Discontinuation of Treatment Using Anticholinergic.21

Original Research

Discontinuation of Treatment UsingAnticholinergic Medications in PatientsWith Urinary Incontinence

Matthias Kalder, MD, PhD, Konstantinos Pantazis, MD, Konstantinos Dinas, MD, PhD,Ute-Susann Albert, MD, PhD, Christina Heilmaier, MD, and Karel Kostev, PhD

OBJECTIVE: To evaluate the discontinuation rates of

anticholinergics prescribed in patients with urinary

incontinence (UI).

METHODS: Data from a Disease Analyzer database

including 988 general, 95 urologist, and 203 gynecologic

practices were examined. Twenty six thousand eight

hundred thirty-four patients were identified as having

received a first-time anticholinergic prescription for

UI, namely darifenacin, fesoterodine, oxybutynin, propi-

verine, solifenacin, tolterodine, or trospium, between

2005 and 2012. Covariates studied included demographic

data, concomitant diagnoses, and potential drug-

induced side effects. The cumulative discontinuation rate

of initial treatment was estimated using a KaplanMeier

analysis. A Cox proportional hazard regression model

was used to estimate the relationship between discon-

tinuation and the demographic and clinical variables for

up to 36 months.

RESULTS: An increasing discontinuation rate was observed

in years 1, 2, and 3 (74.8%, 77.6%, 87%). Within 3 years,

discontinuation rates were higher for men than for women

(87.9%, 86.5%; P5.056; hazard ratio [HR] 1.14, 95% confi-dence interval [CI] 1.111.18; P,.001), for patients treated in

gynecologic practices and general practices than those trea-

ted in urologist practices (HR 1.60; 95% CI 1.521.67,

P,.001 and HR 1.24, 95% CI 1.201.29, P,.001, respectively)and for younger patients than those older than 80 year old

(60 years or younger, HR 1.27, 95% CI 1.221.33; 6170

years, HR 1.16, 95% CI 1.111.21; 7180 years, HR 1.14,

95% CI 1.091.18, P,.001). Those using propiverine or sol-ifenacin were less likely to discontinue treatment than those

using oxybutynin (HR 0.94, 95% CI 0.880.99, P5.024 andHR 0.93, 95% CI 0.870.98, P5.004, respectively).

CONCLUSION: Patients with UI demonstrate high dis-

continuation rates for anticholinergics with only slight

variations between the various drugs in this category.

(Obstet Gynecol 2014;124:794800)

DOI: 10.1097/AOG.0000000000000468

LEVEL OF EVIDENCE: III

It has been predicted that the worldwide prevalenceof lower urinary tract symptoms will increase by18.4% between 2008 and 2018.1 In 2018, 2.3 billionpersons are expected to have these symptoms, includ-ing an estimated increase in those with urinary incon-tinence (UI) (8.221.6%).1,2

The prevalence of urge UI (UUI) is reported asranging between 1.8% and 30.5% in Europe, 1.736.4% in the United States, and 1.515.2% in Asiaand is known to depend on gender and age.3 Currentevidence reveals that UUI represents a substantialeconomic burden on patients and communities world-wide. In several cost-of-illness studies for UUI, theestimated costs ranged from $9.6 to $66 billion(2005, 2007). According to current forecasts, costs willincrease noticeably as populations age.3

Side effects and efficacy of anticholinergics in thetreatment of symptoms associated with UUI and over-active bladder have been acknowledged in previousstudies.47 Anticholinergics reduce intravesical pres-sure, increase bladder capacity, and appear to provide

From the Department of Obstetrics and Gynecology, Philipps University ofMarburg, Marburg, FOM University of Applied Sciences, Essen, and IMSHealth, Frankfurt, Germany; and the 1st Department of Obstetrics andGynecology and the 2nd Department of Obstetrics and Gynecology, MedicalSchool, Aristotle University, Thessaloniki, Greece.

Professional English-language editing services were provided by Claudia Jones,MA, Radford, Virginia.

Corresponding author: Matthias Kalder, MD, PhD, Philipps University ofMarburg, Department of Obstetrics and Gynecology, Baldingerstrasse, 35043Marburg, Germany; e-mail: [email protected].

Financial DisclosureDr. Kostev is an employee of IMS Health. The other authors did not report anypotential conflicts of interest.

