英文资料 Safety and efficacy of desmopressin for the treatment of nocturia in elderly patients： a cohort study

Int Urol NephrolDOI 10.1007/s11255-014-0679-0UROLOGY - ORIGINAL PAPERSafety and efcacy of desmopressin for the treatment of nocturiain elderly patients: a cohort studyMiho Song Bum Sik Hong Ji-Youn Chun Ji-Yeon Han Myung-Soo ChooReceived: 14 November 2013 / Accepted: 19 February 2014Springer Science+Business Media Dordrecht 2014AbstractPurpose Desmopressin is used widely to treat nocturnalpolyuria (NP), but there is concern of hyponatremia espe-cially in elderly patients. This study aimed to evaluate thesafety and efcacy of long-term desmopressin treatment inelderly patients with NP.Methods Patients who were C65 years old with NP wereanalyzed. All patients were started on 0.1 mg desmopres-sin, and the dose was escalated to 0.2 mg depending onpatient symptoms. All patients were educated the mecha-follow-up (p = 0.003). Hyponatremia incidence was4.4 %, and all patients recovered by stopping medication.Severe adverse events were not observed. The mean night-time frequency had decreased by 2.1, and the NUV haddecreased by 374.2 261.3 mL at the last follow-up(p 0.001).Conclusions Desmopressin at doses below 0.2 mg is safeand effective in elderly patients with NP if patients are wellinformed and are closely followed up.nism of desmopressin. The voiding diary and serumsodium levels were evaluated at baseline, 37 days afterstarting treatment and every 36 months. Safety wasKeywords Desmopressin Nocturia Hyponatremiaevaluated by hyponatremia, hyponatremic symptoms andother adverse drug events. The mean changes in number ofnocturia and nocturnal urine volume (NUV) were evalu-ated for efcacy.Results A total of 68 patients were included. The meanage was 72.6 (6685) years. The mean night-time fre-quency was 3.0 1.8 day, and the mean serum sodiumlevel was 141.2 2.1 mEq/L at baseline. The mean fol-low-up period was 27.9 months. The mean decrease inserum sodium level was 1.3 3.4 mEq/L at the lastMiho Song and Bum Sik Hong have contributed equally to this work.M. Song B. S. Hong J.-Y. Chun M.-S. Choo ( one because ofdry mouth and one because of weight gain.The mean night-time frequency had decreased by 2.1from 3.0 to 0.9 at the last follow-up, respectively (Table 2).The NUV also decreased signicantly by 374.2 261.3 mL at the last follow-up, respectively, as did NI, NPIand NBCI. In 59 patients (86.7 %) had an improvement innumber of nocturia more than 50 % from baseline. Thepatients with more frequent nocturia at baseline improvedbetter than those with less frequent nocturia in logisticregression analysis (Fig. 1). In the 29 patients who received0.1 mg desmopressin, the treatment successfully reducedthe NUV in 24 (82.7 %). In the 39 patients whose dose wasescalated from 0.1 to 0.2 mg, the treatment was successfulin 31 (79.4 %). The patients whose dose was escalated to0.2 mg desmopressin did not differ from the patients whocontinued to be treated with 0.1 mg in terms of the baselinefrequency of nocturia (2.8 1.4 vs. 3.1 2.1;p = 0.580). There were no predictive factors including thedose for success of desmopressin treatment in logisticregression analysis.Table 2 Effect of desmopressin treatment on nocturnal polyuriaThe dose was escalated to 0.2 mg desmopressin in 39(57.4 %) patients.The mean decrease in serum sodium level wasVariablesaNight-time frequencyBaseline3.0 1.8Aftermedication0.9 0.8p value 0.0011.3 3.4 mEq/L at the last follow-up (p = 0.003). Thepatient cohort was divided according to whether the baselineNocturnal urine volume(mL)832.5 414.5 458.2 240.7 0.001sodium level was 140 or C140 mEq/L. The two groups didnot differ in terms of the change from baseline in sodium level(- 1.1 3.6 vs. - 1.3 3.3; p = 0.817). In total, six patientsNocturnal indexNocturnal polyuria indexNocturnal bladder2.7 1.00.5 0.11.1 0.71.6 0.70.33 0.150.5 0.4 0.001 0.001 0.001(8.8 %) had one or more adverse drug events. Of these capacity indexpatients, two patients