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Does Structured Withdrawal of Desmopressin Improve RelapseRates in Patients with Monosymptomatic Enuresis? A Prospective,Randomized, Placebo Controlled, Multicenter Study

Mehmet _Ilker G€okce,* Parviz Hajıyev, Evren S€uer, Yusuf Kibar, Mesrur Selcuk Sılay,

Serhat G€urocak, Hasan Serkan Do�gan, Hasan Cem Irkılata, Tayfun Oktar, B€ulent €Onal,

Erim Erdem, Y€uksel Cem Ayg€un, Can Balcı, Ahmet R€uknettin Arslan, Cevdet Kaya,

Tarkan Soyg€ur, Saban Sarıkaya, Serdar Tekg€ul and Berk Burgu

From the Department of Urology (M _IG, PH, ES) and Department of Pediatric Urology (TS, BB), Ankara University School of

Medicine, Department of Urology, Gulhane Military Medical School (YK, HCI), Department of Pediatric Urology, Gazi

University School of Medicine (SG), Department of Pediatric Urology, Hacettepe University School of Medicine (HSD, ST)

and Department of Urology, Baskent University School of Medicine (YCA), Ankara, Department of Pediatric Urology, Bezmi

Alem School of Medicine (MSS), Department of Pediatric Urology, Istanbul School of Medicine (TO) and Department of

Pediatric Urology, Cerrahpasa School of Medicine (BO), Istanbul University, Department of Urology, Taksim Education and

Research Hospital (CB), and Department of Urology, Haydarpasa Education and Research Hospital (ARA, CK), Istanbul,

Department of Urology, Mersin University School of Medicine, Mersin (EE) and Department of Pediatric Urology, Samsun

University School of Medicine, Samsun (SS), Turkey

Abbreviations

and Acronyms

MNE ¼ monosymptomaticnocturnal enuresis

Accepted for publication January 24, 2014.* Correspondence: €Uroloji A.D., Ankara

€Universitesi Tıp Fakultesi, _Ibni Sina Hastanesi,Sıhhıye Ankara, Turkey (telephone: 90-532-370-85-25; FAX: 90-312-508-22-58; e-mail: migokce@yahoo.com).

8081828384858687888990919293949596979899

100101102103104105106107108109110

Purpose: Relapse after cessation of desmopressin is an important problem intreating patients with enuresis. Structured withdrawal of desmopressin tabletshas been shown to decrease relapse rates. However, scientific data are lackingon the structured withdrawal of the fast melting oral formulation of desmo-pressin. We compared relapse rates of structured withdrawal using placebo anddirect cessation in a population of patients with enuresis who were desmopressinresponders.

Materials and Methods: Patients diagnosed with enuresis and respondingto desmopressin from 13 different centers were involved in the study. Pa-tients were randomized into 4 groups. Two different structured withdrawalstrategies were compared to placebo and direct withdrawal. Sample size wasestimated as 240 (60 patients in each group), with a power of 0.80 and aneffect size of 30%. Randomization was performed using NCSS statisticalsoftware (NCSS, Kaysville, Utah) from a single center. The relapse rates ofthe groups were compared using chi-square testing. Logistic regressionanalysis was performed to define the independent factors having an effecton relapse rates.

Results: Desmopressin treatment was initiated in 421 patients, and 259 patientswere eligible for randomization. Relapse rates were 39 (1%) and 42 (4%) for thestructured withdrawal groups, which were significantly less than for directwithdrawal (55, 3%) and placebo (53, 1%). Logistic regression analysis revealedthat initial effective dose of 240 mcg, greater number of wet nights beforetreatment and nonstructured withdrawal were associated with higher relapserates.

Conclusions: We found that structured withdrawal with the fast meltingoral formulation of desmopressin results in decreased relapse rates. Applicationof a structured withdrawal program was also an independent factor associatedwith reduced relapse rates, together with lower initial effective dose and numberof wet nights per week. Relapse after cessation of desmopressin is an important

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0022-5347/14/1922-0001/0

THE JOURNAL OF UROLOGY®

© 2014 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC.

http://dx.doi.org/10.1016/j.juro.2014.01.094

Vol. 192, 1-5, August 2014

Printed in U.S.A.www.jurology.com j 1

2 WITHDRAWAL OF DESMOPRESSIN IN PATIENTS WITH MONOSYMPTOMATIC ENURESIS

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problem, and in this study structured withdrawal was observed to be associated with decreased relapse ratescompared to placebo and direct withdrawal.