2014 by The American College of Obstetricians and Gynecologists. Publishedby Lippincott Williams & Wilkins.ISSN: 0029-7844/14

794 VOL. 124, NO. 4, OCTOBER 2014 OBSTETRICS & GYNECOLOGY

significant symptomatic relief to those with urinaryurgency and frequency and UUI or mixed UI. Theside effect profile (for instance xerostomia, obstipation,and headache) in this class is reported to be relativelymild. However, long-term discontinuation rates ina population-based setting are rarely reported.8,9

The primary aim of the present study was toassess the discontinuation rate of anticholinergics inpatients diagnosed with UI. Secondary aims were toevaluate the discontinuation rates for the variousanticholinergics and to identify contributing factorsfor discontinuation among urologist, gynecologist,and general practitioner practices.

MATERIALS AND METHODS

We collected data from the Disease Analyzer database(IMS Health), a nationwide electronic database thatcompiles drug prescription, diagnosis, and other basicmedical and demographic data obtained directly fromlocal computer systems in the practices of generalpractitioners and specialists throughout Germany.10

Diagnoses (International Statistical Classification ofDiseases and Related Health Problems, 10th Revision),prescriptions (Anatomical Therapeutic Chemical Clas-sification System), and the quality of reported data arecontinuously monitored by IMS Health on the basis ofa number of criteria, which include completeness ofdocumentation, consistency of diagnoses and prescrip-tions, etc. Data are entered directly in the physicianspractices through a standardized interface and providedaily routine information on patient diseases and ther-apies. A practice transmits patient data stored on thephysicians computer to IMS Health on a monthlybasis; all data are anonymized and the terms patient,doctor, medical practice, prescriber, and phar-macy do not refer to personal data but rather to exclu-sively anonymous information (in accordance withSection 36 of the German Federal Data ProtectionAct). Data are also encrypted on transmission for dataprotection purposes in connection with data and figuresused in terms. The validity of the Disease Analyzerdata has already been evaluated and described.10,11 Ithas formed the basis of a number of studies and peer-reviewed scientific publications in the fields of epide-miology as well as research on treatment discontinua-tion rates for several medical conditions.12,13

We included patients with first-time prescriptionof a UI product (Anatomical Therapeutic ChemicalClassification System: G04D4) between the indexdates of January 1, 2005, and December 31, 2012,with a diagnosis of stress UI (SUI) (N39.3) or otherspecified UI (N39.4); the latest follow-up date was setas December 31, 2013.

Patients with a follow-up time of less than 365days before the index date were excluded to allow forthe correct identification of treatment initiation. Fur-ther inclusion criteria included age at the index date(older than 18 years).

The main outcome measure was treatment dis-continuation rate for UI within 36 months after theindex date. Treatment discontinuation was defined asa period of 90 days without prescription of UI therapybut with at least one visit to the same doctor after 90days.8 A longitudinal medication supply data set wasestablished and the UI therapy discontinuation ratecalculated for each individual patient. The numberof days of drug supply was calculated on the basis ofthe quantity and dosage information associated witheach prescription record.

Demographic data included age, health insurancetype (private or statutory), treating physician specialty(general practitioner, gynecologist, or urologist), andpractice region (East compared with West Germany).Medical costs were either covered by private or bystatutory health insurance bodies including coveragefrom the social welfare system. Although the Germanhealth system is available to anyone in the country,the range of medical services provided to patients withprivate and statutory health insurance variesconsiderably.

The anticholinergics included in the study were:darifenacin, fesoterodine, oxybutynin, propiverine,solifenacin, tolterodine, and trospium. Codiagnoseswere determined on the basis of primary carediagnoses within 365 days before the index date andthese included diabetes mellitus (E10E14), depres-sion (F32, F33), neurologic disease associated withdementia (F01, F03, G30), overweight or adiposity(E6568), obstipation (K59.0), movement disordersincluding Parkinsons disease (G2026), epilepsy(G4041), migraine (G43), and multiple sclerosis(G35). We defined an adverse drug reaction as thediagnosis of xerostomia (K11.7, R68.2), fatigue(R53), headache (R51), obstipation (K59.0), and stom-ach upset (R10) within 183 days after the index date.Glaucoma (H40), which is a contraindication, wasincluded in the adverse drug reaction list and wasstudied as a covariate for drug continuation with thelimitation that it is probably a reflection of clinicianawareness and readiness to refer patients to ophthal-mology rather than a true side effect in terms ofepidemiology.