had hyponatremia, 120, 127 mEq/L, and Serum sodium level 141.2 2.1 139.9 2.9 0.0031 patient had hyponatremic symptoms (weight gain). Thesethree patients were 73, 76 and 73 years old, and their sodium a(mEq/L)The data are shown as mean SD123DiscussionThe present study evaluated the systemic adverse reactionsespecially hyponatremia and long-term effect of desmo-pressin in older patients with NP. Desmopressin was shownto be safe if patients are well informed about the diseaseand closely followed up under the 0.2 mg desmopressinand effective treatment for patient more than 65 years withNP in the present study. The hyponatremia was occurredonly three patients (4.4 %) after dose escalation to 0.2 mg.Nocturia is one of the most bothersome storage symp-toms in the elderly 12. In 2002, the ICS dened nocturia aswaking up one or more times at night to void 13. The needto wake up at night may also elevate the risk that thesesubjects have accidental falls, cerebral vascular attack andeven depression. It was accepted that a major contributingfactor to nocturia is the nocturnal overproduction of urinebeyond functional bladder capacity 14, 15.NP may be caused by various age-associated changesnamely decreased renal concentrating capacity or sodiumconserving ability, loss of the circadian rhythm of antidi-uretic hormone secretion, decreased secretion of reninangiotensinaldosterone and/or increased secretion of atrialnatriuretic hormone 4, 16. These ndings led to the use ofdesmopressin a synthetic analogue of arginine vasopressin,to decrease nocturnal dieresis 17. The antidiuretic effectof desmopressin increases the water permeability in thecollecting tubules in the kidney, and the resulting waterreabsorption leads to a decreased urine volume andincreased urine osmolality 18. Desmopressin has beenused for 50 years to treat neurogenic diabetes insipidus andfor 30 years to treat nocturnal enuresis. It is not onlyeffective for primary or secondary nocturnal enuresis, itcan also be used in older men if there are changes in thecircadian rhythm of antidiuretic hormone 16, 19, 20.Hvistendahl et al. 21 reported that elderly patients withNP differ signicantly from young controls in terms of thecircadian rhythm of diuresis during the night-time and mid-afternoon. They suggested that a single dose of desmo-pressin can restore the circadian rhythm of diuresis in NPand postpones the peak diuresis of the day in elderlypeople.The most notable adverse effect of desmopressin inadults with nocturia is hyponatremia, which has beenreported to occur in 4.9 % of such patients 22. Moreover,hyponatremia occurs more frequently in older patients.Lose et al. 23 reported that patients who were 65 years orolder had a relatively higher incidence of treatment-relatedadverse drug events than younger patients (27 vs. 21 % inmales; 41 vs. 19 % in females) and a greater risk ofhyponatremia. Most physicians do not prescribe desmo-pressin for NP, there is concern about complications ofhyponatremia and uid overload in the elderly 24.123Int Urol NephrolIn the present study, desmopressin treatment that wastaken on average for 25.8 months was successful in 59patients (86.7 %), namely the treatment reduced the night-time frequency by 50 % in these patients. The night-timefrequency decreased from 3.0 to 0.9, while the NUVdecreased by 374.2 261.3 mL. And only one patient dis-continued the medication due to no effect of desmopressintreatment. This efcacy is similar to that reported by severalrandomized placebo-controlled trials on desmopressin treat-ment in elderly patients. These studies included the ran-domized controlled trial of Vaughan et al. 25 who examinedthe effect of oral desmopressin 0.1 mg at bedtime for 4 weeksin older men. Of the 30 patients, 20 patients (66.7 %) reporteda good response with reduced nocturnal frequency and urinevolume. Five of the 30 patients (16.7 %) reported adversedrug events including hyponatremia in one case. In anotherplacebo-controlled clinical trial, 60 