Key Words: deamino arginine vasopressin, enuresis, recurrence

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ENURESIS is defined as any type of wetting episodethat occurs in discrete amounts during sleep. Thecondition is divided into 2 groups, ie mono-symptomatic and nonmonosymptomatic enuresis.Patients with monosymptomatic nocturnal enuresisare those without any other lower urinary tractsymptoms (nocturia excluded) and without a historyof bladder dysfunction.1 The prevalence of mono-symptomatic nocturnal enuresis is reportedly 3.8%,ranging from 0.5% to 1% in adolescence to 10%in early childhood.2e5

In addition to being highly prevalent, the effectof enuresis on the psychology and social status ofchildren and their parents makes this an importanthealth problem whose definitive treatment isimportant.6 Treatment alternatives include phar-macological and psychological/ behavioral thera-peutic modalities. Desmopressin is the first-linemedication for patients with MNE with nocturnalpolyuria and normal bladder function.7 Desmo-pressin has been used in the treatment of enuresissince 1972, and a fast melting oral lyophilisateformulation has been available since 2005.8 Patientsrespond well and rapidly to desmopressin therapy.However, relapse after treatment is an importantproblem that affects up to 83% of patients.9 Forthis reason structured withdrawal of desmopressintablets as reported by Marschall-Kehrel and Harmshas been widely accepted.10

The current literature lacks studies on structuredwithdrawal using the fast melting oral formulationof desmopressin. There is only 1 current studycomparing abrupt cessation and a structured with-drawal program (60 mcg daily for 15 days, and then60 mcg every second evening for another 15 days) in47 patients, without a placebo group.11We comparedthe relapse rates of 2 different withdrawal programsconsisting of structured withdrawal with placeboand abrupt cessation. Additionally we sought toidentify independent risk factors for relapse aftercessation of desmopressin. To our knowledge this isthe first prospective, randomized, placebo controlledtrial comparing 2 different structured withdrawalprotocols of desmopressin cessation.

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PATIENTS AND METHODSThis multicenter study was planned by the Turkish As-sociation of Pediatric Urology. Patients from 13 differentcenters were involved in the study between May 2011 andDecember 2012. Inclusion criteria consisted of age greater

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than 5 years and MNE, defined as bedwetting at leasttwice weekly in the last 3 months. Exclusion criteriaconsisted of the presence of daytime incontinence, ur-gency, treatment with desmopressin within 3 monthspreceding the study, presence of neurogenic bladderdysfunction, presence of diabetes insipidus and post-voidresidual volume greater than 100 ml.

Before treatment with desmopressin all children un-derwent evaluation consisting of history, physical exami-nation, International Bladder Symptom Score,12 voidingdiaries for at least 2 days, uroflowmetry (2 times), uri-nalysis and serum creatinine, sodium and chloride levels.Initially all patients were given 120 mcg desmopressin andthe response was evaluated after 2 weeks. Patients whodid not respond were tapered to 240 mcg. All patients wereinformed and warned about fluid restriction. Responsewas defined as no wet nights and was reevaluated at4 weeks of treatment. Responders were given desmo-pressin for 12 weeks, while nonresponders were excludedfrom the study.

At the end of treatment period patients were random-ized to 4 different groups. Patients in group 1 receivedhalf of the effective dose, those in group 2 received theeffective dose every other day, those in group 3 underwentimmediate cessation and those in group 4 received pla-cebo. The cessation programs were applied for 2 weeks,and patients were evaluated for relapse at the 2-week and4-week periods. Matching placebo materials identical tothe fast melting oral formulation of desmopressin weregiven to patients in the placebo group. Nonrelapsing pa-tients were scheduled for control after 12 weeks and pa-tients were questioned regarding bedwetting episodes.

Relapse was defined as bedwetting occurring morethan 2 nights monthly. The primary outcome measure ofthe study was to determine the relapse rates after cessa-tion of desmopressin in the different groups. The second-ary outcome measure was to evaluate the effect of age,gender, initial effective dose and structured withdrawalon relapse rates.

Sample SizeSample size was estimated based on the assumption thatpatients receiving placebo and undergoing unstructuredwithdrawal would experience a 60% relapse rate, whilethose in the structured withdrawal groups would experi-ence a 40% relapse rate. A sample size of 240 randomizedpatients (60 in each group) provided 80% power to detect a30% difference in proportions of relapse rates.