The cumulative discontinuation rate of initialtreatment was estimated using a KaplanMeier anal-ysis. A Cox proportional hazards regression modelwas used to estimate the relationship between

VOL. 124, NO. 4, OCTOBER 2014 Kalder et al Discontinuation of Incontinence Treatment 795

discontinuation and the demographic and clinical var-iables described previously for a maximum follow-upperiod of 36 months. A stepwise selection procedurewith an entry criterion of P,.1 was used to select thefinal optimal model. The adjusted hazard ratios (HRs)and 95% confidence intervals are presented for theindependent variables.

The proportional hazard assumption was assessedand upheld for all analyses. Furthermore, potentialconfounders (age, urologist, gynecologist and generalpractitioner care, private health insurance, and prac-tice situated in West Germany), codiagnoses, andadverse side effects were included as independentvariables. Two-sided tests were used and a P value of,.05 was considered statistically significant. All calcu-lations were carried out using SAS 9.3. Best-practicemethods for retrospective database studies were takeninto consideration.14

The study was conducted in accordance with theDeclaration of Helsinki; it was reviewed by theinstitutional review board of IMS Health and wasconsidered exempt from the requirement for ethicalapproval.

RESULTS

Altogether, 26,834 patients with first-time prescriptionsof a UI product were identified (Fig. 1). These patientswere treated in 203 gynecologic, 95 urological, and 988general practices. Patient characteristics are shown sep-arately for each substance prescribed initially (Table 1).Mean age was 69.4 years (standard deviation 13.2) and64.0% of patients were female. The proportion offemale patients was different for urologists (43.5%)and general practitioners (74.9%). Only female patientswere treated in gynecologic practices.

An increasing discontinuation rate of 74.8% inyear 1, 77.6% in year 2, and 87% in year 3 wasobserved (Fig. 2). After 1 year of follow-up, 74.6% offemale and 75.1% of male patients had discontinuedtheir treatment (refill gap of 90 days). Within 3 yearsof follow-up, discontinuation rates increased to 86.5%for women and 87.9% for men (P5.056).

We also investigated whether discontinuation wasdependent on the doctor specialty and found a signif-icant difference in the discontinuation rate within 3years for patients treated by gynecologists (92.0%),urologists (85.7%), and general practitioners (86.8%)(P,.001). Moreover, the proportion of patients whodiscontinued therapy depended on age; it was 89.7%in patients aged 60 years or younger, 87.9% inpatients aged 6170 years, 86.8% in patients aged7180 years, and 83.0% in patients aged older than80 years (reference group; P,.001).

The proportion of patients who experienced sideeffects of UI treatment defined in the study was verysimilar for each of the study substances. Thirty-two to38% of patients received a referral to an ophthalmologistand 0.31.2% of patients was diagnosed with glaucomafor the first time. A diagnosis of upset stomach wasrecorded in 4.28.6% of patients, obstipation in 5.49.8%, headache in 2.23.6%, and fatigue in 2.83.5%.A diagnosis of xerostomia was documented in just 0.30.6% of patients receiving UI treatment (Table 1).

The multivariate HRs of the Cox regressionmodels are shown in Table 2. Hazard ratios for riskof therapy discontinuation at 36 months were adjustedfor demographic and clinical variables. There wasa significantly higher risk of treatment discontinuationin male patients (HR 1.14; P,.001) than in femalepatients. Patients treated in gynecologic practicesand general practices demonstrated significantly high-er discontinuation rates than those who obtained theirprescriptions in a urologist practice (HR 1.60, P,.001and HR 1.24, P,.001, respectively). Patients in youn-ger age groups were more likely to discontinue ther-apy than the reference group of patients older than80 years, whereas discontinuation rates were higher in

Diagnosis of stress urinary incontinence (ICD-10: N39.3) or other specified urinary incontinence (ICD-10: N39.4),

January 1, 2005December 31, 2012(n=199,563)

Patients with first-time prescription of an anticholinergic within the index dates, January 1, 2005December 31, 2012 (n=59,492) Patients in general practices: 14,340 Patients in urologist practices: 37,173 Patients in gynecologist practices: 7,979

Patients without a first-time prescription of an anticholinergic

within the index dates,January 1, 2005December 31, 2012

(n=140,071)

Patients with a follow-up time of less than 365 days

prior to the index date(n=32,658)

Patients with a follow-up time of at least 365 days prior to the index date (n=26,834) Patients in general practices: 10,158 Patients in urologist practices: 12,615 Patients in gynecologist practices: 4,061

Fig. 1. Study design. ICD-10, International Classification ofDiseases, 10th Revision.