older men with a meanage of 63.3 years were enrolled and half were randomlyassigned to receive 0.1 mg desmopressin for 8 weeks 26.Before and after desmopressin treatment, the mean numbersof nocturia episodes were 2.6 and 1.6, respectively. Seriousadverse events were not observed. Juul et al. 27 also foundthat the response to desmopressin was sustained over52 weeks of treatment. Moreover, they reported that after40 weeks of desmopressin treatment, the numbers of noc-turnal voids decreased 0.8, 1.5 and 1.5 voids in the 100, 200and 400 lg groups, respectively.Although many trials show that desmopressin is effectivefor nocturia, its safety remains unclear. In a multicenterstudy examining the effect of 1012 months of desmo-pressin treatment on 249 patients with nocturia, 35 (14 %)developed hyponatremia, although it was not clinicallyrelevant in 33. The remaining two patients had symptomatichyponatremia 23. Moreover, in a large randomized pla-cebo-controlled study that examined the effect of 4 weeksof desmopressin treatment on nocturia, 24 patients (3 %)had serum sodium levels that exceeded 130 mmol/L duringthe study 28. Of these, nine patients (1.1 %) had serumsodium reductions below 125 mmol/L and this effect wasmore common in patients who were C65 years old. How-ever, when Kuo et al. 29 examined the effect of 4 weeksof treatment with 0.1 mg desmopressin on patients whowere C65 years old and had severe nocturia, it was found tobe both safe and effective. Only one patient (3.3 %)developed signicant hyponatremia and hypokalemia. Allof these studies were relatively short-term studies with onlyone study having a follow-up time that exceeded 4 weeks.Since the problem of nocturia probably requires ongoingmanagement, it is difcult to determine the hyponatremiaincidence in subjects who remain on desmopressin for alonger time on the basis of such short-term studies 30.To our knowledge of all the studies examining the safetyof desmopressin in older patients with nocturia, the presentInt Urol Nephrolstudy has the longest follow-up period. Hyponatremia didnot occur when the patients received the low 0.1 mg dose,but three patients (4.4 %) developed hyponatremia afterdose escalation to 0.2 mg. This incidence of hyponatremiais similar to the incidences reported by the shorter-termstudies of hyponatremia. The hyponatremia events occur-red within 3 months after dose escalation and wereresolved with conservative treatment.This study has some limitations. This study is retro-spective study and might have selection bias. Patients withseveral conditions that are known to affect NP such aschronic renal insufciency and ischemic heart disease werenot excluded; 91.2 % of patients took the medication dueto benign prostate hyperplasia or overactive bladder.Though these condition inuence nocturia, however, inclinical situation many patients with nocturia were com-bined these conditions. Therefore, we believe that ourresults also were a meaningless. All patients were educatedrestriction of uid at night that affects the result and weused reduction dose of 0.1 mg desmopressin that is not arecommend dose in patients with NP.ConclusionsLong-term treatment with desmopressin is safe and effec-tive for NP in elderly patients if the patients are wellinformed about the disease and are closely followed up.Conict of interest Miho Song, Bum Sik Hong, Ji-Youn Chun, Ji-Yeon Han and Myung-Soo Choo have no conict of interest.References1. Asplund R (2006) Hip fractures, nocturia, and nocturnal polyuriain the elderly. Arch Gerontol Geriatr 43:3193262. Lundgren R (2004) Nocturia: a new perspective on an oldsymptom. Scand J Urol Nephrol 38:1121163. Matthiesen TB, Rittig S, Norgaard JP, Pedersen EB, Djurhuus JC(1996) Nocturnal polyuria and natriuresis in male patients withnocturia and lower urinary tract symptoms. J Urol156:129212994. Chang SC, Lin AT, Chen KK, Chang LS (2006) Multifactorialnature of male nocturia. Urology 67:5415445. 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