Statistical Analysis and RandomizationRandomization was performed using NCSS software froma single center. For blinding purposes physicians whoprocessed controls and questioned relapse rates wereblinded to the withdrawal procedure. Statistical analysiswas performed by SPSS�, version15.0. Relapse rates ofthe groups were compared using chi-square testing.

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½F1�

½T1�

½F2�½T2�

Figure 2. Relapse rates after cessation of desmopressin at 4 and

12 weeks.

Figure 1. Flow chart of study participants

WITHDRAWAL OF DESMOPRESSIN IN PATIENTS WITH MONOSYMPTOMATIC ENURESIS 3

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Paired samples t-test and independent samples t-testwere used for continuous variables. To define the inde-pendent factors having an effect on relapse rates, multi-variate logistic regression analysis was performed. Ap value of 0.05 was used for statistical significance.

½T3�

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RESULTSDuring the active treatment period desmopressintherapy was initiated in 421 children. A total of15 children were lost to followup and could notbe evaluated for response at 12 weeks. Of theremaining 406 patients 284 (69.9%) were full re-sponders and 122 (30.1%) were not full responders.Randomization was performed, and at the end of12-week followup after cessation there were 64 pa-tients in group 1, 66 in group 2, 65 in group 3 and64 in group 4 eligible for analysis. A total of 25children were lost to followup after randomizationand could not be evaluated for relapse rates. Therewere 7, 5, 5 and 7 patients lost to follow up in groups1, 2, 3 and 4, respectively. The flow of study par-ticipants is illustrated in the figure 1.

Baseline characteristics of the groupswere similarand are outlined in table 1. The relapse rates aftercessation of desmopressin at 4 weeks and 12 weekswere significantly less in groups 1 and 2 comparedto groups 3 and 4 (fig. 2, table 2). The differencebetween group 1 and group 2 was not statisticallysignificant. The initial effective dose was 120 mcg and

Table 1. Baseline characteristics of patient groups

Parameter Group 1 Group 2

Mean � SD age (yrs) 7.5 � 2.3 7.1 � 2.4No. gender (%):Male 41 (64.1) 39 (59.1)Female 23 (35.9) 27 (40.9)

Mean � SD wet nights/wk 4.29 � 1.3 4.32 � 1.6

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240 mcg in 43.2% and 56.8% of the patients, respec-tively, and the ratios were similar for all groups(table 2). Adverse events related to desmopressin usewere not observed in any patient, and no patient wasexcluded from the study due to side effects.

Logistic regression analysis demonstrated thatinitial effective dose of 240 mcg, greater number ofwet nights before treatment and nonstructuredwithdrawal (placebo and full cessation) were asso-ciated with higher relapse rates. However, age andgender were not associated with increased relapserates. The results of logistic regression analysis aresummarized in table 3.

DISCUSSIONDesmopressin is the first-line treatment for patientswith enuresis and has high efficacy rates, althoughrelapse after cessation of treatment is a majorconcern. In the present study relapse rates of abruptcessation and withdrawal in 2 different structuredmethods were evaluated in comparison to placebo.Relapse rates were significantly lower in the struc-tured withdrawal groups.

There have been studies published previouslyon structured withdrawal of desmopressin. Struc-tured withdrawal programs can be grouped as timedependent, ie approaches that maintain constantdoses of medication with increasing time in-tervals,13,14 and dose dependent, ie approaches thatdecrease the doses of desmopressin after certaintime intervals.15 In the study by Marschall-Kehrel

Group 3 Group 4 p Value

7.3 � 2.2 7.4 � 2.2 0.5410.352

43 (66.1) 40 (62.5)22 (33.9) 24 (37.5)4.08 � 1.8 4.65 � 2.1 0.511

334335336337338339340341342

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Table 3. Results of logistic regression analysis

Parameter Odds Ratio (95% CI) p Value

Age 1.116 (0.867e1.554) 0.122Male gender 1.121 (0.751e1.882) 0.688No. wet nights/wk 1.828 (1.598e2.023) 0.004Initial effective dose 240 mcg 2.233 (1.275e3.877) 0.001Nonstructured withdrawal 4.291 (2.382e7.127) 0.0001

Table 2. Relapse rates at weeks 4 and 12 and initial effectivedoses

Parameter Group 1 Group 2 Group 3 Group 4 p Value

No. relapse (%): 0.001Wk 4 23 (35.9) 27 (40.9) 36 (55.3) 32 (50.0)Wk 12 25 (39.1) 28 (42.4) 36 (55.3) 34 (53.1)