Kalder. Discontinuation of Incontinence Treatment. Obstet Gynecol2014.

796 Kalder et al Discontinuation of Incontinence Treatment OBSTETRICS & GYNECOLOGY

patients with private health insurance than in thosewith statutory insurance.

Not surprisingly, there was a much higher risk oftreatment discontinuation in patients experiencingside effects, namely headache (HR 1.27; P5.002),stomach upset (HR 1.20; P,.001), and glaucoma(HR 1.46; P,.001).

By contrast, a significantly lower risk of treatmentdiscontinuation was recorded in patients using propi-verine (HR 0.94; P5.022) or solifenacin (HR 0.93;

P5.003) as compared with oxybutynin; however,the absolute difference was relatively small. The pres-ence of comorbidities such as diabetes, Parkinsonsdisease, epilepsy, dementia, and multiple sclerosiswas associated with decreased risk of treatment dis-continuation, whereas patients with a prior diagnosisof migraine ran a higher risk of discontinuation.

No significant correlation was found betweena diagnosis of SUI, localization in West Germany, orcomedications and risk of treatment discontinuation.

Table 1. Baseline Characteristics, Comorbidities, and Side Effects of Study Patients

Variable Darifenacin Fesoterodine Oxybutynin Propiverine Solifenacin Tolterodine Trospium P

n 1,995 811 3,813 2,714 4,844 1,814 10,843Demographics

Age (y) 70.3612.6 69.3613.5 68.8613.6 66.3618.2 68.0613.7 69.4613.4 70.1613.2 ,.001General practitioners 43.3 40.9 38.5 31.6 35.8 56.4 35.4 ,.001Gynecologists 11.4 11.6 16.5 4.6 29.6 19.1 11.1 ,.001Urologists 45.3 47.5 45.0 63.8 33.7 24.5 53.5 ,.001Male gender 37.4 36.3 32.7 42.5 27.1 27.0 41.2 ,.001Private insurance 12.7 12.7 3.2 5.6 10.0 12.1 5.6 ,.001West Germany 84.0 85.6 87.8 74.5 79.9 89.3 89.6 ,.001

ComorbiditiesStress incontinence 25.2 24.5 23.9 23.5 23.4 23.2 23.7 .241Other incontinence 89.5 88.9 89.8 87.6 91.6 89.1 90.0 .205

Diagnoses at baselineDiabetes 28.5 32.2 29.4 27.5 29.4 25.1 30.7 .392Overweight or

adiposity11.7 17.2 13.4 11.3 13.0 11.8 13.5 .589

Obstipation 11.4 14.8 10.6 10.3 10.3 9.9 13.7 .015Depression 31.3 30.4 29.5 25.4 30.2 28.7 31.6 .218Movement disorders or

Parkinsons disease8.7 12.1 7.2 7.5 9.0 7.2 9.1 .503

Epilepsy 2.4 1.8 1.8 2.5 2.0 2.9 2.1 .913Migraine 6.5 4.5 5.3 4.9 4.8 4.8 4.9 .116Dementia including

Alzheimersdisease

9.9 11.5 9.1 9.8 9.7 9.2 11.2 .085

Multiple sclerosis 1.4 0.3 1.6 1.5 1.2 2.2 1.5 .383Glaucoma 3.1 3.0 2.9 4.8 3.7 3.6 4.2 .153Prescription of

physical therapywithin 6 mo beforeindex date

4.6 5.6 2.9 3.9 4.4 4.4 4.1 .697

Referral toophthalmologistswithin 3 mo aftertherapy start

35.7 31.6 35.5 36.5 37.7 31.3 35.1 .621

Side effectsConfirmed diagnosis

of glaucoma0.8 1.2 0.3 0.9 0.6 0.6 0.6 .665

Xerostomia 0.5 0.6 0.3 0.6 0.3 0.3 0.3 .525Fatigue 3.2 3.3 3.4 2.8 3.3 3.5 3.5 .582Headache 3.6 3.3 2.5 2.7 2.2 2.2 2.7 .290Stomach upset 6.3 7.8 8.6 7.0 8.0 4.2 8.0 .714Obstipation 7.1 8.4 6.0 5.4 7.0 7.5 9.8 ,.001Dry eyes 0.4 0.0 0.5 0.6 0.3 0.4 0.5 .793

