a slower rate of bladder filling (29) and regulated bladder activity to decrease nocturia by affecting bladder-related neurons in the micturition center (30). Further, if the nocturnal

6 Desmopressin in nocturia with or without nocturnal polyuria 377 urine output can be reduced, nocturnal frequency because of detrusor overactivity or small bladder capacity can also be reduced in these elderly patients. These finding may partially explain the effect of desmopressin in non-np patients. Comparing with non-np group, hypertension is more common in our NP group and with statistical significance (p = 0.012). The same findings were reported by Matthiesen et al. who presented a positive correlation between NUV and daytime mean arterial blood pressure (31) and by Homma et al. who presented higher mean blood pressure in men with NP than in controls (32). A recent research also demonstrated that NP was associated with nocturia, systolic blood pressure and IPSS (33). Another author proposed that NP and essential hypertension are manifestations of the same pathophysiological process (21). Thus we should pay much attention to the nocturia patients with NP in their cardiovascular health. Diabetes mellitus (DM) and LUTS/BPH are common disorder in elderly men. It is well known that DM can affect urinary function (34). Chung et al. conducted a study in DM patients attending to outpatient diabetic clinic. Of 1301 consecutive subjects, 25.3% reported having severe nocturia (35). Wen et al. presented their research to identify the risk factors of nocturia in Chinese people older than 40 years (36). Several mechanisms have been suggested to explain the relationship between DM and LUTS. It is well established that frequency and nocturia result from hyperosmolality and polydipsia secondary to hyperglycemia in DM (37). Whether DM affects desmopressin treatment effect in nocturia is still unclear. The high incidence of undetected obstructive sleep apnoea (OSA) in subjects with DM with nocturia suggests that nocturia, OSA and DM frequently coexist and may be interrelated (38,39). It has been postulated that in patients with OSA, the negative intra-thoracic pressure and stretching of the myocardium releases atrial natriuretic peptide (ANP). This, in turn, causes vasodilatation and inhibits aldosterone resulting in excess sodium and water excretion (40,41). It seems to be advantageous for desmopressin in treating nocturic patients with DM and OSA. However, the difference of response in desmopressin between DM and non-dm patient needs to be elucidated with further studies in the future. The safety profile of desmopressin is well documented in preschool children with nocturnal enuresis and in nocturia with NP in recent years. Most adverse effects have been proven mild and infrequent (42,43). The only potentially serious adverse effect is hyponatremia, which can occur because desmopressin reduces urine excretion. Short-term randomised controlled trials (9,44,45) showed the incidence of hyponatraemia (< 130 mmol/l) caused by desmopressin treatment in elderly patients as about %. One Korean report showed the hyponatraemia incidence was about 4.4% in elderly patients with more than 24 months of ongoing management (42). In contrast, our results showed a higher incidence of hyponatraemia of 9.1% in non- NP group and 8.6% in NP group respectively (< 130 mmol/l). We speculate that more comorbidities and relative low baseline serum sodium level in our groups ( in non-np, in NP, in Korean study) may be the causes of this discrepancy. Our baseline serum potassium level is statistically significant higher in NP group compared with non-np group. More hypertensive population in NP group may contribute the results. In our report, no serum potassium level drop phenomena caused by desmopressin treatment was observed as Chang et al. reported (46). Both of our groups patients have relatively high nocturnal voids ( in non-np, in NP) compared with a recent German nocturia report (47), with void/per night and Korean nocturia report (48) void/ per night. However, our patients had lower baseline IPSS QoL ( , ) compared with previous reports, , respectively. We presume that cultural differences and most of our population are older veterans who have higher endurance threshold may interpret these phenomena. This study has some limitations. This study is a retrospective study and might have inherent bias. Secondly, most of our patients were initially and ongoing treated with a-blocker (78% vs. 79.2%) after initiation of desmopressin management. We doubt whether a-blocker will contaminate the desmopressin-only treatment effect or not. A recent reference reported a decrease in nocturia frequency by 53% (from 3.8 to 1.7 nocturnal voids) with desmopressin monotherapy, but the combination of desmopressin and a-blocker did not show any synergistic effect (47). Thirdly, we only categorised nocturia into NP and non-np by a single FVC. However, our patient population was poorly compliant with multiple-day diaries because of veteran with comorbidities. Fourthly, this study showed that DM was 3.7% in non-np, but 0% in NP patients. It seems that the prevalence of DM in current report is lower in nocturic patients. Most of patients treating in our hospital are older veterans who are often reluctant to manage their DM and nocturia in different clinics. Thus, we should enrol DM and urologic clinic patients in the future study. Lastly, nocturia

7 378 Desmopressin in nocturia with or without nocturnal polyuria without NP includes decreased nocturnal bladder capacity, OAB and sleep disturbance or a combination of these factors. We did not specify the exact pathophysiology of nocturia without NP which limits the extrapolation. These confounders seem not to skew our aim to test the efficacy and safety of desmopressin in older refractory nocturia patients with LUTS/BPH in real-life practice. Further randomised controlled protocol and large population studies are needed to elucidate the long-term efficacy and safety of desmopressin in nocturia with different etiologies. Conclusions Long-term treatment with low-dose desmopressin is safe and effective for nocturia with or without NP in elderly men during real-life practice. Patients should be well informed about the disease and are closely followed. Acknowledgement None. Author contributions Yu-Hui Huang, Tung-Wei Hung contributed to study design, and interpretation of results. 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