No. initial effectivedose (%):

0.650

120 mcg 29 (45.3) 28 (42.4) 27 (41.5) 28 (43.7)240 mcg 35 (54.7) 38 (57.6) 38 (58.5) 36 (56.3)

4 WITHDRAWAL OF DESMOPRESSIN IN PATIENTS WITH MONOSYMPTOMATIC ENURESIS

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and Harms 0.2 and 0.4 mg tablets of desmopressinwere given daily, and structured withdrawal wasobserved to result in lower relapse rates.10 Thismulticenter study offers strong evidence in favor ofstructured withdrawal. In a review of 13 studiesand 1,457 children Alloussi et al reported lowerrelapse rates with time dependent (mean 6.3%,range 3.7% to 17.6%) and dose dependent (16.8%,10.7% to 21.0%) structured withdrawal programscompared to abrupt cessation (56.9%, 10.8% to90.0%).16 However, none of these studies evaluatedthe fast melting oral formulation of desmopressin,which is currently the standard formulation. Inaddition, based on these series, no conclusionregarding preference for time or dose dependentapproach can be reached, as direct comparison of2 different approaches has not been performed.

Recently abrupt cessation of the fast melting oralformulation of desmopressin was compared to asingle withdrawal program of 60 mcg desmopressindaily for 15 days and then 60 mcg every secondevening for another 15 days.11 Patients were fol-lowed prospectively, and there were 24 and 23children in the abrupt cessation and structuredwithdrawal groups, respectively. The authors re-ported 45.83% and 47.83% relapse rates of abruptwithdrawal and structured withdrawal groups after4 weeks of followup, respectively, a difference thatwas statistically insignificant (p ¼ 0.89). Relapserate with structured withdrawal in that studyseems to be higher compared to groups 1 and 2 inour study, and closer to groups 3 and 4. This findingmay be due to the greater effectiveness of structuredwithdrawal methods in our series.

In our study structured withdrawal programswere associated with lower relapse rates comparedto abrupt cessation and placebo (p ¼ 0.001). Patientsin group 1 were under a dose dependent withdrawalprogram with a relapse rate of 39.1%, while those ingroup 2 were under a time dependent withdrawalprogram with a relapse rate of 42.4% at 12 weeks offollowup. This is the first known study to comparethese 2 types of withdrawal methods, and althoughrelapse rate was slightly higher in the time depen-dent approach group, the difference between the2 groups was not statistically significant.

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The greater number of patients and presence of aplacebo group increase the strength of our results.Also longer followup duration (up to 12 weeks) isimportant to show intermediate term effectivenessof the structured withdrawal programs.

Our secondary outcome measures were to iden-tify factors associated with increased relapserates. Age and gender were not associated withincreased relapse rates. However, number of wetnights per week, initial effective dose of 240 mcg andwithdrawal in a nonstructured manner were asso-ciated with higher relapse rates. Number of wetnights per week and higher initial effective dose areassociated with greater nocturnal urine output,which explains the association with higher relapserates after cessation of desmopressin. Nonstruc-tured withdrawal had the greatest odds ratio amongthose factors evaluated in logistic regression anal-ysis. This finding necessitates further comparativestudies of different withdrawal programs.

The only known limitation of this study is theinclusion of a single placebo group. The 2 differentwithdrawal arms could have had their own placebogroups, that is 1 group receiving placebo every otherday and 1 group receiving placebo daily. Creation ofthese groups was not done so that we could decreasethe number of groups, which mediates higher powerfor the study with fewer patients. The multicenternature is not thought to be a limitation because allpatients were included and followed with a standardschedule, and randomization was performed at asingle center.

CONCLUSIONSStructured withdrawal with the fast melting oralformulation of desmopressin mediates decreasedrelapse rates after 4 and 12 weeks of followup. Timedependent and dose dependent withdrawal strate-gies were observed to be effective, and the differencebetween the 2 methods was not significant. Applica-tion of a structured withdrawal program was also anindependent factor associatedwithdecreased relapserates, together with smaller initial effective dose anddecreased number of wet nights per week. Additionalplacebo controlled studies for comparison of differentmethods of withdrawal should be conducted to definethe best method of structured withdrawal.

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WITHDRAWAL OF DESMOPRESSIN IN PATIENTS WITH MONOSYMPTOMATIC ENURESIS 5

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