Data are mean6standard deviation or % unless otherwise specified.


DISCUSSION

Like previous reports, this study revealed an increas-ing high discontinuation rate for treatment withanticholinergics in patients with UI at 12, 24, and 36months (74.8%, 77.6%, and 87%, respectively).8,1517

These findings are consistent with previous studies, inwhich discontinuation rates between 62% and 77.2%at 12 months and 92% at 36 months were reported.8,9

Our study focused on the symptom of UI ratherthan overactive bladder and notably the type ofincontinence did not appear to represent a significantprognostic factor for the treatment discontinuationrate. Although the study data set did not provideinformation on the rationale of prescribing anticholi-nergics to patients with SUI, the similar discontinua-tion rate for all types of incontinence raises concernsin its own right regarding the long-term effectivenessof the treatment.

The discontinuation rate at 3 years was higher inthe younger age groups than in the oldest (89.7% inpatients 60 years or younger compared with 83.0% inthose 80 years old or older), which confirms theresults of a recent study.9 This is an interesting findingconsidering that a common belief among clinicians isthat the elderly are less tolerant to side effects.

Those patients who were prescribed the anticho-linergic by a urologist were less likely to stop themedication than those prescribed treatment by a gyne-cologist (85.7% and 92%, respectively, by 3 years);this cannot be attributed to gender differences becausethe male gender was associated with increased risk oftreatment discontinuation (HR 1.14). Significant dif-ferences were also observed between gynecologistsand general practitioners (92% and 86.8%, respec-tively, by 3 years). Although it is impossible to deducea causative relationship between the prescribingdoctors specialty and differences in discontinuationrates, it is important to bring the findings to the atten-tion of physicians; physicians awareness may lead toadequate counseling and regular reassessment forthese patients, especially of young ones. Counselingshould address improvement of symptoms, obviatingthe need for continued therapy.

The most common side effect reported wasobstipation (5.49.8%) followed by gastric disturban-ces (4.28.6%). Those taking propiverine and solife-nacin were less likely to discontinue treatment,because these drugs are known to have milder sideeffects than oxybutynin.9,18,19 Overall, the side effectswere most likely underreported as a result of the

0

Con

tinua

tion

rate

(%)

20

Months since start of therapy

10

30

40

50

60

70

80

90

100

0 6 12 24 3618 30

Patients at risk 26,834 7,979 4,820 3,281 2,381 1,743 1,291

Fig. 2. KaplanMeier curves for continuation over 36 months in patients with urinary incontinence treatment (refill gap of90 days).

Kalder. Discontinuation of Incontinence Treatment. Obstet Gynecol 2014.


nature of the database and rarer than in clinicaltrials.18,19

Discontinuation of treatment was lower amongthose with chronic diseases (movement disorders andParkinsons disease, epilepsy, dementia, and multiplesclerosis). This finding is puzzling unless one pre-sumes that it may be indicative of lifestyle adjustmentsthat affect treatment, for instance patients with seriouscomorbidities who are exhibiting higher compliancewith treatment.

Pelvic floor physiotherapy was administered toa modest 4.6% of patients, although SUI was presentin one fourth of the study population. This may be theresult of reimbursement restrictions in the health system.

Individuals with private health insurance haveeasier access to prescriptions in Germany than thosewith statutory cover. Therefore, the significant dis-continuation rate (P,.001) in patients with privatehealth insurance is quite reasonable, because startingor discontinuing treatment is cost-neutral for them.These findings may be applicable to different healthcare systems that have private health insuranceavailable.20

Our analysis has several strengths. This study isa country-wide, population-based study on long-termdiscontinuation rates of seven different anticholinergicdrugs. Therefore, findings are based on clinicallyindicated prescriptions and represent an accurate

Table 2. Association Between Treatment Discontinuation Within 36 Months and Defined Variables (CoxRegression Analysis)

Outcome Variable Crude HR (95% CI) P Adjusted HR* (95% CI) P

Propiverine 0.89 (0.840.94) ,.001 0.94 (0.880.99) .024Solifenacin 0.98 (0.941.03) .514 0.93 (0.870.98) .004Fesoterodine 1.00 (0.921.09) .993Tolterodine 1.06 (0.991.12) .085Trospium 0.97 (0.931.01) .146Darifenacin 1.00 (0.941.06) .926Age (y)

60 or younger 1.33 (1.271.39) ,.001 1.27 (1.221.33) ,.0016170 1.22 (1.171.28) ,.001 1.16 (1.111.21) ,.0017180 1.16 (1.121.21) ,.001 1.14 (1.091.18) ,.001

Male gender 1.01 (0.981.04) .561 1.14 (1.111.18) ,.001Private insurance 1.16 (1.101.22) ,.001 1.14 (1.081.20) ,.001West Germany 1.04 (1.001.08) .062Stress incontinence 1.11 (1.081.15) ,.001Gynecologists 1.56 (1.501.62) ,.001 1.60 (1.521.67) ,.001General practitioners 1.14 (1.111.17) ,.001 1.24 (1.201.29) ,.001Diabetes 0.85 (0.810.88) ,.001 0.88 (0.850.91) ,.001Depression 1.08 (1.031.12) .001 1.06 (1.021.10) .005Obstipation 1.06 (1.001.12) .064Overweight or obesity 0.98 (0.941.02) .316Movement disorders or Parkinsons disease 0.85 (0.800.91) ,.001 0.88 (0.820.94) ,.001Epilepsy 0.81 (0.710.92) .009 0.76 (0.670.87) ,.001Migraine 1.38 (1.261.50) ,.001 1.21 (1.111.32) ,.001Dementia 0.71 (0.660.76) ,.001 0.75 (0.701.80) ,.001Multiple sclerosis 0.78 (0.69-0.89) ,.001 0.74 (0.650.85) ,.001Glaucoma 1.37 (1.091.72) .007 1.46 (1.161.84) .001Headache 1.37 (1.211.55) ,.001 1.27 (1.121.43) ,.001Stomach upset 1.25 (1.171.33) ,.001 1.20 (1.121.27) ,.001Xerostomia 1.00 (0.911.09) .956Fatigue 1.01 (0.901.13) .886Dry eyes 1.16 (0.851.59) .339

HR, hazard ratio; CI, confidence interval.* Stepwise selection; adjusted for age, physician specialty (general practitioner, gynecologist, urologist), gender, private health insurance,

region (Western or Eastern Germany), urinary incontinence diagnosis (stress or other), diagnoses at baseline (diabetes, overweight orobesity, obstipation, depression, movement disorders or Parkinsons disease, epilepsy, migraine, dementia including Alzheimers disease(%), multiple sclerosis, glaucoma, dry eyes.

Reference is oxybutynin. Reference is age group older than 80 y. Reference is urologists.


estimation of the effect of treatment in the affectedpopulation. Furthermore, we revealed an associationbetween a considerable number of confounders anddiscontinuation rates for the first time on this subject;the relationship to chronic disease in particular isreported clearly in our study.

This study has some limitations, most of whichare inherent to database studies. First, the documen-tation of side effects (such as constipation) of anticho-linergic treatment available in the database cannot beconsidered exhaustive. In addition, the assessment ofcomorbidities relies exclusively on diagnosis codes.Data on socioeconomic status and lifestyle-related riskfactors that were likely to affect discontinuation rateswere not obtainable.

This study reflects the results of previous studiesin the same area, revealing that discontinuation ratesfor treatment with anticholinergics are quite high andsheds further light onto the factors that contribute tothis disappointing finding. Considering that UI, par-ticularly when associated with idiopathic overactivebladder, is a long-lasting and frequently recurringcondition, it appears necessary to consider treatments(such as bladder training and pelvic floor physiother-apy) as a mandatory addition to drug therapy; besides,patients concerned need adequate counseling andregular reassessment to enhance long-term adherenceto anticholinergic treatment.

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